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bile acids inhibit ferroptosis sensitivity through activating farnesoid X receptor in gastric cancer cells

World Journal of Gastroenterology 2024年第5期30卷 485-498页

作者： Chu-Xuan Liu Ying Gao Xiu-Fang Xu Xin Jin Yun Zhang Qian Xu Huan-Xin Ding Bing-Jun Li Fang-Ke Du Lin-Chuan Li Ming-Wei Zhong Jian-Kang Zhu Guang-Yong Zhang Department of General Surgery Shandong Provincial Qianfoshan HospitalShandong UniversityJinan 250014Shandong ProvinceChina Department of General Surgery Linyi People's HospitalLinyi 276034Shandong ProvinceChina Department of Nursing Huantai TCM HospitalZibo 256400Shandong ProvinceChina Center for Translational medical Research The First Affiliated Hospital of Shandong First Medical UniversityJinan 250014Shandong ProvinceChina Department of General Surgery The First Affiliated Hospital of Shandong First Medical UniversityJinan 250014Shandong ProvinceChina

BACKGROUND Gastric cancer(GC)is associated with high mortality *** acids(BAs)reflux is a well-known risk factor for GC,but the specific mechanism remains *** GC development in both humans and animals,BAs serve as signaling molecules that induce metabolic *** confers additional cancer phenotypes,including ferroptosis *** is a novel mode of cell death characterized by lipid peroxidation that contributes universally to malignant ***,it is not fully defined if BAs can influence GC progression by modulating *** To reveal the mechanism of BAs regulation in ferroptosis of GC *** In this study,we treated GC cells with various stimuli and evaluated the effect of BAs on the sensitivity to *** used gain and loss of function assays to examine the impacts of farnesoid X receptor(FXR)and BTB and CNC homology 1(BACH1)overexpression and knockdown to obtain further insights into the molecular mechanism *** Our data suggested that BAs could reverse erastin-induced ferroptosis in GC *** effect correlated with increased glutathione(GSH)concentrations,a reduced GSH to oxidized GSH ratio,and higher GSH peroxidase 4(GPX4)expression ***,we confirmed that BAs exerted these effects by activating FXR,which markedly increased the expression of GSH synthetase and ***,BACH1 was detected as an essential intermediate molecule in the promotion of GSH synthesis by BAs and ***,our results suggested that FXR could significantly promote GC cell proliferation,which may be closely related to its anti-ferroptosis *** This study revealed for the first time that BAs could inhibit ferroptosis sensitivity through the FXR-BACH1-GSHGPX4 axis in GC *** work provided new insights into the mechanism associated with BA-mediated promotion of GC and may help identify potential therapeutic targets for GC patients with BAs reflux.

关键词： Gastric cancer Ferroptosis bile acids Chenodeoxycholic acid Farnesoid X receptor Glutathione

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bile acids and coronavirus disease 2019

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Acta Pharmaceutica Sinica B 2024年第5期14卷 1939-1950页

作者： Xiaoru Huang Xuening Liu Zijian Li Department of Pharmacy Peking University Third HospitalBeijing 100191China Department of Pharmaceutical Management and Clinical Pharmacy College of PharmacyPeking UniversityBeijing 100191China Department of Cardiology and Institute of Vascular Medicine Peking University Third HospitalBeijing Key Laboratory of Cardiovascular Receptors ResearchKey Laboratory of Cardiovascular Molecular Biology and Regulatory PeptidesMinistry of HealthState Key Laboratory of Vascular Homeostasis and RemodelingPeking UniversityBeijing 100191China

The coronavirus disease 2019(COVID-19)pandemic,caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has been significantly ***,long-term health effects and prevention strategy remain ***,it is essential to explore the pathophysiological mechanisms and intervention for SARS-CoV-2 *** research indicates a link between COVID-19 and bile acids,traditionally known for facilitating dietary fat *** bile acid ursodeoxycholic acid potentially protects against SARS-CoV-2 infection by inhibiting the farnesoid X receptor,a bile acid nuclear *** activation of G-protein-coupled bile acid receptor,another membrane receptor for bile acids,has also been found to regulate the expression of angiotensin-converting enzyme 2,the receptor through which the virus enters human ***,we review the latest basic and clinical evidence linking bile acids to SARS-CoV-2,and reveal their complicated pathophysiological mechanisms.

