Aspirin-Mediated Attenuation of Intervertebral Disc Degeneration by Ameliorating Reactive Oxygen Species <i>In Vivo</i> and <i>In Vitro</i>

Liu, Yu; Lin, Jiayi; Wu, Xiexing; Guo, Xiaobin; Sun, Houyi; Yu, Binqing; Shen, Junqi; Bai, Jiaxiang; Chen, Zhanghuan; Yang, Huilin; Mao, Haiqing

doi:10.1155/2019/7189854

Cited by 56 publications

(46 citation statements)

References 48 publications

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“…Therefore, these results provide strong evidence that require further investigations. On the other hand, previous studies have shown that increased oxidative stress and inflammatory response might account for the progression of IDD [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of HDAC4 by GSK3β leads to downregulation of KLF5 and ASK1 and prevents the progression of intravertebral disc degeneration

et al. 2021

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Background Intervertebral disc degeneration (IDD) is a major cause of lower back pain. This study aimed at exploring the effects of histone deacetylase 4 (HDAC4) and its upstream and downstream signaling molecules on IDD development. Methods A murine IDD model was established by inducing a needle puncture injury to the vertebrate, whereupon we isolated and transfected of nucleus pulposus (NP) cells. Disc height index (DHI) of the mice was determined by X-ray tomography, while the pain experienced by the IDD mice was evaluated by mechanical and thermal sensitivity tests. Next, the interaction between GSK3β and HDAC4 as well as that between HDAC4 and KLF5 acetylation was assessed by co-immunoprecipitation, while the promoter region binding was assessed identified by chromatin immunoprecipitation. By staining methods with TUNEL, Safranin O fast green, and hematoxylin and eosin, the NP cell apoptosis, degradation of extracellular matrix, and morphology of intervertebral disc tissues were measured. Furthermore, mRNA and protein expressions of GSK3β, HDAC4, KLF5, and ASK1, as well as the extent of HDAC4 phosphorylation, were determined by RT-qPCR and Western blotting. Results GSK3β was identified to be downregulated in the intervertebral disc tissues obtained from IDD mice, while HDAC4, KLF5, and ASK1 were upregulated. HDAC4 silencing alleviated IDD symptoms. It was also found that GSK3β promoted the phosphorylation of HDAC4 to increase its degradation, while HDAC4 promoted ASK1 expression through upregulating the expression of KLF5. In IDD mice, GSK3β overexpression resulted in increased DHI, inhibition of NP cell apoptosis, alleviation of disc degeneration, and promoted mechanical and thermal pain thresholds. However, HDAC4 overexpression reversed these effects by promoting ASK1 expression. Conclusion Based on the key findings of the current study, we conclude that GSK3β can promote degradation of HDAC4, which lead to an overall downregulation of the downstream KLF5/ASK1 axis, thereby alleviating the development of IDD.

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Section: Discussionmentioning

confidence: 99%

Inhibition of HDAC4 by GSK3β leads to downregulation of KLF5 and ASK1 and prevents the progression of intravertebral disc degeneration

et al. 2021

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“…pSTAT3 can enter the nucleus as an active dimer and turn on the transcription of related functional genes (such as atrophy related genes) (12). Aspirin has been reported to reduce the production of inflammatory cytokines (IL-1β, IL-6 and TNF-α) in nucleus pulposus cells (NPCs) induced by lipopolysaccharide (LPS) (30), inhibit the JAK/STAT3 signaling pathway in patients with rheumatoid arthritis, promote the apoptosis of fibroblast-like synoviocytes and inhibit their proliferation (31). In BV-2 microglia, Aspirin inhibited the activation of IL6/JAK2/STAT3 signaling pathway induced by lipopolysaccharide (10).…”

Section: Discussionmentioning

confidence: 99%

Aspirin alleviates denervation-induced muscle atrophy via regulating the Sirt1/PGC-1α axis and STAT3 signaling

