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Natural Plants Compounds as Modulators of Epithelial-to-Mesenchymal Transition

Lorena Avila-Carrasco, Pedro Majano, José Antonio Sánchez-Toméro and 4 more

Frontiers in Pharmacology · 2019 · Review · CC BY

doi:10.3389/fphar.2019.00715

Abstract

Epithelial to mesenchymal transition (EMT) is a self-regulated physiological process required for tissue repair that in non-controled conditions may lead to fibrosis, angiogenesis, loss of normal organ function or cancer. Although several molecular pathways involved in EMT regulation has been described, this process does not have any specific treatment. This article introduces a systematic review of effective natural plant compounds and their extract that modulates the pathological EMT or its deleterious effects through acting on different cellular signal transduction pathways both in vivo and in vitro. Thereby, cryptotanshinone, resveratrol, oxymatrine, ligustrazine, osthole, codonolactone, betanin, tannic acid, gentiopicroside, curcumin, genistein, paeoniflorin, gambogic acid and cinnamomum cassia extracts, inhibit EMT acting on TGF-β/smads signaling pathway. Gedunin, carnosol, celastrol, black rice anthocyanins, duchesnea indica, cordycepin and celastrus orbiculatus extract downregulate vimectin, fibronectin, and N-cadherin. Sulforaphane, luteolin, celastrol, curcumin, arctigenin inhibit β- catenin signaling pathway. Salvianolic acid-A and plumbagin block oxidative stress, while, honokiol, gallic acid, piperlongumine, brusatol and paeoniflorin inhibit EMT transcription factors such as SNAIL, TWIST and ZEB. Plectranthoic acid, resveratrol, genistein, baicalin, polyphyllin I, cairicoside E, luteolin, berberine, nimbolide, curcumin, withaferin-A, jatrophone, ginsenoside-Rb1, honokiol, parthenolide, phoyunnanin-E, epicatechin-3-gallate, gigantol, eupatolide, baicalin and baicalein and nitidine chloride inhibit EMT acting on other signaling pathways (SIRT1, p38 MAPK, NFAT1, SMAD, IL-6, STAT3, AQP5, notch 1, PI3K/Akt, Wnt/β- catenin, NF-kB, FAK/AKT, Hh). Despite the huge amount of preclinical data regarding EMT modulation by plants natural compounds, clinical translation is poor. Additionally, this review highlights some relevant examples of clinical trials using natural plant compound to modulate EMT and its deleterious effects. In overall, this opens up new therapeutic alternatives in cancer, inflammatory and fibrosing diseases through the control of EMT process.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 22, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Epithelial-to-mesenchymal transition (EMT) is a tightly regulated physiological process implicated in tissue repair and in embryogenesis. During EMT, epithelial cells undergo multiple morphologic, biochemical and genetic rearranges that gradually enable them to acquire a mesenchymal phenotype.

We could consider two types of EMT, a physiological and a pathological EMT. The main characteristic of the physiological EMT is its ability to self-regulate, and it is related to embryonic development, organ formation, wound healing and tissue regeneration. In contrast, pathological EMT usually accompanies diseases and does not self-regulate. In this last case, EMT is an irreversible process and contributes to the failure of diseased organs, which justifies the scientific investment into controlling such a process. Pathological EMT is present in many inflammatory and immunological diseases and leads to tissue fibrosis, angiogenesis, loss of organ function, cancer progression and metastasis.

Although the involvement of EMT in some organ fibrosis, such as of the kidney, is controversial, more evidence about the role of pathological EMT has been reported in other organ fibrosis including that of the lung, the peritoneum and the heart, as well as in cancer progression.

EMT starts with the dissociation of intercellular junctions and the loss of microvilli and apical-basal polarity, followed bythe acquirement of a front to back polarity and an increased migratory capacity. In the latest stages of EMT, the cell increases its capacity to degrade the basement membrane and to invade the fibrotic compact zone. Cells that have undergone a mesenchymal conversion possess increased capacity to synthesize extracellular matrix (ECM) components as well as a large number of pro-inflammatory, fibrotic and angiogenic factors, including vascular endothelial growth factor (VEGF), inducing angiogenesis.

To control the pathological EMT, many drugs and molecular measures with variable results have been tested, but this therapeutic target remains a challenge for current medicine. Targeting EMT can be a really interesting weapon for the treatment of many fibroproliferative, cardiovascular and autoimmune diseases, and other pathologies such as cancer.

Molecular Mechanisms Involved in EMT Regulation

Mechanistically, EMT is a complex, dynamic and progressive process that affects the cellular architecture and requires a deep molecular reprogramming with new biochemical instructions. The EMT process results from an integration of diverse signals transduction pathways and multiple triggering factors, including inflammatory cytokines, advanced glycation end products (AGEs), oxidative stress and hypoxia, transforming growth factor-β1 (TGF-β1)/Smads pathway, tyrosine kinase receptors, delta-like jagged Notch, caveolin (cav)-1, angiotensin receptor and integrins ( Figure 1 ). A master molecule in the EMT induction appears to be TGF-β, nontheless the number of molecules and routes implicated in EMT is still growing. The binding of the TGF-β1 to its “primary receptor” (receptor type II) permits the recruitment, trans-phosphorylation, and activation of the “signaling receptor” (receptor type I), also known as activin receptor-like kinase 5 (ALK5). Then, ALK5 is able to exert its activity to phosphorylate Smad2 and Smad3. These receptor-activated Smads (R-Smads) form heterodimers with Smad4, a common mediator of the Smad pathways. These resulting Smad heterocomplexes are translocated into the nucleus, where they bind directly to DNA to regulate the transcription of target genes. Another group of Smads, known as “inhibitory Smads” (e.g. Smad7), control TGF-β1-induced Smad signaling by preventing the phosphorylation and/or nuclear translocation of R-Smads and inducing receptor heterocomplex degradation.

Among the R-Smads, Smad-3 appears to be the key mediator in TGF-β-induced fibrosis and EMT. In this context, it has been shown that the inhibition of Smad3 activation and nuclear translocation blocks EMT and tissue fibrosis. Translocated Smad-3 into the nucleus controls TGF-β-responsive genes encoding integrin-linked kinase (ILK). The activation of ILK by β1-integrins lead to protein kinase B (Akt) and glycogen synthase kinase-3 (GSK-3)-beta phosphorylation.

Phosphorylated-Akt activates nuclear factor-κB (NF-κB), which induces the expression of Smad-7 emphasizing the self-regulated nature of the whole EMT process ( Figure 1 ). On the other hand, phosphorylated-GSK-3β is inactive, what subsequently stabilizes β-catenin, released from the adherens junction, and activator protein-1 (AP-1). When stabilized, β-catenin per se may induce EMT, while AP-1 activates matrix metalloproteinase (MMP)-9 expression inducing the invasion of the ECM.

The Smad-dependent pathways are not the only ways by which TGF-β1 regulate the EMT process. Smad-independent pathways also participate in TGF-β1-induced EMT. These pathways can either potentiate or modulate the outcome of TGF-β1-induced Smad signaling. Amain Smad-independent signalling pathway activated by TGF-β1/receptor I interaction is the Ras homolog gene family member A (RhoA)/rho-associated, coiled-coil-containing protein kinase 1 (ROCK1) pathway. This route regulates cytoskeleton remodelling and cellular migration and invasion. RhoA also induces the expression of alpha smooth muscle actin (α-SMA) in a ROCK-independent manner.

TGF-β1 also activates the H-Ras/Raf/extracellular signal-regulated kinase (ERK) pathway, necessary for the induction of transcription factor SNAIL1 expression and of EMT, cooperating with fibroblast growth factor (FGF), a potent inducer of the mentioned route. SNAIL1 regulates EMT by inhibiting E-cadherin and by inducing growth arrest and survival, which confer advantage to migrating transdifferentiated cells.

The Notch signalling pathway is another EMT-activating route, able to induce SNAIL1 and SNAIL2 expression, down-regulating E-cadherin. The TGFβ/Smads classical pathway is able to cooperate with different signaling routes. The association of the tumor necrosis factor (TNF)-receptor associated factor 6 (TRAF6) with the TGFβ receptor heterocomplex activates TGFβ-activated kinase 1 (TAK1) and, as a result, p38 and c-Jun N-terminal kinase (JNK). Other stimuli such as advanced glycation endproducts AGEs are able to induce EMT by acting on specific cellular receptors (RAGE). Reactive oxygen species (ROS) can also directly activate TGF-β, the production of ECM, MMP and RAS ( Figure 1 ). Finally, the activation of mammalian target of rapamycin (mTOR) induces inflammatory processes mediated by T helper 17 (Th17) cells, TH17, which in turn also triggers EMT.

Active Substances Derived from Plants Capable of Regulating EMT

Natural plant compounds (NPCs) have been used for many years as a source of therapeutic substances and a structural basis for drug elaboration. Unique architectures that can lead to novel therapeutic agents are provided by nature (; Song et al., 2014; ).

NPCs are bioactive elements isolated from natural sources (plants) that can regulate the EMT through anti-inflammatory, anti-fibrotic or antioxidant mechanisms. Bioactive natural components are presented in this review which delves into their mechanisms of action against EMT ( Table 1 ).

Arctigenin (ARC). It has been proposed as an anti-inflammatory and anti-cancer substance. In human lung cancer cells, ARC has been shown to inhibit TGF-β-induced phosphorylation, smad2/3 transcriptional activity, snail and N-cadherin expression, by contrast increasing the expression of E-cadherin in dose and time dependent manners. It blocks ERK-phosphorylation and β-catenin transcriptional activity. Through these mechanisms, ARC represses TGF-β-induced EMT.

Baicalin and baicalein. These molecules significantly decreased the TGF-β1-mediated EMT, by reducing the Slug expression and NF-κB signaling pathway in mammary epithelial cells. Likewise, both molecules decremented growth and cell migration capacities of human breast cancer cells. In the same way, baicalin also inhibited SMADs 2 and 3 phosphorylation and suppressed migration and invasion in pancreatic cancer cells.

Berberine. It exhibits strong anti-cancer, anti-inflammatory, and anti-microbial effects. Kou et al. detected that berberine markedly upregulated E-cadherin and downregulated N-cadherin, fibronectin and vimentin expressions. Cadherin-bound β-catenin, which is required for cell adhesion, was also inhibited. The therapeutic espectrum of berberine also involved the downregulation of Snail, Slug and zinc finger E-box binding homeobox 1 (Zeb1) as well as the regulation of PI3K/Akt and retinoic acid receptor alpha and beta (RARα/RARβ) signaling, acting on the proliferation capacity of various cancer cells.

Betanin. It presents powerful anti-oxidative and anti-inflammatory activities. Studies from Sutariya and Brijesh showed that betanin reduces streptozotocin (STZ) fibrosis induced in diabetic nephropathy model, by modulating EMT associated markers such as of TGF-β, type IV collagen, α-SMA and E-cadherin expression. Therefore, betanin can efficiently suppress renal fibrosis in diabetic nephropathy and may slow down the advancing to end-stage renal disease by regulating TGF-β pathway.

