PHYTOMEDICINE
·
2024
·
IF 6.7
Zhenxiu Liu,Lin Chen,Mingyun Chen,Lang Linghu,Zhihua Liao,Min Chen,Guowei Wang
Background Farnesoid X receptor (FXR) is a vital receptor for bile acids and plays an important role in the treatment of cholestatic liver disease. In addition to traditional bile acid-based steroidal agonists, synthetic alkaloids are the most commonly reported non-steroidal FXR agonists. Sarmentol H is a nor-sesquiterpenoid obtained from Sedum sarmentosum Bunge, and in vitro screening experiments have shown that it might be related to the regulation of the FXR pathway in a previous study. Purpose To investigate the therapeutic effects of sarmentol H on cholestasis and to determine whether sarmentol H directly targets FXR to mitigate cholestasis. Furthermore, this study aimed to explore the key amino acid residues involved in the binding of sarmentol H to FXR through site-directed mutagenesis. Methods An intrahepatic cholestasis mouse model was established to investigate the therapeutic effects of sarmentol H on cholestasis. In vitro experiments, including Co-Ip and FXR-EcRE-Luc assays, were performed to assess whether sarmentol H activates FXR by recruiting the receptor coactivator SRC1. CETSA, SIP, DARTS, and ITC were used to determine the binding of sarmentol H to FXR protein. The key amino acid residues for sarmentol H binding to FXR were analyzed by molecular docking and site-directed mutagenesis. Finally, we conducted in vivo experiments on wild-type and Fxr −/− mice to further validate the anticholestatic target of sarmentol H. Results Sarmentol H had significant ameliorative effects on the pathological conditions of cholestatic mice induced with ANIT. In vitro experiments suggested that it is capable of activating FXR and regulating downstream signaling pathways by recruiting SRC1. The target validation experiments showed that sarmentol H had the ability to bind to FXR as a ligand (K D = 2.55 μmol/L) and enhance the stability of its spatial structure. Moreover, site-directed mutagenesis revealed that THR292 and TYR365 were key binding sites for sarmentol H and FXR. Furthermore, knockout of the Fxr gene resulted in a significantly higher degree of ANIT-induced cholestatic liver injury than that in wild-type cholestatic mice, and the amelioration of cholestasis or regulatory effects on FXR downstream genes by sarmentol H also disappeared in Fxr −/− cholestatic mice. Conclusion Sarmentol H is an FXR agonist. This is the first study to show that it exerts a significant therapeutic effect on cholestatic mice, and can directly bind to FXR and activate it by recruiting the coactivator SRC1.
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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生物化学
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DOI
PubMed
高影响因子
TOXICOLOGY IN VITRO
·
2025
·
IF 2.7
Yuhui Yan,Wenyu Wang,Aiwen Yan,Haonan Zhu,Qiang Meng
Cholestasis, a condition marked by bile acid accumulation in the liver and body systems, leads to liver dysfunction and cirrhosis. Currently, ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are the only two FDA-approved drugs for Cholestasis. Thus, new therapeutic approaches need to be developed. In this study, we validated the liver-protective properties of β-sitosterol (SIT), a key bioactive element abundant in plants, against hepatic toxicity and cholestasis induced by alpha-naphthylisothiocyanate(ANIT), while elucidating its mechanisms of action both in vivo and in vitro. SIT's FXR activation was confirmed via molecular docking and dual-luciferase assays. In the mechanisms of SIT hepatoprotection, the expression levels of bile salt export pump (Bsep) and multidrug resistance protein2 (Mrp2) which are bile acid efflux transporter, and sulfate transferase 2a1 (Sult2a1) which is a bile acid metabolizing enzyme were all increased by SIT, whereas the expression of uptake transporter sodium taurocholate transporting polypeptide (Ntcp), bile acid synthesis enzyme cholesterol 7α-hydroxylase (Cyp7a1) and oxysterol 12α-hydroxylase (Cyp8b1) was decreased by SIT. In addition, SIT alleviated liver inflammation by suppressing inflammatory factor expression. However, FXR antagonist guggulsterone and FXR siRNA abolished SIT's improvements in liver histology, bile acid transporters, and enzymes. Conclusively, through activating FXR, SIT provides a protective effect against hepatotoxicity and cholestasis. SIT might serve as a new potential therapeutic strategy for the treatment of cholestatic liver diseases.
