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TRP (transient receptor potential) ion channel family: structures, biological functions and therapeutic interventions for diseases

Miao Zhang, Yueming Ma, Xianglu Ye and 3 more

Signal Transduction and Targeted Therapy · 2023 · Review · CC BY

Abstract

Transient receptor potential (TRP) channels are sensors for a variety of cellular and environmental signals. Mammals express a total of 28 different TRP channel proteins, which can be divided into seven subfamilies based on amino acid sequence homology: TRPA (Ankyrin), TRPC (Canonical), TRPM (Melastatin), TRPML (Mucolipin), TRPN (NO-mechano-potential, NOMP), TRPP (Polycystin), TRPV (Vanilloid). They are a class of ion channels found in numerous tissues and cell types and are permeable to a wide range of cations such as Ca 2+ , Mg 2+ , Na + , K + , and others. TRP channels are responsible for various sensory responses including heat, cold, pain, stress, vision and taste and can be activated by a number of stimuli. Their predominantly location on the cell surface, their interaction with numerous physiological signaling pathways, and the unique crystal structure of TRP channels make TRPs attractive drug targets and implicate them in the treatment of a wide range of diseases. Here, we review the history of TRP channel discovery, summarize the structures and functions of the TRP ion channel family, and highlight the current understanding of the role of TRP channels in the pathogenesis of human disease. Most importantly, we describe TRP channel-related drug discovery, therapeutic interventions for diseases and the limitations of targeting TRP channels in potential clinical applications.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

1Transient receptor potential (TRP) channels, which were first discovered in 1969, they are multimodal ion channels that act as sensors of chemically toxic and physical stimuli. These channels are widely distributed in various tissues and play a variety of roles. Despite having been studied for a long time, the significance of TRP channels remains unclear. In addition, changes in TRP channels have been observed in a variety of diseases. More importantly, the regulation of TRP channels can be exploited to prevent or treat diseases. In this review, we present a historical perspective on TRP channels. We then discuss the structure and function of TRP channels and summarize their different types, focusing on their key roles in various physiological and pathological conditions, particularly in pain, inflammatory bowel disease (IBD) and its complications, respiratory diseases, neurological disorders, and cardiovascular diseases (CVDs). We also highlight therapeutic interventions, including physical and pharmacological ones, regarding TRP channels. Finally, we conclude this review with a summary of frequent adverse events that occur during treatments.

History of TRP channels

2TRP channels were first proposed over 50 years ago (Fig. 1). In 1969, Cosens et al. identified a visual mutant in Drosophila. The mutant showed a transient rather than a continuous response to bright light stimuli. Minke et al. were the first to name the mutant “transient receptor potential” (trp) in 1975 based on its electrophysiological phenotype. In 1989, Montell et al. and Wong et al. successively cloned the trp gene and recognized it as a transmembrane protein. Since then, researchers have focused on expanding the understanding of trp.

3Minke’s group was the first to establish a link between trp mutants and Ca2+. Shortly thereafter, Minke and Selinger confirmed that the trp protein is a plasma membrane component (or part of one) that oscillates between Ca2+-transporting and non-transporting states. A strong compelling evidence demonstrated that TRP is a light-activated and Ca2+, permeable channel, as discovery by Hardie and Minke. Meanwhile, Kelly and colleagues observed that TRP-like proteins are typical of voltage-gated channels. They also identified the ankyrin repeats in the known amino acid (aa) sequence of TRP. After the 1990s, the presence of TRPs was confirmed in various types of cell lines., These reports provided a glimpse into the biological functions of TRPs. In addition, TRPs are widely present in healthy human tissues.

4In 2002, Montell et al. and Clapham et al. undertook work to unify the TRP nomenclature. The 28 channel subunit genes were subdivided into seven subfamilies, namely, TRPA (ankyrin), TRPC (canonical), TRPM (melastatin), TRPML (mucolipin), TRPN (NO-mechano-potential, NOMP), TRPP (polycystin) and TRPV (vanilloid), based on their gene sequences. Mammals are represented in all subfamilies. Research on diseases based on TRPs has received a great deal of attention in the last two decades. In particular, the development of molecular biology technologies has improved the understanding of TRPs.

Classifications of TRP

5Based on sequence and topological differences, mammalian TRPs can be categorized into the following seven subfamilies: group 1 with five subfamily members (TRPC, TRPV, TRPM, TRPN, and TRPA), and group 2 with two subfamilies (TRPP and TRPML) (Table 1 and Fig. 2). An additional subfamily, TRPY, consists of yeast TRPs, which are distantly related to group 1 and group 2 TRPs. The first and second groups both have six transmembrane structural domains and are permeable to cations. TRPA, TRPV, and TRPC channels contain ankyrin repeat sequences in their intracellular N-terminal structural domains, whereas TRPC and TRPM subfamilies possess a proline-rich “TRP structural domain” in the C-terminal region near the presumed transmembrane segment. Group 2 channels also have high sequence homology in their transmembrane structural domains and are only distally related to the genes of group 1 channels because they contain a large lumenal/extracellular domain between transmembrane helix 1 (S1) and S2.

TRPC

6TRPC channels were the first identified members of the TRP family. TRPC channels are nonselective cation channels. They range from a few tens to a few hundred kilodaltons. In 1995, the full sequence of the first human homolog (TRPC1) was reported. Since then, seven mammalian TRPC proteins (TRPC1–7) have been described. Based on aa similarities, mammalian TRPCs fall into four subsets: TRPC1, TRPC2, TRPC3/6/7, and TRPC4/5. TRPC channel proteins are expressed in excitable and non-excitable cells. TRPCs have a broad tissue-specific distribution and are therefore involved in various pathophysiological functions.

TRPV

7TRPV channels are a part of the TRP channel superfamily and named for their sensitivity to vanilloid and capsaicin., TRPVs are divided into two types. TRPV1–4 can be thermally activated and are therefore called thermal TRP channels. One of the first clues toward understanding the functional diversity of TRPV channels came from the structural studies of the N-terminal ankyrin repeat domain. In most tissues, these domains serve as sensors for different pain stimuli (heat, pressure, and pH) and contribute to the homeostasis of electrolytes, the maintenance of barrier functions, and the development of macrophages., Given fundamental role in a multitude of physiological and pathophysiological processes, TRPV channels are promising targets for drug development.

TRPA

8In 1999, the first human TRPA protein, TRPA1, was discovered during a screening of downregulated genes following the oncogenic transformation of fibroblasts. TRPA1 is the only TRPA protein present in humans., TRPA1 was previously called ANKTM1 because the protein consists of numerous N-terminal ankyrin repeats. TRPA1 is a sensor for diverse noxious external stimuli such as intense cold, irritating compounds, mechanical stimuli, reactive chemicals, and endogenous signals associated with cellular damage. This diversity of functions and expression in nociceptive nerve fibers, epithelial cells, and various other cells make this channel relevant to a wide range of diseases and an attractive therapeutic target.

TRPM

9Since the first cloning of TRPM1 in 1998, tremendous progress has been made in the identification of novel members of the TRPM subfamily and their functions. The TRPM subfamily consists of eight members; TRPM1–TRPM8. TRPMs have been involved in several physiological and pathological processes, including cellular proliferation, temperature sensing, vascular development, cancer progression, neurological diseases, endothelial dysfunction, inflammation, type II diabetes, and many other processes. TRPM channels possess a large cytosolic domain consisting of 732 and 1611 aa for each subunit, making them the largest members of the TRP superfamily.

TRPN

10The TRPN subfamily was named based on the founding member, Drosophila NOMPC. Mammals do not encode any TRPN members. TRPNs are found in worms, flies, and zebrafish. Genetic screening, calcium imaging, and electrophysiological analysis have identified TRPN as a mechanically gated channel in eukaryotes. A TRPN channel protein is essential for sensory transduction in insect mechanosensory neurons and in vertebrate hair cells. However, without a molecular marker for the protein, its exact location and role in transduction are uncertain.

TRPP and TRPML

11TRPP and TRPML belong to group 2 of TRP channels and have limited homology similarity to group 1. Furthermore, the large loop between transmembrane domains (TMD) 1 and 2, which discriminates them from group 1. Invertebrate TRPPs have been described in C. elegans, Drosophila (AMO), and the sea urchin (suPC2). The three human genes encoding for the TRPP protein family are polycystic kidney disease 2 (PKD2 and TRPP2), PKD2-like 1 (PKD2L1 and TRPP3), and PKD2-like 2 (PKD2L2 and TRPP5). TRPPs may comprise the most primitive TRP subfamily given that as microbial homologs of TRPP2 are found in yeast. In addition to functioning as a cation influx channel, TRPP2 is also localized in the endoplasmic reticulum (ER) membrane where it is proposed to serve as a new type of Ca2+-release channel.

12The mucolipin family of the ion channel TRP superfamily (TRPML) includes three members: TRPML1, TRPML2, and TRPML3. The molecular weights of TRPMLs are around 65 kDa. TRPML1, was cloned during the search for the genetic determinants of the lysosomal storage disease MCOLN. Mutations of this protein are characterized by severe neurodegeneration. Defects in TRPML function are predicted to have important effects on organelle acidification, vesicle fusion, endosome maturation, and signaling; thus, suggesting that this protein family plays a key role in normal and pathological conditions.,

Structures of TRP channels

13Since the discovery of TRPs, researchers have systematically analyzed their structure TRPs through technical means (Table 2 and Fig. 3). The progressive development of sequencing and analytical techniques has revealed several key structural features of TRPs. TRP channels have six transmembrane spanning domains (S1–S6), with a pore-forming loop between S5 and S6, and both the C and N termini are located intracellularly. The cytoplasmic end of the S6 helix forms to form the lower gate, which opens and closes to regulate cation entry into the channel. The S1–S4 domains may gate the pore in response to ligand binding, but the paucity of positively charged arginine in the S4 helix indicates the weak voltage sensitivity of TRP channels. All elements outside the S5–S6 region provide means of either subunit association. They also act as a linker for the elements that control the gating. Cryo-electron microscopy (cryo-EM) confirmed that TRPs have a structure similar to that of voltage-gated ion channels. Most TRPs form functional channels as homotetramers, but heteromultimerization is frequently observed. This condition creates a potential problem for drug discovery efforts because heteromultimers (which are difficult to recreate in heterologous expression systems) may have distinct pharmacological properties.

TRPVs

14The earliest structural information obtained for the TRPV subfamily was the X-ray crystal structures of the isolated cytoplasmic ankyrin repeat domain from TRPV2 in 2006, immediately followed by similar structures for other TRPV channels., As is true for all TRP channels, TRPV channels are tetrameric and each monomer features the classic six transmembrane helix architecture of voltage-gated ion channels in its TMD. The overall sequence similarity of TRPVs is more than 40%. TRPV protein has an ~400–450-residue N-terminal domain with 3–6 intracellular ankyrin repeats, which are essential for channel function., An ~150-residue C-terminus that acts as a platform for interactions with other proteins and ligands.

15Liao et al. used advances in EM to determine the structure of the mammalian TRPV1 channel at a resolution of 3.4 Å. S1–S4 form a bundle similar to the voltage-sensing domain in voltage-sensitive ion channels. S5 and S6 extend from the S1–S4 bundle, and the conserved “TRP structural domain” interacts with the S4–S5 linker., TRPV1 has a wide extracellular “mouth” with short selective filtering. This domain-swapped pore domain consists of S5 and S6, which form the central pore and lower gate, whereas a short loop and helix between S5 and S6, termed the pore helix (PH), forms the upper gate or selectivity filter. The dynamic communication between the upper and lower gates may be the basis for the integration of various physiological signals. Notably, the motion of S6 in the TRPV1 structure can be roughly described as small, medium, or large. When the motion is small, the π-helix is retained, and the channel gate is formed by I679. In the intermediate category, the π-helix transitions to the α-helix, and the gate is formed by M682. When S5/S6 motion is large, the π-helix conformation is observed, and the open gate (9.8 Å) is formed by I679. However, transitions between π and α have also been observed in TRPV2 and V3 structures, but the functional consequences of such transitions remain to be fully understood.,

TRPCs

16Given the great advancements in single-particle cryo-EM technology, high-resolution structures of TRPCs became available in 2018. TRPC2 is thought to be a pseudogene in humans. The overall architecture of the homologous TRPC3, TRPC4, TRPC5, and TRPC6 is consistent with that of TRP.– The structure of TRPCs is similar to the voltage sensor structural domains of voltage-gated K+, Na+ and Ca2+ channels, with S5–S6 forming a structurally conserved ion conductance or pore domain common to all TRP channels, voltage-gated channels, inwardly-rectifying K channels, and bacterial K and Na channels., All TRPC structures contain a three-helix region designated as the pre-S1 elbow and pre-S1 helix before the transmembrane S1 helix., This region is halfway embedded in the membrane, with its N-terminal exposed to the cytoplasmic side to connect with a long stretch of tightly folded linker helices located at the proximal N-terminus of each protomer. Immediately before the linker helices are the four ankyrin-like repeats that form the outskirt of the cytoplasmic architecture, which completely surrounds the four helical bundles composed of the second C-terminal helix.

17Currently, the resolved region of the cytoplasmic structural domain of TRPC4 reaches approximately 80 Å, which is relatively short compared with that of other TRP channels. Helices S5 and S6 are exchanged with the respective helix of the adjacent protomer and form a pore at the center of the quaternary channel with a negatively charged extracellular opening; residue E555 at the top end of the pore tower is conserved in TRPC1, TRPC4 and TRPC5 and forms a salt bridge with R556 of the adjacent protomer. Fan et al. proposed that TRPC3 is in a lipid-occupied closed state with a structure of 3.3 Å. TRPC3 has four elbow-like membrane reflux helices before the first transmembrane helix. The third transmembrane helix, S3, is very long, forms a unique transmembrane structural domain and constitutes an extracellular structural domain that may act as a sensor for external stimuli.

TRPA

18The TRPA1 gene encodes a large protein consisting of about 1100 aa (1119 aa in humans, 1125 aa in rats, 1115 aa in mice, 1120 aa in zebrafish, 1197 aa in Drosophila, and 1193 aa in C. elegans), with an estimated molecular mass between 120 and 130 kDa. TRPA1 has distinctively large intracellular NH2 and COOH termini, which together account for about 80% of its molecular mass. Each subunit of TRPA1 consists of six transmembrane alpha sheets (S1–S6) plus a re-entrant pore loop between S5 and S6; homotetramers are formed by “domain exchange” interactions and establish a conserved transmembrane core., The distinguishing feature of TRPA1 is its long N-terminus with 14–18 predicted ankyrin repeats, each consisting of 33 aa., A structural domain containing a sequence of five ankyrin repeats surrounds the coiled coil and connects to another extended feature, which forms a crescent-shaped element. TRPA1 also possesses a distinct tetrameric coiled coil at the center of the channel, beneath the permeation pore. This stalk-like structure is stabilized by the interaction of positively charged residues on the exterior surface of the coiled coil with inositol polyphosphates. These interactions are essential for TRPA1 channel activity.,,

TRPMs

19In late 2017, several TRPM structures were solved using single-particle cryo-EM. TRPMs have four shared homologous regions: a TMD consisting of six transmembrane helices, a TRP helix, and C-terminal domains containing the conserved TRP domain followed by a coiled-coil region that differs among members., Despite their common structural features, the members of the TRPM subfamily are less conserved than those of other subfamilies. Several TRPM channels, such as TRPM2, uniquely contain a functional nucleoside diphosphate linked to another moiety/ADP ribose domain and a kinase domain that resembles to protein kinase A to a certain extent., TRPM2 is structurally characterized by its C-terminal NUDT9-H structural domain, a homologue of the human ADP-ribose pyrophosphatase NUDT912. In other words, these TRPMs combine features of ion channels and enzymes and are thus referred to by some as “chanzymes”.– The ion conductance pore of TRPM2 is restricted at two locations, a selective filter located close to the extracellular entrance, which is formed by a hinge connecting the PH and the P ring, and a gate lined by S6 near the inner end of the cell.

20TRPM4 consists of three layers, namely, the N-terminal nucleotide-binding domain, ankyrin repeat domain, and the C-terminal coiled-coil helix, which form the base layer of TRPM4. The middle layer consists of a linking helix structure containing 12 helices and forming a scaffold for multiple interactions between structures within the subunit. The S1–S6 and TRP structural domains embedded in lipid form the top layer of the channel. The C-end coiled spiral structure forms a parallel disc-shaped coil. The discoid coil is surrounded by a large, intertwined cytoplasmic structural domain consisting of four N-terminal TRPM homology regions (MHR1–4), which are highly conserved in the TRPM subfamily.,, Of these, MHR1–2 contain an eight-stranded β-sheet surrounded by eight α-sheets. By contrast, MHR3–4 are composed of stacked α-sheets and connected to the transmembrane structural domain via MHR4, which clasps the TRP structural domain; as a result, an interaction occurs between the cytoplasmic structural domain and the transmembrane core., In 2018, Autzen et al. compared the structures of Ca2+-free and Ca2+-bound TRPM4 and observed an additional density in the hydrophilic pocket on the cytoplasmic side of the S1–S4 structural domain (this density represents a true bound Ca2+).

21The mouse TRPM8 channel is a three-layer homologous structure. The top transmembrane channel region consists of the pre-S1 structural domain, TMD, and TRP structural domain. The TMD consists of a voltage-sensor-like structure (VSLD) consisting of transmembrane helices S1 to S4, and a pore domain formed by S5 and S6 helices,, similar to the previously identified TRPV structure., The TMD of TRPM8 also has several features that distinguish it from the structure of other TRP ion channels. First, relative to the structure of apo TRPV1, the PH of TRPM8FA is positioned 12 Å away from the central axis, tilted by 8°, and shifted by 5 Å toward the outside of the cell. Second, no non-α helical elements (e.g., 310 or π helices) can be found in the TMs of TRPM8, which in other TRP channels are proposed to provide helical bending points for channel gating. Finally, although TRPV channels have a pre-cellular S1 helix, TRPM8FA contains three additional helices between S1 and the presumed pre-cellular S1 helix in the membrane region. Diver et al. observed a substantial rearrangement in the S4–S5 linker in the TRPM8 structure, and it repositioned the S1–S4 and pore domains relative to the TRP helix.

TRPPs

22The TRPP subfamily has three members (TRPP2, TRPP3, and TRPP5). The PKD1 and PKD2 genes encoding polycystin-1 and polycystin-2 proteins, respectively, were originally named TRPP1 and TRPP2.– However, members of the PKD1 family do not belong to the TRP family. PKD proteins are divided into two groups based on sequence homology: typical isoforms with 6 TMs (PKD2 subfamily), such as TRPP2, TRPP3, and TRPP5; and another group with 11 TMs and a short intracellular C-terminal tail (PKD1 subfamily), represented by PKD1, PKD1L1, PKD1L2, PKD1L3 and PKD-REJ7. The TRPP protein can form homotetramers and heterotetramers,, such as the PKD1/TRPP2 and PKD1L3/TRPP3 complexes, with members of the PKD1 family.–

23PKD1 is a 4,303-aa, 465-kDa integral membrane protein containing a large N-terminal extracellular structural domain and an intracellular C-terminal structural domain. Unlike PKD1, TRPP2 is a 968-aa, 110-kDa protein with 6 TMs and a pore-forming loop, and has intracellular amino and carboxyl termini. Shen et al. showed that TRPP2 is a Na/K conducting channel with low permeability and small single-channel conductance to Ca2+. The complexes of PKD1 and TRPP2 exhibit a 1:3 structural ratio. TRPP2 and PKD1 bind directly through their C-termini to form a complex containing three TRPP2 and one PKD1. This association involves a coiled-coil structure at the C-terminus of both proteins. R807X, E837X, and R872X of TRPP2 and R4227X and Y4236X of PKD1 can lead to deletion of the coiled-coil structural domain, which results in the mutation of ADPKD.,

24TRPP3 (polycystin-2 like 1 (PKD2L1)) and TRPP2 share high sequence similarity (79% homology and 62% identity). Unlike TRPP2, the PH and S6 of TRPP3 are involved in the opening of the upper and lower gates to adopt an open conformation. Su et al. suggested that the simultaneous occurrence of gate opening and voltage-sensing domain (VSD) conformational changes in TRPP3 is caused by coupling between the VSD and pore domains. PKD1L3/TRPP3 complexes form calcium-permeable, non-selective cation channels., The structure of PKD1L3/TRPP3 in the apo and Ca2+-loaded states shows two Ca2+ binding sites at selectivity filter and VSDIII respectively. It also has a 1:3 stoichiometry TRP structure protected by Lys2069 of PKD1L3 and Asp523 from the three subunits of TRPP3.

TRPN and TRPMLs

25Drosophila NOMPC protein is the first member of the TRPN subfamily. The Drosophila NOMPC protein shares significant homology with the TRP superfamily. The N-terminus of NOMPC contains 29 ankyrin repeats, the largest number among TRP channels. Unlike other TRP family proteins, the ankyrin repeat structure of NOMPC is a quadruple structure, with each structural domain acting like a helical spring. The TMD of each NOMPC subunit consists of six transmembrane α-helices (S1–S6) and a re-entrant pore loop located between S5 and S6. The TRP structural domain is sandwiched between the linker helix and the S4–S5 linker. The short helix following the TRP structural domain is wrapped around the elbow in front of S2 and S1. However, the C-terminus is mostly unstructured, with a short helix fragment interacting with the linker domain. No TRPN has been found in mammals.

26The TRPML subfamily is defined by a human protein, mucolipin 1. Mucolipin 1 (TRPML1) is a 580 aa-long protein probably restricted to intracellular vesicles. TRPML1 contains two proline-rich regions, namely, a lipase serine active site in the N-terminus and a dileucine motif suggestive of lysosomal targeting in the C-terminus. TRPML1 is characterized by its longer S2 helix than that of PKD2 and protrudes from the membrane bilayer-embedded portion of the cell membrane, with an extension of the N-terminal S1 helix (pre-S1) that includes two small alpha helices (α1 and α2) rich in many basic aa. Several aromatic and hydrophobic residues in the PH 1, S5, and S6 helices of TRPML1 and the S6 helix of the adjacent subunit form a hydrophobic cavity to accommodate the agonist. Phosphatidylinositol-3,5-bisphosphate binds to the N-terminal end of TRPML1, that is away from the pore, and a helix-turn-helix extension between the S2 and S3 segments may link ligand binding to pore opening. Two other members of the TRPML subfamily, namely, TRPML2 and TRPML3, are encoded by MCOLN2 and MCOLN3 genes, respectively. Similar to TRPML1, they are active in late endosomes and lysosomes. TRPML3 is divided into an extracellular structural domain (ECD), a TMD, and a cytosolic structural domain. The ECD consists of two β-sheets and two extracellular helices that form a ring that caps the extracellular side of the channel and is structurally similar to the ECD of TRPML1 and PKD2.,,, Unlike PKD2, in which the ECD interacts extensively with the TMD, in TRPML3, minimal interaction exists between the ECD and the TMD.,

Agonists and antagonists

27Various stimuli, including noxious and innocuous heat or cold stimuli, changes in osmolarity, proton gradients, and irritant compounds, have the potential to activate TRP channels. The activity of TRP channels is also modulated by several natural products, herbs, and compounds of plant origin. For stimulation by temperature, each temperature-sensing TRP channel has a specific activation threshold. Notably, numerous TRP agonists and antagonists are not specific; cross-reactivity can be observed between different TRP channels.

28Several potent small-molecule agonists and inhibitors of TRPV1, TRPV4, and TRPA1 have entered clinical trials for the treatment of inflammatory, neuropathic, and visceral pain; however, the therapeutic mechanism of action of these compounds is unclear. The TRPA1 agonist cinnamaldehyde improves the capability of glucose metabolism by slowing down the gastric emptying rate and food intake via the TRPA1-ghrelin pathway. In addition, oral administration of HC-030031, an inhibitor of TRPA1, significantly reversed mechanical hypersensitivity in a spinal nerve ligation model of complete Freund’s adjuvant (CFA)-induced inflammatory pain and neuropathic pain in rats. However, the mechanism by which it regulates TRPA1 is unclear.

29Capsaicin is the most classic TRPV1 agonist, and it has a role in enhancing pain. Capsaicin has a “tail up, head down” conformation. Molecular dynamic simulations revealed that the capsaicin molecule flips from extracellular to intracellular and can subsequently enter the intracellular TRPV1 binding site. Oral administration of GSK1016790A activates TRPV4 and reduces atherosclerotic plaque formation.

30Menthol is known to be an agonist of TRPM8. However, the mechanism by which TRPM8 channels respond to this drug is not well understood. Mutations in residues within the transmembrane and TRP structural domains impair the efficacy of menthol, such as Y745, R842, and L1009 (all residue numbers belong to mouse TRPM8), impair the efficacy of menthol, which suggests that this structural domain affects initial binding downstream. Later, in a cryo-EM of the structure of full-length avian TRPM8, the menthol binding site was located within a voltage-sensor-like structural domain. The cavity near Y745 and R842 was identified as the binding pocket for menthol. Recently, Xu et al. proposed that menthol, with its hydroxyl group as a hand, specifically grasps R842, and with its isopropyl group as a leg, it stands on I846 and L843, combining TRPM8 by a “grasp and stand” mechanism. Thus, numerous agonists and antagonists of TRPs have been reported (Table 3).

Signaling pathways affected by TRP channels

31TRP channels exhibit ion selectivity. For example, TRPV5 and TRPV6 are selective toward Ca2+ and have a selective filter similar to that of voltage-gated potassium channels. Monovalent, divalent, and large organic cations pass through TRPV1, V2, V3, and TRPA1 and may allow dynamic ion selectivity. TRPM3 is found to be a constitutive Ca2+ and Mn2+ permeable channel, as shown by in vitro studies. TRPM4 and TRPM5 are voltage-regulated and conduct monovalent cations, such as Na+ or K+, without significant Ca2+ penetration. The activity of TRPM7 is regulated by intracellular Ca2+ and Mg2+ and is permeable to almost all physiological divalent cations and trace metals such as Ni2+. TRPM6 is also permeable to trace metals, including Mg2+ and Ca2+, and is inhibited by intracellular Mg2+. Activation of TRP channels causes ionic changes inside and outside the cell to trigger downstream pathways. Multiple signaling pathways are affected by TRPs, and these pathways include the mitogen-activated protein kinase (MAPK) pathway, transforming growth factor (TGF)-β signaling pathway, nuclear factor kappa-B (NF-κB) pathway, and AMP-activated protein kinase (AMPK) pathway.

MAPK pathway

32The MAPK pathway includes extracellular signal-regulated kinases (ERK MAPK), c-Jun N-terminal kinases (JNK) or stress-activated protein kinases, and p38 MAPK. MAPK pathways regulate processes ranging from proliferation and differentiation to apoptosis. They affect gene expression, metabolism, cell division, cell morphology, and cell survival.

33In most cases, inflammatory stimulation of cells causes an inward flow of calcium. Several members of TRP channels act as calcium-permeable channels, and their activation induces calcium influx, which is involved in the regulation of the MAPK signaling pathway. In human corneal epithelial cells, the activation of TRPV1 receptor was followed by an increase in Ca2+ influx, which led to MAPK activation, followed by the increased release of interleukin (IL)-6 and IL-8, inducing an inflammatory response. Upregulated TRPV5 expression was observed in chondrocytes from rats with osteoarthritis, which regulated a Ca2+ influx to activate the phosphorylation of calmodulin-dependent kinase II (CaMKII). Activated p-CaMKII causes extracellular signaling-regulating phosphorylation of ERK 1/2, JNK, and p38 and plays a key role in chondrocyte apoptosis. Furthermore, activation of TRPM8 in human bronchial epithelial cells promotes Ca2+ influx, which subsequently leads to increased expressions of IL-6, IL-8, and tumor necrosis factor (TNF)-α via the upregulation of p-ERK and activation of NF-κB, which amplify inflammation.

34Activation of the ERK1/2 pathway in neurons may be involved in acute visceral pain. This activation is induced by TRPA1. Experimental results by Kondo et al. suggested that mechanical stimulation by TRPA1 may generate action potentials that lead to phosphorylation of ERK1/2 and p38 in dorsal root ganglion (DRG) neurons, which are further involved in the development of visceral pain. Activation of TRPV4 regulates the MAPK and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathways, which regulate cell death and survival. When TRPV4 channels are activated, the protein levels of p-p38 MAPK are significantly increase, which induces the apoptosis, which is associated with cerebral ischemic injury.

35TRP channel regulation of the MAPK signaling pathway not only affects pain and inflammation but may also be involved in the fibrotic process. Inhibition of TRPM7 expression reduces liver fibrosis by suppressing the activation and proliferation of hepatic stellate cells, a process that possibly involves the MAPK signaling pathway. In addition, TRPV4-mediated Ca2+ influx is involved in regulating the differentiation of human ventricular cardiac fibroblasts to myofibroblasts via the MAPK/ERK pathway.

