TOXICOLOGICAL SCIENCES
·
2016
·Vol. 152
·期 2
·417-428
·
IF 3.88
Guo Hong-Li,Hassan Hozeifa M.,Zhang Yun,Dong Si-Zhe,Ding Ping-Ping,Wang Tao,Sun Li-Xin,Zhang Lu-Yong,Jiang Zhen-Zhou
Pyrazinamide (PZA) is an indispensable first-line drug used for the treatment of tuberculosis which may cause serious hepatotoxicity; however, the mechanisms underlying these toxicities are poorly understood. Cholestasis plays an important role in drug-induced liver injury. Since there were no previous published works reported cholestasis and PZA hepatotoxicity relationship, this study aimed to identify whether PZA can induce liver injury with characterized evidences of cholestasis and to clarify expression changes of proteins related to both bile acid synthesis and transport in PZA-induced liver injury. PZA (2 g/kg) was administered for 7 consecutive days by oral gavage. Results showed there were 2-fold elevation in both ALT and AST serum levels in PZA-treated rats. In addition, a 10-fold increment in serum total bile acid was observed after PZA administration. The mRNA and protein expressions of bile acid synthesis and transport parameters were markedly altered, in which FXR, Bsep, Mrp2, Mdr2, Ostα/β, Oatp1a1, Oatp1b2, and Cyp8b1 were decreased (P < .05), while Mrp3, Ntcp, Oatp1a4, and Cyp7a1 were increased (P < .05). Moreover, treatment with the FXR agonist obeticholic acid (OCA) generated obvious reductions in serum ALT, AST, and TBA levels in PZA-treated rats. Those effects were due to transcriptional regulation of pre-mentioned target genes by OCA. Taken together, these results suggested that PZA-induced cholestatic liver injury was related to FXR inhibition, leading to the dysfunction in bile acid synthesis and transport.
研究领域:
药理学
·
毒理学
·
肝病学
✓ 已验证
DOI
PubMed
高影响因子
Bioresources and Bioprocessing
·
2015
·Vol. 2
·期 1
·1-9
·
IF 0
Huang Xiaomei,Cao Xuejun
Background Ursodeoxycholic acid (UDCA) is an important clinical drug in the treatment of liver disease. In previous work, ursodeoxycholic acid was prepared by traditional organic synthesis. The preparation of ursodeoxycholic acid through an electrochemical method with higher stereoselectivity and environmental friendliness is described herein. Results Dimethyl sulfoxide (DMSO), dimethylformamide (DMF), and N -methyl-2-pyrrolidone (NMP) were used as stereoselectivity additives during electroreduction. With 107.5 mM DMSO in methanol containing potassium bromide and a continuous current of 20 mA, 936 Coulombs was passed into the electrolysis system, achieving 88.5 % conversion of 7-ketone lithocholic acid (7K-LCA), while the yield of UDCA reached 72.8 %. Cyclic voltammetry (CV) was used to explore the electrochemical behavior of the reaction, and the electrolysis results were consistent with the cyclic voltammograms. Conclusions Ursodeoxycholic acid can be prepared by electroreduction with high stereoselectivity. The method developed here offers a potential application for large-scale production of ursodeoxycholic acid and an interesting reference to asymmetric electrochemical reduction of the keto group.
研究领域:
药学
·
有机化学
✓ 已验证
产品关联
DOI
KOREAN JOURNAL OF CHEMICAL ENGINEERING
·
2014
·Vol. 31
·期 7
·1276-1280
·
IF 1.241
Yuan Xiangxi,Ma Xiaolei,Cao Xuejun
A novel method of producing ursodeoxycholic acid was developed through direct electro-reduction of 7-ketolithocholic acid in a divided electrolytic cell. Titanium ruthenium mesh electrode was used as the anode, while high purity lead plate was used as the cathode. The process was optimized with regards to the electrolyte, temperature, concentration of methanol, current density and concentration of anolyte. When potassium bromide was used as the electrolyte, the saturated solution of 7-ketolithocholic acid in 85–93% (v/v) methanol, current density 9.52–28.6 A/m 2 and concentration of anolyte at 4–6% (w/w), the maximum percentage yield of ursodeoxycholic acid could be 47%. The method will provide a potential approach for large-scale production of ursodeoxycholic acid.
