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The PI3K/Akt pathway: a critical player in intervertebral disc degeneration

Zhi-Hua Ouyang, Wen-Jun Wang, Yi-Guo Yan and 2 more

Oncotarget · 2017 · Review

doi:10.18632/oncotarget.18628

Abstract

Intervertebral disc degeneration (IDD) is thought to be the primary cause of low back pain, a severe public health problem worldwide. Current therapy for IDD aims to alleviate the symptoms and does not target the underlying pathological alternations within the disc. Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway protects against IDD, which is attributed to increase of ECM content, prevention of cell apoptosis, facilitation of cell proliferation, induction or prevention of cell autophagy, alleviation of oxidative damage, and adaptation of hypoxic microenvironment. In the current review, we summarize recent progression on activation and negative regulation of the PI3K/Akt signaling pathway, and highlight its impact on IDD. Targeting this pathway could become an attractive therapeutic strategy for IDD in the near future.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 26, 2026. Paragraph numbers are ours, so an answer can point at one.

INTRODUCTION

Low back pain (LBP) is a major public health problem worldwide, resulting in a huge socioeconomic burden. Although the etiology of LBP is complex, intervertebral disc degeneration (IDD) has been regarded as the primary cause. It is acknowledged that genetic predisposition, aging and lifestyles including occupational exposure, smoking, and alcohol consumption are implicated in disc degeneration. Although its pathogenesis is not fully elucidated, loss of active IVD cells, progressive breakdown of extracellular matrix (ECM), alternation of intervertebral disc (IVD) cell phenotypes, and excessive inflammatory response have been proposed as critical contributors to IDD. Current therapy for IDD aims to relieve pain and control symptom rather than interfere with its pathophysiology. Although several biological strategies capable of slowing mild and moderate disc degeneration through induction of ECM remodeling have been considered, their clinical efficacy remains to be determined. Therefore, a better understanding of its pathogenesis is essential to develop effective treatments.

The intervertebral disc (IVD) is made up of the central nucleus pulposus (NP), the peripheral annulus fibrosus (AF) enclosing NP, and the upper and lower cartilaginous endplates (CEPs). These three distinct anatomic regions form a complicated structure for maintaining spinal stability. The IVD is the biggest avascular tissue in human body, with limited blood supply via peripheral capillaries. Given the fact that the IVD resides in a nutrient deficient environment, disc degeneration is prone to occur if nutrition is depleted or impeded.

Dysregulation of multiple signaling pathways has been shown to be implicated in disc degeneration. As a main intracellular signaling pathways, activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway can modulate cell proliferation, apoptosis, autophagy and differentiation under the physiological and pathological conditions by interacting with multiple downstream target proteins, including mammalian target of rapamycin (mTOR) and forkhead box O1 (FoxO1). More importantly, targeting this pathway has shown promise for the prevention or reversal of IDD. In this review, after introduction of the PI3K/Akt pathway, we explore its role in disc degeneration.

Activation of the PI3K/Akt signaling pathway and downstream effectors

As a unique family of intracellular lipid kinases, PI3Ks contain three classes (Class I, II and III). Among these, Class I is the most studied, which is subdivided into class IA (PI3Kα, β and δ) and class IB (PI3Kγ). Class I PI3Ks are heterodimer that are made up of a catalytic subunit (p110α, β, γ or δ,) and a regulatory subunit (p85α, β or γ). Akt, a serine/threonine kinase, includes three isoforms (Akt1, 2, and 3). These isoforms have high homology.

Class IA and class IB PI3Ks are activated by different agents. Receptor tyrosine kinases (RTKs) are transmembrane glycoproteins with enzymatic activity. PI3Kα, PI3Kβ and PI3Kδ are activated when an extracellular ligand binds to a RTK. In contrast, both G-protein-coupled receptors (GPCRs) and small GTPase Ras are responsible for PI3Kγ activation. Once activated, PI3Ks convert membrane-bound phosphatidylinositol 4,5-biphosphate (PIP2) into phosphatidylinositol 3,4,5-triphosphate (PIP3). PIP3 then recruits phosphoinositide- dependent kinase 1 (PDK1) to phosphorylate Akt at threonine 308 (Thr308). Subsequently, mTOR complex 2 (mTORC2) phosphorylates Akt at serine 473 (Ser473) for full AKT activation. Thereafter, activated Akt interacts with downstream target proteins to regulate multiple biological processes, including apoptosis, autophagy and cell cycle progression (Figure 1).

As an evolutionarily conserved serine/threonine protein kinase from yeast to mankind, mTOR interacts with other proteins to form two multiprotein complexes: mTORC1 and mTORC2. The mTORC1 is extremely sensitive to rapamycin, whereas mTORC2 is insensitive to rapamycin. The activated Akt reduces the formation of tuberous sclerosis complex (TSC) 1/2 and then inhibits the conversion of GTP-Rheb to GDP-Rheb. Increased GTP-Rheb activates mTORC1. Subsequently, mTORC1 induces the phosphorylation of ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). Once phosphorylated, the latter stimulates the release of eukaryotic translation initiation factor 4E (eIF4E). Both S6K and eIF4E finally promote protein translation and cell proliferation.

Besides mTORC1, Akt is capable of deactivating both glycogen synthase kinase 3β (GSK3β) and FoxO1 by stimulating their phosphorylation. Inactivation of GSK3β increases the biogenesis of cyclin D1 and then accelerates cell cycle. FoxO1 contains a conserved forkhead domain and three putative phosphorylation sites for Akt. Decreased activity of FoxO1 restrains the transcription of p27 and p21, two inhibitors of cyclin-dependent kinase (CDK), resulting in cell cycle progression. Activated PI3K/Akt signaling can also facilitate cell survival via attenuating pro-apoptotic Bad, Bax and p53 levels as well as enhancing anti-apoptotic Bcl-2 and Bcl-xl levels.

Negative regulators

The major negative regulator of this pathway is phosphatase and tensin homolog (PTEN) that converts PIP3 back to PIP2, an opposite action with PI3K (Figure 1). Notably, the activated PI3K/Akt pathway can also facilitate ubiquitin-mediated proteasomal cleavage of PTEN by upregulating the expression of NEDD4-1 (an E3 ligase), leading to permanent activation of this pathway in a positive feedback loop. In addition to PTEN, there are some specific inhibitors targeting PI3K or Akt. The PI3K inhibitors primarily contain LY294002, BYL719 and BKM120. The Akt inhibitors consist of MK-2206, GSK690693 and RX0201.