Black rice anthocyanins (BRACs). These NPCs are extracted from the black rice, considered as a healthy food due to its effects on the liver and gastrointestinal tract. Anthocyanins happen to have potential beneficial effects such as antioxidant, anti-inflammatory, anti-cancerous and anti-metastatic effects. Zhou et al. observed that focal adhesion kinase (FAK) signaling pathway plays a function in the anti-metastatic properties of BRACs, decreasing the adhesion, migration and invasion of human HER-2-positive breast cancer cells in vitro. Likewise, these NPCs significantly modified the morphology of those cells from a mesenchymal to an epithelial phenotype. BRACs elevated the expression of E-cadherin and reduced the expression of fibronectin and vimentin.

Brusatol (BR). This NPC strongly inhibits pancreatic tumor action in vitro. Research sugests that BR could sensitize the current first-line chemotherapeutic agents to pancreatic cancer via inhibition of the EMT process. It has been proven that BR increased E-cadherin while decreasing vimentin protein expressions, and also reducing Twist mRNA expression.

Carnosol (CAR) is a naturally occurring phenolic diterpene located in several Mediterranean herbs and is a main component of rosemary (Rosmarinus officinalis L). It has been reported that the CAR anti-proliferative actions is preferentially directed towards cancer cells, as reported in both animal and in vitro models. Furthermore, CAR presented a favourable therapeutic option in glioblastoma cells. CAR could interfere with the diverse processes implicated in cancer resistance and aggressiveness, such as cancer stem cells (CSC) formation, proliferation and self-renewal. Fascinatingly, also diminished the influence of the cancer microenvironment by reducing the cytokine- induced EMT that underlies the possession of the mesenchymal phenotype. Likewise, CAR had the ability to reactivate the p53 functionality promoting CSC proliferation control and decreasing EMT was highlighted for the first time.

It also possesses anti-cancer effects on several tumor types. It has shown to promote apoptotic cell death through p53 functional reactivation and to control the TNF-α/TGF-β-induced EMT, counteracting the effects of the cytokine on EMT master regulator genes (Slug, Snail, Twist and ZEB1). It has also been demonstrated that CAR is able to modulate the activation of miR-200c, a key player in the EMT process. Finally, CAR increase the temozolomide anti-proliferative effects in vitro.

Cairicoside E (CE). It has been published that this compound down-regulates the Aquaporin-5 (AQP5) expression and suppressed the EMT process in colon-rectal cancer cells. Research suggested that TGF-β1 increased the expression of AQP5 and activated the EMT byincreasing the expressions of p-Smad2/3, while silence of AQP5 with CE blocked the levels of p-Smad2/3.

Celastrol. It is a pharmacologically active element that demonstrates significant therapeutic actions in chronic inflammatory, autoimmune, cancer, and neurodegenerative disorders. Recently, Divya et al. suggested that celastrol decreased the N‐cadherin, snail, slug, vimentin and β‐catenin expression in a Bleomycin‐induced lung fibrosis rat model. They, likewise, feature this anti-EMT effect to the inhibition of heat shock protein 90 inhibition. Other research established that celastrol suppresses inflammatory reactions, as well as regulates oncogenic proteins including β-catenin. Celastrol also decreases pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) serum concentrations, down-regulates cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS), N-cadherin, Vimentin and Snail expressions, inactivates NF-κB and upregulates E-cadherin.

Celastrus orbiculatus Thunb extract (COE). The extracts from the stems of this plant constitute 11 compounds. The ethyl acetate of COE constrains the proliferation, EMT (targeting VEGF, activating MAPK and inhibiting Akt signaling pathways), invasion and metastatic faculties of tumor cells. Moreover, COE is used in the antiinflammatory and analgesic handling of various diseases. In human gastric cancer AGS cells, it has been observed that Cofilin 1, Ncadherin, vimentin, MMP2 and MMP9 proteins expressions were significantly reduced by COE, whereas the Ecadherin expression was increased.

Cinnamomum cassia extracts (CCE). Fifteen compounds were isolated from the bark extract of C. cassia growing in China. These extracts were shown to diminish the TGF-β1-induced motility and invasive capacities of A549 and H1299 cells by inhibiting MMP-2 and urokinase-type plasminogen activator. Moreover, they impaired cell adhesion associated with collagen production. CCE also down-regulated vimentin and fibronectin and upregulated E-cadherin expressions.

Codonolactone (CLT). It inhibited the expression of acquired EMT’s mesenchymal markers such as N-cadherin and vimentin in a dose-dependent manner in in vivo and in vitro experiments in breast cancer. Likewise, it blocked the expression of transcription factors Snail, Slug, Twist-1 (TGF-β signaling) and the Runx2 phosphorylation.

Cordycepin. Its properties have been evaluated on a human oral squamous cell carcinoma xenograft model, through its administration in a regular, low-dose upregulated E-cadherin and downregulated N-cadherin protein expressions, inhibiting EMT.

Cryptotanshinone (CTS). It exhibits multiple pharmacological benefits, involving anti-cancer, anti-oxidative stress, and anti-cardiac fibrosis properties via downregulation of COX-2, NADPH oxidase 2 and 4 and MMP-2. The antifibrotic mechanism proposed for CTS is the inhibition of Smad2 phosphorylation. Although it did not inhibit Smads 3 and 4 or mitogen-activated protein kinase (MAPK) signals, the ECM accumulation was importantly reduced in a renal fibrosis model.

Curcumin. This NPC inhibit EMT in CoCl2-treated hepatocytes. This action might be due to its capacity to diminish TGF-β-R1 expression in these cells. This effect suggests a disruption on the downstream signal transduction transmitted by SMADs pathway. Moreover, it was found that SMADs2 and 3 phosphorylation was inhibited by curcumin, pointing its powerful action blocking upstream the EMT pathway signaling. Another mechanism by which curcumin inhibits these pathways is by suppressing the cav-1 phosphorylation, stabilizating β-catenin. Recently, it has been published that curcumin inhibits the superoxide dismutase-induced invasion and migration of pancreatic cancer cells by inhibiting the PI3K/Akt/NF-κB signaling pathway. Curcumin was not related to toxicity including high dose administration, in human clinical trials.

Jatrophone (JA). This diterpene shows a broad assortment of biological actions, counting antitumoral, cytotoxic, anti-inflammatory, anti-malarial and fungicidal properties. It has been demostrated that JA reduces mRNA expression of Slug, fibronectin and vimentin, but not ZEB1, and also exhibits an anti-proliferative and anti-migratory effect acting on Wnt/β-catenin signaling in triple-negative breast cancer.

Duchesnea extracts. Duchesnea chrysantha and Duchesnea indica belong to the Rosaceae family, and their extracts show a diversity of biological properties, involving anti-biotic, anti-oxidative, anti-inflammatory and some cytotoxic features. These extracts involve a range of chemical compounds such as triterpenes, triterpene glycodides, flavonoid glycodides and sterols. An in vivo research showed that tumor growth was importantly diminished in BALB/c nude mouse xenograft model orally treated with Duchesnea indica extracts (DIE). In the same study, DIE also inhibited highly metastatic cells by reducing the secretions of MMP‐2 and urokinase‐type plasminogen activator (uPA). It was also able to decrease the cell adhesion capacity, down-regulate the N-cadherin, fibronectin, and vimentin and increase the E-cadherin expression. Another protective mechanism related with DIE is its antioxidant action which can also modulate the EMT.

Epicatechin-3-gallate (ECG). It elicits several anti-oxidant and anti-inflammatory activities and is one of the four types of catechins mainly detected in green tea, together with epicatechin, epigallocatechin and epigallocatechin-3-gallate (EGCG). In human lung cancer cells, ECG also reverts the TGF-β1-induced EMT by upregulating epithelial markers (E-cadherin) and downregulating mesenchymal markers (fibronectin). Moreover, it also phosphorylates FAK. Based on these facts, it has been recommended that ECG may be administered as an effective agent against TGF-β1-induced EMT.

Eupatolide. It shows anti-inflammatory, anti-proliferative and anti-migratory effects. It has also been suggested that eupatolide might be employed as an inhibitor of the TGF-β1 signaling pathway to suppress EMT. Moreover, eupatolide suppress TGF-β1-induced EMT via downregulation of Smad3 phosphorylation and decreasing the TGF-β type 1 receptor.

Gallic acid. In vivo experiments with this NPC diminished vascular calcification, cardiac hypertrophy, cardiac fibrosis and hypertension. Gallic acid also inhibited pathological changes in the lungs, such as pulmonary fibrosis. Moreover, it reduced the expression of fibrosis-related genes, including collagen types I and III, fibronectin, connective tissue growth factor (CTGF), and Smad3. In a mouse model, Garlic acid blocked the of EMT-related genes expression, such as N-cadherin, vimentin, Snail, and TWIST1.

Gambogic acid (GA). It has been proved in vitro that this compound reverses TGF-β1-mediated EMT and endothelial–mesenchymal transition (EndoMT) in human lung fibroblasts (HLF-1). It also prevents pulmonary fibrosis in vivo and attenuates the EMT by modulating the TGFβ1/Smad3 pathway.

Gedunin. It has been shown to have potential anti-cancer activity. Recent research suggests that gedunin inhibits EMT by reducing the expression of the mesenchymal markers N-Cadherin, Slug, Snail, Vimentin, Notch 1 and 2, and Zeb whereas increasing the E-cadherin expression.

Genistein (GEN). Soybeans and most soy products contain large amounts of isoflavones called soy phytoestrogens, and one of the most concentrated is the GEN. GEN is a phytoestrogen known for its chemopreventive effects in several types of cancers. It suppresses the EMT response induced by 17β-estradiol and two estrogens-like compounds, bisphenol-A and nonylphenol. Thus, it reduces the protein expressions of vimentin, cathepsin D, and MMP-2, increases E-cadherin expression and downregulates TGF-β.. In ovarian cancer derived cells, GEN inhibits the NF-κB and Akt signaling pathways, playing important roles in keeping the homeostatic balance between cell survival and apoptosis. It has been considered as a potencial antiangiogenic, antioxidant and anticancer agent.

Gentiopicroside (GPS). It has been proved that in bronchoalveolar cells isolated from fluids of lungs pulmonary fibrosis in a mouse model, GPS decreased the levels of proinflammatory cytokines, including TNF-α and IL-1β, and downregulated TGF-β1 and CTGF expression. In vitro, GPS inhibited the EMT of A549 cells stimulated by TGF-β1 to induce transdifferentiation at a dose-dependent manner.

Gigantol. It has been described to have anti-proliferative, anti-apoptosis and anti-metastatic properties. Recent publications suggest that gigantol considerably reduces lung cancer cells’ viability in a detached condition. It also shrinkages EMT biomarkers including N-cadherin, vimentin and Slug, leading to a meaningful suppression of AKT, ERK, and cav-1 survival pathways.

