Chinese Medicine
·
2026
·Vol. 21
·期 1
·34
·
IF 5.7
Fan Haibo,Hou Yalei,Li Yue,Zheng Zhiwen,Wang Xuelun,Li Yunfeng,Li Yongmin
Background Metabolic-associated fatty liver disease (MAFLD) is a common metabolic disease with complex pathogenesis and lack of effective treatment. Si-Ni-San (SNS), a traditional Chinese medicine, has emerged as a promising candidate for MAFLD treatment. However, the protective mechanism remains unclear. Methods C57BL/6N mice were fed with high-fat diet (HFD) for 12 weeks to establish MAFLD mouse model. Concurrently, oleic acid-induced HepG2 cells were used in vitro as a cellular model for MAFLD. The effects of SNS and the positive drug obeticholic acid on hepatic lipid droplets deposition in MAFLD mice and cell models were evaluated. The expression levels of farnesoid X receptor (FXR) and glycerol 3-phosphate acyltransferase 4 (GPAT4) were detected by western blot. The siRNA and dual-luciferase reporter assay were used to detect the interaction between FXR and GPAT4. High-performance liquid chromatography (HPLC) was used to identify the active components in the SNS aqueous solution, and their binding affinities to targets were detected through molecular docking, molecular dynamics simulations, and surface plasmon resonance (SPR). Results The active ingredients of SNS were identified by HPLC. SNS ameliorated hepatic lipid droplets deposition in both mouse and cellular models of MAFLD. SNS up-regulated the expression of FXR and down-regulated the expression of GPAT4 in hepatic tissues, thereby modulating proteins involved in hepatic lipolysis and lipophagy. FXR reduced lipid droplets accumulation by inhibiting GPAT4. The dual-luciferase reporter assay confirmed that FXR transcriptionally regulated and inhibited GPAT4 expression. Furthermore, molecular docking and molecular dynamics simulations predicted potential interactions between the active components of SNS and the FXR and GPAT4 proteins, with the binding affinity for FXR being subsequently confirmed through SPR analysis. Conclusion This study provided a new mechanistic exploration for FXR in improving MAFLD and broadened the research direction on the mechanisms by which SNS reduced hepatic lipid droplets deposition. It also offers a molecular dynamics basis for subsequent studies on how active components in SNS exert their effects through binding to FXR.
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高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2017
·
IF 2.759
Lingli Zheng,Lianhong Yin,Lina Xu,Yan Qi,Hua Li,Youwei Xu,Xu Han,Kexin Liu,Jinyong Peng
Our previous works showed that dioscin, a natural product, could protect liver from acute liver damages induced by dimethylnitrosamine , ethanol, carbon tetrachloride and acetaminophen . However, the effect of dioscin on thioacetamide (TAA)-induced acute liver injury still remained unknown. The purpose of this study was to investigate whether dioscin confers a protective effect against TAA-induced acute liver injury in rats and mice. The results showed that dioscin decreased the serum levels of ALT, AST, and rehabilitated histopathological changes compared with the model groups. In addition, dioscin obviously increased the levels of GSH, GSH-Px, SOD, and significantly reduced MDA levels compared with the model groups. Mechanistic study showed that dioscin significantly up-regulated the expression levels of FXR , p -AMPKα, and then increased the expression levels of Nrf2, HO-1, NQO-1, GCLM and GST. Furthermore, dioscin obviously down-regulated the expression levels of NF-κB (p65), ICAM-1, HMGB1, COX-2, TNF-α, IL-1β and IL-6. Taken together, dioscin showed protective effect against TAA-induced acute liver injuries in rats and mice and the effects might be obtained through inhibiting oxidative stress and inflammation via FXR/AMPK signal pathway . These findings provided a new insight on the role of doscin in the treatment of acute liver injury.
