JOURNAL OF HAZARDOUS MATERIALS
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2024
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IF 12.2
Haining Du,Lili Cui,Xinyi Zhao,Ziteng Yu,Tianyue He,Boya Zhang,Xingpei Fan,Meimei Zhao,Ruijiao Zhu,Ziyi Zhang,Mengcong Li,Jiaxin Li,Yuri Oh,Ning Gu
Butylparaben, a common preservative, is widely used in food, pharmaceuticals and personal care products. Epidemiological studies have revealed the close relationship between butylparaben and diabetes; however the mechanisms of action remain unclear. In this study, we administered butylparaben orally to mice and observed that exposure to butylparaben induced glucose intolerance and hyperlipidemia. RNA sequencing results demonstrated that the enrichment of differentially expressed genes was associated with lipid metabolism, bile acid metabolism, and inflammatory response. Western blot results further validated that butylparaben promoted hepatic lipogenesis, inflammation, gluconeogenesis, and insulin resistance through the inhibition of the farnesoid X receptor (FXR) pathway. The FXR agonists alleviated the butylparaben-induced metabolic disorders. Moreover, 16 S rRNA sequencing showed that butylparaben reduced the abundance of Bacteroidetes , S24–7, Lactobacillus, and Streptococcus , and elevated the Firmicutes / Bacteroidetes ratio. The gut microbiota dysbiosis caused by butylparaben led to decreased bile acids (BAs) production and increased inflammatory response, which further induced hepatic glycolipid metabolic disorders. Our results also demonstrated that probiotics attenuated butylparaben-induced disturbances of the gut microbiota and hepatic metabolism. Taken collectively, the findings reveal that butylparaben induced gut microbiota dysbiosis and decreased BAs production, which further inhibited FXR signaling, ultimately contributing to glycolipid metabolic disorders in the liver.
研究领域:
药理学
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代谢学
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微生物学
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分子生物学
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DOI
PubMed
高影响因子
Journal of Natural Medicines
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2024
·
IF 2.5
Gao Chong,Hu Zhong-He,Cui Zhen-Yu,Jiang Yu-Chen,Dou Jia-Yi,Li Zhao-Xu,Lian Li-Hua,Nan Ji-Xing,Wu Yan-Ling
Angelica dahurica (A. dahurica) has a wide range of pharmacological effects, including analgesic, anti-inflammatory and hepatoprotective effects. In this study, we investigated the effect of A. dahurica extract (AD) and its effective component bergapten (BG) on hepatic fibrosis and potential mechanisms. Hepatic fibrosis was induced by intraperitoneal injection with carbon tetrachloride (CCl 4 ) for 1 week, and mice were administrated with AD or BG by gavage for 1 week before CCl 4 injection. Hepatic stellate cells (HSCs) were stimulated by transforming growth factor-β (TGF-β) and cultured with AD, BG, GW4064 (FXR agonist) or Guggulsterone (FXR inhibitor). In CCl 4 -induced mice, AD significantly decreased serum aminotransferase, reduced excess accumulation of extracellular matrix (ECM), inhibited caspase-1 and IL-1β, and increased FXR expressions. In activated HSCs, AD suppressed the expressions of α-SMA, collagen I, and TIMP-1/MMP-13 ratio and inflammatory factors, functioning as FXR agonist. In CCl 4 -induced mice, BG significantly improved serum transaminase and histopathological changes, reduced ECM excessive deposition, inflammatory response, and activated FXR expression. BG increased FXR expression and inhibited α-SMA and IL-1β expressions in activated HSCs, functioning as GW4064. FXR deficiency significantly attenuated the decreasing effect of BG on α-SMA and IL-1β expressions in LX-2 cells. In conclusion, AD could regulate hepatic fibrosis by regulating ECM excessive deposition and inflammation. Activating FXR signaling by BG might be the potential mechanism of AD against hepatic fibrosis.