ROLES OF THE PI3K/AKT PATHWAY IN THE PATHOGENESIS OF IDD

IDD is a complicated disease involving numerous pathologic processes. As expected, the PI3K/Akt pathway takes part in disc degeneration through multiple mechanisms (Figure 2), which will be discussed in detail below.

Increase of ECM content

The hallmark of IDD is progressive loss of ECM components due to increased production of matrix metalloproteinases (MMPs) and a disintegrin and metalloprotease with thrombospondin motifs (ADAMTSs). Insulin-like growth factor-1 (IGF-1) has a significant protective effect against IDD. Serum (IGF-1) levels were lower in lumbar disc degeneration patients than those of healthy controls, and addition of IGF-1 to human NP SV40 cells induced Akt phosphorylation and then inactivated FoxO1, leading to inhibition of MMP-3 transcription. In rat endplate chondrocytes, addition of IGF-1 dramatically decreased the expression and activity of MMP-13 by activating the PI3K/Akt pathway, which increased type II collagen (Col II) content. Additionally, treatment of bovine NP cells with IGF-1 combined bone morphogenetic protein 7 (BMP-7) synergistically promoted aggrecan accumulation by enhancing Akt activity. Accumulating evidence suggests that dysregulation of microRNAs (miRNAs) participates in disc degeneration. Recently, Liu and colleagues observed that miR-4458 levels were significantly increased in degenerative human lumbar disc specimens. They also found that transfection of human NP cells with miR-4458 mimic inhibited the PI3K/Akt signaling via silencing of insulin-like growth factor 1 receptor (IGF-1R), leading to increased ECM breakdown. Collectively, activated PI3K/Akt pathway contributes to prevention of disc ECM degradation.

In addition to blockade of ECM catabolism, activation of this pathway promotes its anabolism. Sox9 is an important transcriptional factor that can drive aggrecan gene expression. It has been reported that miR-30a attenuates aggrecan content by targeting Sox9 in primary chondrocytes from cartilage isolated from osteoarthritis donors. In contrast, overexpression of Sox9 dramatically facilitated aggrecan production in cultured human articular chondrocytes. Similarly, activation of the PI3K/AKT signaling increased Sox9 expression and activity, which subsequently induced transcription of aggrecan gene in rat NP cells.

Inhibition of cell apoptosis

In general, apoptosis occurs via two well-characterized pathways in mammalian cells: the death receptor or extrinsic pathway and mitochondria or intrinsic pathway. IVD cell loss resulting from excessive apoptosis has long been considered to be an important cause of reduced ECM synthesis during disc degeneration. In addition to modulation of intradiscal ECM metabolism, this pathway can suppress apoptosis of IVD cells. Administration of 17β-estradiol combined with resveratrol (a natural polyphenol compound) promoted Akt phosphorylation and decreased caspase-3 activity, leading to apoptosis inhibition in rat NP cells treated with interleukin-1β (IL-1β). Transforming growth factor-β1 (TGF-β1) is a key factor during the development of both cartilage and spine tissues. Mesenchymal stem cell transplantation with pure fibrinous gelatin-TGF-β1 markedly decreased degenerative degree in a rabbit IDD model. Treatment of rat AF cells with TGF-β1 was found to reduce apoptosis incidence by activating the PI3K/AKT/mTOR pathway under serum deprivation. Conversely, miR-27a overexpression induced apoptosis of human degenerated NP cells via silencing of PI3K. Thus, in vivo delivery of miR-27a inhibitors might be a promising therapeutic strategy to restore the number of viable NP cells for IDD patients.

Sirtuin 1 (SIRT1) is a NAD+-dependent class III histone deacetylase. The protective effects of SIRT1 against disc degeneration are primarily derived from its abilities to promote ECM anabolism, inhibit inflammatory response and alleviate senescence of CEP cells. It has been demonstrated that SIRT1 markedly decreases the rate of apoptosis in multiple cell types, such as osteoblast-like MC3T3-E1 cells, human kidney proximal tubule epithelial cells, cardiomyocytes, and chondrocytes. In human degenerative NP cells, SIRT1 was also reported to protect against apoptosis via autophagic induction. Notably, resveratrol-induced SIRT1 activation stimulated Akt phosphorylation and reduced apoptotic incidence of human NP cells, whereas either Akt knockdown or LY294002 abrogated the inhibitory effect of SIRT1 on NP cell apoptosis. In a later study, miR-138-5p knockdown upregulated the expression of its target gene SIRT1 and then inhibited apoptosis in human NP cells treated by tumor necrosis factor-α (TNF-α). Mechanistically, upregulation of SIRT1 decreased PTEN levels to activate the PI3K/Akt pathway. These findings reveal the PI3K/AKT signaling as another important mechanism for SIRT1-mediated inhibition of NP cell apoptosis. Targeting this pathway might have enormous potential for retarding or reversing disc degeneration.

Promotion of cell proliferation

Appropriate proliferation of IVD cells represents a tissue repair process during disc degeneration. In addition to blockade of IVD cell apoptosis, this pathway can raise the number of viable IVD cells by promoting cell proliferation. In human IVD cells, exogenous treatment with either PDGF or IGF-1 stimulated DNA synthesis, which was at least partially attributed to activation of this pathway. A similar effect was also observed in bovine coccygeal NP and AF cells. Conversely, high osmolality significantly reduced Akt phosphorylation and then inhibited PDGF or IGF-I-induced synthesis of novel DNA in bovine NP cells. Leptin belongs to a peptide hormone, and its plasma levels are significantly increased in obesity patients. It can be produced by fibrocartilaginous tissues, such as articular cartilage and IVD, besides adipose tissues. Recently, Zhao et al. reported that human herniated disc tissues expressed leptin and its functional receptor, and administration of leptin could stimulate rat NP cell proliferation. Leptin also promoted the proliferation of primary cultured human NP cells. Mechanistically, leptin increased cyclin D1 expression via inhibition of Akt phosphorylation. Thus, the PI3K/AKT signaling may function as a cross-talk between obesity and IDD.

