AIM： TO investigate the effects of ursodeoxycholic acid （UDCA） on chenodeoxycholic acid （CDCA）-induced liver injury in hamsters, and to elucidate a correlation between liver injury and bile acid profiles in the l...AIM： TO investigate the effects of ursodeoxycholic acid （UDCA） on chenodeoxycholic acid （CDCA）-induced liver injury in hamsters, and to elucidate a correlation between liver injury and bile acid profiles in the liver.METHODS： Liver injury was induced in hamsters by administration of 0.5% （w/w） CDCA in their feed for 7 d. UDCA （50 mg/kg and 150 mg/kg） was administered for the last 3 d of the experiment.RESULTS： At the end of the experiment, serum alanine aminotransferase （ALl） increased more than 10 times and the presence of liver injury was confirmed histologically. Marked increase in bile acids was observed in the liver. The amount of total bile acids increased approximately three-fold and was accompanied by the increase in hydrophobic bile acids, CDCA and lithocholic acid （LCA）. UDCA （50 mg/kg and 150 mg/kg） improved liver histology, with a significant decrease （679.3 ±77.5 U/L vs 333.6 ± 50.4 U/L and 254.3 ±35.5 U/ L, respectively, P 〈 0.01） in serum ALT level. UDCA decreased the concentrations of the hydrophobic bile acids, and as a result, a decrease in the total bile acid level in the liver was achieved.CONCLUSION： The results show that UDCA improves oral CDCA-induced liver damage in hamsters. The protective effects of UDCA appear to result from a decrease in the concentration of hydrophobic bile acids, CDCA and LCA, which accumulate and show the cytotoxicity in the liver.展开更多
A novel type of chiral molecular tweezers has been designed and synthesized by using chenodeoxy cholic acid as spacer and the aromatic compounds as arm. Their structures were characterized by 1HNMR, IR, MS spectra an...A novel type of chiral molecular tweezers has been designed and synthesized by using chenodeoxy cholic acid as spacer and the aromatic compounds as arm. Their structures were characterized by 1HNMR, IR, MS spectra and elemental analysis. These chiral molecular tweezers showed good enantioselectivity for D-amino acid methyl esters.展开更多
Nutritional diarrhea and subsequent performance degradation in weaned piglets are major challenges for the pig industry.Bile acids(BA)can be added to the diet as emulsifiers.This experiment was conducted to investigat...Nutritional diarrhea and subsequent performance degradation in weaned piglets are major challenges for the pig industry.Bile acids(BA)can be added to the diet as emulsifiers.This experiment was conducted to investigate the effects of chenodeoxycholic acid(CDCA),a major primary BA,on growth performance,serum metabolic profiles and gut health in weaned piglets.A total of 72 healthy weaned piglets were randomly assigned to the control(CON)and the CDCA groups,which were feed a basal diet and the basal diet supplemented with 200 mg/kg CDCA for 30 d,respectively.Our results demonstrated that CDCA significantly increased final BW and average daily gain(ADG),decreased feed-to-gain(F:G)ratio and tended to reduce diarrhea incidence.In addition,CDCA increased the villus height-to-crypt depth(V:C)ratio,elevated goblet cell numbers and the expression of tight junction proteins,suggesting the enhancement of intestinal barrier function.As an emulsifier,CDCA increased jejunal lipase activity and the mRNA expression of pancreatic lipases.CDCA supplementation also altered the serum metabolic profiles,including increasing the levels of indole 3-acetic acid,N'-formylkynurenine and theobromine that were beneficial for gut health.Moreover,the relative abundance of 2 beneficial gut bacteria,Pre-votella 9 and Prevotellaceae TCG-001,were increased,whereas the relative abundance of a harmful bacteria,Dorea,was decreased in the gut of weaned piglets supplemented with CDCA.Importantly,the altered serum metabolic profiles showed a strong correlation with the changed gut bacteria.In conclusion,CDCA improved the growth performance of weaned piglets by improving intestinal morphology and barrier function,and enhancing lipid digestion,accompanied by alterations of serum metabolic profiles,and changes in relative abundance of certain gut bacteria.展开更多
