Resveratrol Suppresses Annulus Fibrosus Cell Apoptosis through Regulating Oxidative Stress Reaction in an Inflammatory Environment

Abstract

During disc degeneration, the increase of inflammatory cytokines and decrease of disc cell density are two prominent features. Enhanced inflammatory reaction contributes to disc annulus fibrosus (AF) cell apoptosis. In this study, we investigated whether resveratrol can suppress AF cell apoptosis in an inflammatory environment. Rat disc AF cells were cultured in medium with or without tumor necrosis factor-α (TNF-α). Resveratrol was added along with the culture medium supplemented with TNF-α. Caspase-3 activity, cell apoptosis ratio, expression of apoptosis-associated molecules (Bcl-2, Bax, caspase-3, cleaved PARP, and cleaved caspase-3), reactive oxygen species (ROS) content, and the total superoxide dismutase (SOD) activity were measured. Our results showed that TNF-α significantly increased caspase-3 activity and AF cell apoptosis ratio and upregulated gene/protein expression of Bax, caspase-3, cleaved caspase-3, and cleaved PARP, whereas it downregulated the expression of Bcl-2. Moreover, TNF-α significantly increased ROS content but decreased the total SOD activity. Further analysis demonstrated that resveratrol partly attenuated the effects of TNF-α on AF cell apoptosis-associated parameters, decreased ROS content, and increased the total SOD activity in the AF cells treated with TNF-α. In conclusion, resveratrol attenuates inflammatory cytokine TNF-α-induced AF cell apoptosis through regulating oxidative stress reaction in vitro. This study sheds a new light on the protective role of resveratrol in alleviating disc degeneration.

Targeting Endogenous Reactive Oxygen Species Removal and Regulating Regenerative Microenvironment at Annulus Fibrosus Defects Promote Tissue Repair

“…33−35 Oxidative stress after AF injury can cause cell apoptosis and ECM degradation and further hinder AF repair. 36 The main endogenous biological antioxidants of the body include SOD, CAT, glutathione peroxidase, glutathione reductase, peroxidase reductase, etc. SOD and CAT are the main anti-ROS enzymes.…”

“…Excessive accumulation of ROS can act on biological macromolecules and destroy cellular structure. Oxidative stress is involved in the pathogenesis of many diseases, including IDD. − Oxidative stress after AF injury can cause cell apoptosis and ECM degradation and further hinder AF repair . The main endogenous biological antioxidants of the body include SOD, CAT, glutathione peroxidase, glutathione reductase, peroxidase reductase, etc.…”

Plant-Derived Senotherapeutics for the Prevention and Treatment of Intervertebral Disc Degeneration and Aging

“…The naturally occurring nonflavonoid polyphenol resveratrol (3,5,4′-trihydroxy-trans-stilbene) ( Figure 1 ) is a phytoalexin, produced as a stress response in plants for their protection against fungal infections [ 240 , 241 ]. It can be isolated from the roots of the herbaceous perennial plant Polygonum cuspidatum of the knotweed and buckwheat family Polygonaceae, but its presence has also been documented in trees (i.e., eucalyptus and spruce), in flowering plants (i.e., the lily species Veratrum grandiflorum and Veratrum formosanum ), in peanuts and groundnuts and in grapevines, grapes and red wine [ 242 , 243 , 244 ].…”

“…In nature, resveratrol can be found in cis- and trans-isomers, with the latter forms being the more biologically active due to the lower steric hindrance of their side chains [ 244 ]. Resveratrol’s health benefits have long been recognized because numerous studies have shown its protective effects against various diseases, such as cancer, ischemic disease, neurodegenerative diseases, cardiovascular diseases, diabetes and OA [ 240 , 242 , 244 ], as well as its ability to increase lower organisms’ lifespan and to generally improve the health of mammals [ 245 ]. The wide protective effect of resveratrol on different cell types is mediated by several signaling pathways and molecules, including NF-κB, MAPK, COX-2, AMPK and p53, that regulate its anti-inflammatory, anti-aging, anti-cancer and cartilage-protective properties [ 246 , 247 ].…”

“…Specifically for the IVD tissue, resveratrol has been shown to exert anti-apoptotic, anti-oxidant, anti-inflammatory, anti-catabolic and anabolic activities in vitro and using animal models through multiple signal transduction pathways towards IVD regeneration [ 244 ]. Resveratrol partly attenuated TNF-α-induced apoptosis, decreased ROS levels and increased SOD activity in rat AF IVD cells in vitro [ 240 ]. It also improved cell proliferation, inhibited apoptosis and cell cycle arrest and increased HSP90, N-cadherin, type II collagen and aggrecan expression levels in a human NP cell line by blocking the IL-6/JAK/STAT3 pathway [ 248 ].…”