研究领域:
药理学
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肝病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Food Bioscience
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2025
·
IF 5.9
Zhe Zhao,Guijie Chen,Danyang Li,Qi Zhang,Guoyuan Xiong,Chuanlai Du,Xiaoxiong Zeng,Chunxu Chen
The 3,5-dicaffeoylquinic acid (3,5-DiCQA), a key component of Chuzhou chrysanthemum, one of the “Four Major Edible Chrysanthemums” in China, has been shown to enrich beneficial gut bacteria and reduce lipid synthesis based on its hydroxycinnamic acid structures. However, its low lipophilicity limits bioactivity, necessitating the development of more stable derivatives. Therefore, this study synthesized and characterized a novel esterified derivative 3,5-DiCQA dodecyl ester (3,5-DiCQAD) with markedly enhanced lipophilicity and bioactivity. In high-fat diet (HFD)-induced male C57BL/6J mice, 3,5-DiCQAD showed remarkable metabolic regulatory effects, including improvements in glucose metabolism, lipid homeostasis, BA signaling, and thermogenesis. Furthermore, 3,5-DiCQAD effectively reshaped the gut microbiota, enriching beneficial bacteria such as Lactobacillus plantarum . Moreover, the strain L. plantarum ZZ 240321 was isolated, and its fermentation of 3,5-DiCQAD generated metabolites that modulated bile acid (BA) metabolism through the FXR/SHP/LRH-1 pathway, alleviating obesity-related symptoms in antibiotic-treated mice. This research provides a novel perspective for developing plant-derived polyphenols as anti-obesity treatments. It also broadens the understanding of DiCQA's probiotic potential in the gut microbiome, highlighting its promising role in managing metabolism-associated disorders.
研究领域:
营养学
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微生物学
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代谢生物学
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药理学
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产品关联
DOI
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2023
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IF 7.5
Guoqin Zhang,Jianhua Sun,Meiqi Liu,Zhixiang Tian,Zicheng Ma,Bingyu Hao,Jintang Ning,Xiaoliang Ren,Meng Wang,Ping Wang,Jiunian Li,Hailin Li,Jian Ni,Yi Liu
Polygoni multiflori radix (PM) is a well-known tonic herb. It has been reported that PM could cause idiosyncratic inflammatory liver injury in some individuals. In this study, we investigated the mechanism of PM-induced idiosyncratic inflammatory liver injury in zebrafish and rat models based on pharmacodynamics and pharmacokinetics. The zebrafish were administered with polygoni multiflori radix extract (PME), emodin (EMO), and 2,3,5,4′-tetrahydroxystilbene-2-Ο-β- D -glucoside (TSG) after lipopolysaccharide (LPS) treatment, to establish an idiosyncratic inflammation model. In zebrafish with idiosyncratic inflammation, PME, EMO, and TSG decreased liver area and brightness and increased the number of immune cells around the colliculi. PME+LPS produced hepatocyte damage, aggravated mitochondrial and endoplasmic reticulum damage, and increased AST and ALT activity. RT-PCR showed that PME and EMO up-regulated the expression of IL-6, IL-1β, and INF-γ, and PME down-regulated expression of FXR and SHP. In rats with idiosyncratic inflammation, AST and ALT activities increased significantly, and liver tissues showed pathological damage. An efficient and sensitive LC-MS/MS method was established for the pharmacokinetic study of EMO and TSG in rats with idiosyncratic inflammation. The AUC 0−t was higher for EMO and TSG in the model group compared with the normal group. The MRT 0−t was significantly prolonged in EMO, while CL z/F was significantly reduced. The present results suggested that the absorption of potentially toxic components of PM increased and metabolism slowed down under inflammatory stress, and PM induced idiosyncratic liver injury via the FXR-SHP axis.
研究领域:
药理学
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毒理学
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肝病学
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药代动力学
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斑马鱼模型
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大鼠模型
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DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
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2025
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IF 7.7
Yu-Chen Jiang,Jia Guo,Sai-Hu Liu,Xu Dai,Chen-Yu Wang,Li-Hua Lian,Zhen-Yu Cui,Ji-Xing Nan,Yan-Ling Wu