研究领域:
药理学
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分子生物学
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肝脏疾病
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2025
·
IF 6.2
Zhouya Bai,Yunhui Zhang,Xiaojun Huang,Denglin Luo,Shaobin Gu,Kangyi Zhang,Shaoping Nie
The gut microbiota is vital in regulating glycolipid metabolism through bile acid pathways, while pectin maintains gut flora balance. Polysaccharides from red kidney beans (RKPs), particularly pectic types, lower blood sugar and lipids, although the mechanism is unclear. Our findings showed that RKP intervention significantly affects primary bile acid synthesis, especially conjugated bile acids, notably taurocholic acid (TCA). Correspondingly, FXR and TGR5 were identified as key receptors in glucolipid metabolism. Further, Akkermansia was proven to be a vital strain and to effectively improve glycolipid metabolism associated with regulating the activity of bile salt hydrolases (BSHs) and bile acid composition, especially for TCA in diabetic mice. Our results provide an antidiabetic mechanism of RKP and suggest that enriched Akkermansia via regulating the vitality of BSH is altered in response to the composition of bile acid, especially for TCA, thereby alleviating glycolipid metabolism through the TCA-FXR/TGR5 axis.
研究领域:
微生物组学
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代谢生物学
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内分泌学
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营养科学
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分子药理学
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胆汁酸代谢
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肠道菌群与宿主互作
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产品关联
DOI
PubMed
高影响因子
Clinical and Experimental Gastroenterology
·
2023
·
IF 2.4
Meng Xu,Ke Che,Cong Wang,Ya-Ru Chen,Meng-Yuan Chen,Guang-Lei Zhang,Hao Yu,Hao-Nan Xu,Ya-Bao Li,Ping Sheng,Hao Chen
Introduction Cholestasis is a common liver disorder that currently has limited treatment options. Gardenia Iridoid Glucosides (GIG) have been found to possess various physiological activities, such as cholagogic, hypoglycemic, antibacterial, and anti-inflammatory effects. The objective of this study was to investigate the effects of GIG on bile acid enterohepatic circulation and explore the underlying mechanism in cholestatic rats.Methods In order to identify key pathways associated with cholestasis, we conducted Gene Ontology (GO) Enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. In vivo experiments were then performed on alpha-naphthylisothiocyanate (ANIT)-treated rats to assess the impact of GIG. We measured bile flow and various biomarkers including total bilirubin (TB), total bile acids (TBA), total cholesterol (TC), malondialdehyde (MDA), glutamic-pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), and total superoxide dismutase (T-SOD) in the serum. We also examined the expression levels of bile salt export pump (BSEP), ATP-binding cassette subfamily B member 4 (ABCB4), far-nesoid X receptor (FXR), small heterodimer partner (SHP), cholesterol 7α-hydroxylase (CYP7A1), and sodium taurocholate cotransporting polypeptide (NTCP) in liver tissue. In vitro experiments were conducted on primary hepatocytes to further investigate the mechanism of action of GIG on the expression of SHP, CYP7A1, NTCP, and FXR.Results Our in vivo experiments demonstrated that GIG significantly increased bile flow and reduced the levels of TB, TBA, TC, MDA, GPT, and GOT, while increasing T-SOD levels in ANIT-treated rats. Addi-tionally, GIG ameliorated liver tissue damage induced by ANIT, upregulated the expression of BSEP and ABCB4, and modulated the protein expression of FXR, SHP, CYP7A1, and NTCP in model rats. In vitro experiments further revealed that GIG inhibited the expression of SHP, CYP7A1, and NTCP by suppressing the expression of FXR.Conclusion This study provides new insights into the therapeutic potential of GIG for the treatment of cholestasis. GIG demonstrated beneficial effects on bile acid enterohepatic circulation and liver biomarkers in cholestatic rats. The modulation of FXR and its downstream targets may contribute to the mechanism of action of GIG. These findings highlight the potential of GIG as a therapeutic intervention for cholangitis.