TGF-β signaling pathway

36The TGF-β superfamily consists of TGF-β1-3, activins and inhibins, growth differentiation factors, myostatin, and BMPs. Dysregulation of TGF-β family signaling can lead to a plethora of developmental disorders and diseases, including cancer, immune dysfunction, and fibrosis.,

37TGF-β signaling underlies cardiac fibrosis. Activation of TRPV3 was observed in stress-overloaded rats, and it upregulated protein expressions of collagen I, collagen III, TGF-β1, cyclin E, and cell cycle protein-dependent kinase 2 (CDK2). Meanwhile, blocking the TGF-β1 pathway partially reversed the effect of TRPV3 activation. This finding suggests that TRPV3 activation exacerbated fibrosis in pressure-overloaded rat hearts by promoting the proliferation of cardiac fibroblasts through the TGF-β1/CDK2/cyclin E pathway.

38Changes in TRPC3 expression and atrial fibrosis are closely related. Angiotensin (Ang) II induces migration and proliferation of atrial fibroblasts and upregulates the expression levels of TRPC3 and fibrosis biomarkers. The TRPC3-selective blocker Pyr3 significantly attenuated Ang II-induced upregulation of TRPC3, collagen I, collagen III, and TGF-β1 through the molecular mechanism of the TGF-β/Smad2/3 signaling pathway and attenuates neonatal rat atrial fibroblast migration and proliferation.

39TRPV1 exerts protective effect against cardiac and renal fibrosis, mainly through the TGF-β signaling pathway. TRPV1 was significantly downregulated in human liver fibrotic tissues. By contrast, knockdown of TRPV1 resulted in a significant increase in the expression of various liver fibrosis markers, and enhanced the promotion of TGF-β in hematopoietic stem cell proliferation, cell cycle, apoptosis and extracellular matrix expression. Selective activation of TRPV1 in mice with renal fibrosis inhibited α-smooth muscle actin (SMA) but promoted E-cadherin expression in human proximal tubular epithelial cells primarily through the inhibition of TGF-β1-Smad2/3 signaling. These data suggest that TRPV1 activation attenuates the progression of cardiac and renal fibrosis by inhibiting TGF-β and its downstream regulatory signaling pathways, and exerts cardioprotective and renoprotective effects.

Canonical NF-κB pathway

40The canonical NF-κB is activated by various stimuli to transduce rapid but transient transcriptional activity to regulate the expressions of various proinflammatory genes and also serves as a critical mediator of the inflammatory response.

41Kang et al. observed that by blocking TRPA1 induced a decrease in IL-6 and IL-13 levels were induced. Furthermore, blockade of NF-κB inhibited TRPA1 expression, whereas blockade of TRPA1 had no significant effect on NF-κB activation. However, several researchers have come to the opposite conclusion. Lee et al. concluded that inhibition of TRPA1 channel activity inhibited the production of pro-inflammatory cytokines and the activity of NF-κB.

42In a model of cisplatin-induced nephrotoxicity, blockade of TRPA1 alleviated apoptosis, reduced the levels of IL-1β, IL-6, TNF-α, and interferon (IFN)-γ, decreased the levels of cleaved caspase-3, cleaved poly (ADP-ribose) polymerase PARP, and inducible nitric oxide synthase (iNOS), reduced the expression of p-IKKβ, p-JNK, p-ERK and p-p38, and enhanced the expression of IκBα. TRPA1 expression was increased in renal tubular epithelial cells from patients with acute kidney injury. Activation of TRPA1 increased intracellular Ca2+ levels, increased NADPH oxidase activity, activated MAPK/NF-κB signaling, and increased IL-8 levels. In conclusion, TRPA1 regulates inflammation through the MAPK/NF-κB signaling pathway.

43TRPV4 is involved in the molecular mechanisms of inflammation mainly through NF-κB. In a mouse model of temporal lobe epilepsy, activation of TRPV4 increased Toll-like receptor 4 (TLR4) expression, which led to the phosphorylation of IκK and IκBα; as a result, NF-κB activation and nuclear translocation occurred, with a resulting increase in the levels of pro-inflammatory cytokines. Thus, blocking TRPV4 downregulates high mobility group box 1 (HMGB1)/TLR4/IκK/κBα/NF-κB signaling, which produces an anti-inflammatory response and neuroprotective capacity.

44Scholars have proposed the involvement of TRPM8 channels in the DRG, through the regulation of NF-κB signaling, in the pathogenesis of hyperalgesia in neuropathic pain rats. Activation of TRPM8, which inhibits nuclear localization of NF-κB, led to the repression of TNF (encoding TNF-α) gene transcription.

45TRPC6 is beneficial in alleviating inflammation and apoptosis. Activated TRPC6 reduces Ca2+ entry into cells, which inhibits nuclear translocation and phosphorylation of NF-κB and reduces apoptosis, cytotoxicity, and inflammatory responses. By contrast, TRPC1 channels cause a Ca2+ influx downstream of Ca2+/calmodulin-dependent protein kinase β (CaMKKβ), which promotes NF-κB activation.

AMPK pathway

46The AMPK pathway promotes mitochondrial health and homeostasis and plays a major role in the regulation of cellular energy homeostasis. Inhibition of TRPV1 attenuates rutaecarpine-induced intracellular Ca2+ levels and phosphorylation of CaMKII, CaMKKβ, AMPK, and endothelial NO synthase. In addition, increased expression of TRPV1 in patients with blistering skin injury led to an upregulation of intracellular Ca2+ levels and CaMKKβ, AMPK, unc-51-like kinase 1 and mammalian target of rapamycin (mTOR) activities, which cause skin toxicity through excessive activation of autophagy.

47Upregulation of TRPC5 protein expression levels mediates cell survival autophagy via the CaMKKβ/AMPKα/mTOR pathway. Notably, not all TRP channels regulate the AMPK signaling pathway. By contrast, activation of AMPK normalizes TRPC6 expression.

48Altogether, these results suggest that TRPs can perform important biological functions by regulating downstream signaling pathways to influence disease development. Targeting key molecules and pathways that mediate abnormal states may be critical for the management of TRP channel-related diseases.

Physiological functions of TRP channels

49TRPs have long been an important topic in the scientific community, with a growing number of publications suggesting their involvement in various of biological processes. TRPs are distributed in a variety of tissues, and have a wide range of physiological functions. Thus, the biological functions of TRPs must be explored to further understand the development and progression of diseases.

Pain

50Pain is the primary reason why people seek medical care. Until the 1960s, pain was considered an inevitable sensory response to tissue damage. Pain can be categorized as nociceptive (from tissue injury), neuropathic (from nerve injury), or nociplastic (from a sensitized nervous system), all of which affect work-up and treatment decisions at every level. Opioids are effective pain relievers, but acting on the brain, they can become addictive. Pain exerts an enormous personal and economic burden., A rational strategy to avoid the side effects of opioid is to target the starting point of the pain pathway: the neuroreceptors that produce pain. Certain members of the TRP family (TRPV, TRPA, and TRPM) constitute key detectors and transducers of nociceptive stimuli. Therefore, researchers have expressed great interest in the analysis of TRP channels.

Activation of TRPA1 induces pain

51TRPA1 plays a role in various forms of pain, including neuropathic cold pain, inflammatory pain, and hereditary episodic pain syndromes., As shown by dermal experiments, the activation of TRPA1 by certain compounds triggers pain and heat sensations.– Sustained activation of TRPA1 by endogenous substances induces chronic pain involved in various disorders, including fibromyalgia, osteoarthritis, inflammation, diabetes, obesity, migraine, neuropathy, bronchitis, and emphysema.

52Chembridge-5861528 blocks TRPA1 and relieves mechanical nociception after nerve injury. Koh et al. observed that inhibition of TRPA1 expression reduced the development of mechanical, thermal, and cold heterosensitivity. The experimental results of Sagalajev et al. showed that injury-induced oxidative stress in the amygdala stimulated TRPA1 to promote neuropathic pain behavior. This pain perception involved the inhibition of medullary serotonergic feedback inhibition acting on spinal 5-HT1A receptors, which was reversed by TRPA1 antagonists., In Schwann cells, activation of TRPA1 induces NADPH oxidase 1-dependent H2O2 release, maintains macrophage infiltration of injured nerves, and sends paracrine signals to activate TRPA1 in phagocytosed nociceptors to maintain mechanical nociception (Fig. 4).

53Activation of TRPA1 channels leads to an influx of sodium and calcium ions, which induces the depolarization of nociceptive nerve ending that is needed to generate the centrally propagating nociceptive signal. TRPA1 is expressed not only on peripheral but also on central terminals of nociceptive primary afferent nerve fibers. On central terminals located within the spinal dorsal horn, TRPA1 amplifies glutamate release and thereby transmission of nociceptive signals to spinal interneurons and projection neurons.,

54Topical administration of selective TRPA1 agonists in vivo induced nociceptive behavior in experimental animals and pain sensation in human beings., Bautista et al. used TRPA1-deficient mice to better demonstrate that environmental stimulants and endogenous analgesics depolarize nociceptive receptors via TRPA1 to elicit inflammatory pain. TRPA1 antagonists showed no effect on all pain. Intrathecal application of a low dose of TRPA1 antagonist attenuated formalin-induced tactile allodynia but had no effect on acute pain behavior. In addition, systemic administration of HC-030031 (TRPA1 antagonist) showed to have anti-isokinetic and inflammatory pain efficacy in a CFA model. Interestingly, low doses of intrathecal HC-030031 can also able to attenuate pain. By contrast, a similar dose of a TRPA1 antagonist had no effect on healthy rats.,

TRPVs in pain

55TRPV1 is a heat-activated cation channel modulated by inflammatory mediators and contributes to acute and chronic pain. About 30% of the TRPA1-expressing neurons co-express TRPV1. TRPV1, which is widely expressed in bipolar neurons, transmits sensory information from the periphery to the somatosensory cortex via the spinal cord., Stimulation of TRPV1 evokes a burning sensation, which reflects the central role of the channel in pain.

56Trpv1 knockout mice in an inflammatory model exhibited attenuated thermal nociception, which sparked great interest among researchers to develop TRPV1 antagonists with analgesic properties., TRPV1 is involved in toxic chemicals and heat-induced pain and promotes peripheral sensitization. Analgesics may enhance nociceptive receptor activity by increasing TRPV1 expression.

57In the case of cutaneous and visceral pain, the downregulation of TRPV1 activity produces antinociceptive effects., TRPV1 in skin non-neuronal cells may release pro-inflammatory agents acting on nociceptive endings, which sensitizes neuron-expressed TRPV1 channels and triggers pain signals.,

58TRPV4 primarily mediates inflammatory pain and neuropathic pain. Colonic mechanical pain and nociception were significantly relieved in Trpv4 knockout mice. In mice, topical treatment with a TRPV4-selective inhibitor decreased UVB-evoked pain behavior, epidermal tissue damage, and endothelin-1 expression. In sunburned humans, elevated expressions of epidermal TRPV4 and endothelin-1 were observed. Activation of TRPV4 induced the transcriptional regulation and release of cytokines and tachykinins (substance P (SP) and calcitonin gene-related peptides (CGRP)), which ultimately led to chronic pain. Elevated prostaglandin E2 (PGE2) is also thought to contribute to TRPV4-mediated nociceptive behavior, which is important in pathological pain states associated with multiple diseases. In addition, TRPV4 plays a role in chronic DRG compression-induced neuropathic mechanical pain via the p38 MAPK pathway.

59Although studies on TRPVs related to pain have mainly focused on TRPV1 and TRPV4. TRPV2 and TRPV3 are also promising targets. TRPV2 is widely expressed in neuronal and non-neuronal cells., Increased expression of TRPV2 is associated with thermal hyperalgesia and mechanical thermal after oral mucosal incision. However, the role of TRPV2 in sensory neurons is currently unknown, and a limited number of studies have been conducted in relation to pain.

60By contrast, TRPV3 does not act as extensively as other channels, and its studies have focused on skin diseases. TRPV3 has been suggested as a candidate transducer contributing to pain hypersensitivity associated with inflammatory states., Analgesic effects were observed in a model of pruritus treated with selective and potent inhibitors of the TRPV3 channel by Han et al.. TRPVs are a promising therapeutic target in pain research.

TRPMs in pain

61Numerous studies have linked the TRPM8 channel to pain. The channel is mainly expressed on peripheral sensory neurons and is known as a cold temperature sensor. However, it is also expressed in deep viscera. The administration of TRPM8 antagonists, knockdown of the TRPM8 gene, or ablation of primary afferent neurons expressing TRPM8 can be effectively relieve the cold pain associated with tissue and nerve damage., The experimental results of Zuo et al. demonstrated that TRPM8 played a role in cold soreness and hyperalgesia following chronic trigeminal nerve injury. Activation of TRPM8 effectively reduces the painful behavior caused by chemical irritation, toxic heat, and inflammation., TRPM8 can also amplify the analgesic effects of their agonists by forming complexes with 5-HT-1B receptors. In addition, when TRPM8 od TRPA1 and TRPV1 are co-activated, an analgesic effect is produced.

62In addition to TRPM8, significant advances have been made in the role of TRPM2 in pain. Exposure of TRPM2 to H2O2 significantly increased mRNA and protein levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and a chemokine (CXCL2)., Remarkably, the inhibition of TRPM2 expression can affect the elevated levels of cytokines and chemokines. TRPM2 may play a role in inflammatory pain. In animal experiments, TRPM2-deficient mice were unresponsive to mechanical and thermal nociception in a model of keratin-induced inflammation and exhibited reduced edema. Therefore, TRPM2 contributes to inflammatory pain by promoting peripheral immune functions.

63TRPM2 and TRPM8 are the most relevant members of the family of TRPMs regarding pain, but the role of other members of the family in pain should not be underestimated. Pharmacological and genetic studies have shown that TRPM3 is associated with various pain patterns. Su et al. concluded that TRPM3 plays a role in thermal hyperalgesia and spontaneous pain but not in cold and mechanical hyperalgesia. The heat-activated TRPM3 ion channel is a potential target for new analgesics, but its mechanism in relation to pain is unknown and needs to be explored.

64TRPs are arguably the most widely studied analgesic targets today. TRPV1 has been validated as a target for analgesic drugs in preclinical studies, and its side effects should not be underestimated. Whether other pain-related TRP channels act as the sole mediators of nociception, and the mechanisms of analgesia remains to be determined.

IBD and complications

65IBD, which is one of the global disorders of the 21st century, is a chronic recurrent disease of the gastrointestinal (GI) tract characterized by an inflammatory process that requires lifelong medication. Over the past decades, IBD has been regarded as a worldwide public healthcare challenge, and it can usually be classified into two major forms: Crohn’s disease (CD) and ulcerative colitis (UC). IBD was prevalent in Western countries in the past, but a significantly increasing incidence has been observed in developing countries more recently.

66The pathogenesis of IBD is complicated. Multiple factors constitute a confluence of risk factors for IBD, and they may include genetic and environmental changes that cause dysregulation of the intestinal barrier, immune responses, and microbiota. It not only affects the GI tract but is also a major causative factor of a number of complications, such as nonalcoholic fatty liver disease (NAFLD) and psoriasis., NAFLD in particular has been considered a leading cause of liver disease in IBD patients, with a prevalence of 8–40%. Meta-analyses have shown that patients with psoriasis are 1.70 times more likely to have CD and 1.75 times more likely to have UC. Therefore, among the numerous complications of IBD, NAFLD, and psoriasis negatively affect the health of patients and are difficult to cure. Thus, they bring a heavy burden to patients and families.

Alleviating IBD symptoms: emerging TRP targets

67Traditional strategies for the treatment of IBD have relied on the frequent administration of high doses of drugs, including antibiotics, anti-inflammatory agents (such as 5-aminosalicylic acid and corticosteroids), and biological and immunosuppressive agents (azathioprine, 6-mercaptopurine, methionine, cyclosporin-A, and tacrolimus), to reduce inflammation. The emergence of monoclonal antibodies as biological therapies has significantly increased the treatment options for IBD. Numeros TNF-α antibodies, such as adalimumab or certolizumab, are used in the clinical treatment of IBD. Antibodies targeting IL-12 and IL-23, such as ustekinumab and natalizumab, have also been proposed for clinical approval. These drugs can effectively relieve early inflammatory symptoms, but their long-term use can cause toxicity and damage organs. These problems may be effectively avoided when certain TRP modulators are used.

TRPVs in IBD

68Activation of TRPV4 receptors in the GI tract can trigger inflammation. TRPV4 is expressed and functional in human colon samples, human intestinal epithelial cell lines (Caco-2 and T84), and inflamed colons of mice; 4α-phorbol-12,13-didecanoate (4αPDD) activated TRPV4 in the GI tract and increased the intracellular calcium ion concentration, which ultimately leads to chemokine release and colitis. Cenac et al. demonstrated that 4αPDD selectively activated TRPV4 in colonic sensory neurons, which affected visceral nociception and hypersensitivity. Fichna et al. first observed the significantly higher expression of TRPV4 mRNA in the tissues of IBD patients compared with those of non-IBD patients. Activation of TRPV4 receptors in the GI tract has a pro-inflammatory effect, and selective blockade of TRPV4 in an animal model of IBD alleviated colitis and the pain associated with intestinal inflammation. De Petrocellis et al. showed that activation and desensitization of TRPV channels mediated intracellular Ca2+ concentrations. Interference with TRPV1–4 channel activity and expression may have multiple potential therapeutic applications for IBD.

69Increased TRPV1 nerve fibers in patients with IBD correlated with abdominal pain severity. Upregulation of TRPV1 protein expression in IBD patients affected nerve endings and immune cells, which suggests the importance of TRPV1 in colonic immune regulation of the inflammatory response and in the pathogenesis of IBD. Over 20% of patients with IBD have significantly elevated TRPV1 expression in the rectum, which is a key point in mediating inflammatory pain. The process of producing neuropathic pain in patients with IBD is associated with the activation of TRPV1 because it promotes the release of neuropeptides, such as SP and CGRPs from peripheral terminals (Fig. 5). Moreover, increased levels of TRPV1 were observed in patients with acute exacerbations of IBD and in experimental models of acute colitis. Pretreatment of the IBD model with the TRPV1 antagonist JYL1421 reduced visceral hypersensitivity, inhibited colorectal dilation, and improved microscopic colonic inflammation. All these findings support the idea that TRPVs at least partially participate in the regulation of IBD.

Activation of TRPM8 for the treatment of IBD

70TRPM8 mRNA is highly expressed in colonic DRG neurons, and TRPM8 protein is distributed throughout the nerve fibers of the colon wall. Harrington et al. suggested that TRPM8, which is present in colonic sensory neurons, couples to TRPV1 and TRPA1 and inhibits their downstream chemosensory and mechanosensory effects. In animal models of post-inflammatory colonic allergy, increased TRPM8 expression significantly attenuated hypersensitivity to mechanical stimuli and reduced the symptoms of colonic allergy.

71Inflammation in mouse colitis models can be alleviated by the activation of TRPM8. Selective activation of TRPM8 reduces the release of inflammatory neuropeptides, inhibits the release of pro-inflammatory cytokines and chemokines, and prevents the accumulation of leukocytes in the colon. Inhibitors of phospholipase A2 (PLA2) reduce the response of TRPM8 to cold and agonists, and lysophospholipids as products of PLA2 have the opposite effect on TRPM8. Notably, PLA2 levels are elevated in patients with CD and UC, whereas levels of lysophospholipids are clearly decreased. These changes may also have implications for the function of TRPM8 during colitis.

TRPA1 agonists

72Ample evidence indicates that TRPA1 plays a major role in the development of IBD. 2,4,6-Trinitrobenzene sulfonic acid (TNBS) induces colitis with colonic dilation and increases sensitivity to chemical stimuli; TRPA1 expression is upregulated in the colonic afferent DRG neurons. Intrathecal administration of the TRPA1 antisense oligodeoxynucleotide inhibitor resulted in the downregulation of TRPA1 expression in the DRG and inhibited IBD-induced nociceptive hypersensitivity, colonic dilation, and allyl intracolonic isothiocyanate. Dinitrobenzene sulfonic acid (DNBS) binds to the intracytoplasmic N-terminal cysteine residue of the TRPA1 protein; thus, effective treatment of DNBS-induced colitis is achieved by antagonizing TRPA1 or genetic deletion of TRPA1, and therefore, TRPA1 is considered a direct target of DNBS-induced IBD.

73Application of TRPA1 agonists alleviated DNBS-induced colitis inflammation in mice. Activation of TRPA1 restored the integrity of the colonic epithelial mucosa, inhibited the production of nitric oxide, IL-10, and IFN-γ, and significantly reduced nitrite levels. These data suggest the significant role of TRPA1 in restoring intestinal mucosal integrity and reducing inflammatory factors after IBD. It may also be used to provide a new therapeutic strategy for the relief of IBD.

Complications of IBD: NAFLD

74NAFLD is one of the most prevalent complications of IBD, and it may occur at any stage of the natural course of the disease. The prevalence of NAFLD ranges from 1.5% to 55% in UC and from 1.5% to 39.5% in CD (with an overall mean prevalence of 23%). Patients with IBD with NAFLD tend to have stable liver disease that is stable for 4–6 years. NAFLD is also the most common liver disease, with a prevalence of up to 25% worldwide; thus, it imposes a significant economic burden on patients and leads to a health-related decline in quality of life. It is characterized by fibrosis, inflammation, fatty deformation, and lipid deposition in hepatic parenchymal cells.

TRPV as a therapeutic target in NAFLD

75Activation of TRPV1 increases energy metabolism and prevents the accumulation of visceral fat. Monoacylglycerols (MGs) with unsaturated long-chain fatty acids are new TRPV1 agonists that along with capsaicin, are found in food and capsaicin to prevent the accumulation of visceral fat. Iwasaki et al. tested a diet of MGs that activated TRPV1 and found a reduction in the weight of white adipose tissue and lower levels of serum glucose, total cholesterol, and free fatty acids. Activation of TRPV1 also enhanced energy expenditure and increased thermogenesis, which further reduced visceral fat accumulation in mice and prevented NAFLD. Therefore, activation of TRPV1 is considered an important candidate for reducing the risk of diseases, such as NAFLD (Fig. 6).

76Long-term activation of TRPV1 in tissues causes upregulation of hepatic uncoupling protein 2 (UCP2), which effectively prevented high-fat diet-induced NAFLD in mice. Previous studies have shown that TRPV1 activation by dietary capsaicin resulted in the upregulation of UCP2 expression in a wild-type (WT) mouse liver model but not in Trpv1 knockout mice. These results suggest that the mechanism by which TRPV1 is activated to prevent exacerbation of fatty liver may be associated with increased UCP2-mediated hepatic β-oxidation. Thus, dietary capsaicin may serve as a promising intervention for people at high risk of fatty liver disease. However, whether TRPV1 is involved in the regulation of lipid accumulation and the underlying mechanisms involved in this process are currently unclear.

77Song et al. observed that ruthenium red or a synthetic siRNA against TRPV4 inhibited the proliferation of HSC-T6 cells, which caused downregulation of myofibroblast markers, including α-SMA and Col1α1. Seth et al. reported that TRPV4 responded to the cytotoxic environment of the liver and negatively regulated cytochrome p450 enzymes (CYP2E1). Activation of TRPV4, which releases NO to act on neighboring hepatocytes, inactivates CYP2E1-induced redox toxicity (Fig. 6). TRPV4 acts as a cellular stress sensor in diseased tissues of patients with NAFLD, and thus, it constitutes an endogenous defense molecule that may act as a novel regulator in a protective manner for hepatocytes.

TRPM and TRPC channel involvement in NAFLD

78Assessment of acetaminophen-induced liver injury based on blood liver enzyme concentrations and liver histology revealed significantly less severe liver injury in Trpm2 knockout mice than in WT mice. TRPM2 channels are integral in the mechanism of acetaminophen-induced hepatocellular death. Thus, TRPM2-mediated cell death is an important mechanism in the pathogenesis of NAFLD-induced liver injury (Fig. 6). However, blockade of TRPM7 inhibits the activation and proliferation of primary hematopoietic stem cells and induces apoptosis in activated cells; ER stress was identified as a possible underlying molecular basis. TRPM2 and TRPM7 are valuable future therapeutic targets for NAFLD and serve as basis for discoveries related to in this disease.

79Arterial flow-regulated diastolic function, which leads to atherosclerosis, is lower in patients with NAFLD than in the healthy population. TRPC3-related endothelial mechanisms that promote NAFLD drive the progression of atherosclerosis. In vitro, TRPC3 is inhibited in hepatic sinusoidal endothelial cells, which makes them less sensitive to ER stress-induced apoptosis; therefore, the pro-apoptotic influence of TRPC3 may increase other fibrotic factors in vivo. A positive correlation was found among enhanced expression of endothelial TRPC channels, development of early steatohepatitis, and atherosclerotic load in a mouse model of nonalcoholic fatty liver hyperlipidemia fed with a traditional Western-style diet.

80Nishiyama et al. speculated that TRPC3 or TRPC6 may be involved in the fibrotic process of NAFLD. However, systemic deletion of either TRPC3 or TRPC6 does not attenuate liver fibrosis, inflammation, nor steatosis. These findings suggest that TRPC3 and TRPC6 are unlikely to be implicated in liver dysfunction and fibrosis in NAFLD mouse models. No effective therapy is available for NAFLD, and its exact pathogenesis remains to be elucidated. All these data indicate that TRP channels may be an interesting target for drug development for the treatment of NAFLD.

Extraintestinal complications of IBD: psoriasis

81A distinct bidirectional association exists between psoriasis and IBD. At the epidemiological level, patients with psoriasis are at increased risk of developing IBD, and vice versa. On the skin, TRPs are interesting pharmacological targets because they allow for topical treatment and may reduce the risk of severe harmful effects. TRP channels are widely expressed in various skin cell types, including keratinocytes, melanocytes, nerve endings, and immune cells. Their functions involve hair growth, wound healing, skin cell proliferation and differentiation, immunity, skin barrier function, and skin inflammation and pruritus., IBD and psoriasis are relatively common diseases that require long-term treatment. Immunosuppressive drugs are currently the most commonly used treatment in clinical practice and a significant overlap has been observed between effective drugs for the treatment of IBD and psoriasis. The development of potent targeted therapies for TRPs is changing the outlook for chronic inflammatory diseases such as IBD and psoriasis.

Remitting effect of inhibition of TRPVs on psoriasis

82TRP channels contribute differently to various psoriasis symptoms. Activation of TRPV1 and TRPC4 was found to be detrimental to psoriasis, whereas TRPA1 was found beneficial in preclinical studies. Lee et al. reported that the inhibition of TRPV1 activity, which activates ALX/FPR2 receptors, coupled with the control over CGRP release, significantly alleviated psoriasis-like pruritus and inflammation in an imiquimod (IMQ) animal model of psoriasis.

83The TRPV1 and NaV1.8 neuroreceptors control the cutaneous immune response by interacting with dermal dendritic cells to inhibit the production of several key effector cytokines in psoriatic dermatitis and regulate the IL-23/IL-17 pathway. Neurons expressing TRPV1 can mediate itch signaling. However, intrathecal injection of capsaicin (10 μg) disrupts the central terminals of TRPV1-expressing neurons. Therefore, we hypothesize that TRPVs are considered novel targets for the treatment of psoriasis by suppressing itching to relieve psoriasis symptoms.

Modulation of TRPM and TRPC channels

84Cold activation of TRPM8 reduces pruritus caused by psoriasis. This mechanism possibly occurs through blocking of histaminergic and non-histaminergic pruritic pathways by pharmacological hypothermic cooling. Activation of TRPM8 also reduces inflammation-induced psoriasis due to its capability to strongly improve edema, inhibit mechanical nociception, and decrease levels of inflammatory cytokines (IL-1β, TNF-α, and IL-6); as a result, the inflammatory response is reduced. In conclusion, these studies provide strong evidence that TRPM8 is a major cold sensor for amelioration of pruritus and inflammation in various dermatological conditions; it enables the use of TRP channel modulators in the treatment of psoriasis.

85In the IMQ-induced psoriasis mouse model, activation of TRPM8 channels stimulated Ca2+ responses in cervical DRG neurons, reduced scratching behavior in IMQ mice, attenuated IMQ-induced morphological changes in lesions, and controlled the infiltration of dermal neutrophils, dendritic cells, and Th17 cells. Activation of TRPM8 channels also significantly inhibited the generation of iNOS, cyclooxygenase (COX)-2, TNF-α, and IL-6, and prevented the phosphorylation of IκBα, NF-κB p65, ERK, JNK, and p38 MAPKs. Thus, activation of TRPM8 channels is thought to be effective in ameliorating the symptoms of IMQ-induced pruritus and psoriasis-like inflammation, which make it a promising strategy for the treatment of psoriasis.

86The level of 5-HT is higher in the skin of patients with psoriasis than that in healthy individuals. Specific inhibition of TRPC4 immediately controlled the neuronal activity induced by α-methyl-5HT in dermal nerve preparations. Interestingly, visual signs of skin inflammation, such as erythema and desquamation, were significantly improved after TRPC4 inhibition and were accompanied by a reduction in epidermal thickness and inflammatory cell infiltration. This effect was achieved by silencing TRPC4 in the DRG and showed an effective reduction in psoriatic pruritus even after repeated applications of IMQ. Therefore, TRPC4 antagonists may soon be used clinically for the treatment of acute pruritus and psoriasis.