Approach to highly efficient dye-sensitized solar cells(DSSCs)by co-sensitization of organic dyes,AZ6+AZ5 with co-adsorbent chenodeoxycholic acid(CDCA)is presented.The power conversion efficiencies(PCEs)of 8.55%and 8....Approach to highly efficient dye-sensitized solar cells(DSSCs)by co-sensitization of organic dyes,AZ6+AZ5 with co-adsorbent chenodeoxycholic acid(CDCA)is presented.The power conversion efficiencies(PCEs)of 8.55%and 8.31%are obtained from DSSCs co-sensitized by AZ6(0.3 mmol/L)+AZ5(0.1 mmol/L)with CDCA concentration of 5 and 20 mmol/L in one step cocktail,respectively.The latter shows high stability in a period of 653 h under ambient conditions.展开更多
BACKGROUND Gastric cancer(GC)is associated with high mortality rates.Bile acids(BAs)reflux is a well-known risk factor for GC,but the specific mechanism remains unclear.During GC development in both humans and animals...BACKGROUND Gastric cancer(GC)is associated with high mortality rates.Bile acids(BAs)reflux is a well-known risk factor for GC,but the specific mechanism remains unclear.During GC development in both humans and animals,BAs serve as signaling molecules that induce metabolic reprogramming.This confers additional cancer phenotypes,including ferroptosis sensitivity.Ferroptosis is a novel mode of cell death characterized by lipid peroxidation that contributes universally to malignant progression.However,it is not fully defined if BAs can influence GC progression by modulating ferroptosis.AIM To reveal the mechanism of BAs regulation in ferroptosis of GC cells.METHODS In this study,we treated GC cells with various stimuli and evaluated the effect of BAs on the sensitivity to ferroptosis.We 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 involved.RESULTS Our data suggested that BAs could reverse erastin-induced ferroptosis in GC cells.This effect correlated with increased glutathione(GSH)concentrations,a reduced GSH to oxidized GSH ratio,and higher GSH peroxidase 4(GPX4)expression levels.Subsequently,we confirmed that BAs exerted these effects by activating FXR,which markedly increased the expression of GSH synthetase and GPX4.Notably,BACH1 was detected as an essential intermediate molecule in the promotion of GSH synthesis by BAs and FXR.Finally,our results suggested that FXR could significantly promote GC cell proliferation,which may be closely related to its anti-ferroptosis effect.CONCLUSION This study revealed for the first time that BAs could inhibit ferroptosis sensitivity through the FXR-BACH1-GSHGPX4 axis in GC cells.This 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.展开更多
BACKGROUND Disorders of primary bile acid synthesis may be life-threatening if undiagnosed,or not treated with primary bile acid replacement therapy. To date, there are few reports on the management and follow-up of p...BACKGROUND Disorders of primary bile acid synthesis may be life-threatening if undiagnosed,or not treated with primary bile acid replacement therapy. To date, there are few reports on the management and follow-up of patients with Δ4-3-oxosteroid 5β-reductase(AKR1 D1) deficiency. We hypothesized that a retrospective analysis of the responses to oral bile acid replacement therapy with chenodeoxycholic acid(CDCA) in patients with this bile acid synthesis disorder will increase our understanding of the disease progression and permit evaluation of this treatment regimen as an alternative to the Food and Drug Administration(FDA) approved drug cholic acid, which is currently unavailable in China.AIM To evaluate the therapeutic responses of patients with AKR1 D1 deficiency to oral bile acid therapy, specifically CDCA.METHODS Twelve patients with AKR1 D1 deficiency, confirmed by fast atom bombardment ionization-mass spectrometry analysis of urine and by gene sequencing for mutations in AKR1 D1, were treated with differing doses of CDCA or ursodeoxycholic acid(UDCA). The clinical