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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高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2023
·
IF 3.3
Jing Zhao,Guochao Song,Fengyi Weng,Yue Li,Bin Zou,Jingyi Jin,Dongming Yan,Xin Sun,Chenghai Liu,Fu-rong Qiu
The aim of this study was to determine the effect of tauroursodeoxycholic acid (TUDCA) on the alpha-naphthylisothiocyanate (ANIT)-induced model of cholestasis in mice. Wild-type and farnesoid X receptor (FXR)-deficient ( Fxr −/− ) mice were used to generate cholestasis models by gavage with ANIT. Obeticholic acid (OCA) was used as a positive control. In wild-type mice, treatment with TUDCA for 7 days resulted in a dramatic increase in serum levels of alanine aminotransferase (ALT), with aggravation of bile infarcts and hepatocyte necrosis with ANIT-induction. TUDCA activated FXR to upregulate the expression of bile salt export pump (BSEP), increasing bile acids (BAs)-dependent bile flow, but aggravating cholestatic liver injury when bile ducts were obstructed resulting from ANIT. In contrast, TUDCA improved the liver pathology and decreased serum ALT and alkaline phosphatase (ALP) levels in ANIT-induced Fxr −/− mice. Furthermore, TUDCA inhibited the expression of cleaved caspase-3 and reduced the area of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining in the model mice. TUDCA also upregulated anion exchanger 2 (AE2) protein expression, protecting cholangiocytes against excessive toxic BAs. Our results showed that TUDCA aggravated cholestatic liver injury via the FXR/BSEP pathway when bile ducts were obstructed, although TUDCA inhibited apoptotic activity and protected cholangiocytes against excessive toxic BAs.
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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PubMed
高影响因子
Nutrients
·
2023
·Vol. 15
·期 23
·4929
·
IF 5.9
Lin Zhu,Shuaizhen Fang,Hong Zhang,Xiangjun Sun,Puyu Yang,Jianchun Wan,Yaqiong Zhang,Weiying Lu,Liangli Yu
In this study, the impact ofsn-2 palmitic triacyclglycerols (TAGs) in combination with their ratio of two major TAGs (1-oleoyl-2-palmitoyl-3-linoleoylglycerol (OPL) to 1,3-dioleoyl-2-palmitoylglycerol (OPO)) in human milk fat substitute (HMFS) on bile acid (BA) metabolism and intestinal microbiota composition was investigated in newly-weaned Sprague–Dawley rats after four weeks of high-fat feeding. Compared to those of control group rats, HMFS-fed rats had significantly increased contents of six hepatic primary BAs (CDCA, αMCA, βMCA, TCDCA, TαMCA and TβMCA), four ileal primary BAs (UDCA, TCA, TCDCA and TUDCA) and three secondary BAs (DCA, LCA and ωMCA), especially for the HMFS with the highestsn-2 palmitic acid TAGs of 57.9% and OPL to OPO ratio of 1.4. Meanwhile, the inhibition of ileal FXR-FGF15 and activation of TGR5-GLP-1 signaling pathways in HMFS-fed rats were accompanied by the increased levels of enzymes involved in BA synthesis (CYP7A1, CYP27A1 and CYP7B1) in the liver and two key thermogenic proteins (PGC1α and UCP1) in perirenal adipose tissue, respectively. Moreover, increasingsn-2 palmitic TAGs and OPL to OPO ratio in HMFS also altered the microbiota composition both on the phylum and genus level in rats, predominantly microbes associated with bile-salt hydrolase activity, short-chain fatty acid production and reduced obesity risk, which suggested a beneficial effect on host microbial ecosystem. These observations provided important nutritional evidence for developing new HMFS products for infants.Keywords:sn-2 palmitic triacylglycerols;human milk fat substitute;BA metabolism;FXR;TGR5;gut microbiota
研究领域:
营养学
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微生物学
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代谢学
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分子生物学
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PubMed
高影响因子
PHYTOMEDICINE
·
2021
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IF 5.34
Kaihui Zhang,Yufeng Yao,Meiqi Wang,Fangle Liu,Qian Wang,Huanhuan Ma,Yuanyuan Xie,Yunxia Ma,Pengyu Dai,Chenchen Zhu,Chaozhan Lin
Background Rabdosia Serra, the dried aerial parts of Rabdosia serra (Maxim.) Hara (RS) from the Labiatae family, is a traditional Chinese herbal medicine called Xihuangcao. Although RS has been found to exert a therapeutic effect on cholestasis, the underlying molecular mechanism remains unclear. Purpose This study was designed to investigate the pharmacological effect and mechanism of RS on cholestatic rats using metabolomics platform. Methods Histopathology and biochemical evaluations were performed to determine the therapeutic effect of RS and developed a rapid metabolite detection technology method based on UPLC-MS/MS to perform metabolomics research. Further, quantitative real-time polymerase chain reaction (RT-qPCR) was used to study the effect of RS on the bile acid metabolism pathway at the transcriptional level. Results RS significantly reduced the bile flow rates in cholestatic rats and decreased the levels of ALT, AST, TBA, T-BIL, and LDH, which were increased in the model group. Histological analysis showed that RS alleviated the liver injury induced by ANIT. Serum metabolomics results revealed 33 of the 37 biomarkers were found to be significantly altered by ANIT, and 26 were considerably changed following treatment with RS. Metabolic pathway analysis revealed four pathways such as primary bile acid