Ethyl acetate extract of Tibetan medicine Rhamnella gilgitica ameliorated type II collagen-induced arthritis in rats via regulating JAK-STAT signaling pathway. (1st March 2021)

• Record Type: Journal Article
• Authors: Su, Jinsong; Li, Qiuyue; Liu, Jia; Wang, Hongling; Li, Xuanhao; Wüntrang, Dhondrup; Liu, Chuan; Zhao, Qian; RuyuYao, ; Meng, Xianli; Zhang, Yi
• Is Part Of: Journal of ethnopharmacology. Volume 267(2021)
• Publication Date: 2021-03-01
• Subjects: Rhamnella gilgitica -- Rheumatoid arthritis -- Apoptosis -- Inflammation -- JAK-STAT pathway; AA adjuvant-induced arthritis -- Bcl-2 B-cell lymphoma 2 -- Bax B-cell lymphoma -2-associated X -- BSA bovine serum albumin -- CIA collagen-induced arthritis -- DMARDs disease-modifying antirheumatic drugs -- ELISA enzyme linked immunosorbent assay -- IL-1β interleukin 1 beta -- IL-6 interleukin 6 -- IL-17 interleukin 17 -- IL-4 interleukin 4 -- IL-10 interleukin 10 -- INF-γ interferon-γ -- JAK2 janus-activated kinase 2 -- JAK-STAT pathway janus-activated kinase-signal transducer and activator of transcription pathway -- NSAIDs non-steroidal anti-inflammatory drugs -- PBS phosphate buffer saline -- RA Rheumatoid arthritis -- RG Rhamnella gilgitica Mansf. et Melch. -- RGEA ethyl acetate extract of R. gilgitica -- RT-qPCR real-time quantitative polymerase chain reaction -- STAT3 signal transducer and activator of transcription 3 -- SOCS1 suppressor of cytokine signaling 1 -- SOCS3 suppressor of cytokine signaling 3 -- TNF-α tumor necrosis factor alpha -- TUNEL terminal deoxynucleotidyl transferase dUTP nick-end labelling -- UPLC-Q-TOF-MS ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry; Ethnopharmacology -- Periodicals; Pharmacognosy -- Periodicals; Herbs -- Periodicals; Herbs -- Periodicals; Pharmacognosy -- Periodicals; Pharmacognosie -- Périodiques; Herbes -- Périodiques; 615.1
• DOI: 10.1016/j.jep.2020.113514
• Languages: English
• ISSNs: 0378-8741

Abstract

Abstract: Ethnopharmacological relevance: Rhamnella gilgitica Mansf. et Melch. (སེང་ལྡེང་།, RG) is a traditional Tibetan medicinal plant that is currently grown throughout Tibet. According to the theory of Tibetan medicine, RG is efficient for removing rheumatism, reducing swelling, and relieving pain. Hence, it has been used for the treatment of rheumatoid arthritis (RA) in Tibet for many years. However, there are no previous reports on the anti-RA activities of ethyl acetate extract of RG (RGEA). Aim of the study: This study aimed to explore the anti-RA effect and mechanism of RGEA on collagen-induced arthritis (CIA) in rats. Materials and methods: The CIA model was established in male Wister rats by intradermal injection of bovine type II collagen and Complete Freund's Adjuvant at the base of the tail and left sole, respectively. The rats were orally administered with RGEA (9.71, 19.43, or 38.85 mg/kg) for 23 days. The body weight, swelling volume, arthritis index score, thymus and spleen indices, and pathological changes were observed to evaluate the effect of RGEA on RA. Furthermore, the inflammatory cytokines in serum, such as interleukin1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), interleukin6 (IL-6), interleukin17 (IL-17), interferon-γ (INF-γ), interleukin4 (IL-4), and interleukin10 (IL-10) were measured by enzyme linked immunosorbent assay (ELISA) to explore the anti-inflammatory effects of RGEA. The terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining was used to examine apoptosis. Finally, the protein and gene expression of B-cell lymphoma-2-associated X (Bax), B-cell lymphoma 2 (Bcl-2), Caspase3, janus-activated kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), suppressor of cytokine signaling1 (SOCS1), and 3 (SOCS3) in synovial tissue were detected using immunohistochemistry and real-time quantitative polymerase chain reaction (RT-qPCR). Results: After the treatment with RGEA, the body weight of rats was restored, both the arthritis index and paw swelling were suppressed, and spleen and thymus indices were decreased. RGEA reduced the inflammatory cells and synovial hyperplasia in the synovial tissue of the knee joint, and suppressed bone erosion. Meanwhile, RGEA decreased the levels of IL-1β, IL-6, IL-17, TNF-α, and INF-γ, while increased the levels of IL-4 and IL-10. TUNEL fluorescence apoptosis results confirmed that RGEA obviously promoted the apoptosis of synovial cells. Further studies showed that RGEA inhibited the proteins and mRNAs expression of JAK2 and STAT3 as well as increased the proteins and mRNAs expression of SOCS1 and SOCS3. In addition, RGEA upregulated the expression of Bax and Caspase3, and downregulated the expression of Bcl-2. Conclusion: The anti-RA effectof RGEA might be related to the promotion of apoptosis and inhibition of inflammation, which regulated the JAK-STAT pathway. Graphical abstract: Image 1 Highlights: For the first time, we studied the anti-rheumatoid arthritis effect of RGEA. For the first time, we have studied the therapeutic effect of RGEA by regulating JAK-STAT pathway. For the first time, we discussed the pathogenesis of rheumatoid arthritis based on theory of Tibetan medicine. .