研究领域:
药学
·
有机化学
✓ 已验证
产品关联
DOI
高影响因子
AQUACULTURE
·
2024
·
IF 3.9
Xing Ren,Xiaojie Lu,Fan Wang,Jia Xu,Yueyuan Tan,Aiping Feng
The grouper aquaculture industry flavors high lipid diets for economic reasons, yet this inevitably produces negative effects on the growth performance and intestinal function. Bile acids have been extensively reported to mitigate the negative effects on fish fed a high lipid diet, but it remains unclear whether this mechanism is bile acid type dependent. Therefore, an eight-week feeding trial was conducted to investigate the response of growth and intestinal health parameters in pearl gentian grouper Epinephelus fuscoguttatus ♂ × E. lanceolatus ♀ fed with high lipid diets to different types of bile acids. A high lipid diet (diet HL) containing 167 g/kg crude lipid served as the control diet, and three of primary bile acids glycocholic acid, taurocholic acid, and cholic acid were added at a dose of 900 mg/kg to generate the bile acid diets HBG, HBT, and HBC, respectively. Results revealed that dietary supplementation with glycocholic acid, taurocholic acid, or cholic acid does not affect the feed intake and growth of pearl gentian grouper fed a high lipid diet, while increasing the relative abundance of intestinal opportunistic pathogens such as Staphylococcus and Pseudomonas in this species. Dietary supplementation with glycocholic acid or cholic acid decreases muscle layer thickness and villus height, while increases intestinal injury score. Grouper fed with taurocholic acid showed higher villus width and serum antioxidant enzyme activity, along with lower intestinal injury score and serum lipid peroxidation level. For the protein and gene involved in the PI3K/AKT/mTOR pathways, S6K1 signaling, and bile acids metabolism, grouper fed with taurocholic acid exhibited an increase in the protein expression of P P70 and the mRNA expression of nrf2 , pi3k , pdk1 , tsc2 , akt , mtorc1, fxr and tgr5 . Moreover, the serum metabolites can be significantly influenced by the intestinal bacteria. Overall, dietary supplementation of 900 mg/kg taurocholic acid is recommended when feeding high lipid diets to grouper.
研究领域:
水产养殖
·
营养学
·
分子生物学
·
微生物学
✓ 已验证
产品关联
DOI
高影响因子
Bioresources and Bioprocessing
·
2023
·Vol. 10
·期 1
·1-12
·
IF 4.6
Dai Mohan,Xu Binpeng,Guo Qing,Wan Junfen,Cao Xuejun
Ursodeoxycholic acid (UDCA) is not only safer than chenodeoxycholic acid in the treatment of hepatobiliary diseases, but also has a wide range of applications in Acute Kidney Injury and Parkinson’s Disease. The purpose of this experiment is to improve the conversion rate of 7-ketocholic acid (7K-LCA) and the yield of ursodeoxycholic acid in aprotic solvents during electrochemical reduction process. Three aprotic solvents were investigated as electrolytes. 1,3-Dimethyl-2-imidazolidinone (DMI) has a stable five-membered ring structure, and 7K-LCA has undergone two nucleophilic reactions and “Walden” inversion, the 7K-LCK was stereoselectively reduced to UDCA. Hexamethylphosphoramide (HMPA) and 1,3-methyl-3,4,5,6-Tetrahydro-2(1 H )-pyrimidinone (DMPU) can be attacked by chloride ions to produce by-products. Molecular orbital theory-based simulations were conducted to study the reducibility of three aprotic solvents [hexamethylphosphoramide (HMPA), 1,3-methyl-3,4,5,6-Tetrahydro-2(1 H )-pyrimidinone (DMPU), and 1,3-Dimethyl-2-imidazolidinone (DMI)] in combination with experiments. Choose the best solvent based on the simulation results, the electrolysis reaction can be carried out by applying current and voltage when lithium chloride is used as electrolytes. Calculations using Materials Studio showed that Cu, Pb, Hg–Cu, and Ni exhibited the highest binding energies to the substrate in this system. Using Cu as the electrode when the solvent is a 1:1 mix of DMI and HMPA, the conversion rate of 7-ketocholic acid (could reach 98%, the yield of ursodeoxycholic acid was up to 80%. Under the same conditions, linear voltammetry was performed on the electrochemical workstation to study the electrolysis behavior, and the obtained results were consistent with the experiment. Graphical Abstract
