PHYTOMEDICINE
·
2023
·
IF 7.9
Li Xiao,Guangfu Xu,Silong Chen,Yumin He,Fan Peng,Chengfu Yuan
Background Alcoholic liver disease (ALD) is characterized by the disturbance of bile acids homeostasis, which further deteriorates ALD. Bile acid metabolism and its related signal molecules have become new therapeutic targets for alcoholic liver disease. This study aimed to investigate the impact of kaempferol (KAE) on ALD and elucidate its underlying mechanisms. Methods C57BL/6 N mice were utilized to establish Binge-on-Chronic alcohol exposure mice model. KAE was administered as an interventional drug to chronic alcohol-fed mice for four weeks to assess its effects on liver damage and bile acid metabolism. And Z-Guggulsterone (Z-Gu), a global FXR inhibitor, was used to investigate the impact of intestinal FXR-FGF15 signal in ALD mice. Additionally, intestinal epithelial cells were exposed to alcohol or specific bile acid to induce the damage of FXR activity in vitro. The dual luciferase activity assay was employed to ascertain the interplay between KAE and FXR activity. Results The results indicated that KAE treatment exhibited a significant hepatoprotective effect against chronic alcohol-fed mice. Accompanied by the intestinal FXR activation, the administration of KAE suppressed hepatic bile acid synthesis and promoted intestinal bile acid excretion in chronic ALD mice. And the notable alterations in total bile acid levels and composition were observed in mice after chronic alcohol feeding, which were reversed by KAE supplementation. And more, the protective effects of KAE on ALD mice were deprived by the inhibition of intestinal FXR activation. In vitro experiments demonstrated that KAE effectively activated FXR-FGF15 signaling, mitigated the damage to FXR activity in intestinal epithelial cells caused by alcohol or specific bile acids. Additionally, luciferase activity assays revealed that KAE directly promoted FXR expression, thereby enhancing FXR activity. Conclusion KAE treatment inhibited hepatic bile acids synthesis, maintained bile acids homeostasis in ALD mice by directly activating intestinal FXR-FGF15 signaling, which effectively alleviated liver injury induced by chronic alcohol consumption.
研究领域:
药理学
·
肝病学
·
分子生物学
·
胃肠病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2026
·
IF 5.4
Nan Hu,Minyan Qian,Yanru Liu,Zhenwei Jiang,Caomei Xu,Wenting Zhang,Jingting Jiang
Backgroud Immunosuppressant tacrolimus (TAC) induces glucose metabolism disorder and diabetes mellitus (DM) closely associated with intestinal microbiota dysbiosis and reduced bile acid levels, and this study aimed to explore the ameliorative effect and underlying mechanism of hyodeoxycholic acid (HDCA) on TAC-induced DM in rat models. Methods We first verified the critical role of intestinal microbiota and bile acids in the pathogenesis of TAC-induced DM via antibiotic-induced gut microbiota depletion, then orally administered HDCA (100 mg/kg) to TAC-induced diabetic rats to evaluate its protective efficacy, detecting glycolipid metabolism indices, targeted bile acid omics, FXR/TGR5 protein expression, serum and ileal GLP/FGF15 levels, and mRNA levels of key metabolic genes including Cyp7a1, Cyp27a1, Cyp7b1, Cyp8b1, Fgfr4, Creb1 and Ppargc1a . Results Antibiotic treatment significantly reduced BSH-active gut microbiota such as Bacteroides and Lactobacillus , disrupting the serum bile acid pool and exacerbating diabetic symptoms by altering the gut microbiota-bile acid axis; while HDCA administration markedly improved glucose tolerance and reshaped bile acid profiles in TAC-induced diabetic rats, specifically lowering serum and fecal 12-OH/Non-12-OH BAs ratio via downregulating hepatic Cyp7a1 and upregulating hepatic Cyp8b1 expression. HDCA also suppressed enteroendocrine cell-derived GLP-1 secretion, decreased serum and ileal FGF15 levels, and reduced the expression of ileal FXR as well as hepatic Creb1 and Ppargc1a. Conclusions Collectively, HDCA exerts a significant ameliorative effect on TACinduced DM by regulating metabolic enzymes and altering bile acid profiles, with the core mechanism involving inhibited enterohepatic FXR-FGF15 axis, increased GLP-1 secretion and suppressed hepatic gluconeogenesis, all of which play key regulatory roles in this protective process.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2024
·
IF 8.2
Xiaoyuan Wang,Yinchuan Lv,Xin Qiang,Shumin Liang,Ruosi Li,Jing Zhan,Jiaying Liu