and biochemical responses to therapy were monitored over a period ranging 0.5-6.4 years. Dose adjustment, to optimize the therapeutic dose, was based on changes in serum biochemistry parameters,notably liver function tests, and suppression of the urinary levels of atypical hepatotoxic 3-oxo-Δ4-bile acids measured by mass spectrometry.RESULTS Physical examination, serum biochemistry parameters, and sonographic findings improved in all 12 patients during bile acid therapy, except one who underwent liver transplantation. Urine bile acid analysis confirmed a significant reduction in atypical hepatotoxic 3-oxo-Δ4 bile acids concomitant with clinical and biochemical improvements in those patients treated with CDCA. UDCA was ineffective in down-regulating endogenous bile acid synthesis as evidenced from the inability to suppress the urinary excretion of atypical 3-oxo-Δ4-bile acids. The dose of CDCA required for optimal clinical and biochemical responses varied from 5.5-10 mg/kg per day among patients based on maximum suppression of the atypical bile acids and improvement in serum biochemistry parameters, and careful titration of the dose was necessary to avoid side effects from CDCA.CONCLUSION The primary bile acid CDCA is effective in treating AKR1 D1 deficiency but the therapeutic dose requires individualized optimization. UDCA is not recommended for long-term management.展开更多
The coronavirus disease 2019(COVID-19)pandemic,caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has been significantly alleviated.However,long-term health effects and prevention strategy remain un...The coronavirus disease 2019(COVID-19)pandemic,caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has been significantly alleviated.However,long-term health effects and prevention strategy remain unresolved.Thus,it is essential to explore the pathophysiological mechanisms and intervention for SARS-CoV-2 infection.Emerging research indicates a link between COVID-19 and bile acids,traditionally known for facilitating dietary fat absorption.The bile acid ursodeoxycholic acid potentially protects against SARS-CoV-2 infection by inhibiting the farnesoid X receptor,a bile acid nuclear receptor.The 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 cells.Here,we review the latest basic and clinical evidence linking bile acids to SARS-CoV-2,and reveal their complicated pathophysiological mechanisms.展开更多
Body is equipped with organic cation transporters(OCTs).These OCTs mediate drug transport and are also involved in some disease process.We aimed to investigate whether liver failure alters intestinal,hepatic and renal...Body is equipped with organic cation transporters(OCTs).These OCTs mediate drug transport and are also involved in some disease process.We aimed to investigate whether liver failure alters intestinal,hepatic and renal Oct expressions using bile duct ligation(BDL)rats.Pharmacokinetic analysis demonstrates that BDL decreases plasma metformin exposure,associated with decreased intestinal absorption and increased urinary excretion.Western blot shows that BDL significantly downregulates intestinal Oct2 and hepatic Oct1 but upregulates renal and hepatic Oct2.In vitro cell experiments show that chenodeoxycholic acid(CDCA),bilirubin and farnesoid X receptor(FXR)agonist GW4064 increase OCT2/Oct2 but decrease OCT1/Oct1,which are remarkably attenuated by glycine-β-muricholic acid and silencing FXR.Significantly lowered intestinal CDCA and increased plasma bilirubin levels contribute to different Octs regulation by BDL,which are confirmed using CDCA-treated and bilirubin-treated rats.A disease-based physiologically based pharmacokinetic model characterizing intestinal,hepatic and renal Octs was successfully developed to predict metformin pharmacokinetics in rats.In conclusion,BDL remarkably downregulates expressions of intestinal Oct2 and hepatic Oct1 protein while upregulates expressions of renal and hepatic Oct2 protein in rats,finally,decreasing plasma exposure and impairing hypoglycemic effects of metformin.BDL differently regulates Oct expressions via Fxr activation by CDCA and bilirubin.展开更多