Ginsenoside. It has been registered in pharmacopeias for thousands of years due to its abundant content of saponins. One of the most extensively known saponins in the rhizome of ginseng is ginsenoside-Rb1. In vivo studies mention that Rb1 showed cardioprotective, hepatoprotective and anti-inflammatory effects. Likewise, it inhibits cell proliferation, angiogenesis and apoptosis stimulation. A recent publication shows that ginsenoside-Rb1, especially its metabolite compound K, particularly sensitize cancer stem/tumor-initiating cells from ovarian cancer to chemotherapy through the inhibition of Wnt/β-catenin signaling and EMT.

Honokiol (HNK). It has been associated with anti-tumor and more recently anti-EMT effects. For instance, in breast cancer cells, Avtanski et al. demonstrated that HNK inhibited signal transducer and activator of transcription 3 (Stat3) phosphorylation and transactivation activity and Zeb1 expression, which plays a main role in EMT initiation. More than that, HNK induces an increase in E‐cadherin. Additionally, it has been published that HNK inhibits EMT motility and migration by targeting cellular FLICE (FADD-like, IL-1β-converting enzyme)-inhibitory protein (c-FLIP), considered a master anti-apoptotic regulator in non-small-cell lung cancer.

Isoviolanthin extracted from the leaves of Dendrobium officinale inhibits transforming growth factor (TGF)-β1-induced EMT in hepatocellular carcinoma (HCC) cells, it is the most significant constituents responsible for the antimetastasis activity of Dendrobium officinale. Recent publications report that isoviolanthin targets the TGF-β/Smad and PI3K/Akt/mTOR pathways to repress TGF-β1-induced EMT phenotypes in HepG2 and Bel-7402 HCC cells. Furthermore, these results confirm that isoviolanthin could be a favorable natural compound with low toxicity for the treatment of metastatic HCC by affecting TGF-β1-induced EMT.

Ligustrazine (LIG). In a model of renal tubulointerstitial fibrosis, LIG showed pleyotropic effects acting at different levels of EMT induction. LIG ​​decreased the mRNA expression of TGF-β1, CTGF, monocyte chemoattractant protein-1 (MCP-1) and osteopontin, and, subsequently cytokeratin-18 expression decreased. Mainly, this molecule increased the expression of the natural inhibitors of TGF-β, hepatocyte growth factor (HGF) and bone morphogenetic protein (BMP)-7.

Luteolin. Many biological properties of luteolin, such as anti-inflammation, anti-allergy, antioxidant, anticancer and anti-microbial effects have been described. In breast cancer (in vivo and in vitro), epithelial markers such as E-cadherin and claudin were upregulated in response to luteolin while mesenchymal markers N-cadherin, vimentin, Snail and Slug were downregulated at dose-dependent manner. Researchers found that these positive effects of luteolin were extinguished by overexpression of β-catenin, indicating that downregulation of β-catenin expression may mediate the inhibitory effects of luteolin on EMT. Same results were found by Zang et al., who described that other pathways such as Notch1 were also blocked by Luteolin.

Nimbolide. Recent studies indicate that treatment with this agent reduces the expression of Notch-2, N-cadherin, vimentin and transcription factors (Snail, Slug and Zeb) in pancreatic cancer cell lines. Moreover, nimbolide treatment likewise increased the expression of E-cadherin. Additionally, the generation of ROS mediated by nimbolide reduces cell proliferation (via reduction of PI3K/AKT/mTOR and ERK signaling) and metastasis (via reduction of EMT, invasion, migration and colony forming abilities) through mitochondrial-mediated apoptotis but not through autophagy.

Nitidine chloride (NC). It has been shown to exert antimalarial, anti-inflammatory, anti-angiogenic, and anticancer effects. Likewise, NC inhibited the cellular migration and invasion through suppression of FAK-associated pathway in breast cancer metastasis. It has also been recently proposed that inactivation of Hedgehog signaling pathway by NC led to significantly decreased Smo and Gli expressions, targeting breast cancer metastasis. Thus, NC could be suitable for the prevention and treatment of breast cancer through dual-blocking EMT.

Osthole. It inhibits growth and metastasis in many types of cancer. It has also been proposed that osthole mediated the EMT by downregulating Snail and cell-invasive capability, suppressing the TGF-β/Akt/MAPK pathway.

Oxymatrine (OM). Many studies have proved that OM shows an anti-fibrotic effect on liver, pulmonary, myocardial and skin scar tissue fibrosis through inhibition of the TGF-β1/Smad signaling cascade. Thus, Liu et al. demonstrated that OM inhibits the high glucose-induced renal tubular EMT, decreasing the degradation of SnoN mediated by a E3 ubiquitin ligase (Arkadia), and that promotes EMT amplifying TGF-β signalling through Smad7 degradation.

Paeoniflorin (PF). Pharmacological reports have shown that it prevents pulmonary EMT inhibiting collagen type-I synthesis, downregulating Snail and Slug and up-regulatining Smad7. These properties provide PF a protective action against cellular transdifferentiation in a lung bleomycin-induced fibrosis model in mice. It has also been demonstrated that PF down-regulates TGF-β1, maintains BMP-7 expression and inhibits Smad2/3 in a renal fibrosis model. Likewise, PF blocks EMT in gliblastoma cells, and reduces TGF-β, Snail, N-cadherin, Vimentin and MMP2/9 expression at doses depended manner.

Paeonol. It is an aspirin analogue extracted from numerous medicinal herbs including Moutan Cortex, Cynanchi paniculati Radix et rhizome, and Paeoniae Radix rubra. Paeonol was discovered to present comprehensive pharmacological activities, such as antioxidant, anti-inflammatory, anti-aging, and anti-cancer activities. Another author reported that paeonol influenced antioxidative stress activity in endothelial cells by controlling the expressions of Sirt1. It has been described, too, that paeonol ameliorated colitis related colorectal cancer by suppressing cytokine-induced EMT and NF-jB activation. Likewise, suggested that paeonol inactivated ERK and TGF-beta1/Smad pathway leading to regulation of relevant EMT markers. These results suggest that paeonol might be developed as a potential agent used for oxidative stress injury and EMT in premalignant lesion.

Parthenolide (PTL). It has been conventionally used for the treatment of headaches and arthritis. Recent analyses suggest that PTL is a valuable antitumor and anti-inflammatory NPC, and it was evaluated in clinical studies for leukemia and neurological tumors. These effects of PTL in tumors and inflammatory diseases primarily happen via the inhibition of NF-κB signaling pathways. Current studies have established that PTL inhibit pulmonary fibrosis increasing E-Cadherin and decreasing vimentin NF-κB and Snail expression in TGF-β1-treated primary lung epithelial cells.

Plectranthoic acid (PA). It induces cell cycle arrest and apoptosis in prostate cancer cells. Recent research demonstrates that PA-exposed cells exhert considerably reduced cell migration capacity and a reversal of TGF-β induced EMT, representing the potential effectiveness of PA against prostate cancer, throughout regulation of Rac1 signaling.

Phoyunnanin-E. Recent publications suggest that Phoyunnanin E decreased the E-cadherin to N-cadherin switch and reduced upregulation of mesenchymal markers such as vimentin and snail, as well as slug expression. Phoyunnanin-E has also been shown to inhibit migration and growth and promote EMT suppression, reduce migratory-associated integrins αv and β3, and suppress FAK/AKT cascade, which subsequently suppressed downstream migratory proteins in lung cancer cells.

Piperlongumine (PL). It has been identified as a powerful cytotoxic element highly selective to cancer cells. PL has also been demonstrated to accurately suppress bladder cancer development both in vitro and in vivo, via inhibition of EMT. Thereby, the expression of EMT-associated factors such as Slug, β-catenin, zeb1, N-Cadherin, Claudin-1, and zonula occludens-1 (ZO-1) were importantly decreased.

Plumbagin (PLB). It presents anti-inflammatory, anti-atherosclerotic, anti-bacterial, anti-fungal, and anti-cancer properties shown both in vitro and in vivo. The anti-EMT effect of the PLB can be vinculated by its ability to adjust epithelial adherent junctions in human tongue squamous carcinoma cells. PLB also boosted the expression of E-cadherin and decreased of N-cadherin in these cells. Moreover, it reduced the expression of Snail, Slug, TCF-8/zeb1, β-catenin, and vimentin, whereas increased the expression of claudin-1 and ZO-1. Notably, PLB inhibited the translocation of nuclear factor erythroid 2-related factor (Nrf2) from cytosol to nucleus, causing an inhibition in the expression of downstream targets.

Polyphyllin (PP) I. It has been broadly investigated for its anti-inflammatory and anti-cancer activities. PPI exhibited inhibitory effect on various cancer types, involving hepatocarcinoma, non-small cell lung cancer, osteosarcoma, chronic myeloid leukemia, ovarian cancer and glioma cells. Recent investigation described that PPI was capable to reverse EMT in osteosarcoma cells. Likewise, ZH-2, a compound derived from PP VII, exherts anti-chemoresistance properties through inhibiting EMT. In anacquired-erlotinib-resistant cell line, PPI inhibited IL-6/STAT3 signaling pathways and stimulates epithelial marker expression, reversing EMT. Significantly, PPI exhibited an inhibitory effect on epidermal growth factor (EGF) receptor tyrosine kinase inhibitors, which has a mutagenic and pro-EMT action in non-small cell lung cancer.

Resveratrol (RSV). RSV has been published to have many pharmacological activities, such as protection against coronary heart disease, anti-inflammatory properties, chemo-prevention of cancer, anti-oxidative and antiasthmatic effects. It can be obtained from grapes, wine, mulberries and peanuts. It also reduced renal injury and renal fibrosis by suppressing the inflammatory activity and by inhibiting lipid peroxidation (; De Jesus et al., 2007). The inhibitory effect of RSV on EMT has been demostrated in prostate, ovarian,breast and pancreatic cancer. Recent papers show that RSV inhibits EMT in renal tubular cells by antagonizing the hedgehog signaling pathway. Likewise, Gao et al. suggested that RSV prevents from cancer cell invasion and metastasis in vitro by inhibiting the hedgehog pathway and EMT. In this context, RSV downregulates the EMT-inducting transcription factor (including Zeb-1, Slug and Snail) to reduce migration and invasion in pancreatic cancer cells. EGF is a well-known EMT-inducer in human breast cancer cells. RSV blocks EGF-induced EMT by repressing EGF-induced ERK. Furthermore, it is known that renal injury has a close relationship with the development of renal fibrosis and, during this process, tubular epithelial cells in the kidney undergo EMT via upregulating β-catenin/lymphoid enhancer-binding factor 1 (LEF1) signaling and MMP-7. A current study using RSV showed that this product attenuated renal injury and fibrosis through inhibition of EMT. Authors suggested that this inhibition was due to the fact that RSV up-regulated sirtuin 1 (SIRT1), which deacetylated Smad4 and inhibited the expression of MMP-7. Other findings also demonstrate that RSV modulates EMT by suppressing MMP-2 and MMP-9 via MAPK and NF-κb signals in lung cancer invasion and metastatic cells. Moreover, RSV has been recently shown to limit EMT by controlling gene expression at post-transcriptional level (it favors the epithelial-type alternative splicing of pre-mRNAs that encode crucial factors in adhesion and migration, and enhances the expression of some RNA-Binding Proteins). It also inhibits TGF-β1-induced EMT and suppresses lung cancer invasion and metastasis

Salvianolic acid A (SAA). It exerts many pharmacological actions, such as myocardial protection, anti-thrombosis, anti-fibrosis, and the prevention of diabetes complications. Investigations have revealed that SAA treatment effectively decreased lung parenchymal injury and collagen deposition and diminished the apoptosis and lung fibrosis on a pulmonary arterial hypertension rat model. Furthermore, in pulmonary tissue, SAA treatment upregulated BMP type II receptor (BMPRII) expression and augmented the Smad1/5 phosphorylation. Both molecules showed an anti-EMT effect. An anti-EndoMT capacity was also discovered in bleomycin-induced pulmonary fibrosis in mice, acting on Nrf2/HO-1 signaling pathway.