Respiratory system

87Various TRP channels are widely distributed in the lungs and are involved in pathophysiological processes. A growing body of research suggests that TRP channels may become targets for drug use in the treatment of respiratory diseases.

2019 coronavirus disease (COVID 19)

88The COVID-19 pandemic, which is caused by severe acute respiratory disease coronavirus 2 (SARS-CoV-2), has resulted in hundreds of millions of confirmed cases worldwide. Calcium channel blockers are protective against death from SARS-CoV-2 infection and inhibit the infectivity of SARS-CoV-2 in epithelial lung cells. Given that coronaviruses require Ca2+ ions to enter host cells, Ca2+ are considered essential for viral entry into host cells. Interestingly, most TRP channels are highly permeable to Ca2+., Therefore, the researchers hypothesized that TRP channels are involved in certain processes in COVID-19.

89The report by Leidinger et al. points to the idea that TRPC6 channels are involved in physiology of normal human lungs and in COVID-19 pneumonia. They suggested that TRPC6 may exacerbate SARS-2-induced inflammation, but the molecular mechanism remains to be elucidated. Several patients with COVID-19 will develop acute respiratory distress syndrome (ARDS)., Khodadadi et al. found increased expression of TRP cation channels after the treatment of ARDS. Drugs may exert their protective effect against ARDS through TRPs.

90Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has also been defected in some COVID-19 patients.– Clinical studies have shown that TRPM3 channel activity is impaired in patients with post-COVID-19 conditions, which suggests impaired ion mobilization; such condition may impede cellular function and lead to chronic post-infection symptoms such as ME/CFS.

91Symptoms of COVID-19 associated with TRPA1/TRPV1 include the following: cough, smell, and taste disturbances,– loss of appetite, nausea, vomiting, inflammatory responses, and pain. However, several clinical studies targeted TRP channels for the treatment of COVID-19. TRPA1 and TRPV1 may provide a breakthrough in the treatment of symptoms of COVID-19.

92Given that a common denominator of COVID-19-related symptoms is impaired redox homeostasis, which is responsible for reactive oxygen species (ROS) accumulation, several TRP channels are also involved in oxidative stress. Bousquet et al. hypothesized the involvement of TRPA1 and TRPV1 in COVID-19. In another direction of thought, harmful stimuli activate TRPV1 and increase the release of SP and pro-inflammatory cytokines, which exacerbate the symptoms of patients infected with COVID-19.

93TRPV4 channels are involved in the recruitment of neutrophils and macrophages during lung injury. In addition, TRPV4 has been associated with pulmonary edema and pulmonary fibrosis. Therefore, TRPV4 is a novel target for COVID-19 treatment. TRPs are involved in pathophysiological processes that largely overlap with the symptoms of COVID-19. Published papers on COVID-19 have proliferated, but the mechanisms underlying the disease and TRPs remain inconclusive. TRP channels represent promising targets for the relief of multiple symptoms of COVID-19.

Cough

94Cough is a reflex action of the respiratory tract for clearing the upper airways. It is globally prevalent across all age groups. Stimulation of bronchopulmonary vagal C-fibers by inflammatory mediators can also cause cough., TRPV1 is expressed in the C-fiber sensory nerves of the vagus in the lungs and is involved in the afferent sensory loop of the cough reflex. Trevisani et al. noted the pathogenic role of TRPV1 in cough in animal experiments. Iodo-resiniferatoxin (a potent TRPV1 inhibitor) significantly reduced cough induced by inhalation of capsaicin or citric acid in conscious guinea pigs. Therefore, inhibition of TRPV1 expression is a potential target for cough treatment.

95TRPV4 plays a role in increasing sensitivity in the afferent arm the cough reflex. Selective activation of TRPV4 caused depolarization of airway sensory nerves and cough symptoms in experimental animals. Conversely, TRPV4 antagonists can reverse this phenomenon., In addition, the selective P2X3 antagonist AF-353 inhibits TRPV4-induced neural depolarization and coughing in animals and humans, which suggests that TRPV4 can cause ATP release and relieve cough. Thus, activation of TRPV4, through the release of ATP is likely to be a pathological cause of the cough.

96The TRPA1 receptor (not activated by capsaicin) has become a topic of interest in the field of cough treatment because it is known to be activated by ligands such as acrid smoke. Birrell et al. found in normal humans and guinea pigs that inhalation of cinnamaldehyde (a TRPA1 agonist) produced a dose-related increase in cough. Glenmark’s compound GRC 17536, a potent and specific TRPA1 antagonist, effectively suppressed the cough induced by a citric acid challenge in guinea pigs. A clinical study was subsequently conducted but was terminated due to the lack of clinical efficacy.

97TRPM2 may participate in oxidative stress at the cough center by regulating cough. In the case of TRPM8, menthol prevents coughing by activating TRPM8. Neurophysiological, immunohistochemical and molecular analyses suggest that the cough suppressant effect of peppermint occurs via a reflex initiated from nasal TRPM8., Based on the properties of TRPs, TRPM8 is undoubtedly one of the targets of cough. Most clinical studies targeting TRPs for the treatment of cough have ended with no drug efficacy. Future research should focus on new strategies to targeting this channel.

Chronic obstructive pulmonary disease (COPD) and asthma

98Asthma and COPD both cause airway obstruction and are associated with chronic inflammation of the airways; they are also very common respiratory diseases., A key risk factor for developing respiratory disease is smoking., The use of TRPV1 and TRPV4 antagonists inhibits cigarette smoke-induced ATP release from human bronchial epithelial cells and may be associated with COPD-influenced increases in pulmonary ATP. Activation of TRPV4 and opening of pannexin 1 channels leads to ATP release, which contributes to the pathogenesis of COPD. Baxter et al. also noted that TRPV4 gene expression was increased in the lung tissue of COPD patients. At the genetic level, 7 of the 20 single-nucleotide polymorphisms of TRPV4 tested have been associated with COPD, which suggests a potential relationship between TRPV4 protein structure and disease pathogenesis.

99Contraction of airway smooth muscle in human and guinea pig tissues was observed in vitro with TRPV4 agonists, and this condition may exacerbate asthma. McAlexander et al. suggested that activation of TRPV4 leads to airway constriction in humans and is entirely dependent on the production of cysteine leukotrienes. Therefore, activation of TRPV4 may exacerbate symptoms in patients with asthma.

100Several endogenous TRPV1 agonists are present in diseased lungs, such as those affected by COPD and asthma. The products of lipoxygenase metabolism of arachidonic acid, such as 12-(S)- and 15-(S)-hydroperoxyeicosatetraenoic acid, are released during asthma attacks and have a stimulatory effect on TRPV1. Another endogenous agonist of TRPV1, anandamide, is also synthesized in the lungs. The increased sensitivity of patients with COPD or asthma to inhaled capsaicin may explain the involvement of TRPV1 in the exacerbation of symptoms of these diseases.

101In contrast to TRPV1 and TRPV4, little is known about TRPV2. TRPV2 acts in the early stages of receptor-mediated phagocytosis by macrophages. Its relevance to alterations in macrophage responsiveness and host defense in COPD still needs to be determined.

102Andre et al. demonstrated that bronchial ring constriction produced by cigarette smoke extracts and acrolein or crotonaldehyde was inhibited by TRPA1 inhibitors. Furthermore, TRPA1 activation and increased Ca2+ influx promoted neuropeptide release from the isolated guinea pig airway tissue. These data suggest that airway neurogenic inflammation is mediated via TRPA1 stimulation, and suggest that TRPA1 may play a role in the pathogenesis of COPD.

103Notably, TRPC6 mRNA expression significantly increases in alveolar macrophages from COPD patients, whereas there was no difference has been observed in the expressions of other TRPC subfamily members., TRPC6 is a potential candidate target for COPD, but its role in the regulation of macrophage function under physiological and pathophysiological conditions remains to be determined.

104A novel truncated functional TRPM8 variant activated by cold and menthol has been identified in human bronchial epithelial cells. Whether TRPM8 expression is altered in the airway nerves or airway epithelium of individuals with cold-induced asthma and disease exacerbation remains to be elucidated.

Other respiratory diseases

105Idiopathic pulmonary fibrosis (IPF) is a prototype of chronic, progressive, and fibrotic lung disease. Rahaman et al. determined that TRPV4 activity was upregulated in lung fibroblasts from IPF patients, and mediated the onset of lung fibrosis. TRPV4 also plays an important role in the formation of pulmonary edema and acute lung injury., TRPV4 agonists caused pulmonary endothelial permeability, which was inhibited by the non-selective TRP blocker ruthenium red and was absent in Trpv4 knockout mice. Evidence showing that activation of TRPV4 may be involved in disrupting the integrity of the epithelial and endothelial barriers suggests the possible role of TRPV4 in edema formation. Studies also reported that TRPC6 is involved in pulmonary edema formation. Selective TRPC6 blockers were found to inhibit pulmonary ischemia-reperfusion-induced edema.

106A number of TRP channel modulators have entered clinical trials and significant progress has been made in describing the physiopathological function of TRP channels in the respiratory system.

Nervous system

107Neurological disorders are the leading cause of disability and the second leading cause of death worldwide. TRP channels are widely distributed in neurons and the brain,, and are thought to be associated with neurological disorders. They are involved in neurological disorders such as epilepsy, stroke, dementia, anxiety, neurodegenerative diseases, and depression.

TRPC

108TRPC is involved in chemokine ligand 2-mediated neuroprotection. Specific blockade of TRPC1 and TRPC5 inhibited ERK/cAMP response element binding protein activation and provided neuroprotection. TRPCs have also been linked to Parkinson’s disease (PD) and Alzheimer’s disease (AD). TRPC1 overexpression may exert PD protection by mediating an inward calcium flow, inhibiting cytochrome c release in mitochondria, and reducing MPP-induced neurotoxicity and apoptosis. In AD, each member of the TRPC channel performs a different role. TRPC1, TRPC3, and TRPC4 are found to be involved in neuroprotection,, TRPC3 may be involved in the dysregulation of tau proteins in AD, and TRPC5 possibly participates is involved in neurodegeneration.

109In addition to these disorders, the TRPC channels are involved in neurological disorders, such as autism, bipolar disorder (BD), and mental retardation. Griesi-Oliveira et al. found that the sequence of the TRPC6 gene on chromosome 11 was disrupted in autistic patients, resulting in haploinsufficient function. Later, they studied the effects of TRPC6 disruption on pluripotent stem cell-derived cortical neuronal cells. They observed that alterations in neurons of autistic patients were associated with disrupted expression of TRPC6. A behavioral study of Trpc6 knockout mice by Griesi et al. found no alterations in social or repetitive behavior, but a reduction in exploratory behavior may be associated with clinical signs of autism.

110Evidence from functional studies points to the involvement of TRPC3 and TRPC7 in BD. Clinical results demonstrated reduced TRPC7 expression in a subgroup of BD patients. Interestingly, this reduction was inversely correlated with the basal level of Ca2+ in B lymphocyte lines (BLCLs) from BD patients. Andreopoulos et al. treated BD rats with chronic lithium and TRPC3 protein levels were significantly reduced, whereas mRNA levels were not. In a study by Roedding et al. investigated whether TRPC3 expression and function were affected by oxidative stress in BD and control BLCLs; chronic mitochondrial-generated oxidative stress reduced TRPC3 protein levels and Ca2+ influx through these channels, but no significant difference was observed between the two groups. Thus, TRPC3 is probably not an ideal target for BD.

111Depression is a common psychological disorder in the society and is also a neurological disorder. Hypericin acts as a non-selective neurotransmitter reuptake inhibitor and has antidepressant effects. It produces a partial antidepressant effect by activating TRPC6 channels, increasing sodium permeability in the presynaptic membrane, reducing the sodium gradient driving neurotransmitter reuptake through the transporter, and increasing the levels of monoamine neurotransmitters in the synaptic cleft. To a certain extent, depression is also associated with brain-derived neurotrophic factors (BDNF). TRPC channel-induced calcium transients regulate the density and morphology of dendritic spines in BDNF, to produce antidepressant effects.,

112TRPC channels play an important role in vasospasm in hemorrhagic stroke, neuronal death and survival in ischemic stroke, and thrombin-induced pathological changes in astrocytes, and triggering of stroke by affecting blood pressure and atherosclerosis. In Ca2+ imaging experiments, Ca2+ influx through TRPC6 activated MAPK signaling and promoted the neuroprotective chemokine CXCL1, which protects nerves following stroke. The unique channel characteristics and downstream pathways of TRPCs render them potential new targets for the treatment of neurological diseases.

PD.

113To address the accumulation of fibrillar alpha-synuclein in PD patients. Yuan et al. found that regulating the opening of TRPV1 channels on the surface of microglia enhanced autophagy, phagocytosis and degradation of α-syn in microglia, which improved the status of PD. TRPV4 contributed to the loss of dopamine neurons and motor deficits in the substantia nigra of PD mice by mediating ER stress and inflammatory pathways. Furthermore, activation of TRPV1 channels on astrocytes activated endogenous neuroprotective mechanisms in vivo, which prevented active degeneration of dopamine neurons; this condition led to behavioral recovery via CNTF receptor alpha in nigrostriatal dopamine neurons. These studies provide a new perspective on future molecular targets and gene therapies for the treatment of PD.

AD.

114One of the features of AD mentioned earlier is the deposition of amyloid in the brain.– Metabolic facilitation with TRPV1 agonists reduced amyloid lesions and reversed memory impairment in a mouse model of AD. In addition, the activation of TRPV1 inhibited endocytosis of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor of GluA2 and improved cognition and synaptic function in the AD mouse model. Furthermore, HC067047 (a TRPV4 inhibitor) enhanced the expression of the neurogenic marker DCX in cognitively impaired mice and increased the levels of the mature neuronal marker NeuN, which indicated the neuroprotective potential for the treatment of dementia with learning and memory loss.

Stroke.

115Activation of TRPV2 induces the release of nerve growth factor (NGF) and regulated blood-brain barrier (BBB) function, which may be associated with ischemic stroke. TRPV4 alleviates ischemic injury by increasing glutamate and overloading Ca2+, thereby reducing neurotoxicity. Preservation of microcirculation and BBB function shortly after ischemic stroke is a key neuroprotective effect of TRPV4 inhibition, which suggests a contribution of TRPV4 to postischemic brain injury.

TRPA1

116The toxic effects of amyloid-β on astrocytes triggered by TRPA1 channel activation are key to the progression of AD. Furthermore, mitochondria have an important role in the pathogenesis of AD. TRPA1 channels reduces the intracellular Ca2+ concentration, apoptosis and intracellular ROS, and this may have a role in the treatment of AD. TRPA1 activity, if inhibited, will exacerbate astrocytic lesions, inhibit the production of pro-inflammatory cytokines as well as the activity of astrocytes and the transcription factors NF-κB and nuclear factor of calcineurin-activated T cells (NFAT), and play a key role in the pathogenesis of AD.

117Prolonged activation of TRPA1 by trans-cinnamaldehyde leads to increased epileptic activity. In contrast, HC030031 (a TRPA1 antagonist) promotes anticonvulsant effects, and preventes TRPA1 upregulation during seizures.

118Increased NADPH oxidase and superoxide dismutase activities and TRPA1 endogenous agonist levels (hydrogen peroxide and 4-hydroxynonenal) were reported in a mouse model of progressive multiple sclerosis-experimental autoimmune encephalomyelitis. Thus, TRPA1 may be involved in depression and anxiety-like behaviors. TRPA1 also exerts tonic control and promotes anxiety and depression. Antagonists of TRPA1 are a potential drug category for the treatment of anxiety and mood disorders.

119In hypoxia, endothelial TRPA1 channels cause vasodilation, which reduces ischemic damage, a set of phenomena thought to be associated with ischemic stroke. In combination with these findings, TRPA1 can be included as a candidate for therapeutic targets in neurological diseases.

TRPM

120TRPM2-mediated cellular and molecular crosstalk with amyloid β peptide or oxidative damage results in the formation of AD lesions. TRPM2 plays an important role in mediating cell death induced by various oxidative stress-induced pathological factors, including ischemia and reperfusion, the neurotoxic amyloid β-peptide, and MPTP/MPP+, which lead to neuronal death in the brain., Activation of TRPM2 alters intracellular ion homeostasis, which leads to abnormal initiation of various cell death pathways, making it an important mechanism in the pathogenesis of ischemic stroke and neurodegenerative diseases.

121Hazalin et al. found that inhibition of TRPM4 expression at the mRNA and protein levels improved cognitive deficits in chronically underperfused rats, but did not affect their motor function. It has also been suggested that TRPM4 plays a key role in the treatment of ischemic stroke. Chen et al. examined the link between TRPM4 and ischemic stroke through in vivo assessment and observed that inhibition of TRPM4 improved BBB integrity after reperfusion in ischemic stroke.

122The TRP channel may represent a promising therapeutic strategy for neurological disorders. Future research and development should focus on the TRPC channel because it is more widely distributed in the nervous system and existing studies are not sufficiently advanced.

Cardiovascular system

123Given the distribution and function of TRP channels in excitatory and non-excitatory cells of the cardiovascular system, they can be a potential therapeutic target for CVD. Different TRP family members have various potential functions in CVD, and are mainly involved in hypertrophy, heart failure, arrhythmias, and vascular regulation.

Cardiac hypertrophy and heart failure

124Cardiac hypertrophy and heart failure are closely related. Ang II-induced cardiac hypertrophy is the key to the pathological process of heart failure., Using siRNA, Onohara et al. demonstrated that TRPC3 and TRPC6 were required for Ang II-induced NFAT translocation in cultured rat myocytes, which is a key step in cardiac hypertrophy. Furthermore, Ang II stimulation resulted in a significant increase in apoptosis in cultured neonatal rat cardiomyocytes transfected with TRPC7, accompanied by a decrease in atrial natriuretic factor expression and destruction of actin fibers. Ang II/phenylephrine-infused TRPC3 transgenic mice showed increased activation of NFAT in vivo, cardiomyopathy, and increased hypertrophy following stimulation with neuroendocrine agonists or pressure overload. Mice lacking TRPC1 channels maintained cardiac function, which prevented cardiac hypertrophy, when subjected to hemodynamic stress and neurohormonal overload. TRPV3 expression also increased in Ang II-induced cardiomyocyte hypertrophy in vitro, accompanied by an increased intracellular calcium ion concentration, which promoted the expression of calcineurin and phosphorylated CaMKII protein and enhanced nuclear translocation of NFATc3.

125Feng et al. observed clinically that TRPM4 currents were more than twofold larger in fibroblasts from heart failure patients than from controls, and this finding implies the possible role of TRPM4 in cardiac fibrosis in heart failure. Moreover, dietary activation of TRPV1 by capsaicin may prevent the cardiac hypertrophy caused by a high-salt diet by improving cardiac mitochondrial dysfunction.

High blood pressure

126High blood pressure is associated with vasoconstriction., Evidence showing the involvement of TRP channels in the regulation of vasoconstriction is lacking. Furthermore, impaired TRPV1 signaling may contribute to the pathogenesis of hypertension. Anandamide activates TRPV1 on perivascular sensory nerves, which leads to the release of CGRP to reduce vasoconstriction. Anandamide also inhibits vasoconstriction by activating the TRPV1 receptor in the endothelium, which causes the acute release of NO.

127TRPV4 and TRPM4 also have a regulatory effects on systemic blood pressure. Plasma adrenaline concentrations and urinary excretion of catecholamine metabolites, which may reduce hypertension, greatly increased in Trpm4 knockout mice. Furthermore, in Trpv4 knockout mice, the odds of hypertension induced by inhibition of NOS were greater, which was mainly related to the involvement of TRPV4 in vasodilation, this finding suggests the vasoprotective effect of endothelial TRPV4.

Atherosclerosis

128Atherosclerosis is the process of plaque formation that leads to the development of a number of CVDs., In addition, atherosclerosis may be associated with the apoptosis of macrophages. Tano et al. discovered that Trpc3 knockout mice exhibited reduced macrophage apoptosis and necrosis and increased collagen content. Specific inhibition of TRPA1 exacerbated oxidized low-density lipoprotein-induced lipid accumulation in macrophages, and atherosclerotic lesions and hyperlipidemia aggravated. Upregulation of TRPM2 enhanced 5-HT vascular reactivity during the development of atherosclerosis.

Vascular complications

129Autosomal dominant PKD is caused by mutations in PKD1 and PKD2 and often associated with vascular abnormalities., PKD1 and PKD2 encode polycystins TRPP1 and TRPP2, respectively. Abnormal intracellular Ca2+ regulation associated with PKD2 haploinsufficiency reduces vascular smooth muscle cell contractions. This condition is essential for maintaining the structural and functional integrity of blood vessels. Overall, these observations suggest that TRP channels may be an avenue for mitigating CVD.

Endocrine system and metabolism

130TRP channels also have a wide range of physiological functions in the endocrine system and metabolism, including in diseases such as cancer, obesity, kidney disease, metabolic syndrome, and diabetes.,,

Cancer

131TRP channels play a key role in cancer progression. Changes in the expression of TRP channels have been found in a number of cancers, including prostate, breast, colorectal, pancreatic, liver, and gastric cancers. Such finding was mainly due to the inhibition of cell migration and invasion, and tumor cell growth and proliferation caused by TRP channels. Researchers need to further elucidate the functional role of TRP channels in cancer and their changes.

Obesity

132Obesity is characterized by excessive fat accumulation in the body. Notably, TRP channels are expressed in adipose tissue. In response to exogenous stimulation, TRP channel receptors activate the sympathetic nervous system norepinephrine brown adipose tissue axis to enhance thermogenesis and thereby suppress obesity. Oral capsaicin reduces abdominal fat and enhances brown fat thermogenesis, white fat browning, fatty acid β-oxidation, and energy expenditure in obese patients. The function of these TRP channels identifies them as potential targets for obesity.

Kidney disease

133TRPC6 is expressed in glomerular podocytes. Increased expression levels of TRPC6 were observed in patients with focal segmental glomerulosclerosis (FSGS), membranous nephropathies, minimal change nephrosis, and diabetic nephropathy. TRPC6 mutations are involved in FSGS at the genetic level. TRPC 6 plays a cytoprotective role in membranous nephropathy. Aberrant expression of TRPC6 channels may be an important causative factor in kidney disease, but its clinical application needs further study.

Metabolic syndrome

134Metabolic syndrome is a common metabolic disorder that results from the increased prevalence of obesity. As mentioned earlier, TRP channels are involved in CVD and obesity. The dysfunction of TRP channels is likely to contribute to increased cardiovascular risk in patients with metabolic syndrome. Although no experimental evidence indicates that TRP channels directly affect metabolic syndrome, TRP channels can be investigated as a medicinal target because of their role in related disorders.

Diabetes

135TRP channels are related to several aspects of the pathology of diabetes, including insulin release from pancreatic beta cells and secondary diseases such as diabetic neuropathy, nephropathy, and vasculopathy. Chung et al. observed that the gene expression of TRPC4 was upregulated by 22%, and the protein expressions of TRPC1 and TRPC6 were downregulated by 50% in blood vessels of diabetic patients compared with non-diabetic controls. They suggested that diabetes affected capacitive calcium entry by regulating TRPCs. In addition, activation of TRPV4 affects insulin secretion and influences the level of insulin mRNA in cells. TRP channels have distinct clinical potential for the treatment or prevention of diabetes and its complications. However, given that TRP channels have a number of conflicting indications, clinical drug development will face a number of challenges.

Urogenital system

136Preclinical studies suggested that modulators of TRPs improve genitourinary disorders,, including neurogenic bladder, interstitial cystitis, and overactive bladder. Extracellular ATP-gated P2X receptors are trimeric non-selective cation channels that are important for nerve conduction. After posterior tibial nerve stimulation of neurogenic bladder in rats, inflammatory cell infiltration in bladder tissue was significantly reduced, and TRP and P2X expressions in the bladder and DRG were partially restored. Clinical studies have revealed significantly increased levels of TRPM8 mRNA and protein expression in bladder tissue from patients with interstitial cystitis/bladder pain syndrome. In addition, the secretion of inflammatory mediators and oxidative stress by TRPA1 into the periphery may influence the pathogenesis of interstitial cystitis/bladder pain syndrome.

137TRPV1 plays a role in the pathophysiology and treatment of overactivity of the detrusor muscle. TRPV1 expression was significantly elevated in the urothelium of patients with overactive bladder disease. NGF-induced bladder overactivity depends on the interaction of NGF with TRPV1. In addition, selective antagonism of TRPM8 inhibits the exaggerated activity of mechanosensitive bladder C-fibers and reduces bladder overactivity. These studies suggest that TRP channel modulators may be of value in urogenital disorders.

Immune regulation

138Growing evidence demonstrates functional TRP channel expression in immune cells with important implications for immunology. TRP channel activation induces immunomodulatory effects on multiple levels.

139IL-31 is a key neuroimmune link between TH2 cells and sensory nerves in the generation of T cell-mediated pruritus. IL-31-induced pruritus was significantly reduced in Trpv1 and Trpa1 knockout mice. This finding suggests that TRPV1 and TRPA1 are involved in immune response.

140To date, the expression of TRPA1 in immune cells has been poorly studied. Expression of TRPA1 was upregulated in atherosclerotic macrophages from mice deficient in lipoprotein E (Apoe−/−). Selective inhibition of TRPA1 increased the levels of serum triglycerides, high-density lipoprotein, total cholesterol, pro-inflammatory cytokines, and macrophage inflammatory protein-2 (MIP-2) in Apoe−/− mice. This result suggests that TRPA1 performs a regulatory function in macrophage foam cell cholesterol metabolism. Activation of TRPA1 also stimulated the release of TNF-α and IL-8 from the human macrophage line U937.

141In RAW 264.7 macrophages, the TRPM8 agonist icilin activated TRPM8-like channels. In vitro, anti-inflammatory effects were produced in mouse peritoneal macrophages by activation of TRPM8. Activation of TRPM8 also inhibited the production of pro-inflammatory cytokines in human monocytes and lymphocytes in vitro.

142TRPV1 is activated in bone marrow-derived macrophages, which attenuates lipid accumulation and reduces the production of monocyte chemoattractant protein (MCP-1), MIP-2 and IL-6. Activation of TRPV1 in RAW264.7 cells in an inflammatory state inhibited the release of iNOS and NO, COX-2 and PGE2. Acharya et al. observed that activation of TRPV1, which induces anandamide production by myeloid cells acting on CB2 receptors, increased the number and immunosuppressive function of regulatory CX3CR1hi macrophages.

143TRPV4 is expressed and functions in immune cells, including macrophages, monocytes, neutrophils and T cells. In alveolar macrophages of WT mice, activation of TRPV4 caused calcium influx and superoxide and nitric oxide production, but this phenomenon was absent in Trpv4 knockout mice. Majhi et al. revealed that in vitro activation of TRPV4 in T cells led to T cell proliferation and production of pro-inflammatory cytokines IFN-γ, TNF-α and IL-2. These results suggest that TRP channels are involved in the coordination of immune response in immune cells.

144TRP channels are also involved in the pathogenesis of immune-mediated chronic inflammatory diseases. They regulate macrophage polarization, chemokine and cytokine production, phagocytosis, and proliferation and survival. In the future, the expressions of TRP channels in immune cells and the signaling pathways for TRP channel activation in different immune-mediated diseases must be clarified to identify new molecular mechanisms for the treatment of these diseases.

Therapeutic interventions

145TRP channels have important functions in diseases. Thus, the use of TRPs as a drug target has therapeutic potential.

Pharmaceutical interventions

146In recent years, several modulators of TRPs of chemical, biological, and natural origin have entered clinical trials and they have been used to treat inflammatory, neuropathic, and visceral pain although the therapeutic mechanism of action of these compounds is unclear.

TRPV1 agonists and antagonists

147Various TRPV1 antagonists have been evaluated at various stages of clinical trials for different indications. TRPV1 antagonists show promise for pain treatment. ABT-102, a structurally novel TRPV1 antagonist, has been tested in phase I clinical trials for pain associated with inflammation, tissue damage, and ischemia. ABT-102 was clinically well tolerated by repeated dosage but caused a short-term increase in the mean core body temperature in healthy volunteers. Phase II clinical trials have been completed for the use of AZD1386, also an antagonist of TRPV1, for neuropathic pain, dental pain, nonerosive reflux disease, and osteoarthritis. However, in patients with osteoarthritis and nonerosive reflux disease, the clinical trial was terminated because there was no significant reduction in pain was observed.,

148Capsaicin in chili peppers bestows the sensation of spiciness and is a common component found in the fruits of Capsicum., It is a classical TRPV1 agonist. Studies have reported the beneficial effects of capsaicin acting on TRPV1 in obesity, cardiovascular and GI, various cancers, neurogenic bladder, and skin diseases.

149A randomized trial assessing the effects of TRPV1 antagonist SB705498 on pruritus induced by histamine and cowhage in healthy volunteers has progressed to phase I. However, the results of SB705498 on atopic dermatitis showed that it is not clinically relevant for pruritus due to dermatitis. SB705498 has also been investigated for the treatment of migraine (ClinicalTrials.gov: NCT00269022), toothache (ClinicalTrials.gov: NCT00281684) and rectal pain (ClinicalTrials.gov: NCT00461682), all of which have now completed Phase II clinical trials. The results of these clinical studies have not been published to date.

