Breast cancer is the most common malignancy in women worldwide.Triplenegative breast cancer(TNBC),refers breast cancer negative for estrogen receptor,progesterone receptor and human epidermal growth factor receptor 2,...Breast cancer is the most common malignancy in women worldwide.Triplenegative breast cancer(TNBC),refers breast cancer negative for estrogen receptor,progesterone receptor and human epidermal growth factor receptor 2,characterized by high drug resistance,high metastasis and high recurrence,treatment of which is a difficult problem in the clinical treatment of breast cancer.In order to better treat TNBC clinically,it is a very urgent task to explore the mechanism of TNBC resistance in basic breast cancer research.Pregnane X receptor(PXR)is a nuclear receptor whose main biological function is to participate in the metabolism,transport and clearance of allobiological agents in PXR.PXR plays an important role in drug metabolism and clearance,and PXR is highly expressed in tumor tissues of TNBC patients,which is related to the prognosis of breast cancer patients.This reviews synthesized the important role of PXR in the process of high drug resistance to TNBC chemotherapeutic drugs and related research progress.展开更多
AIM To ascertain whether cholestasis affects the expression of two CYP3 A isoforms(CYP3 A1 and CYP3 A2) and of pregnane X receptor(PXR) and constitutive androstane receptor(CAR).METHODS Cholestasis was induced by bile...AIM To ascertain whether cholestasis affects the expression of two CYP3 A isoforms(CYP3 A1 and CYP3 A2) and of pregnane X receptor(PXR) and constitutive androstane receptor(CAR).METHODS Cholestasis was induced by bile duct ligation in 16 male Wistar rats; whereas 8 sham-operated rats were used as controls. Severity of cholestasis was assessed on histological examination of liver sections, and serum concentrations of albumin, AST, ALT, GGT, ALPK and bilirubin. Gene and protein expressions of PXR, CAR, CYP3 A1 and CYP3 A2 were assessed by means of q RT-PCR and Western blot, respectively. Alterations in CYP3 A activity were measured by calculating the kinetic parameters of 4-OH and 1'-OH-midazolam hydroxylation, marker reactions for CYP3 A enzymes.RESULTS The m RNA and protein expression of CYP3 A1 increased significantly in mild cholestasis(P < 0.01). At variance, m RNA and protein expression of CYP3 A2 didn't change in mild cholestasis, whereas the expression and activity of both CYP3 A1 and CYP3 A2 decreased dramatically when cholestasis became severe. Consistently with these observations, the nuclear expression of both PXR and CAR, which was measured because they both translocate into the cell nucleus after their activation, virtually disappeared in the late stage of cholestatic injury, after an initial increase. These results indicate that early-and late-stage cholestasis affects CYP3 Amediated drug metabolism differently, probably as consequence of the different activation of PXR and CAR.CONCLUSION Early-and late-stage cholestasis affects CYP3 Amediated drug metabolism differently. PXR and CAR might be targeted therapeutically to promote CYP3 Amediated liver detoxification.展开更多
Bacterial translocation(BT) has been impeccably implicated as a driving factor in the pathogenesis of a spectrum of chronic liver diseases(CLD). Scientific evidence accumulated over the last four decades has implied t...Bacterial translocation(BT) has been impeccably implicated as a driving factor in the pathogenesis of a spectrum of chronic liver diseases(CLD). Scientific evidence accumulated over the last four decades has implied that the disease pathologies in CLD and BT are connected as a loop in the gut-liver axis and exacerbate each other. Pregnane X receptor(PXR) is a ligandactivated transcription factor and nuclear receptor that is expressed ubiquitously along the gut-liver-axis. PXR has been intricately associated with the regulation of various mechanisms attributed in causing BT. The importance of PXR as the mechanistic linker molecule in the gutliver axis and its role in regulating bacterial interactions with the host in CLD has not been explored. Pub Med was used to perform an extensive literature search using the keywords PXR and bacterial translocation, PXR and chronic liver disease including cirrhosis. In an adequate expression state, PXR acts as a sensor for bile acid dysregulation and bacterial derived metabolites, and in response shapes the immune profile beneficial to the host. Activation of PXR could be therapeutic in CLD as it counter-regulates endotoxin mediated inflammation and maintains the integrity of intestinal epithelium. This review mainly focuses PXR function and its regulation in BT in the context of chronic liver diseases.展开更多