Sedum sarmentosum Bunge (SSBE). Pharmacological reports have shown that SSBE has significant antiinflammatory, anti-tumor and anti-angiogenic effects. Other authors demonstrated that SSBE has marked effects against renal fibrosis, down-regulating hedgehog signaling pathway (which promotes renal fibrogenesis fostering the formation of myofibroblasts from different cell types through an EMT process). SSBE also reduced the ECM accumulation and angiogenesis.

Sulforaphane. Numerous studies have observed the effects of sulforaphane in control of tumor generation or cancer progression, such as in lung, breast and prostate, and also digestive system neoplasms. Other authors demonstrated that reduced expression of the micro RNA miR-616-5p, transcriptionally induced by sulforaphane management, contributes to the suppression of EMT in non-small cell lung cancer and in lung cancer metastasis through the miR-616-5p/GSK3β/β-catenin signaling pathway.

Tannic acid (TA). This molecule acts upstairs in the EMT induction process, in lung epithelial cells. It reduces the expression of TGF-β and N-cadherin and decreases the SMADs 2 and 3 phosphorylation and the production of ECM (fibronectin and vimentin). Moreover, cell proliferation in G0/G1 phase and the mitogenic activity of protein kinase (ERK1/2, JNK1/2, and p38) also decrease.

Withaferin-A (WA). Pharmacological reports have shown anti-cancer effects in rodent experiments. Withanolide-D (witha-D) is an active element of WA that partially inhibits EMT acting on Wnt/β-catenin signaling and recovering E-Cadherin expression in a human pancreatic tumour cell line.

Alpha-Solanine. This NPC presents pharmacological activities involving anti-proliferation, anti-apoptosis and anti-angiogenesis. Alpha-solanine also reduced ERK and PI3K/Akt phosphorylation. Likewise, this component also reduces the expression of MMP-2/9 and vimentin and induces the expression of E-cadherin.

Potential Therapeutic Effects of Natural Plants Compounds

Currently, there is growing evidence for potential plant-derived compounds as inhibitors in several stages of tumourgenesis and inflammatory and fibrosis processes. In several clinical trials it has been demonstrated that NPCs have elicited anti‐aging, anti‐cancer and other health‐enhancing effects. A key target of the effects of NPCs may be in suppressing oxidative stress and the induction of 5′AMP-activated Kinase (AMPK), or suppression of the WNT/beta-catenin, PI3K/Akt/mTOR and RAS/MEK/ERK signaling pathways, among others, which results in cell death or prevents aging, diabetes, cardiovascular, cancer and other diseases.

One NPC is Berberine, which has been tested in a wide spectrum of clinical applications. Oral administration of berberine significantly reduced the familial adenomatous polyposis patients’ polyp size along with the inhibition of cyclin D1 expression in polyp samples. These statements suggest that berberine inhibits colon tumour formation through inhibition of Wnt/β-catenin signalling and might be a favorable drug for the prevention of colon cancer. Additionally, it has been described that Berberine shows an extensive array of pharmacological effects, being effective against gastroenteritis, abdominal pain and diarrhea, and having antimicrobial, antidiabetic and antiinflammatory properties. Another beneficial effect of berberine has been reported on the treatment of type II diabetes. This natural compound has an explicit potential as a drug in a wide spectrum of already defined clinical purposes. Numerous pharmacological reports have suggested the cardiovascular effects of berberine and B. vulgaris, such as preventing ischemia induced ventricular tachyarrhythmia, improving cardiac contractility and lowering peripheral vascular resistance and blood pressure.

Likewise, RSV is being examined in many clinical trials, on age-related disease, cancer, cardiovascular problems, chronic renal insufficiency and other disorders.

Clinical trials show that RSV has been shown to activate sirtuins and such activation is able to explain most of the beneficial properties of the mediterranean diet (MD). While observational studies and meta-analysis have demonstrated an antiageing effect of MD accompanied by a reduced risk of age-related pathologies, such as cardiovascular, metabolic and neurodegenerative diseases, as well as cancer.

Other studies that involved healthy volunteers established that RSV synchronized the carcinogen metabolizing enzyme cytochrome P450 and phase II detoxification enzymes, which repressed carcinogen metabolism and subsequently prevented carcinogenesis.

In the same way, Curcumin is being evaluated in numerous clinical trials for various disorders such as acute kidney injury, neurodegenerative diseases, cancer cardiovascular abnormalities, psychiatric disorders, osteoarthritis, type 2 diabetes mellitus, ulcerative colitis, rheumatoid arthritis, lupus nephritis, multiple sclerosis and other health problems. Its efficacy appears to be related to the induction of glutathione S-transferase enzymes, inhibition of prostaglandin E2 (PGE2) production, or the suppression of oxidative DNA adduct formation. Oral curcumin was administered to patients with advanced colorectal cancer refractory to standard chemotherapies to explore its pharmacodynamics in humans. In this study, the authors concluded that administration of 0.5 to 3.6 g/day for up to 4 months is associated with mild diarrhea as its only toxicity, and that a dosis of 3.6 g/day generates detectable levels of parent compound and conjugates in plasma and urine, causing inhibition of PGE2 production in blood leukocytes measured ex vivo. They proposed that an oral dose of 3.6 g/day is suitable for evaluation in Phase II trials. In fact, curcumin has been found to be safe when administered at doses up to 10 g/day. All of these studies suggest that curcumin has enormous potential in the prevention and therapy of cancer. Another study showed that curcumin is not toxic to humans up to 8 g/day when taken orally for 3 months.

Likewise, epigallocatechin-3-gallate (EGCG) have been studied in a wide range of illnesses related to excessive oxidative stress, involving cancers, cardiovascular diseases, metabolic syndromes, diabetes, cerebral ischemic stroke, lung diseases, and neurodegenerative disorders. Recently, EGCG has been studied for management and prevention of various kidney diseases, which are usually associated with oxidative stress and inflammation.

Meanwhile, baicalin decreases blood lipids and inflammation in patients with coronary artery disease and rheumatoid arthritis, supporting its further clinical application. This NPC exhibits high clinical value, having anti-inflammatory, anti-arrhythmic and anti-hypertensive effects.

The therapeutic usefulness and anti-inflammatory properties of celastrol have been studied in numerous inflammatory diseases, involving rheumatoid arthitis, ankylosing spondylitis, systemic lupus erythematosus, inflammatory bowel disease, osteoarthritis, allergies, and skin inflammation. Celastrol exhibits beneficial effects decreasing cardiovascular symptoms involving hypertension. Researchers investigated the treatment outcome against preeclampsia with a combined use of celastrol and nifedipine in clinical trials. A total of 626 patients with preeclampsia were enrolled, screened, and assigned randomly to groups receiving either nifedipine + placebo or nifedipine + celastrol orally. This study provides evidence for the potential role of celastrol serving as an effective and safe adjuvant to oral nifedipine against hypertension in patients with preeclampsia. The therapeutic effects such as the anti-inflammatory, anticancer, and neuroprotective properties of celastrol can be mainly attributed to its capacity to inhibit NF-κB, a central player in inflammation, cancer and neurodegenerative diseases.

Clinical investigation shows that gallic acid (GA) inhibits oxidative stress in diabetic patients. A small amount of GA prevents oxidative DNA injury and decreases markers which reflect inflammation and augmented risks of cancer and cardiovascular diseases.

Clinical reports in asthma patients show that Genistein exerts antioxidant effects and could inhibit the pathway of NF-κB and TNF-α in these patients.

It has been reported that Ginsenoside Rb1 (GS-Rb1) treatment was efficient in decreasing the extent of oxidative stress and inflammation in chronic kidney disease, whereas persistent deterioration was observed in the placebo group. Thus, extended treatments using GS-Rb1 may represent an interesting approach to slow the development of this disease at early stages.

Limitations

Although NPCs are promising therapeutic agents, they need in vivo studies (animal models) mainly analyzing the specificity of their therapeutic action as well as toxic, mutagenic or side effects. Scientists must identify the components of each extract as well as the therapeutically active molecule/s. Moreover, previous prospective clinical trials are mandatory to recommend their use in clinical practice.

Conclusion

EMT is a physiological and self-regulated process of tissue repair. However, pathologic EMT is characterized by its irreversibility and loss of self-regulation being a pathogenic part of many diseases. Thus, EMT is a therapeutic target with no established treatment yet. Natural products appear as therapeutic alternatives that need deep studies to be used in humans. Synergy and antagonism with other agents and interactions with prescription drugs should be studied in order to develop clinical trials.

The use of natural plant compounds versus standard drugs offers therapeutic advantages, such as the potential lower price and ease of being obtained, as they do not need to be artificially syntethized. Moreover, some of them are usually employed in the diet, like curcumin, although other routes of administration should be analyzed to calculate potential doses. Moreover, although many new drugs are made by synthetic chemistry and novel approaches to drug discovery such as combinatorial chemistry and computer-based design have been developed, they cannot replace the role of plant compounds in drug discovery, serving as chemical templates for the design and synthesis of new therapeutical drugs.

The relevance of this study lies on the necessity of finding effective therapies against EMT, which is a process involved in many diseases.

Author Contributions

All the authors contributed to and approved the final manuscript.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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    Fang Z. Tang Y. Jiao W. Xing Z. Guo Z. Wang W. (2013 ). Nitidine chloride inhibits renal cancer cell metastasis via suppressing AKT signaling pathway. Food Chem. Toxicol. 60, 246–251.

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    The natural compound Jatrophone interferes with Wnt/β-catenin signaling and inhibits proliferation and EMT in human triple-negative breast cancer. · 2017
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    Ferk F. Kundi M. Brath H. Szekeres T. Al-Serori H. Mišík M. (2018 ). Gallic acid improves health-associated biochemical parameters and prevents oxidative damage of DNA in type 2 diabetes patients: results of a placebo-controlled pilot study. Mol. Nutr. Food Res. 62 (4), 1–30.

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    Frémont L. (2000 ). Biological effects of resveratrol. Life Sci. 66 (8), 663–673.

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    Fujita M. Itokawa H. Sashida Y. (1973 ). Studies on the components of Magnolia obovata Thunb. III. Occurrence of magnolol and honokiol in M. obovata and other allied plants. Yakugaku Zasshi 93, 429–434.

