FR429 from Polygonum capitatum Demonstrates Potential as an Anti-hepatic Injury Agent by Modulating PI3K/Akt Signaling Pathway.

IF 1.7 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Yaru Yang, Lei He, Minghui He, Xu Zhang, Shanggao Liao, Zhu Zeng, Yan Lin, Bo Tu
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Abstract

FR429, an ellagitannin isolated and purified from the whole herb Polygonum capitatum (P. capitatum), possesses a robust pharmacological profile, which is particularly noteworthy for its anti-inflammatory and anticancer properties. Despite these established effects, its potential in mitigating hepatic injury remains to be fully explored. The present investigation delineates the hepatoprotective efficacy of FR429 and unveils its underlying molecular mechanisms. Initially, of the tested compounds, 10 compounds (specifically, compounds 2, 4, 5, 6, 7, 8, 9, 12, 13, and 14) exhibited significant protective effects at a concentration of 10 μM, elevating HepG2 (human liver cancer cell) cell viability from 43.4 to 70% following carbon tetrachloride (CCl4) exposure. Among them, compounds 2 (FR429, half-maximum effective concentration (EC50) = 6.46 μM) and 6 (2"-O-galloylquercitrin, EC50 = 5.36 μM) demonstrated the highest cytoprotective activities. In the murine model, FR429 dramatically attenuated serum levels of alanine transaminase, aspartate transaminase, and alkaline phosphatase, indicative of its hepatoprotective potential. Histopathological evaluation further substantiated these findings, as FR429 noticeably mitigated CCl4-induced hepatic lesions, involving necrosis, ballooning degeneration, and neutrophil infiltration. Transcriptomic analysis unveiled 178 differentially expressed genes in FR429-treated mice liver tissue, with significant alterations indicative of a hepatoprotective response. Mechanistic investigations revealed that FR429's hepatoprotective effects involve modulation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, evidenced by downregulation of toll-like receptor 2, phosphorylated PI3K, phosphorylated Akt, nuclear factor-kappa-B, interleukin-1 beta, and tumor necrosis factor-alpha expression. Furthermore, FR429 modulated the gene and protein expression levels of apoptotic markers (apoptotic protein (Bax) and B-lymphoblastoma-2 gene (Bcl2)), reinforcing its anti-hepatic damage efficacy. This study represents the first report establishing FR429 as an effective hepatoprotective compound, paving the way for further investigation into its therapeutic applications.

首蓼FR429通过调节PI3K/Akt信号通路显示抗肝损伤药物的潜力
FR429是从蓼属植物中分离纯化的鞣花单宁,具有良好的药理作用,尤其值得注意的是其抗炎和抗癌特性。尽管有这些既定的效果,但其减轻肝损伤的潜力仍有待充分探索。本研究描述了FR429的肝保护作用,并揭示了其潜在的分子机制。最初,在所测试的化合物中,有10种化合物(特别是化合物2、4、5、6、7、8、9、12、13和14)在浓度为10 μM时表现出显著的保护作用,将四氯化碳(CCl4)暴露后的HepG2(人肝癌细胞)细胞存活率从43.4提高到70%。其中化合物2 (FR429,半最大有效浓度(EC50) = 6.46 μM)和6(2′- o -没食子酰基槲皮苷,EC50 = 5.36 μM)的细胞保护活性最高。在小鼠模型中,FR429显著降低血清丙氨酸转氨酶、天冬氨酸转氨酶和碱性磷酸酶水平,表明其具有保护肝脏的潜力。组织病理学评估进一步证实了这些发现,因为FR429显著减轻了ccl4诱导的肝脏病变,包括坏死、球囊变性和中性粒细胞浸润。转录组学分析揭示了fr429治疗小鼠肝组织中178个差异表达基因,这些基因的显著改变表明有肝保护反应。机制研究表明,FR429的肝保护作用涉及调节磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B (Akt)信号通路,通过下调toll样受体2、磷酸化PI3K、磷酸化Akt、核因子-kappa-B、白细胞介素-1 β和肿瘤坏死因子- α的表达来证明。此外,FR429调节凋亡标志物(凋亡蛋白(Bax)和b淋巴母细胞瘤-2基因(Bcl2))的基因和蛋白表达水平,增强其抗肝损伤的作用。该研究首次证实FR429是一种有效的肝保护化合物,为进一步研究其治疗应用铺平了道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
3.50
自引率
5.00%
发文量
247
审稿时长
2 months
期刊介绍: Biological and Pharmaceutical Bulletin (Biol. Pharm. Bull.) began publication in 1978 as the Journal of Pharmacobio-Dynamics. It covers various biological topics in the pharmaceutical and health sciences. A fourth Society journal, the Journal of Health Science, was merged with Biol. Pharm. Bull. in 2012. The main aim of the Society’s journals is to advance the pharmaceutical sciences with research reports, information exchange, and high-quality discussion. The average review time for articles submitted to the journals is around one month for first decision. The complete texts of all of the Society’s journals can be freely accessed through J-STAGE. The Society’s editorial committee hopes that the content of its journals will be useful to your research, and also invites you to submit your own work to the journals.
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