MiR-21 functions as an inducer of cell proliferation. Interestingly, transfection of human NP cells with miR-21 mimic dramatically increased Akt activity via targeting PTEN, leading to upregulation of cyclin D1 expression and subsequent cell proliferation. It is worth noting that overexpression of miR-21 could also stimulate these cell proliferation via silencing of programmed cell death 4 (PDCD4). Recently, Li et al. identified growth arrest specific gene 1 (GAS1) as a direct and functional target of miR-184. Moreover, ectopic expression of miR-184 markedly attenuated GAS1 levels, which promoted Akt phosphorylation and human NP cell proliferation. Like miR-21 and miR-184, miR-10b is also a multi-functional miRNA. Aberrant expression of this miRNA contributed to the proliferation of malignant tumor cells. Similar to these reports, transfection of human NP cells downregulated homeobox D10 (HOXD10) expression, leading to increased Akt phosphorylation and cell proliferation. However, restored expression of HOXD10 or Akt suppression reversed the mitogenic effect of miR-10b. Taken together, miR-21, miR-184 and miR-10b promote NP cell proliferation by activating the PI3K/AKT signaling.

Regulation of cell autophagy

Autophagy is an orchestrated homeostatic process involving the degradation and digestion of intracellular components by lysosomes. Recent studies have focused on the relationship between autophagy and IDD. There is a low basal level of autophagy in normal NP and AF cells. In contrast, degenerative NP and AF cells exhibited a significant increase in the autophagic activity. When compared with healthy controls, human degenerated AF tissues showed more autophagic vacuolization and autophagosomes. In NP cells isolated from rat lumbar discs, hydrogen peroxide (H2O2) induced an early autophagic response via the extracellular signal-regulated kinase (ERK)/mTOR pathway; however, prevention of autophagy by 3-methyladenine (3-MA) markedly attenuated the apoptosis of H2O2-treated NP cells. On the other hand, human degenerative NP cells exhibited a marked decrease in autophagy activity. Importantly, activation of autophagy by rapamycin suppressed IL-1β-induced ECM degradation in rat NP cells. Thus, autophagy acts as a double-edged sword in the development of IDD, depending on the stimuli.

The PI3K/Akt pathway is closely associated with autophagy. Recently, Ni et reported that treatment of rat AF cells with TGF-β1 markedly decreased autophagy incidence by activating the PI3K/AKT/mTOR signaling pathway under serum deprivation, leading to increased viable cell number. Notably, IGF1 promoted the survival of human NP cells exposed to compression via autophagy induction, which was abrogated by the specific Akt inhibitor LY294002. These findings reveal a complex role of this pathway in regulating IVD cell autophagy. This discrepancy may be attributed to the differences in stimuli, cell types and downstream effectors. However, both alterations of autophagy activity contribute to its protection against IDD (Figure 3).

Alleviation of oxidative damage

Oxidative stress is a critical contributor to disc degeneration, because it not only reinforces ECM degradation and inflammatory response, but also reduces the viability and number of IVD cells. Once activated, the PI3K/Akt pathway can enhance endogenous antioxidant ability in multiple cell types, such as macrophages, human umbilical vascular endothelial cells, and intestinal epithelial cells. Epigallocatechin 3-gallate (EGCG) is known to delay painful disc degeneration by reducing inflammation and catabolism. Recently, Krupkova et al. reported that EGCG administration protected human degenerative NP cells from oxidative stress by promoting Akt phosphorylation. This reveals a novel mechanism by which EGCG protects against IDD. It has been believed that activation of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway stimulates the synthesis of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT) and glutathione-peroxidase (GSH-Px), leading to enhancement of antioxidant defense system. Moreover, activated PI3K/Akt signaling can promote nuclear translocation of Nrf2 and subsequent upregulation of HO-1 expression under oxidative stress. Thus, it is likely that activation of Nrf2/HO-1 pathway by the PI3K/Akt signaling is, at least partially, responsible for EGCG-mediated attenuation of oxidative damage during IDD.

Mitochondrion dysfunction is a major cause of excessive reactive oxygen species (ROS) production, the hallmark of oxidative stress. ROS has been shown to induce NP and AF cell apoptosis through the mitochondria pathway. Noticeably, the PI3K/Akt signaling pathway can affect ROS-stimulated apoptosis in these cells. For example, administration of chlorogenic acid markedly decreased ROS production and inhibited apoptosis by activating the PI3K/Akt signaling in H2O2-treated rat NP cells. In human degenerative NP cells exposed to H2O2, EGCG promoted the phosphorylation of Akt, leading to decreased mitochondrial membrane depolarization and increased cellular survival. Taking these findings into account, activating this signaling cascade may be an important approach for alleviation of intradiscal oxidative damage by blocking the mitochondria apoptotic pathway.

Adaptation of hypoxic microenvironment

Since the disc is avascular, the main components within the disc, including water, aggrecan and fibrillar collagens, proportionally vary considerably depending on the location across the disc. Moreover, there is always a steep concentration gradient of oxygen across the disc, with pO2 falling to as low as 1 % in the center of the disc. Therefore, the IVD resides in a hypoxic microenvironment, which is essential for maintaining its normal physiological functions, including cellular metabolism and protein synthesis.

The IVD cells have developed some important mechanisms to ensure their survival in the hypoxic microenvironment of the disc. Hypoxia-inducible factor-1α (HIF-1α), an important transcription factor, is responsible for the induction of genes that facilitates adaptation and survival of cells and tissues under hypoxia condition. Risbud et al. detected HIF-1α expression in rat, human, and sheep NP cells in the presence of either hypoxia or normoxia, and found that these cells consistently expressed functionally active HIF-1α in the presence of hypoxia. Given the fact that activation of the PI3K/Akt signaling can upregulate HIF-1α expression under hypoxia in multiple cell types, this pathway may be also implicated in upregulation of HIF-1α expression induced by hypoxia in NP cells. On the other hand, Risbud et al. observed that under serum starvation condition, hypoxic contributed to attenuating apoptosis of rat NP cells. Moreover, cell survival in response to hypoxia was associated with activation of the PI3K/Akt/GSK3β signaling pathway. Thus, activated PI3K/Akt pathway can enhance the adaptation of NP cells to hypoxic microenvironment.