The whole plants of Ypsilandra thibetica have been analyzed as part of a systematic study on saponin constituents of medicinal plants.This has resulted in the isolation of two new bisdesmosidic furostanol saponins,nam...The whole plants of Ypsilandra thibetica have been analyzed as part of a systematic study on saponin constituents of medicinal plants.This has resulted in the isolation of two new bisdesmosidic furostanol saponins,named ypsilandroside P(1)and ypsilandroside Q(2),and one new pregnane glycoside,named ypsilandroside R(3),together with nine known steroidal glycosides.Their structures were elucidated on the basis of extensive spectroscopic analysis,including that of 2D NMR data,and the results of acidic hydrolysis.Ypsilandroside P(1)was cytotoxicity against two human tumor cell lines.展开更多
A novel pregnane glycoside, biondianoside E, was isolated from the roots of Biondia chinensis. By the spectroscopic and chemical methods, this structure was elucidated as 3B, 5B, 14B, 205, 21-pentahydroxypregnane 3-O-...A novel pregnane glycoside, biondianoside E, was isolated from the roots of Biondia chinensis. By the spectroscopic and chemical methods, this structure was elucidated as 3B, 5B, 14B, 205, 21-pentahydroxypregnane 3-O-B-D-glucopyranosyl-(1-4)-B-D-cymaropyranoside .展开更多
A new minor pregnane glycoside was isolated from the fermented leaves of Agave americana. Its structure was elucidated as (20S)-5a-pregnane-3? 20-diol 20-O--D-glucopyrano- side (1) by spectral methods.
Human pregnane X receptor (PXR) is of vital importance in pharmaceutical and exogenous compound metabolism within the body. This provides strong motivation for investigating this orphan receptor’s activation by vario...Human pregnane X receptor (PXR) is of vital importance in pharmaceutical and exogenous compound metabolism within the body. This provides strong motivation for investigating this orphan receptor’s activation by various pharmaceuticals, xenobiotics, and endocrine disrupting chemicals (EDCs). A nanomechanical transducer is developed to study xenobiotic and EDC interactions with the bioreceptor PXR’s ligand binding domain (LBD). The combination of immobilized LBD PXR with a nanostructured microcantilever (MC) platform allows for the sensitive, label-free study of ligand interaction with the receptor. PXR shows real-time, reversible responses when exposed to a specific pharmaceutical, EDCs, and xenobiotic ligands. Three EDCs binding interactions are tested, which include phthalic acid, nonylphenol, and bisphenol A, with PXR. PXR LBD was exposed to rifampicin, a potent PXR activator, with various injection and recovery times to study their interaction. A two protein array of PXR and estrogen receptor ? (ER-?) directly compares the nanomechanical responses of these receptors with rifampicin on a single platform.展开更多
To search for pharmacologically active constituents of folk medicine, a new pregnane, 2α,3α,15β-trihydroxy-20(S)-tigloyl-pregnane (compound 1), and nine known compounds, geranylgeraniol (compound 2), β-dauco...To search for pharmacologically active constituents of folk medicine, a new pregnane, 2α,3α,15β-trihydroxy-20(S)-tigloyl-pregnane (compound 1), and nine known compounds, geranylgeraniol (compound 2), β-daucosterol (compound 3), 6-hydroxystigmast-4oen-3-one (compound 4), sitoindoside Ⅰ (compound 5), sitoindoside Ⅱ (compound 6), β-sitosterol (compound 7), kaempferol (compound 8), quercetin (compound 9), and rutin (compound 10), were isolated from the ethanol extract of whole plants of Munronia delavayi Franch using chromatographic methods. The structures of compounds 1-10 were elucidated on the basis of spectral data.展开更多