The disruption of per- and polyfluoroalkyl substances (PFASs) on bile acid (BA) homeostasis has raised public concerns, making the evaluation of their effects and underlying mechanisms a high priority. Although the use of perfluorooctanoic acid (PFOA) has been restricted, it remains a widespread legacy PFAS in the environment. Concurrently, the use of its prevalent short-chain alternative, perfluorobutanoic acid (PFBA), is increasing, yet the toxicity assessment of PFBA remains inadequate. In this study, C57BL/6N mice were exposed to PFOA and PFBA (0.4 or 10 mg/kg body weight) by gavage for 28 days. The results showed that both PFOA and PFBA significantly increased hepatic weight, although PFBA exhibited lower bioaccumulation than PFOA in the liver. Targeted metabolomics revealed that PFOA significantly decreased total BA levels and altered their composition. Conversely, PFBA, without significantly altering total BA levels, notably changed their composition, such as increasing the proportion of cholic acid. Further investigations using in vivo and in vitro assays suggested that PFOA inhibited the expression of Cyp7A1, a key BA synthetase, potentially via PPARα activation, thereby reducing BA levels. In contrast, PFBA enhanced Cyp7A1 expression, associated with the inhibition of intestinal Farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF15) pathway. This study evaluated the differences in the BA-interfering effects of PFOA and PFBA and shed light on the potential mechanisms, which will provide new insights into the health risks of legacy PFASs and their alternatives.
研究领域:
毒理学
·
环境健康
·
代谢组学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2021
·Vol. 35
·期 7
·3799-3811
·
IF 5.882
Min Wen,Yubei Liu,Ruiying Chen,Ping He,Feihua Wu,Rui Li,Yining Lin
Sclerosing cholangitis, characterized by biliary inflammation, fibrosis, and stricturing, remains one of the most challenging conditions of clinical hepatology. Geniposide (GE) has anti-inflammatory, hepatoprotective, and cholagogic effects. Whether GE provides inhibition on the development of sclerosing cholangitis is unknown. Here, we investigated the role of GE in a mouse model in which mice were fed with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) for 4 weeks to induce sclerosing cholangitis. The results demonstrated that the increased hepatic gene expressions of pro-inflammatory (IL-6, VCAM-1, MCP-1, and F4/80) and profibrogenic markers (Col1α1, Col1α2, TGF-β, and α-SMA) in DDC feeding mice were reversed after treatment with GE. GE also suppressed expressions of CK19 and Ki67 in DDC-fed mice, suggesting that GE could ameliorate DDC-induced hepatocytes and cholangiocytes proliferation. In addition, GE significantly increased bile acids (BAs) secretion in bile, which correlated with induced expressions of hepatic FXR, BAs secretion transporters (BSEP, MRP2, MDR1, and MDR2), and reduced CYP7A1 mRNA expression. Furthermore, higher expressions of ileal FXR-FGF15 signaling and reduced ASBT were also observed after GE treatment. Taken together, these data showed that GE could modulate inflammation, fibrosis, and BAs homeostasis in DDC-fed mice, which lead to efficiently delay the progression of sclerosing cholangitis.
研究领域:
肝病学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
·
IF 5.7
Jiangzhou Song,Yi Wang,Rongrong Guo,Kang Wang,Yang Hu,Ming Cui,Guangji Wang,Haiping Hao,Hong Wang,Xiaowei Xu
Maintaining bile acids (BAs) homeostasis is a recognized key strategy for treating primary biliary cholangitis (PBC), with the farnesoid X receptor (FXR) playing a significant regulatory role in this process. Compared to systemic FXR agonists, activation of intestinal FXR also benefit to BAs homeostasis, which have limited target genes, intestinal FXR activation may cause milder side effects. In this study, we evaluated the therapeutic efficacy, mechanism of action, and pharmacokinetic properties of Fex3 (fexaramine-3, an intestinal-restricted FXR agonist previously synthesized by our team) for cholestasis therapy. Results showed that Fex3 effectively alleviated cholestatic liver injury by activating the intestinal FXR-fibroblast growth factor 15 (FGF15) signaling pathway, which subsequently suppressed hepatic cholesterol 7α-hydroxylase (CYP7A1) expression. In mouse models, Fex3 demonstrated good tolerability and an excellent safety profile. These findings indicate that the intestinal-restricted FXR agonist Fex3 represents a promising novel therapeutic agent for PBC, providing a new insight into intervention for PBC targeting FXR.