CONCLUSIONS AND FUTURE PERSPECTIVES

Although activated PI3K/Akt pathway has been shown to protect against disc degeneration through multiple mechanisms, there are a number of outstanding issues that need to be addressed. One of the most important aspects is the fact that no signaling pathway operates in isolation, which necessitates further investigation into how this pathway interacts with other signaling mediators. Establishment and application of chemically defined culture conditions would greatly promote such investigations and diminish non-associated signaling interference. The nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways have been frequently reported to be implicated in disc degeneration. Considering NF-κB and MAPK as downstream effectors of Akt, it is also important to clarify whether this pathway affects the development of IDD via regulation of NF-κB and MAPK. Hyperactivation of the PI3K/Akt pathway has been frequently reported in a wide variety of malignant tumors. Whether targeting this pathway in disc degeneration would lead to tumorigenesis is a considerable issue. Like MMPs, ADAMTSs are responsible for the degradation of Col II and aggrecan. It remains unclear whether this pathway inhibits ECM catabolism in the disc through downregulation of ADAMTS expression. In summary, more research into this pathway contribute to developing novel biological treatments for disc degeneration.

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    Wang SZ, Rui YF, Lu J, Wang C. Cell and molecular biology of intervertebral disc degeneration: current understanding and implications for potential therapeutic strategies. Cell Prolif. 2014;47:381-90.

    Not in our library10.1111/cpr.12121

  45. 45.

    Wang WJ, Yu XH, Wang C, Yang W, He WS, Zhang SJ, Yan YG, Zhang J. MMPs and ADAMTSs in intervertebral disc degeneration. Clin Chim Acta. 2015;448:238-46.

    Not in our library10.1016/j.cca.2015.06.023

  46. 46.

    Vo NV, Hartman RA, Yurube T, Jacobs LJ, Sowa GA, Kang JD. Expression and regulation of metalloproteinases and their inhibitors in intervertebral disc aging and degeneration. Spine J. 2013;13:331-41.

    Not in our library10.1016/j.spinee.2012.02.027

  47. 47.

    Asfour S, Travascio F, Elmasry S, de Rivero Vaccari JP. A computational analysis on the implications of age-related changes in the expression of cellular signals on the role of IGF-1 in intervertebral disc homeostasis. J Biomech. 2015;48:332-39.

    Not in our library10.1016/j.jbiomech.2014.11.021

  48. 48.

    Li B, Zheng XF, Ni BB, Yang YH, Jiang SD, Lu H, Jiang LS. Reduced expression of insulin-like growth factor 1 receptor leads to accelerated intervertebral disc degeneration in mice. Int J Immunopathol Pharmacol. 2013;26:337-47.

    Not in our library10.1177/039463201302600207

  49. 49.

    Zhang CC, Zhou JS, Hu JG, Wang X, Zhou XS, Sun BA, Shao C, Lin Q. Effects of IGF-1 on IL-1β-induced apoptosis in rabbit nucleus pulposus cells in vitro. Mol Med Rep. 2013;7:441-44.

    Not in our library10.3892/mmr.2012.1238

  50. 50.

    Liu Z, Zhou K, Fu W, Zhang H. Insulin-Like Growth Factor 1 Activates PI3k/Akt Signaling to Antagonize Lumbar Disc Degeneration. Cell Physiol Biochem. 2015;37:225-32.

    Not in our library10.1159/000430347

  51. 51.

    Zhang M, Zhou Q, Liang QQ, Li CG, Holz JD, Tang D, Sheu TJ, Li TF, Shi Q, Wang YJ. IGF-1 regulation of type II collagen and MMP-13 expression in rat endplate chondrocytes via distinct signaling pathways. Osteoarthritis Cartilage. 2009;17:100-06.

    Not in our library10.1016/j.joca.2008.05.007

  52. 52.

    Kim JS, Ellman MB, An HS, van Wijnen AJ, Borgia JA, Im HJ. Insulin-like growth factor 1 synergizes with bone morphogenetic protein 7-mediated anabolism in bovine intervertebral disc cells. Arthritis Rheum. 2010;62:3706-15.

    Not in our library10.1002/art.27733

  53. 53.

    Lan PH, Liu ZH, Pei YJ, Wu ZG, Yu Y, Yang YF, Liu X, Che L, Ma CJ, Xie YK, Hu QJ, Wan ZY, Wang HQ. Landscape of RNAs in human lumbar disc degeneration. Oncotarget. 2016;7:63166-76.

    Not in our library10.18632/oncotarget.11334

  54. 54.

    Ye D, Dai L, Yao Y, Qin S, Xie H, Wang W, Liang W. miR-155 Inhibits Nucleus Pulposus Cells' Degeneration through Targeting ERK 1/2. Dis Markers. 2016;2016:6984270.

    Not in our library10.1155/2016/6984270

  55. 55.

    Liu ZQ, Fu WQ, Zhao S, Zhao X. Regulation of insulin-like growth factor 1 receptor signaling by microRNA-4458 in the development of lumbar disc degeneration. Am J Transl Res. 2016;8:2309-16.

    Not in our library

  56. 56.

    Paul R, Haydon RC, Cheng H, Ishikawa A, Nenadovich N, Jiang W, Zhou L, Breyer B, Feng T, Gupta P, He TC, Phillips FM. Potential use of Sox9 gene therapy for intervertebral degenerative disc disease. Spine. 2003;28:755-63.

    Not in our library

  57. 57.

    Sive JI, Baird P, Jeziorsk M, Watkins A, Hoyland JA, Freemont AJ. Expression of chondrocyte markers by cells of normal and degenerate intervertebral discs. Mol Pathol. 2002;55:91-97.

    Not in our library10.1136/mp.55.2.91

  58. 58.

    Ren S, Liu Y, Ma J, Liu Y, Diao Z, Yang D, Zhang X, Xi Y, Hu Y. Treatment of rabbit intervertebral disc degeneration with co-transfection by adeno-associated virus-mediated SOX9 and osteogenic protein-1 double genes in vivo. Int J Mol Med. 2013;32:1063-68.

    Not in our library10.3892/ijmm.2013.1497

  59. 59.

    Chang T, Xie J, Li H, Li D, Liu P, Hu Y. MicroRNA-30a promotes extracellular matrix degradation in articular cartilage via downregulation of Sox9. Cell Prolif. 2016;49:207-18.

    Not in our library10.1111/cpr.12246

  60. 60.

    Tew SR, Pothacharoen P, Katopodi T, Hardingham TE. SOX9 transduction increases chondroitin sulfate synthesis in cultured human articular chondrocytes without altering glycosyltransferase and sulfotransferase transcription. Biochem J. 2008;414:231-36.