150Phase II clinical trials of XEND0501 for the treatment of chronic cough and COPD (ClinicalTrials.gov: NCT022233699 and NCT022233686) have been completed. Although XEND0501 was well tolerated, it was not clinically meaningful for patients with refractory cough.

151PAC-14028 completed a Phase II clinical trial for the topical treatment of pruritus, rosacea, and atopic dermatitis (ClinicalTrials.gov: NCT02052531, NCT02052999 and NCT02583022, respectively). In 2019, the results of the clinical Phase IIb trial of PAC-14028 cream met safety and efficacy metrics. In addition to the TRPV1 antagonists mentioned above, numerous chemical, biological and natural agents, including NEO-6860, JNJ-39439335 and others, have been introduced in clinical trials.

TRPA1 antagonists

152Given its involvement in pain, itching, and respiratory syndromes, TRPA1 has been pursued as a promising drug target. GDC-0334 is a chemical-derived drug that reduced TRPA1 agonist-induced skin blood flow, pain and pruritus in a phase I clinical trial (ClinicalTrials.gov: NCT03381144). GDC-0334 provides a therapeutic basis for assessing TRPA1 inhibition as a clinical treatment for asthma.

153In 2012, Glenmark selected GRC 17536 for clinical development as a TRPA1 antagonist. In September 2014, Glenmark announced positive results obtained in the Phase II clinical trial. GRC 17536 had statistically significant and clinically relevant response in patients with moderate to severe painful diabetic neuropathy. GRC 17536 remains the only TRPA1 antagonist to have completed a Phase IIa study to date.

154In 2015, Orion announced that the TRPA1 antagonist ODM108 (acetylene-containing compound) entered phase I clinical trials for neuropathic pain. However, complex non-linear pharmacokinetics emerged and the clinical trial was discontinued in 2016. A key point of progress in TRPA1 research is the efficient oral utilization of the substance. A problem with all TRPA1 antagonists developed to date is that they are highly lipophilic and relatively insoluble. Addressing this issue is necessary for the drug development involving TRPA1.

Regulation of TRPM8

155The TRPM8 channel is responsible for the sensation of cold environmental temperatures, it is also clinically associated with pain, itching, and obesity. PF-05105679 is a moderately potent TRPM8 blocker that has been evaluated for the treatment of cold pain sensitivity. Winchester et al. observed in clinical trials of PF-05105679 that the compound showed significant pain inhibition in the cold press test and no effect on core body temperature was observed. These results suggest that TRPM8 plays a role in acute cold pain signaling, and its dose does not result in a lower than normal body temperature.

156Menthol is a natural source of TRPM8 agonists. Topical menthol activates nociceptors on the skin and then desensitizes them. When topically applied, menthol can also act as a vasorelaxant, but the mechanism is unclear. Menthol is also used clinically for migraines, neuropathy, and muscle pain. It provides a cooling effect, leaving human subjects with a cool sensation on the skin and significantly less discomfort than ice.

157Another TRPM8-related compound, isopulegol (Phase II, ClinicalTrials.gov: NCT02193438), had no positive biomechanical or neurophysiological effects on patients with oral dysphagia due to stroke or neurodegenerative disease no significant adverse events were observed.

158Peppermint oil is another TRPM8 agonist of a natural origin. Winchester et al. investigated the role of peppermint oil in a mouse model of colitis. The results showed that peppermint oil, activated TRPM8 and the treated mice showed improvements in macroscopic and microscopic parameters and reduced weight loss during colitis. In addition, Peiris et al. observed that the use of TRPM8 agonist icilin for irritable bowel syndrome resulted in reduced release of inflammatory cytokines IL-1β, IL-6, and TNF-α in patient biopsies. These results suggest that specific activation of TRPM8 may alleviate experimental colitis and irritable bowel syndrome and may be a promising additional therapy for the treatment of IBD.

Other medicinal TRP uses

159TRPV1, TRPA1, and TRPM8 are currently being studied in clinical trials, but clinical studies of other channels should not be overlooked. A TRPV4 inhibitor, GSK2798745 was launched by GlaxoSmithKline as a clinical candidate. In 2019, GSK2798745 underwent its first clinical study (ClinicalTrials.gov: NCT02119260). Positive results were obtained; GSK2798745 was well tolerated in healthy volunteers and in patients with stable heart failure, which allowed further evaluation in long-term clinical studies of heart failure and in other indications.

160Preclinical studies have provided a certain rationale to support the development of TRPV3 antagonists for the treatment of inflammatory skin diseases, pruritus and pain. However, to date, only one TRPV3 inhibitor (GRC15300) has entered clinical trial targeting osteoarthritis and neuropathic pain. Moreover, by the end of 2013, these trials were discontinued. The Sanofi–Glimark agreement was terminated in 2014, and no further developments have been reported since then. Although numerous TRP channel drugs have entered clinical trials, only a few have been approved by the US Food and Drug Administration (FDA) (Table 4). In summary, researchers have made progress in understanding the role of TRPs in health and diseases. TRPs show promise as therapeutic targets for the treatment of inflammation, pain, itching, and other conditions.

Physical interference methods

161Numerous methods of physical interference are used for TRP channels, and they include moxibustion, acupuncture, photothermal therapy, and electroacupuncture. Moxibustion, acupuncture, and electro-acupuncture are all traditional Chinese medicine treatments. These methods are applied to the body surface to avoid the adverse events associated with medication. They are mainly used clinically for the relief of pain and inflammation.,

162The effectiveness of moxibustion therapy is reportedly determined by the activation of TRPV1–4. In one study, moxibustion treatment of Trpv1 knockout mice did not produce the significant increase in thermal pain thresholds exhibited by normal mice. This result suggested that TRPV1 was involved in the process of increasing the thermal pain threshold in the moxibustion-stimulated mouse spinal cord at L5 and L6. In visceral nociceptive rats, the expression of TRPV1 and heat shock protein 70 was increased. This increase was reversed by moxibustion treatment, which also significantly reduced abdominal withdrawal reflex scores and increased the pain threshold pressure. Pain treatment of moxibustion may be accomplished by downregulating TRPV1 expression.

163Acupuncture significantly increases TRPV1 expression in subcutaneous nerve fibers and modulates TRPV channels in the brain and spinal cord. Acupuncture also activates the expression of TRPV1 and TRPV4 in the anatomical layers of the Zusanli acupoint (ST36), including the muscle and epithelial layers. Given that the components of calcium wave propagation, which occurs during acupuncture are also expressed in the TRPV1-rich ST36 anatomical surface, TRPV1 may be involved in the analgesic effects associated with acupuncture. The researchers used knockout mice to further validate the relationship between TRPV channels and electroacupuncture treatment. Huang et al. noticed that in Trpv2 knockout male mice, acupuncture-induced analgesia was suppressed, and activation of mast cells in stimulated acupoints was reduced.

164Analgesic effects similar to those observed in acupuncture treatment were also detected in electroacupuncture treatment and mainly related to TRPV channel modulation.– Electroacupuncture may improve acid–base-induced chronic pain through its action on TRPV1 and related molecular pathways. In addition, inhibition of TRPV1 expression by electroacupuncture plays a role in the neuroinflammatory regulation of PD, and downregulation of cytokine levels. For the pain treatment of cancer patients, electroacupuncture treatment downregulated the overexpression of TLR4, myeloid differentiation primary response 88, and TRPV1 in the DRG. This condition reduced the activation of spinal glial cells and thus relieved pain. Electroacupuncture modulation of TRPV1 for CVD has also been reported. Electroacupuncture pretreatment enhanced TRPV1 and CGRP signaling, downregulated NF-κB p65 protein expression, reduced the myocardial inflammatory response status, improved acute myocardial ischemic injury and reduced myocardial infarct size.

165With the development of scientific research technology, nanoparticles are becoming more widely used. Gold nanorods are pseudo one-dimensional rod-shaped nanoparticles that can be used for thermal therapy when exposed to near-infrared radiation. Zhou et al. showed that gold nanorods activated TRPV1 channels through photothermal conversion during exposure to near-infrared irradiation. This nano-loaded anesthetic can produced selective, long-lasting regional anesthetic effects in a rat model of sciatic nerve block. In addition, semi-conducting photothermal nano loads of capsaicin were followed by a photothermal trigger to induce release. The results showed high local concentrations of TRPV1 agonist at the tumor site.

166Current physical interventions in TRP channels focus on electroacupuncture and acupuncture for the treatment of diseases. Based on several properties of the TRP channels, we believe that influencing the TRP channels through cold and heat compresses to relieve pain and inflammation is a promising direction to be confirmed by researchers.

Therapeutic application limitations

167The clinical development of TRP channel modulators has provided a scientific basis and new insights into the further use of TRP channels as biomarkers for disease treatment. Despite the appeal of TRP channels in the clinical treatment of pain and inflammation, a number of challenges remain.

168In clinical studies, heat and pain are the most common adverse effects of treatment targeting TRP channels. In a study of the effect of inhibition of TRPM8 channels on human pain, the effect on core body temperature and experimental cold pain was assessed by the cold pressor test after PF-05105679 administration. A total of 23% and 36% of volunteers (at doses of 600 and 900 mg, respectively) reported hot sensations mainly in the perioral region; two volunteers showed intolerance towards the treatment.

169Capsaicin has long been considered clinically effective for the treatment of bladder disorders; however, capsaicin in the bladder is unacceptable for a number of patients because it causes burning pain. Capsaicin also causes profuse sweating and a burning sensation on the mucous membranes of the tongue and mouth, which dissipates after repeated challenges (“desensitization”). This desensitization is also known as a persistent refractory state following a painful reaction, which can last for up to several months.

170Most antagonists of the TRPV1 channel elevate body temperature. Most patients had a slight increase in body temperature after oral administration of AZD1386 (mean value of 0.4 °C), and only one exceeded 38 °C. In addition, Amgen’s Phase 1b clinical trial using AMG 517 in dental pain elicited a prolonged (1–4 days) and significant febrile response (up to 40.2 °C) in human volunteers.

171TRPV1 channel antagonists can elevate the threshold of toxic heat sensation and lead to burns. Previously, Merck/Neurogenics developed MK-2295 for the treatment of pain and cough. This compound significantly increased the threshold for toxic heat pain in humans, and several volunteer subjects even perceived scalding water as cold. Similar results were observed by AstraZeneca and GlaxoSmithKline on a TRPV1 channel antagonist (SB-705498). In addition, mild burns on the mouth (gums) and skin were noted in patients using the TRPV1 channel antagonist JNJ-39439335.

172As TRP channels are expressed in various tissues, systemic administration in the clinical setting may cause varied adverse effects. Among these effects, dizziness, hypertension, heat tremors, headache, nausea, chills, decreased body temperature and paresthesia are more common and should be the focus of researchers (Table 5). Volunteers treated with ticlopidine, clopidogrel and prasugrel (TRPA1 agonists) often complained of GI discomfort such as nausea, vomiting, and diarrhea. Activation of TRPV1 by RTX has antiemetic and hypothermic effects, but it can also cause hypertension. The most frequently reported events in subjects taking NEO6860 (TRPV1 antagonist) orally were feeling of hotness, headache, paresthesia, nausea and dizziness. Therefore, current clinical research can focus on the topical delivery of TRP channel modulators, including topical patches, mucosal sprays, and nano-delivery systems.

173The specificity of TRP channel agonists and antagonists needs to be enhanced. As some TRP modulators, such as hydroxy-α-sanshool, activate not only TRPA1, but also TRPV1. Voacangine is an antagonist of TRPV1 and TRPM8, but is also an agonist of TRPA1.

174Efficient and specific modulation of TRP channels is a promising to be a new approach to the treatment of various diseases in the future. The above-mentioned adverse events should be considered in clinical studies.

Conclusions and perspectives

175With rapid advances in the field of TRPs, numerous publications have demonstrated that TRPs function as important channels intracellularly, and their abnormalities serve as a pathological triggers for diseases. Herein, we summarized all types of TRPs and demonstrated their functions in multiple biological processes. Furthermore, this review summarized the structures and therapeutic interventions and limitations of TRPs from a historical perspective. However, a number of adverse events remain to be addressed in this area, such as fever, pain, nausea, and even lack of therapeutic efficacy in clinical trials of some studies. The cause of these adverse events may be due to the wide distribution of TRP channels in the body, and modulation of TRP channels can cause systemic reactions. In addition, the specificity of existing drugs for TRP channels needs to be enhanced. To overcome some of these side effects, low doses, topical treatment and precise targeted drug delivery can be used.

176To address the issue of precise targeted drug delivery, scholars must ensure the specificity of developed drugs for TRP channels, which will reduce cross-infection caused by TRP channels and reduce damage to other tissues. Second, there is a need to clarify the mechanisms by which drugs modulate TRP channels must be clarified. Finally, new and more effective compounds that can reduce the amount of drugs used must be developed.

177Improving the targeting of existing drugs, nano-delivery systems are an interesting topic. In future research, on the one hand, the modification of nanoparticles with TRP channel modulators can be explored in order to exert targeted effects. On the other hand, given that graphene can be combined with metal nanostructures, it can the ability to absorb light by relying on the friction of carbon atoms to generate heat and thus modulate thermally activated TRP channels. Both directions are yet to be examined.

178In clinical practice, a mixture of modalities is commonly used to treat diseases. Therefore, a combination of physical interventions and drugs can be proposed to exert a synergistic or amplifying effect on the treatment of diseases associated with TRPs. Multiple treatment combinations can be used with a combination of Western and Chinese medicine. Chemical drugs and physical stimulation methods, such as acupuncture and electroacupuncture are used together. We predict that new therapeutic modalities such as hyperthermia, cold compresses, drug delivery, targeted, Synergistic treatment with multiple modalities, and gene based therapies will be increasingly explored in the future for the treatment of human TRP channel-related diseases.

