Punicalagin Exerts Protective Effects against Ankylosing Spondylitis by Regulating NF-κB-TH17/JAK2/STAT3 Signaling and Oxidative Stress

Abstract

Background. Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by sacroiliitis and spinal rigidity of the axial joints. The role of oxidative stress and increased proinflammatory cytokines is well documented in AS pathogenesis. Punicalagin (2,3-hexahydroxydiphenoyl-gallagyl-D-glucose), an ellagitannin widely present in pomegranates, is found to exhibit potent anti-inflammatory, antiproliferative, and antioxidative effects. The present study was undertaken to investigate the effects of punicalagin in a rodent model of AS. Methods. BALB/c mice induced spondylitis were sacrificed 24 h after the last injection of proteoglycan extract. Histological scoring was done to assess the degree of the disease. The expression of JAK2/STAT3 proteins and proteins of the nuclear factor-κB (NF-κB) pathway was determined by immunoblotting. Serum levels of inflammatory mediators—TNF-α, IL-1β, IL-6, IL-17A, and IL-23—were assessed. Levels of lipid peroxidation and reactive oxygen species (ROS) were quantified. Antioxidant status as a measure of activities of antioxidant enzymes—catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD)—was determined. Results. Punicalagin effectively improved antioxidant status and decreased lipid peroxidation, ROS production, and serum levels of inflammatory mediators. NF-κB pathway and JAK2/STAT3 signaling were significantly (p<0.05) downregulated. Punicalagin effectively regulated the production of cytokines by the Th17 cells and the IL-17A/IL-23 axis. Conclusion. The observations suggest that punicalagin exerts a protective role in AS via reducing oxidative stress and regulating NF-κB/TH17/JAK2/STAT3 signal. Punicalagin thus could be explored further as a potent candidate compound in the treatment of AS.

Punicalagin Inhibited Inflammation and Migration of Fibroblast-Like Synoviocytes Through NF-κB Pathway in the Experimental Study of Rheumatoid Arthritis

“… 32 Another study also suggested the punicalagin exerted a protective role in ankylosing spondylitis via reducing oxidative stress and the production of inflammation cytokines by the Th17 cells and the IL-17A/IL-23 axis. 33 In our findings, we demonstrated that the treatments of punicalagin significantly down-regulated the expression and secretion of IL-1β, IL-6, IL-8 and IL-17A. These findings make punicalagin a promising target for anti-inflammatory therapies of RA.…”

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

“…Punicalagin (PUN) is a polyphenol isolated from pomegranate and displays a variety of pharmacological activities, of which antioxidant and anti-inflammatory are the most important [125,126]. It seems that antioxidant activity of PUN is mediated via its impact on Nrf2 signaling pathway.…”

Punicalagin Regulates Signaling Pathways in Inflammation-Associated Chronic Diseases

“…The activated JAK/STAT3 signaling pathway and increased levels of ROS both were found to be involved in pathological formation of ankylosing spondylitis [ 78 , 79 ]. In ankylosing the spondylitis mouse model, ROS and malonaldehyde levels were increased, and punicalagin treatment significantly reduced ROS and malonaldehyde levels, and effectively improved antioxidant status in ankylosing spondylitis BALB/c mice [ 80 ]. This effect may be conducted by regulating the major pathway of inflammatory response JAK/STAT3 signaling [ 80 ].…”

“…In ankylosing the spondylitis mouse model, ROS and malonaldehyde levels were increased, and punicalagin treatment significantly reduced ROS and malonaldehyde levels, and effectively improved antioxidant status in ankylosing spondylitis BALB/c mice [ 80 ]. This effect may be conducted by regulating the major pathway of inflammatory response JAK/STAT3 signaling [ 80 ]. In other research, punicalagin (250 mg/kg) pretreated with concanavalin A-induced autoimmune hepatitis mice down-regulated the levels of IL-6, TNF-α and IFN-γ, and reduced the infiltration of activated CD4 + and CD8 + T cells in liver [ 81 ].…”