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    Garodia P. Ichikawa H. Malani N. Sethi G. Aggarwal B. B. (2007 ). From ancient medicine to modern medicine: ayurvedic concepts of health and their role in inflammation and cancer. J. Soc. Integr. Oncol. 5, 25–37.

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    Ge P. Ji X. Ding Y. Wang X. Fu S. Meng F. (2010 ). Celastrol causes apoptosis and cell cycle arrest in rat glioma cells. Neurol. Res. 32 (1), 94–100.

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    Giacomelli C. Natali L. Trincavelli M.L. Daniele S. Bertoli A. Flamini G. (2016 ). New insights into the anticancer activity of carnosol: p53 reactivation in the U87MG human glioblastoma cell line. Int. J. Biochem. Cell. Biol. 74, 95–108.

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    Giacomelli C. Daniele S. Natali L. Iofrida C. Flamini G. Braca A. (2017 ). Carnosol controls the human glioblastoma stemness features through the epithelial-mesenchymal transition modulation and the induction of cancer stem cell apoptosis. Sci. Rep. 7 (1), 15174.

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    Ghantous A. Sinjab A. Herceg Z. Darwiche N. (2013 ). Parthenolide: from plant shoots to cancer roots. Drug Discov. Today 18 (17–18), 894–905.

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    Grande M. T. Sanchez-Laorden B. Lopez-Blau C. De Frutos C. A. Boutet A. Arevalo M. (2015 ). Snail1-induced partial epithelial-tomesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. Nat. Med. 21, 989–997.

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    Gu L. Feng J. Zheng Z. Xu H. Yu W. (2016 ). Polyphyllin I inhibits the growth of ovarian cancer cells in nude mice. Oncol. Lett. 12, 4969–4974.

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    Gupta S. C. Patchva S. Aggarwal B. B. (2013 ). Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J. 15 (1), 195–218.

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    Gliemann L. Nyberg M. Hellsten Y. (2016 ). Effects of exercise training and resveratrol on vascular health in aging. Free Radic. Biol. Med. 98, 165–176.

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    Han L. Zhang H. W. Zhou W. P. Chen G. M. Guo K. J. (2012 ). The effects of genistein on transforming growth factor-β1-induced invasion and metastasis in human pancreatic cancer cell line Panc-1 in vitro. Chin. Med. (Eng) 125 (11), 2032–2040.

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    Hang Y. Qin X. Ren T. Cao J. (2018 ). Baicalin reduces blood lipids and inflammation in patients with coronary artery disease and rheumatoid arthritis: a randomized, double-blind, placebo-controlled trial. Lipids Health Dis. 17 (1), 146.

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    Hao F. Kumar S. Yadav N. Chandra D. (2014 ). Neem components as potential agents for cancer prevention and treatment. Biochim. Biophys. Acta 1846, 247–257.

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    Hao J. Zhu H. Zhang Z. Yang S. Li H. (2015 ). Identification of anthocyanins in black rice (Oryza sativa L). by UPLC/Q-TOF-MS and their in vitro and in vivo antioxidant activities. J. Cereal Sci. 64, 92–99.

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    He D. X. Li G. H. Gu X. T. Zhang L. Mao A. Q. Wei J. (2016 ). A new agent developed by biotransformation of polyphyllin VII inhibits chemoresistance in breast cancer. Oncotarget 7, 31814–31824.

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    Hehner S. P. Hofmann T. G. Dröge W. Schmitz M. L. (1999 ). The antiinflammatory sesquiterpene lactone parthenolide inhibits NF-kappa B by targeting the I kappa B kinase complex. J. Immunol. 163 (10), 5617–5623.

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    Hertig A. Anglicheau D. Verine J. Pallet N. Touzot M. Ancel P. Y. (2008 ). Early epithelial phenotypic changes predict graft fibrosis. J. Am. Soc. Nephrol. 19 (8), 1584–1591.

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    Howells L. M. Berry D. P. Elliott P. J. Jacobson E. W. Hoffmann E. Hegarty B. (2011 ). Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases—safety, pharmacokinetics, and pharmacodynamics. Cancer Prev. Res. (Phila.) 4 (9), 1419–25.

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    Hou D. X. (2003 ). Potential mechanisms of cancer chemoprevention by anthocyanins. Curr. Mol. Med. 3, 149–159.

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    Hou Y. L. Tsai Y. H. Lin Y. H. Chao J. C. (2014 ). Ginseng extract and ginsenoside Rb1 attenuate carbon tetrachloride-induced liver fibrosis in rats. BMC Complement. Altern. Med. 14, 415.

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    Hu W. Han W. Huang C. Wang M. H. (2011 ). Protective effect of the methanolic extract from Duchesnea indica against oxidative stress in vitro and in vivo. Environ. Toxicol. Pharmacol. 31 (1), 42–50.

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    Hu W. Shen W. Wang M. H. (2009 ). Free radical scavenging activity and protective ability of methanolic extract from Duchesnea indica against protein oxidation and DNA damage. J. Food Sci. Nutr. 14, 77–282.

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    Huang S. F. Horng C. T. Hsieh Y. S. Hsieh Y. H. Chu S. C. Chen P. N. (2016 ). Epicatechin-3-gallate reverses TGF-β1-induced epithelial-to-mesenchymal transition and inhibits cell invasion and protease activities in human lung cancer cells. Food Chem. Toxicol. 94, 1–10.

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    Huang W. H. Lee A. R. Yang C. H. (2006 ). Antioxidative and anti-inflammatory activities of polyhydroxyflavonoids of Scutellaria baicalensis GEORGI. Biosci. Biotechnol. Biochem. 70 (10), 2371–2380.

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    Huang Y. Tsang S. Y. Yao X. Chen Z. Y. (2005 ). Biological properties of baicalein in cardiovascular system. Curr. Drug Targets Cardiovasc. Haematol. Disord. 5 (2), 177–184.

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    Hui H. Tang G. Go V. L. (2009 ). Hypoglycemic herbs and their action mechanisms. Chin Med. 4, 11.

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    Huber M. A. Azoitei N. Baumann B. Grünert S. Sommer A. Pehamberger H. (2004 ). NF-kB is essential for epithelial–mesenchymal transition and metastasis in a model of breast cancer progression. J. Clin. Invest. 114, 569–581.

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    Imanshahidi M. Hosseinzadeh H. (2008 ). Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine. Phytother. Res. 22 (8), 999–1012.

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    Jeon Y. K. Yoo D. R. Jang Y. H. Jang S. Y. Nam M. J. (2011 ). Sulforaphane induces apoptosis in human hepatic cancer cells through inhibition of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4, mediated by hypoxia inducible factor-1-dependent pathway. Biochim. Biophys. Acta 1814, 1340–1348.

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    Resveratrol suppresses epithelial-to-mesenchymal transition in colorectal cancer through TGF-β1/Smads signaling pathway mediated Snail/E-cadherin expression · 2015
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    Ji Y. Dou Y. Zhao Q. Zhang J. Yang Y. Wang T. (2016 ). Paeoniflorin suppresses TGF-β mediated epithelial mesenchymal transition in pulmonary fibrosis through a Smad- dependent pathway. Acta Pharmacol. Sin. 37 (6), 794–804.

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    Jia L. Zhao Y. (2009 ). Current evaluation of the millennium phytomedicine- ginseng (I): etymology, pharmacognosy, phytochemistry, market and regulations. Curr. Med. Chem. 16, 2475–2484.

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    Jiang L. L. Zhou S. J. Zhang X. M. Chen H. Q. Liu W. (2016 ). Sulforaphane suppresses in vitro and in vivo lung tumorigenesis through downregulation of HDAC activity. Biomed. Pharmacother. 78, 74–80.

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    Jin H. J. Xie X. L. Ye J. M. Li C. G. (2013 ). TanshinoneIIA and cryptotanshinone protect against hypoxia-induced mitochondrial apoptosis in H9c2 cells. PLoS One 8 (1), e51720.

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    Jin L. Piao Z. H. Sun S. Liu B. Ryu Y. Choi S. Y. (2017 ). Gallic acid attenuates pulmonary fibrosis in a mouse model of transverse aortic contraction-induced heart failure. Vascul. Pharmacol. 99, 74–82.

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    Jo E. Park S. J. Choi Y. S. Jeon W. K. Kim B. C. (2015 ). Kaempferol suppresses transforming growth factor-β1-induced epithelial-to-mesenchymal transition and migration of A549 lung cancer cells by inhibiting Akt1-mediated phosphorylation of Smad3 at Threonine-179. Neoplasia 17, 525–537.

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    Johanson J. J. (2011 ). Carnosol: a promising anti-cancer and infammatory agent. Cancer Lett. 305 (1), 1–7.

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    Jung H. J. Kang H. J. Song Y. S. Park E. H. Kim Y. M. Lim C. J. (2008 ). Anti-inflammatory, anti-angiogenic and anti-nociceptive activities of Sedum sarmentosum extract. J. Ethnopharmacol. 116, 138–143.

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    Kalluri R. (2009 ). EMT: when epithelial cells decide to become mesenchymal-like cells. J. Clin. Invest. 119 (6), 1417–1419.

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    Kamath S. G. Chen N. Xiong Y. Wenham R. Apte S. Humphrey M. (2009 ). Gedunin, a novel natural substance, inhibits ovarian cancer cell proliferation. Int. J. Gynecol. Cancer 19, 1564–1569.

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    Kanlaya R. Thongboonkerd V. (2019 ). Protective effects of epigallocatechin-3-gallate from green tea in various kidney diseases. Adv. Nutr. 110 (1), 112–121.

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    Kao S. J. Su J. L. Chen C. K. Yu M. C. Bai K. J. Chang J. H. (2012 ). Osthole inhibits the invasive ability of human lung adenocarcinoma cells via suppression of NF-kappaB-mediated matrix metalloproteinase-9 expression. Toxicol. Appl. Pharmacol. 261, 105–115.

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    Kee H. J. Cho S. N. Kim G. R. Choi S. Y. Ryu Y. Kim I. K. (2014 ). Gallic acid inhibits vascular calcification through the blockade of BMP2-Smad1/5/8 signaling pathway. Vasc. Pharmacol. 63 (2), 71–78.

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    Khan A. L. Hussain J. Hamayun M. Gilani S. A. Ahmad S. Rehman G. (2010 ). Secondary metabolites from Inula britannica L. and their biological activities. Molecules 15 (3), 1562–1577.

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    PhytoNanotechnology: Enhancing Delivery of Plant Based Anti-cancer Drugs · 2018
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    Kida Y. Asahina K. Teraoka H. Gitelman I. Sato T. (2007 ). Twist relates to tubular epithelial-mesenchymal transition and interstitial fibrogenesis in the obstructed kidney. J. Histochem. Cytochem. 55 (7), 661–673.

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    Kim D. H. Sung B. Kang Y. J. Hwang S. Y. Kim M. J. Yoon J. H. (2015 ). Sulforaphane inhibits hypoxia-induced HIF-1alpha and VEGF expression and migration of human colon cancer cells. Int. J. Oncol. 47, 2226–2232.