Background and Purpose Vincamine has extensive biological and pharmaceutical activity. We examined the hepatoprotective effects and mechanisms by which vincamine suppresses hepatic fibrosis. Experimental Approach Hepatic stellate cells (HSCs), TGF- β stimulated, were cultured with either vincamine, farnesoid X receptor (NR1H4; FXR) agonist or antagonist. Further, C57BL/6 mice were given thioacetamide (TAA) to induce hepatic fibrosis and subsequently treated with vincamine or curcumin. Key Results Vincamine regulated the deposition of extracellular matrix (ECM), inflammatory factors and S100A4, and up-regulated FXR and TGR5 (GPBA receptor) in activated HSCs, by activating FXR. FXR deficiency blocked vincamine effect on FXR, TGR5, α -smooth muscle actin ( α -SMA) and IL1R1 in activated LX-2 cells. Vincamine corrected ECM imbalance, inflammatory secretion and FXR/TGR5 down-regulation in activated LX-2 cells with stimulating medium from LPS-primed THP-1 cells. S100A4 deficiency increased FXR and TGR5, and decreased IL-1β expression in activated THP-1. Further, S100A4 deficiency in activated macrophages could elevate FXR and TGR5 expression in activated LX-2, strengthening the impact of vincamine on α -SMA and IL-1β expression. Further, vincamine reduced serum ALT/AST levels, liver and intestinal histopathological changes, and caused ECM accumulation and protected the intestinal barrier in thioacetamide-induced hepatic fibrosis mice. Vincamine decreased inflammatory factors e.g. caspase 1 and IL-1β, and inhibited the S100A4-mediated FXR-TGR5 pathway. Conclusion and Implications Vincamine significantly reverses hepatic fibrosis via inhibiting S100A4 involved in the crosstalk between macrophages and HSCs, and by activating the FXR-TGR5 pathway. Targeting the S100A4-mediated FXR dependence on modulating the liver environment may be the key target of vincamine in inhibiting hepatic fibrosis. Graphical
研究领域:
药理学
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肝脏病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
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2021
·Vol. 35
·期 6
·3351-3364
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IF 5.882
Junxiao Li,Chuhe Liu,Zhenyu Zhou,Baokai Dou,Jinwen Huang,Leilei Huang,Peiyong Zheng,Shengjie Fan,Cheng Huang
Farnesoid X receptor (FXR) agonist obeticholic acid (OCA) has emerged as a potential therapy for nonalcoholic fatty liver disease (NAFLD). However, the side effects of OCA may limit its application in clinics. We identified previously that isotschimgine (ITG) is a non-steroidal FXR selective agonist and has potent therapeutic effects on NAFLD in mice. Here, we aimed to evaluate the therapeutic effects of ITG on nonalcoholic steatohepatitis (NASH) and fibrosis in mice. We used methionine and choline deficient (MCD) diet-induced NASH mice, bile duct ligation (BDL), and carbon tetrachloride (CCl 4 )-treated hepatic fibrosis mice to investigate the effects of ITG on NASH, fibrosis, and cholestatic liver injury. Our results showed that ITG improved steatosis and inflammation in the liver of MCD diet-fed mice, as well as alleviated fibrosis and inflammation in the liver of CCl 4 -treated mice. Furthermore, ITG attenuated serum bile acid levels, and reduced vacuolization, inflammatory infiltration, hepatic parenchymal necrosis, and collagen accumulation in the liver of BDL mice. Mechanistically, ITG increased the expression of FXR target genes. These data suggest that ITG is an FXR agonist and may be developed as a novel therapy for NASH, hepatic fibrosis, or primary biliary cholangitis.
研究领域:
肝病学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Cell and Developmental Biology
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2025
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IF 4.3
Qiang Pang,Shansong Huang,Xiaodong Li,Jiaqing Cao
Background: The high morbidity and mortality rates of colorectal cancer (CRC) have been a public health concern globally, and the search for additional therapeutic options is imminent. Hyodeoxycholic acid (HDCA) has been receiving attention in recent years and has demonstrated potent efficacy in several diseases. Nonetheless, the antitumor effects and molecular pathways of HDCA in CRC remain largely unexplored.Methods: In this study, we investigated how HDCA influences the growth potential of CRC cells using techniques such as flow cytometry, Edu assay, CCK-8, colony formation assay, Western blot analysis, and animal experiments.Results: It was found that HDCA treatment of CRC cells was able to significantly inhibit the proliferative capacity of the cells. Furthermore, it was discovered that HDCA primarily stimulated Farnesoid X Receptor (FXR) rather than Takeda G protein coupled receptor 5 (TGR5) to suppress CRC growth. It was also confirmed that HDCA inhibited the Epiregulin (EREG)/Epidermal Growth Factor Receptor (EGFR) pathway by activating FXR, and a negative correlation between FXR and EREG was analyzed in CRC tissue samples. Finally, in vivo animal studies confirmed that HDCA inhibited CRC proliferation without hepatotoxicity.Conclusion: Our findings indicate that HDCA suppresses the EREG/EGFR signaling route by activating FXR, thereby hindering the growth of CRC cells and demonstrating a tumor-inhibiting effect in CRC. This study may provide a new therapeutic strategy to improve the prognosis of CRC.
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2026
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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.