    Not in our library10.1042/bj20080262

  61. 61.

    Cheng CC, Uchiyama Y, Hiyama A, Gajghate S, Shapiro IM, Risbud MV. PI3K/AKT regulates aggrecan gene expression by modulating Sox9 expression and activity in nucleus pulposus cells of the intervertebral disc. J Cell Physiol. 2009;221:668-76.

    Not in our library10.1002/jcp.21904

  62. 62.

    Khan M, Maryam A, Qazi JI, Ma T. Targeting Apoptosis and Multiple Signaling Pathways with Icariside II in Cancer Cells. Int J Biol Sci. 2015;11:1100-12.

    Not in our library10.7150/ijbs.11595

  63. 63.

    Gruber HE, Hanley EN. Analysis of aging and degeneration of the human intervertebral disc. Comparison of surgical specimens with normal controls. Spine. 1998;23:751-57.

    Not in our library10.1097/00007632-199804010-00001

  64. 64.

    Ha KY, Koh IJ, Kirpalani PA, Kim YY, Cho YK, Khang GS, Han CW. The expression of hypoxia inducible factor-1alpha and apoptosis in herniated discs. Spine. 2006;31:1309-13.

    Not in our library10.1097/01.brs.0000219493.76081.d6

  65. 65.

    Ahsan R, Tajima N, Chosa E, Sugamata M, Sumida M, Hamada M. Biochemical and morphological changes in herniated human intervertebral disc. J Orthop Sci. 2001;6:510-18.

    Not in our library10.1007/s007760100006

  66. 66.

    Yang SD, Ma L, Yang DL, Ding WY. Combined effect of 17β-estradiol and resveratrol against apoptosis induced by interleukin-1β in rat nucleus pulposus cells via PI3K/Akt/caspase-3 pathway. PeerJ. 2016;4:e1640.

    Not in our library10.7717/peerj.1640

  67. 67.

    Sanford LP, Ormsby I, Gittenberger-de Groot AC, Sariola H, Friedman R, Boivin GP, Cardell EL, Doetschman T. TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. Development. 1997;124:2659-70.

    Not in our library10.1242/dev.124.13.2659

  68. 68.

    Baffi MO, Slattery E, Sohn P, Moses HL, Chytil A, Serra R. Conditional deletion of the TGF-beta type II receptor in Col2a expressing cells results in defects in the axial skeleton without alterations in chondrocyte differentiation or embryonic development of long bones. Dev Biol. 2004;276:124-42.

    Not in our library10.1016/j.ydbio.2004.08.027

  69. 69.

    Yang H, Wu J, Liu J, Ebraheim M, Castillo S, Liu X, Tang T, Ebraheim NA. Transplanted mesenchymal stem cells with pure fibrinous gelatin-transforming growth factor-beta1 decrease rabbit intervertebral disc degeneration. Spine J. 2010;10:802-10.

    Not in our library10.1016/j.spinee.2010.06.019

  70. 70.

    Ni BB, Li B, Yang YH, Chen JW, Chen K, Jiang SD, Jiang LS. The effect of transforming growth factor β1 on the crosstalk between autophagy and apoptosis in the annulus fibrosus cells under serum deprivation. Cytokine. 2014;70:87-96.

    Not in our library10.1016/j.cyto.2014.07.249

  71. 71.

    Liu G, Cao P, Chen H, Yuan W, Wang J, Tang X. MiR-27a regulates apoptosis in nucleus pulposus cells by targeting PI3K. PLoS One. 2013;8:e75251.

    Not in our library10.1371/journal.pone.0075251

  72. 72.

    Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000;403:795-800.

    Not in our library10.1038/35001622

  73. 73.

    Xia X, Guo J, Lu F, Jiang J. SIRT1 Plays a Protective Role in Intervertebral Disc Degeneration in a Puncture-induced Rodent Model. Spine. 2015;40:E515-24.

    Not in our library10.1097/brs.0000000000000817

  74. 74.

    Shen J, Fang J, Hao J, Zhong X, Wang D, Ren H, Hu Z. SIRT1 Inhibits the Catabolic Effect of IL-1β Through TLR2/SIRT1/NF-κB Pathway in Human Degenerative Nucleus Pulposus Cells. Pain Physician. 2016;19:E215-26.

    Not in our library

  75. 75.

    Zhou N, Lin X, Dong W, Huang W, Jiang W, Lin L, Qiu Q, Zhang X, Shen J, Song Z, Liang X, Hao J, Wang D, Hu Z. SIRT1 alleviates senescence of degenerative human intervertebral disc cartilage endo-plate cells via the p53/p21 pathway. Sci Rep. 2016;6:22628.

    Not in our library10.1038/srep22628

  76. 76.

    Wu JW, Wang JJ, Chen JB, Huang YL, Wang H, Liu GH, Li LF, Kang M, Wang XG, Cai HH. Resveratrol could reverse the expression of SIRT1 and MMP-1 in vitro. Genet Mol Res. 2015;14:12386-93.

    Not in our library10.4238/2015.october.16.5

  77. 77.

    Gu X, Han D, Chen W, Zhang L, Lin Q, Gao J, Fanning S, Han B. SIRT1-mediated FoxOs pathways protect against apoptosis by promoting autophagy in osteoblast-like MC3T3-E1 cells exposed to sodium fluoride. Oncotarget. 2016;7:65218-30.

    Not in our library10.18632/oncotarget.11573

  78. 78.

    Wang XL, Wu LY, Zhao L, Sun LN, Liu HY, Liu G, Guan GJ. SIRT1 activator ameliorates the renal tubular injury induced by hyperglycemia in vivo and in vitro via inhibiting apoptosis. Biomed Pharmacother. 2016;83:41-50.

    Not in our library10.1016/j.biopha.2016.06.009

  79. 79.

    Yang B, Ma S, Wang YB, Xu B, Zhao H, He YY, Li CW, Zhang J, Cao YK, Feng QZ. Resveratrol exerts protective effects on anoxia/reoxygenation injury in cardiomyocytes via miR-34a/Sirt1 signaling pathway. Eur Rev Med Pharmacol Sci. 2016;20:2734-41.

    Not in our library

  80. 80.

