RSC Advances
·
2018
·Vol. 8
·期 65
·37117-37128
·
IF 2.936
Guixin Wu,Min Wen,Lin Sun,Huitao Li,Yubei Liu,Rui Li,Feihua Wu,Rong Yang,Yining Lin
Geniposide (GE) is a major component isolated from Gardenia jasminoides Ellis, which has been used to treat cholestasis liver diseases. Our previous study has shown that GE could notably increase mRNA and protein expressions of BSEP in cholestatic rats. BSEP plays a critical role in maintenance of the enterohepatic circulation of bile acids. BSEP could be regulated by the transactivation pathway of farnesoid X receptor (FXR) and nuclear factor erythroid 2-related factor (Nrf2). Here the mechanisms for BSEP regulation by GE were investigated. GE induced the mRNA levels of BSEP in HepG2 cells and cholestatic mice, and knockdown of FXR and Nrf2 reduced the mRNA expression of BSEP at varying degrees after treatment of GE. FXR acts as the major regulator of BSEP transcription. The involvement of FXR regulated BSEP expression by GE was further investigated. An enhancement was observed in FXR-dependent BSEP promoter activation using luciferase assay. ChIP assay further confirmed the interaction between FXR and BSEP after GE treatment. Using siRNA and ChIP assays, we demonstrated that peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α) and co-activator-associated arginine methyltransferase 1 (CARM1) were predominantly recruited to the BSEP promoter upon FXR activation by GE. In conclusion, GE regulated the expression of BSEP through FXR and Nrf2 signaling pathway. The FXR transactivation pathway was enhanced by increasing recruitment of coactivators PGC-1α and CARM1 upon GE treatment, coupled with an increased binding of FXR to the BSEP promoter.
研究领域:
药理学
·
分子生物学
·
肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2021
·
IF 5.279
Ruiqian Duan,Xiao Guan,Kai Huang,Yu Zhang,Sen Li,Ji’an Xia,Meng Shen
A high-fat diet (HFD) causes hyperlipidemia, which worsens disturbances in bile acid (BA) metabolism and gut microbiota. This study aimed to investigate the regulation of flavonoids from whole-grain oat (FO) on BA metabolism and gut microbiota in HFD-induced hyperlipidemic mice. The experiment results showed that FO improved serum lipid profiles and decreased body weight and lipid deposition in HFD-fed mice. Through real-time qualitative polymerase chain reaction (RT-qPCR) and Western blot assays, by up-regulating the expression of PPARα, CPT-1, CYP7A1, FXR, TGR5, NTCP, and BSTP, and down-regulating those of SREBP-1c, FAS, and ASBT, FO suppressed lipogenesis, promoted lipolysis and BA synthesis, and efflux to faeces via the FXR pathway. 16s rRNA sequencing revealed that FO significantly increased Akkermansia and significantly decreased Lachnoclostridium, Blautia, Colidextribacter, and Desulfovibrio. Spearman’s correlation analysis showed that these bacteria were strongly correlated with hyperlipidemia-related parameters. Therefore, our results indicated that FO possessed an antihyperlipidemic effect via regulating the gut–liver axis, i.e., BA metabolism and gut microbiota.
研究领域:
营养学
·
生物化学
·
微生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Food Chemistry-X
·
2023
·
IF 6.1
Xin Zhang,Fuqiang Zhao,Tingting Ma,Yuanping Zheng,Jun Cao,Chuan Li,Kexue Zhu
This study aimed to use metabolomic methods to explore how Holothuria leucospilota polysaccharides (HLP) improved metabolism disorders in the liver of Goto-Kakizaki (GK) rats with spontaneous type 2 diabetes. The results showed that HLP effectively improved the metabolic disorder. Based on KEGG functional analysis, five key biomarkers associated with bile acid metabolism were detected and screened ( P < 0.05). The results of serum total bile acid levels and liver damage in diabetic rats further showed the regulatory effects of HLP on bile acid metabolism. The results of bile acid-related gene expression in the liver showed that HLP inhibited liver farnesoid X Receptor - small heterodimer partner (FXR-SHP) signalling and increased the expression of bile acid synthesis genes ( P < 0.05). Our results explored the underlying mechanisms by which HLP accelerated cholesterol consumption to anti-hypercholesterolemia and anti-diabetic by inhibiting liver FXR-SHP signaling. HLP's effect on bile acid regulation provides insights into treating T2DM.
