Zhao Yichen, Zhang Jiahui, Yan Wei, Jiang Ping, Li Juncheng, He Haojun, Ma Honghong, Zhang Yuxin, Yang Kai, Jiang Min, Xi Xiaobing
Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Department of Clinical Laboratory, Wuxi Branch of Ruijin Hospital Shanghai Jiao Tong University School of Medicine, Wuxi, 214111, China.
Chin Med. 2025 Feb 28;20(1):28. doi: 10.1186/s13020-025-01081-6.
Acute gout arthritis (AGA) is a common metabolic joint disease and urgently needs a safer alternative therapy due to the significant side effects from long-term use of primary medications. Folium Hibisci Mutabilis, a traditional medicinal herb, has demonstrated promising therapeutic efficacy in the clinical management of AGA, but its pharmacological mechanisms remain to be elucidated.
Folium Hibisci Mutabili was isolated and refined into the Folium Hibisci Mutabilis Extract (FHME). Then, monosodium urate-induced AGA animal models were applied to identify the anti-inflammatory and analgesic effects of FHME in vivo through various techniques, including ultrasonography, Paw withdrawal thresholds, histological staining, etc. We used RNA-seq, qRT-PCR, ELISA, and flow cytometry to evaluate the efficacy of FHME on M1 polarization. Utilizing transmission electron microscope and oxygen consumption rate examinations in conjunction with Mito-Tracker staining, we observed the effects of FHME on mitochondrial morphology and function. Finally, we employed proteomics analysis, siRNA, qRT-PCR, western blot and other techniques to investigate the underlying mechanism of FHME's actions between the two phenotypes and the key targets.
We observed a notable reduction in inflammation and pain, as well as the decreased infiltration of inflammatory cells and expression of IL-1β in synovial tissue of AGA mice upon treatment with FHME. FHME suppressed TNF-α, IL-1β, iNOS, and IL-18 expression in BMDM-derived macrophages and inhibited the formation of F4/80CD86 cells. Mechanically, FHME protected mitochondrial morphology and stimulated the expression of key oxidative phosphorylation proteins, such as Ubiquinol Cytochrome c Reductase Core Protein I (UQCRC1), UQCRC2, CYCS, and NDUFA4. Additionally, it enhanced the activity of respiratory complex III, recovered cellular aerobic respiration under LPS and MSU induction. FHME lost its effect to downregulate M1 macrophage polarization with the presence of rotenone or si-UQCRC1. Finally, 10 compounds were identified from FHME having potential binding affinity with the UQCRC1 protein.
The therapeutic potential of FHME for AGA is associated with the maintenance of mitochondrial function to inhibit M1 macrophage polarization, which is intimately linked to the UQCRC1. Our findings highlight the potential of Folium Hibisci Mutabilis as a safe and effective approach for AGA.
急性痛风性关节炎（AGA）是一种常见的代谢性关节疾病，由于长期使用一线药物存在显著副作用，迫切需要更安全的替代疗法。扶桑花，一种传统草药，在AGA的临床治疗中已显示出有前景的治疗效果，但其药理机制仍有待阐明。
分离并提纯扶桑花得到扶桑花提取物（FHME）。然后，应用尿酸钠诱导的AGA动物模型，通过多种技术，包括超声检查、爪部退缩阈值、组织学染色等，在体内鉴定FHME的抗炎和镇痛作用。我们使用RNA测序、qRT-PCR、酶联免疫吸附测定（ELISA）和流式细胞术来评估FHME对M1极化的疗效。利用透射电子显微镜和氧消耗率检查结合线粒体追踪染色，我们观察了FHME对线粒体形态和功能的影响。最后，我们采用蛋白质组学分析、小干扰RNA（siRNA）、qRT-PCR、蛋白质免疫印迹等技术，研究FHME在两种表型之间作用的潜在机制和关键靶点。
我们观察到，用FHME治疗后，AGA小鼠的炎症和疼痛显著减轻，滑膜组织中炎性细胞浸润减少，白细胞介素-1β（IL-1β）表达降低。FHME抑制骨髓来源巨噬细胞中肿瘤坏死因子-α（TNF-α）、IL-1β、诱导型一氧化氮合酶（iNOS）和IL-十八的表达，并抑制F4/80CD86细胞的形成。机制上，FHME保护线粒体形态，并刺激关键氧化磷酸化蛋白的表达，如泛醇细胞色素c还原酶核心蛋白I（UQCRC1）、UQCRC2、细胞色素c（CYCS）和NADH脱氢酶（泛醌）1α亚基（NDUFA4）。此外，它增强了呼吸复合体III的活性，在脂多糖（LPS）和尿酸单钠（MSU）诱导下恢复了细胞有氧呼吸。在鱼藤酮或si-UQCRC1存在的情况下，FHME失去了下调M1巨噬细胞极化的作用。最后，从FHME中鉴定出10种与UQCRC1蛋白具有潜在结合亲和力的化合物。
FHME对AGA的治疗潜力与维持线粒体功能以抑制M1巨噬细胞极化有关，这与UQCRC1密切相关。我们的研究结果突出了扶桑花作为AGA一种安全有效治疗方法的潜力。