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    Kim K. Lu Z. Hay E. D. (2002 a). Direct evidence for a role of beta-catenin/LEF-1 signaling pathway in induction of EMT. Cell Biol. Int. 26, 463–476.

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    Kim I. G. Jung I. L. Oh T. J. Kim K. C. Shim H. W. (2002 b). Polysaccharide-enriched fraction isolated from Duchesnea chrysantha protects against oxidative damage. Biotechnol. Lett. 24, 1299–1305.

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    Kim N. Hwangbo C. Lee S. Lee J. H. (2013 ). Eupatolide inhibits PDGF-induced proliferation and migration of aortic smooth muscle cells through ROS-dependent heme oxygenase-1 induction. Phytother. Res. 27, 1700–1707.

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    Kim K. C. Kim J. S. Son J. K. Kim I. G. (2007 ). Enhanced induction of mitochondrial damage and apoptosis in human leukemia HL-60 cells by the Ganoderma lucidum and Duchesnea chrysantha extracts. Cancer Lett. 246, 210–217.

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    Kim Y. S. Choi K. C. Hwang K. A. (2015 ). Genistein suppressed epithelial-mesenchymal transition and migration efficacies of BG-1 ovarian cancer cells activated by estrogenic chemicals via estrogen receptor pathway and downregulation of TGF-beta signaling pathway. Phytomedicine 22, 993–999.

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    Klongkumnuankarn P. Busaranon K. Chanvorachote P. Sritularak B. Jongbunprasert V. Likhitwitayawuid K. (2015 ). Cytotoxic and Antimigratory activities of phenolic compounds from dendrobium brymerianum. J. Evid. Based Complement. Altern Med. 2015, 1–9.

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    Kong D. Zhang F. Shao J. Wu L. Zhang X. Chen L. (2015 ). Curcumin inhibits cobalt chloride-induced epithelial-to-mesenchymal transition associated with interference with TGF-β/Smad signaling in hepatocytes. Lab. Invest. 95 (11), 1234–1245.

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    Kong M. Fan J. Dong A. Cheng H. Xu R. (2010 ). Effects of polyphyllin I on growth inhibition of human non-small lung cancer cells and in xenograft. Acta Biochim. Biophys. Sin. 42, 827–833.

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    Kong S. Kim D. J. Oh S. K. Choi I. S. Jeong H. S. Lee J. (2012 ). Black rice bran as an ingredient in noodles: chemical and functional evaluation. J. Food Sci. 77, C303–C307.

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    Kou Y. Li L. Li H. Tan Y. Li B. Wang K. (2016 ). Berberine suppressed epithelial mesenchymal transition through cross-talk regulation of PI3K/AKT and RARα/RARβ in melanoma cells. Biochem. Biophys. Res. Commun. 479 (2), 290–296.

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    Kulkarni S. K. Dhir A. (2010 ). Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders. Phytother. Res. 24, 317–324.

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    la Porte C. Voduc N. Zhang G. Seguin I. Tardiff D. Singhal N. (2010 ). Steady-State pharmacokinetics and tolerability of trans-resveratrol 2000 mg twice daily with food, quercetin and alcohol (ethanol) in healthy human subjects. Clin. Pharmacokinet. 49 (7), 449–454.

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    Lee D. G. Jang S. I. Kim Y. R. Yang K. E. Yoon S. J. Lee Z. W. (2016 ). Anti-proliferative effects of ginsenosides extracted from mountain ginseng on lung cancer. Chin. J. Integr. Med. 22 (5), 344–352.

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    Lee J. Hahm E. R. Marcus A. I. Singh S. V. (2013 ). Withaferin a inhibits experimental epithelial-mesenchymal transition in MCF-10A cells and suppresses vimentin protein level in vivo in breast tumors. Mol. Carcinog. 54 (6), 417–429.

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    Lee J. Hwangbo C. Lee J. J. Seo J. Lee J. H. (2010 a). The sesquiterpene lactone eupatolide sensitizes breast cancer cells to TRAIL through down-regulation of c-FLIP expression. Oncol. Rep. 23, 229–237.

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    Lee J. Tae N. Lee J. J. Kim T. Lee J. H. (2010 b). Eupatolide inhibits lipopolysaccharide-induced COX-2 and iNOS expression in RAW264.7 cells by inducing proteasomal degradation of TRAF6. Eur. J. Pharmacol. 636, 173–180.

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    Lee J. Jung E. Park J. Jung K. Lee S. Hong S. (2005 ). Anti-inflammatory effects of magnolol and honokiol are mediated through inhibition of the downstream pathway of MEKK-1 in NF-kappaB activation signaling. Planta Med. 71, 338–343.

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    Lee J. M. Dedhar S. Kalluri R. Thompson E. W. (2006 ). The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J. Cell Biol. 172 (7), 973-981.

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    Lee J. Y. Kim H. S. Song Y. S. (2012 ). Genistein as a potential anticancer agent against ovarian cancer. J. Tradit. Complement. Med. 2 (2), 96–104.

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    Lee I. R. Yang M. Y. (1994 ). Phenolic compounds from Duchesnea chrysantha and their cytotoxic activities in human cancer cell. Arch. Pharm. Res. 17, 476–479.

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    Li J. Chong T. Wang Z. Chen H. Li H. Cao J. (2014 ). A novel anti-cancer effect of resveratrol: reversal of epithelial-mesenchymal transition in prostate cancer cells. Mol. Med. Rep. 10, 1717–1724.

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    Li J. Yang J. Lü F. Qi Y. T. Liu Y. Q. Sun Y. (2012 a). Chemical constituents from the stems of Celastrus orbiculatus. Chin. J. Nat. Med. 10 (4), 279–283. ISSN 1875-5364.

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    Li J. Shao Z. H. Xie J. T. Wang C. Z. Ramachandran S. Yin J. J. (2012 b). The effects of ginsenoside Rb1 on JNK in oxidative injury in cardiomyocytes. Arch. Pharm. Res. 35, 1259–1267.

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    Li W. Ma J. Ma Q. Li B. Han L. Liu J. (2013 ). Resveratrol inhibits the epithelial-mesenchymal transition of pancreatic cancer cells via suppression of the PI-3 K/Akt/NF-κB pathway. Curr. Med. Chem. 20, 4185–4194.

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    Li W. Saud S. M. Young M. R. Colburn N. H. Hua B. (2015 ). Cryptotanshinone, a Stat3 inhibitor, suppresses colorectal cancer proliferation and growth in vitro. Mol. Cell Biochem. 406 (1–2), 63–73.

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    Parthenolide attenuated bleomycin-induced pulmonary fibrosis via the NF-κB/Snail signaling pathway · 2018
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    Li W. Jiang Z. Xiao X. Wang Z. Wu Z. Ma Q. (2018 b). Curcumin inhibits superoxide dismutase-induced epithelial-to-mesenchymal transition via the PI3K/Akt/NF-κB pathway in pancreatic cancer cells. Int. J. Oncol. 52, 1593–1602.

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    Liappas G. Gónzalez-Mateo G. T. Majano P. Sánchez-Tomero J. A. Ruiz-Ortega M. Rodrigues Díez R. (2015 ). T helper 17/regulatory T Cell balance and experimental models of peritoneal dialysis-induced damage. Biomed. Res. Int. 2017, 6130208.

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    Lin C. Y. Hsieh Y. H. Yang S. F. Chu S. C. Chen P. N. Hsieh Y. S. (2017 ). Cinnamomum cassia extracts reverses TGF-β1-induced epithelial–mesenchymal transition in human lung adenocarcinoma cells and suppresses tumor growth in vivo. Environ. Toxicol. 32 (7), 1878–1887.

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    Lin D. Kuang G. Wan J. Zhang X. Li H. Gong X. (2016 ). Luteolin suppresses the metastasis of triple-negative breast cancer by reversing epithelial-to-mesenchymal transition via downregulation of β-catenin expression. Oncol. Rep. 37 (2), 895–902.

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    Lin X. Yi Z. Diao J. Shao M. Zhao L. Cai H. (2014 ). ShaoYao decoction ameliorates colitis-associated col- orectal cancer by downregulating proinflammatory cytokines and promoting epithelial-mesenchymal transition. J. Transl. Med. 12, 105.

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    Lin Y. Shi R. Wang X. Shen H. M. (2008 ). Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr. Cancer Drug Targets 8, 634–646.

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    Lin L. Sun Y. Wang D. Zheng S. Zhang J. Zheng C. (2015 ). Celastrol ameliorates ulcerative colitis-related colorectal cancer in mice via suppressing inflammatory responses and epithelial-mesenchymal transition. Front. Pharmacol. 6, 320.

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    Liu D. Qiu X. Y. Wu X. Hu D. X. Li C. Y. Yu S. B. (2017 ). Piperlongumine suppresses bladder cancer invasion via inhibiting epithelial mesenchymal transition and F-actin reorganization. Biochem. Biophys. Res. Commun. 494 (1–2), 165–172.

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    Liu L. Lu W. Ma Z. Li Z. (2012 ). Oxymatrine attenuates bleomycin-induced pulmonary fibrosis in mice via the inhibition of inducible nitric oxide synthase expression and the TGF-β/Smad signaling pathway. Int. J. Mol. Med. 29 (5), 815–822.

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  157. 157.

    Liu Q. R. Liu J. M. Chen Y. Xie X. Q. Xiong X. X. Qiu X. Y. (2014 ). Piperlongumine inhibits migration of glioblastoma cells via activation of ROS-dependent p38 and JNK signaling pathways. Oxidative Med. Cell. Longev. 2014, 653732.

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    Liu C. Wang Z. Song Y. Wu D. Zheng X. Li P. (2015 ). Effects of berberine on amelioration of hyperglycemia and oxidative stress in high glucose and high fat diet-induced diabetic hamsters in vivo. Biomed. Res. Int. 2015, 313808.

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    Liu L. Wang Y. Yan R. Li S. Shi M. Xiao Y. (2016 ). Oxymatrine inhibits renal tubular EMT induced by high glucose via upregulation of snoN and inhibition of TGF-β1/Smad signaling pathway. PLoS One 11 (3), e0151986.

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    Liu P. L. Tsai J. R. Charles A. L. Hwang J. J. Chou S. H. Ping Y. H. (2010 a). Resveratrol inhibits human lung adenocarcinoma cell metastasis by suppressing heme oxygenase 1-mediated nuclear factor-kappaB pathway and subsequently downregulating expression of matrix metalloproteinases. Mol. Nutr. Food Res. 54 (Suppl. 2), S196–S204.

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    Liu X. J. Zhao J. Gu X. Y. (2010 b). The effects of genistein and puerarin on the activation of nuclear factor-kappaB and the production of tumor necrosis factor-alpha in asthma patients. Pharmazie 65 (2), 127–131.

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    Lopez-Cabrera M. (2014 ). Mesenchymal conversion of mesothelial cells is a key event in the pathophysiology of the peritoneum during peritoneal dialysis. Adv. Med. 2014, 473134.