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
Food Bioscience
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2025
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IF 5.9
Shasha Chen,Wenwen Li,Xinran Zhu,Yanlu Han,Mengyao Wang,Ke Gong,Jie Xiao,Chenzhong Liao,Yajun Duan,Xiaohua Jiang,Shuang Zhang
Estrogen-induced cholestasis (EIC) is a condition associated with intrauterine fetal death, preterm delivery, and meconium in amniotic fluid. The role of sesamol, a major bioactive compound in sesame oil, in alleviating cholestasis remains unclear. In this study, we investigated the mechanisms underlying the protective effects of sesamol against cholestatic liver injury using C57BL/6 male mice with 17α-ethynylestradiol (EE)-induced cholestasis, combined with network pharmacology, 16S rRNA sequencing, and the in vitro assays. Our results demonstrate that sesamol alleviates cholestatic liver injury by inhibiting inflammation, oxidative stress, and apoptosis. Mechanistically, sesamol activates EGFR/FXR/CYP7A1 signaling pathway, thereby improving bile acid metabolism. Additionally, sesamol modulates the gut microbiota by increasing the relative abundance of Firmicutes and Bacteroidota ( P < 0.05), which are crucial for bile acid metabolism. Furthermore, we observed a positive correlation ( P < 0.05) between serum liver injury and cholestasis relative markers and the abundance of certain harmful bacteria ( Anaerovorax, Erysipelatoclostridium, Fusobacterium ), suggesting that sesamol may protect against EIC through modulation of the liver-gut axis, contributing to the restoration of bile acid homeostasis. This study provides new insights into the potential of sesamol as a functional food ingredient for the prevention and treatment of cholestasis.
研究领域:
药理学
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分子生物学
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微生物学
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产品关联
DOI
高影响因子
Drug Design Development and Therapy
·
2025
·
IF 5.1
Xuehui Deng,Bingfeng Lin,Wenlong Xiao,Fang Wang,Pingcui Xu,Nani Wang
Background Specnuezhenide (SPN) is an iridoid glycoside isolated from Fructus Ligustri Lucidi, an herb prescribed for the treatment of senile osteoporosis. However, the direct role of SPN on bone metabolism remains unclear. In this study, the effects of SPN on d-galactose (d-gal)-induced mice, bone marrow mesenchymal stem cells (BMSCs), and nuclear factor-κB ligand-induced osteoclasts were examined.Methods Micro-computed tomography was used to observe the bone microstructure. Osteogenesis was examined using Western blotting and alkaline phosphatase staining. Osteoclastogenesis was examined using Western blotting and F-actin ring staining. Senescence-associated β-galactosidase was used to detect cell senescence. In addition, the expression of Takeda G protein-coupled receptor 5 (TGR5)/farnesoid X receptor (FXR) signaling pathway-related genes and proteins was determined through quantitative real-time polymerase chain reaction and immunofluorescence.Results Oral administration of SPN improved the bone microstructure in d-gal-induced mice and increased bone mineral density, bone volume, trabecular thickness, and trabecular number. SPN also upregulated the expression of the osteogenesis markers osteocalcin, bone morphogenetic protein 2, and runt-related transcription factor 2 and downregulated the expression of the osteoclasis markers tartrate-resistant acid phosphatase, nuclear factor-κB, and nuclear factor of activated T-cells in the d-gal-induced bone. Furthermore, SPN increased alkaline phosphatase staining, inhibited F-actin ring formation, and reduced the activity of senescence-associated β-galactosidase in vitro. Mechanistically, SPN activated the TGR5/FXR pathway in d-gal-induced BMSCs and osteoclasts. The protective effects of SPN were abolished after addition of the TGR5 inhibitor SBI-115 or FXR inhibitor DY268. Moreover, SPN could elevate the protein and mRNA levels of TGR5, FXR, and the downstream small heterodimer partner in d-gal-induced bone.Conclusion SPN alleviated senile osteoporosis and cell senescence by activating the TGR5/FXR pathway.
