Bioresources and Bioprocessing
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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
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有机化学
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产品关联
DOI
STEROIDS
·
2017
·
IF 2.282
Xiao-Long He,Yajing Xing,Xiang-Zhong Gu,Jie-Xin Xiao,Ying-Ying Wang,Zhengfang Yi,Wen-Wei Qiu
In this paper, a new and concise synthetic route of lithocholic acid (LCA) using commercially available steroid source deoxycholic acid is reported. A series of amide derivatives of LCA were also synthesized and investigated for their activity against the growth of MCF-7 and MCF-7/ADR cells using the sulforhodamine B assay. For MCF-7, the most potent compound 20 showed a 20-fold higher antitumor activity than LCA. For MCF-7/ADR, the most potent compound 24 showed a 22-fold higher antitumor activity than LCA. The transwell migration assay of 20 was evaluated on MDA-MB-231 cells. The colony formation and apoptosis assays of 20 were performed on MCF-7 and MCF-7/ADR cell lines.
研究领域:
药理学
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有机合成化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2018
·
IF 3.997
Hui Ma,Qi Kang,Tao Wang,Jianhong Xiao,Li Yu
A simple, low-cost and label-free strategy for detecting lithocholic acid (LCA) was designed at the liquid crystals (LCs)/aqueous interface via competitive host-guest inclusion. In this method, sodium dodecyl sulfate (SDS) was initially adsorbed on the fluid interface and induced LCs to adopt the homeotropic ordering. Inclusion complexation of SDS and β-cyclodextrin (β-CD) disturbed interaction between LCs and SDS and evoked LCs to keep a tilted alignment. When injecting LCA into the mixed solution of SDS and β-CD, SDS excluded from the cavity of β-CD by competitive host-guest inclusion and could be re-adsorbed at the LCs/aqueous interface, resulting in the orientational transition of LCs from tilted to homeotropic state. Correspondingly, a bright-to-dark optical response was observed under polarized optical microscope (POM). The as-prepared LCs-based sensor could detect LCA as low as about 2 μM in aqueous solution. Moreover, the practicability of the approach was validated by monitoring the known amount of LCA in human urine. This work offers an appealing approach for the detection of LCA which has a great potentiality in clinical diagnosis.
研究领域:
分析化学
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生物医学工程
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DOI
PubMed
高影响因子
KOREAN JOURNAL OF CHEMICAL ENGINEERING
·
2014
·Vol. 31
·期 7
·1276-1280
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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
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有机化学
✓ 已验证
产品关联
DOI
高影响因子
SPECTROSCOPY LETTERS
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2019
·
IF 1.081
Yanbin Su,Chengyu Sun,Ning Jiang,Qingsong Zhang
The purposes of this study were to explore the factors contributing to the generation of the toxic trans-crotonaldehyde in mitochondria of glioma and to look for the elimination effects of the toxic trans-crotonaldehyde by the lithocholic acid. Ultraviolet-visible absorption spectroscopy and mitochondrial isolation and extraction from glioma were used in this study. Research findings showed that the factors contributing to the generation of the toxic trans-crotonaldehyde were hydrogen peroxide, mitochondria of glioma, and their appropriate interaction, respectively. The appropriate quantity of the toxic trans-crotonaldehyde could be induced by hydrogen peroxide (0.16 mmol), mitochondria of glioma (3 mg protein/ml), and 30 min of their interaction, respectively. The most suitable conditions for the lithocholic acid to eliminate the toxic trans-crotonaldehyde were the weakly alkaline of mitochondria of glioma (pH 8.0), the lithocholic acid (0.15 mmol), and 15 min of interaction, respectively. The conclusion was that the lithocholic acid efficiently eliminated the toxic trans-crotonaldehyde in mitochondria of glioma in real time and opened up a new way to treat glioma.