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    Lou W. Chen Y. Zhu K. Y. Deng H. Wu T. Wang J. (2017 ). Polyphyllin I Overcomes EMT-associated resistance to erlotinib in lung cancer cells via IL-6/STAT3 pathway inhibition. Biol. Pharm. Bull. 40 (8), 1306–1313.

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    Lovisa S. LeBleu V. S. Tampe B. Sugimoto H. Vadnagara K. Carstens J. L. (2015 ). Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nat. Med. 21, 998–1009.

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    Lu Z. Lai Z.-Q. Leung A. W. N. Leung P. S. Li Z.-S. Lin Z.-X. (2017 ). Exploring brusatol as a new anti-pancreatic cancer adjuvant: biological evaluation and mechanistic studies. Oncotarget 8 (49), 84974–84985.

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    Lu L. Qin Y. Chen C. Guo X. (2018 ). Beneficial effects exerted by paeonol in the management of atherosclerosis. Oxid. Med. Cell Longev. 2018, 1098617.

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    Lv X. Q. Qiao X. R. Su L. Chen S. Z. (2016 ). Honokiol inhibits EMT-mediated motility and migration of human non-small cell lung cancer cells in vitro by targeting c-FLIP. Acta Pharmacol. Sin. 37 (12), 1574–1586.

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    Ma S. Yang D. Wang K. Tang B. Li D. Yang Y. (2012 ). Cryptotanshinone attenuates isoprenaline-induced cardiac fibrosis in mice associated with upregulation and activation of matrix metalloproteinase-2. Mol. Med. Rep. 6 (1), 145–150.

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    Ma Y. Li H. Yue Z. Guo J. Xu S. Xu J. (2014 ). Cryptotanshinone attenuates cardiac fibrosis via downregulation of COX-2, NOX-2, and NOX-4. J. Cardiovasc. Pharmacol. 64 (1), 28–37.

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    Marin-Neto J. A. Maciel B. C. Secches A. L. Gallo L. (1988 ). Cardiovascular effects of berberine in patients with severe congestive heart failure. Clin. Cardiol. 11, 253–260.

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    Massagué J. Wotton D. (2000 ). Transcriptional control by the TGF-b/Smad signaling. EMBO 19, 1745–1754.

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    Masszi A. Di Ciano C. Sirokmány G. Arthur W. T. Rotstein O. D. Wang J. (2003 ). Central role for Rho in TGF-beta1-induced alpha-smooth muscle actin expresion during epithelial-mesenchymal transition. Am. J. Physiol. Renal Physiol. 284, F911–F924.

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    Masszi A. Kapus A. (2011 ). Smaddening complexity: the role of Smad3 in epithelial-myofibroblast transition. Cells Tissues Organs 193, 41–52.

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    Mohsenikia M. Alizadeh A. M. Khodayari S. Khodayari H. Kouhpayeh S. A. Karimi A. (2013 ). The protective and therapeutic effects of alpha-solanine on mice breast cancer. Eur. J. Pharmacol. 718, 1–9.

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    Morikawa T. Zhang Y. Nakamura S. Matsuda H. Muraoka O. Yoshikawa M. (2007 ). Bioactive constituents from Chinese natural medicines. XXII. Absolute structures of new megastigmane glycosides, sedumosides E1, E2, E3, F1, F2 and G, from Sedum sarmentosum (Crassulaceae). Chem. Pharm. Bull. 55, 435–441.

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    Moshiri A. Puppo M. Rossi M. Gherzi R. Briata P. (2017 ). Resveratrol limits epithelial to mesenchymal transition through modulation of KHSRP/hnRNPA1-dependent alternative splicing in mammary gland cells. Biochim. Biophys. Acta Gene Regul Mech. 1860 (3), 291–298.

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    Nagalingam A. Arbiser J. L. Bonner M. Y. Saxena N. K. Sharma D. (2012 ). Honokiol activates AMP-activated protein kinase in breast cancer cells via an LKB1-dependent pathway and inhibits breast carcinogenesis. Breast Cancer Res. 14 (1), R35.

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    Newman D. J. Cragg G. M. (2007 ). Natural products as sources of new drugs over the last 25 years. J. Nat. Prod. 70, 461–477.

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    Ninomiya K. Morikawa T. Zhang Y. Nakamura S. Matsuda H. Muraoka O. (2007 ). Bioactive constituents from Chinese natural medicines. XXIII. Absolute structures of new megastigmane glycosides, sedumosides A(4), A(5), A(6), H, and I, and hepatoprotective megastigmanes from Sedum sarmentosum. Chem. Pharm. Bull. 55, 1185–1191.

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    Oh H. Kang D. G. Kwon J. W. Kwon T. O. Lee S. Y. Lee D. B. (2004 ). Isolation of angiotensin converting enzyme (ACE) inhibitory flavonoids from Sedum sarmentosum. Biol. Pharm. Bull. 27, 2035–2037.

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    Ong R. C. Lei J. Lee R. K. Cheung J. Y. Fung K. P. Lin C. (2008 ). Polyphyllin D induces mitochondrial fragmentation and acts directly on the mitochondria to induce apoptosis in drugresistant HepG2 cells. Cancer Lett. 261, 158–164.

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    Padhye S. Dandawate P. Yusufi M. Ahmad A. Sarkar F. H. (2012 ). Perspectives on medicinal properties of plumbagin and its analogs. Med. Res. Rev. 32 (6), 1131–1158.

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    Padmavathi B. Rath P. C. Rao A. R. Singh R. P. (2005 ). Roots of Withania somnifera inhibit forestomach and skin carcinogenesis in mice. Evid. Based Complement. Alternat. Med. 2, 99–105.

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    Pan S.-T. Qin Y. Zhou Z.-W. He Z.-X. Zhang X. Yang T. (2015 ). Plumbagin suppresses epithelial to mesenchymal transition and stemness via inhibiting Nrf2-mediated signaling pathway in human tongue squamous cell carcinoma cells. Drug Des. Dev. Ther. 9, 5511–5551.

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    Pattarayan D. Sivanantham A. Krishnaswami V. Loganathan L. Palanichamy R. Natesan S. (2018 ). Tannic acid attenuates TGF-β1-induced epithelial-to-mesenchymal transition by effectively intervening TGF-β signaling in lung epithelial cells. J. Cell Physiol. 233 (3), 2513–2525.

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    Patwardhan C. A. Fauq A. Peterson L. B. Miller C. Blagg B. S. Chadli A. (2013 ). Gedunin inactivates the co-chaperone p23 protein causing cancer cell death by apoptosis. J. Biol. Chem. 288, 7313–7325.

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    Peinado H. Quintanilla M. Cano A. (2003 ). Transforming growth factor b-1 induces snail transcription factor in epithelial cell lines. J. Biol. Chem. 278, 21113–21123.

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    Peng C. H. Chyau C. C. Wang C. J. Lin H. T. Huang C. N. Ker Y. B. (2016 ). Abelmoschus esculentus fractions potently inhibited the pathogenic targets associated with diabetic renal epithelial to mesenchymal transition. Food Funct. 7 (2), 728–740.

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    Petpiroon N. Sritularak B. Chanvorachote P. (2017 ). Phoyunnanin E inhibits migration of non-small cell lung cancer cells via suppression of epithelial-to-mesenchymal transition and integrin αv and integrin β3. BMC Complement. Altern. Med. 17, 553.

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    Popat R. Plesner T. Davies F. Cook G. Cook M. Elliott P. (2013 ). A phase 2 study of SRT501 (resveratrol) with bortezomib for patients with relapsed and or refractory multiple myeloma. Br. J. Haematol. 160 (5), 714–717.

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    Poser I. Dominguez D. de Herreros A. G. Varnai A. Buettner R. Bosserhoff A. K. (2001 ). Loss of E-cadherin expression in melanoma cells involves up-regulation of the transcriptional repressor snail. J. Biol. Chem. 276, 24661–24666.

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    Qian Y. Y. Zhang H. Hou Y. Yuan L. Li G. Q. Guo S. Y. (2012 ). Celastrus orbiculatus extract inhibits tumor angiogenesis by targeting vascular endothelial growth factor signaling pathway and shows potent antitumor activity in hepatocarcinomas in vitro and in vivo. Chin. J. Integr. Med. 18, 752–760.

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    Qiao W. Yao Z. Zhang W. Duan H. Q. (2009 ). Two new triterpenes from Duchesnea indica. Chin. Chem. Lett. 20, 572–575.

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    Qu Y. Zhang G. Ji Y. Zhua H. Lv C. Jiang W. (2016 ). Protective role of gambogic acid in experimental pulmonary fibrosis in vitro and in vivo. Phytomedicine 23 (4), 350–358.

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    Raj L. Ide T. Gurkar A. U. Foley M. Schenone M. Li X. (2011 ). Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature 475, 231e234.

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    Rastaldi M. P. (2006 ). Epithelial-mesenchymal transition and its implications for the development of renal tubulointerstitial fibrosis. J. Nephrol. 19 (4), 407–412.

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    Russo M. A. Sansone L. Polletta L. Runci A. Rashid M. M. De Santis E. (2014 ). Sirtuins and resveratrol-derived compounds: a model for understanding the beneficial effects of the Mediterranean diet. Endocr. Metab. Immune Disord. Drug Targets 14 (4), 300–308. Review.

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    Ryu Y. Jin L. Kee H. J. Piao Z. H. Cho J. Y. Kim G. R. (2016 ). Gallic acid prevents isoproterenol-induced cardiac hypertrophy and fibrosis through regulation of JNK2 signaling and Smad3 binding activity, Sci. Rep. 6, 34790.

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    Sarkar S. Mandal C. Sangwan R. Mandal C. (2014 ). Coupling G2/M arrest to the Wnt/β-catenin pathway restrains pancreatic adenocarcinoma. Endocr. Relat. Cancer 21 (1), 113–125.

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    Sato M. Muragaki Y. Saika S. Roberts A. B. Ooshima A. (2003 ). Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J. Clin. Invest. 112 (10), 1486–1494.

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    Savagner P. (2010 ). The epithelial-mesenchymal transition (EMT) phenomenon. Ann. Oncol. 21 (Suppl 7), vii89–vii92.

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    Sehitoglu M. H. Farooqi A. A. Qureshi M. Z. Butt G. Aras A. (2014 ). Anthocyanins: targeting of signaling networks in cancer cells. Asian Pac. J. Cancer Prev. 15, 2379–2381.

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    Shakibaei M. Harikumar K. B. Aggarwal B. B. (2009 ). Resveratrol addiction: to die or not to die. Mol. Nutr. Food Res. 53, 115–128.

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    Resveratrol Inhibits Pancreatic Cancer Stem Cell Characteristics in Human and KrasG12D Transgenic Mice by Inhibiting Pluripotency Maintaining Factors and Epithelial-Mesenchymal Transition · 2011
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    Sharma R. A. Euden S. A. Platton S. L. Cooke D. N. Shafayat A. Hewitt H. R. (2004 ). Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clin. Cancer Res. 10, 6847–6854.