biosynthesis, biosynthesis of unsaturated fatty acids, and arachidonic acid and tryptophan metabolism. The bile acid secretion process and the inflammation and oxidative stress processes are the major biochemical reactions following treatment with ANIT and RS. Bile acid-targeted metabolomics study showed that TCA, GCA, GCDCA, and GDCA might be sensitive biomarkers that induced liver injury. we found that treatment with RS regulated the levels of bile acid in the serum and liver and restored the proportion of bile acids, especially CA and conjugated bile acids, such as TCA and GCA, in the bile duct. RS increased the mRNA expression levels of FXR, SHP, BSEP , and MRP2 in livers, and IBABP, OST-α , and OST-β in the ileum. Conclusion : In this study, RS was found to protect the liver by regulating multiple metabolic pathways and promoting the excretion of bile acids. Simultaneously, RS played an essential role in reversing the imbalance of bile acids and protected against cholestasis by regulating the expression of transporters associated with bile acids. We demonstrated the correlation between molecular mechanisms and metabolites, provide a reference for the fabrication of extracts that can be used to treat cholestasis.
研究领域:
药理学
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代谢组学
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传统中药
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肝脏疾病
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高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2023
·
IF 4.3
Peng Cao,Jun Gan,Sanlan Wu,Yixin Hu,Bin Xia,Xiaoyue Li,Hongan Zeng,Bingyu Cheng,Huifan Yu,Fei Li,Luqin Si,Jiangeng Huang
Cholestatic liver injury is caused by toxic action or allergic reaction , resulting in abnormality of bile formation and excretion. Few effective therapies have become available for the treatment of cholestasis . Herein, we found that tectorigenin (TG), a natural isoflavone , showed definite protective effects on alpha-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury, significantly reversing the abnormality of plasma alanine/aspartate aminotransferase, total/direct bilirubin and alkaline phosphatase , as well as hepatic reactive oxygen species , catalase and superoxide dismutase . Importantly, the targeted metabolomic determination found that BA homeostasis could be well maintained in TG-treated cholestatic mice, especially the levels of glycocholic acid , tauromuricholic acid, taurocholic acid , taurolithocholic acid , tauroursodeoxycholic acid and taurodeoxycholic acid . Overall, primary/secondary and amidated/unamidated bile acid (BA) levels were significantly altered upon ANIT stimulation but could be restored by TG intervention to certain extents. In addition, TG boosted the expression of farnesoid x receptor (FXR), which in turn upregulated multidrug resistance protein 2 (MRP2) and bile salt export pump (BSEP) to accelerate the excretion of BA. Meanwhile, TG enhanced the expression of Nrf2 and its upstream genes PI3K/Akt and downstream target genes HO-1, NQO1, GCLC and GCLM to strengthen the antioxidant capacity . Taken together, TG plays a vital role in maintaining BA homeostasis and ameliorating cholestatic liver injury through regulating FXR-mediated BA efflux and Nrf2-mediated antioxidative pathways.
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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高影响因子
PeerJ
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2020
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IF 2.379
Xiaoyan Li,Yiyan Lu,Xiaojun Ou,Sijing Zeng,Ying Wang,Xiaoxiao Qi,Lijun Zhu,Zhongqiu Liu
Background This study aimed to systematically profile the alterations and sex- and age-related differences in the drug metabolizing enzymes (DMEs) in a KRAS-mutant mouse model of lung cancer (KRAS mice). Methodology In this study, the LC-MS/MS approach and a probe substrate method were used to detect the alterations in 21 isoforms of DMEs, as well as the enzymatic activities of five isoforms, respectively. Western blotting was applied to study the protein expression of four related receptors. Results The proteins contents of CYP2C29 and CYP3A11, were significantly downregulated in the livers of male KRAS mice at 26 weeks (3.7- and 4.4-fold, respectively, p < 0.05). SULT1A1 and SULT1D1 were upregulated by 1.8- to 7.0- fold at 20 ( p = 0.015 and 0.017, respectively) and 26 weeks ( p = 0.055 and 0.031, respectively). There were positive correlations between protein expression and enzyme activity for CYP2E1, UGT1A9, SULT1A1 and SULT1D1 ( r 2 ≥ 0.5, p < 0.001). Western blotting analysis revealed the downregulation of AHR, FXR and PPARα protein expression in male KRAS mice at 26 weeks. For sex-related differences, CYP2E1 was male-predominant and UGT1A2 was female-predominant in the kidney. UGT1A1 and UGT1A5 expression was female-predominant, whereas UGT2B1 exhibited male-predominant expression in liver tissue. For the tissue distribution of DMEs, 21 subtypes of DMEs were all expressed in liver tissue. In the intestine, the expression levels of CYP2C29, CYP27A1, UGT1A2, 1A5, 1A6a, 1A9, 2B1, 2B5 and 2B36 were under the limitation of quantification. The subtypes of CYP7A1, 1B1, 2E1 and UGT1A1, 2A3, 2B34 were detected in kidney tissue. Conclusions This study, for the first time, unveils the variations and sex- and age-related differences in DMEs in C57 BL/6 (WT) mice and KRAS mice.