Objective To study the chemical constituents from the stems of Marsdenia tenacissima.Methods The chemical constituents were isolated by various column chromatography and their structures were identified by spectral an...Objective To study the chemical constituents from the stems of Marsdenia tenacissima.Methods The chemical constituents were isolated by various column chromatography and their structures were identified by spectral and chemical analysis.Results Two pregnane glycosides were isolated from the stems of M.tenacissima and identified as 3-O-β-D-glucopyranosyl-(1→4)-6-deoxy-3-O-methyl-β-D-allopyranosyl-(1→4)-β-D-oleandropyranosyl-11α-O- tigloyltenacigenin B,named as tenacigenoside I(1)and 3-O-β-D-glucopyranosyl-(1→4)-6-deoxy-3-O-methyl-β-D- allopyranosyl-(1→4)-β-D-oleandropyranosyl-11α,12β-di-O-acetyltenacigenin B,named as tenacigenoside K(2).Conclusion Compound 1 is a new compound,1H-NMR and 13C-NMR data of compound 2 are reported for the first time.展开更多
During the last decade, much progress has been made in exploring the mechanisms of alterations elicited by foreign compounds in xeno- and endobiotic metabolism regulated by the human nuclear pregnane X receptor (PXR...During the last decade, much progress has been made in exploring the mechanisms of alterations elicited by foreign compounds in xeno- and endobiotic metabolism regulated by the human nuclear pregnane X receptor (PXR). PXR, identified as a human nuclear receptor in 1998 and generally regarded as a sensor activated by exogenous and endogenous chemicals, regulates a large number of enzymes and transporters involved in the response of mammals to their chemical environment.展开更多
Background and aims:The herbal supplement Gancao,also known as licorice,belongs to the genus Glycyrrhiza and has been used worldwide for its hepatoprotective effect.Recent studies have raised concerns about potential ...Background and aims:The herbal supplement Gancao,also known as licorice,belongs to the genus Glycyrrhiza and has been used worldwide for its hepatoprotective effect.Recent studies have raised concerns about potential herb-drug interactions associated with Gancao via pregnane X receptor(PXR)-mediated induction of hepatic cytochrome P4503A4(CYP3A4).The current work aimed to determine the phytochemicals in Gancao that activate PXR and induce CYP3A4.Methods:DPX2 cells were used for cell-based PXR reporter assays.The phytochemicals in Gancao extract were identified using a metabolomics approach.The effects of PXR activators identified from in vitro studies were further investigated in PXR-and CYP3A4-humanized mouse models.Results:Gancao was verified to be a PXR-activating herb.Two major phytochemicals in Gancao,gly-cyrrhizin(GZ)and glycyrrhetinic acid(GA),did not activate PXR in the cell-based reporter assays.However,glabridin was shown to activate PXR in a dose-dependent manner.In vivo studies confirmed that GZ is not a PXR activator and glabridin is a weak PXR activator.Although GA did not active PXR in vitro,it induced CYP3A4 expression in a PXR-dependent manner in the PXR-and CYP3A4-humanized mice.展开更多
The pregnane X receptor(PXR)is a ligand activated nuclear receptor that is highly expressed in the liver and regulates many cellular functions including drug metabolism,endobiotic metabolism,oxidative stress response,...The pregnane X receptor(PXR)is a ligand activated nuclear receptor that is highly expressed in the liver and regulates many cellular functions including drug metabolism,endobiotic metabolism,oxidative stress response,apoptosis,inflammation,cell proliferation and regeneration.PXR activation promotes drug-induced liver injury(DILI)through its ability to increase the expression of phaseⅠand phaseⅡdrug metabolizing enzymes.The PXR also increases lipid synthesis and fatty acid uptake into the liver,leading to lipid accumulation and steatosis.In recent years,PXR has been explored as an important target in DILI and liver diseases.This review will highlight the roles of PXR in modulating DILI.PXR polymorphisms that have been associated with DILI will also be discussed.展开更多
