ETHNOPHARMACOLOGICAL RELEVANCESwertia cincta is a traditional remedy for cholestasis commonly utilised in Yunnan, China. Despite its widespread use, the specific active components and underlying mechanisms of action remain poorly understood.AIM OF THIS STUDYThis study aimed to investigate the therapeutic properties, mechanisms, and active compounds of Swertia cincta in an animal model of cholestasis induced by alpha-naphthylisothiocyanate (ANIT).MATERIALS AND METHODSUHPLC/Q-TOF-MS and high-performance liquid chromatography (HPLC) were utilised to analyse the blood components of Swertia cincta. An ANIT-induced cholestatic liver injury animal model was established, and metabolomics was employed to explore the potential mechanisms of Swertia cincta in treating cholestatic liver injury. Hepatocellular injury induced by taurochenodeoxycholic acid was evaluated in vitro, and key bioactive components of Swertia cincta for cholestatic liver injury treatment were identified and confirmed using the ANIT-induced mouse model.RESULTSThe established HPLC method demonstrates good specificity and reproducibility, enabling the simultaneous determination of six components in Swertia cincta. Results from serum biochemical indicators and liver pathology analysis indicated that Swertia cincta exhibits promising anti-cholestasis liver injury effects. Specifically, gentiopicroside, loganic acid, and isoorientin were identified as key active ingredients in treating cholestatic liver injury. Their mechanism of action primarily involves regulating PPAR-α, FXR, CYP3A4, NTCP, CAR, and CPT2. By modulating PPAR-α and bile acid metabolism-related proteins, reducing pro-inflammatory factors, enhancing bile acid transport, and promoting fatty acid oxidation to reduce lipid accumulation, Swertia cincta exerts protective and therapeutic effects against cholestatic liver injury. Notably, gentian bitter glycosides appear to be the most critical components for this effect.CONCLUSIONSwertia cincta may improve cholestatic liver injury by activating the peroxisome proliferator-activated receptor alpha pathway, and the key active compounds were gentiopicroside, loganic acid, and isoorientin.

2024-11-01·Journal of Ethnopharmacology

Integrated serum metabolomics, 16S rRNA sequencing and bile acid profiling to reveal the potential mechanism of gentiopicroside against nonalcoholic steatohepatitis in lean mice

Article

作者: Tang, Ruiting ; Li, Chenhao ; Li, Zeyun ; Zou, Yuanyuan ; Zhu, Xueya ; Liu, Shuaibing

ETHNOPHARMACOLOGICAL RELEVANCELean nonalcoholic steatohepatitis (NASH) poses a serious threat to public health worldwide. Herbs of the genus Gentiana have been used for centuries to treat hepatic disease or have been consumed for hepatic protection efficiency. Gentiopicroside (GPS), the main bioactive component of Gentiana herbs, has been shown to be beneficial for protecting the liver, improving intestinal disorders, modulating bile acid profiles, ameliorating alcoholic hepatosteatosis, and so on. It is plausible to speculate that GPS may hold potential as a therapeutic strategy for lean NASH. However, no related studies have been conducted thus far.AIM OF THE STUDYThe present work aimed to investigate the benefit of GPS on NASH in a lean mouse model.MATERIALS AND METHODSNASH in a lean mouse model was successfully established via a published method. GPS of 50 and 100 mg/kg were orally administered to verify the effect. Untargeted metabolomics, 16S rDNA sequencing and bile acid (BA) profiling, as well as qPCR and Western blotting analysis were employed to investigate the mechanism underlying the alleviating effect.RESULTSGPS significantly reduced the increase in serum biochemicals and liver index, and attenuated the accumulation of fat in the livers of lean mice with NASH. Forty-two potential biomarkers were identified by metabolomics analysis, leading to abnormal metabolic pathways of primary bile acid biosynthesis and fatty acid biosynthesis, which were subsequently rebalanced by GPS. A decreased Firmicutes/Bacteroidetes (F/B) ratio and disturbed BA related GM profiles were revealed in lean mice with NASH but were partially recovered by GPS. Furthermore, serum profiling of 23 BAs confirmed that serum BA levels were elevated in the lean model but downregulated by GPS treatment. Pearson correlation analysis validated associations between BA profiles, serum biochemical indices and related GM. qPCR and Western blotting analysis further elucidated the regulation of genes associated with liver lipid synthesis and bile acid metabolism.CONCLUSIONSGPS may ameliorate steatosis in lean mice with NASH, regulating the metabolomic profile, BA metabolism, fatty acid biosynthesis, and BA-related GM. All these factors may contribute to its beneficial effect.