研究领域:
药理学
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肿瘤学
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分子生物学
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PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Shuting Xu,Guangyi Liao,Tingting Li,Wenmin Li,Wanli Huang,Lihaopeng Cao,Shanshan Chen,Xiao Yang,Tianle Qin,Yuqing Zhou,Rong Yu,Chuanquan Lin
Ethnopharmacological relevance Dandelion (also known as Taraxaci Herba), a plant used in traditional Chinese medicine for both medicinal and dietary purposes, serves as a key ingredient in various liver-protecting herbal formulations. Its primary bioactive compound, taraxasterol (TAR), exhibits antioxidant and anti-inflammatory properties and can inhibit lipid synthesis. Nevertheless, the specific mechanism underlying its role in metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. Materials and methods The study integrated ethnopharmacological knowledge with modern techniques. Following in vitro assessment of lipid clearance in mouse hepatocytes, network pharmacology analysis was performed to identify potential targets. The therapeutic effects of TAR were subsequently validated in a high-fat diet-induced MASLD mouse model, with a focus on the FXR signaling pathway. Results TAR effectively reduced hepatic lipid accumulation and inflammation, confirming its ethnopharmacological relevance. Network analysis revealed that TAR's multi-target effects converge on the FXR signaling pathway. In vivo experiments demonstrated that TAR significantly alleviated HFD-induced metabolic dysregulation and liver injury through FXR activation, with efficacy abolished upon FXR knockdown. Conclusion TAR ameliorates HFD-induced MASLD by modulating and enhancing the expression of hepatic FXR, thereby normalizing glucolipid metabolism and restraining oxidative and inflammatory damage. These findings position TAR as a promising plant-derived candidate for MASLD therapy and provide mechanistic insight into its hepatoprotective action.
研究领域:
民族药理学
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肝病学
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代谢性疾病
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天然产物研究
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分子生物学
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高影响因子
Pharmaceuticals
·
2021
·Vol. 14
·期 5
·452
·
IF 5.863
Jiaxiong Ming,Qianqian Xu,Limin Gao,Yanfang Deng,Jie Yin,Qun Zhou,Qingyi Tong,Yonghui Zhang
Cholestasis is an important predisposing factor of liver diseases, such as hepatocyte necrosis, liver fibrosis and primary biliary cirrhosis. In this study, we aimed to investigate the effects of Kinsenoside (KD), a natural active ingredient ofAnoectochilus roxburghii, on estrogen-induced cholestatic liver injury in Sprague-Dawley rats and the underlying mechanism. The rats were randomly divided into six groups: control group, model group, low-dose KD group (50 mg/kg body weight, KD-L), medium-dose KD group (100 mg/kg body weight, KD-M), high-dose KD group (200 mg/kg body weight, KD-H) and ursodeoxycholic acid group (40 mg/kg body weight, UDCA). 17α-Ethinylestradiol (EE) was used to establish an experimental animal model of estrogen-induced cholestasis (EIC). The results demonstrated that KD alleviated liver pathologic damage, serum biochemical status and inhibited hepatocellular microstructure disorder and bile duct hyperplasia in EE-induced cholestatic rats. Mechanically, KD alleviated EE-induced cholestatic liver injury by inhibiting inflammatory responses and regulating bile acid homeostasis. Concretely, KD reduced the expression of IL-1β and IL-6 by inhibiting NF-κB p65 to suppress EE-mediated inflammation in rat liver. KD enhanced the expression of FXR and inhibited EE-mediated reduction of FXR in vitro and in vivo. It was the potential mechanism that KD mitigates cholestasis by increasing efflux and inhibiting uptake of bile acids via FXR-mediated induction of bile salt export pump (BSEP) and reduction of Na+-dependent taurocholate cotransport peptide (NTCP) to maintain bile acid homeostasis. Moreover, KD repressed the bile acid synthesis through reducing the expression of synthetic enzyme (CYP7A1), thereby normalizing the expression of metabolic enzyme (SULT2A1) of bile acid. In conclusion, our results revealed that KD may be an effective drug candidate for the treatment of cholestasis.Keywords:kinsenoside;17α-ethinylestradiol;inflammation;cholestasis
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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PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2026
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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.