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Yu Y, et al. Molecular mechanism of the assembly of an acid-sensing receptor ion channel complex. Nat. Commun. 2012;3:1252.
Not in our library10.1038/ncomms2257
127.
Hughes J, et al. The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nat. Genet. 1995;10:151-160.
Not in our library10.1038/ng0695-151
128.
Mochizuki T, et al. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science. 1996;272:1339-1342.
Not in our library10.1126/science.272.5266.1339
129.
Zhang P, et al. The multimeric structure of polycystin-2 (TRPP2): structural-functional correlates of homo- and hetero-multimers with TRPC1. Hum. Mol. Genet. 2009;18:1238-1251.
Not in our library10.1093/hmg/ddp024
130.
Shen PS, et al. The structure of the polycystic kidney disease channel PKD2 in lipid nanodiscs. Cell. 2016;167:763-773.e711.
Not in our library10.1016/j.cell.2016.09.048
131.
Su Q, et al. Structure of the human PKD1-PKD2 complex. Science. 2018;361:eaat9819.
Not in our library10.1126/science.aat9819
132.
Qian F, et al. PKD1 interacts with PKD2 through a probable coiled-coil domain. Nat. Genet. 1997;16:179-183.
Not in our library10.1038/ng0697-179
133.
Rossetti S, et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 2007;18:2143-2160.
Not in our library10.1681/asn.2006121387
134.
Perrichot R, et al. Identification of 3 novel mutations (Y4236X, Q3820X, 11745 + 2 ins3) in autosomal dominant polycystic kidney disease 1 gene (PKD1). Hum. Mutat. 2000;15:582.
Not in our library10.1002/1098-1004(200006)15:6<582::aid-humu20>3.0.co;2-b
135.
Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. Lancet. 2007;369:1287-1301.
Not in our library10.1016/s0140-6736(07)60601-1
136.
Cryo-EM structure of the polycystic kidney disease-like channel PKD2L1 · 2018
Not checked
137.
Inada H, et al. Off-response property of an acid-activated cation channel complex PKD1L3-PKD2L1. EMBO Rep. 2008;9:690-697.
Not in our library10.1038/embor.2008.89
138.
Fujimoto C, et al. The single pore residue Asp523 in PKD2L1 determines Ca2+ permeation of the PKD1L3/PKD2L1 complex. Biochem. Biophys. Res. Commun. 2011;404:946-951.
Not in our library10.1016/j.bbrc.2010.12.086
139.
Su Q, et al. Structural basis for Ca(2+) activation of the heteromeric PKD1L3/PKD2L1 channel. Nat. Commun. 2021;12:4871.
Not in our library10.1038/s41467-021-25216-z
140.
Littleton JT, Ganetzky B. Ion channels and synaptic organization: analysis of the Drosophila genome. Neuron. 2000;26:35-43.
Not in our library10.1016/s0896-6273(00)81135-6
141.
Zhang W, et al. Ankyrin repeats convey force to gate the NOMPC mechanotransduction channel. Cell. 2015;162:1391-1403.
Not in our library10.1016/j.cell.2015.08.024
142.
Jin P, et al. Electron cryo-microscopy structure of the mechanotransduction channel NOMPC. Nature. 2017;547:118-122.
Not in our library10.1038/nature22981
143.
Dong XP, et al. The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature. 2008;455:992-996.
Not in our library10.1038/nature07311
144.
Sun M, et al. Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel. Hum. Mol. Genet. 2000;9:2471-2478.
Not in our library10.1093/hmg/9.17.2471
145.
Schmiege P, Fine M, Blobel G, Li X. Human TRPML1 channel structures in open and closed conformations. Nature. 2017;550:366-370.
Not in our library10.1038/nature24036
146.
Chen Q, et al. Structure of mammalian endolysosomal TRPML1 channel in nanodiscs. Nature. 2017;550:415-418.
Not in our library10.1038/nature24035
147.
Pathophysiological Role of Transient Receptor Potential Mucolipin Channel 1 in Calcium-Mediated Stress-Induced Neurodegenerative Diseases · 2020
Not checked
148.
Plesch E, et al. Selective agonist of TRPML2 reveals direct role in chemokine release from innate immune cells. Elife. 2018;7:e39720.
Not in our library10.7554/elife.39720
149.
Li M, et al. Structural basis of dual Ca(2+)/pH regulation of the endolysosomal TRPML1 channel. Nat. Struct. Mol. Biol. 2017;24:205-213.
Not in our library10.1038/nsmb.3362
150.
Grieben M, et al. Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2). Nat. Struct. Mol. Biol. 2017;24:114-122.
Not in our library10.1038/nsmb.3343
151.
Wilkes M, et al. Molecular insights into lipid-assisted Ca(2+) regulation of the TRP channel Polycystin-2. Nat. Struct. Mol. Biol. 2017;24:123-130.
Not in our library10.1038/nsmb.3357
152.
Vincent F, Duncton MA. TRPV4 agonists and antagonists. Curr. Top. Med. Chem. 2011;11:2216-2226.
Not in our library10.2174/156802611796904861
153.
Brederson JD, Kym PR, Szallasi A. Targeting TRP channels for pain relief. Eur. J. Pharm. 2013;716:61-76.
Not in our library10.1016/j.ejphar.2013.03.003
154.
Zhu R, et al. Cinnamaldehyde in diabetes: a review of pharmacology, pharmacokinetics and safety. Pharm. Res. 2017;122:78-89.
Not in our library10.1016/j.phrs.2017.05.019
155.
HC-030031, a TRPA1 Selective Antagonist, Attenuates Inflammatory- and Neuropathy-Induced Mechanical Hypersensitivity · 2008
No notice
156.
Knotkova H, Pappagallo M, Szallasi A. Capsaicin (TRPV1 Agonist) therapy for pain relief: farewell or revival? Clin. J. Pain. 2008;24:142-154.
Not in our library10.1097/ajp.0b013e318158ed9e
157.
Understand spiciness: mechanism of TRPV1 channel activation by capsaicin · 2017
No notice
158.
Sullivan MN, et al. Optical recording reveals novel properties of GSK1016790A-induced vanilloid transient receptor potential channel TRPV4 activity in primary human endothelial cells. Mol. Pharm. 2012;82:464-472.
Not in our library10.1124/mol.112.078584
159.
Bandell M, et al. High-throughput random mutagenesis screen reveals TRPM8 residues specifically required for activation by menthol. Nat. Neurosci. 2006;9:493-500.
Not in our library10.1038/nn1665
160.
Molecular mechanisms underlying menthol binding and activation of TRPM8 ion channel · 2020
Not checked
161.
Dang S, et al. Structural insight into TRPV5 channel function and modulation. Proc. Natl Acad. Sci. USA. 2019;116:8869-8878.
Not in our library10.1073/pnas.1820323116
162.
Grimm C, et al. Molecular and functional characterization of the melastatin-related cation channel TRPM3. J. Biol. Chem. 2003;278:21493-21501.
Not in our library10.1074/jbc.m300945200
163.
Launay P, et al. TRPM4 is a Ca2+-activated nonselective cation channel mediating cell membrane depolarization. Cell. 2002;109:397-407.
Not in our library10.1016/s0092-8674(02)00719-5
164.
Monteilh-Zoller MK, et al. TRPM7 provides an ion channel mechanism for cellular entry of trace metal ions. J. Gen. Physiol. 2003;121:49-60.
Not in our library10.1085/jgp.20028740
165.
Voets T, et al. TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. J. Biol. Chem. 2004;279:19-25.
Not in our library10.1074/jbc.m311201200
166.
Fang JY, Richardson BC. The MAPK signalling pathways and colorectal cancer. Lancet Oncol. 2005;6:322-327.
Not in our library10.1016/s1470-2045(05)70168-6
167.
Wu HH, et al. Asenapine maleate inhibits angiotensin II-induced proliferation and activation of cardiac fibroblasts via the ROS/TGFbeta1/MAPK signaling pathway. Biochem. Biophys. Res. Commun. 2021;553:172-179.
Not in our library10.1016/j.bbrc.2021.03.042
168.
Scutellariae Radix and Coptidis Rhizoma Improve Glucose and Lipid Metabolism in T2DM Rats via Regulation of the Metabolic Profiling and MAPK/PI3K/Akt Signaling Pathway · 2018
No notice
169.
Dalal PJ, Muller WA, Sullivan DP. Endothelial cell calcium signaling during barrier function and inflammation. Am. J. Pathol. 2020;190:535-542.
Not in our library10.1016/j.ajpath.2019.11.004
170.
Zitt C, Halaszovich CR, Luckhoff A. The TRP family of cation channels: probing and advancing the concepts on receptor-activated calcium entry. Prog. Neurobiol. 2002;66:243-264.
Not in our library10.1016/s0301-0082(02)00002-3
171.
Zhang F, et al. Transient receptor potential vanilloid 1 activation induces inflammatory cytokine release in corneal epithelium through MAPK signaling. J. Cell Physiol. 2007;213:730-739.
Not in our library10.1002/jcp.21141
172.
Wei Y, et al. The transient receptor potential channel, vanilloid 5, induces chondrocyte apoptosis via Ca2+ CaMKII-dependent MAPK and Akt/ mTOR pathways in a rat osteoarthritis model. Cell Physiol. Biochem. 2018;51:2309-2323.
Not in our library10.1159/000495874
173.
Transient Receptor Potential Melastatin 8 (TRPM8)-Based Mechanisms Underlie Both the Cold Temperature-Induced Inflammatory Reactions and the Synergistic Effect of Cigarette Smoke in Human Bronchial Epithelial (16HBE) Cells · 2019
Not checked
174.
Sakurai J, et al. Activation of extracellular signal-regulated protein kinase in sensory neurons after noxious gastric distention and its involvement in acute visceral pain in rats. Gastroenterology. 2008;134:1094-1103.
Not in our library10.1053/j.gastro.2008.01.031
175.
Kondo T, et al. Transient receptor potential A1 mediates gastric distention-induced visceral pain in rats. Gut. 2009;58:1342-1352.
Not in our library10.1136/gut.2008.175901
176.
Kondo T, Sakurai J, Miwa H, Noguchi K. Activation of p38 MAPK through transient receptor potential A1 in a rat model of gastric distension-induced visceral pain. Neuroreport. 2013;24:68-72.
Not in our library10.1097/wnr.0b013e32835c7df2
177.
Zhu Z, Li R, Stricker R, Reiser G. Extracellular alpha-crystallin protects astrocytes from cell death through activation of MAPK, PI3K/Akt signaling pathway and blockade of ROS release from mitochondria. Brain Res. 1620;17–28:2015.
Not in our library10.1016/j.brainres.2015.05.011
178.
Jie P, et al. Activation of transient receptor potential vanilloid 4 induces apoptosis in hippocampus through downregulating PI3K/Akt and upregulating p38 MAPK signaling pathways. Cell Death Dis. 2015;6:e1775.
Not in our library10.1038/cddis.2015.146
179.
Cai S, et al. Carvacrol alleviates liver fibrosis by inhibiting TRPM7 and modulating the MAPK signaling pathway. Eur. J. Pharm. 2021;898:173982.
Not in our library10.1016/j.ejphar.2021.173982
180.
Ahn MS, et al. Transient receptor potential channel TRPV4 mediates TGF-beta1-induced differentiation of human ventricular fibroblasts. Cardiol. J. 2020;27:162-170.
Not in our library10.5603/cj.a2019.0050
181.
Signaling pathways in obesity: mechanisms and therapeutic interventions · 2022
Corrected
182.
Massague J. TGFbeta in cancer. Cell. 2008;134:215-230.
Not in our library10.1016/j.cell.2008.07.001
183.
Targeting TGFβ signal transduction for cancer therapy · 2021
No notice
184.
Khalil H, et al. Fibroblast-specific TGF-beta-Smad2/3 signaling underlies cardiac fibrosis. J. Clin. Invest. 2017;127:3770-3783.
Not in our library10.1172/jci94753
185.
Liu Y, et al. Transient receptor potential vanilloid-3 (TRPV3) activation plays a central role in cardiac fibrosis induced by pressure overload in rats via TGF-beta(1) pathway. Naunyn Schmiedebergs Arch. Pharm. 2018;391:131-143.
Not in our library10.1007/s00210-017-1443-7
186.
Han L, et al. Protective mechanism of SIRT1 on Hcy-induced atrial fibrosis mediated by TRPC3. J. Cell Mol. Med. 2020;24:488-510.
Not in our library10.1111/jcmm.14757
187.
He R, et al. Upregulation of transient receptor potential canonical type 3 channel via AT1R/TGF-beta1/Smad2/3 induces atrial fibrosis in aging and spontaneously hypertensive rats. Oxid. Med. Cell Longev. 2019;2019:4025496.
Not in our library10.1155/2019/4025496
188.
Yu SQ, Ma S, Wang DH. Ablation of TRPV1-positive nerves exacerbates salt-induced hypertension and tissue injury in rats after renal ischemia-reperfusion via infiltration of macrophages. Clin. Exp. Hypertens. 2021;43:254-262.
Not in our library10.1080/10641963.2020.1860078
189.
Qian K, et al. Transient receptor potential vanilloid-1 (TRPV1) alleviates hepatic fibrosis via TGF-beta signaling. Dis. Markers. 2022;2022:3100943.
Not in our library10.1155/2022/3100943
190.
Liu Z, et al. Capsaicin ameliorates renal fibrosis by inhibiting TGF-beta1-Smad2/3 signaling. Phytomedicine. 2022;100:154067.
Not in our library10.1016/j.phymed.2022.154067
191.
Wang Y, Wang DH. Protective effect of TRPV1 against renal fibrosis via inhibition of TGF-beta/Smad signaling in DOCA-salt hypertension. Mol. Med. 2011;17:1204-1212.
Not in our library10.2119/molmed.2011.00063
192.
Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study · 2020
No notice
193.
Kang J, et al. TRPA1 mediated aggravation of allergic contact dermatitis induced by DINP and regulated by NF-kappaB activation. Sci. Rep. 2017;7:43586.
Not in our library10.1038/srep43586
194.
Lee KI, et al. Role of transient receptor potential ankyrin 1 channels in Alzheimer’s disease. J. Neuroinflammation. 2016;13:92.
Not in our library10.1186/s12974-016-0557-z
195.
Yuan J, et al. TRPA1 promotes cisplatin-induced nephrotoxicity through inflammation mediated by the MAPK/NF-kappaB signaling pathway. Ann. Transl. Med. 2021;9:1578.
Not in our library10.21037/atm-21-5125
196.
Wu CK, et al. Renal tubular epithelial TRPA1 acts as an oxidative stress sensor to mediate ischemia-reperfusion-induced kidney injury through MAPKs/NF-kappaB signaling. Int. J. Mol. Sci. 2021;22:2309.
Not in our library10.3390/ijms22052309
197.
An, D. et al. Blockage of TRPV4 downregulates the nuclear factor-kappa B signaling pathway to inhibit inflammatory responses and neuronal death in mice with pilocarpine-induced status epilepticus. Cell Mol. Neurobiol. 43, 1283–1300 (2023).
Not in our library10.1007/s10571-022-01249-w
198.
Cao S, et al. Intrathecal TRPM8 blocking attenuates cold hyperalgesia via PKC and NF-kappaB signaling in the dorsal root ganglion of rats with neuropathic pain. J. Pain. Res. 2019;12:1287-1296.
Not in our library10.2147/jpr.s197168
199.
Wang XP, et al. TRPM8 in the negative regulation of TNFalpha expression during cold stress. Sci. Rep. 2017;7:45155.
Not in our library10.1038/srep45155
200.
TRPC6 Attenuates Cortical Astrocytic Apoptosis and Inflammation in Cerebral Ischemic/Reperfusion Injury · 2021
Not checked
201.
Bair AM, et al. Ca2+ entry via TRPC channels is necessary for thrombin-induced NF-kappaB activation in endothelial cells through AMP-activated protein kinase and protein kinase Cdelta. J. Biol. Chem. 2009;284:563-574.
Not in our library10.1074/jbc.m803984200
202.
Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol. 2018;19:121-135.
Not in our library10.1038/nrm.2017.95
203.
Lee GH, et al. Rutaecarpine increases nitric oxide synthesis via eNOS phosphorylation by TRPV1-dependent CaMKII and CaMKKbeta/AMPK signaling pathway in human endothelial cells. Int. J. Mol. Sci. 2021;22:9407.
Not in our library10.3390/ijms22179407
204.
Chen M, et al. Targeting TRPV1-mediated autophagy attenuates nitrogen mustard-induced dermal toxicity. Signal Transduct. Target Ther. 2021;6:29.
Not in our library10.1038/s41392-020-00389-z
205.
Zou Y, et al. TRPC5-induced autophagy promotes the TMZ-resistance of glioma cells via the CAMMKbeta/AMPKalpha/mTOR pathway. Oncol. Rep. 2019;41:3413-3423.
Not in our library10.3892/or.2019.7095
206.
Szrejder M, et al. Metformin reduces TRPC6 expression through AMPK activation and modulates cytoskeleton dynamics in podocytes under diabetic conditions. Biochim. Biophys. Acta Mol. Basis Dis. 2020;1866:165610.
Not in our library10.1016/j.bbadis.2019.165610
207.
Toro CA, Arias LA, Brauchi S. Sub-cellular distribution and translocation of TRP channels. Curr. Pharm. Biotechnol. 2011;12:12-23.
Not in our library10.2174/138920111793937899
208.
Steglitz J, Buscemi J, Ferguson MJ. The future of pain research, education, and treatment: a summary of the IOM report “Relieving pain in America: a blueprint for transforming prevention, care, education, and research”. Transl. Behav. Med. 2012;2:6-8.
Not in our library10.1007/s13142-012-0110-2
209.
Loeser JD, Melzack R. Pain: an overview. Lancet. 1999;353:1607-1609.
Not in our library10.1016/s0140-6736(99)01311-2
210.
Cohen SP, Vase L, Hooten WM. Chronic pain: an update on burden, best practices, and new advances. Lancet. 2021;397:2082-2097.
Not in our library10.1016/s0140-6736(21)00393-7
211.
Strategies to Identify Patient Risks of Prescription Opioid Addiction When Initiating Opioids for Pain · 2019
No notice
212.
Woolf CJ, et al. Towards a mechanism-based classification of pain? Pain. 1998;77:227-229.
Not in our library10.1016/s0304-3959(98)00099-2
213.
Szallasi A, Cortright DN, Blum CA, Eid SR. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat. Rev. Drug Discov. 2007;6:357-372.
Not in our library10.1038/nrd2280
214.
Nociceptive TRP Channels: Sensory Detectors and Transducers in Multiple Pain Pathologies · 2016
Not checked
215.
Fujita F, et al. Methyl p-hydroxybenzoate causes pain sensation through activation of TRPA1 channels. Br. J. Pharm. 2007;151:153-160.
Not in our library10.1038/sj.bjp.0707219
216.
Namer B, Seifert F, Handwerker HO, Maihofner C. TRPA1 and TRPM8 activation in humans: effects of cinnamaldehyde and menthol. Neuroreport. 2005;16:955-959.
Not in our library10.1097/00001756-200506210-00015
217.
Mizushima T, et al. Noxious cold stimulation induces mitogen-activated protein kinase activation in transient receptor potential (TRP) channels TRPA1- and TRPM8-containing small sensory neurons. Neuroscience. 2006;140:1337-1348.
Not in our library10.1016/j.neuroscience.2006.03.024
218.
Koivisto ASustained. TRPA1 activation in vivo. Acta Physiol. 2012;204:248-254.
Not in our library10.1111/j.1748-1716.2011.02318.x
219.
TRP Channels as Therapeutic Targets in Diabetes and Obesity · 2016
Not checked
220.
Wei H, et al. Mechanical antihypersensitivity effect induced by repeated spinal administrations of a TRPA1 antagonist or a gap junction decoupler in peripheral neuropathy. Pharm. Biochem. Behav. 2016;150-151:57-67.
Not in our library10.1016/j.pbb.2016.09.007
221.
Koh WU, et al. Perineural pretreatment of bee venom attenuated the development of allodynia in the spinal nerve ligation injured neuropathic pain model; an experimental study. BMC Complement Alter. Med. 2014;14:431.
Not in our library10.1186/1472-6882-14-431
222.
Sagalajev B, et al. Oxidative stress in the amygdala contributes to neuropathic pain. Neuroscience. 2018;387:92-103.
Not in our library10.1016/j.neuroscience.2017.12.009
223.
Hansson E. Long-term pain, neuroinflammation and glial activation. Scand. J. Pain. 2010;1:67-72.
Not in our library10.1016/j.sjpain.2010.01.002
224.
Sagalajev B, Viisanen H, Wei H, Pertovaara A. Descending antinociception induced by secondary somatosensory cortex stimulation in experimental neuropathy: role of the medullospinal serotonergic pathway. J. Neurophysiol. 2017;117:1200-1214.
Not in our library10.1152/jn.00836.2016
225.
Schwann cell TRPA1 mediates neuroinflammation that sustains macrophage-dependent neuropathic pain in mice · 2017
No notice
226.
Earley S. TRPA1 channels in the vasculature. Br. J. Pharm. 2012;167:13-22.
Not in our library10.1111/j.1476-5381.2012.02018.x
227.
How Cold is It? TRPM8 and TRPA1 in the Molecular Logic of Cold Sensation · 2005
No notice
228.
Pertovaara A, Koivisto A. TRPA1 ion channel in the spinal dorsal horn as a therapeutic target in central pain hypersensitivity and cutaneous neurogenic inflammation. Eur. J. Pharm. 2011;666:1-4.
Not in our library10.1016/j.ejphar.2011.05.027
229.
Kumamoto E, Fujita T. Differential activation of TRP channels in the adult rat spinal substantia gelatinosa by stereoisomers of plant-derived chemicals. Pharmaceuticals. 2016;9:46.
Not in our library10.3390/ph9030046
230.
Bandell M, et al. Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron. 2004;41:849-857.
Not in our library10.1016/s0896-6273(04)00150-3
231.
Bautista DM, et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell. 2006;124:1269-1282.
Not in our library10.1016/j.cell.2006.02.023
232.
Wei H, et al. Spinal transient receptor potential ankyrin 1 channel contributes to central pain hypersensitivity in various pathophysiological conditions in the rat. Pain. 2011;152:582-591.
Not in our library10.1016/j.pain.2010.11.031
233.
da Costa DSM, et al. The involvement of the transient receptor potential A1 (TRPA1) in the maintenance of mechanical and cold hyperalgesia in persistent inflammation. Pain. 2010;148:431-437.
Not in our library10.1016/j.pain.2009.12.002
234.
Koivisto A, et al. TRPA1: a transducer and amplifier of pain and inflammation. Basic Clin. Pharm. Toxicol. 2014;114:50-55.
Not in our library10.1111/bcpt.12138
235.
Abbas MA. Modulation of TRPV1 channel function by natural products in the treatment of pain. Chem. Biol. Interact. 2020;330:109178.
Not in our library10.1016/j.cbi.2020.109178
236.
Bevan S, Quallo T, Andersson DA. Trpv1. Handb. Exp. Pharm. 2014;222:207-245.
Not in our library10.1007/978-3-642-54215-2_9
237.
Choi SI, et al. Emerging role of spinal cord TRPV1 in pain exacerbation. Neural Plast. 2016;2016:5954890.
Not in our library10.1155/2016/5954890
238.
Iftinca M, Defaye M, Altier C. TRPV1-targeted drugs in development for human pain conditions. Drugs. 2021;81:7-27.
Not in our library10.1007/s40265-020-01429-2
239.
Caterina MJ, et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science. 2000;288:306-313.
Not in our library10.1126/science.288.5464.306
240.
Davis JB, et al. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature. 2000;405:183-187.
Not in our library10.1038/35012076
241.
Malek N, et al. The importance of TRPV1-sensitisation factors for the development of neuropathic pain. Mol. Cell Neurosci. 2015;65:1-10.
Not in our library10.1016/j.mcn.2015.02.001
242.
Camprubi-Robles M, Planells-Cases R, Ferrer-Montiel A. Differential contribution of SNARE-dependent exocytosis to inflammatory potentiation of TRPV1 in nociceptors. FASEB J. 2009;23:3722-3733.
Not in our library10.1096/fj.09-134346
243.
Serafini M, et al. Targeting transient receptor potential vanilloid 1 (TRPV1) channel softly: the discovery of passerini adducts as a topical treatment for inflammatory skin disorders. J. Med. Chem. 2018;61:4436-4455.
Not in our library10.1021/acs.jmedchem.8b00109
244.
Huang YK, et al. Cytokine activin C ameliorates chronic neuropathic pain in peripheral nerve injury rodents by modulating the TRPV1 channel. Br. J. Pharm. 2020;177:5642-5657.
Not in our library10.1111/bph.15284
245.
TRP Channels in Skin Biology and Pathophysiology · 2016
No notice
246.
Mehta D, Granstein RD. Immunoregulatory effects of neuropeptides on endothelial cells: relevance to dermatological disorders. Dermatology. 2019;235:175-186.
Not in our library10.1159/000496538
247.
Brierley SM, et al. Selective role for TRPV4 ion channels in visceral sensory pathways. Gastroenterology. 2008;134:2059-2069.
Not in our library10.1053/j.gastro.2008.01.074
248.
Moore C, et al. UVB radiation generates sunburn pain and affects skin by activating epidermal TRPV4 ion channels and triggering endothelin-1 signaling. Proc. Natl Acad. Sci. USA. 2013;110:E3225-E3234.
Not in our library10.1073/pnas.1312933110
249.
Moran MM, McAlexander MA, Biro T, Szallasi A. Transient receptor potential channels as therapeutic targets. Nat. Rev. Drug Discov. 2011;10:601-620.
Not in our library10.1038/nrd3456
250.
Vergnolle N, et al. A role for transient receptor potential vanilloid 4 in tonicity-induced neurogenic inflammation. Br. J. Pharm. 2010;159:1161-1173.
Not in our library10.1111/j.1476-5381.2009.00590.x
251.
Alessandri-Haber N, et al. TRPV4 mediates pain-related behavior induced by mild hypertonic stimuli in the presence of inflammatory mediator. Pain. 2005;118:70-79.
Not in our library10.1016/j.pain.2005.07.016
252.
Levine JD, Alessandri-Haber N. TRP channels: targets for the relief of pain. Biochim Biophys. Acta. 2007;1772:989-1003.
Not in our library10.1016/j.bbadis.2007.01.008
253.
Qu YJ, et al. Effect of TRPV4-p38 MAPK pathway on neuropathic pain in rats with chronic compression of the dorsal root ganglion. Biomed. Res. Int. 2016;2016:6978923.
Not in our library10.1155/2016/6978923
254.
Lewinter RD, Skinner K, Julius D, Basbaum AI. Immunoreactive TRPV-2 (VRL-1), a capsaicin receptor homolog, in the spinal cord of the rat. J. Comp. Neurol. 2004;470:400-408.
Not in our library10.1002/cne.20024
255.
Stokes AJ, et al. Formation of a physiological complex between TRPV2 and RGA protein promotes cell surface expression of TRPV2. J. Cell Biochem. 2005;94:669-683.
Not in our library10.1002/jcb.20331
256.
Urata K, et al. Involvement of transient receptor potential vanilloid 2 in intra-oral incisional pain. Oral. Dis. 2018;24:1093-1100.
Not in our library10.1111/odi.12853
257.
Moqrich A, et al. Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science. 2005;307:1468-1472.
Not in our library10.1126/science.1108609
258.
Smith GD, et al. TRPV3 is a temperature-sensitive vanilloid receptor-like protein. Nature. 2002;418:186-190.
Not in our library10.1038/nature00894
259.
Gunthorpe MJ, Benham CD, Randall A, Davis JB. The diversity in the vanilloid (TRPV) receptor family of ion channels. Trends Pharm. Sci. 2002;23:183-191.
Not in our library10.1016/s0165-6147(02)01999-5
260.
Han Y, et al. A plant-derived TRPV3 inhibitor suppresses pain and itch. Br. J. Pharm. 2021;178:1669-1683.
Not in our library10.1111/bph.15390
261.
Bautista DM, et al. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature. 2007;448:204-208.
Not in our library10.1038/nature05910
262.
Colburn RW, et al. Attenuated cold sensitivity in TRPM8 null mice. Neuron. 2007;54:379-386.
Not in our library10.1016/j.neuron.2007.04.017
263.
Zuo X, Ling JX, Xu GY, Gu JG. Operant behavioral responses to orofacial cold stimuli in rats with chronic constrictive trigeminal nerve injury: effects of menthol and capsazepine. Mol. Pain. 2013;9:28.
Not in our library10.1186/1744-8069-9-28
264.
Klein AH, et al. Topical application of L-menthol induces heat analgesia, mechanical allodynia, and a biphasic effect on cold sensitivity in rats. Behav. Brain Res. 2010;212:179-186.
Not in our library10.1016/j.bbr.2010.04.015
265.
Klein AH, et al. Topical hindpaw application of L-menthol decreases responsiveness to heat with biphasic effects on cold sensitivity of rat lumbar dorsal horn neurons. Neuroscience. 2012;219:234-242.
Not in our library10.1016/j.neuroscience.2012.05.061
266.
Vinuela-Fernandez I, et al. The TRPM8 channel forms a complex with the 5-HT(1B) receptor and phospholipase D that amplifies its reversal of pain hypersensitivity. Neuropharmacology. 2014;79:136-151.
Not in our library10.1016/j.neuropharm.2013.11.006
267.
Anderson EM, Jenkins AC, Caudle RM, Neubert JK. The effects of a co-application of menthol and capsaicin on nociceptive behaviors of the rat on the operant orofacial pain assessment device. PLoS ONE. 2014;9:e89137.
Not in our library10.1371/journal.pone.0089137
268.
CXCL1/CXCR2 signaling in pathological pain: Role in peripheral and central sensitization · 2017
Not checked
269.
Chung MK, et al. The role of TRPM2 in hydrogen peroxide-induced expression of inflammatory cytokine and chemokine in rat trigeminal ganglia. Neuroscience. 2015;297:160-169.
Not in our library10.1016/j.neuroscience.2015.03.067
270.
Haraguchi K, et al. TRPM2 contributes to inflammatory and neuropathic pain through the aggravation of pronociceptive inflammatory responses in mice. J. Neurosci. 2012;32:3931-3941.
Not in our library10.1523/jneurosci.4703-11.2012
271.
Su S, et al. TRPM3 channels play roles in heat hypersensitivity and spontaneous pain after nerve injury. J. Neurosci. 2021;41:2457-2474.
Not in our library10.1523/jneurosci.1551-20.2020
272.
Szallasi A, Sheta M. Targeting TRPV1 for pain relief: limits, losers and laurels. Expert Opin. Investig. Drugs. 2012;21:1351-1369.
Not in our library10.1517/13543784.2012.704021
273.
Kaplan GG. The global burden of IBD: from 2015 to 2025. Nat. Rev. Gastroenterol. Hepatol. 2015;12:720-727.
Not in our library10.1038/nrgastro.2015.150
274.
Nutrition, IBD and Gut Microbiota: A Review · 2020
No notice
275.
Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007;369:1627-1640.
Not in our library10.1016/s0140-6736(07)60750-8
276.
Kaplan GG, Windsor JW. The four epidemiological stages in the global evolution of inflammatory bowel disease. Nat. Rev. Gastroenterol. Hepatol. 2021;18:56-66.
Not in our library10.1038/s41575-020-00360-x
277.
Ng SC, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2017;390:2769-2778.
Not in our library10.1016/s0140-6736(17)32448-0
278.
Ramos GP, Papadakis KA. Mechanisms of disease: inflammatory bowel diseases. Mayo Clin. Proc. 2019;94:155-165.
Not in our library10.1016/j.mayocp.2018.09.013
279.
Vavricka SR, et al. Extraintestinal manifestations of inflammatory bowel disease. Inflamm. Bowel Dis. 2015;21:1982-1992.
Not in our library10.1097/mib.0000000000000392
280.
Argollo M, et al. Comorbidities in inflammatory bowel disease: a call for action. Lancet Gastroenterol. Hepatol. 2019;4:643-654.
Not in our library10.1016/s2468-1253(19)30173-6
281.
Restellini S, Chazouilleres O, Frossard JL. Hepatic manifestations of inflammatory bowel diseases. Liver Int. 2017;37:475-489.
Not in our library10.1111/liv.13265
282.
Perez-Carreras M, et al. Non-alcoholic fatty liver disease in patients with intestinal, pulmonary or skin diseases: inflammatory cross-talk that needs a multidisciplinary approach. World J. Gastroenterol. 2021;27:7113-7124.
Not in our library10.3748/wjg.v27.i41.7113
283.
Fu Y, Lee CH, Chi CC. Association of psoriasis with inflammatory bowel disease: a systematic review and meta-analysis. JAMA Dermatol. 2018;154:1417-1423.
Not in our library10.1001/jamadermatol.2018.3631
284.