关键词： bile acids COVID-19 Farnesoid X receptor G-protein-coupled bile acid receptor SARS-CoV-2 Angiotensin-converting enzyme 2 Ursodeoxycholic acid Chenodeoxycholic acid

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Sulfation of chondroitin and bile acids converges to antagonize Wnt/β-catenin signaling and inhibit APC deficiency-induced gut tumorigenesis

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1241-1256页

作者： Pengfei Xu Yue Xi Jong-Won Kim Junjie Zhu Min Zhang Meishu Xu Songrong Ren Da Yang Xiaochao Ma Wen Xie Center for Pharmacogenetics and Department of Pharmaceutical Sciences University of PittsburghPittsburghPA 15261USA Department of Hepatobiliary and Pancreatic Surgery Zhongnan Hospital of Wuhan UniversitySchool of Pharmaceutical SciencesWuhan UniversityWuhan 430071China Department of Pharmacology&Chemical Biology University of PittsburghPittsburghPA 15261USA

Sulfation is a crucial and prevalent conjugation reaction involved in cellular processes and mammalian physiology.3’-Phosphoadenosine 5’-phosphosulfate(PAPS)synthase 2(PAPSS2)is the primary enzyme to generate the universal sulfonate donor *** involvement of PAPSS2-mediated sulfation in adenomatous polyposis coli(APC)mutation-promoted colonic carcinogenesis has not been ***,we showed that the expression of PAPSS2 was decreased in human colon tumors along with cancer stages,and the lower expression of PAPSS2 was correlated with poor prognosis in advanced colon *** epithelial-specific heterozygous Apc deficient and Papss2-knockout(Apc^(Δgut-Het)Papss2^(Δgut))mice were created,and the phenotypes were compared to the spontaneous intestinal tumorigenesis of Apc^(Δgut-Het)***^(Δgut-Het)Papss2^(Δgutmice) were more sensitive to gut tumorigenesis,which was mechanistically accounted for by the activation of Wnt/β-catenin signaling pathway due to the suppression of chondroitin sulfation and inhibition of the farnesoid X receptor(FXR)-transducin-like enhancer of split 3(TLE3)gene regulatory *** sulfate supplementation in Apc^(Δgut-Het)Papss2^(Δgutmice) alleviated intestinal *** summary,we have uncovered the protective role of PAPSS2-mediated chondroitin sulfation and bile acids-FXR-TLE3 activation in the prevention of gut carcinogenesis via the antagonization of Wnt/β-catenin *** sulfate may be explored as a therapeutic agent for Papss2 deficiency-associated colonic carcinogenesis.

关键词： Colon cancer APC Wnt/b-catenin PAPSS2 Chondroitin sulfate Sulfation bile acids FXR

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bile acids and sphingolipids in non-alcoholic fatty liver disease

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Chinese Medical Journal 2022年第10期135卷 1163-1171页

作者： Kaitlyn G.Jackson Grayson W.Way Huiping Zhou Department of Microbiology and Immunology Virginia Commonwealth University School of MedicineRichmondVA 23298USA Center for Clinical and Translational Research Virginia Commonwealth University School of MedicineRichmondVA 23298USA Central Virginia Veterans Healthcare System RichmondVA 23249USA.

