PMID- 38179736 OWN - NLM STAT- MEDLINE DCOM- 20240108 LR - 20240220 IS - 2768-6698 (Electronic) IS - 2768-6698 (Linking) VI - 28 IP - 12 DP - 2023 Dec 15 TI - A Study on the Pharmacological Effects and Mechanism of Rhodojaponin III in Rheumatoid Arthritis. PG - 337 LID - 10.31083/j.fbl2812337 [doi] AB - BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease with a high rate of disability accompanied by various complications. The pathogenesis of RA is complex with multiple targets and links. This study aims to investigate pharmacological effects and mechanism of Rhodojaponin III in RA. METHODS: The bovine type II collagen-induced arthritis (CIA) rat model and tumor necrosis factor-alpha (TNF-alpha) induced human umbilical vein endothelial cells (HUVECs) model were constructed. Different concentrations of Rhodojaponin III were utilized for intervention. The progression of CIA was assessed by the arthritis index (AI). Pathological changes in knee joints and synovium were observed. The expressions of angiogenesis-related cytokines were detected. The proliferation, migration, invasion, and angiogenesis of HUVECs were detected. The levels of pro-inflammatory cytokines were determined. The expressions of nuclear factor kappa B-inducing kinase (NIK) pathway-related proteins were analyzed. The binding of Rhodojaponin III to NIK was simulated by molecular docking. RESULTS: Rhodojaponin III suppressed cartilage damage and bone erosion in the knee joints. Rhodojaponin III inhibited expressions of platelet endothelial cell adhesion molecule-1 (CD31) and vascular endothelial cell growth factor (VEGF) to decrease vascular density. Rhodojaponin III suppressed the proliferation, migration, invasion, and angiogenesis of HUVECs, and decreased the levels of interleukin (IL)-6, IL-1beta, and TNF-alpha. Molecular docking showed that Rhodojaponin III could spontaneously bind to NIK. Rhodojaponin III decreased the expression of NIK, p52, and C-X-C motif chemokine ligand 12 (CXCL12) and the phosphorylation level of IkappaB kinase-alpha (IKKalpha) in the synovium of CIA rats and TNF-alpha-induced HUVECs. NIK overexpression reversed the inhibitory effect of Rhodojaponin III on activation of the NIK/NF-kappaB pathway, migration, invasion, and angiogenesis of HUVECs, and the secretion of pro-inflammatory cytokines. CONCLUSIONS: Rhodojaponin III affected the angiogenesis and inflammation of CIA rats and TNF-alpha-induced HUVECs by regulating the NIK/IKKalpha/CXCL12 pathway. These findings suggest that Rhodojaponin III has potential as a therapeutic agent for RA. Further studies are needed to explore its precise mechanism of action and evaluate its clinical efficacy. CI - (c) 2023 The Author(s). Published by IMR Press. FAU - Liu, Xiaorong AU - Liu X AD - College of Pharmacy, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China. FAU - Li, Shuofu AU - Li S AD - Department of Orthopaedics, The First Hospital of Hunan University of Chinese Medicine, 410007 Changsha, Hunan, China. FAU - Xu, Yin AU - Xu Y AD - Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, 410007 Changsha, Hunan, China. FAU - Mei, Wenya AU - Mei W AD - College of Pharmacy, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China. FAU - Zhou, Ribao AU - Zhou R AD - College of Pharmacy, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China. LA - eng GR - 2022JJ80086/Natural Science Foundation of Hunan Province/ GR - 2023JJ60342/Natural Science Foundation of Hunan Province/ GR - D202302078705/Project of Hunan Provincial Health and Health Commission/ GR - 2022-5313/Project of Hunan Provincial Student Innovation and Entrepreneurship Training Program/ GR - 19C1384/Scientific research project of Hunan Provincial Education Department/ GR - 2021161/Hunan Provincial Administration of Traditional Chinese Medicine Scientific Research Program/ GR - 2020ZYX01/Hunan University of Traditional Chinese Medicine Primary Discipline Open Fund Project in Chinese Medicine/ GR - [2017]25/Hunan University of Traditional Chinese Medicine Youth Program/ GR - 202302/Key Discipline Project on Chinese Pharmacology of Hunan University of Chinese Medicine/ GR - [2020]248/construction point of first-class specialty in Hunan Province in 2020: Chinese medicine resources and development/ GR - [2021]7/National first-class undergraduate major construction in 2020/ GR - B2023150/Scientific Research Project of Hunan Provincial Administration of Traditional Chinese Medicine/ PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - Singapore TA - Front Biosci (Landmark Ed) JT - Frontiers in bioscience (Landmark edition) JID - 101612996 RN - C7FEJ7QWQE (rhodojaponin III) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 2.7.11.10 (I-kappa B Kinase) RN - 0 (Cytokines) RN - 0 (NF-kappa B) SB - IM MH - Rats MH - Humans MH - Animals MH - Cattle MH - Tumor Necrosis Factor-alpha MH - I-kappa B Kinase MH - Molecular Docking Simulation MH - *Arthritis, Rheumatoid/drug therapy/metabolism MH - Cytokines/metabolism MH - NF-kappa B/metabolism MH - Human Umbilical Vein Endothelial Cells/metabolism MH - *Arthritis, Experimental/drug therapy/metabolism OTO - NOTNLM OT - Rhodojaponin III OT - angiogenesis OT - inflammation OT - nuclear factor kappa B-inducing kinase OT - rheumatoid arthritis COIS- The authors declare no conflict of interest. EDAT- 2024/01/05 06:42 MHDA- 2024/01/08 06:43 CRDT- 2024/01/05 05:29 PHST- 2023/05/15 00:00 [received] PHST- 2023/07/19 00:00 [revised] PHST- 2023/07/25 00:00 [accepted] PHST- 2024/01/08 06:43 [medline] PHST- 2024/01/05 06:42 [pubmed] PHST- 2024/01/05 05:29 [entrez] AID - S2768-6701(23)00983-8 [pii] AID - 10.31083/j.fbl2812337 [doi] PST - ppublish SO - Front Biosci (Landmark Ed). 2023 Dec 15;28(12):337. doi: 10.31083/j.fbl2812337.