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    Shen K. H. Liao A. C. Hung J. H. Lee W. J. Hu K. C. Lin P. T. (2014 ). α-Solanine inhibits invasion of human prostate cancer cell by suppressing epithelial-mesenchymal transition and MMPs expression. Molecules 1119 (8), 11896–11914.

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    Shen X. C. Yang Y. P. Xiao T. T. Peng J. Liu X. D. (2011 ). Protective effect of oxymatrine on myocardial fibrosis induced by acute myocardial infarction in rats involved in TGF-β1-Smad signal pathway. J. Asian Nat. Prod. Res. 13 (3), 215–224.

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    Sheu M. L. Chiang C. K. Tsai K. S. Ho F. M. Weng T. I. Wu H. Y. (2008 ). Inhibition of NADPH oxidase-related oxidative stress-triggered signaling by honokiol suppresses high glucose-induced human endothelial cell apoptosis. Free Radic. Biol. Med. 44, 2043–2050.

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    Shi G. F. Li Q. (2005 ). Effects of oxymatrine on experimental hepatic fibrosis and its mechanism in vivo. World J. Gastroenterol. 11 (2), 268–271.

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    Shibata S. Marushima H. Asakura T. Matsuura T. Eda H. Aoki K. (2009 ). Three-dimensional culture using a radial flow bioreactor induces matrix metalloprotease 7-mediated EMT-like process in tumor cells via TGFbeta1/Smad pathway. Int. J. Oncol. 34 (5), 1433–1448.

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    Song Y. H. Sun H. Zhang A. Yan G. Han Y. Wang X. (2014 ). Plant-derived natural products as leads to anti-cancer drugs. J. Med. Plant Herb. Ther. Res. 2, 6–15.

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    Su N.-W. Wu S.-H. Chi C.-W. Liu C.-J. Tsai T.-H. Chen Y.-J. (2017 ). Metronomic cordycepin therapy prolongs survival of oral cancer-bearing mice and inhibits epithelial-mesenchymal transition. Molecules 22, 629.

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    Nimbolide inhibits pancreatic cancer growth and metastasis through ROS-mediated apoptosis and inhibition of epithelial-to-mesenchymal transition · 2016
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    Subramani R. Gonzalez E. Nandy S. B. Arumugam A. Camacho F. Medel J. (2017 ). Gedunin inhibits pancreatic cancer by altering sonic hedgehog signaling pathway. Oncotarget 8 (7), 10891–10904.

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    Sun L. N. Chen Z. X. Liu X. C. Liu H. Y. Guan G. J. Liu G. (2014 ). Curcumin ameliorates epithelial-to mesenchymal transition of podocytes in vivo and in vitro via regulating caveolin-1. Biomed. Pharmacother. 68 (8), 1079–1088.

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    Sun M. Zhang N. Wang X. Cai C. Cun J. Li Y. (2014 ). Nitidine chloride induces apoptosis, cell cycle arrest, and synergistic cytotoxicity with doxorubicin in breast cancer cells. Tumour Biol. 35 (10), 10201–10212.

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    Sun M. Zhang N. Wang X. Li Y. Qi W. Zhang H. (2016 ). Hedgehog pathway is involved in nitidine chloride induced inhibition of epithelial-mesenchymal transition and cancer stem cells-like properties in breast cancer cells. Cell Biosci. 6, 44.

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    Sutariya Brijesh S. (2017 ). Betanin, isolated from fruits of Opuntia elatior Mill attenuates renal fibrosis in diabetic rats through regulating oxidative stress and TGF-β pathway. J. Ethnopharmacol. 198, 432–443.

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    Tan C. Mui A. Dedhar S. (2002 ). Integrin-linked kinase regulate inducible nitric oxide synthase and cyclooxygenase-2 expression in an NF-kB-dependent manner. J. Biol. Chem. 277, 3109–3116.

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    Troussard A. A. Costello P. Yoganathan T. N. Kumagai S. Roskelley C. D. Dedhar S. (2000 ). The integrin linked kinase (ILK) induces an invasive phenotype via AP-1 transcription factordependent upregulation of matrix metalloproteinase 9 (MMP-9). Oncogene 16, 5444–5452.

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    Tsai J. H. Hsu L. S. Lin C. L. Hong H. M. Pan M. H. Way T.-D. (2013 ). 3,5,4′-Trimethoxystilbene, a natural methoxylated analog of resveratrol, inhibits breast cancer cell invasiveness by downregulation of PI3K/Akt and Wnt/beta-catenin signaling cascades and reversal of epithelial-mesenchymal transition. Toxicol. Appl. Pharmacol. 272, 746–756.

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    Unahabhokha T. Chanvorachote P. Pongrakhananon V. (2016 ). The attenuation of epithelial to mesenchymal transition and induction of anoikis by gigantol in human lung cancer H460 cells. Tumour Biol. 37 (7), 8633–8641.

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    Vega S. Morales A. V. Ocaña O. H. Valdés F. Fabregat I. Nieto M. A. (2004 ). Snail blocks the cell cycle and confers resistance to cell death. Gene Dev. 18, 1131–1143.

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    Venkatesha S. H. Yu H. Rajaiah R. Tong L. Moudgil K. D. (2011 ). Celastrus-derived celastrol suppresses autoimmune arthritis by modulating antigen-induced cellular and humoral effector responses. J. Biol. Chem. 286 (17), 15138–15146.

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    Vergara D. Valente C. M. Tinelli A. Siciliano C. Lorusso V. Acierno R. (2011 ). Resveratrol inhibits the epidermal growth factor-induced epithelial mesenchymal transition in MCF-7 cells. Cancer Lett. 310 (1), 1–8.

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    Vergara D. (2014 ). Antitumor activity of the dietary diterpene carnosol against a panel of human cancer cell lines. Food Funct. 5, 1261–1269.

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    von Gise A. Pu W. T. (2012 ). Endocardial and epicardial epithelial to mesenchymal transitions in heart development and disease. Circ. Res. 110 (12), 1628–1645.

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    Vuddanda P. R. Chakraborty S. Singh S. (2010 ). Berberine: a potential phytochemical with multispectrum therapeutic activities. Expert Opin. Invest. Drugs 19, 1297–1307.

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    Wallerath T. Deckert G. Ternes T. Anderson H. Li H. Witte K. (2002 ). Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation 106 (13), 1652–1658.

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    Wang J. Qiao L. Li Y. Yang G. (2008 ). Ginsenoside Rb1 attenuates intestinal ischemia-reperfusion-induced liver injury by inhibiting NF-κB activation. Exp. Mol. Med. 40, 686–698.

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    Wang Z. Jiang W. Zhang Z. Qian M. Du B. (2012 ). Nitidine chloride inhibits LPS-induced inflammatory cytokines production via MAPK and NF-kappaB pathway in RAW 264.7 cells. J. Ethnopharmacol. 144 (1), 145–150.

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    Wang H. Zhang H. Tang L. Chen H. Wu C. Zhao M. (2013 ). Resveratrol inhibits TGF-β1-induced epithelial-to-mesenchymal transition and suppresses lung cancer invasion and metástasis. Toxicología 303, 139–146.

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    Wang D. Zou Y. Zhuang X. Chen S. Lin Y. Li W. (2017 a). Sulforaphane suppresses EMT and metastasis in human lung cancer through miR-616-5p-mediated GSK3β/β-catenin signaling pathways. Acta Pharmacol. Sin. 38 (2), 241–251.

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    Wang H. Gu H. Feng J. Qian Y. Yang L. Jin F. (2017 b). Celastrus orbiculatus extract suppresses the epithelial-mesenchymal transition by mediating cytoskeleton rearrangement via inhibition of the Cofilin 1 signaling pathway in human gastric cancer. Oncol. Lett. 14 (3), 2926–2932.

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    Wang W. Zhou P. H. Hu W. Xu C. G. Zhou X. J. Liang C. Z. (2017 c). Cryptotanshinone hinders renal fibrosis and epithelial transdifferentiation in obstructive nephropathy by inhibiting TGF β1/Smad3/integrin β1 signal. Oncotarget 9 (42), 26625–26637.

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    Wang Z. Liu Z. Yu G. Nie X. Jia W. Liu R. (2018 ). Paeoniflorin inhibits migration and invasion of human glioblastoma cells via suppression transforming growth factor β-induced epithelial–mesenchymal transition. Neurochem. Res. 43 (3), 760–774.

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    Wen Y. C. Lee W. J. Tan P. Yang S. F. Hsiao M. Lee L. M. (2015 ). By inhibiting snail signaling and miR-23a-3p, osthole suppresses the EMT-mediated metastatic ability in prostate cancer. Oncotarget 6 (25), 21120–21136.

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    Widodo N. Kaur K. Shrestha B. G. Takagi Y. Ishii T. Wadhwa R. (2007 ). Selective killing of cancer cells by leaf extract of Ashwagandha: identification of a tumor-inhibitory factor and the first molecular insights to its effect. Clin. Cancer Res. 13, 2298–2306.

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    White C. M. Lee J. Y. (2019 ). The impact of turmeric or its curcumin extract on nonalcoholic fatty liver disease: a systematic review of clinical trials. Pharm. Pract. (Granada) 17 (1), 1350.

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    Wong K. F. Yuan Y. Luk J. M. (2012 ). Tripterygium wilfordii bioactive compounds as anticancer and anti-inflammatory agents. Clin. Exp. Pharmacol. Physiol. 39 (3), 311–320.

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    Zhang H. Qian Y. Liu Y. Li G. Cui P. Zhu Y. (2012 a). Celastrus orbiculatus extract induces mitochon- drial-mediated apoptosis in human hepatocellular carcinoma cells. J. Tradit. Chin. Med. 32, 621–626.

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    Zhang L. Tao L. Shi T. Zhang F. Sheng X. Cao Y. (2015 ). Paeonol inhibits B16F10 melanoma metastasis in vitro and in vivo via disrupting proin- flammatory cytokines-mediated NF-kappaB and STAT3 pathways. IUBMB Life 67, 778–788.

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    The plant alkaloid tetrandrine inhibits metastasis via autophagy-dependent Wnt/β-catenin and metastatic tumor antigen 1 signaling in human liver cancer cells · 2018
    Not checked
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    Zheng Y. Nan H. Hao M. Song C. Zhou Y. Gao Y. (2013 ). Antiproliferative effects of protopanaxadiol ginsenosides on human colorectal cancer cells. Biomed. Rep. 1, 555–558.

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    Zhou J. Zhu Y. F. Chen X. Y. Han B. Li F. Chen J. Y. (2017 ). Black rice-derived anthocyanins inhibit HER-2-positive breast cancer epithelial-mesenchymal transition-mediated metastasis in vitro by suppressing FAK signaling. Int. J. Mol. Med. 40 (6), 1649–1656.

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    Zhu Z. Zhao Y. Li J. Tao L. Shi P. Wei Z. (2016 ). Cryptotanshinone, a novel tumor angiogenesis inhibitor, destabilizes tumor necrosis factor-α mRNA via decreasing nuclear-cytoplasmic translocation of RNA-binding protein HuR. Mol. Carcinog. 55 (10), 1399–1410.

    Not in our library10.1002/mc.22383

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