研究领域:
药理学
·
有机化学
·
生物化学
✓ 已验证
DOI
高影响因子
Food Bioscience
·
2024
·
IF 4.8
Xue Dong,Yongchao Cai,Hui Liao,Yao Wang,Zehua Chen,Yong Zhou,Jianrong Wu,Yi Luo,Fengyun Sheng,Zhemin Zhou,Xiaole Xia
Obesity and hyperlipidemia, chronic diseases resulting from excessive energy intake and abnormal lipid metabolism, respectively, are intricately associated with cardiovascular disease and diabetes and have become global health problems. Monascus ruber ( M. ruber ), a filamentous fungus with edible properties, produces bio-functional metabolites including a good deal of enzymes. In this study, the effect of the biological transformation of fermented food on obesity and hyperlipidemia, was systematically investigated using the mixture of medicine and food homology (MFH) hawthorn and millet as fermentation substrate. Results showed that fermentation promoted the release of bioactive compounds such as phenolic compounds. Pancreas lipase assay indicated that the inhibition rate and IC 50 of free phenolic compounds in fermented MFH food were 70.51% ± 2.59%, and 1.34 mg/mL, respectively. In vitro , the binding rates of free phenolic compounds in fermented MFH food to Sodium cholate (SC), sodium glycinate (SGC) and sodium taurocholate (STC) were 84.99% ± 6.59%, 80.29% ± 6.23%, and 79.68% ± 6.18%. Further, Monascus -fermented hawthorn and millet (MFHM) of fermented MFH food markedly suppressed lipid accumulation in oleic acid (OA)-induced HepG2, with cell triglycerides (TG) and total cholesterol (TC) clearance of 24.31% ± 1.81% and 73.88% ± 2.72%, respectively. These findings implied that the fermentation of a mixture of MFH millet and hawthorn by M. ruber holds promise for reducing obesity and lowering lipid levels, thereby serving as a valuable foundation and reference for future research on the development of multifunctional food products.
研究领域:
食品科学
·
营养学
·
药理学
·
生物化学
✓ 已验证
产品关联
DOI
高影响因子
Cell Reports
·
2019
·
IF 7.815
Kai Wang,Mingfang Liao,Nan Zhou,Li Bao,Ke Ma,Zhongyong Zheng,Yujing Wang,Chang Liu,Wenzhao Wang,Jun Wang,Shuang-Jiang Liu,Hongwei Liu
Summary We demonstrated the metabolic benefits of Parabacteroides distasonis (PD) on decreasing weight gain, hyperglycemia, and hepatic steatosis in ob/ob and high-fat diet (HFD)-fed mice. Treatment with live P. distasonis (LPD) dramatically altered the bile acid profile with elevated lithocholic acid (LCA) and ursodeoxycholic acid (UDCA) and increased the level of succinate in the gut. In vitro cultivation of PD demonstrated its capacity to transform bile acids and production of succinate. Succinate supplementation in the diet decreased hyperglycemia in ob/ob mice via the activation of intestinal gluconeogenesis (IGN). Gavage with a mixture of LCA and UDCA reduced hyperlipidemia by activating the FXR pathway and repairing gut barrier integrity. Co-treatment with succinate and LCA/UDCA mirrored the benefits of LPD. The binding target of succinate was identified as fructose-1,6-bisphosphatase, the rate-limiting enzyme in IGN. The succinate and secondary bile acids produced by P. distasonis played key roles in the modulation of host metabolism.