研究领域:
肿瘤学
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药理学
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生物化学
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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
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有机化学
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生物化学
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DOI
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
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2017
·Vol. 174
·期 8
·672-688
·
IF 5.491
Hang Zeng,Yiming Jiang,Pan Chen,Xiaomei Fan,Dongshun Li,Aiming Liu,Xiaochao Ma,Wen Xie,Peiqing Liu,Frank J Gonzalez,Min Huang,Huichang Bi
Background and Purpose Currently, ursodeoxycholic acid and obeticholic acid are the only two FDA-approved drugs for cholestatic liver diseases. Thus, new therapeutic approaches need to be developed. Here we have evaluated the anti-cholestasis effects of Schisandrol B (SolB), a bioactive compound isolated from Schisandra sphenanthera . Experimental Approach Hepatoprotective effect of SolB against intrahepatic cholestasis, induced by lithocholic acid (LCA), was evaluated in mice. Metabolomic analysis and gene analysis were used to assess involvement of pregnane X receptor (PXR). Molecular docking, cell-based reporter gene analysis and knockout mice were used to demonstrate the critical role of the PXR pathway in the anti-cholestasis effects of SolB. Key Results SolB protected against LCA-induced intrahepatic cholestasis. Furthermore, therapeutic treatment with SolB decreased mortality in cholestatic mice. Metabolomics and gene analysis showed that SolB accelerated metabolism of bile acids, promoted bile acid efflux into the intestine, and induced hepatic expression of the PXR-target genes Cyp3a11, Ugt1a1 , and Oatp2, which are involved in bile acid homeostasis. Mechanistic studies showed that SolB activated human PXR and up-regulated PXR target genes in human cell lines. Additionally, SolB did not protect Pxr -null mice from liver injury induced by intrahepatic cholestasis, thus providing genetic evidence that the effect of SolB was PXR-dependent. Conclusion and Implications These findings provide direct evidence for the hepatoprotective effects of SolB against cholestasis by activating PXR. Therefore, SolB may provide a new and effective approach to the prevention and treatment of cholestatic liver diseases.
研究领域:
肝病学
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药理学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Molecular Catalysis
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2023
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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
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医药化学
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酶工程
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产品关联
DOI
高影响因子
Biotechnology Journal
·
2025
·Vol. 20
·期 7
·e70070
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IF 3.1
Ci Song,Xiaomin Zheng,Zhenru Zhou,Yundong Yu,Lei Zhang,Shan Li
Ursodeoxycholic acid (UDCA), a natural bile acid, is widely utilized in treating hepatobiliary disorders due to its ability to reduce bile concentration and protect liver function. While the CYP107D1 (OleP) triple-mutant F84Q/S240A/V291G is the first identified bacterial monooxygenase capable of directly converting lithocholic acid (LCA) to UDCA via C7β-hydroxylation, its industrial application has been hindered by low catalytic efficiency. The study implemented a semi-rational design strategy combined with a cell-free enzyme catalysis method, utilizing the OleP triple mutant as a template, to screen for mutants with enhanced 7β-hydroxylation activity. The superior quadruple-mutant G294A/N236H/F321W/V297A was engineered through iterative combinatorial mutagenesis, which catalyzed the production of about 0.68 mM UDCA from 1 mM substrate LCA. This variant exhibited a 50% increase in catalytic activity and a 40% improvement in regioselectivity compared to the template OleP triple-mutant. Molecular docking and kinetic simulations further demonstrated that the quadruple mutant stabilized the enzyme-substrate complex through optimized binding interactions, thereby enhancing catalytic proficiency. Our findings elucidate critical structural determinants governing C7-hydroxylation of LCA.