Zhang M. & Merlin, D. Nanoparticle-based oral drug delivery systems targeting the colon for treatment of ulcerative colitis. Inflamm. Bowel Dis. 2018;24:1401-1415.
Not in our library10.1093/ibd/izy123
285.
Yang C. & Merlin, D. Nanoparticle-mediated drug delivery systems for the treatment of IBD: current perspectives. Int. J. Nanomed. 2019;14:8875-8889.
Not in our library10.2147/ijn.s210315
286.
Neurath MF. Current and emerging therapeutic targets for IBD. Nat. Rev. Gastroenterol. Hepatol. 2017;14:269-278.
Not in our library10.1038/nrgastro.2016.208
287.
Arora Z, Shen B. Biological therapy for ulcerative colitis. Gastroenterol. Rep. 2015;3:103-109.
Not in our library10.1093/gastro/gou070
288.
Dretzke J, et al. A systematic review and economic evaluation of the use of tumour necrosis factor-alpha (TNF-alpha) inhibitors, adalimumab and infliximab, for Crohn’s disease. Health Technol. Assess. 2011;15:1-244.
Not in our library10.3310/hta15060
289.
Vergnolle N. TRPV4: new therapeutic target for inflammatory bowel diseases. Biochem. Pharm. 2014;89:157-161.
Not in our library10.1016/j.bcp.2014.01.005
290.
D’Aldebert E, et al. Transient receptor potential vanilloid 4 activated inflammatory signals by intestinal epithelial cells and colitis in mice. Gastroenterology. 2011;140:275-285.
Not in our library10.1053/j.gastro.2010.09.045
291.
Cenac N, et al. Transient receptor potential vanilloid-4 has a major role in visceral hypersensitivity symptoms. Gastroenterology. 2008;135:937-946.946.
Not in our library10.1053/j.gastro.2008.05.024
292.
Fichna J, et al. Transient receptor potential vanilloid 4 blockade protects against experimental colitis in mice: a new strategy for inflammatory bowel diseases treatment? Neurogastroenterol. Motil. 2012;24:e557-e560.
Not in our library10.1111/j.1365-2982.2012.01999.x
293.
De Petrocellis L, et al. Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation. Acta Physiol. 2012;204:255-266.
Not in our library10.1111/j.1748-1716.2011.02338.x
294.
Akbar A, et al. Expression of the TRPV1 receptor differs in quiescent inflammatory bowel disease with or without abdominal pain. Gut. 2010;59:767-774.
Not in our library10.1136/gut.2009.194449
295.
Upregulation of the Transient Receptor Potential Ankyrin 1 Ion Channel in the Inflamed Human and Mouse Colon and Its Protective Roles · 2014
No notice
296.
Molodecky NA, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142:46-54.e42.
Not in our library10.1053/j.gastro.2011.10.001
297.
Basso L, Altier C. Transient Receptor Potential Channels in neuropathic pain. Curr. Opin. Pharm. 2017;32:9-15.
Not in our library10.1016/j.coph.2016.10.002
298.
Engel MA, et al. The proximodistal aggravation of colitis depends on substance P released from TRPV1-expressing sensory neurons. J. Gastroenterol. 2012;47:256-265.
Not in our library10.1007/s00535-011-0495-6
299.
Miranda A, et al. The role of transient receptor potential vanilloid 1 in mechanical and chemical visceral hyperalgesia following experimental colitis. Neuroscience. 2007;148:1021-1032.
Not in our library10.1016/j.neuroscience.2007.05.034
300.
Harrington AM, et al. A novel role for TRPM8 in visceral afferent function. Pain. 2011;152:1459-1468.
Not in our library10.1016/j.pain.2011.01.027
301.
Adam B, et al. A combination of peppermint oil and caraway oil attenuates the post-inflammatory visceral hyperalgesia in a rat model. Scand. J. Gastroenterol. 2006;41:155-160.
Not in our library10.1080/00365520500206442
302.
Ramachandran R, et al. TRPM8 activation attenuates inflammatory responses in mouse models of colitis. Proc. Natl Acad. Sci. USA. 2013;110:7476-7481.
Not in our library10.1073/pnas.1217431110
303.
Andersson DA, Nash M, Bevan S. Modulation of the cold-activated channel TRPM8 by lysophospholipids and polyunsaturated fatty acids. J. Neurosci. 2007;27:3347-3355.
Not in our library10.1523/jneurosci.4846-06.2007
304.
Minami T, et al. Elevation of phospholipase A2 protein in sera of patients with Crohn’s disease and ulcerative colitis. Am. J. Gastroenterol. 1993;88:1076-1080.
Not in our library
305.
Braun A, et al. Alterations of phospholipid concentration and species composition of the intestinal mucus barrier in ulcerative colitis: a clue to pathogenesis. Inflamm. Bowel Dis. 2009;15:1705-1720.
Not in our library10.1002/ibd.20993
306.
Izzo AA, et al. Inhibitory effect of cannabichromene, a major non-psychotropic cannabinoid extracted from Cannabis sativa, on inflammation-induced hypermotility in mice. Br. J. Pharm. 2012;166:1444-1460.
Not in our library10.1111/j.1476-5381.2012.01879.x
307.
Yang J, et al. Transient receptor potential ankyrin-1 participates in visceral hyperalgesia following experimental colitis. Neurosci. Lett. 2008;440:237-241.
Not in our library10.1016/j.neulet.2008.05.093
308.
Engel MA, Becker C, Reeh PW, Neurath MF. Role of sensory neurons in colitis: increasing evidence for a neuroimmune link in the gut. Inflamm. Bowel Dis. 2011;17:1030-1033.
Not in our library10.1002/ibd.21422
309.
Romano B, et al. The cannabinoid TRPA1 agonist cannabichromene inhibits nitric oxide production in macrophages and ameliorates murine colitis. Br. J. Pharm. 2013;169:213-229.
Not in our library10.1111/bph.12120
310.
Gibiino G, et al. The other side of malnutrition in inflammatory bowel disease (IBD): Non-alcoholic fatty liver disease. Nutrients. 2021;13:2772.
Not in our library10.3390/nu13082772
311.
Fousekis FS, et al. Hepatobiliary manifestations and complications in inflammatory bowel disease: a review. Gastroenterol. Res. 2018;11:83-94.
Not in our library10.14740/gr990w
312.
Harbord M, et al. The First European Evidence-based Consensus on Extra-intestinal Manifestations in Inflammatory Bowel Disease. J. Crohns Colitis. 2016;10:239-254.
Not in our library10.1093/ecco-jcc/jjv213
313.
Ritaccio G, et al. Nonalcoholic fatty liver disease is common in IBD patients however progression to hepatic fibrosis by noninvasive markers is rare. Dig. Dis. Sci. 2021;66:3186-3191.
Not in our library10.1007/s10620-020-06588-6
314.
Cotter TG, Rinella M. Nonalcoholic Fatty Liver Disease 2020: The State of the Disease. Gastroenterology. 2020;158:1851-1864.
Not in our library10.1053/j.gastro.2020.01.052
315.
Younossi ZM. Non-alcoholic fatty liver disease - A global public health perspective. J. Hepatol. 2019;70:531-544.
Not in our library10.1016/j.jhep.2018.10.033
316.
Ma L, et al. Activation of TRPV1 reduces vascular lipid accumulation and attenuates atherosclerosis. Cardiovasc. Res. 2011;92:504-513.
Not in our library10.1093/cvr/cvr245
317.
Iwasaki Y, et al. TRPV1 agonist monoacylglycerol increases UCP1 content in brown adipose tissue and suppresses accumulation of visceral fat in mice fed a high-fat and high-sucrose diet. Biosci. Biotechnol. Biochem. 2011;75:904-909.
Not in our library10.1271/bbb.100850
318.
Tobita N, et al. Sweet scent lactones activate hot capsaicin receptor, TRPV1. Biochem. Biophys. Res. Commun. 2021;534:547-552.
Not in our library10.1016/j.bbrc.2020.11.046
319.
Li L, et al. TRPV1 activation prevents nonalcoholic fatty liver through UCP2 upregulation in mice. Pflug. Arch. 2012;463:727-732.
Not in our library10.1007/s00424-012-1078-y
320.
Sun XD, Yu YR. The protective effects of rosiglitazone on kidney in diet-induced obese rats. Sichuan Da Xue Xue Bao Yi Xue Ban. 2014;45:24-28.
Not in our library
321.
TRPV4 channel inhibits TGF-β1-induced proliferation of hepatic stellate cells. · 2014
Not checked
322.
Seth RK, et al. TRPV4 activation of endothelial nitric oxide synthase resists nonalcoholic fatty liver disease by blocking CYP2E1-mediated redox toxicity. Free Radic. Biol. Med. 2017;102:260-273.
Not in our library10.1016/j.freeradbiomed.2016.11.047
323.
Kheradpezhouh E, et al. TRPM2 channels mediate acetaminophen-induced liver damage. Proc. Natl Acad. Sci. USA. 2014;111:3176-3181.
Not in our library10.1073/pnas.1322657111
324.
Malko P, Jiang LH. TRPM2 channel-mediated cell death: an important mechanism linking oxidative stress-inducing pathological factors to associated pathological conditions. Redox Biol. 2020;37:101755.
Not in our library10.1016/j.redox.2020.101755
325.
Zhu Y, et al. Blockage of TRPM7 channel induces hepatic stellate cell death through endoplasmic reticulum stress-mediated apoptosis. Life Sci. 2014;94:37-44.
Not in our library10.1016/j.lfs.2013.10.030
326.
Smedlund K, Dube P, Vazquez G. Early steatohepatitis in hyperlipidemic mice with endothelial-specific gain of TRPC3 function precedes changes in aortic atherosclerosis. Physiol. Genomics. 2016;48:644-649.
Not in our library10.1152/physiolgenomics.00067.2016
327.
Nishiyama K, et al. Deletion of TRPC3 or TRPC6 fails to attenuate the formation of inflammation and fibrosis in non-alcoholic steatohepatitis. Biol. Pharm. Bull. 2021;44:431-436.
Not in our library10.1248/bpb.b20-00903
328.
Yu CJ, et al. TRUSS exacerbates NAFLD development by promoting ikappabalpha degradation in mice. Hepatology. 2018;68:1769-1785.
Not in our library10.1002/hep.30066
329.
Alinaghi F, et al. Global prevalence and bidirectional association between psoriasis and inflammatory bowel disease-a systematic review and meta-analysis. J. Crohns Colitis. 2020;14:351-360.
Not in our library10.1093/ecco-jcc/jjz152
330.
Bernstein CN, Wajda A, Blanchard JF. The clustering of other chronic inflammatory diseases in inflammatory bowel disease: a population-based study. Gastroenterology. 2005;129:827-836.
Not in our library10.1053/j.gastro.2005.06.021
331.
Koivisto AP, Belvisi MG, Gaudet R, Szallasi A. Advances in TRP channel drug discovery: from target validation to clinical studies. Nat. Rev. Drug Discov. 2022;21:41-59.
Not in our library10.1038/s41573-021-00268-4
332.
Kambiz S, et al. Thermo-sensitive TRP channels in peripheral nerve injury: a review of their role in cold intolerance. J. Plast. Reconstr. Aesthet. Surg. 2014;67:591-599.
Not in our library10.1016/j.bjps.2013.12.014
333.
Ho JC, Lee CH. TRP channels in skin: from physiological implications to clinical significances. Biophysics (Nagoya-shi). 2015;11:17-24.
Not in our library10.2142/biophysics.11.17
334.
Neuberger A, Nadezhdin KD, Sobolevsky AI. TRPV3 expression and purification for structure determination by Cryo-EM. Methods Enzymol. 2021;652:31-48.
Not in our library10.1016/bs.mie.2021.02.006
335.
Roles of Epithelial and Mesenchymal TRP Channels in Mediating Inflammatory Fibrosis · 2022
Not checked
336.
Bertin S, Raz E. Transient receptor potential (TRP) channels in T cells. Semin Immunopathol. 2016;38:309-319.
Not in our library10.1007/s00281-015-0535-z
337.
Maglie R, et al. The Role of TRPA1 in Skin Physiology and Pathology. Int. J. Mol. Sci. 2021;22:3065.
Not in our library10.3390/ijms22063065
338.
Toth BI, Olah A, Szollosi AG, Biro T. TRP channels in the skin. Br. J. Pharm. 2014;171:2568-2581.
Not in our library10.1111/bph.12569
339.
Sensory TRP channels contribute differentially to skin inflammation and persistent itch · 2017
No notice
340.
Abrahamsen B, et al. The cell and molecular basis of mechanical, cold, and inflammatory pain. Science. 2008;321:702-705.
Not in our library10.1126/science.1156916
341.
Lee SH, et al. Resolvin D3 controls mouse and human TRPV1-positive neurons and preclinical progression of psoriasis. Theranostics. 2020;10:12111-12126.
Not in our library10.7150/thno.52135
342.
Riol-Blanco L, et al. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature. 2014;510:157-161.
Not in our library10.1038/nature13199
343.
Imamachi N, et al. TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms. Proc. Natl Acad. Sci. USA. 2009;106:11330-11335.
Not in our library10.1073/pnas.0905605106
344.
Cavanaugh DJ, et al. Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli. Proc. Natl Acad. Sci. USA. 2009;106:9075-9080.
Not in our library10.1073/pnas.0901507106
345.
Bromm B, Scharein E, Darsow U, Ring J. Effects of menthol and cold on histamine-induced itch and skin reactions in man. Neurosci. Lett. 1995;187:157-160.
Not in our library10.1016/0304-3940(95)11362-z
346.
Palkar R, et al. Cooling relief of acute and chronic itch requires TRPM8 channels and neurons. J. Invest. Dermatol. 2018;138:1391-1399.
Not in our library10.1016/j.jid.2017.12.025
347.
Caceres AI, et al. Transient Receptor Potential Cation Channel Subfamily M Member 8 channels mediate the anti-inflammatory effects of eucalyptol. Br. J. Pharm. 2017;174:867-879.
Not in our library10.1111/bph.13760
348.
Liu B, Jordt SE. Cooling the Itch via TRPM8. J. Invest. Dermatol. 2018;138:1254-1256.
Not in our library10.1016/j.jid.2018.01.020
349.
van der Fits L, et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J. Immunol. 2009;182:5836-5845.
Not in our library10.4049/jimmunol.0802999
350.
Wang W, et al. Thymol activates TRPM8-mediated Ca(2+) influx for its antipruritic effects and alleviates inflammatory response in Imiquimod-induced mice. Toxicol. Appl. Pharm. 2020;407:115247.
Not in our library10.1016/j.taap.2020.115247
351.
Liang D, et al. Thymol inhibits LPS-stimulated inflammatory response via down-regulation of NF-kappaB and MAPK signaling pathways in mouse mammary epithelial cells. Inflammation. 2014;37:214-222.
Not in our library10.1007/s10753-013-9732-x
352.
Younes SF, Bakry OA. Immunohistochemical evaluation of role of serotonin in pathogenesis of psoriasis. J. Clin. Diagn. Res. 2016;10:EC05-EC09.
Not in our library10.7860/jcdr/2016/22692.8719
353.
Lee SH, et al. Peripheral serotonin receptor 2B and transient receptor potential channel 4 mediate pruritus to serotonergic antidepressants in mice. J. Allergy Clin. Immunol. 2018;142:1349-1352.e1316.
Not in our library10.1016/j.jaci.2018.05.031
354.
Lee SH, et al. Sensory neuron-expressed TRPC4 is a target for the relief of psoriasiform itch and skin inflammation in mice. J. Invest. Dermatol. 2020;140:2221-2229.e2226.
Not in our library10.1016/j.jid.2020.03.959
355.
Belvisi MG, Birrell MA. The emerging role of transient receptor potential channels in chronic lung disease. Eur. Respir. J. 2017;50:1601357.
Not in our library10.1183/13993003.01357-2016
356.
Safiabadi Tali, S. H. et al. Tools and techniques for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/COVID-19 detection. Clin. Microbiol. Rev. 34, 10.1128/CMR.00228-20 (2021).
Not in our library10.1128/cmr.00228-20
357.
Straus MR, et al. Inhibitors of L-type calcium channels show therapeutic potential for treating SARS-CoV-2 infections by preventing virus entry and spread. ACS Infect. Dis. 2021;7:2807-2815.
Not in our library10.1021/acsinfecdis.1c00023
358.
Yelshanskaya MV, Nadezhdin KD, Kurnikova MG, Sobolevsky AI. Structure and function of the calcium-selective TRP channel TRPV6. J. Physiol. 2021;599:2673-2697.
Not in our library10.1113/jp279024
359.
Singh AK, McGoldrick LL, Twomey EC, Sobolevsky AI. Mechanism of calmodulin inactivation of the calcium-selective TRP channel TRPV6. Sci. Adv. 2018;4:eaau6088.
Not in our library10.1126/sciadv.aau6088
360.
Leidinger G, et al. TRPC6 is altered in COVID-19 pneumonia. Chem. Biol. Interact. 2022;362:109982.
Not in our library10.1016/j.cbi.2022.109982
361.
Meyer NJ, Gattinoni L, Calfee CS. Acute respiratory distress syndrome. Lancet. 2021;398:622-637.
Not in our library10.1016/s0140-6736(21)00439-6
362.
Gibson PG, Qin L, Puah SH. COVID-19 acute respiratory distress syndrome (ARDS): clinical features and differences from typical pre-COVID-19 ARDS. Med. J. Aust. 2020;213:54-56 e51.
Not in our library10.5694/mja2.50674
363.
A potential role for cannabichromene in modulating TRP channels during acute respiratory distress syndrome · 2021
Not checked
364.
Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)—A Systemic Review and Comparison of Clinical Presentation and Symptomatology · 2021
No notice
365.
Paul, B. D., Lemle, M. D., Komaroff, A. L. & Snyder, S. H. Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome. Proc. Natl Acad. Sci. USA118, 10.1073/pnas.2024358118 (2021).
Not in our library10.1073/pnas.2024358118
366.
Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS) · 2022
No notice
367.
Transient receptor potential melastatin 3 dysfunction in post COVID-19 condition and myalgic encephalomyelitis/chronic fatigue syndrome patients · 2022
Not checked
368.
Hu Y, et al. Prevalence and severity of corona virus disease 2019 (COVID-19): a systematic review and meta-analysis. J. Clin. Virol. 2020;127:104371.
Not in our library10.1016/j.jcv.2020.104371
369.
Lechien JR, et al. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur. Arch. Otorhinolaryngol. 2020;277:2251-2261.
Not in our library10.1007/s00405-020-05965-1
370.
Izquierdo-Dominguez A, Rojas-Lechuga MJ, Mullol J, Alobid I. Olfactory dysfunction in the COVID-19 outbreak. J. Investig. Allergol. Clin. Immunol. 2020;30:317-326.
Not in our library10.18176/jiaci.0567
371.
Neurological manifestations of COVID-19: a systematic review · 2020
No notice
372.
Salmon Ceron D, et al. Self-reported loss of smell without nasal obstruction to identify COVID-19. The multicenter Coranosmia cohort study. J. Infect. 2020;81:614-620.
Not in our library10.1016/j.jinf.2020.07.005
373.
Mao R, et al. Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis. Lancet Gastroenterol. Hepatol. 2020;5:667-678.
Not in our library10.1016/s2468-1253(20)30126-6
374.
Fuhrer M, Dejaco C, Kopp B, Hammer J. Gastric administration of garlic powder containing the trpa1- agonist allicin induces specific epigastric symptoms and gastric relaxation in healthy subjects. Neurogastroenterol. Motil. 2019;31:e13470.
Not in our library10.1111/nmo.13470
375.
Transient receptor potential (TRP) channels as drug targets for diseases of the digestive system · 2011
No notice
376.
Bousquet J, et al. Potential Interplay between Nrf2, TRPA1, and TRPV1 in nutrients for the control of COVID-19. Int. Arch. Allergy Immunol. 2021;182:324-338.
Not in our library10.1159/000514204
377.
Nahama A, Ramachandran R, Cisternas AF, Ji H. The role of afferent pulmonary innervation in ARDS associated with COVID-19 and potential use of resiniferatoxin to improve prognosis: a review. Med. Drug Discov. 2020;5:100033.
Not in our library10.1016/j.medidd.2020.100033
378.
Balakrishna S, et al. TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury. Am. J. Physiol. Lung Cell Mol. Physiol. 2014;307:L158-L172.
Not in our library10.1152/ajplung.00065.2014
379.
Rosenbaum T, et al. TRPV4: a physio and pathophysiologically significant ion channel. Int. J. Mol. Sci. 2020;21:3837.
Not in our library10.3390/ijms21113837
380.
Mazzotta S, et al. Design, synthesis and in vitro experimental validation of novel TRPV4 antagonists inspired by labdane diterpenes. Mar. Drugs. 2020;18:519.
Not in our library10.3390/md18100519
381.
Chung KF, Pavord ID. Prevalence, pathogenesis, and causes of chronic cough. Lancet. 2008;371:1364-1374.
Not in our library10.1016/s0140-6736(08)60595-4
382.
Chung KF, et al. Cough hypersensitivity and chronic cough. Nat. Rev. Dis. Prim. 2022;8:45.
Not in our library10.1038/s41572-022-00370-w
383.
Undem BJ, Sun H. Molecular/ionic basis of vagal bronchopulmonary C-fiber activation by inflammatory mediators. Physiology. 2020;35:57-68.
Not in our library10.1152/physiol.00014.2019
384.
Grace MS, et al. Transient receptor potential (TRP) channels in the airway: role in airway disease. Br. J. Pharm. 2014;171:2593-2607.
Not in our library10.1111/bph.12538
385.
Trevisani M, et al. Antitussive activity of iodo-resiniferatoxin in guinea pigs. Thorax. 2004;59:769-772.
Not in our library10.1136/thx.2003.012930
386.
Anderson GP. TRPV1 and cough. Thorax. 2004;59:730-731.
Not in our library10.1136/thx.2003.016782
387.
Bonvini SJ, Birrell MA, Smith JA, Belvisi MG. Targeting TRP channels for chronic cough: from bench to bedside. Naunyn Schmiedebergs Arch. Pharm. 2015;388:401-420.
Not in our library10.1007/s00210-014-1082-1
388.
Bonvini SJ, et al. Transient receptor potential cation channel, subfamily V, member 4 and airway sensory afferent activation: role of adenosine triphosphate. J. Allergy Clin. Immunol. 2016;138:249-261.e212.
Not in our library10.1016/j.jaci.2015.10.044
389.
Buday T, Kovacikova L, Ruzinak R, Plevkova J. TRPV4 antagonist GSK2193874 does not modulate cough response to osmotic stimuli. Respir. Physiol. Neurobiol. 2017;236:1-4.
Not in our library10.1016/j.resp.2016.10.010
390.
Morice AH. TRPA1 receptors in chronic cough. Pulm. Pharm. Ther. 2017;47:42-44.
Not in our library10.1016/j.pupt.2017.05.004
391.
Birrell MA, et al. TRPA1 agonists evoke coughing in guinea pig and human volunteers. Am. J. Respir. Crit. Care Med. 2009;180:1042-1047.
Not in our library10.1164/rccm.200905-0665oc
392.
Mukhopadhyay I, et al. Transient receptor potential ankyrin 1 receptor activation in vitro and in vivo by pro-tussive agents: GRC 17536 as a promising anti-tussive therapeutic. PLoS ONE. 2014;9:e97005.
Not in our library10.1371/journal.pone.0097005
393.
Ji Z, et al. Melatonin attenuates chronic cough mediated by oxidative stress via transient receptor potential melastatin-2 in guinea pigs exposed to particulate matter 2.5. Physiol. Res. 2018;67:293-305.
Not in our library10.33549/physiolres.933654
394.
Plevkova J, et al. The role of trigeminal nasal TRPM8-expressing afferent neurons in the antitussive effects of menthol. J. Appl. Physiol. 2013;115:268-274.
Not in our library10.1152/japplphysiol.01144.2012
395.
Fisher JT. TRPM8 and dyspnea: from the frigid and fascinating past to the cool future? Curr. Opin. Pharm. 2011;11:218-223.
Not in our library10.1016/j.coph.2011.06.004
396.
Nassenstein C, et al. Expression and function of the ion channel TRPA1 in vagal afferent nerves innervating mouse lungs. J. Physiol. 2008;586:1595-1604.
Not in our library10.1113/jphysiol.2007.148379
397.
Barnes PJ. Cellular and molecular mechanisms of asthma and COPD. Clin. Sci. 2017;131:1541-1558.
Not in our library10.1042/cs20160487
398.
Barnes PJ. Asthma-COPD overlap. Chest. 2016;149:7-8.
Not in our library10.1016/j.chest.2015.08.017
399.
Bateman ED, Reddel HK, van Zyl-Smit RN, Agusti A. The asthma-COPD overlap syndrome: towards a revised taxonomy of chronic airways diseases? Lancet Respir. Med. 2015;3:719-728.
Not in our library10.1016/s2213-2600(15)00254-4
400.
Zhou JS, et al. Cigarette smoke-initiated autoimmunity facilitates sensitisation to elastin-induced COPD-like pathologies in mice. Eur. Respir. J. 2020;56:2000404.
Not in our library10.1183/13993003.00404-2020
401.
Papi A, Brightling C, Pedersen SE, Reddel HK. Asthma. Lancet. 2018;391:783-800.
Not in our library10.1016/s0140-6736(17)33311-1
402.
Baxter M, et al. Role of transient receptor potential and pannexin channels in cigarette smoke-triggered ATP release in the lung. Thorax. 2014;69:1080-1089.
Not in our library10.1136/thoraxjnl-2014-205467
403.
Basoglu OK, Barnes PJ, Kharitonov SA, Pelleg A. Effects of aerosolized adenosine 5’-triphosphate in smokers and patients with COPD. Chest. 2015;148:430-435.
Not in our library10.1378/chest.14-2285
404.
Zhu G, et al. Association of TRPV4 gene polymorphisms with chronic obstructive pulmonary disease. Hum. Mol. Genet. 2009;18:2053-2062.
Not in our library10.1093/hmg/ddp111
405.
Jia Y, et al. Functional TRPV4 channels are expressed in human airway smooth muscle cells. Am. J. Physiol. Lung Cell Mol. Physiol. 2004;287:L272-L278.
Not in our library10.1152/ajplung.00393.2003
406.
McAlexander MA, Luttmann MA, Hunsberger GE, Undem BJ. Transient receptor potential vanilloid 4 activation constricts the human bronchus via the release of cysteinyl leukotrienes. J. Pharm. Exp. Ther. 2014;349:118-125.
Not in our library10.1124/jpet.113.210203
407.
Direct activation of capsaicin receptors by products of lipoxygenases: Endogenous capsaicin-like substances · 2000
Not checked
408.
Lin YS, et al. Sensitization of capsaicin-sensitive lung vagal afferents by anandamide in rats: role of transient receptor potential vanilloid 1 receptors. J. Appl Physiol. 2009;106:1142-1152.
Not in our library10.1152/japplphysiol.91229.2008
409.
Doherty MJ, Mister R, Pearson MG, Calverley PM. Capsaicin induced cough in cryptogenic fibrosing alveolitis. Thorax. 2000;55:1028-1032.
Not in our library10.1136/thorax.55.12.1028
410.
Banner KH, Igney F, Poll C. TRP channels: emerging targets for respiratory disease. Pharm. Ther. 2011;130:371-384.
Not in our library10.1016/j.pharmthera.2011.03.005
411.
Link TM, et al. TRPV2 has a pivotal role in macrophage particle binding and phagocytosis. Nat. Immunol. 2010;11:232-239.
Not in our library10.1038/ni.1842
412.
Andre E, et al. Cigarette smoke-induced neurogenic inflammation is mediated by alpha,beta-unsaturated aldehydes and the TRPA1 receptor in rodents. J. Clin. Invest. 2008;118:2574-2582.
Not in our library10.1172/jci34886
413.
Barnes PJ. Alveolar macrophages as orchestrators of COPD. COPD. 2004;1:59-70.
Not in our library10.1081/copd-120028701
414.
Finney-Hayward TK, et al. Expression of transient receptor potential C6 channels in human lung macrophages. Am. J. Respir. Cell Mol. Biol. 2010;43:296-304.
Not in our library10.1165/rcmb.2008-0373oc
415.
Sabnis AS, Shadid M, Yost GS, Reilly CA. Human lung epithelial cells express a functional cold-sensing TRPM8 variant. Am. J. Respir. Cell Mol. Biol. 2008;39:466-474.
Not in our library10.1165/rcmb.2007-0440oc
416.
Peier AM, et al. A TRP channel that senses cold stimuli and menthol. Cell. 2002;108:705-715.
Not in our library10.1016/s0092-8674(02)00652-9
417.
Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet. 2017;389:1941-1952.
Not in our library10.1016/s0140-6736(17)30866-8
418.
Rahaman SO, et al. TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice. J. Clin. Invest. 2014;124:5225-5238.
Not in our library10.1172/jci75331
419.
Hamanaka K, et al. TRPV4 channels augment macrophage activation and ventilator-induced lung injury. Am. J. Physiol. Lung Cell Mol. Physiol. 2010;299:L353-L362.
Not in our library10.1152/ajplung.00315.2009
420.
Alvarez DF, et al. Transient receptor potential vanilloid 4-mediated disruption of the alveolar septal barrier: a novel mechanism of acute lung injury. Circ. Res. 2006;99:988-995.
Not in our library10.1161/01.res.0000247065.11756.19
421.
Weissmann N, et al. Activation of TRPC6 channels is essential for lung ischaemia-reperfusion induced oedema in mice. Nat. Commun. 2012;3:649.
Not in our library10.1038/ncomms1660
422.
Hafner S, et al. A (+)-Larixol congener with high affinity and subtype selectivity toward TRPC6. ChemMedChem. 2018;13:1028-1035.
Not in our library10.1002/cmdc.201800021
423.
Feigin VL, et al. The global burden of neurological disorders: translating evidence into policy. Lancet Neurol. 2020;19:255-265.
Not in our library10.1016/s1474-4422(19)30411-9
424.
Sisignano M, Bennett DL, Geisslinger G, Scholich K. TRP-channels as key integrators of lipid pathways in nociceptive neurons. Prog. Lipid Res. 2014;53:93-107.
Not in our library10.1016/j.plipres.2013.11.002
425.
Kuppusamy M, Ottolini M, Sonkusare SK. Role of TRP ion channels in cerebral circulation and neurovascular communication. Neurosci. Lett. 2021;765:136258.
Not in our library10.1016/j.neulet.2021.136258
426.
Yao H, et al. Involvement of TRPC channels in CCL2-mediated neuroprotection against tat toxicity. J. Neurosci. 2009;29:1657-1669.
Not in our library10.1523/jneurosci.2781-08.2009
427.
Bollimuntha S, Ebadi M, Singh BB. TRPC1 protects human SH-SY5Y cells against salsolinol-induced cytotoxicity by inhibiting apoptosis. Brain Res. 2006;1099:141-149.
Not in our library10.1016/j.brainres.2006.04.104
428.
Bollimuntha S, et al. TRPC1-mediated inhibition of 1-methyl-4-phenylpyridinium ion neurotoxicity in human SH-SY5Y neuroblastoma cells. J. Biol. Chem. 2005;280:2132-2140.
Not in our library10.1074/jbc.m407384200
429.
Kim JH, et al. Capacitative Ca2+ entry is involved in regulating soluble amyloid precursor protein (sAPPalpha) release mediated by muscarinic acetylcholine receptor activation in neuroblastoma SH-SY5Y cells. J. Neurochem. 2006;97:245-254.
Not in our library10.1111/j.1471-4159.2006.03734.x
430.
Li HS, Xu XZ, Montell C. Activation of a TRPC3-dependent cation current through the neurotrophin BDNF. Neuron. 1999;24:261-273.
Not in our library10.1016/s0896-6273(00)80838-7
431.
Yamamoto S, et al. Transient receptor potential channels in Alzheimer’s disease. Biochim. Biophys. Acta. 2007;1772:958-967.
Not in our library10.1016/j.bbadis.2007.03.006
432.
Griesi-Oliveira K, Suzuki AM, Muotri AR. TRPC channels and mental disorders. Adv. Exp. Med. Biol. 2017;976:137-148.
Not in our library10.1007/978-94-024-1088-4_12
433.
Griesi-Oliveira K, et al. Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons. Mol. Psychiatry. 2015;20:1350-1365.
Not in our library10.1038/mp.2014.141
434.
Shinozaki G, Potash JB. New developments in the genetics of bipolar disorder. Curr. Psychiatry Rep. 2014;16:493.
Not in our library10.1007/s11920-014-0493-5
435.
Yoon IS, et al. Altered TRPC7 gene expression in bipolar-I disorder. Biol. Psychiatry. 2001;50:620-626.
Not in our library10.1016/s0006-3223(01)01077-0
436.
Andreopoulos S, et al. Chronic lithium treatment of B lymphoblasts from bipolar disorder patients reduces transient receptor potential channel 3 levels. Pharmacogenomics J. 2004;4:365-373.
Not in our library10.1038/sj.tpj.6500266
437.
Zaeri S, Farjadian S, Emamghoreishi M. Decreased levels of canonical transient receptor potential channel 3 protein in the rat cerebral cortex after chronic treatment with lithium or valproate. Res. Pharm. Sci. 2015;10:397-406.
Not in our library
438.