文摘AIM： TO investigate the effects of ursodeoxycholic acid （UDCA） on chenodeoxycholic acid （CDCA）-induced liver injury in hamsters, and to elucidate a correlation between liver injury and bile acid profiles in the liver.METHODS： Liver injury was induced in hamsters by administration of 0.5% （w/w） CDCA in their feed for 7 d. UDCA （50 mg/kg and 150 mg/kg） was administered for the last 3 d of the experiment.RESULTS： At the end of the experiment, serum alanine aminotransferase （ALl） increased more than 10 times and the presence of liver injury was confirmed histologically. Marked increase in bile acids was observed in the liver. The amount of total bile acids increased approximately three-fold and was accompanied by the increase in hydrophobic bile acids, CDCA and lithocholic acid （LCA）. UDCA （50 mg/kg and 150 mg/kg） improved liver histology, with a significant decrease （679.3 ±77.5 U/L vs 333.6 ± 50.4 U/L and 254.3 ±35.5 U/ L, respectively, P 〈 0.01） in serum ALT level. UDCA decreased the concentrations of the hydrophobic bile acids, and as a result, a decrease in the total bile acid level in the liver was achieved.CONCLUSION： The results show that UDCA improves oral CDCA-induced liver damage in hamsters. The protective effects of UDCA appear to result from a decrease in the concentration of hydrophobic bile acids, CDCA and LCA, which accumulate and show the cytotoxicity in the liver.
文摘A novel type of chiral molecular tweezers has been designed and synthesized by using chenodeoxy cholic acid as spacer and the aromatic compounds as arm. Their structures were characterized by 1HNMR, IR, MS spectra and elemental analysis. These chiral molecular tweezers showed good enantioselectivity for D-amino acid methyl esters.
基金the National Natural Science Foundation of China(31672508,31972636,31790411)the National Key Research and Development Program of China(2017YFD0500501)+2 种基金South China Agricultural University Doctoral Innovative Talent Cultivation Program(CX2019N006)Guangdong Key areas Research and Development Project(2019B020218001)Guangdong Provincial Promotion Project on Preservation and Utilization of Local Breed of Livestock and Poultry.
文摘Nutritional diarrhea and subsequent performance degradation in weaned piglets are major challenges for the pig industry.Bile acids(BA)can be added to the diet as emulsifiers.This experiment was conducted to investigate the effects of chenodeoxycholic acid(CDCA),a major primary BA,on growth performance,serum metabolic profiles and gut health in weaned piglets.A total of 72 healthy weaned piglets were randomly assigned to the control(CON)and the CDCA groups,which were feed a basal diet and the basal diet supplemented with 200 mg/kg CDCA for 30 d,respectively.Our results demonstrated that CDCA significantly increased final BW and average daily gain(ADG),decreased feed-to-gain(F:G)ratio and tended to reduce diarrhea incidence.In addition,CDCA increased the villus height-to-crypt depth(V:C)ratio,elevated goblet cell numbers and the expression of tight junction proteins,suggesting the enhancement of intestinal barrier function.As an emulsifier,CDCA increased jejunal lipase activity and the mRNA expression of pancreatic lipases.CDCA supplementation also altered the serum metabolic profiles,including increasing the levels of indole 3-acetic acid,N'-formylkynurenine and theobromine that were beneficial for gut health.Moreover,the relative abundance of 2 beneficial gut bacteria,Pre-votella 9 and Prevotellaceae TCG-001,were increased,whereas the relative abundance of a harmful bacteria,Dorea,was decreased in the gut of weaned piglets supplemented with CDCA.Importantly,the altered serum metabolic profiles showed a strong correlation with the changed gut bacteria.In conclusion,CDCA improved the growth performance of weaned piglets by improving intestinal morphology and barrier function,and enhancing lipid digestion,accompanied by alterations of serum metabolic profiles,and changes in relative abundance of certain gut bacteria.