研究领域:
生物化学
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酶学
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生物催化
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蛋白质工程
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结构生物学
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工业微生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Sustainable Chemistry & Engineering
·
2021
·
IF 8.198
Hai-Peng Li,Zhi-Neng You,Yuan-Yang Liu,Gao-Wei Zheng,Heng Gong,Yiming Mo,Ning Zhu,Yun-Peng Bai,Jian-He Xu
Water-forming NAD(P)H oxidases (NOXs) constitute a clean NAD(P)+ regeneration strategy for NAD(P)+-dependent biotransformations to produce high value-added chemicals because they only consume oxygen and generate water. However, the application of NOXs is still challenging because of limited oxygen transfer in batch reactions. Here, we report an efficient continuous-flow microreactor (CFMR) to improve the oxygen transfer and reaction performance in NAD+-dependent chenodeoxycholic acid oxidation catalyzed by 7α-hydroxysteroid dehydrogenase (7α-HSDH) for the production of 7-oxo-lithocholic acid, a key precursor of ursodeoxycholic acid. The recycling efficiency of NAD+ by NOX from Streptococcus mutans (SmNOX) was significantly improved in this CFMR. Compared with a conventional batch stirred tank reactor, the space–time yield of production of 7-oxo-lithocholic acid was increased by 96-fold. Furthermore, the total turnover number of NAD+ was improved 10-fold, and the enzyme consumption number was decreased 7-fold. Combining the NOX/O2 system with this microreactor technology provides a general platform that enables various NAD(P)+-dependent biotransformations in a green and sustainable manner, which will be helpful in the design of ecofriendly bioprocesses for production of functional chemicals on a large scale.
研究领域:
生物化学
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合成生物学
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绿色化学
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产品关联
DOI
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2019
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IF 3.414
Shicheng Fan,Conghui Liu,Yiming Jiang,Yue Gao,Yixin Chen,Kaili Fu,Xinpeng Yao,Min Huang,Huichang Bi
Ethnopharmacological relevance Cholestasis is a clinical syndrome caused by toxic bile acid retention that will lead to serious liver diseases. Ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are the only two FDA-approved drugs for its treatment. Thus, there is a clear need to develop new therapeutic approaches for cholestasis. Here, anti-cholestasis effects of the lignans from a traditional Chinese herbal medicine, Schisandra sphenanthera , were investigated as well as the involved mechanisms. Materials and methods Adult male C57BL/6J mice were randomly divided into 9 groups including the control group, LCA group, LCA with specific lignan treatment of Schisandrin A (SinA), Schisandrin B (SinB), Schisandrin C (SinC), Schisandrol A (SolA), Schisandrol B (SolB), Schisantherin A (StnA) and Schisantherin B (StnB), respectively. Mice were treated with each drug (qd) for 7 days, while the administration of lithocholic acid (LCA) (bid) was launched from the 4th day. Twelve hours after the last LCA injection, mice were sacrificed and samples were collected. Serum biochemical measurement and histological analysis were conducted. Metabolomics analysis of serum, liver, intestine and feces were performed to study the metabolic profile of bile acids. RT-qPCR and Western blot analysis were conducted to determine the hepatic expression of genes and proteins related to bile acid homeostasis. Dual-luciferase reporter gene assay was performed to investigate the transactivation effect of lignans on human pregnane X receptor (hPXR). RT-qPCR analysis was used to detect induction effects of lignans on hPXR-targeted genes in HepG2 cells. Results Lignans including SinA, SinB, SinC, SolA, SolB, StnA, StnB were found to significantly protect against LCA-induced intrahepatic cholestasis , as evidenced by significant decrease in liver necrosis , serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) activity. More importantly, serum total bile acids (TBA) and total bilirubin (Tbili) were also significantly reduced. Metabolomics analysis revealed these lignans accelerated the metabolism of bile acids and increased the bile acid efflux from liver into the intestine or feces. Gene analysis revealed these lignans induced the hepatic expressions of PXR-target genes such as Cyp3a11 and Ugt1a1 . Luciferase reporter gene assays illustrated that these bioactive lignans can activate hPXR. Additionally, they can all upregulate hPXR-regulate genes such as CYP3A4 , UGT1A1 and OATP2 . Conclusion These results clearly demonstrated the lignans from Schisandra sphenanthera exert hepatoprotective effects against LCA-induced cholestasis by activation of PXR. These lignans may provide an effective approach for the prevention and treatment of cholestatic 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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民族药理学
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产品关联
DOI
PubMed
高影响因子
Communications Biology
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2024
·Vol. 7
·期 1
·1-13
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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
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微生物学
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内分泌学
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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）