Non-alcoholic fatty liver disease (NAFLD) is one of the fastest-growing diseases, and its global prevalence is estimated to increase >50% by 2030. NAFLD is comorbid with metabolic syndrome, obesity, type 2 diabetes, and insulin resistance. Despite extensive research efforts, there are no pharmacologic or biological therapeutics for the treatment of NAFLD. bile acids and sphingolipids are well-characterized signaling molecules. Over the last few decades, researchers have uncovered potential mechanisms by which bile acids and sphingolipids regulate hepatic lipid metabolism. Dysregulation of bile acid and sphingolipid metabolism has been linked to steatosis, inflammation, and fibrosis in patients with NAFLD. This clinical observation has been recapitulated in animal models, which are well-accepted by experts in the hepatology field. Recent transcriptomic and lipidomic studies also show that sphingolipids are important players in the pathogenesis of NAFLD. Moreover, the identification of bile acids as activators of sphingolipid-mediated signaling pathways established a novel theory for bile acid and sphingolipid biology. In this review, we summarize the recent advances in the understanding of bile acid and sphingolipid-mediated signaling pathways as potential contributors to NAFLD. A better understanding of the pathologic effects mediated by bile acids and sphingolipids will facilitate the development of new diagnostic and therapeutic strategies for NAFLD.

关键词： bile acids Sphingolipids Non-alcoholic fatty liver disease Non-alcoholic steatohepatitis

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bile acids and their receptors: Potential therapeutic targets in inflammatory bowel disease

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World Journal of Gastroenterology 2023年第27期29卷 4252-4270页

作者： Xiong-Quan Long Ming-Zhu Liu Zi-Hao Liu Lv-Zhou Xia Shi-Peng Lu Xiao-Ping Xu Ming-Hao Wu Department of Gastroenterology The First Affiliated Hospital of Hunan Normal University(Hunan Provincial People's Hospital)Changsha 410005Hunan ProvinceChina

Chronic and recurrent inflammatory disorders of the gastrointestinal tract caused by a complex interplay between genetics and intestinal dysbiosis are called inflammatory bowel *** a result of the interaction between the liver and the gut microbiota,bile acids are an atypical class of steroids produced in mammals and traditionally known for their function in food *** the development of genomics and metabolomics,more and more data suggest that the pathophysiological mechanisms of inflammatory bowel disease are regulated by bile acids and their *** acids operate as signalling molecules by activating a variety of bile acid receptors that impact intestinal flora,epithelial barrier function,and intestinal *** bowel disease can be treated in new ways by using these potential *** paper mainly discusses the increasing function of bile acids and their receptors in inflammatory bowel disease and their prospective therapeutic *** addition,we explore bile acid metabolism and the interaction of bile acids and the gut microbiota.

关键词： bile acids Inflammatory bowel disease Intestinal immunology bile acid receptors bile acid metabolism Gut microbiota

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bile acids and microbes in metabolic disease

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World Journal of Gastroenterology 2022年第48期28卷 6846-6866页

作者： Dhiraj Kumar Sah Archana Arjunan Sun Young Park Young Do Jung Department of Biochemistry Chonnam National UniversityGwangju 501190South Korea Department of Internal Medicine Chonnam National UniversityGwangju 501190South Korea

bile acids(BAs)serve as physiological detergents that enable the intestinal absorption and transportation of nutrients,lipids and *** are primarily produced by humans to catabolize cholesterol and play crucial roles in gut metabolism,microbiota habitat regulation and cell ***-activated nuclear receptors regulate the enterohepatic circulation of BAs which play a role in energy,lipid,glucose,and drug *** gut microbiota plays an essential role in the biotransformation of BAs and regulates BAs composition and ***,altered gut microbial and BAs activity can affect human metabolism and thus result in the alteration of metabolic pathways and the occurrence of metabolic diseases/syndromes,such as diabetes mellitus,obesity/hypercholesterolemia,and cardiovascular *** and their metabolites are used to treat altered gut microbiota and metabolic *** review explores the increasing body of evidence that links alterations of gut microbial activity and BAs with the pathogenesis of metabolic ***,we summarize existing research on gut microbes and BAs in relation to intracellular pathways pertinent to metabolic ***,we discuss how therapeutic interventions using BAs can facilitate microbiome functioning and ease metabolic diseases.