2024-10-22·mSystems

Targeted discovery of gut microbiome-remodeling compounds for the treatment of systemic inflammatory response syndrome

Article

作者: Lü, Xin ; Zhang, Junhua ; Yi, Yanglei ; Liu, Luyao ; Liu, Huan ; Zhao, Xin ; Ma, Lin ; Li, Pu ; Zhao, Fan

ABSTRACT Systemic inflammatory response syndrome (SIRS) is a severe inflammatory response that can lead to organ dysfunction and death. Modulating the gut microbiome is a promising therapeutic approach for managing SIRS. This study assesses the therapeutic potential of the Xuanfei Baidu (XFBD) formula in treating SIRS. The results showed that XFBD administration effectively reduced mortality rates and inflammation in SIRS mice. Using 16S rRNA sequencing and fecal microbiota transplantation (FMT), we substantiated that the therapeutic effects of XFBD are partly attributed to gut microbiota modulation. We conducted in vitro experiments to accurately assess the gut microbiome remodeling effects of 51 compounds isolated from XFBD. These compounds exhibited varying abilities to induce a microbial structure that closely resembles that of the healthy control group. By quantifying their impact on microbial structure and clustering their regulatory patterns, we devised multiple gut microbiome remodeling compound (GMRC) cocktails. GMRC cocktail C, comprising aucubin, gentiopicroside, syringic acid, gallic acid, p-hydroxybenzaldehyde, para-hydroxybenzoic acid, and isoimperatorin, demonstrated superior efficacy in treating SIRS compared to a single compound or to other cocktails. Finally, in vitro experiments showcased that GMRC cocktail C effectively rebalanced bacteria composition in SIRS patients. This study underscores XFBD’s therapeutic potential in SIRS and highlights the importance of innovative treatment approaches for this disease by targeting the gut microbiota. IMPORTANCEDeveloping effective treatment strategies for systemic inflammatory response syndrome (SIRS) is crucial due to its severe and often life-threatening nature. While traditional treatments like dexamethasone have shown efficacy, they also come with significant side effects and limitations. This study makes significant strides by demonstrating that the Xuanfei Baidu (XFBD) formula can substantially reduce mortality rates and inflammation in SIRS mice through effective modulation of the gut microbiota. By quantitatively assessing the impact of 51 compounds derived from XFBD on the gut microbiome, we developed a potent gut microbiome remodeling compound cocktail. This cocktail outperformed individual compounds and other mixtures in efficacy against SIRS. These findings highlight the potential of XFBD as a therapeutic solution for SIRS and underscore the critical role of innovative strategies targeting the gut microbiota in addressing this severe inflammatory condition.

项与 Gentiopicrin 相关的新闻（医药）

2022-07-11

·生物谷

GPS是一种潜在的治疗糖尿病的药物，恢复胰岛素信号通路

2型糖尿病(T2 DM)是以脂糖代谢紊乱为特征的疾病，临床表现主要为胰岛素抵抗和相对胰岛素缺乏。在生理条件下，胰岛素激活肝脏胰岛素信号通路，增加肝脏糖原储备，抑制肝脏糖异生，调节脂肪合成，是维持糖脂代谢动态平衡的最重要机制。众所周知，肝脏胰岛素抵抗(Hir)是2型糖尿病和非酒精性脂肪性肝病等代谢性疾病发展的关键因素。非酒精性脂肪肝的全球流行影响着超过55%的II型糖尿病患者，而非酒精性脂肪性肝炎(NASH)在II型糖尿病患者中的患病率估计为37%。近日，来自中山大学的研究者们在Acta Pharmaceutica Sinica B杂志上发表了题为“Gentiopicroside targets PAQR3 to activate the PI3K/AKT signaling pathway and ameliorate disordered glucose and lipid metabolism”的文章，该研究确定GPS是一种潜在的治疗糖尿病的药物，它可以抑制PAQR3的表达，并直接靶向PAQR3，恢复胰岛素信号通路。图片来源: https://doi.org/10.1016/j.apsb.2021.12.023胰岛素受体后信号传导受阻是胰岛素抵抗糖尿病的主要发病机制。孕激素和ADIPOQ受体3(PAQR3)是炎症和代谢的关键调节因子，可以负向调节PI3K/AKT信号通路。在本研究中，研究者报道了龙胆苦苷(GPS)，龙胆环烯醚萜糖苷的主要生物活性成分，在棕榈酸(PA)处理的HepG2细胞中，减少了脂质的合成，增加了葡萄糖的利用。此外，GPS改善了链脲佐菌素(STZ)治疗高脂饮食(HFD)诱导的糖尿病小鼠的糖脂代谢。本研究结果表明，GPS通过促进DNA结合蛋白2(DDB2)介导的PAQR3泛素化降解来促进PI3K/AKT轴的激活。此外，表面等离子体共振(SPR)、微量热电泳法(MST)和热位移法(TSA)的结果表明，GPS直接与PAQR3结合。分子对接和细胞热漂移分析(CETSA)结果表明，GPS直接与PAQR3 NH2末端的Leu40、Asp42、Glu69、Tyr125和Ser129等氨基酸结合，并在空间上抑制PAQR3与PI3K催化亚基(P110a)的相互作用，恢复PI3K/AKT信号通路。全球定位系统改善胰岛素抵抗机制的图解图片来源: https://doi.org/10.1016/j.apsb.2021.12.023本研究阐明了GPS改善胰岛素抵抗的一个新靶点。研究者发现GPS通过促进DDB2介导的PAQR3泛素降解来抑制PAQR3的表达。重要的是，研究者证明了GPS直接与PAQR3的末端结合，并在空间上抑制了PAQR3和P110a之间的相互作用，从而恢复了PI3K/AKT信号通路。本研究结果为应用GPS恢复糖尿病患者的胰岛素敏感性提供了理论依据。参考文献：Haiming Xiao et al. Gentiopicroside targets PAQR3 to activate the PI3K/AKT signaling pathway and ameliorate disordered glucose and lipid metabolism. Acta Pharm Sin B. 2022 Jun;12(6):2887-2904. doi: 10.1016/j.apsb.2021.12.023.

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