Pregnane X receptor(PXR)is the major regulator of xenobiotic metabolism.PXR itself is controlled by various signaling molecules including glucocorticoids.Moreover,negative feed-back regulation has been proposed at the...Pregnane X receptor(PXR)is the major regulator of xenobiotic metabolism.PXR itself is controlled by various signaling molecules including glucocorticoids.Moreover,negative feed-back regulation has been proposed at the transcriptional level.We examined the involvement of the 3’-untranslated region(3’-UTR)of NR1I2 mRNA and microRNAs in PXR-and glucocorticoid receptor(GR)-mediated regulation of NR1I2 gene expression.PXR ligands were found to significantly downregulate NR1I2 mRNA expression in a set of 14 human hepatocyte cultures.Similarly,PXR was downregulated by PCN in the C57/BL6 mice liver.In mechanistic studies with the full-length 3’-UTR cloned into luciferase reporter or expression vectors,we showed that the 3’-UTR reduces PXR expression.From the miRNAs tested,miR-18a-5p inhibited both NR 112 expression and CYP3A4 gene induction.Importantly,we observed significant upregulation of miR-18a-5p expression 6 h after treatment with the PXR ligand rifampicin,which indicates a putative mechanism underlying NR1I2 negative feed-back regulation in hepatic cells.Additionally,glucocorticoids upregulated NR1I2 expression not only through the promoter region but also via 3’-UTR regulation,which likely involves downregulation of miR-18a-5p.We conclude that miR-18a-5p is involved in the down-regulation of NR1I2expression by its ligands and in the upregulation of NR1I2 mRNA expression by glucocorticoids in hepatic cells.展开更多
Background and Aims:Hepatitis B virus(HBV)infection has been found to increase hepatocellular sensitivity to carcinogenic xenobiotics,by unknown mechanisms,in the generation of hepatocellular carcinoma.The pregnane X ...Background and Aims:Hepatitis B virus(HBV)infection has been found to increase hepatocellular sensitivity to carcinogenic xenobiotics,by unknown mechanisms,in the generation of hepatocellular carcinoma.The pregnane X receptor(PXR)is a key regulator of the body’s defense against xenobiotics,including xenobiotic carcinogens and clinical drugs.In this study,we aimed to investigate the molecular mechanisms of HBV X protein(HBx)-PXR signaling in the synergistic effects of chemical carcinogens in HBV-associated hepatocarcinogenesis.Methods:The expression profile of PXR-cytochrome p4503A4(CYP3A4)signaling was determined by PCR,western blotting,and tissue microarray.Cell viability and aflatoxin B1(AFB1)cytotoxicity were measured using the cell counting kit-8 assay.Target gene expression was evaluated using transient transfection and real time-PCR.The genotoxicity of AFB1 was assessed in newborn mice with a single dose of AFB1.Results:HBx enhanced the hepatotoxicity of AFB1 by activating CYP3A4 and reducing glutathione Stransferase Mu 1(GSTM1)in cell lines.Activation of PXR by pregnenolone 16α-carbonitrile increased AFB1-induced liver tumor incidence by up-regulating oncogenic KRAS to enhance interleukin(IL)-11:IL-11 receptor subunit alpha-1(IL11RA-1)-mediated inflammation in an HBx transgenic model.Conclusions:Our finding regarding AFB1 toxicity enhancement by an HBx-PXR-CYP3A4/GSTM1-KRASIL11:IL11RA signaling axis provides a rational explanation for the synergistic effects of chemical carcinogens in HBV infection-associated hepatocarcinogenesis.展开更多
The central nervous system is susceptible to the modulation of various neurophysiological processes by the cytochrome P450 enzyme(CYP),which plays a crucial role in the metabolism of neurosteroids.The antiepileptic dr...The central nervous system is susceptible to the modulation of various neurophysiological processes by the cytochrome P450 enzyme(CYP),which plays a crucial role in the metabolism of neurosteroids.The antiepileptic drug phenytoin(PHT)has been observed to induce neuronal side effects in patients,which could be attributed to its induction of CYP expression and testosterone(TES)metabolism in the hippocampus.While pregnane X receptor(PXR)is widely known for its regulatory function of CYPs in the liver,we have discovered that the treatment of mice with pregnenolone 16α-carbonitrile(PCN),a PXR agonist,has differential effects on CYP expression in the liver and hippocampus.Specifically,the PCN treatment resulted in the