Wan¹,

Zhang²,

Huang³

et al. 2020

Ann Transl Med

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Background: Our prior studies have shown that inflammation may play an important triggering role during the process of denervated muscle atrophy. The nonsteroidal anti-inflammatory drug aspirin exhibits the effect of anti-inflammatory factors. This study will investigate the protective effect of aspirin on denervated muscle atrophy and the underlying mechanism.Methods: Mouse models of denervated muscle atrophy were established. The protective effect of aspirin (20 mg/kg/d, i.p.) on denervated muscle atrophy was analyzed using the wet weight ratio of tibialis anterior (TA) muscle and muscle fiber cross-sectional area (CSA). The levels of inflammatory factors were detected using quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Sirtuins1 (SIRT1)/Peroxisome Proliferator-Activated Receptor γ Co-Activator 1α (PGC-1α) and Signal transducer and activator of transcription 3 (STAT3) signaling pathway and the muscle fiber type related proteins in TA muscle after denervation were analyzed by western blot assay.Results: Intraperitoneal injection of aspirin (20 mg/kg/d) effectively alleviated denervation-induced muscle atrophy. This mainly manifested as follows: The wet weight ratio of TA muscle and muscle fiber CSA of mice treated with aspirin were significantly greater compared with mice treated with normal saline. The level of myosin heavy chain (MHC) increased, and the levels of muscle specific E3 ubiquitin ligase Muscle-specific RING finger-1 (MuRF-1) and muscle atrophy F-box (MAFbx) were decreased. Mitochondrial vacuolation and autophagy were inhibited, as evidenced by reduced level of autophagy related proteins PINK1, BNIP3, LC3B and Atg7 in mice treated with aspirin compared with mice treated with saline. In addition, aspirin treatment inhibited the slow-to-fast twitch muscle fiber conversion, which were related with triggering the expression of Sirt1 and PGC-1α. Moreover, aspirin reduced the levels of inflammatory factors interleukin-6, interleukin-1β and tumor necrosis factor-α and decreased the activation of STAT3 signaling pathway.Conclusions: This is the first study to find that aspirin can alleviate denervation-induced muscle atrophy and inhibit the type I-to-type II muscle fiber conversion and mitophagy possibly through regulating the STAT3 inflammatory signaling pathway and Sirt1/PGC-1α signal axis. This study expands our knowledge

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“…Recently, increasing studies have indicated that oxidative stress plays a critical role in the initiation and development of IVD degeneration [25,26]. In the process of oxidative stress, excess amounts of ROS, including H 2 O 2 , hydroxyl radicals, superoxide anions, and hypochlorite ions are generated in IVD, which can cause the disruption of extracellular matrix (ECM) homeostasis, inflammatory response, and cell loss of IVD cells, such as NP cells, directly resulting in IVD degeneration [27]. In consideration of the fact that NPMSCs and NP cells are in the same oxidative stress microenvironment, we speculated that oxidative stress could probably lead to IVD degeneration indirectly by impairing NPMSCs and hindering endogenous repair.…”

Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1-Mediated Autophagy Protects against Oxidative Damage in Rat Nucleus Pulposus-Derived Mesenchymal Stem Cells

Chen

Liu

Zhao

et al. 2020

Oxidative Medicine and Cellular Longevity

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Although endogenous nucleus pulposus-derived mesenchymal stem cell- (NPMSC-) based regenerative medicine has provided promising repair strategy for intervertebral disc (IVD) degeneration, the hostile microenvironments in IVD, including oxidative stress, can negatively affect the survival and function of the NPMSCs and severely hinder the endogenous repair process. Therefore, it is of great importance to reveal the mechanisms of the endogenous repair failure caused by the adverse microenvironments in IVD. The aim of this study was to investigate the effect of oxidative stress on the rat NPMSCs and its underlying mechanism. Our results demonstrated that oxidative stress inhibited cell viability, induced apoptosis, and increased the production of reactive oxygen species (ROS) in NPMSCs. In addition, the results showed that the expression level of heme oxygenase-1 (HO-1) increased at an early stage but decreased at a late stage when NPMSCs were exposed to oxidative stress, and the oxidative damages of NPMSCs could be partially reversed by promoting the expression of HO-1. Further mechanistic analysis indicated that the protective effect of HO-1 against oxidative damage in NPMSCs was mediated by the activation of autophagy. Taken together, our study revealed that oxidative stress could inhibit cell viability, induce apoptosis, and increase ROS production in NPMSCs, and HO-1-mediated autophagy might act as a protective response to the oxidative damage. These findings might enhance our understanding on the mechanism of the endogenous repair failure during IVD degeneration and provide novel research direction for the endogenous repair of IVD degeneration.

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Aspirin-Mediated Attenuation of Intervertebral Disc Degeneration by Ameliorating Reactive Oxygen Species In Vivo and In Vitro

Cited by 56 publications

References 48 publications

Inhibition of HDAC4 by GSK3β leads to downregulation of KLF5 and ASK1 and prevents the progression of intravertebral disc degeneration

Inhibition of HDAC4 by GSK3β leads to downregulation of KLF5 and ASK1 and prevents the progression of intravertebral disc degeneration

Aspirin alleviates denervation-induced muscle atrophy via regulating the Sirt1/PGC-1α axis and STAT3 signaling

Heme Oxygenase-1-Mediated Autophagy Protects against Oxidative Damage in Rat Nucleus Pulposus-Derived Mesenchymal Stem Cells

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