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Stroke, especially ischemic stroke, is an important cause of neurological morbidity and mortality worldwide. Growing evidence suggests that the immune system plays an intricate function in the pathophysiology of stroke. Gelsevirine (Gs), an alkaloid from Gelsemium elegans , has been proven to decrease inflammation and neuralgia in osteoarthritis previously, but its role in stroke is unknown. In this study, the middle cerebral artery occlusion (MCAO) mice model was used to evaluate the protective effect of Gs on stroke, and the administration of Gs significantly improved infarct volume, Bederson score, neurobiological function, apoptosis of neurons, and inflammation state in vivo . According to the data in vivo and the conditioned medium (CM) stimulated model in vitro , the beneficial effect of Gs came from the downregulation of the over-activity of microglia, such as the generation of inflammatory factors, dysfunction of mitochondria, production of ROS and so on. By RNA-seq analysis and Western-blot analysis, the JAK-STAT signal pathway plays a critical role in the anti-inflammatory effect of Gs. According to the results of molecular docking, inhibition assay, and thermal shift assay, the binding of Gs on JAK2 inhibited the activity of JAK2 which inhibited the over-activity of JAK2 and downregulated the phosphorylation of STAT3. Over-expression of a gain-of-function STAT3 mutation (K392R) abolished the beneficial effects of Gs. So, the downregulation of JAK2-STAT3 signaling pathway by Gs contributed to its anti-inflammatory effect on microglia in stroke. Our study revealed that Gs was benefit to stroke treatment by decreasing neuroinflammation in stroke as a potential drug candidate regulating the JAK2-STAT3 signal pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xing, Lv, Zhu, Cong, Bian, Zhang, Gu, Chen, Tan, Su and Zhang.)

Low-grade and chronic inflammation is recognized as an important mediator of the pathogenesis of osteoarthritis (OA). The aim of current work was to test the therapeutic effects of gelsevirine on age-related and surgically induced OA in mice and elucidate the underlying mechanism. The in vitro studies revealed that gelsevirine treatment mitigated IL-1β-induced inflammatory response and degeneration in cultured chondrocytes, evidenced by reduced apoptosis and expression of MMP3, MMP9, MMP13, IFNβ, TNFɑ, and Il6, and increased expression of Col2A and Il10. Furthermore, gelsevirine treatment in IL-1β-stimulated chondrocytes reduced the protein expression of stimulator of IFN genes (STING, also referred to Tmem173) and p-TBK1. Importantly, gelsevirine treatment did not provide further protection in STING-deficient chondrocytes against IL-1β stimulation. The in vivo studies revealed that gelsevirine treatment mitigated articular cartilage destruction in age-related and destabilization of the medial meniscus (DMM)-induced OA. Similarly, gelsevirine treatment did not provide further beneficial effects against OA in STING deficient mice. Mechanistically, gelsevirine promoted STING K48-linked poly-ubiquitination and MG-132 (a proteasome inhibitor) reversed the inhibitive effects of gelsevirine on IL-1β-induced activation of STING/TBK1 pathway in chondrocytes. Collectively, we identify that gelsevirine targets STING for K48 ubiquitination and degradation and improves age-related and surgically induced OA in mice., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Gelsemium is a small genus of flowering plants from the family Loganiaceae comprising five species, three of which, Gelsemium sempervirens (L.) J. St.-Hil., G. elegans Benth and G. rankinii Small, are particularly popular. Compared with other alkaloids from G. elegans, gelsemine, gelsevirine and koumine exhibit equally potent anxiolytic effects and low toxicity. Although the pharmacological activities and metabolism of koumine and gelsemine have been reported in previous studies, the species differences of gelsevirine metabolism have not been well studied. In this study, the metabolism of gelsevirine was investigated by using liver microsomes of humans, pigs, goats and rats by means of HPLC-QqTOF/MS. The results indicated that the metabolism of gelsevirine in liver microsomes had qualitative and quantitative species differences. Based on the results, the possible metabolic pathways of gelsevirine in liver microsomes were proposed. Investigation of the metabolism of gelsevirine will provide a basis for further studies of the in vivo metabolism of this drug., (© 2021 The Authors Veterinary Medicine and Science Published by John Wiley & Sons Ltd.)