研究领域:
代谢组学
·
药理学
·
糖尿病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2020
·Vol. 24
·期 9
·5168-5184
·
IF 4.486
Huan Nie,Yuanjun Deng,Chuiyang Zheng,Maoxing Pan,Jiqian Xie,Yupei Zhang,Qinhe Yang
The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is still not fully understood, and currently, no effective pharmacotherapy is available. Nuclear receptors (NRs) are important biological participants in NAFLD that exhibit great therapeutic potential. Chaihu Shugan powder (CSP) is a traditional Chinese medicine (TCM) formula that has a wide therapeutic spectrum including NAFLD, but the effective components and functional mechanisms of CSP are unclear. We adopted a network pharmacology approach using multiple databases for Gene Ontology (GO) enrichment analysis and the molecular complex detection (MCODE) method for a protein-protein interaction (PPI) analysis, and we used molecular docking method to screen the NR targets and determine the corresponding CSP components. The screening results were validated through a NAFLD rat model that was used to explain the possible relationship between CSP and NAFLD. Finally, we screened PPARγ, FXR, PPARα, RARα and PPARδ as target genes and quercetin , kaempferol , naringenin , isorhamnetin and nobiletin as target compounds. The five components were detected through high-performance liquid chromatography-mass spectrometry (HPLC-MS), the results of which aligned with the docking experiments of PPARγ, PPARα and PPARδ. After CSP intervention, the NAFLD rat model showed ameliorated effects in terms of bodyweight, hepatic histopathology, and serum and liver lipids, and the mRNA levels of PPARγ, FXR, PPARα and RARα were significantly changed. The results from this study indicate that CSP exhibits healing effects in an NAFLD model and that the network pharmacology approach to screening NR targets and determining the corresponding CSP components is a practical strategy for explaining the mechanism by which CSP ameliorates NAFLD.
研究领域:
药理学
·
中药学
·
分子生物学
·
病理学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Advanced Research
·
2024
·
IF 11.4
Xue Bai,Zhiguang Duan,Jianjun Deng,Zhuo Zhang,Rongzhan Fu,Chenhui Zhu,Daidi Fan
Introduction Dysbiosis of the gut microbiota is emerging as a pivotal factor in the pathogenesis of colorectal cancer (CRC). Ginsenoside Rh4 (Rh4) is an active compound isolated from ginseng with beneficial effects in modulating intestinal inflammation and gut microbiota dysbiosis, but how Rh4 regulates the gut microbiota to alleviate CRC remains underexplored. Objectives We investigated the impact of Rh4 on CRC and the mechanism of its action in inhibiting CRC via modulation of gut microbiota. Methods We used the AOM/DSS model and employed transcriptomics, genomics and metabolomics techniques to explore the inhibitory impact of Rh4 on CRC. Furthermore, we employed experiments involving antibiotic treatment and fecal microbiota transplantation (FMT) to investigate the role of the gut microbiota. Finally, we elucidated the pivotal role of key functional bacteria and metabolites regulated by Rh4 in CRC. Results Our research findings indicated that Rh4 repaired intestinal barrier damage caused by CRC, alleviated intestinal inflammation, and inhibited the development of CRC. Additionally, Rh4 inhibited CRC in a gut microbiota-dependent manner. Rh4 increased the diversity of gut microbiota, enriched the probiotic Akkermansia muciniphila ( A. muciniphila ), and alleviated gut microbiota dysbiosis caused by CRC. Subsequently, Rh4 regulated A. muciniphila -mediated bile acid metabolism. A. muciniphila promoted the production of UDCA by enhancing the activity of 7α-hydroxysteroid dehydrogenase (7α-HSDH). UDCA further activated FXR, modulated the TLR4-NF-κB signaling pathway, thus inhibiting the development of CRC. Conclusion Our results confirm that Rh4 inhibits CRC in a gut microbiota-dependent manner by modulating gut microbiota-mediated bile acid metabolism and promoting the production of UDCA, which further activates the FXR receptor and regulates the TLR4-NF-κB signaling pathway. Our results confirm that Rh4 has the potential to be used as a modulator of gut microbiota for preventing and treatment of CRC.
