S-Allylmercaptocysteine Targets Nrf2 in Osteoarthritis Treatment Through NOX4/NF-κB Pathway.

Abstract

PURPOSE:

This study aimed to explore the potential role and mechanism of garlic-derived S-allylmercaptocysteine (SAMC), the major water-soluble fraction of garlic, in osteoarthritis (OA) both in vivo and in vitro.

METHODS:

The effect of SAMC in a surgical-induced OA model was examined by X-ray, staining, ELISA, and immunoblotting. Then the key role of Nrf2 by SAMC treatment in IL-1β stimulated chondrocytes in vitro was determined by gene-knockdown technique.

RESULTS:

SAMC could stabilize the extracellular matrix (ECM) by decreasing metalloproteinase (MMPs) expression to suppress type II collagen degradation in OA rats. The inflammatory cytokines, such as IL-1β, TNF-α, and IL-6, were elevated in OA, which could be down-regulated by SAMC treatment. This effect was parallel with NF-κB signaling inhibition by SAMC. As oxidative stress has been shown to participate in the inflammatory pathways in OA conditions, the key regulator Nrf2 in redox-homeostasis was evaluated in SAMC-treated OA rats. Nrf2 and its down-stream gene NQO-1 were activated in the SAMC-treated group, accompanied by NAD(P)H oxidases 4 (NOX4) expression down-regulated. As a result, the toxic lipid peroxidation byproduct 4-hydroxynonenal (4HNE) was reduced in articular cartilage. In IL-1β-stimulated primary rat chondrocytes, which could mimic OA in vitro, SAMC could ameliorate collagen destruction, inhibit inflammation, and maintain redox-homeostasis. Interestingly, after Nrf2 gene knockdown by adenovirus, the protective effect of SAMC in IL-1β-stimulated chondrocytes disappeared.

CONCLUSION:

Overall, our study demonstrated that SAMC targeted Nrf2 to protect OA both in vivo and in vitro, which would be a new pharmaceutical way for OA therapy.

• Authors: Guang Yang, Shui Sun, Jian Wang, Wei Li, Xianquan Wang, Lin Yuan, Siying Li
• Journal: Drug design, development and therapy (Drug Des Devel Ther) Vol. 14 Pg. 4533-4546 ( 2020) ISSN: 1177-8881 [Electronic] New Zealand
• PMID: 33149551 (Publication Type: Journal Article)
• Copyright: © 2020 Yang et al.

Chemical References

• Antineoplastic Agents, Phytogenic
• NF-E2-Related Factor 2
• NF-kappa B
• Nfe2l2 protein, rat
• S-allylmercaptocysteine
• NADPH Oxidase 4
• Nox4 protein, rat
• Cysteine

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Cells, Cultured
• Cysteine (analogs & derivatives, pharmacology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Male
• Molecular Structure
• NADPH Oxidase 4 (antagonists & inhibitors, metabolism)
• NF-E2-Related Factor 2 (antagonists & inhibitors, metabolism)
• NF-kappa B (antagonists & inhibitors, metabolism)
• Osteoarthritis (drug therapy, metabolism, surgery)
• Rats
• Rats, Sprague-Dawley
• Structure-Activity Relationship