Roedding AS, et al. Effect of oxidative stress on TRPM2 and TRPC3 channels in B lymphoblast cells in bipolar disorder. Bipolar Disord. 2012;14:151-161.
Not in our library10.1111/j.1399-5618.2012.01003.x
439.
Snaith RPDefining. “depression”. Am. J. Psychiatry. 1987;144:828-829.
Not in our library10.1176/ajp.144.6.828
440.
Ng QX, Venkatanarayanan N, Ho CY. Clinical use of Hypericum perforatum (St John’s wort) in depression: a meta-analysis. J. Affect Disord. 2017;210:211-221.
Not in our library10.1016/j.jad.2016.12.048
441.
Leuner K, et al. Hyperforin modulates dendritic spine morphology in hippocampal pyramidal neurons by activating Ca(2+) -permeable TRPC6 channels. Hippocampus. 2013;23:40-52.
Not in our library10.1002/hipo.22052
442.
Malhi GS, Mann JJDepression. Lancet. 2018;392:2299-2312.
Not in our library10.1016/s0140-6736(18)31948-2
443.
Amaral MD, Pozzo-Miller L. TRPC3 channels are necessary for brain-derived neurotrophic factor to activate a nonselective cationic current and to induce dendritic spine formation. J. Neurosci. 2007;27:5179-5189.
Not in our library10.1523/jneurosci.5499-06.2007
444.
Huang J. TRPC channels and stroke. Adv. Exp. Med. Biol. 2017;976:61-71.
Not in our library10.1007/978-94-024-1088-4_6
445.
Shirakawa H, et al. Sphingosine-1-phosphate induces Ca(2+) signaling and CXCL1 release via TRPC6 channel in astrocytes. Glia. 2017;65:1005-1016.
Not in our library10.1002/glia.23141
446.
Chahine LM, et al. In vivo distribution of alpha-synuclein in multiple tissues and biofluids in Parkinson disease. Neurology. 2020;95:e1267-e1284.
Not in our library10.1212/wnl.0000000000010404
447.
Yuan J, et al. Controlled activation of TRPV1 channels on microglia to boost their autophagy for clearance of alpha-synuclein and enhance therapy of Parkinson’s disease. Adv. Mater. 2022;34:e2108435.
Not in our library10.1002/adma.202108435
448.
TRPV4 contributes to ER stress and inflammation: implications for Parkinson’s disease · 2022
Not checked
449.
Nam JH, et al. TRPV1 on astrocytes rescues nigral dopamine neurons in Parkinson’s disease via CNTF. Brain. 2015;138:3610-3622.
Not in our library10.1093/brain/awv297
450.
Sevigny J, et al. The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature. 2016;537:50-56.
Not in our library10.1038/nature19323
451.
Qiang W, et al. Structural variation in amyloid-beta fibrils from Alzheimer’s disease clinical subtypes. Nature. 2017;541:217-221.
Not in our library10.1038/nature20814
452.
History and progress of hypotheses and clinical trials for Alzheimer’s disease · 2019
Corrected
453.
Luo R, et al. A novel missense variant in ACAA1 contributes to early-onset Alzheimer’s disease, impairs lysosomal function, and facilitates amyloid-beta pathology and cognitive decline. Signal Transduct. Target Ther. 2021;6:325.
Not in our library10.1038/s41392-021-00748-4
454.
Lu J, et al. TRPV1 sustains microglial metabolic reprogramming in Alzheimer’s disease. EMBO Rep. 2021;22:e52013.
Not in our library10.15252/embr.202052013
455.
Du Y, et al. TRPV1 activation alleviates cognitive and synaptic plasticity impairments through inhibiting AMPAR endocytosis in APP23/PS45 mouse model of Alzheimer’s disease. Aging Cell. 2020;19:e13113.
Not in our library10.1111/acel.13113
456.
Deng Y, et al. Amelioration of scopolamine-induced learning and memory impairment by the TRPV4 inhibitor HC067047 in ICR mice. Neurosci. Lett. 2022;767:136209.
Not in our library10.1016/j.neulet.2021.136209
457.
Luo H, et al. Cannabidiol increases proliferation, migration, tubulogenesis, and integrity of human brain endothelial cells through TRPV2 activation. Mol. Pharm. 2019;16:1312-1326.
Not in our library10.1021/acs.molpharmaceut.8b01252
458.
Li L, et al. Activation of transient receptor potential vanilloid 4 increases NMDA-activated current in hippocampal pyramidal neurons. Front. Cell Neurosci. 2013;7:17.
Not in our library10.3389/fncel.2013.00017
459.
Tanaka K, et al. Reduced post-ischemic brain injury in transient receptor potential vanilloid 4 knockout mice. Front. Neurosci. 2020;14:453.
Not in our library10.3389/fnins.2020.00453
460.
Paumier A, et al. Astrocyte-neuron interplay is critical for Alzheimer’s disease pathogenesis and is rescued by TRPA1 channel blockade. Brain. 2022;145:388-405.
Not in our library10.1093/brain/awab281
461.
Pradeepkiran JA, Reddy PH. Defective mitophagy in Alzheimer’s disease. Ageing Res. Rev. 2020;64:101191.
Not in our library10.1016/j.arr.2020.101191
462.
Ozsimsek A, Ovey IS. Potential effects of melatonin on TRPA1 channels in the prevention and treatment of Alzheimer’s disease. Noro Psikiyatr Ars. 2022;59:188-192.
Not in our library10.29399/npa.28183
463.
Gunaydin C, Arslan G, Bilge SS. Proconvulsant effect of trans-cinnamaldehyde in pentylenetetrazole-induced kindling model of epilepsy: The role of TRPA1 channels. Neurosci. Lett. 2020;721:134823.
Not in our library10.1016/j.neulet.2020.134823
464.
Heydari FS, et al. The blockade of transient receptor potential ankyrin 1 (TRPA1) protects against PTZ-induced seizure. Metab. Brain Dis. 2023;38:621-630.
Not in our library10.1007/s11011-022-01123-0
465.
Peres DS, et al. TRPA1 involvement in depression- and anxiety-like behaviors in a progressive multiple sclerosis model in mice. Brain Res. Bull. 2021;175:1-15.
Not in our library10.1016/j.brainresbull.2021.07.011
466.
de Moura JC, et al. The blockade of transient receptor potential ankirin 1 (TRPA1) signalling mediates antidepressant- and anxiolytic-like actions in mice. Br. J. Pharm. 2014;171:4289-4299.
Not in our library10.1111/bph.12786
467.
Neuroprotective effects of TRPA1 channels in the cerebral endothelium following ischemic stroke · 2018
Not checked
468.
Jiang LH, et al. The TRPM2 channel nexus from oxidative damage to Alzheimer’s pathologies: an emerging novel intervention target for age-related dementia. Ageing Res. Rev. 2018;47:67-79.
Not in our library10.1016/j.arr.2018.07.002
469.
Huang Q, et al. The role of transient receptor potential channels in blood-brain barrier dysfunction after ischemic stroke. Biomed. Pharmacother. 2020;131:110647.
Not in our library10.1016/j.biopha.2020.110647
470.
Xie YF, Macdonald JF, Jackson MF. TRPM2, calcium and neurodegenerative diseases. Int. J. Physiol. Pathophysiol. Pharm. 2010;2:95-103.
Not in our library
471.
Hazalin N, Liao P, Hassan Z. TRPM4 inhibition improves spatial memory impairment and hippocampal long-term potentiation deficit in chronic cerebral hypoperfused rats. Behav. Brain Res. 2020;393:112781.
Not in our library10.1016/j.bbr.2020.112781
472.
Chen B, et al. TRPM4-specific blocking antibody attenuates reperfusion injury in a rat model of stroke. Pflug. Arch. 2019;471:1455-1466.
Not in our library10.1007/s00424-019-02326-8
473.
Chen B, et al. Non-invasive multimodality imaging directly shows TRPM4 inhibition ameliorates stroke reperfusion injury. Transl. Stroke Res. 2019;10:91-103.
Not in our library10.1007/s12975-018-0621-3
474.
Inoue R, et al. The transient receptor potential protein homologue TRP6 is the essential component of vascular alpha(1)-adrenoceptor-activated Ca(2+)-permeable cation channel. Circ. Res. 2001;88:325-332.
Not in our library10.1161/01.res.88.3.325
475.
Gan L, et al. CD38 deficiency alleviates Ang II-induced vascular remodeling by inhibiting small extracellular vesicle-mediated vascular smooth muscle cell senescence in mice. Signal Transduct. Target Ther. 2021;6:223.
Not in our library10.1038/s41392-021-00625-0
476.
Zhao H, et al. Inhibition of intermittent calcium-activated potassium channel (SK4) attenuates Ang II-induced hypertrophy of human-induced stem cell-derived cardiomyocytes via targeting Ras-Raf-MEK1/2-ERK1/2 and CN-NFAT signaling pathways. Cell Biol. Int. 2023;47:480-491.
Not in our library10.1002/cbin.11948
477.
Onohara N, et al. TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy. EMBO J. 2006;25:5305-5316.
Not in our library10.1038/sj.emboj.7601417
478.
Heineke J, Molkentin JD. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat. Rev. Mol. Cell Biol. 2006;7:589-600.
Not in our library10.1038/nrm1983
479.
Satoh S, et al. Transient receptor potential (TRP) protein 7 acts as a G protein-activated Ca2+ channel mediating angiotensin II-induced myocardial apoptosis. Mol. Cell Biochem. 2007;294:205-215.
Not in our library10.1007/s11010-006-9261-0
480.
Nakayama H, Wilkin BJ, Bodi I, Molkentin JD. Calcineurin-dependent cardiomyopathy is activated by TRPC in the adult mouse heart. FASEB J. 2006;20:1660-1670.
Not in our library10.1096/fj.05-5560com
481.
Seth M, et al. TRPC1 channels are critical for hypertrophic signaling in the heart. Circ. Res. 2009;105:1023-1030.
Not in our library10.1161/circresaha.109.206581
482.
Zhang Q, et al. Activation of transient receptor potential vanilloid 3 channel (TRPV3) aggravated pathological cardiac hypertrophy via calcineurin/NFATc3 pathway in rats. J. Cell Mol. Med. 2018;22:6055-6067.
Not in our library10.1111/jcmm.13880
483.
Feng J, et al. Upregulation of transient receptor potential melastatin 4 (TRPM4) in ventricular fibroblasts from heart failure patients. Pflug. Arch. 2021;473:521-531.
Not in our library10.1007/s00424-021-02525-2
484.
Lang H, et al. Activation of TRPV1 attenuates high salt-induced cardiac hypertrophy through improvement of mitochondrial function. Br. J. Pharm. 2015;172:5548-5558.
Not in our library10.1111/bph.12987
485.
Poulter NR, Prabhakaran D. & Caulfield, M. Hypertension. Lancet. 2015;386:801-812.
Not in our library10.1016/s0140-6736(14)61468-9
486.
Desai AN. High blood pressure. JAMA. 2020;324:1254-1255.
Not in our library10.1001/jama.2020.11289
487.
Hollis M, Wang DH. Transient receptor potential vanilloid in blood pressure regulation. Curr. Opin. Nephrol. Hypertens. 2013;22:170-176.
Not in our library10.1097/mnh.0b013e32835c8d4c
488.
Zygmunt PM, et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature. 1999;400:452-457.
Not in our library10.1038/22761
489.
Poblete IM, et al. Anandamide elicits an acute release of nitric oxide through endothelial TRPV1 receptor activation in the rat arterial mesenteric bed. J. Physiol. 2005;568:539-551.
Not in our library10.1113/jphysiol.2005.094292
490.
Mathar I, et al. Increased catecholamine secretion contributes to hypertension in TRPM4-deficient mice. J. Clin. Invest. 2010;120:3267-3279.
Not in our library10.1172/jci41348
491.
Earley S, et al. TRPV4-dependent dilation of peripheral resistance arteries influences arterial pressure. Am. J. Physiol. Heart Circ. Physiol. 2009;297:H1096-H1102.
Not in our library10.1152/ajpheart.00241.2009
492.
Basatemur GL, et al. Vascular smooth muscle cells in atherosclerosis. Nat. Rev. Cardiol. 2019;16:727-744.
Not in our library10.1038/s41569-019-0227-9
493.
Inflammation and atherosclerosis: signaling pathways and therapeutic intervention · 2022
No notice
494.
A macrophage-specific lncRNA regulates apoptosis and atherosclerosis by tethering HuR in the nucleus · 2020
No notice
495.
Tano JY, et al. Bone marrow deficiency of TRPC3 channel reduces early lesion burden and necrotic core of advanced plaques in a mouse model of atherosclerosis. Cardiovasc. Res. 2014;101:138-144.
Not in our library10.1093/cvr/cvt231
496.
Zhao JF, et al. Transient receptor potential ankyrin 1 channel involved in atherosclerosis and macrophage-foam cell formation. Int. J. Biol. Sci. 2016;12:812-823.
Not in our library10.7150/ijbs.15229
497.
Dai YQ, et al. Transient receptor potential melastatin 2 enhances vascular reactivity during development of atherosclerosis in mice. Am. J. Hypertens. 2021;34:121-122.
Not in our library10.1093/ajh/hpaa154
498.
Perrone RD, Malek AM, Watnick T. Vascular complications in autosomal dominant polycystic kidney disease. Nat. Rev. Nephrol. 2015;11:589-598.
Not in our library10.1038/nrneph.2015.128
499.
Bergmann C, et al. Polycystic kidney disease. Nat. Rev. Dis. Prim. 2018;4:50.
Not in our library10.1038/s41572-018-0047-y
500.
Qian Q, et al. Pkd2 haploinsufficiency alters intracellular calcium regulation in vascular smooth muscle cells. Hum. Mol. Genet. 2003;12:1875-1880.
Not in our library10.1093/hmg/ddg190
501.
Yue Z, et al. Role of TRP channels in the cardiovascular system. Am. J. Physiol. Heart Circ. Physiol. 2015;308:H157-H182.
Not in our library10.1152/ajpheart.00457.2014
502.
The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives · 2021
No notice
503.
Yin X, et al. The evolving view of thermogenic fat and its implications in cancer and metabolic diseases. Signal Transduct. Target Ther. 2022;7:324.
Not in our library10.1038/s41392-022-01178-6
504.
Yang D, Kim J. Emerging role of transient receptor potential (TRP) channels in cancer progression. BMB Rep. 2020;53:125-132.
Not in our library10.5483/bmbrep.2020.53.3.016
505.
Perrouin-Verbe MA, et al. Overexpression of certain transient receptor potential and Orai channels in prostate cancer is associated with decreased risk of systemic recurrence after radical prostatectomy. Prostate. 2019;79:1793-1804.
Not in our library10.1002/pros.23904
506.
So CL, Milevskiy MJG, Monteith GR. Transient receptor potential cation channel subfamily V and breast cancer. Lab Invest. 2020;100:199-206.
Not in our library10.1038/s41374-019-0348-0
507.
Rizopoulos T, Assimakopoulou M. Transient receptor potential (TRP) channels in human colorectal cancer: evidence and perspectives. Histol. Histopathol. 2021;36:515-526.
Not in our library10.14670/hh-18-308
508.
Huang J, Liu J, Qiu L. Transient receptor potential vanilloid 1 promotes EGFR ubiquitination and modulates EGFR/MAPK signalling in pancreatic cancer cells. Cell Biochem. Funct. 2020;38:401-408.
Not in our library10.1002/cbf.3483
509.
Hu Z, et al. Transient receptor potential vanilloid-type 2 targeting on stemness in liver cancer. Biomed. Pharmacother. 2018;105:697-706.
Not in our library10.1016/j.biopha.2018.06.029
510.
Kim BJ, et al. The role of transient receptor potential channel blockers in human gastric cancer cell viability. Can. J. Physiol. Pharm. 2012;90:175-186.
Not in our library10.1139/y11-114
511.
The Transient Receptor Potential Melastatin 7 Channel Regulates Pancreatic Cancer Cell Invasion through the Hsp90α/uPA/MMP2 pathway · 2017
Not checked
512.
Zeng X, et al. Novel role for the transient receptor potential channel TRPM2 in prostate cancer cell proliferation. Prostate Cancer Prostatic Dis. 2010;13:195-201.
Not in our library10.1038/pcan.2009.55
513.
Sun W, et al. Involvement of TRP channels in adipocyte thermogenesis: an update. Front. Cell Dev. Biol. 2021;9:686173.
Not in our library10.3389/fcell.2021.686173
514.
Yoneshiro T, Saito M. Transient receptor potential activated brown fat thermogenesis as a target of food ingredients for obesity management. Curr. Opin. Clin. Nutr. Metab. Care. 2013;16:625-631.
Not in our library10.1097/mco.0b013e3283653ee1
515.
Snitker S, et al. Effects of novel capsinoid treatment on fatness and energy metabolism in humans: possible pharmacogenetic implications. Am. J. Clin. Nutr. 2009;89:45-50.
Not in our library10.3945/ajcn.2008.26561
516.
Yoneshiro T, et al. Nonpungent capsaicin analogs (capsinoids) increase energy expenditure through the activation of brown adipose tissue in humans. Am. J. Clin. Nutr. 2012;95:845-850.
Not in our library10.3945/ajcn.111.018606
517.
Lejeune MP, Kovacs EM, Westerterp-Plantenga MS. Effect of capsaicin on substrate oxidation and weight maintenance after modest body-weight loss in human subjects. Br. J. Nutr. 2003;90:651-659.
Not in our library10.1079/bjn2003938
518.
Inoue N, Matsunaga Y, Satoh H, Takahashi M. Enhanced energy expenditure and fat oxidation in humans with high BMI scores by the ingestion of novel and non-pungent capsaicin analogues (capsinoids). Biosci. Biotechnol. Biochem. 2007;71:380-389.
Not in our library10.1271/bbb.60341
519.
Moller CC, et al. Induction of TRPC6 channel in acquired forms of proteinuric kidney disease. J. Am. Soc. Nephrol. 2007;18:29-36.
Not in our library10.1681/asn.2006091010
520.
Reiser J, et al. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat. Genet. 2005;37:739-744.
Not in our library10.1038/ng1592
521.
Yu S, Yu L. Dexamethasone resisted podocyte injury via stabilizing TRPC6 expression and distribution. Evid. Based Complement. Altern. Med. 2012;2012:652059.
Not in our library10.1155/2012/652059
522.
Sonneveld R, et al. Glucose specifically regulates TRPC6 expression in the podocyte in an AngII-dependent manner. Am. J. Pathol. 2014;184:1715-1726.
Not in our library10.1016/j.ajpath.2014.02.008
523.
Zhang Q, et al. Screening of ACTN4 and TRPC6 mutations in a Chinese cohort of patients with adult-onset familial focal segmental glomerulosclerosis. Contrib. Nephrol. 2013;181:91-100.
Not in our library10.1159/000348471
524.
Kistler AD, et al. Transient receptor potential channel 6 (TRPC6) protects podocytes during complement-mediated glomerular disease. J. Biol. Chem. 2013;288:36598-36609.
Not in our library10.1074/jbc.m113.488122
525.
Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:1415-1428.
Not in our library10.1016/s0140-6736(05)66378-7
526.
Liu D, Zhu Z, Tepel M. The role of transient receptor potential channels in metabolic syndrome. Hypertens. Res. 2008;31:1989-1995.
Not in our library10.1291/hypres.31.1989
527.
Colsoul B, Nilius B, Vennekens R. Transient receptor potential (TRP) cation channels in diabetes. Curr. Top. Med. Chem. 2013;13:258-269.
Not in our library10.2174/1568026611313030004
528.
Chung AW, et al. Diabetes modulates capacitative calcium entry and expression of transient receptor potential canonical channels in human saphenous vein. Eur. J. Pharm. 2009;613:114-118.
Not in our library10.1016/j.ejphar.2009.04.029
529.
Billert M, et al. TRPV4 regulates insulin mRNA expression and INS-1E cell death via ERK1/2 and NO-dependent mechanisms. Cell Signal. 2017;35:242-249.
Not in our library10.1016/j.cellsig.2017.03.018
530.
Deruyver Y, et al. Intravesical activation of the cation channel TRPV4 improves bladder function in a rat model for detrusor underactivity. Eur. Urol. 2018;74:336-345.
Not in our library10.1016/j.eururo.2018.05.020
531.
Everaerts W, et al. Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis. Proc. Natl Acad. Sci. USA. 2010;107:19084-19089.
Not in our library10.1073/pnas.1005333107
532.
Szallasi A, Blumberg PM. Vanilloid (Capsaicin) receptors and mechanisms. Pharm. Rev. 1999;51:159-212.
Not in our library
533.
Liu BL, et al. Increased severity of inflammation correlates with elevated expression of TRPV1 nerve fibers and nerve growth factor on interstitial cystitis/bladder pain syndrome. Urol. Int. 2014;92:202-208.
Not in our library10.1159/000355175
534.
Kawate T. P2X receptor activation. Adv. Exp. Med. Biol. 2017;1051:55-69.
Not in our library10.1007/5584_2017_55
535.
Song J, et al. Posterior tibial nerve stimulation improves neurogenic bladder in rats with spinal cord injury through transient receptor potential/P2X signaling pathway. Neurourol. Urodyn. 2022;41:756-764.
Not in our library10.1002/nau.24885
536.
Wu L, Zhang J, Zhou F, Zhang P. Increased transient receptor potential melastatin 8 expression in the development of bladder pain in patients with interstitial cystitis/bladder pain syndrome. Urology. 2020;146:301.e301-301 e306.
Not in our library10.1016/j.urology.2020.09.037
537.
Furuta A, et al. Transient receptor potential A1 receptor-mediated neural cross-talk and afferent sensitization induced by oxidative stress: implication for the pathogenesis of interstitial cystitis/bladder pain syndrome. Int. J. Urol. 2012;19:429-436.
Not in our library10.1111/j.1442-2042.2012.02966.x
538.
Andersson KE, Gratzke C, Hedlund P. The role of the transient receptor potential (TRP) superfamily of cation-selective channels in the management of the overactive bladder. BJU Int. 2010;106:1114-1127.
Not in our library10.1111/j.1464-410x.2010.09650.x
539.
Zhang HY, et al. Expression and diagnosis of transient receptor potential vanilloid1 in urothelium of patients with overactive bladder. J. Biol. Regul. Homeost. Agents. 2015;29:875-879.
Not in our library
540.
Frias B, et al. Transient receptor potential vanilloid 1 mediates nerve growth factor-induced bladder hyperactivity and noxious input. BJU Int. 2012;110:E422-E428.
Not in our library10.1111/j.1464-410x.2012.11187.x
541.
Nakanishi O, et al. KPR-5714, a novel transient receptor potential melastatin 8 antagonist, improves overactive bladder via inhibition of bladder afferent hyperactivity in rats. J. Pharm. Exp. Ther. 2020;373:239-247.
Not in our library10.1124/jpet.119.263616
542.
Functional Role of Transient Receptor Potential Channels in Immune Cells and Epithelia · 2018
No notice
543.
Interleukin-31 promotes fibrosis and T helper 2 polarization in systemic sclerosis · 2021
Not checked
544.
Cevikbas F, et al. A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: Involvement of TRPV1 and TRPA1. J. Allergy Clin. Immunol. 2014;133:448-460.
Not in our library10.1016/j.jaci.2013.10.048
545.
Facchinetti F, et al. Alpha,beta-unsaturated aldehydes in cigarette smoke release inflammatory mediators from human macrophages. Am. J. Respir. Cell Mol. Biol. 2007;37:617-623.
Not in our library10.1165/rcmb.2007-0130oc
546.
Wu SN, Wu PY, Tsai ML. Characterization of TRPM8-like channels activated by the cooling agent icilin in the macrophage cell line RAW 264.7. J. Membr. Biol. 2011;241:11-20.
Not in our library10.1007/s00232-011-9358-6
547.
Khalil M, et al. Transient receptor potential melastatin 8 ion channel in macrophages modulates colitis through a balance-shift in TNF-alpha and interleukin-10 production. Mucosal Immunol. 2016;9:1500-1513.
Not in our library10.1038/mi.2016.16
548.
Juergens UR, et al. Inhibitory activity of 1,8-cineol (eucalyptol) on cytokine production in cultured human lymphocytes and monocytes. Pulm. Pharm. Ther. 2004;17:281-287.
Not in our library10.1016/j.pupt.2004.06.002
549.
Zhao JF, et al. Activation of TRPV1 prevents OxLDL-induced lipid accumulation and TNF-alpha-induced inflammation in macrophages: role of liver X receptor alpha. Mediators Inflamm. 2013;2013:925171.
Not in our library10.1155/2013/925171
550.
Kim CS, et al. Capsaicin exhibits anti-inflammatory property by inhibiting IkB-a degradation in LPS-stimulated peritoneal macrophages. Cell Signal. 2003;15:299-306.
Not in our library10.1016/s0898-6568(02)00086-4
551.
Acharya N, et al. Endocannabinoid system acts as a regulator of immune homeostasis in the gut. Proc. Natl Acad. Sci. USA. 2017;114:5005-5010.
Not in our library10.1073/pnas.1612177114
552.
Henry CO, et al. In vitro and in vivo evidence for an inflammatory role of the calcium channel TRPV4 in lung epithelium: potential involvement in cystic fibrosis. Am. J. Physiol. Lung Cell Mol. Physiol. 2016;311:L664-675.
Not in our library10.1152/ajplung.00442.2015
553.
Majhi RK, et al. Functional expression of TRPV channels in T cells and their implications in immune regulation. FEBS J. 2015;282:2661-2681.
Not in our library10.1111/febs.13306
554.
Santoni G, et al. “Immuno-transient receptor potential ion channels”: the role in monocyte- and macrophage-mediated inflammatory responses. Front. Immunol. 2018;9:1273.
Not in our library10.3389/fimmu.2018.01273
555.
Beceiro S, et al. TRPM2 ion channels regulate macrophage polarization and gastric inflammation during Helicobacter pylori infection. Mucosal Immunol. 2017;10:493-507.
Not in our library10.1038/mi.2016.60
556.
Yamamoto S, et al. TRPM2-mediated Ca2+influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration. Nat. Med. 2008;14:738-747.
Not in our library10.1038/nm1758
557.
Serafini N, et al. The TRPM4 channel controls monocyte and macrophage, but not neutrophil, function for survival in sepsis. J. Immunol. 2012;189:3689-3699.
Not in our library10.4049/jimmunol.1102969
558.
Surowy CS, et al. (R)-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)-urea (ABT-102) blocks polymodal activation of transient receptor potential vanilloid 1 receptors in vitro and heat-evoked firing of spinal dorsal horn neurons in vivo. J. Pharm. Exp. Ther. 2008;326:879-888.
Not in our library10.1124/jpet.108.138511
559.
Honore P, et al. Repeated dosing of ABT-102, a potent and selective TRPV1 antagonist, enhances TRPV1-mediated analgesic activity in rodents, but attenuates antagonist-induced hyperthermia. Pain. 2009;142:27-35.
Not in our library10.1016/j.pain.2008.11.004
560.
Garami A, et al. Hyperthermia induced by transient receptor potential vanilloid-1 (TRPV1) antagonists in human clinical trials: Insights from mathematical modeling and meta-analysis. Pharm. Ther. 2020;208:107474.
Not in our library10.1016/j.pharmthera.2020.107474
561.
Krarup AL, et al. Randomized clinical trial: inhibition of the TRPV1 system in patients with nonerosive gastroesophageal reflux disease and a partial response to PPI treatment is not associated with analgesia to esophageal experimental pain. Scand. J. Gastroenterol. 2013;48:274-284.
Not in our library10.3109/00365521.2012.758769
562.
Miller F, Bjornsson M, Svensson O, Karlsten R. Experiences with an adaptive design for a dose-finding study in patients with osteoarthritis. Contemp. Clin. Trials. 2014;37:189-199.
Not in our library10.1016/j.cct.2013.12.007
563.
Munjuluri S, et al. Capsaicin and TRPV1 channels in the cardiovascular system: the role of inflammation. Cells. 2022;11:18.
Not in our library10.3390/cells11010018
564.
Sharma SK, Vij AS, Sharma M. Mechanisms and clinical uses of capsaicin. Eur. J. Pharm. 2013;720:55-62.
Not in our library10.1016/j.ejphar.2013.10.053
565.
Gibson RA, et al. A randomised trial evaluating the effects of the TRPV1 antagonist SB705498 on pruritus induced by histamine, and cowhage challenge in healthy volunteers. PLoS ONE. 2014;9:e100610.
Not in our library10.1371/journal.pone.0100610
566.
Szallasi A, Cruz F, Geppetti P. TRPV1: a therapeutic target for novel analgesic drugs? Trends Mol. Med. 2006;12:545-554.
Not in our library10.1016/j.molmed.2006.09.001
567.
Belvisi MG, et al. XEN-D0501, a novel transient receptor potential vanilloid 1 antagonist, does not reduce cough in patients with refractory cough. Am. J. Respir. Crit. Care Med. 2017;196:1255-1263.
Not in our library10.1164/rccm.201704-0769oc
568.
Lim KM, Park YH. Development of PAC-14028, a novel transient receptor potential vanilloid type 1 (TRPV1) channel antagonist as a new drug for refractory skin diseases. Arch. Pharm. Res. 2012;35:393-396.
Not in our library10.1007/s12272-012-0321-6
569.
Song PI, Armstrong CA. Novel therapeutic approach with PAC-14028 cream, a TRPV1 antagonist, for patients with mild-to-moderate atopic dermatitis. Br. J. Dermatol. 2019;180:971-972.
Not in our library10.1111/bjd.17777
570.
Chen H, Terrett JA. Transient receptor potential ankyrin 1 (TRPA1) antagonists: a patent review (2015-2019). Expert Opin. Ther. Pat. 2020;30:643-657.
Not in our library10.1080/13543776.2020.1797679
571.
Balestrini, A. et al. A TRPA1 inhibitor suppresses neurogenic inflammation and airway contraction for asthma treatment. J. Exp. Med. 218, e20201637 (2021).
Not in our library10.1084/jem.20201637
572.
Preti D, Saponaro G, Szallasi A. Transient receptor potential ankyrin 1 (TRPA1) antagonists. Pharm. Pat. Anal. 2015;4:75-94.
Not in our library10.4155/ppa.14.60
573.
Skerratt S. Recent progress in the discovery and development of TRPA1 modulators. Prog. Med. Chem. 2017;56:81-115.
Not in our library10.1016/bs.pmch.2016.11.003
574.
Gosset JR, et al. A cross-species translational pharmacokinetic-pharmacodynamic evaluation of core body temperature reduction by the TRPM8 blocker PF-05105679. Eur. J. Pharm. Sci. 2017;109S:S161-S167.
Not in our library10.1016/j.ejps.2017.06.009
575.
Winchester WJ, et al. Inhibition of TRPM8 channels reduces pain in the cold pressor test in humans. J. Pharm. Exp. Ther. 2014;351:259-269.
Not in our library10.1124/jpet.114.216010
576.
Barkin RL. The pharmacology of topical analgesics. Postgrad. Med. 2013;125:7-18.
Not in our library10.1080/00325481.2013.1110566911
577.
Craighead DH, McCartney NB, Tumlinson JH, Alexander LM. Mechanisms and time course of menthol-induced cutaneous vasodilation. Microvasc. Res. 2017;110:43-47.
Not in our library10.1016/j.mvr.2016.11.008
578.
Lasanen R, Julkunen P, Airaksinen O, Toyras J. Menthol concentration in topical cold gel does not have significant effect on skin cooling. Ski. Res. Technol. 2016;22:40-45.
Not in our library10.1111/srt.12226
579.
Tomsen N, et al. A randomized clinical trial on the acute therapeutic effect of TRPA1 and TRPM8 agonists in patients with oropharyngeal dysphagia. Neurogastroenterol. Motil. 2020;32:e13821.
Not in our library10.1111/nmo.13821
580.
Peiris M, et al. A putative anti-inflammatory role for TRPM8 in irritable bowel syndrome-An exploratory study. Neurogastroenterol. Motil. 2021;33:e14170.
Not in our library10.1111/nmo.14170
581.
Brooks CA, et al. Discovery of GSK2798745: a clinical candidate for inhibition of transient receptor potential vanilloid 4 (TRPV4). ACS Med. Chem. Lett. 2019;10:1228-1233.
Not in our library10.1021/acsmedchemlett.9b00274
582.
Goyal N, et al. Clinical pharmacokinetics, safety, and tolerability of a novel, first-in-class TRPV4 ion channel inhibitor, GSK2798745, in healthy and heart failure subjects. Am. J. Cardiovasc. Drugs. 2019;19:335-342.
Not in our library10.1007/s40256-018-00320-6
583.
Nilius B, Biro T. TRPV3: a ‘more than skinny’ channel. Exp. Dermatol. 2013;22:447-452.
Not in our library10.1111/exd.12163