关键词： bile acids Metabolic diseases Gut microbe Diabetic mellitus Obesity Hypercholesterolemia

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The direct and gut microbiota-mediated effects of dietary bile acids on the improvement of gut barriers in largemouth bass(Micropterus salmoides)

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Animal Nutrition 2023年第3期14卷 32-42页

作者： Rui Xia Qingshuang Zhang Dongmei Xia Qiang Hao Qianwen Ding Chao Ran Yalin Yang Aizhi Cao Zhen Zhang Zhigang Zhou China-Norway Joint Lab on Fish Gut Microbiota Institute of Feed ResearchChinese Academy of Agricultural SciencesBeijing 100081China Norway-China Joint Lab on Fish Gut Microbiota Institute of BiologyNorwegian University of Science and TechnologyTrondheimNorway Key Laboratory for Feed Biotechnology of the Ministry of Agriculture and Rural Affairs Institute of Feed ResearchChinese Academy of Agricultural SciencesBeijing 100081China Shandong Longchang Animal Health Care Co. Ltd.Jinan 251100China Institute of Animal Husbandry and Veterinary Jiangxi Academy of Agricultural ScienceJiangxi 330000China

Fish gut barrier damage under intensive culture model is a significant concern for aquaculture *** study aimed to investigate the effects of bile acids(BAs)on gut barriers in Micropterus salmoides.A germ-free(GF)zebrafish model was employed to elucidate the effects of the direct stimulation of BAs and the indirect regulations mediated by the gut microbiota on gut barrier *** diets were formulated with BAs supplemented at 0,150,300 and 450 mg/kg,and these 4 diets were defined as control,BA150,BA300 and BA450,*** 5 weeks of feeding experiment,the survival rate of fish fed with BA300 diet was increased(P0.05).The results of the gut microbiota transferring experiment demonstrated an upregulation of gut barrier-related genes,including immunoglobulin Z/T(Ig Z/T),IL-6,IL-1βand IL-10,by the gut microbiota transferred from the BA300 group compared with the control(P<0.05).Feeding the BA300 diet directly to GF zebrafish resulted in enhanced expression of Ig M,Ig Z/T,lysozyme

关键词： bile acids Gut barrier Gut microbiota Largemouth bass Germ-free zebrafish

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bile reflux and bile acids in the progression of gastric intestinal metaplasia

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Chinese Medical Journal 2022年第14期135卷 1664-1672页

作者： Xiaodong Qu Yongquan Shi State Key Laboratory of Cancer Biology National Clinical Research Center for Digestive DiseasesXijing HospitalAir Force Medical UniversityXi’anShaanxi 710032China

Gastric intestinal metaplasia(GIM)is a precancerous lesion of gastric cancer(GC)and is considered an irreversible point of progression for *** pylori infection can cause GIM,but its eradication still does not reverse the *** reflux is also a pathogenic factor in GIM and can continuously irritate the gastric mucosa,and bile acids in refluxed fluid have been widely reported to be associated with *** paper reviews in detail the relationship between bile reflux and GIM and the mechanisms by which bile acids induce GIM.

关键词： bile acids bile reflux Farnesoid X receptor Gastric intestinal metaplasia Hepatocyte nuclear factor 4α Methylation Nuclear factor-κB

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Serum metabolic profiling of targeted bile acids reveals potentially novel biomarkers for primary biliary cholangitis and autoimmune hepatitis

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World Journal of Gastroenterology 2022年第39期28卷 5764-5783页

作者： Zhen-Hua Ma Xiao-Mei Wang Rui-Hong Wu Da-Lin Hao Li-Chao Sun Pan Li Jun-Qi Niu Department of Infection and Hepatology The Affiliated Hospital of Beihua UniversityJilin 132011Jilin ProvinceChina Department of Hepatology The First Hospital of Jilin UniversityChangchun 130061Jilin ProvinceChina Department of Pathology The Affiliated Hospital of Beihua UniversityJilin 132011Jilin ProvinceChina