研究领域:
癌症生物学
·
微生物学
·
药理学
·
分子生物学
·
胃肠病学
✓ 已验证
产品关联
DOI
PubMed
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
RENAL FAILURE
·
2024
·
IF 3
Danyang Jing,Jingfeng Liu,Da Qin,Jin Lin,Tian Li,Yu Li,Meili Duan
Acute kidney injury (AKI), a common complication of sepsis, might be caused by overactivated inflammation, mitochondrial damage, and oxidative stress. However, the mechanisms underlying sepsis-induced AKI (SAKI) have not been fully elucidated, and there is a lack of effective therapies for AKI. To this end, this study aimed to investigate whether obeticholic acid (OCA) has a renoprotective effect on SAKI and to explore its mechanism of action. Through bioinformatics analysis, our study confirmed that the mitochondria might be a critical target for the treatment of SAKI. Thus, a septic rat model was established by cecal ligation puncture (CLP) surgery. Our results showed an evoked inflammatory response via the NF-κB signaling pathway and NLRP3 inflammasome activation in septic rats, which led to mitochondrial damage and oxidative stress. OCA, an Farnesoid X Receptor (FXR) agonist, has shown anti-inflammatory effects in numerous studies. However, the effects of OCA on SAKI remain unclear. In this study, we revealed that pretreatment with OCA can inhibit the inflammatory response by reducing the synthesis of proinflammatory factors (such as IL-1β and NLRP3) via blocking NF-κB and alleviating mitochondrial damage and oxidative stress in the septic rat model. Overall, this study provides insight into the excessive inflammation-induced SAKI caused by mitochondrial damage and evidence for the potential use of OCA in SAKI treatment.
研究领域:
药理学
·
免疫学
·
肾脏生理学
·
分子生物学
·
传染病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2020
·
IF 3.69
Meijing Liu,Guohui Zhang,Shuangcheng Wu,Meng Song,Jueyu Wang,Weibin Cai,Suiqing Mi,Changhui Liu
Ethnopharmacology relevance The farnesoid X receptor (FXR) is a therapeutic target of for the treatment of non-alcoholic fatty liver disease (NAFLD) owing to its regulatory role in lipid homeostasis. Schaftoside (SS) is a bioactive compound of Herba Desmodii Styracifolii , which has traditionally been used to treat hepatitis and cholelithiasis . However, the potential hepatoprotective effect of SS against NAFLD and the underlying mechanisms remain unknown. Aim of the study We investigated whether SS could improve NAFLD-induced liver injury by decreasing lipid accumulation via the activation of FXR signalling. Materials and methods In vivo , the effects of SS on high-fat diet (HFD)-induced lipid accumulation in the liver of mice were evaluated by serum biochemical parameters and histopathological analysis. In vitro , the intracellular triglyceride (TG) level and Oil Red O staining were used to evaluate the lipid removal ability of SS in Huh-7 cells or FXR knockout mouse primary hepatocytes (MPHs) induced by oleic acid (OA). Moreover, FXR/sterol regulatory element-binding protein 1 (SREBP1) mRNA and protein expression levels were detected. Results SS reduced HFD-induced lipid accumulation in the liver, as indicated by decreased aspartate aminotransferase (AST), cholesterol (Ch), and TG levels in serum and TG levels in liver tissue, and subsequently resulting in attenuation of liver histopathological injury. Gene expression profiles demonstrated that SS dose-dependently prevented HFD-induced decrease of FXR expression and inversely inhibited SREBP1 expression in the nucleus. Furthermore, SS significantly suppressed excessive TG accumulation and decreased intracellular TG level in Huh-7 cells or MPHs via the upregulation of FXR and inhibition of SREBP1 expression in the nucleus. Conclusion Our results suggest that SS ameliorates HFD-induced NAFLD by the decrease of lipid accumulation via the control of FXR-SREBP1 signalling.
