Activation of the Nrf2/HO-1 signaling pathway by dimethyl fumarate ameliorates complete Freund's adjuvant-induced arthritis in rats

Lal, Roshan; Dhaliwal, Jatinder; Dhaliwal, Navneet; Dharavath, Ravinder Naik; Chopra, Kanwaljit

doi:10.1016/j.ejphar.2021.174044

Cited by 32 publications

(18 citation statements)

References 62 publications

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“… 6 , 9 Su et al 28 showed that the activation of p62/Nrf2 signaling was sufficient to inhibit ROS production, thus alleviating bone erosion in rheumatoid arthritis. Moreover, Lal et al 29 confirmed that Nrf2/HO-1 signaling pathway activation improved arthritis in rats. Our data indicated that Nrf2 activation occurs in the synovial tissue of ACLT model mice, and this activity was enhanced by Nrf2 overexpression.…”

Section: Discussionmentioning

confidence: 94%

Nrf2 Regulates CHI3L1 to Suppress Inflammation and Improve Post-Traumatic Osteoarthritis

Song¹,

Hao²,

Jiang³

et al. 2021

JIR

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Introduction: Post-traumatic osteoarthritis (PTOA) is an inflammatory condition that occurs following mechanical joint trauma and that results in joint degeneration. This study sought to evaluate the regulatory function of nuclear factor erythroid 2-related factor 2 (Nrf2) in a murine model of anterior cruciate ligament transection (ACLT)-induced PTOA and in an in vitro model of synoviocyte inflammation induced by LPS treatment with the goal of exploring the role of chitinase 3-like-1 (CHI3L1) in this pathogenic context. Methods: PTOA model mice were intra-articularly injected with Nrf2 overexpression lentiviral vector, and safranin O-fast green staining as well as the Osteoarthritis Research Society International (OARSI) Scoring System were used to evaluate the severity of cartilage damage. Protein expression in the synovial tissue was evaluated by Western blotting, immunohistochemical staining, and ELISA. Additionally, murine synoviocytes were infected with Nrf2 overexpression lentivirus and stimulated with LPS. The levels of inflammatory cytokines were detected by ELISA. ROS levels were measured using dihydroethidium (DHE) dye. Results: We determined that the overexpression of Nrf2 was sufficient to reduce cartilage degradation in the context of PTOA in vivo, and we observed a significant decrease in the expression of matrix metalloproteinase 13 (MMP13) in the articular cartilage of samples from mice overexpressing Nrf2 relative to control mice. Synovial CHI3L1 expression and serum TNF-α, IL-1β, and IL-6 levels were reduced in animals overexpressing this transcription factor relative to PTOA model controls. Consistent with these findings, murine synoviocytes treated with LPS exhibited dose-dependent increases in ROS, TNF-α, IL-1β, IL-6, Nrf2, and CHI3L1 levels, whereas Nrf2 overexpression was sufficient to suppress these increases. Conclusion:Our data indicated that Nrf2 negatively regulates CHI3L1, suggesting that this signaling axis may regulate PTOA progression and may thus be a viable therapeutic target in individuals affected by this condition.

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Section: Discussionmentioning

confidence: 94%

Nrf2 Regulates CHI3L1 to Suppress Inflammation and Improve Post-Traumatic Osteoarthritis

Song¹,

Hao²,

Jiang³

et al. 2021

JIR

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“…Dimethyl fumarate (DMF), which targets the Nrf2 pathway, was approved by FDA for the clinical treatment of multiple sclerosis (MS), which is another autoimmune disease. The latest report shows that DMF ameliorates complete Freund's adjuvant-induced arthritis in rats through the activation of the Nrf2/HO-1 signaling pathway [ 17 ]. Hence, Nrf2 serves as an important target for inflammation interference and OS of macrophages and RASFs in RA; therefore, it can be adopted as an effective therapeutic approach in the future.…”

Section: Introductionmentioning

confidence: 99%

Importance of Gedunin in Antagonizing Rheumatoid Arthritis via Activating the Nrf2/ARE Signaling

