Vitexin alleviates ER-stress-activated apoptosis and the related inflammation in chondrocytes and inhibits the degeneration of cartilage in rats

Xie, Chenglong; Li, Junli; Xue, Enxing; Dou, Haicheng; Lin, Jinti; Chen, Kai; Wu, Hongqiang; Wu, Long; Xuan, Jun; Huang, Qi-Shan

doi:10.1039/c8fo01509k

Cited by 35 publications

(23 citation statements)

References 55 publications

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“…In hypoxia, GRP78/GRP94 levels in control cells were already overexpressed in comparison to control cells cultured in normoxic conditions. Nevertheless, co-treatment with both TUDCA and HA significantly decreased expression of these chaperone proteins in comparison to stimulation with IL-1β alone, which is also in partial agreement with previous reports [8,22,27]. Husa et al demonstrated that IL-1β signaling can stimulate UPR activation in chondrocytes [27].…”

Section: Discussionsupporting

confidence: 90%

“…Chondrocytes are responsible for synthesis and turnover of extracellular matrix (ECM) 2 of 24 components, making them a key regulators of growth, mechanical support, and proper functioning of diarthrodial joints [6,7]. One of the main features of cartilage degeneration was found to be apoptosis of chondrocyte cells [6,8]. Thus, loss of chondrocytes due to apoptotic cell death has been proposed as a possible mechanism of OA pathology [6].…”

Section: Introductionmentioning

confidence: 99%

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Molecular and Cellular Effects of Chemical Chaperone—TUDCA on ER-Stressed NHAC-kn Human Articular Chondrocytes Cultured in Normoxic and Hypoxic Conditions

et al. 2021

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Osteoarthritis (OA) is considered one of the most common arthritic diseases characterized by progressive degradation and abnormal remodeling of articular cartilage. Potential therapeutics for OA aim at restoring proper chondrocyte functioning and inhibiting apoptosis. Previous studies have demonstrated that tauroursodeoxycholic acid (TUDCA) showed anti-inflammatory and anti-apoptotic activity in many models of various diseases, acting mainly via alleviation of endoplasmic reticulum (ER) stress. However, little is known about cytoprotective effects of TUDCA on chondrocyte cells. The present study was designed to evaluate potential effects of TUDCA on interleukin-1β (IL-1β) and tunicamycin (TNC)-stimulated NHAC-kn chondrocytes cultured in normoxic and hypoxic conditions. Our results showed that TUDCA alleviated ER stress in TNC-treated chondrocytes, as demonstrated by reduced CHOP expression; however, it was not effective enough to prevent apoptosis of NHAC-kn cells in either normoxia nor hypoxia. However, co-treatment with TUDCA alleviated inflammatory response induced by IL-1β, as shown by down regulation of Il-1β, Il-6, Il-8 and Cox2, and increased the expression of antioxidant enzyme Sod2. Additionally, TUDCA enhanced Col IIα expression in IL-1β- and TNC-stimulated cells, but only in normoxic conditions. Altogether, these results suggest that although TUDCA may display chondoprotective potential in ER-stressed cells, further analyses are still necessary to fully confirm its possible recommendation as potential candidate in OA therapy.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Molecular and Cellular Effects of Chemical Chaperone—TUDCA on ER-Stressed NHAC-kn Human Articular Chondrocytes Cultured in Normoxic and Hypoxic Conditions

et al. 2021

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“…Furthermore, the mitochondria release proapoptotic factors such as Cyt c to activate caspase-9, thereby initiating programmed cell death [ 36 ]. A study by Xie et al showed that VT was capable of alleviating ER stress-activated apoptosis and the related inflammation in rat chondrocytes [ 37 ]. Furthermore, Min et al showed that VT protected against hypoxic-ischemic injury by inhibiting Ca 2+ /calmodulin-dependent protein kinase II and apoptosis signaling in the neonatal mouse brain [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Vitexin Mitigates Myocardial Ischemia/Reperfusion Injury in Rats by Regulating Mitochondrial Dysfunction via Epac1‐Rap1 Signaling