研究领域:
药理学
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骨生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
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IF 7.7
Zixuan Tang,Mingli Zhong,Houkang Cao,Yongwang Wang,Guoqiang Guan,Gang Wang,Jianzhao Wu,Fei Han,Ya Gao,Kefeng Zhang
Dicliptera chinensis (L.) Juss., is an herb known for its anti-inflammatory and anti-oxidant properties. In the previous studies, the chemical composition of the polysaccharide from Dicliptera chinensis (L.) Juss. (DCP) has been characterized as consisting of DCP 1 and DCP 2 , of which DCP 2 has hepatoprotective effects. The study examined the hepatoprotective potential of DCP 2 against alpha-naphthyl isothiocyanate (ANIT)-induced cholestatic liver disease (CLD). In this study, RNA sequencing identified key research pathways involving bile acid metabolism, oxidative stress, and inflammation. Furthermore, qRT-PCR and Western blot analyses were conducted to further characterize these pathways. Additionally, the study included in vitro experiments with HepG2 cells to further investigate the effects of DCP 2 on bile acid metabolism. In summary, the protective effect of DCP 2 on the liver was reflected in alleviating the inflammatory response and oxidative stress, regulating the metabolism of bile acids, and mitigating liver damage caused by bile acids. This study further elucidated the hepatoprotective effects of DCP 2 by examining its ability to counteract ANIT-induced CLD, suggesting that DCP 2 is a promising biomacromolecule for hepatoprotection.
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
PHYTOMEDICINE
·
2023
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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
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肝病学
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分子生物学
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
PLoS One
·
2025
·Vol. 20
·期 7
·e0328000
·
IF 2.6
Shuaijun Peng,Ruiqin Sun,Hui Liu,Baoying Wang,Yucheng Li
Gastric mucosal injury can lead to significant gastrointestinal disorders, including inflammation, ulcers, and intestinal metaplasia in severe cases. Although bile acids are known contributors to mucosal damage due to their acidity, the role of chenodeoxycholic acid (CDCA), a primary bile acid, in gastric mucosal injury remains unclear. This study investigates the role of CDCA in inducing gastric mucosal injury and its underlying mechanisms, with a focus on apoptosis and FXR activation, to identify potential therapeutic targets. Mice were administered varying doses of CDCA to evaluate changes in body weight, food intake, and gastric mucosal pathology using hematoxylin-eosin (HE) and alcian blue-periodic acid-Schiff (AB-PAS) staining. Expression levels of apoptosis-related genes (BAX, BCL-2) and the intestinal metaplasia marker gene (CDX2) were analyzed via RT-PCR and Western blotting (WB). GES-1 cells were treated with different CDCA concentrations to assess cell viability via the CCK-8 assay. Apoptosis rates were measured using flow cytometry, and FXR inhibitors were applied to examine their impact on CDCA-induced effects. CDCA administration in mice resulted in weight loss, reduced food and water intake, gastric epithelial shedding, and intestinal metaplasia. CDCA exposure upregulated Bax and CDX2 expression, while reducing BCL-2 levels. In vitro, CDCA inhibited GES-1 cell viability and increased apoptosis rates, effects that were reversed by FXR inhibition. CDCA induces gastric mucosal injury through apoptosis and FXR activation. These findings provide insights into the mechanisms of bile acid-mediated mucosal damage and highlight FXR as a potential therapeutic target for gastric mucosal disorders.