584.
Broad LM, et al. TRPV3 in drug development. Pharmaceuticals. 2016;9:55.
Not in our library10.3390/ph9030055
585.
Acar HV. Acupuncture and related techniques during perioperative period: a literature review. Complement Ther. Med. 2016;29:48-55.
Not in our library10.1016/j.ctim.2016.09.013
586.
Mao JJ, et al. Effectiveness of electroacupuncture or auricular acupuncture vs usual care for chronic musculoskeletal pain among cancer survivors: the PEACE randomized clinical trial. JAMA Oncol. 2021;7:720-727.
Not in our library10.1001/jamaoncol.2021.0310
587.
Ulloa L. Electroacupuncture activates neurons to switch off inflammation. Nature. 2021;598:573-574.
Not in our library10.1038/d41586-021-02714-0
588.
Jiang J, Wang X, Wu X, Yu Z. Analysis of factors influencing moxibustion efficacy by affecting heat-activated transient receptor potential vanilloid channels. J. Tradit. Chin. Med. 2016;36:255-260.
Not in our library10.1016/s0254-6272(16)30036-x
589.
Li J, Jiang J. Role of transient receptor potential vanilloid subetype 1 in the increase of thermal pain threshold by moxibustion. J. Tradit. Chin. Med. 2015;35:583-587.
Not in our library10.1016/s0254-6272(15)30143-6
590.
Zou W, et al. Moxibustion relieves visceral hyperalgesia via inhibition of transient receptor potential vanilloid 1 (TRPV1) and heat shock protein (HSP) 70 expression in rat bone marrow cells. Acupunct. Med. 2016;34:114-119.
Not in our library10.1136/acupmed-2015-010788
591.
Inprasit C, et al. Targeting TRPV1 to relieve motion sickness symptoms in mice by electroacupuncture and gene deletion. Sci. Rep. 2018;8:10365.
Not in our library10.1038/s41598-018-23793-6
592.
Ji B, Hu J, Ma S. Effects of electroacupuncture Zusanli (ST36) on food intake and expression of POMC and TRPV1 through afferents-medulla pathway in obese prone rats. Peptides. 2013;40:188-194.
Not in our library10.1016/j.peptides.2012.10.009
593.
Huang M, et al. Critical roles of TRPV2 channels, histamine H1 and adenosine A1 receptors in the initiation of acupoint signals for acupuncture analgesia. Sci. Rep. 2018;8:6523.
Not in our library10.1038/s41598-018-24654-y
594.
Yen CM, Hsieh CL, Lin YW. Electroacupuncture reduces chronic fibromyalgia pain through attenuation of transient receptor potential vanilloid 1 signaling pathway in mouse brains. Iran. J. Basic Med. Sci. 2020;23:894-900.
Not in our library10.22038/ijbms.2020.39708.9408
595.
Zhong X, et al. Effects of electroacupuncture on gastrointestinal motility function, pain, and inflammation via transient receptor potential vanilloid 1 in a rat model after colonic anastomoses. Dis. Markers. 2022;2022:5113473.
Not in our library10.1155/2022/5113473
596.
Lin YW, Chou AIW, Su H, Su KP. Transient receptor potential V1 (TRPV1) modulates the therapeutic effects for comorbidity of pain and depression: the common molecular implication for electroacupuncture and omega-3 polyunsaturated fatty acids. Brain Behav. Immun. 2020;89:604-614.
Not in our library10.1016/j.bbi.2020.06.033
597.
Yu Z, et al. Electroacupuncture at ST25 inhibits jejunal motility: role of sympathetic pathways and TRPV1. World J. Gastroenterol. 2016;22:1834-1843.
Not in our library10.3748/wjg.v22.i5.1834
598.
Tsai ST, et al. Transient receptor potential V1 modulates neuroinflammation in Parkinson’s disease dementia: molecular implications for electroacupuncture and rivastigmine. Iran. J. Basic Med. Sci. 2021;24:1336-1345.
Not in our library10.22038/ijbms.2021.56156.12531
599.
Electroacupuncture Alleviates Paclitaxel-Induced Peripheral Neuropathic Pain in Rats via Suppressing TLR4 Signaling and TRPV1 Upregulation in Sensory Neurons · 2019
No notice
600.
Wu JH, et al. [Effect of electroacupuncture pretreatment on transient receptor potential vanilloid 1(TRPV1)/calcitonin gene-related peptide(CGRP) signal and NF-kappaB p65 protein expression in rats with acute myocardial ischemia]. Zhen Ci Yan Jiu. 2021;46:58-63.
Not in our library10.13702/j.1000-0607.200905
601.
Zheng J, et al. Gold nanorods: the most versatile plasmonic nanoparticles. Chem. Rev. 2021;121:13342-13453.
Not in our library10.1021/acs.chemrev.1c00422
602.
Zhou C, et al. Gold nanorods-based thermosensitive hydrogel produces selective long-lasting regional anesthesia triggered by photothermal activation of transient receptor potential vanilloid type-1 channels. Colloids Surf. B Biointerfaces. 2018;171:17-23.
Not in our library10.1016/j.colsurfb.2018.07.002
603.
Zhen X, et al. Semiconducting photothermal nanoagonist for remote-controlled specific cancer therapy. Nano Lett. 2018;18:1498-1505.
Not in our library10.1021/acs.nanolett.7b05292
604.
Maggi CA, et al. Cystometric evidence that capsaicin-sensitive nerves modulate the afferent branch of micturition reflex in humans. J. Urol. 1989;142:150-154.
Not in our library10.1016/s0022-5347(17)38701-3
605.
Szallasi A. Some like it hot (ever more so in the tropics): a puzzle with no solution. Temp. (Austin). 2016;3:54-55.
Not in our library10.1080/23328940.2016.1139964
606.
Szallasi A. Vanilloid-sensitive neurons: a fundamental subdivision of the peripheral nervous system. J. Peripher. Nerv. Syst. 1996;1:6-18.
Not in our library
607.
Krarup AL, et al. Randomised clinical trial: the efficacy of a transient receptor potential vanilloid 1 antagonist AZD1386 in human oesophageal pain. Aliment Pharm. Ther. 2011;33:1113-1122.
Not in our library10.1111/j.1365-2036.2011.04629.x
608.
Gavva NR, et al. Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain. 2008;136:202-210.
Not in our library10.1016/j.pain.2008.01.024
609.
Eid SR. Therapeutic targeting of TRP channels–the TR(i)P to pain relief. Curr. Top. Med. Chem. 2011;11:2118-2130.
Not in our library10.2174/156802611796904898
610.
Moran MM, Szallasi A. Targeting nociceptive transient receptor potential channels to treat chronic pain: current state of the field. Br. J. Pharm. 2018;175:2185-2203.
Not in our library10.1111/bph.14044
611.
Materazzi S, et al. TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism. Pflug. Arch. 2012;463:561-569.
Not in our library10.1007/s00424-011-1071-x
612.
Schulze A, Hartung P, Schaefer M, Hill K. Transient receptor potential ankyrin 1 (TRPA1) channel activation by the thienopyridine-type drugs ticlopidine, clopidogrel, and prasugrel. Cell Calcium. 2014;55:200-207.
Not in our library10.1016/j.ceca.2014.02.014
613.
Rudd JA, et al. The involvement of TRPV1 in emesis and anti-emesis. Temp. (Austin). 2015;2:258-276.
Not in our library10.1080/23328940.2015.1043042
614.
Brown W, et al. Safety, pharmacokinetics, and pharmacodynamics study in healthy subjects of oral NEO6860, a modality selective transient receptor potential vanilloid subtype 1 antagonist. J. Pain. 2017;18:726-738.
Not in our library10.1016/j.jpain.2017.01.009
615.
Gerhold KA, Bautista DM. Molecular and cellular mechanisms of trigeminal chemosensation. Ann. N. Y Acad. Sci. 2009;1170:184-189.
Not in our library10.1111/j.1749-6632.2009.03895.x
616.
Terada Y, et al. Activation and inhibition of thermosensitive TRP channels by voacangine, an alkaloid present in Voacanga africana, an African tree. J. Nat. Prod. 2014;77:285-297.
Not in our library10.1021/np400885u
617.
Elzamzamy OM, Penner R, Hazlehurst LA. The role of TRPC1 in modulating cancer progression. Cells. 2020;9:388.
Not in our library10.3390/cells9020388
618.
Yildirim E, et al. Severely blunted allergen-induced pulmonary Th2 cell response and lung hyperresponsiveness in type 1 transient receptor potential channel-deficient mice. Am. J. Physiol. Lung Cell Mol. Physiol. 2012;303:L539-549.
Not in our library10.1152/ajplung.00389.2011
619.
Lof C, Viitanen T, Sukumaran P, Tornquist K. TRPC2: of mice but not men. Adv. Exp. Med. Biol. 2011;704:125-134.
Not in our library10.1007/978-94-007-0265-3_6
620.
Tornquist K, et al. Canonical transient receptor potential channel 2 (TRPC2): old name-new games. Importance in regulating of rat thyroid cell physiology. Pflug. Arch. 2014;466:2025-2034.
Not in our library10.1007/s00424-014-1509-z
621.
Zhu X, et al. trp, a novel mammalian gene family essential for agonist-activated capacitative Ca2+ entry. Cell. 1996;85:661-671.
Not in our library10.1016/s0092-8674(00)81233-7
622.
Hofmann T, Schaefer M, Schultz G, Gudermann T. Subunit composition of mammalian transient receptor potential channels in living cells. Proc. Natl Acad. Sci. USA. 2002;99:7461-7466.
Not in our library10.1073/pnas.102596199
623.
Tiruppathi C, et al. Impairment of store-operated Ca2+ entry in TRPC4(-/-) mice interferes with increase in lung microvascular permeability. Circ. Res. 2002;91:70-76.
Not in our library10.1161/01.res.0000023391.40106.a8
624.
Veliceasa D, et al. Transient potential receptor channel 4 controls thrombospondin-1 secretion and angiogenesis in renal cell carcinoma. FEBS J. 2007;274:6365-6377.
Not in our library10.1111/j.1742-4658.2007.06159.x
625.
Zhu Y, et al. Enhancement of vascular endothelial growth factor release in long-term drug-treated breast cancer via transient receptor potential channel 5-Ca(2+)-hypoxia-inducible factor 1alpha pathway. Pharm. Res. 2015;93:36-42.
Not in our library10.1016/j.phrs.2014.12.006
626.
TRPC5 channels participate in pressure-sensing in aortic baroreceptors · 2016
Not checked
627.
Ma X, et al. Essential role for TrpC5-containing extracellular vesicles in breast cancer with chemotherapeutic resistance. Proc. Natl Acad. Sci. USA. 2014;111:6389-6394.
Not in our library10.1073/pnas.1400272111
628.
Corteling RL, et al. Expression of transient receptor potential C6 and related transient receptor potential family members in human airway smooth muscle and lung tissue. Am. J. Respir. Cell Mol. Biol. 2004;30:145-154.
Not in our library10.1165/rcmb.2003-0134oc
629.
Staruschenko A, Spires D, Palygin O. Role of TRPC6 in progression of diabetic kidney disease. Curr. Hypertens. Rep. 2019;21:48.
Not in our library10.1007/s11906-019-0960-9
630.
Okada T, et al. Molecular and functional characterization of a novel mouse transient receptor potential protein homologue TRP7. Ca(2+)-permeable cation channel that is constitutively activated and enhanced by stimulation of G protein-coupled receptor. J. Biol. Chem. 1999;274:27359-27370.
Not in our library10.1074/jbc.274.39.27359
631.
Caterina MJ, et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 1997;389:816-824.
Not in our library10.1038/39807
632.
Voets T, et al. The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels. Nature. 2004;430:748-754.
Not in our library10.1038/nature02732
633.
Tominaga M, et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron. 1998;21:531-543.
Not in our library10.1016/s0896-6273(00)80564-4
634.
Becker D, Blase C, Bereiter-Hahn J, Jendrach M. TRPV4 exhibits a functional role in cell-volume regulation. J. Cell Sci. 2005;118:2435-2440.
Not in our library10.1242/jcs.02372
635.
de Groot T, Bindels RJ, Hoenderop JG. TRPV5: an ingeniously controlled calcium channel. Kidney Int. 2008;74:1241-1246.
Not in our library10.1038/ki.2008.320
636.
Bachinger D, et al. Immunolocalization of calcium sensing and transport proteins in the murine endolymphatic sac indicates calciostatic functions within the inner ear. Cell Tissue Res. 2019;378:163-173.
Not in our library10.1007/s00441-019-03062-2
637.
Lieben L, et al. Trpv6 mediates intestinal calcium absorption during calcium restriction and contributes to bone homeostasis. Bone. 2010;47:301-308.
Not in our library10.1016/j.bone.2010.04.595
638.
Oancea E, Wicks NL. TRPM1: new trends for an old TRP. Adv. Exp. Med. Biol. 2011;704:135-145.
Not in our library10.1007/978-94-007-0265-3_7
639.
Hirschler-Laszkiewicz I, et al. The human ion channel TRPM2 modulates neuroblastoma cell survival and mitochondrial function through Pyk2, CREB, and MCU activation. Am. J. Physiol. Cell Physiol. 2018;315:C571-C586.
Not in our library10.1152/ajpcell.00098.2018
640.
Behrendt M. Transient receptor potential channels in the context of nociception and pain - recent insights into TRPM3 properties and function. Biol. Chem. 2019;400:917-926.
Not in our library10.1515/hsz-2018-0455
641.
TRPM3_miR-204: a complex locus for eye development and disease · 2020
Not checked
642.
Wang H, et al. Gain-of-function mutations in TRPM4 activation gate cause progressive symmetric erythrokeratodermia. J. Invest. Dermatol. 2019;139:1089-1097.
Not in our library10.1016/j.jid.2018.10.044
643.
Guinamard R, Salle L, Simard C. The non-selective monovalent cationic channels TRPM4 and TRPM5. Adv. Exp. Med. Biol. 2011;704:147-171.
Not in our library10.1007/978-94-007-0265-3_8
644.
Gwanyanya A, et al. Magnesium-inhibited, TRPM6/7-like channel in cardiac myocytes: permeation of divalent cations and pH-mediated regulation. J. Physiol. 2004;559:761-776.
Not in our library10.1113/jphysiol.2004.067637
645.
TRPM7, Magnesium, and Signaling · 2019
No notice
646.
Gonzalez-Muniz R, Bonache MA, Martin-Escura C, Gomez-Monterrey I. Recent progress in TRPM8 modulation: an update. Int. J. Mol. Sci. 2019;20:2618.
Not in our library10.3390/ijms20112618
647.
Cantiello HF. Regulation of calcium signaling by polycystin-2. Am. J. Physiol. Ren. Physiol. 2004;286:F1012-1029.
Not in our library10.1152/ajprenal.00181.2003
648.
Huang AL, et al. The cells and logic for mammalian sour taste detection. Nature. 2006;442:934-938.
Not in our library10.1038/nature05084
649.
Chen Y, et al. Expression of Pkd2l2 in testis is implicated in spermatogenesis. Biol. Pharm. Bull. 2008;31:1496-1500.
Not in our library10.1248/bpb.31.1496
650.
Taft RA, Denegre JM, Pendola FL, Eppig JJ. Identification of genes encoding mouse oocyte secretory and transmembrane proteins by a signal sequence trap. Biol. Reprod. 2002;67:953-960.
Not in our library10.1095/biolreprod.102.005546
651.
Chen CS, Bach G, Pagano RE. Abnormal transport along the lysosomal pathway in mucolipidosis, type IV disease. Proc. Natl Acad. Sci. USA. 1998;95:6373-6378.
Not in our library10.1073/pnas.95.11.6373
652.
Song Y, Dayalu R, Matthews SA, Scharenberg AM. TRPML cation channels regulate the specialized lysosomal compartment of vertebrate B-lymphocytes. Eur. J. Cell Biol. 2006;85:1253-1264.
Not in our library10.1016/j.ejcb.2006.08.004
653.
Grimm C, et al. A helix-breaking mutation in TRPML3 leads to constitutive activity underlying deafness in the varitint-waddler mouse. Proc. Natl Acad. Sci. USA. 2007;104:19583-19588.
Not in our library10.1073/pnas.0709846104
654.
Nagata K, et al. The varitint-waddler (Va) deafness mutation in TRPML3 generates constitutive, inward rectifying currents and causes cell degeneration. Proc. Natl Acad. Sci. USA. 2008;105:353-358.
Not in our library10.1073/pnas.0707963105
655.
Structural basis of TRPC4 regulation by calmodulin and pharmacological agents · 2020
Not checked
656.
Structural basis for human TRPC5 channel inhibition by two distinct inhibitors · 2021
Not checked
657.
Kwon DH, et al. Heat-dependent opening of TRPV1 in the presence of capsaicin. Nat. Struct. Mol. Biol. 2021;28:554-563.
Not in our library10.1038/s41594-021-00616-3
658.
Molecular mechanism of TRPV2 channel modulation by cannabidiol · 2019
No notice
659.
Shimada H, et al. The structure of lipid nanodisc-reconstituted TRPV3 reveals the gating mechanism. Nat. Struct. Mol. Biol. 2020;27:645-652.
Not in our library10.1038/s41594-020-0439-z
660.
Inada H, Procko E, Sotomayor M, Gaudet R. Structural and biochemical consequences of disease-causing mutations in the ankyrin repeat domain of the human TRPV4 channel. Biochemistry. 2012;51:6195-6206.
Not in our library10.1021/bi300279b
661.
Fluck EC, Yazici AT, Rohacs T, Moiseenkova-Bell VY. Structural basis of TRPV5 regulation by physiological and pathophysiological modulators. Cell Rep. 2022;39:110737.
Not in our library10.1016/j.celrep.2022.110737
662.
McGoldrick LL, et al. Opening of the human epithelial calcium channel TRPV6. Nature. 2018;553:233-237.
Not in our library10.1038/nature25182
663.
Suo Y, et al. Structural insights into electrophile irritant sensing by the human TRPA1 channel. Neuron. 2020;105:882-894.e885.
Not in our library10.1016/j.neuron.2019.11.023
664.
Zhao C, MacKinnon R. Structural and functional analyses of a GPCR-inhibited ion channel TRPM3. Neuron. 2023;111:81-91.e87.
Not in our library10.1016/j.neuron.2022.10.002
665.
Ruan Z, et al. Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition. Nat. Struct. Mol. Biol. 2021;28:604-613.
Not in our library10.1038/s41594-021-00607-4
666.
Duan J, et al. Structure of the mammalian TRPM7, a magnesium channel required during embryonic development. Proc. Natl Acad. Sci. USA. 2018;115:E8201-E8210.
Not in our library10.1073/pnas.1810719115
667.
Zhao C, et al. Structures of a mammalian TRPM8 in closed state. Nat. Commun. 2022;13:3113.
Not in our library10.1038/s41467-022-30919-y
668.
Gan, N. et al. Structural mechanism of allosteric activation of TRPML1 by PI(3,5)P(2) and rapamycin. Proc. Natl Acad. Sci. USA119, 10.1073/pnas.2120404119 (2022).
Not in our library10.1073/pnas.2120404119
669.
Viet KK, et al. Structure of the human TRPML2 Ion channel extracytosolic/lumenal domain. Structure. 2019;27:1246-1257.e1245.
Not in our library10.1016/j.str.2019.04.016
670.
Thapak P, Bishnoi M, Sharma SS. Tranilast, a transient receptor potential vanilloid 2 channel (TRPV2) inhibitor attenuates amyloid beta-induced cognitive impairment: possible mechanisms. Neuromol. Med. 2022;24:183-194.
Not in our library10.1007/s12017-021-08675-x
671.
Laragione T, Harris C, Gulko PS. Combination therapy of a TRPV2 agonist with a TNF inhibitor achieves sustained suppression of disease severity and reduced joint damage. Clin. Exp. Immunol. 2022;211:233-238.
Not in our library10.1093/cei/uxac124
672.
Zhang L, et al. Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function. Nat. Commun. 2022;13:7483.
Not in our library10.1038/s41467-022-35163-y
673.
Wang Y, et al. TRPV3 enhances skin keratinocyte proliferation through EGFR-dependent signaling pathways. Cell Biol. Toxicol. 2021;37:313-330.
Not in our library10.1007/s10565-020-09536-2
674.
Su W, et al. TRPV3: structure, diseases and modulators. Molecules. 2023;28:774.
Not in our library10.3390/molecules28020774
675.
Lawhorn BG, Brnardic EJ, Behm DJ. Recent advances in TRPV4 agonists and antagonists. Bioorg. Med. Chem. Lett. 2020;30:127022.
Not in our library10.1016/j.bmcl.2020.127022
676.
Xing Y, et al. Stimulating TRPM7 suppresses cancer cell proliferation and metastasis by inhibiting autophagy. Cancer Lett. 2022;525:179-197.
Not in our library10.1016/j.canlet.2021.10.043
677.
Cabanas H, et al. Potential therapeutic benefit of low dose naltrexone in myalgic encephalomyelitis/chronic fatigue syndrome: role of transient receptor potential melastatin 3 ion channels in pathophysiology and treatment. Front. Immunol. 2021;12:687806.
Not in our library10.3389/fimmu.2021.687806
678.
Jiang LH, Gamper N, Beech DJ. Properties and therapeutic potential of transient receptor potential channels with putative roles in adversity: focus on TRPC5, TRPM2 and TRPA1. Curr. Drug Targets. 2011;12:724-736.
Not in our library10.2174/138945011795378568
679.
Lu M, et al. A Selective TRPC3 inhibitor Pyr3 attenuates myocardial ischemia/reperfusion injury in mice. Curr. Med. Sci. 2020;40:1107-1113.
Not in our library10.1007/s11596-020-2293-y
680.
Nagib MM, et al. Inhibition of TRPC3 channels by a novel pyrazole compound confers antiseizure effects. Epilepsia. 2022;63:1003-1015.
Not in our library10.1111/epi.17190
681.
Doleschal B, et al. TRPC3 contributes to regulation of cardiac contractility and arrhythmogenesis by dynamic interaction with NCX1. Cardiovasc. Res. 2015;106:163-173.
Not in our library10.1093/cvr/cvv022
682.
Zernov N, et al. New positive TRPC6 modulator penetrates blood-brain barrier, eliminates synaptic deficiency and restores memory deficit in 5xFAD mice. Int. J. Mol. Sci. 2022;23:13552.
Not in our library10.3390/ijms232113552
683.
Pu Y, et al. TRPC6 ameliorates renal ischemic reperfusion injury by inducing Zn(2+) influx and activating autophagy to resist necrosis. Ann. Transl. Med. 2022;10:249.
Not in our library10.21037/atm-21-5837
684.
Ding M, et al. Pyrazolo[1,5-a]pyrimidine TRPC6 antagonists for the treatment of gastric cancer. Cancer Lett. 2018;432:47-55.
Not in our library10.1016/j.canlet.2018.05.041
685.
Morelli MB, et al. Transient receptor potential mucolipin-1 channels in glioblastoma: role in patient’s survival. Cancers. 2019;11:525.
Not in our library10.3390/cancers11040525
686.
Xia Z, et al. ML-SA1, a selective TRPML agonist, inhibits DENV2 and ZIKV by promoting lysosomal acidification and protease activity. Antivir. Res. 2020;182:104922.
Not in our library10.1016/j.antiviral.2020.104922
687.
Kriegler K, Leser C, Mayer P, Bracher F. Effective chiral pool synthesis of both enantiomers of the TRPML inhibitor trans-ML-SI3. Arch. Pharm. 2022;355:e2100362.
Not in our library10.1002/ardp.202100362
688.
Brown DC, Agnello K, Iadarola MJ. Intrathecal resiniferatoxin in a dog model: efficacy in bone cancer pain. Pain. 2015;156:1018-1024.
Not in our library10.1097/j.pain.0000000000000115
689.
Peppin JF, et al. Tolerability of NGX-4010, a capsaicin 8% patch for peripheral neuropathic pain. J. Pain Res. 2011;4:385-392.
Not in our library10.2147/jpr.s22954
690.
Inoue M, Fujita T, Goto M. & Kumamoto, E. Presynaptic enhancement by eugenol of spontaneous excitatory transmission in rat spinal substantia gelatinosa neurons is mediated by transient receptor potential A1 channels. Neuroscience. 2012;210:403-415.
Not in our library10.1016/j.neuroscience.2012.02.040
691.
Brown DC. Resiniferatoxin: the evolution of the “molecular scalpel” for chronic pain relief. Pharmaceuticals. 2016;9:47.
Not in our library10.3390/ph9030047
692.
Manitpisitkul P, et al. A multiple-dose double-blind randomized study to evaluate the safety, pharmacokinetics, pharmacodynamics and analgesic efficacy of the TRPV1 antagonist JNJ-39439335 (mavatrep). Scand. J. Pain. 2018;18:151-164.
Not in our library10.1515/sjpain-2017-0184
693.
NEO6860, modality-selective TRPV1 antagonist: a randomized, controlled, proof-of-concept trial in patients with osteoarthritis knee pain · 2018
Not checked
694.
Khalid S, et al. Transient receptor potential vanilloid 1 (TRPV1) antagonism in patients with refractory chronic cough: a double-blind randomized controlled trial. J. Allergy Clin. Immunol. 2014;134:56-62.
Not in our library10.1016/j.jaci.2014.01.038
695.
Round P, Priestley A, Robinson J. An investigation of the safety and pharmacokinetics of the novel TRPV1 antagonist XEN-D0501 in healthy subjects. Br. J. Clin. Pharm. 2011;72:921-931.
Not in our library10.1111/j.1365-2125.2011.04040.x
696.
Privitera R, Anand P. Capsaicin 8% patch Qutenza and other current treatments for neuropathic pain in chemotherapy-induced peripheral neuropathy (CIPN). Curr. Opin. Support Palliat. Care. 2021;15:125-131.
Not in our library10.1097/spc.0000000000000545
697.
Lee YW, et al. Efficacy and safety of PAC-14028 cream - a novel, topical, nonsteroidal, selective TRPV1 antagonist in patients with mild-to-moderate atopic dermatitis: a phase IIb randomized trial. Br. J. Dermatol. 2019;180:1030-1038.
Not in our library10.1111/bjd.17455
698.
Borbiro I, et al. Activation of transient receptor potential vanilloid-3 inhibits human hair growth. J. Invest. Dermatol. 2011;131:1605-1614.
Not in our library10.1038/jid.2011.122
699.
Othman AA, Nothaft W, Awni WM, Dutta S. Pharmacokinetics of the TRPV1 antagonist ABT-102 in healthy human volunteers: population analysis of data from 3 phase 1 trials. J. Clin. Pharm. 2012;52:1028-1041.
Not in our library10.1177/0091270011407497
700.
Othman AA, Nothaft W, Awni WM, Dutta S. Effects of the TRPV1 antagonist ABT-102 on body temperature in healthy volunteers: pharmacokinetic/ pharmacodynamic analysis of three phase 1 trials. Br. J. Clin. Pharm. 2013;75:1029-1040.
Not in our library10.1111/j.1365-2125.2012.04405.x
701.
Moreno-Montanes J, Bleau AM, Jimenez AI. Tivanisiran, a novel siRNA for the treatment of dry eye disease. Expert Opin. Investig. Drugs. 2018;27:421-426.
Not in our library10.1080/13543784.2018.1457647
702.
Heber S, et al. TRPV1 antagonist BCTC inhibits pH 6.0-induced pain in human skin. Pain. 2020;161:1532-1541.
Not in our library10.1097/j.pain.0000000000001848
703.
Abdulqawi R, et al. P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2015;385:1198-1205.
Not in our library10.1016/s0140-6736(14)61255-1
704.
Kuebler WM, Jordt SE, Liedtke WB. Urgent reconsideration of lung edema as a preventable outcome in COVID-19: inhibition of TRPV4 represents a promising and feasible approach. Am. J. Physiol. Lung Cell Mol. Physiol. 2020;318:L1239-L1243.
Not in our library10.1152/ajplung.00161.2020
705.
Klein AH, Carstens MI, Carstens E. Eugenol and carvacrol induce temporally desensitizing patterns of oral irritation and enhance innocuous warmth and noxious heat sensation on the tongue. Pain. 2013;154:2078-2087.
Not in our library10.1016/j.pain.2013.06.025
706.
Kim HO, Jin Cheol K. Yu Gyeong, K. & In Suk, K. Itching caused by TRPV3 (transient receptor potential vanilloid-3) activator application to skin of burn patients. Medicina (Kaunas). 2020;56:560.
Not in our library10.3390/medicina56110560
707.
Duchatelet S, et al. A new TRPV3 missense mutation in a patient with Olmsted syndrome and erythromelalgia. JAMA Dermatol. 2014;150:303-306.
Not in our library10.1001/jamadermatol.2013.8709
708.
Matsumura T, et al. A pilot study of tranilast for cardiomyopathy of muscular dystrophy. Intern. Med. 2018;57:311-318.
Not in our library10.2169/internalmedicine.8651-16
709.
Robbins, N. et al. Probenecid improves cardiac function in patients with heart failure with reduced ejection fraction in vivo and cardiomyocyte calcium sensitivity in vitro. J. Am. Heart Assoc. 7, 10.1161/JAHA.117.007148 (2018).
Not in our library10.1161/jaha.117.007148
710.
Chan P, et al. Translational and pharmacokinetic-pharmacodynamic application for the clinical development of GDC-0334, a novel TRPA1 inhibitor. Clin. Transl. Sci. 2021;14:1945-1954.
Not in our library10.1111/cts.13049
711.
Wetzels S, et al. Methylglyoxal-derived advanced glycation endproducts accumulate in multiple sclerosis lesions. Front. Immunol. 2019;10:855.
Not in our library10.3389/fimmu.2019.00855
712.
Dull MM, et al. Methylglyoxal causes pain and hyperalgesia in human through C-fiber activation. Pain. 2019;160:2497-2507.
Not in our library10.1097/j.pain.0000000000001644
713.
Gyamfi OA, et al. Analysis of TRPA1 antagonist, A-967079, in plasma using high-performance liquid chromatography tandem mass-spectrometry. J. Pharm. Anal. 2020;10:157-163.
Not in our library10.1016/j.jpha.2019.12.005
714.
Behringer M, Nowak S, Leyendecker J, Mester J. Effects of TRPV1 and TRPA1 activators on the cramp threshold frequency: a randomized, double-blind placebo-controlled trial. Eur. J. Appl. Physiol. 2017;117:1641-1647.
Not in our library10.1007/s00421-017-3653-6
715.
Kanezaki M, Terada K, Ebihara S. Effect of olfactory stimulation by L-menthol on laboratory-induced dyspnea in COPD. Chest. 2020;157:1455-1465.
Not in our library10.1016/j.chest.2019.12.028
716.
Colvin LA, et al. From bench to bedside: a case of rapid reversal of bortezomib-induced neuropathic pain by the TRPM8 activator, menthol. J. Clin. Oncol. 2008;26:4519-4520.
Not in our library10.1200/jco.2008.18.5017
717.
Cool and menthol receptor TRPM8 in human urinary bladder disorders and clinical correlations · 2006
No notice
718.
Weyer AD, Lehto SG. Development of TRPM8 antagonists to treat chronic pain and migraine. Pharmaceuticals. 2017;10:37.
Not in our library10.3390/ph10020037
719.
Horne DB, et al. Discovery of TRPM8 Antagonist (S)-6-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinic Acid (AMG 333), a Clinical Candidate for the Treatment of Migraine. J. Med. Chem. 2018;61:8186-8201.
Not in our library10.1021/acs.jmedchem.8b00518
720.
Amato A, et al. TRPM8 channel activation reduces the spontaneous contractions in human distal colon. Int. J. Mol. Sci. 2020;21:5403.
Not in our library10.3390/ijms21155403
721.
Sugino S, et al. Association between the cool temperature-dependent suppression of colonic peristalsis and transient receptor potential melastatin 8 activation in both a randomized clinical trial and an animal model. J. Neurogastroenterol. Motil. 2022;28:693-705.
Not in our library10.5056/jnm21198
722.
A novel TRPM8 agonist relieves dry eye discomfort · 2017
Not checked
723.
Xu C, et al. Association of the putative susceptibility gene, transient receptor potential protein melastatin type 2, with bipolar disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006;141B:36-43.
Not in our library10.1002/ajmg.b.30239
724.
Dyment DA, et al. De novo substitutions of TRPM3 cause intellectual disability and epilepsy. Eur. J. Hum. Genet. 2019;27:1611-1618.
Not in our library10.1038/s41431-019-0462-x
725.
Cabanas H, Muraki K, Staines D, Marshall-Gradisnik S. Naltrexone restores impaired transient receptor potential melastatin 3 ion channel function in natural killer cells from myalgic encephalomyelitis/chronic fatigue syndrome patients. Front. Immunol. 2019;10:2545.
Not in our library10.3389/fimmu.2019.02545
726.
Norton N, et al. Association of genetic variants at TRPC6 with chemotherapy-related heart failure. Front. Cardiovasc. Med. 2020;7:142.
Not in our library10.3389/fcvm.2020.00142

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