induction of cytochrome P450,family 3,subfamily a,polypeptide 11(CYP3A11),and CYP2B10 expression in the liver,while suppressing their expression in the hippocampus.Functionally,the PCN treatment protected mice from PHT-induced hippocampal nerve injury,which was accompanied by the inhibition of TES metabolism in the hippocampus.Mechanistically,we found that the inhibition of hippocampal CYP expression and attenuation of PHT-induced neurotoxicity by PCN were glucocorticoid receptor dependent,rather than PXR independent,as demonstrated by genetic and pharmacological models.In conclusion,our study provides evidence that PCN can negatively regulate hippocampal CYP expression and attenuate PHT-induced hippocampal neurotoxicity independently of PXR.Our findings suggest that glucocorticoids may be a potential therapeutic strategy for managing the neuronal side effects of PHT.展开更多
cis-Diamminedichloroplatinum(CDDP)is widely used for the treatment of various solid cancers.Here we reported that CDDP increased the expression and enzymatic activities of carboxylesterase 1(CES1)and carboxylesterase ...cis-Diamminedichloroplatinum(CDDP)is widely used for the treatment of various solid cancers.Here we reported that CDDP increased the expression and enzymatic activities of carboxylesterase 1(CES1)and carboxylesterase 2(CES2),along with the upregulation of pregnane X receptor(PXR)and the downregulation of differentiated embryonic chondrocyte-expressed gene 1(DEC1)in human hepatoma cells,primary mouse hepatocytes,mouse liver and intestine.The overexpression or knockdown of PXR alone upregulated or downregulated the CES1 and CES2 expression,respectively.The increases in CES1 and CES2 expression levels induced by CDDP abolished or enhanced by PXR knockdown or overexpression,implying that CDDP induces carboxylesterases through the activation of PXR.Likewise,the overexpression or knockdown of DEC1 alone significantly decreased or increased PXR and its targets.Moreover,the increases of PXR and its targets induced by CDDP were abolished or alleviated by the overexpression or knockdown of DEC1.The overexpression or knockdown of DEC1 affected the response of PXR to CDDP,but not vice versa,suggesting that CDDP increases carboxylesterases by upregulating PXR mediated by the decrease of DEC1.In addition,CDDP did not increase DEC1 mRNA degradation but suppressed DEC1 promoter reporter activity,indicating that it suppresses DEC1 transcriptionally.The combined use of CDDP and irinotecan had a synergistic effect on two cell lines,especially when CDDP was used first.展开更多
The intestinal uptake of paclitaxel is hampered by trans-membrane efflux transporters such as P-glycoprotein(P-gp),and paclitaxel is mainly metabolized by cytochrome P4503A4(CYP3A4)presented in the liver.Our previous ...The intestinal uptake of paclitaxel is hampered by trans-membrane efflux transporters such as P-glycoprotein(P-gp),and paclitaxel is mainly metabolized by cytochrome P4503A4(CYP3A4)presented in the liver.Our previous results demonstrated that flavonoids extracted from Taxus yunnanensis could improve the oral absorption of paclitaxel.The current study was purposed to investigate the effects of the flavonoid extracts on P-gp and CYP3A4 in vitro.The expression and activity of P-gp were detected by western blotting and intracellular rhodamine 123 accumulation assay in Caco-2 cells treated with the flavonoids extract.The expression of CYP3A4 was investigated by western blotting in mouse primary hepatocytes and the activity of CYP3A4 was detected by LC-MS/MS method using rat liver microsomes.Our results showed that the flavonoid extracts from T.yunnanensis could inhibit P-gp activity and concurrently decrease the expression and activity of CYP3A4.In conclusion,activity of P-gp and CYP3A4 could be inhibited by flavonoids extracted from T.yunnanensis which might be potential candidates for development of oral formulation of paclitaxel.展开更多
A pregnane glycoside and a lignan glycoside were isolated from the aerial parts of Rubus amabilis. Their structures were elucidated as 3-O-beta-D-glucopyranosyl-3 beta.15 alpha-dihydroxypregn-5-en-20-one and (-)-secoi...A pregnane glycoside and a lignan glycoside were isolated from the aerial parts of Rubus amabilis. Their structures were elucidated as 3-O-beta-D-glucopyranosyl-3 beta.15 alpha-dihydroxypregn-5-en-20-one and (-)-secoisolariciresinol-O-alpha-L-rhamnopyranoside using spectroscopic and chemical methods.展开更多