    Liu B, Lei M, Hu T, Yu F, Xiao DM, Kang H. Inhibitory effects of SRT1720 on the apoptosis of rabbit chondrocytes by activating SIRT1 via p53/bax and NF-kappaB/PGC-1alpha pathways. J Huazhong Univ Sci Technolog Med Sci. 2016;36:350-355.

    Not in our library10.1007/s11596-016-1590-y

  81. 81.

    Jiang W, Zhang X, Hao J, Shen J, Fang J, Dong W, Wang D, Zhang X, Shui W, Luo Y, Lin L, Qiu Q, Liu B, Hu Z. SIRT1 protects against apoptosis by promoting autophagy in degenerative human disc nucleus pulposus cells. Sci Rep. 2014;4:7456.

    Not in our library10.1038/srep07456

  82. 82.

    Miyazaki S, Kakutani K, Yurube T, Maeno K, Takada T, Zhang Z, Kurakawa T, Terashima Y, Ito M, Ueha T, Matsushita T, Kuroda R, Kurosaka M, Nishida K. Recombinant human SIRT1 protects against nutrient deprivation-induced mitochondrial apoptosis through autophagy induction in human intervertebral disc nucleus pulposus cells. Arthritis Res Ther. 2015;17:253.

    Not in our library10.1186/s13075-015-0763-6

  83. 83.

    Wang D, Hu Z, Hao J, He B, Gan Q, Zhong X, Zhang X, Shen J, Fang J, Jiang W. SIRT1 inhibits apoptosis of degenerative human disc nucleus pulposus cells through activation of Akt pathway. Age (Dordr). 2013;35:1741-53.

    Not in our library10.1007/s11357-012-9474-y

  84. 84.

    Wang B, Wang D, Yan T, Yuan H. MiR-138-5p promotes TNF-α-induced apoptosis in human intervertebral disc degeneration by targeting SIRT1 through PTEN/PI3K/Akt signaling. Exp Cell Res. 2016;345:199-205.

    Not in our library10.1016/j.yexcr.2016.05.011

  85. 85.

    Zhao CQ, Wang LM, Jiang LS, Dai LY. The cell biology of intervertebral disc aging and degeneration. Ageing Res Rev. 2007;6:247-61.

    Not in our library10.1016/j.arr.2007.08.001

  86. 86.

    Pratsinis H, Constantinou V, Pavlakis K, Sapkas G, Kletsas D. Exogenous and autocrine growth factors stimulate human intervertebral disc cell proliferation via the ERK and Akt pathways. J Orthop Res. 2012;30:958-964.

    Not in our library10.1002/jor.22017

  87. 87.

    Pratsinis H, Kletsas D. PDGF, bFGF and IGF-I stimulate the proliferation of intervertebral disc cells in vitro via the activation of the ERK and Akt signaling pathways. Eur Spine J. 2007;16:1858-1866.

    Not in our library10.1007/s00586-007-0408-9

  88. 88.

    Mavrogonatou E, Kletsas D. Effect of varying osmotic conditions on the response of bovine nucleus pulposus cells to growth factors and the activation of the ERK and Akt pathways. J Orthop Res. 2010;28:1276-1282.

    Not in our library10.1002/jor.21140

  89. 89.

    Hui W, Litherland GJ, Elias MS, Kitson GI, Cawston TE, Rowan AD, Young DA. Leptin produced by joint white adipose tissue induces cartilage degradation via upregulation and activation of matrix metalloproteinases. Ann Rheum Dis. 2012;71:455-62.

    Not in our library10.1136/annrheumdis-2011-200372

  90. 90.

    Zhao CQ, Liu D, Li H, Jiang LS, Dai LY. Expression of leptin and its functional receptor on disc cells: contribution to cell proliferation. Spine. 2008;33:E858-64.

    Not in our library10.1097/brs.0b013e31818338e5

  91. 91.

    Li Z, Shen J, Wu WK, Yu X, Liang J, Qiu G, Liu J. Leptin induces cyclin D1 expression and proliferation of human nucleus pulposus cells via JAK/STAT, PI3K/Akt and MEK/ERK pathways. PLoS One. 2012;7:e53176.

    Not in our library10.1371/journal.pone.0053176

  92. 92.

    Li JJ, Chan WH, Leung WY, Wang Y, Xu CS. MicroRNA-21 promotes proliferation of rat hepatocyte BRL-3A by targeting FASLG. Genet Mol Res. 2015;14:4150-60.

    Not in our library10.4238/2015.april.27.30

  93. 93.

    Liu Y, Wang X, Yang D, Xiao Z, Chen X. MicroRNA-21 affects proliferation and apoptosis by regulating expression of PTEN in human keloid fibroblasts. Plast Reconstr Surg. 2014;134:561e-73e.

    Not in our library10.1097/prs.0000000000000577

  94. 94.

    Xu J, Zhang W, Lv Q, Zhu D. Overexpression of miR-21 promotes the proliferation and migration of cervical cancer cells via the inhibition of PTEN. Oncol Rep. 2015;33:3108-16.

    Not in our library10.3892/or.2015.3931

  95. 95.

    Liu H, Huang X, Liu X, Xiao S, Zhang Y, Xiang T, Shen X, Wang G, Sheng B. miR-21 promotes human nucleus pulposus cell proliferation through PTEN/AKT signaling. Int J Mol Sci. 2014;15:4007-18.

    Not in our library10.3390/ijms15034007

  96. 96.
    Effect of microRNA-21 on the proliferation of human degenerated nucleus pulposus by targeting programmed cell death 4 · 2016
    Not checked
  97. 97.

    Li W, Wang P, Zhang Z, Wang W, Liu Y, Qi Q. MiR-184 Regulates Proliferation in Nucleus Pulposus Cells by Targeting GAS1. World Neurosurg. 2017;97:710-715.

    Not in our library10.1016/j.wneu.2016.01.024

  98. 98.

    Wang J, Wang B, Chen LQ, Yang J, Gong ZQ, Zhao XL, Zhang CQ, Du KL. miR-10b promotes invasion by targeting KLF4 in osteosarcoma cells. Biomed Pharmacother. 2016;84:947-953.

    Not in our library10.1016/j.biopha.2016.09.108

  99. 99.

    Chen H, Fan Y, Xu W, Chen J, Xu C, Wei X, Fang D, Feng Y. miR-10b Inhibits Apoptosis and Promotes Proliferation and Invasion of Endometrial Cancer Cells via Targeting HOXB3. Cancer Biother Radiopharm. 2016;31:225-31.