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高影响因子
Frontiers in Nutrition
·
2022
·
IF 6.59
Zhenhui Chen,Ziyu Tang,Jingjing Kong,Lixuan Chen,Jiaxin Liu,Yunting Li,Wanwen Huang,Wendan Li,Junlin Wu,Wei Zhao,Xiaojing Meng,Hongying Fan
Pb poisoning affects infant growth and development. However, dimercaptosuccinic acid (DMSA) as the current therapy for Pb poisoning exerts relatively significant toxic side effects in infants. Therefore, identifying a non-toxic treatment in this regard is particularly important. In this study, we aimed to investigate the therapeutic effect of an infant feces-derived probiotic strain, Lactobacillus casei SYF-08 (SYF-08), on Pb poisoning in young mice. The Pb levels in the organisms were detected via inductively coupled plasma mass spectrometry, while the therapeutic effect of SYF-08 on Pb-induced neural system damage was explored via the Morris water maze test, hematoxylin-eosin staining, and immunohistochemistry. Additionally, the molecular mechanisms underlying the protective effects of SYF-08 against Pb-induced intestinal damage were also explored via histological staining, 16S rRNA sequencing, untargeted metabolomics, qRT-PCR, and western blotting. In vivo experiments revealed that SYF-08 reduced blood and bone Pb levels and increased urinary Pb excretion. Additionally, SYF-08 alleviated Pb-induced pathological damage to the brain and ultimately improved the learning and cognitive abilities of the young mice. This treatment also restored intestinal microflora dysbiosis, regulated bile acid metabolism, and inhibited the FXR-NLRP3 signaling pathway. It also resulted in fewer adverse events than the DMSA treatment. In conclusion, our results provided valuable insights into the therapeutic role of SYF-08 in Pb poisoning and also suggested that its administration can significantly alleviate the Pb-induced damage.
研究领域:
微生物学
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毒理学
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神经科学
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代谢组学
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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2018
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IF 3.04
Yulong Kong,Xiaoguang Gao,Changyuan Wang,Chenqing Ning,Kexin Liu,Zhihao Liu,Huijun Sun,Xiaodong Ma,Pengyuan Sun,Qiang Meng
Accumulation of toxic bile acids in liver could cause cholestasis and liver injury. The purpose of the current study is to evaluate the hepatoprotective effect of yangonin , a product isolated from an edible botanical Kava against lithocholic acid (LCA)-induced cholestasis, and further to elucidate the involvement of farnesoid X receptor (FXR) in the anticholestatic effect using in vivo and in vitro experiments. The cholestatic liver injury model was established by intraperitoneal injections of LCA in C57BL/6 mice. Serum biomarkers and H&E staining were used to identify the amelioration of cholestasis after yangonin treatment. Mice hepatocytes culture, gene silencing experiment, real-time PCR and Western blot assay were used to elucidate the mechanisms underlying yangonin hepatoprotection . The results indicated that yangonin promoted bile acid efflux and reduced hepatic uptake via an induction in FXR-target genes Bsep , Mrp2 expression and an inhibition in Ntcp , all of which are responsible for bile acid transport. Furthermore, yangonin reduced bile acid synthesis through repressing FXR-target genes Cyp7a1 and Cyp8b1, and increased bile acid metabolism through an induction in gene expression of Sult2a1, which are involved in bile acid synthesis and metabolism. In addition, yangonin suppressed liver inflammation through repressing inflammation-related gene NF-κB, TNF-α and IL-1β. In vitro evidences showed that the changes in transporters and enzymes induced by yangonin were abrogated when FXR was silenced. In conclusions, yangonin produces protective effect against LCA-induced hepatotoxity and cholestasis due to FXR-mediated regulation. Yangonin 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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高影响因子
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