研究领域:
胃肠病学
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细胞生物学
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分子生物学
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药理学
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病理学
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产品关联
DOI
PubMed
高影响因子
Hepatology International
·
2024
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IF 5.9
Li Lin,Kong Lina,Xu Shuai,Wang Changyuan,Gu Jiangning,Luo Haifeng,Meng Qiang
Background and purpose Alcoholic liver disease (ALD), a metabolic liver disease caused by excessive alcohol consumption, has attracted increasing attention due to its high prevalence and mortality. Up to date, there is no effective and feasible treatment method for ALD. This study was to investigate whether Farnesoid X receptor (FXR, NR1H4) can alleviate ALD and whether this effect is mediated by inhibiting absent in melanoma 2 (AIM2) inflammasome activation. Methods The difference in FXR expression between normal subjects and ALD patients was analyzed using the Gene Expression Omnibus (GEO) database. Lieber–DeCarli liquid diet with 5% ethanol (v/v) (EtOH) was adopted to establish the mouse ALD model. Liver histopathological changes and the accumulation of lipid droplets were assessed by H&E and Oil Red O staining. Quantitative real-time PCR, Western blotting analysis and immunofluorescence staining were utilized to evaluate the expression levels of related genes and proteins. DCFH–DA staining was adopted to visualize reactive oxidative species (ROS). Results FXR was distinctly downregulated in liver tissues of patients with steatosis compared to normal livers using the GEO database, and in ethanol-induced AML-12 cellular steatosis model. FXR overexpression ameliorated hepatic lipid metabolism disorder and steatosis induced by ethanol by inhibiting the expression of genes involved in lipid synthesis and inducing the expression of genes responsible for lipid metabolism. Besides, FXR overexpression inhibited ethanol-induced AIM2 inflammasome activation and alleviated oxidative stress and ROS production during ethanol-induced hepatic steatosis. However, when FXR was knocked down, the results were completely opposite. Conclusions FXR attenuated lipid metabolism disorders and lipid degeneration in alcohol-caused liver injury and alleviated oxidative stress and inflammation by inhibiting AIM2 inflammasome activation. Graphical abstract
研究领域:
肝病学
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分子生物学
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炎症
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代谢紊乱
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGICAL SCIENCES
·
2016
·Vol. 152
·期 2
·417-428
·
IF 3.88
Guo Hong-Li,Hassan Hozeifa M.,Zhang Yun,Dong Si-Zhe,Ding Ping-Ping,Wang Tao,Sun Li-Xin,Zhang Lu-Yong,Jiang Zhen-Zhou
Pyrazinamide (PZA) is an indispensable first-line drug used for the treatment of tuberculosis which may cause serious hepatotoxicity; however, the mechanisms underlying these toxicities are poorly understood. Cholestasis plays an important role in drug-induced liver injury. Since there were no previous published works reported cholestasis and PZA hepatotoxicity relationship, this study aimed to identify whether PZA can induce liver injury with characterized evidences of cholestasis and to clarify expression changes of proteins related to both bile acid synthesis and transport in PZA-induced liver injury. PZA (2 g/kg) was administered for 7 consecutive days by oral gavage. Results showed there were 2-fold elevation in both ALT and AST serum levels in PZA-treated rats. In addition, a 10-fold increment in serum total bile acid was observed after PZA administration. The mRNA and protein expressions of bile acid synthesis and transport parameters were markedly altered, in which FXR, Bsep, Mrp2, Mdr2, Ostα/β, Oatp1a1, Oatp1b2, and Cyp8b1 were decreased (P < .05), while Mrp3, Ntcp, Oatp1a4, and Cyp7a1 were increased (P < .05). Moreover, treatment with the FXR agonist obeticholic acid (OCA) generated obvious reductions in serum ALT, AST, and TBA levels in PZA-treated rats. Those effects were due to transcriptional regulation of pre-mentioned target genes by OCA. Taken together, these results suggested that PZA-induced cholestatic liver injury was related to FXR inhibition, leading to the dysfunction in bile acid synthesis and transport.
研究领域:
药理学
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毒理学
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肝病学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Functional Foods
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2024
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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
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胃肠病学
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营养学
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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）