    Not in our library10.1089/cbr.2016.1998

  100. 100.

    Wang YY, Li L, Ye ZY, Zhao ZS, Yan ZL. MicroRNA-10b promotes migration and invasion through Hoxd10 in human gastric cancer. World J Surg Oncol. 2015;13:259.

    Not in our library10.1186/s12957-015-0673-8

  101. 101.
    MicroRNA-10b Promotes Nucleus Pulposus Cell Proliferation through RhoC-Akt Pathway by Targeting HOXD10 in Intervetebral Disc Degeneration · 2013
    Retracted
  102. 102.

    Ruocco N, Costantini S, Costantini M. Blue-Print Autophagy: Potential for Cancer Treatment. Mar Drugs. 2016;14:14.

    Not in our library10.3390/md14070138

  103. 103.

    Cohen-Kaplan V, Livneh I, Avni N, Cohen-Rosenzweig C, Ciechanover A. The ubiquitin-proteasome system and autophagy: coordinated and independent activities. Int J Biochem Cell Biol. 2016;79:403-18.

    Not in our library10.1016/j.biocel.2016.07.019

  104. 104.

    Zhang SJ, Yang W, Wang C, He WS, Deng HY, Yan YG, Zhang J, Xiang YX, Wang WJ. Autophagy: A double-edged sword in intervertebral disk degeneration. Clin Chim Acta. 2016;457:27-35.

    Not in our library10.1016/j.cca.2016.03.016

  105. 105.

    Kong CG, Park JB, Kim MS, Park EY. High glucose accelerates autophagy in adult rat intervertebral disc cells. Asian Spine J. 2014;8:543-48.

    Not in our library10.4184/asj.2014.8.5.543

  106. 106.

    Jiang L, Zhang X, Zheng X, Ru A, Ni X, Wu Y, Tian N, Huang Y, Xue E, Wang X, Xu H. Apoptosis, senescence, and autophagy in rat nucleus pulposus cells: I mplications for diabetic intervertebral disc degeneration. J Orthop Res. 2013;31:692-702.

    Not in our library10.1002/jor.22289

  107. 107.

    Ye W, Zhu W, Xu K, Liang A, Peng Y, Huang D, Li C. Increased macroautophagy in the pathological process of intervertebral disc degeneration in rats. Connect Tissue Res. 2013;54:22-28.

    Not in our library10.3109/03008207.2012.715702

  108. 108.

    Gruber HE, Hoelscher GL, Ingram JA, Bethea S, Hanley EN. Autophagy in the Degenerating Human Intervertebral Disc: In vivo Molecular and Morphological Evidence, and Induction of Autophagy in Cultured Annulus Cells Exposed to Proinflammatory Cytokines-Implications for Disc Degeneration. Spine. 2015;40:773-82.

    Not in our library10.1097/brs.0000000000000865

  109. 109.

    Chen JW, Ni BB, Li B, Yang YH, Jiang SD, Jiang LS. The responses of autophagy and apoptosis to oxidative stress in nucleus pulposus cells: implications for disc degeneration. Cell Physiol Biochem. 2014;34:1175-89.

    Not in our library10.1159/000366330

  110. 110.

    Xu K, Chen W, Wang X, Peng Y, Liang A, Huang D, Li C, Ye W. Autophagy attenuates the catabolic effect during inflammatory conditions in nucleus pulposus cells, as sustained by NF-κB and JNK inhibition. Int J Mol Med. 2015;36:661-68.

    Not in our library10.3892/ijmm.2015.2280

  111. 111.

    Heras-Sandoval D, Pérez-Rojas JM, Hernández-Damián J, Pedraza-Chaverri J. The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cell Signal. 2014;26:2694-701.

    Not in our library10.1016/j.cellsig.2014.08.019

  112. 112.

    Zhang J, Zhang JX, Zhang QL. PI3K/AKT/mTOR-mediated autophagy in the development of autism spectrum disorder. Brain Res Bull. 2016;125:152-58.

    Not in our library10.1016/j.brainresbull.2016.06.007

  113. 113.

    Liu ZQ, Zhao S, Fu WQ. Insulin-like growth factor 1 antagonizes lumbar disc degeneration through enhanced autophagy. Am J Transl Res. 2016;8:4346-53.

    Not in our library

  114. 114.
    Excessive reactive oxygen species are therapeutic targets for intervertebral disc degeneration · 2015
    No notice
  115. 115.

    Dimozi A, Mavrogonatou E, Sklirou A, Kletsas D. Oxidative stress inhibits the proliferation, induces premature senescence and promotes a catabolic phenotype in human nucleus pulposus intervertebral disc cells. Eur Cell Mater. 2015;30:89-102.

    Not in our library10.22203/ecm.v030a07

  116. 116.

    Chai J, Luo L, Hou F, Fan X, Yu J, Ma W, Tang W, Yang X, Zhu J, Kang W, Yan J, Liang H. Agmatine Reduces Lipopolysaccharide-Mediated Oxidant Response via Activating PI3K/Akt Pathway and Up-Regulating Nrf2 and HO-1 Expression in Macrophages. PLoS One. 2016;11:e0163634.

    Not in our library10.1371/journal.pone.0163634

  117. 117.

    Chu P, Han G, Ahsan A, Sun Z, Liu S, Zhang Z, Sun B, Song Y, Lin Y, Peng J, Tang Z. Phosphocreatine protects endothelial cells from Methylglyoxal induced oxidative stress and apoptosis via the regulation of PI3K/Akt/eNOS and NF-kappaB pathway. Vascul Pharmacol. 2017;91:26-35.

    Not in our library10.1016/j.vph.2016.08.012

  118. 118.

    Krupkova O, Handa J, Hlavna M, Klasen J, Ospelt C, Ferguson SJ, Wuertz-Kozak K. The Natural Polyphenol Epigallocatechin Gallate Protects Intervertebral Disc Cells from Oxidative Stress. Oxid Med Cell Longev. 2016;2016:7031397.

    Not in our library10.1155/2016/7031397

  119. 119.

    Alfieri A, Srivastava S, Siow RC, Modo M, Fraser PA, Mann GE. Targeting the Nrf2-Keap1 antioxidant defence pathway for neurovascular protection in stroke. J Physiol. 2011;589:4125-36.

    Not in our library10.1113/jphysiol.2011.210294

  120. 120.