✓ 已验证
DOI
PubMed
高影响因子
Advances in Traditional Medicine
·
2026
·
IF 1.4
Wu Huan,Zhou Li,Lin Wei,Zhang Hong-xing,Zhang Zhao-qing,Wang Xiao-fei,Ju Shi-ru,Liu Zhi-gang,Hu Fei
This study aimed to explore the association between the effect of electroacupuncture (EA) in improving hyperlipidemia and changes in the intestinal flora and bile acid metabolism, and to preliminarily investigate its possible molecular basis. Wistar rats were stratified into five groups: control, model, sham EA, EA, and EA+FXR agonist. Comprehensive assessments included hepatic histopathology (H&E staining), serum lipid profiling (TC, TG, LDL-C, HDL-C), 16S rDNA sequencing of gut microbiota, targeted bile acid metabolomics, and molecular analyses (Western blot, immunohistochemistry and qRT-PCR) of FXR/FGF15 pathway components and associated enzymes (CYP7B1, CYP27A1). EA intervention significantly attenuated hyperlipidemia manifestations by reducing body weight, improving hepatic steatosis, and normalizing serum lipid parameters. Gut microbiota analysis revealed EA-enhanced microbial diversity with specific modulations: decreased Firmicutes / Bacteroidota ratio, enriched Akkermansia and Bacteroidota , and reduced Muribaculum abundance. Targeted metabolomics identified EA-mediated restoration of bile acid metabolism, particularly elevation of secondary bile acids. Molecular analyses demonstrated EA activation of the FXR/FGF15 axis with downstream regulation of hepatic CYP7B1 and CYP27A1. The effect of EA in improving hyperlipidemia is significantly associated with the changes in the structure of the intestinal microbiota and the activation of the FXR/FGF15 signaling pathway. This finding suggests that the metabolic benefits of EA may involve the molecular connection of the gut microbiota-bile acid axis.
✓ 已验证
DOI
高影响因子
PHYTOTHERAPY RESEARCH
·
2026
·
IF 8.1
Yuanchuang Wang,Zijun Zhao,Qingqing Li,Lishang Dai,Kaiyue Zhang,Yating Lu,Mengwei Jia,Zilin Song,Min Liu,Shenghui Chu
Chronic alcohol consumption disrupts gut microbiota and metabolic processes, leading to the transfer of microbial toxins from the intestines to the liver and accelerating the progression of alcoholic liver fibrosis (ALF). However, no effective drugs currently exist to treat ALF. Safflower polysaccharide (SPS), a natural compound extracted from safflower, has garnered significant attention in recent years for its potential clinical applications in treating liver-related diseases. However, the efficacy of SPS in improving ALF and its underlying mechanisms remain unclear. Research indicates that SPS alleviates liver injury in ALF mice by modulating inflammation and fibrosis mechanisms through the gut-liver axis and inhibiting hepatic stellate cell activation. SPS promotes the proliferation of beneficial bacteria, improves gut microbiota composition—including Lactobacillus and Bifidobacterium—and alters bile acid pool composition and its metabolites. Notably, the protective effect of SPS in ALF mice is attenuated by FXR inhibition. In vitro experiments confirmed that SPS effectively activates the FXR/FGFR4/FGF15 signaling pathway, counteracting the inhibitory effects of alcohol or specific bile acids on FXR activity. Immunofluorescence and Western blot analyses further confirmed that SPS enhances FXR activity by promoting its expression. These findings reveal a dual mechanism of action for SPS through regulating gut microbiota and bile acid metabolism, providing a theoretical basis for FXR-targeted therapy in ALF and suggesting that the FXR/FGFR4/FGF15 pathway may represent a potential mechanism of action.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food & Function
·
2021
·Vol. 12
·期 14
·6452-6463
·
IF 5.396
Li Meng,Yuehua Jiao,Xiaohong Zhou,Cong Liang,Kexin Yan,Ye Zhao,Xiujie Deng,Xue Han,Yanyan Yang,Hanmin Liu,Pimin Gong,Lanwei Zhang
Despite the health benefits of Vitis vinifera L. leaves, its anti-obesity potential has not been fully explored. In this work, we showed that Vitis vinifera L. leaf extract (VLE) inhibits the pancreatic lipase activity. Intragastric administration of VLE to mice led to a significant decrease in the body weight, tissue fat accumulation, levels of cholesterol, low-density lipoprotein and triglyceride compared to mice fed with high fat diet. We also found a lower level of neuropeptide-Y (NPY) in the serum and hypothalamus and a higher level of fibroblast growth factor 15 in mice supplemented with VLE. These results suggested that VLE regulates both the NPY-mediated pathway and the bile acid-FGF15 pathway to control energy metabolism and body weight gain. The composition of VLE was further investigated by a targeted metabolomics approach, which identified 21 compounds including phenolic acids, flavones, flavanols, flavanones, coumarins, and stilbenes. Taken together, we demonstrated the capacity of grape leaves in reducing obesity, which could be mediated by NPY and bile acids. Identification of putative active compounds in VLE also open the path for further studies to determine their effectiveness individually to treat obesity.