Yang

Xue

Ding

et al. 2021

Oxidative Medicine and Cellular Longevity

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Revascularization is an effective therapy for rescuing myocardial tissue after ischemic events. However, the process of reperfusion can lead to more severe cardiomyocyte damage, called myocardial ischemia-reperfusion (I/R) injury (MIRI). We have previously shown that vitexin (VT) (a flavonoid compound derived from natural products) protects against MIRI; however, the exact mechanisms underpinning this effect require further elucidation. This study is aimed at elucidating the protective mechanism of VT in inhibiting ischemic myocardial mitochondrial dysfunction and reducing cardiomyocyte apoptosis by regulating Epac1-Rap1 signaling. Isolated rat hearts were subjected to MIRI in a Langendorff perfusion system, and H9c2 cells were subjected to hypoxia/reoxygenation (H/R) in vitro. Our analyses show that during I/R, Epac1 expression was upregulated, left ventricular dysfunction deteriorated, mitochondrial dynamics were disrupted, and both myocardial cells and tissues exhibited apoptosis. Furthermore, administration of 8-CPT (an Epac agonist) exacerbated cardiomyocyte injury and mitochondrial dysfunction. Interestingly, suppressing the function of Epac1 through VT or ESI-09 (an Epac inhibitor) treatment during I/R reduced the myocardial infarct size, cardiomyocyte apoptosis, and reactive oxygen species production; alleviated mitochondrial dysfunction by increasing mitochondrial membrane potential; elevated MFN2 expression; and inhibited Drp1 expression. To our knowledge, our results reveal, for the first time, the mechanisms underlying the protective effect of VT in the myocardium of rats with MIRI. Moreover, we provide a new target and theoretical basis for VT in the treatment of ischemic heart disease.

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“…18 Mounting evidence indicates that ER stress can lead to chondrocyte apoptosis and OA progression. [19][20][21] Recent evidence also reports that physiological and pharmacological agent stimulation leads to ER stress in chondrocytes in vitro. 9 Further, ER stress-related protein GRP78 is elevated in ER stress.…”

Section: Discussionmentioning

confidence: 99%

Ablation of PKM2 ameliorated ER stress‐induced apoptosis and associated inflammation response in IL‐1β‐treated chondrocytes via blocking Rspo2‐mediated Wnt/β‐catenin signaling

Wang

Liu

et al. 2020

J of Cellular Biochemistry

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Endoplasmic reticulum (ER) stress and the related apoptosis and inflammation damage play key roles in osteoarthritis development. The aim of the present work was to investigate the exact role and potential underlying mechanism of pyruvate kinase M2 (PKM2) in rat chondrocytes exposed to interleukin‐Iβ (IL‐1β). We observed that IL‐1β stimulation resulted in an apparent enhancement in PKM2 expression. Additionally, loss of PKM2 evidently ascended cell viability in response to IL‐1β exposure. Simultaneously, elimination of PKM2 manifestly repressed IL‐1β‐stimulated chondrocyte apoptosis, concomitant with attenuated in the proapoptotic protein markers Bax and cleaved caspase‐3, and elevated the antiapoptotic protein Bcl‐2. In the meanwhile, knockdown of PKM2 ameliorated ER stress in IL‐1β‐treated chondrocytes, as evidenced by reduced expression of the ER stress‐associated proteins GRP78, CHOP, and cleaved caspase‐12. Furthermore, PKM2 silencing protected chondrocytes against IL‐1β‐triggered inflammatory response, as reflected by the downregulated release of proinflammatory mediators, including tumor necrosis factor‐α, IL‐6, inducible nitric oxide synthase, cyclooxygenase‐2, and prostaglandin E2, as well as decreased nitric oxide generation. More important, abrogating PKM2 expression caused a marked decline in Rspo2 expression, and subsequently blocked Wnt/β‐catenin signaling. Mechanistically, the Wnt/β‐catenin signaling activator Licl effectively impeded the beneficial effects of PKM2 ablation on IL‐1β‐stimulated apoptosis and inflammatory response. These findings collectively implicated that PKM2 inhibition protected against ER stress‐mediated cell apoptosis and inflammatory injury in rat chondrocytes stimulated with IL‐1β by inactivating Rspo2‐mediated Wnt/β‐catenin pathway, and may represented a novel therapeutic target for osteoarthritis.

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Vitexin alleviates ER-stress-activated apoptosis and the related inflammation in chondrocytes and inhibits the degeneration of cartilage in rats

Abstract: Excessive extracellular matrix degradation and chondrocyte apoptosis are the pathological features of osteoarthritis (OA).

Cited by 35 publications

References 55 publications

Molecular and Cellular Effects of Chemical Chaperone—TUDCA on ER-Stressed NHAC-kn Human Articular Chondrocytes Cultured in Normoxic and Hypoxic Conditions

Molecular and Cellular Effects of Chemical Chaperone—TUDCA on ER-Stressed NHAC-kn Human Articular Chondrocytes Cultured in Normoxic and Hypoxic Conditions

Vitexin Mitigates Myocardial Ischemia/Reperfusion Injury in Rats by Regulating Mitochondrial Dysfunction via Epac1‐Rap1 Signaling

Ablation of PKM2 ameliorated ER stress‐induced apoptosis and associated inflammation response in IL‐1β‐treated chondrocytes via blocking Rspo2‐mediated Wnt/β‐catenin signaling

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