Forsythoside A mitigates osteoarthritis and inhibits chondrocyte senescence by promoting mitophagy and suppressing NLRP3 inflammasome via the Nrf2 pathway

Article

作者: Deng, Zengfa ; Zhong, Yanlin ; Li, Changzhao ; Lin, Zhencan ; Li, Wei ; Mao, Guping ; Kang, Yan ; Li, Ming ; Long, Dianbo

BACKGROUNDChondrocyte senescence and inflammation are hallmarks of osteoarthritis (OA). Forsythiaside A (FTA), a phenylethanol glycoside isolated from air-dried fruits of Forsythia, has been reported to have significant anti-inflammatory and antioxidant properties. However, its protective effects against OA have not been elucidated.PURPOSEWe explored the therapeutic efficacy of FTA in inhibiting chondrocyte senescence and inflammation during OA, as well as the potential underlying mechanisms.STUDY DESIGNThis study aimed to investigate the novel mechanism of FTA in alleviating OA in both cell and animal models.METHODSThe protective effect of FTA against tert‑butyl hydroperoxide-induced chondrocyte damage was assessed, and the effects of FTA on cartilage aging and OA progression were evaluated using a medial meniscus (DMM)-induced knee OA mouse model. The regulatory effects of FTA on the NLRP3 Inflammasome, mitophagy, and the PKC/Nrf2 pathway were also explored.RESULTSIn vitro, FTA improved mitochondrial function, enhanced mitophagy, suppressed NLRP3 inflammasome activation, and inhibited chondrocyte senescence; however, these chondroprotective effects were partially reversed after mitophagy inhibition, NLRP3 inflammasome activation, and Nrf2 pathway inhibition. Furthermore, we found that FTA directly interacts with Nrf2 and enhances its phosphorylation by protein kinase C (PKC). In vivo, FTA attenuated the pathological signs of knee OA in a DMM-model mouse model, which was partially reversed by ML385.CONCLUSIONFTA inhibited chondrocyte senescence and OA progression by activating the PKC-Nrf2 pathway. Thus, FTA is a potential novel therapeutic agent for OA.

2024-10-01·International Immunopharmacology

Grp78 regulates NLRP3 inflammasome and participates in Sjogren’s syndrome

Article

作者: Xu, Meimei ; He, Jing ; Chen, Yueyue ; Wu, Suling

OBJECTIVEThe purpose of the present study was to potential effects of forsythiaside A (FA) on Sjogren's syndrome (SS).METHODSEnzyme linked immunosorbent assay for detecting cytokines and Western blotting was used for detecting related protein expression.RESULTSFA effectively reduced the secretion of inflammatory cytokines, the expression of Caspase-1 and NLRP3 proteins and the expression of p65 in SS. FA also effectively inhibited the high expression of Grp78 in SS. When Grp78 expression was silenced, it effectively reduced the secretion of inflammatory cytokines, the expression of Caspase-1 and NLRP3 proteins and the expression of p65 in the nucleus in SS. FA effectively inhibit the secretion of inflammatory cytokines induced by overexpression of Grp78, the expression of Caspase-1 and NLRP3 proteins and the expression of p65 in the nucleus in SS.CONCLUSIONFA induces the degradation of Grp78 protein, regulates the NF-κB signaling pathway in SS and inhibited NLRP3 inflammasome activation and reduced the release of inflammatory cytokines to alleviate SS.

2024-10-01·International Immunopharmacology

Forsythiaside A alleviates acute lung injury via the RNF99/TRAF6/NF-κB signaling pathway

Article

作者: Shan, Lingling ; Xin, Linyan ; Xu, Lisheng ; Zhao, Fang ; Li, Wanrong ; Wang, Jing ; Wang, Weiwei ; Yang, Yang ; Wang, Haichao

The aim of this study was to investigated the effects of forsythiaside A (FA) on acute lung injury (ALI). The lung tissue pathological was detected by hematoxylin-eosin staining (HE) staining. Wet weight/dry weight (w/d) of the lung in mice was measured. Cytokine such as interleukin 1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) were also detected. Compared with the vector group, the protein expression levels of TRAF6 and TAK1 the RNF99 group were significantly reduced. Ubiquitinated TRAF6 protein was increased after knockdown of RNF99. Finally, it was found that FA significantly ameliorated ALI via regulation of RNF99/TRAF6/NF-κB signal pathway. In conclusion, RNF99 was an important biomarker in ALI and FA alleviated ALI via RNF99/ TRAF6/NF-κB signal pathway.

