Andrographolide protects chondrocytes from oxidative stress injury by activation of the Keap1–Nrf2–Are signaling pathway

Abstract

Recent studies have shown that andrographolide (AP) has the potential to be developed as a drug for therapy for osteoarthritis (OA). However, the role of AP in attenuating the progression of OA is still unknown. We hypothesized that its therapeutic effect may be associated with its antioxidant potential. In this study, we investigated the therapeutic effect of AP on chondrocytes injured by H O and the association with the oxidation-related signaling pathways through the detection of cell proliferation, cell viability, the expression of oxidative stress-specific genes (Sod1, Cat, and malonaldehyde [Mda]) and proteins (superoxide dismutase [SOD], catalase [CAT]) after a culture period of 3 and 5 days, respectively. Further exploration of the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) messenger RNA and protein was also performed. The results showed that 0.625 µg/ml and 2.5 µg/ml of AP decreased oxidative stress injury of chondrocytes by increasing cell proliferation reduced by H O and antioxidant enzyme activity, including SOD and CAT. Inflammation factors, such as matrix metallopeptidase 13 (Mmp13), tissue inhibitor of metalloproteinase 1 (Timp1), and interleukin-6 (Il6), were downregulated in the H O group with AP, demonstrating a decrease in the progression of OA. Pathway analyses identified that the kelch-like ECH-associated protein 1 (Keap1)-Nrf2-antioxidant response element (Are) pathway is an important mediator in AP therapy on H O -induced OA. This study indicates that AP exerts protection effects on oxidative stress via activation of the Keap1-Nrf2-Are pathway in chondrocytes injured by H O , which may be promising for the therapy of OA.

Andrographolide, A Natural Antioxidant: An Update

“…In RIN-m lineage, andrographolide conjugated with alpha-lipoic acid increased SOD and CAT activities [79]. Similarly, in chondrocytes isolated from rat articular cartilage, andrographolide at 0.625, and 2.5 µg/mL increased SOD protein content; SOD and CAT activity; and SOD1, SOD2, and CAT expression after exposure with H 2 O 2 [31]. In contrast, in HK-2 human kidney cell line, treatment with andrographolide sodium bisulfate decreased SOD activity by 30 to 120 µM in a dose-dependent manner, and significantly from 60 µM onwards [80].…”

“…Andrographolide contributes to antioxidant defenses [31][32][33]. It acts directly by neutralizing free radicals.…”

A double‐blind, randomized, placebo‐controlled study to assess the efficacy of Andrographis paniculata standardized extract (ParActin®) on pain reduction in subjects with knee osteoarthritis

“…Andrographolide could exert protective effects on oxidative stress via activation of the Keap1-Nrf2-ARE pathway, and initiate the transcription of ARE genes and the upregulation of antioxidant enzymes (Guan et al, 2013;Li et al, 2018;Tan et al, 2017). Finally, in a rodent experimental model of OA, andrographolide reduced prostaglandinendoperoxide synthase 2, MMP13, and NOS2 expression, NO production, and lesions in the joint (Jin et al, 2017).…”

“…Using rat chondrocytes injured with H 2 O 2 , andrographolide was effective in increasing antioxidant enzyme activity, including SOD and CAT and was able to reduce Inflammatory factors such as MMP13, tissue inhibitor of metalloproteinase 1 (TIMP1), and interleukin‐6 (Li et al, ). Andrographolide could exert protective effects on oxidative stress via activation of the Keap1‐Nrf2‐ARE pathway, and initiate the transcription of ARE genes and the upregulation of antioxidant enzymes (Guan et al, ; Li et al, ; Tan et al, ). Finally, in a rodent experimental model of OA, andrographolide reduced prostaglandin‐endoperoxide synthase 2, MMP13, and NOS2 expression, NO production, and lesions in the joint (Jin et al, ).…”

Andrographolide prevents human nucleus pulposus cells against degeneration by inhibiting the NF‐κB pathway

“…Moreover, ANDRO at 6 μg/ml protected the NP cells from degeneration the most, which may due to the dose‐dependent effects of ANDRO on different cells or species and the different product manufacturers would also contribute to it. For instance, 3 μM of ANDRO exerted a chondroprotective effect on rabbit chondrocytes (Luo et al, ), whereas, 0.625 and 2.5 μg/ml of ANDRO protect rat chondrocytes from oxidative stress through the Keap1–Nrf2–Are signaling pathway (B. Li et al, ). In other words, for human degenerative NP cells, 6 μg/ml of ANDRO may be considered a therapeutic dosage.…”