基金Research was supported by the Changjiang Scholars and Innovative Research Team in University(No.IRT1070)the Natural Science Foundation of China(No.51373092)+2 种基金the Specialized Research Fund for the Doc-toral Program of Higher Education of China(No.20130202120010)the Key Science and Technology Program of Shaanxi Province,China(No.2012K08-09)the State Education Ministry and the Fundamental Re-search Funds for the Central Universities(Nos.GK201302036,GK201302037).Our special thanks are also for the Fund of New Energy Devices and Materials provided by Mr.He Chong Ben,Hong Kong.
文摘Approach to highly efficient dye-sensitized solar cells(DSSCs)by co-sensitization of organic dyes,AZ6+AZ5 with co-adsorbent chenodeoxycholic acid(CDCA)is presented.The power conversion efficiencies(PCEs)of 8.55%and 8.31%are obtained from DSSCs co-sensitized by AZ6(0.3 mmol/L)+AZ5(0.1 mmol/L)with CDCA concentration of 5 and 20 mmol/L in one step cocktail,respectively.The latter shows high stability in a period of 653 h under ambient conditions.
基金Supported by the Major Basic Research Project of Natural Science Foundation of Shandong Province,No.ZR2020ZD15.
文摘BACKGROUND Gastric cancer(GC)is associated with high mortality rates.Bile acids(BAs)reflux is a well-known risk factor for GC,but the specific mechanism remains unclear.During GC development in both humans and animals,BAs serve as signaling molecules that induce metabolic reprogramming.This confers additional cancer phenotypes,including ferroptosis sensitivity.Ferroptosis is a novel mode of cell death characterized by lipid peroxidation that contributes universally to malignant progression.However,it is not fully defined if BAs can influence GC progression by modulating ferroptosis.AIM To reveal the mechanism of BAs regulation in ferroptosis of GC cells.METHODS In this study,we treated GC cells with various stimuli and evaluated the effect of BAs on the sensitivity to ferroptosis.We 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 involved.RESULTS Our data suggested that BAs could reverse erastin-induced ferroptosis in GC cells.This effect correlated with increased glutathione(GSH)concentrations,a reduced GSH to oxidized GSH ratio,and higher GSH peroxidase 4(GPX4)expression levels.Subsequently,we confirmed that BAs exerted these effects by activating FXR,which markedly increased the expression of GSH synthetase and GPX4.Notably,BACH1 was detected as an essential intermediate molecule in the promotion of GSH synthesis by BAs and FXR.Finally,our results suggested that FXR could significantly promote GC cell proliferation,which may be closely related to its anti-ferroptosis effect.CONCLUSION This study revealed for the first time that BAs could inhibit ferroptosis sensitivity through the FXR-BACH1-GSHGPX4 axis in GC cells.This 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.
基金Supported by the National Natural Science Foundation of China,No.81570468 and No.81741056Jinshan Science and Technology Commission,No.2014-3-07
文摘BACKGROUND Disorders of primary bile acid synthesis may be life-threatening if undiagnosed,or not treated with primary bile acid replacement therapy. To date, there are few reports on the management and follow-up of patients with Δ4-3-oxosteroid 5β-reductase(AKR1 D1) deficiency. We hypothesized that a retrospective analysis of the responses to oral bile acid replacement therapy with chenodeoxycholic acid(CDCA) in patients with this bile acid synthesis disorder will increase our understanding of the disease progression and permit evaluation of this treatment regimen as an alternative to the Food and Drug Administration(FDA) approved drug cholic acid, which is currently unavailable in China.AIM To evaluate the therapeutic responses of patients with AKR1 D1 deficiency to oral bile acid therapy, specifically CDCA.METHODS Twelve patients with AKR1 D1 deficiency, confirmed by fast atom bombardment ionization-mass spectrometry analysis of urine and by gene sequencing for mutations in AKR1 D1, were treated with differing doses of CDCA or ursodeoxycholic acid(UDCA). The clinical and biochemical responses to therapy were monitored over a period ranging 0.5-6.4 years. Dose adjustment, to optimize the therapeutic dose, was based on changes in serum biochemistry parameters,notably liver function tests, and suppression of the urinary levels of atypical hepatotoxic 3-oxo-Δ4-bile acids measured by mass spectrometry.RESULTS Physical examination, serum biochemistry parameters, and sonographic findings improved in all 12 patients during bile acid therapy, except one who underwent liver transplantation. Urine bile acid analysis confirmed a significant reduction in atypical hepatotoxic 3-oxo-Δ4 bile acids concomitant with clinical and biochemical improvements in those patients treated with CDCA. UDCA was ineffective in down-regulating endogenous bile acid synthesis as evidenced from the inability to suppress the urinary excretion of atypical 3-oxo-Δ4-bile acids. The dose of CDCA required for optimal clinical and biochemical responses varied from 5.5-10 mg/kg per day among patients based on maximum suppression of the atypical bile acids and improvement in serum biochemistry parameters, and careful titration of the dose was necessary to avoid side effects from CDCA.CONCLUSION The primary bile acid CDCA is effective in treating AKR1 D1 deficiency but the therapeutic dose requires individualized optimization. UDCA is not recommended for long-term management.