研究领域:
营养学
·
药理学
·
分子生物学
·
代谢组学
✓ 已验证
DOI
PubMed
高影响因子
Food Frontiers
·
2025
·
IF 6.9
Xiaole Zhao,Bing Zheng,Tianxiang Ao,Jianhua Xie,Yi Chen,Hesham El-Seedi,Hairong Huang,Baoting Liu,Qiang Yu
Polygonatum cyrtonema polysaccharide (PCP-80%) is one of the major active ingredients in Polygonatum cyrtonema . By establishing the type 2 diabetes mellitus (T2DM) rat model and applying multi-omics analysis, the present study aimed to explore the potential mechanism of PCP-80% to alleviate T2DM in terms of the interactions between intestinal microbiota and their metabolites. The results suggested that PCP-80% effectively improve the blood glucose and lipids levels, enhance intestinal barrier function. In addition, PCP-80% restored gut microbiota disorders, increased the secretion of short-chain fatty acids (SCFAs), and enhanced bile acid (BA)-converting enzyme-rich microbiota abundance. Furthermore, PCP-80% intervention significantly ameliorated BA dysmetabolism while enhancing metabolic homeostasis in T2DM rats. These changes activated the G protein-coupled bile acid receptor 1 (TGR5) and farnesoid X receptor (FXR), triggering fibroblast growth factor 15 (FGF15) secretion to ameliorate T2DM-induced intestinal barrier dysfunction and glucose/lipid dysregulation. Mechanistically, PCP-80% exerted therapeutic effects through a microbiota-bile acid crosstalk axis, wherein gut microbiota remodeling enhanced bile acid metabolism and amplified TGR5/FXR-FGF15 signaling, ultimately restoring metabolic homeostasis in T2DM rats.
研究领域:
药理学
·
微生物学
·
内分泌学
·
代谢组学
·
糖尿病研究
·
胃肠病学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE
·
2022
·Vol. 103
·期 3
·1283-1293
·
IF 4.125
Wei Xu,Yingying Kong,Tuo Zhang,Zhihua Gong,Wenjun Xiao
BACKGROUND l -Theanine (LTA) is a biologically active ingredient in tea that shows great potential for regulating lipid metabolism. Bile acids (BA), an important end-product of cholesterol catabolism, participate in the regulation of lipid metabolism and gut microbiota. Here, we investigated the effect of LTA on lipid metabolism and the mechanism by which it regulates BA metabolism and gut microbiota. Male BALB/c mice were treated with LTA for 28 days. RESULTS Daily LTA doses of 100 and 300 mg kg −1 d −1 altered the gut microbiota in mice, predominantly by decreasing Lactobacillus , Streptococcus, Bacteroides , Clostridium and Enterorhabdus microbes associated with bile-salt hydrolase (BSH) activity, thereby decreasing the activity of BSH and increasing the levels of ileum conjugated BA (such as glycocholic acid (GCA) and lithocholic acid), thereby inhibiting the intestinal farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) signaling pathway. Inhibition of FXR-FGF15 signaling was accompanied by upregulation of cholesterol 7α-hydroxylase (CYP7A1) mRNA and protein expression and increased hepatic production of cholic acid, deoxycholic acid, GCA, glycine cholic acid and glycine ursodeoxycholic acid. Meanwhile, increasing hepatic unconjugated BA upregulated the mRNA and protein expression of liver 3-hydroxy-3-methylglutaryl-CoA reductase and downregulated the mRNA and protein expression of stearoyl-CoA desaturase-1, liver low-density lipoprotein receptor and type B scavenger receptor. Therefore, the serum levels of cholesterol and triglycerides decreased. CONCLUSION Our findings indicate that LTA regulates lipid metabolism by modulating the gut microbiota and BA metabolism via the FXR-FGF15-CYP7A1 pathway. © 2022 Society of Chemical Industry.