研究领域:
微生物学
·
代谢学
·
胃肠病学
✓ 已验证
DOI
PubMed
高影响因子
MOLECULAR CARCINOGENESIS
·
2019
·Vol. 58
·期 7
·1155-1167
·
IF 3.411
Sinan Wang,Wenxiao Dong,Li Liu,Mengque Xu,Yu Wang,Tianyu Liu,Yujie Zhang,Bangmao Wang,Hailong Cao
The gut microbiota and the bile acid pool play pivotal roles in maintaining intestinal homeostasis. Bile acids are produced in the liver from cholesterol and metabolized in the intestine by the gut microbiota. Gut dysbiosis has been reported to be associated with colorectal cancer. However, the interplay between bile acid metabolism and the gut microbiota during intestinal carcinogenesis remains unclear. In the present study, we investigated the potential roles of bile acids and the gut microbiota in the cholic acid (CA; a primary bile acid)-induced intestinal adenoma-adenocarcinoma sequence. Apc min/+ mice, which spontaneously develop intestinal adenomas, were fed a diet supplemented with 0.4% CA for 12 weeks. Mice that were fed a normal diet were regarded as untreated controls. In CA-treated Apc min/+ mice, the composition of the gut microbiota was significantly altered, and CA was efficiently transformed into deoxycholic acid (a secondary bile acid) by the bacterial 7α-dehydroxylation reaction. The intestinal adenoma-adenocarcinoma sequence was observed in CA-treated Apc min/+ mice and was accompanied by an impaired intestinal barrier function and IL-6/STAT3-related low-grade inflammation. More importantly, microbiota depletion using an antibiotic cocktail globally compromised CA-induced intestinal carcinogenesis, suggesting a leading role for the microbiota during this process. Overall, our data suggested that the crosstalk between bile acids and the gut microbiota mediated intestinal carcinogenesis, which might provide novel therapeutic strategies against intestinal tumor development.
研究领域:
癌症生物学
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胃肠病学
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微生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Molecular Catalysis
·
2023
·
IF 4.6
Jiang-Tao Xue,Zhi-Neng You,Bing-Yi Yang,Zheng-Yu Huang,Jiang Pan,Chun-Xiu Li,Jian-He Xu
7-Oxo-lithocholic acid (7-oxo-LCA) is a key precursor for the enzymatic synthesis of the therapeutic bile acid ursodeoxycholic acid (UDCA). Chenodeoxycholic acid (CDCA) can be readily converted to 7-oxo-LCA by the 7α-hydroxysteroid dehydrogenase (7α-HSDH). However, the poor substrate tolerance of the current 7α-HSDH limits their practical applications. In this study, a new and natively NAD(+)-dependent Sm 7α-HSDH from Shewanella morhuae was identified, which exhibited a better substrate tolerance compared with other 7α-HSDHs. The purified Sm 7α-HSDH showed a high oxidative activity of 281 U mg −1 protein toward CDCA, with a catalytic efficiency ( k cat /K m ) of 7.47 × 10 3 mM −1 s −1 . In a preparative biotransformation (100 mL scale), 200 mM (∼80 g L −1 ) CDCA was almost completely oxidized to 7-oxo-LCA in 1 h, with a 78% isolated yield and a space-time yield (STY) of up to 1418 g L −1 d −1 , which is so far the highest productivity for biosynthesis of 7-oxo-LCA from CDCA. These results demonstrate the great potential of Sm 7α-HSDH as a promising biocatalyst for UDCA synthesis.
研究领域:
生物化学
·
医药化学
·
酶工程
✓ 已验证
产品关联
DOI
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
Wu Lirong,Wang Jieyi,Lei Jing,Ge Kun,Qu Chun,Liu Jiajian,Huang Fengjie,Sun Dongnan,Chao Xiaowen,Chen Tianlu,Zhao Aihua,Jia Wei,Zheng Xiaojiao,Xie Guoxiang
Background: Porcine bile powder (PBP) is a traditional Chinese medicine that has been used for centuries in various therapeutic applications. However, PBP has not previously undergone comprehensive component analysis and not been evaluated for safety through standard in vivo toxicological studies.Methods: In our study, we characterized the component of PBP by liquid chromatography-mass spectrometry. The acute and subchronic oral toxicity, genotoxicity, and teratogenicity studies of PBP were designed and conducted in Kunming mice and Sprague-Dawley (SD) rats.Results: The chemical analysis of PBP showed that the main components of PBP were bile acids (BAs), especially glycochenodeoxycholic acid. There were no signs of toxicity observed in the acute oral test and the subchronic test. In the genotoxicity tests, no positive results were observed in the bacterial reverse mutation test. Additionally, in the mammalian micronucleus test and mouse spermatocyte chromosomal aberration test, no abnormal chromosomes were observed. In the teratogenicity test, no abnormal fetal development was observed.Conclusion: Our findings demonstrate that PBP, composed mainly of BAs, is non-toxic and safe based on the conditions tested in this study.