基金This study was supported by National Natural Science Foundation of China(NSFC Grant Nos.U21A20336,81820108031,and 91939301)National Key Research and Development Program of China(Grant No.2022YFC3602400)+1 种基金Beijing Municipal Natural Science Foundation(Grant No.7222218,China)Medical research management/basic and clinical research unit of metabolic cardiovascular diseases,Chinese Academy of Medical Sciences(Grant No.2021RU003,China).
文摘The coronavirus disease 2019(COVID-19)pandemic,caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has been significantly alleviated.However,long-term health effects and prevention strategy remain unresolved.Thus,it is essential to explore the pathophysiological mechanisms and intervention for SARS-CoV-2 infection.Emerging research indicates a link between COVID-19 and bile acids,traditionally known for facilitating dietary fat absorption.The bile acid ursodeoxycholic acid potentially protects against SARS-CoV-2 infection by inhibiting the farnesoid X receptor,a bile acid nuclear receptor.The 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 cells.Here,we review the latest basic and clinical evidence linking bile acids to SARS-CoV-2,and reveal their complicated pathophysiological mechanisms.
基金supported by the National Natural Science Foundation of China(Nos.82173884,81872930,82073922 and 81872833)the“Double First-Class”university project(No.CPU2018GY22,China)。
文摘Body is equipped with organic cation transporters(OCTs).These OCTs mediate drug transport and are also involved in some disease process.We aimed to investigate whether liver failure alters intestinal,hepatic and renal Oct expressions using bile duct ligation(BDL)rats.Pharmacokinetic analysis demonstrates that BDL decreases plasma metformin exposure,associated with decreased intestinal absorption and increased urinary excretion.Western blot shows that BDL significantly downregulates intestinal Oct2 and hepatic Oct1 but upregulates renal and hepatic Oct2.In vitro cell experiments show that chenodeoxycholic acid(CDCA),bilirubin and farnesoid X receptor(FXR)agonist GW4064 increase OCT2/Oct2 but decrease OCT1/Oct1,which are remarkably attenuated by glycine-β-muricholic acid and silencing FXR.Significantly lowered intestinal CDCA and increased plasma bilirubin levels contribute to different Octs regulation by BDL,which are confirmed using CDCA-treated and bilirubin-treated rats.A disease-based physiologically based pharmacokinetic model characterizing intestinal,hepatic and renal Octs was successfully developed to predict metformin pharmacokinetics in rats.In conclusion,BDL remarkably downregulates expressions of intestinal Oct2 and hepatic Oct1 protein while upregulates expressions of renal and hepatic Oct2 protein in rats,finally,decreasing plasma exposure and impairing hypoglycemic effects of metformin.BDL differently regulates Oct expressions via Fxr activation by CDCA and bilirubin.