研究领域:
药理学
·
肝病学
·
分子生物学
·
民族药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
·
2022
·
IF 6.633
Huiwen Wang,Jian Zhang,Xiaoxun Zhang,Nan Zhao,Zongtao Zhou,Lijian Tao,Lei Fu,Shifang Peng,Jin Chai
Cholestasis is characterized by intrahepatic accumulation of bile acids (BAs), resulting in liver injury, fibrosis, and liver failure. To date, only ursodeoxycholic acid and obeticholic acid have been approved for the treatment of cholestasis. As fluorofenidone (AKF-PD) was previously reported to play significant anti-fibrotic and anti-inflammatory roles in various diseases, we investigated whether AKF-PD ameliorates cholestasis. A mouse model of cholestasis was constructed by administering a 0.1 % 3,5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) diet for 14 days. Male C57BL/6 J mice were treated with either AKF-PD or pirfenidone (PD) orally in addition to the DDC diet. Serum and liver tissues were subsequently collected and analyzed. We found that AKF-PD significantly reduced the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bile salts (TBA), as well as hepatic bile acids (BAs) levels. Hepatic histological analyses demonstrated that AKF-PD markedly attenuated hepatic inflammation and fibrosis. Further mechanistic analyses revealed that AKF-PD markedly inhibited expression of Cyp7a1, an enzyme key to BAs synthesis, by increasing Fxr nuclear translocation, and decreased hepatic inflammation by attenuating Erk/-Egr-1-mediated expression of inflammatory cytokines and chemokines Tnfα, Il-1β, Il-6, Ccl2, Ccl5 and Cxcl10. Moreover, AKF-PD was found to substantially reduce liver fibrosis via inhibition of Tgfβ1/Smad pathway in our mouse model. Here, we found that AKF-PD effectively attenuates cholestasis and hepatic fibrosis in the mouse model of DDC-induced cholestasis. As such, AKF-PD warrants further investigation as a candidate drug for treatment of cholestasis.
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
Food Science and Human Wellness
·
2024
·
IF 5.6
Lan Li,Shengye Yang,Xinyu Liang,Yameng Liu,Hualing Xu,Xiaozhen Guo,Cen Xie,Xiaojun Xu
Non-alcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease worldwide. Bupleurum is widely used in the treatment of non-alcoholic fatty liver, and saikosaponin D (SSD) is one of the main active components of Bupleurum. The purpose of this study was to investigate the efficacy of SSD in the treatment of NAFLD and to explore the mechanism of SSD in the improvement of NAFLD based on “gut-liver axis”. Our results showed that SSD dose-dependently alleviated high fat diet-induced weight gain in mice, improved insulin sensitivity, and also reduced liver lipid accumulation and injury-related biomarkers aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Further exploration found that SSD inhibited the mRNA expression levels of farnesoid X receptor ( Fxr ), small heterodimer partner ( Shp ), recombinant fibroblast growth factor 15 ( Fgf15 ) and apical sodium dependent bile acid transporter ( Asbt ) in the intestine, suggesting that SSD improved liver lipid metabolism by inhibiting intestinal FXR signaling. SSD can significantly reduce the gut microbiota associated with bile salt hydrolase (BSH) expression, such as Clostridium . Decreased BSH expression reduced the ratio of unconjugated to conjugated bile acids, thereby inhibiting the intestinal FXR. These data demonstrated that SSD ameliorated NAFLD potentially through the gut microbiota-bile acid-intestinal FXR pathway and suggested that SSD is a promising therapeutic agent for the treatment of NAFLD.
研究领域:
药理学
·
胃肠病学
·
微生物学
·
代谢学
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
PHARMACOLOGICAL RESEARCH
·
2019
·
IF 5.574
Rinkiko Suguro,Xiao-cong Pang,Zhong-wen Yuan,Si-yao Chen,Yi-Zhun Zhu,Ying Xie
Silybin (SB) is widely used to treat chronic liver diseases , especially this compound is much efficient for the treatments of alcoholic and non-alcoholic steatohepatitis (NASH). However, low bioavailability seriously limits wide-application of SB in biomedical niche. Prior to this study, we found that tangeretin (TG) could remarkably increase the bioavailability of SB by the inhibition of efflux transporters, which encourges us to therapeutical discovery of SB and TG combitional use against NASH. Here, we revealed that TG is capable of improving hepatic-protective activity of SB in mice with NASH by interfering liver oxidative stress, inflammation, and lipid accumulation. In addition, TG was observed to enhance the exposural level of SB in the plasma and liver of mice. Our metabolome assay confirmed that amino acid metabolism and lipid biosynthesis mostly accounted for combitional use of SB and TG to teat NASH in mice, basically biosynthesis of unsaturated fatty acids was mostly affected. Notably, significant inhibitions in fatty acid generating and transporting proteins such as G6PD, FABP4, LPL and CD36/FAT, and cholesterol metabolism enzyme CYP27A1 as well as nuclear transcription factors FXR , PPAR-γ, and LXR were illustrated to decipher therapeutic mechanisms of SB and TG against experimental NASH . Taken together, the strategy based combitional use of SB and TG has a potential-capacity to treat NASH.
研究领域:
肝病学
·
药理学
·
代谢组学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）