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2026
·Vol. 27
·期 10
·4593
·
IF 5.6
Xiaolin Zhang,Yushan Du,Penghui Yang,Shiji Li,Fengya Cui,Xinran Li,Xinyue Du,Bingyao Sun,Yulu Ma,Wenjie Sui,Min Zhang,Jing Meng
Type II diabetes mellitus (T2DM), a chronic metabolic disorder characterized by insulin resistance, is often accompanied by dysregulated bile acid metabolism. Although gastrodin, a bioactive compound derived from Gastrodia elata, has demonstrated potential in diabetes management, its therapeutic mechanisms remain incompletely understood. The aim of this study is to investigate the therapeutic effects and potential mechanisms of gastrodin on T2DM mice from the perspective of bile acid metabolism. In this study, we found that gastrodin could not only reduce lipid accumulation, reduce inflammation, improve antioxidant capacity, alleviate oxidative stress, change the composition of intestinal flora, and improve the disorder of flora caused by the disease in T2DM mice, but also target Yin yang 1 (YY1) to reduce the expression level of YY1 in the liver under a high-fat diet condition. At the same time, YY1 negatively regulates the expression level of Farnesoid X Receptor (FXR), which increases the expression level of FXR, inhibits the enzyme activity of Cholesterol-7α-hydroxylase (CYP7A1) through Small Heterodimer Partner (SHP), reduces the production of chenodeoxycholic acid (CDCA) in the liver, and further affects the production of secondary bile acids through liver–intestinal circulation, promoting the secretion of Glucagon-Like Peptide-1 (GLP-1) and insulin, thereby reducing blood glucose. At the same time, combined with the results of HE staining, gastrodin can reduce the pathological damage of the liver and pancreas in type II diabetic mice, repairing their normal morphology and function. It provides a direct pathological basis for the improvement of diabetes and liver complications, provides theoretical support for the subsequent research and development of precision targeted drugs, provides experimental basis for the development of new natural hypoglycemic drugs, and promotes the transformation and application of the modernization of traditional Chinese medicine in the field of metabolic diseases.
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DOI
PubMed
高影响因子
Expert Opinion on Drug Metabolism & Toxicology
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2020
·
IF 3.47
Linsheng Liu,Xianglian Li,Chenrong Huang,Yicong Bian,Xiaoxue Liu,Jun Cao,Wenhao Qu,Liyan Miao
Objectives Rifampin (RIF), isoniazid (INH) and pyrazinamide (PZA) are essential components of the short-term first-line anti-tuberculosis (anti-TB) chemotherapy regimen and can cause hepatotoxicity. However, the mechanism of anti-TB drug-induced hepatotoxicity (ATDH) is currently unclear. We investigate the relevant contributions to liver injury and the pathway of the above-mentioned drugs administered alone or in combination.Methods UPLC-Q-TOF/MS-based metabolomics, bile acids (BAs) analysis and FXR/SHP detection were used to evaluate the toxicity of these drugs and clarify the underlying metabolism-related pathway.Results In C57BL/6 mice administered the corrected clinical doses, RIF, INH and PZA could induced hepatotoxicity; with less toxicity in the combination therapy than RIF. The pathological biochemistry, BAs concentration and metabolically regulated FXR/SHP gene expression analyzes in mice were consistent with the metabolomics results. FXR played a role in the hepatotoxicity of anti-tuberculosis drugs in the obeticholic acid treated and FXR-/- mice. Additionally, the purine and lipid metabolic pathways were involved in ATDH.Conclusion ATDH was involved in bile acids and lipid and purine metabolism. The BAs metabolic pathway involvement in mice was validated in TB patients. The noninvasive metabolomics approach is more systemic than routine toxicity evaluation and can be used to assess compound toxicity and the underlying mechanism.
研究领域:
药理学
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毒理学
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代谢
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肝病学
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传染病学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2017
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IF 4.581
Xiaoguang Gao,Ting Fu,Changyuan Wang,Chenqing Ning,Yulong Kong,Zhihao Liu,Huijun Sun,Xiaodong Ma,Kexin Liu,Qiang Meng
Recently obeticholic acid (OCA) which is a farnesoid X receptor (FXR) agonist was approved by FDA to treat cholestatic liver diseases, which provided us a novel therapeutic strategy against cholestasis . Herein, we used a novel computational strategy with two-dimensional virtual screening for FXR agonists. For the first time, we found that auraptene (AUR), a natural product, can activate FXR to exert hepatoprotective effect against cholestatic liver injury in vivo and in vitro . Importantly, AUR was found to significantly decrease the mortality of cholestatic mice. Dynamic change analysis of bile acids and gene analysis revealed that AUR promoted bile acid efflux from liver into intestine via an induction in FXR-target genes Bsep and Mrp2 expression, and reduced hepatic uptake through an inhibition in Ntcp . Furthermore, AUR reduced bile acid synthesis through repressing FXR-target genes Cyp7a1 and Cyp8b1, and increased bile acid metabolism through an induction in Sult2a1 . In addition, AUR promoted liver repair through an induction in liver regeneration-related gene, and suppressed liver inflammation through repressing inflammation-related gene NF-κB, TNF-α, IL-1β and IL-6. However, the changes in these genes and protein, as well as ameliorative liver histology induced by AUR were abrogated by FXR antagonist guggulsterone in vivo and FXR siRNA in vitro . These findings suggest that AUR may be an effective approach for the prevention against cholestatic liver diseases.
研究领域:
药理学
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肝病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
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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
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环境健康
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代谢组学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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