    Demirel U, Yalniz M, Aygün C, Orhan C, Tuzcu M, Sahin K, Ozercan IH, Bahçecioğlu IH. Allopurinol ameliorates thioacetamide-induced acute liver failure by regulating cellular redox-sensitive transcription factors in rats. Inflammation. 2012;35:1549-57.

    Not in our library10.1007/s10753-012-9470-5

  121. 121.

    Li W, Ma F, Zhang L, Huang Y, Li X, Zhang A, Hou C, Zhu Y, Zhu Y. S-Propargyl-cysteine Exerts a Novel Protective Effect on Methionine and Choline Deficient Diet-Induced Fatty Liver via Akt/Nrf2/HO-1 Pathway. Oxid Med Cell Longev. 2016;2016:4690857.

    Not in our library10.1155/2016/4690857

  122. 122.

    Zhang G, Wang Q, Zhou Q, Wang R, Xu M, Wang H, Wang L, Wilcox CS, Liu R, Lai EY. Protective Effect of Tempol on Acute Kidney Injury Through PI3K/Akt/Nrf2 Signaling Pathway. Kidney Blood Press Res. 2016;41:129-38.

    Not in our library10.1159/000443414

  123. 123.

    Yang L, Rong Z, Zeng M, Cao Y, Gong X, Lin L, Chen Y, Cao W, Zhu L, Dong W. Pyrroloquinoline quinone protects nucleus pulposus cells from hydrogen peroxide-induced apoptosis by inhibiting the mitochondria-mediated pathway. Eur Spine J. 2015;24:1702-10.

    Not in our library10.1007/s00586-014-3630-2

  124. 124.

    Cai XY, Xia Y, Yang SH, Liu XZ, Shao ZW, Liu YL, Yang W, Xiong LM. Ropivacaine- and bupivacaine-induced death of rabbit annulus fibrosus cells in vitro: involvement of the mitochondrial apoptotic pathway. Osteoarthritis Cartilage. 2015;23:1763-75.

    Not in our library10.1016/j.joca.2015.05.013

  125. 125.

    Xie RH, Yin M, Yin CC, Cheng XG, Xu ZW, Cao XQ, Chen WC. [Mechanism of chlorogenic acid on apoptosis of rat nucleus pulposus cells induced by oxidative stress]. Zhong Yao Cai. 2014;37:465-69.

    Not in our library

  126. 126.

    Bartels EM, Fairbank JC, Winlove CP, Urban JP. Oxygen and lactate concentrations measured in vivo in the intervertebral discs of patients with scoliosis and back pain. Spine. 1998;23:1-7.

    Not in our library10.1097/00007632-199801010-00001

  127. 127.

    Risbud MV, Schipani E, Shapiro IM. Hypoxic regulation of nucleus pulposus cell survival: from niche to notch. Am J Pathol. 2010;176:1577-83.

    Not in our library10.2353/ajpath.2010.090734

  128. 128.

    Ke Q, Costa M. Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol. 2006;70:1469-80.

    Not in our library10.1124/mol.106.027029

  129. 129.

    Risbud MV, Guttapalli A, Stokes DG, Hawkins D, Danielson KG, Schaer TP, Albert TJ, Shapiro IM. Nucleus pulposus cells express HIF-1 alpha under normoxic culture conditions: a metabolic adaptation to the intervertebral disc microenvironment. J Cell Biochem. 2006;98:152-59.

    Not in our library10.1002/jcb.20765

  130. 130.
    Salternamide A Suppresses Hypoxia-Induced Accumulation of HIF-1α and Induces Apoptosis in Human Colorectal Cancer Cells · 2015
    Not checked
  131. 131.

    Paeng SH, Jung WK, Park WS, Lee DS, Kim GY, Choi YH, Seo SK, Jang WH, Choi JS, Lee YM, Park S, Choi IW. Caffeic acid phenethyl ester reduces the secretion of vascular endothelial growth factor through the inhibition of the ROS, PI3K and HIF-1α signaling pathways in human retinal pigment epithelial cells under hypoxic conditions. Int J Mol Med. 2015;35:1419-26.

    Not in our library10.3892/ijmm.2015.2116

  132. 132.

    Risbud MV, Fertala J, Vresilovic EJ, Albert TJ, Shapiro IM. Nucleus pulposus cells upregulate PI3K/Akt and MEK/ERK signaling pathways under hypoxic conditions and resist apoptosis induced by serum withdrawal. Spine. 2005;30:882-89.

    Not in our library10.1097/01.brs.0000159096.11248.6d

  133. 133.

    Dai T, Zheng H, Fu GS. Hypoxia confers protection against apoptosis via the PI3K/Akt pathway in endothelial progenitor cells. Acta Pharmacol Sin. 2008;29:1425-31.

    Not in our library10.1111/j.1745-7254.2008.00904.x

  134. 134.

    Wang X, Li C, Liang A, Peng Y, Sun J, Huang D, Xu K, Ye W. Regulation of a disintegrins and metalloproteinase with thrombospondin motifs 7 during inflammation in nucleus pulposus (NP) cells: role of AP-1, Sp1 and NF-kappaB signaling. Inflamm Res. 2016;65:951-962.

    Not in our library10.1007/s00011-016-0978-2

  135. 135.

    Yuan FL, Zhao MD, Jiang DL, Jin C, Liu HF, Xu MH, Hu W, Li X. Involvement of acid-sensing ion channel 1a in matrix metabolism of endplate chondrocytes under extracellular acidic conditions through NF-κB transcriptional activity. Cell Stress Chaperones. 2016;21:97-104.

    Not in our library10.1007/s12192-015-0643-7

  136. 136.
    Estrogen Enhances Matrix Synthesis in Nucleus Pulposus Cell through the Estrogen Receptor β-p38 MAPK Pathway · 2016
    Not checked
  137. 137.

    Wang J, Chen H, Cao P, Wu X, Zang F, Shi L, Liang L, Yuan W. Inflammatory cytokines induce caveolin-1/β-catenin signalling in rat nucleus pulposus cell apoptosis through the p38 MAPK pathway. Cell Prolif. 2016;49:362-72.

    Not in our library10.1111/cpr.12254

  138. 138.
    Targeting PI3K/Akt/mTOR Signaling in Cancer · 2014
    No notice
  139. 139.

    Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27:5497-510.

    Not in our library10.1038/onc.2008.245

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