BACKGROUND Primary biliary cholangitis(PBC)and autoimmune hepatitis(AIH)are two unexplained immune *** golden standard for diagnosis of these diseases requires a liver *** biopsy is not widely accepted by patients because of its invasive nature,and atypical liver histology can confuse *** view of the lack of effective diagnostic markers for PBC and AIH,combined with the increasingly mature metabolomics technologies,including full-contour metabolomics and *** To determine non-invasive,reliable,and sensitive biochemical markers for the differential diagnosis of PBC and *** Serum samples from 54 patients with PBC,26 patients with AIH and 30 healthy controls were analyzed by Ultra-high performance liquid chromatographytandem mass spectrometry serum *** metabolites and metabolic pathways were identified,and the metabolic changes,metabolic pathways and inter-group differences between PBC and AIH were *** kinds of target metabolites of bile acids(BAs)were quantitatively analyzed by SRM,and the differential metabolites related to the diagnosis of PBC were screened by receiver operating characteristic curve *** We found the changes in the levels of amino acids,BAs,organic acids,phospholipids,choline,sugar,and sugar alcohols in patients with PBC and ***,the SRM assay of BAs revealed the increased levels of chenodeoxycholic acid,lithocholic acid(LCA),taurolithocholic acid(TLCA),and LCA+TLCA in the PBC group compared with those in the AIH *** levels of BAs may be used as biomarkers to differentiate PBC from AIH *** levels of glycochenodeoxycholic acid,glycochenodeoxycholic sulfate,and taurodeoxycholic acid were gradually elevated with the increase of Child-Pugh class,which was correlated with the severity of *** The results demonstrated that the levels of BAs could serve as potential biomarkers for the early diagnosis and assessment of the severity of PBC a

关键词： Primary biliary cholangitis Autoimmune hepatitis Biomarkers Serum metabolic profiling bile acids Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry

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Duodenal-jejunal bypass increases intraduodenal bile acids and upregulates duodenal SIRT1 expression in high-fat diet and streptozotocin-induced diabetic rats

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World Journal of Gastroenterology 2022年第31期28卷 4338-4350页

作者： Hai-Feng Han Shao-Zhuang Liu Xiang Zhang Meng Wei Xin Huang Wen-Bin Yu Department of General Surgery Qilu HospitalCheeloo College of MedicineShandong UniversityJinan 250012Shandong ProvinceChina

BACKGROUND The mechanisms underlying diabetes remission after duodenal-jejunal bypass(DJB) remain elusive. In DJB surgery, the duodenum is excluded. However, the duodenum has emerged as an important regulator of glucose homeostasis, and elevated duodenal SIRT1 leads to improved hepatic insulin sensitivity. After DJB, bile acids(BAs) in the duodenum are not mixed and diluted by the ingested food. And activation of BA receptors promotes SIRT1 expression in many tissues. We hypothesized that BA-mediated upregulation of SIRT1 may contribute to diabetic control after *** To investigate the surgical effects of DJB on duodenal SIRT1 expression and uncover the potential crosslinks between BAs and *** Twenty diabetic rats were randomly allocated to the sham(n = 10) and DJB(n = 10) groups. Body weight, food intake, fasting blood glucose(FBG), serum and intraduodenal total BA(TBA) levels were measured accordingly. Oral glucose tolerance test(OGTT) and intraperitoneal pyruvate tolerance test(ip PTT) were performed to evaluate the effects of surgeries on systemic glucose disposal and hepatic gluconeogenesis. The key genes of BA signaling pathway in the duodenal mucosa, including farnesoid X receptor(FXR), small heterodimer partner(SHP), and Takeda G-protein-coupled receptor 5(TGR5) were evaluated by real-time quantitative polymerase chain reaction 8 wk postoperatively. The duodenal SIRT1, AMPK, and phosphorylated AMPK(p-AMPK) levels were evaluated by western blotting. Rat small intestine epithelial IEC-6 cells were treated with GW4064 and INT-777 to verify the effects of BAs on SIRT1 expression in *** The DJB group exhibited body weight and food intake comparable to those of the sham group at all postoperative time points. The FBG level and area under the curve for the OGTT and ip PTT were significantly lower in the DJB group. The DJB group exhibited higher fasting and postprandial serum TBA levels than the sham group at both 2 and 8 wk postoperativ

关键词： Duodenal-jejunal bypass Diabetes mellitus bile acids Sirtuin 1 Duodenum High-fat diet

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