Chen

Tian

Liu

et al. 2022

Oxidative Medicine and Cellular Longevity

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Objective. This study assessed the anti-arthritic effect and protection of Gedunin (GDN) on joint tissues and revealed the possible mechanism in suppressing rheumatoid arthritis (RA). Methods. LPS-induced macrophages and TNF-α-stimulated synovial fibroblasts (MH7A) or IL-1β-stimulated primary rheumatoid arthritis synovial fibroblasts (RASFs) were used to evaluate the antiinflammatory effect of GDN. In addition, CIA-induced arthritis was employed here to evaluate the anti-arthritic effect. MTT and BRDU assays were utilized to evaluate the cell viability and proliferation, Q-PCR was conducted to detect the mRNA expression of cytokines, FACS was adopted to monitor ROS production, while western blotting (WB) and siRNA interference were applied in confirming the anti-arthritic effects of GDN via the Nrf2 signaling. Results. In vitro, cell viability was inhibited in macrophages and MH7A cells, but not in RASFs; but the proliferation of RASFs was significantly suppressed in time- and dose-dependent manners. GDN suppressed cytokine levels in LPS-stimulated macrophages and TNF-α-stimulated MH7A cells or RASFs. GDN suppressed ROS expression. Furthermore, GDN treatment notably dose-dependently decreased the mRNA and protein expression of iNOS in LPS-induced macrophages. sip62 interference results showed that GDN cause the less expression of HO-1 and Keap1 and also fail to inhibit cytokines after sip62 interference. In vivo, GDN effectively inhibited paw swelling, arthritis score, and arthritis incidence and cytokines. Conclusions. Our study suggested that GDN exhibited strong antagonistic effect on arthritis both in vitro and in vivo via activation of Nrf2 signaling. Our work will provide a promising therapeutic strategy for RA.

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“…Female Nrf2 and HO-1 concentration in the involved joints [178] Collagen-induced arthritis in DBA/1 mice…”

Section: Systemic Lupus Erythematosusmentioning

confidence: 99%

“…Resveratrol alleviates oxidative stress and apoptosis in hydrogen peroxide-treated fibroblast-like synoviocytes by activating the Nrf2-Keap1 pathway [ 177 ]. In rats, DMF ameliorates complete Freund’s adjuvant-induced arthritis [ 178 ] by suppressing oxidative stress markers and inflammatory mediators, and by increasing Nrf2 and HO-1 levels in the involved joints [ 178 ].…”

Section: Role Of Nrf2 Agonism In Chronic Inflammatory Diseasesmentioning

confidence: 99%

Recent Advances in Understanding Nrf2 Agonism and Its Potential Clinical Application to Metabolic and Inflammatory Diseases

Kim

Jeon

2022

IJMS

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Oxidative stress is a major component of cell damage and cell fat, and as such, it occupies a central position in the pathogenesis of metabolic disease. Nuclear factor-erythroid-derived 2-related factor 2 (Nrf2), a key transcription factor that coordinates expression of genes encoding antioxidant and detoxifying enzymes, is regulated primarily by Kelch-like ECH-associated protein 1 (Keap1). However, involvement of the Keap1–Nrf2 pathway in tissue and organism homeostasis goes far beyond protection from cellular stress. In this review, we focus on evidence for Nrf2 pathway dysfunction during development of several metabolic/inflammatory disorders, including diabetes and diabetic complications, obesity, inflammatory bowel disease, and autoimmune diseases. We also review the beneficial role of current molecular Nrf2 agonists and summarize their use in ongoing clinical trials. We conclude that Nrf2 is a promising target for regulation of numerous diseases associated with oxidative stress and inflammation. However, more studies are needed to explore the role of Nrf2 in the pathogenesis of metabolic/inflammatory diseases and to review safety implications before therapeutic use in clinical practice.

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Activation of the Nrf2/HO-1 signaling pathway by dimethyl fumarate ameliorates complete Freund's adjuvant-induced arthritis in rats

Cited by 32 publications

References 62 publications

Nrf2 Regulates CHI3L1 to Suppress Inflammation and Improve Post-Traumatic Osteoarthritis

Nrf2 Regulates CHI3L1 to Suppress Inflammation and Improve Post-Traumatic Osteoarthritis

Importance of Gedunin in Antagonizing Rheumatoid Arthritis via Activating the Nrf2/ARE Signaling

Recent Advances in Understanding Nrf2 Agonism and Its Potential Clinical Application to Metabolic and Inflammatory Diseases

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