项与连翘苷A 相关的新闻（医药）

2024-06-21

·生物谷

Journal of Advanced Research：连翘苷A通抑制肺和结肠炎症及上皮屏障损伤减轻急性肺损伤

研究表明，连翘苷A在ALI治疗过程中，通过调控PAR-c/RXR-a复合物发挥细胞特异性作用，抑制炎症，减轻肺和结肠上皮屏障损伤。急性肺损伤(ALI)和急性呼吸窘迫综合征(ARDS)是公认的以弥漫性炎性细胞浸润、出血和肺水肿为特征的肺部疾病。可导致ALI/ARDS的直接和间接因素包括吸入、肺炎、败血症、创伤、胰腺炎和输血等。许多研究表明，炎症在ALI/ARDS的发病机制中起关键作用。具体地说，大量的免疫细胞聚集在损伤部位，启动一系列炎症信号转导，释放过量的促炎细胞因子。随后，炎症破坏了肺泡上皮和血管内皮细胞的屏障功能，增加了肺泡毛细血管膜的通透性。这会导致富含蛋白质的水肿液积聚到肺间质中，最终导致肺水肿和组织损伤。目前，除机械通气外，药物干预仍是ALI/ARDS的主要治疗方法。皮质类固醇具有广泛的抗炎活性，被认为是治疗ALI/ARDS的理想药物。然而，皮质类固醇的应用受到许多不良反应的限制，如肌肉无力、身体功能受损、过敏反应和神经认知功能障碍。因此，需要在治疗方法和药物方面为ALI提供额外的支持。图片来源：https://doi.org/10.1016/j.jare.2023.08.006 近日，来自成都中医药大学的研究者们在Journal of Advanced Research杂志上发表了题为“Forsythiaside A alleviates acute lung injury by inhibiting inflammation and epithelial barrier damages in lung and colon through PPAR-c/RXR-a complex”的文章，该研究揭示了连翘苷A通过PPAR-c/RXR-a复合体抑制肺和结肠炎症及上皮屏障损伤减轻急性肺损伤。急性肺损伤(ALI)是一种以炎症为特征的肺部疾病，仍需要进一步的药物开发。连翘苷A是连翘中的活性成分，具有治疗ALI的潜力。本研究目标是从肠肺轴角度探讨连翘苷A通过PPAR-c及其结合物RXR-a治疗ALI的机制。本研究利用脂多糖和肿瘤坏死因子-α建立了体外和体内损伤模型。药物处理采用连翘苷A，RXR-a抑制剂UVI3003干扰细胞内PPAR-c/RXR-a复合体。组织病理学检查采用HE染色。用微量试剂盒检测血清内毒素含量。免疫组织化学染色和Western印迹法检测蛋白表达。采用ELISA法检测细胞培养上清液中促炎症细胞因子的含量。通过CO-IP分析蛋白质间的相互作用。连翘苷A对脂多糖诱导的急性肺损伤小鼠肺和结肠炎症的影响图片来源：https://doi.org/10.1016/j.jare.2023.08.006 体内实验结果表明，连翘苷A可调节PPAR-c/RXR-a，抑制TLR4/MAPK/NF-Jb和MLCK/MLC2信号通路，从而抑制气管内毒素诱导的ALI小鼠肺和结肠的炎症和上皮屏障损伤。PPAR-c/RXR-a在肺中被连翘苷A促进，而在结肠中被连翘苷A抑制。此外，体外实验结果表明，连翘苷A通过调控PPAR-c/RXR-a抑制脂多糖和肿瘤坏死因子-α诱导的TLR4/MAPK/NF-JB和NF-JB/MLCK/MLC2信号通路的激活，从而抑制巨噬细胞和肺/结肠上皮细胞的炎症和上皮屏障损伤。进一步的机制研究表明，连翘苷A对PPAR-c/RXR-a复合体具有细胞特异性调节作用。在脂多糖诱导的巨噬细胞RAW264.7和肿瘤坏死因子-α诱导的肺上皮细胞A549中，连翘苷A可促进PPAR-c/RXR-a蛋白相互作用，而在肿瘤坏死因子-α诱导的结肠上皮细胞SW620中，连翘苷A可抑制PPAR-c/RXR-a蛋白的相互作用。在ALI的治疗中，连翘苷A通过对PPAR-c/RXR-a复合体的调节，抑制肺和结肠的炎症和上皮屏障损伤。机制总结图图片来源：https://doi.org/10.1016/j.jare.2023.08.006 总之，本研究的主要结果如下：(1)连翘苷A(Ⅰ)可调节PPAR-c/RXR-a复合体的活性，抑制TLR4/MAPK/NF-JB和MLCK/MLC2信号通路的活性，抑制脂多糖诱导的ALI小鼠肺和结肠的炎症反应和上皮屏障的损伤。连翘苷A还能促进肺组织中PPAR-c/RXR-a复合物的表达，抑制结肠组织中PPAR-c/RXR-a复合物的过表达; (2)连翘苷A可以调节PPAR-c/RXR-a复合物抑制LPS和tnf -a诱导的TLR4/MAPK/NFjB和NF-jB/MLCK/MLC2信号通路的激活，从而抑制巨噬细胞和肺/结肠上皮细胞的炎症和上皮屏障损伤; (3)连翘苷A对不同细胞的PPAR-c/RXR-a复合物具有细胞特异性调控作用。具体来说，它促进了PPAR-c/RXR-a在lps诱导的巨噬细胞RAW264.7和tnf诱导的肺上皮细胞A549中的蛋白相互作用，而抑制了tnf -a诱导的结肠上皮细胞SW620中的蛋白相互作用。综上所述，连翘苷A在ALI治疗过程中，通过调控PAR-c/RXR-a复合物发挥细胞特异性作用，抑制炎症，减轻肺和结肠上皮屏障损伤。（生物谷 Bioon.com）参考文献: Jing Wang et al. Forsythiaside A alleviates acute lung injury by inhibiting inflammation and epithelial barrier damages in lung and colon through PPAR-c/RXR-a complex. J Adv Res. 2024 Jun:60:183-200. doi: 10.1016/j.jare.2023.08.006.