研究领域:
药理学
·
代谢学
·
微生物学
·
营养学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2024
·
IF 6.8
Yun Wang,Jiawei Wu,Yu Hong,Jiaying Zhu,Youcai Zhang,Jun Zhang,Chujie Ding,Yuan Che,Guangji Wang,Aiqin Jiang,Haiping Hao,Lijuan Cao
Background and Purpose Panax ginseng is widely applied in the adjuvant treatment of cardiometabolic diseases in clinical practice without clear mechanisms. This study aims to clearly define the efficacy and underlying mechanism of P. ginseng and its active components in protecting against atherosclerosis. Experimental Approach The anti-atherogenic efficacy of total ginseng saponin extract (TGS) and its components was evaluated on Ldlr −/− mice. Gut microbial structure was analysed by 16S rRNA sequencing and PCR. Bile acid profiles were revealed using targeted metabolomics with LC–MS/MS analysis. The contribution of gut microbiota to atherosclerosis was assessed by co-housing experiments. Key Results Ginsenoside Rb1, representing protopanaxadiol (PPD)-type saponins, increased intestinal Lactobacillus abundance, resulting in enhanced bile salt hydrolase (BSH) activity to promote intestinal conjugated bile acid hydrolysis and excretion, followed by suppression of enterohepatic farnesoid X receptor (FXR)–fibroblast growth factor 15 (FGF15) signal, and thereby increased cholesterol 7α-hydroxylase (CYP7A1) transcriptional expression and facilitated metabolic elimination of cholesterol. Synergistically, protopanaxatriol (PPT)-type saponins, represented by ginsenoside Rg1, protected against atherogenesis-triggered gut leak and metabolic endotoxaemia. Ginsenoside Rg1 directly induced mucin production to nutritionally maintain Akkermansia muciniphila , which reciprocally inhibited gut permeation. Rb1/Rg1 combination, rather than a single compound, can largely mimic the holistic efficacy of TGS in protecting Ldlr −/− mice from atherogenesis. Conclusion and Implications Our study provides strong evidence supporting TGS and ginsenoside Rb1/Rg1 combinations as effective therapies against atherogenesis, via targeting different signal nodes by different components and may provide some elucidation of the holistic mode of herbal medicines.
研究领域:
药理学
·
心血管疾病
·
微生物学
·
代谢组学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
·
2024
·
IF 3.8
Shuang Wang,Chunyue Zhao,Xueran Huang,Yongfen Gao,Yang Qiu,Rui Jiao,Hanyue Zhu,Huafang Ding,Rui Lin,Zouyan He
Lonicera japonica Thunb. is widely used in Asian countries as a food ingredient to make healthy drinks, with lonicerin, a flavone O -glycoside, as a predominant bioactive compound. This study investigated lonicerin’s effects on high-fat diet-induced hepatic steatosis in mice, compared to its aglycone luteolin. Results showed that lonicerin significantly reduced diet-induced body weight gain and hepatic lipid accumulation in mice, demonstrating greater efficacy than luteolin. This lipid-lowering effect was due to inhibited hepatic fatty acid (FA) biosynthesis and promoted fecal lipid excretion. Moreover, lonicerin favorably modulated gut microbiota by increasing Dubosiella , Eubacterium_brachy_group , and Bilophila , while reducing the pathogenic Desulfovibrionaceae . These changes led to elevated short-chain fatty acid production and altered fecal bile acid (BA) profiles, likely activating the intestinal FXR-FGF15 pathway to inhibit hepatic FA synthesis. In conclusion, lonicerin alleviated diet-induced hepatic steatosis by promoting fecal lipid excretion and inhibiting hepatic FA biosynthesis through modulating the gut microbiota-BA-intestinal FXR axis.
研究领域:
药理学
·
胃肠病学
·
营养学
·
微生物学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）