研究领域:
药理学
·
毒理学
·
传统中药
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Gut Microbes
·
2024
·
IF 12.2
Xiaoqiang Zhu,Xiaojuan Dai,Lijun Zhao,Jing Li,Yanhong Zhu,Wenjuan He,Xinlei Guan,Tao Wu,Li Liu,Hongping Song,Liang Lei
Abdominal obesity-related metabolic syndrome (MetS) has emerged as a significant global public health issue that affects human health. Flavonoids, such as quercetin, have been reported to exert obvious anti-obesity and lipid-lowering effects in both humans and animal models. However, the precise underlying mechanism remains elusive. In this study, we investigated the potential roles of gut microbiota-bile acids (BAs) interactions in quercetin-induced anti-obesity effects and metabolic benefits. Oral administration of quercetin significantly enhanced energy metabolism through activating thermogenesis of brown adipose tissues (BAT) and browning of white adipose tissues (WAT), thus mitigating metabolic dysfunctions in an abdominal obesity-related MetS mouse model. Further mechanistic studies demonstrated that quercetin treatment substantially promoted the generation of non-12α-hydroxylated BAs (non-12OH BAs), particularly ursodeoxycholic acid (UDCA) and lithocholic acid (LCA), in serum via regulating the overall structure of gut microbiota and enriching Lactobacillus. High level of non-12OH BAs bind to Takeda G protein-coupled receptor 5 (TGR5) on adipocytes to stimulate thermogenesis. Remarkably, fecal microbiota transplantation (FMT) from quercetin-treated mice replicated the effects of quercetin on non-12OH BAs generation and energy expenditure, which suggested gut microbiota reshape and concomitant BAs regulation were responsible for the benefits on energy metabolism of quercetin in the MetS mouse model. Our findings not only highlighted the critical role of gut microbiota-BAs crosstalk in mediating quercetin-induced energy expenditure, but also enriched the pharmacological mechanisms of quercetin in ameliorating MetS-related diseases.
研究领域:
药理学
·
代谢学
·
微生物学
·
内分泌学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Communications Biology
·
2024
·Vol. 7
·期 1
·1-13
·
IF 5.2
Chen Song,Hu Zongren,Tang Jianbang,Zhu Haipeng,Zheng Yuhua,Xiao Jiedong,Xu Youhua,Wang Yao,Luo Yi,Mo Xiaoying,Wu Yalan,Guo Jianwen,Zhang Yongliang,Luo Huanhuan
High temperature and humidity in the environment are known to be associated with discomfort and disease, yet the underlying mechanisms remain unclear. We observed a decrease in plasma glucagon-like peptide-1 levels in response to high-temperature and humidity conditions. Through 16S rRNA gene sequencing, alterations in the gut microbiota composition were identified following exposure to high temperature and humidity conditions. Notably, changes in the gut microbiota have been implicated in bile acid synthesis. Further analysis revealed a decrease in lithocholic acid levels in high-temperature and humidity conditions. Subsequent in vitro experiments demonstrated that lithocholic acid increases glucagon-like peptide-1 secretion in NCI-H716 cells. Proteomic analysis indicated upregulation of farnesoid X receptor expression in the ileum. In vitro experiments revealed that the combination of lithocholic acid with farnesoid X receptor inhibitors resulted in a significant increase in GLP-1 levels compared to lithocholic acid alone. In this study, we elucidate the mechanism by which reduced lithocholic acid suppresses glucagon-like peptide 1 via farnesoid X receptor activation under high-temperature and humidity condition.
研究领域:
生理学
·
微生物学
·
内分泌学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）