AIM To investigate the effect of resveratrol on biliary secretion of cholephilic compounds in healthy and bile duct-obstructed rats. METHODS Resveratrol(RSV) or saline were administered to rats by daily oral gavage fo...AIM To investigate the effect of resveratrol on biliary secretion of cholephilic compounds in healthy and bile duct-obstructed rats. METHODS Resveratrol(RSV) or saline were administered to rats by daily oral gavage for 28 d after sham operation or reversible bile duct obstruction(BDO). Bile was collected 24 h after the last gavage during an intravenous bolus dose of the Mdr1/Mrp2 substrate azithromycin. Bile acids,glutathione and azithromycin were measured in bile to quantify their level of biliary secretion. Liver expression of enzymes and transporters relevant for bile production and biliary secretion of major bile constituents and drugs were analyzed at the m RNA and protein levels using q RT-PCR and Western blot analysis,respectively. The TR-FRET PXR Competitive Binding Assay kit was used to determine the agonism of RSV at the pregnane X receptor. RESULTS RSV increased bile flow in sham-operated rats due to increased biliary secretion of bile acids(BA) and glutathione. This effect was accompanied by the induction of the hepatic rate-limiting transporters for bile acids and glutathione,Bsep and Mrp2,respectively. RSV also induced Cyp7 a1,an enzyme that is crucial for bile acid synthesis; Mrp4,a transporter important for BA secretion from hepatocytes to blood; and Mdr1,the major apical transporter for xenobiotics. The findings were supported by increased biliary secretion of azithromycin. The TR-FRET PXR competitive binding assay confirmed RSV as a weak agonist of the human nuclear receptor PXR,which is a transcriptional regulator of Mdr1/Mrp2. RSV demonstrated significant hepatoprotective properties against BDO-induced cirrhosis. RSV also reduced bile flow in BDO rats without any corresponding change in the levels of the transporters and enzymes involved in RSV-mediated hepatoprotection. CONCLUSION Resveratrol administration for 28 d has a distinct effect on bile flow and biliary secretion of cholephilic compounds in healthy and bile duct-obstructed rats.展开更多
基金Supported by Science project of Hunan Provincial Health Commission,No.B202304089304.
文摘Breast cancer is the most common malignancy in women worldwide.Triplenegative breast cancer(TNBC),refers breast cancer negative for estrogen receptor,progesterone receptor and human epidermal growth factor receptor 2,characterized by high drug resistance,high metastasis and high recurrence,treatment of which is a difficult problem in the clinical treatment of breast cancer.In order to better treat TNBC clinically,it is a very urgent task to explore the mechanism of TNBC resistance in basic breast cancer research.Pregnane X receptor(PXR)is a nuclear receptor whose main biological function is to participate in the metabolism,transport and clearance of allobiological agents in PXR.PXR plays an important role in drug metabolism and clearance,and PXR is highly expressed in tumor tissues of TNBC patients,which is related to the prognosis of breast cancer patients.This reviews synthesized the important role of PXR in the process of high drug resistance to TNBC chemotherapeutic drugs and related research progress.
基金Supported by the University of Padova,No.CPDA138721/13
文摘AIM To ascertain whether cholestasis affects the expression of two CYP3 A isoforms(CYP3 A1 and CYP3 A2) and of pregnane X receptor(PXR) and constitutive androstane receptor(CAR).METHODS Cholestasis was induced by bile duct ligation in 16 male Wistar rats; whereas 8 sham-operated rats were used as controls. Severity of cholestasis was assessed on histological examination of liver sections, and serum concentrations of albumin, AST, ALT, GGT, ALPK and bilirubin. Gene and protein expressions of PXR, CAR, CYP3 A1 and CYP3 A2 were assessed by means of q RT-PCR and Western blot, respectively. Alterations in CYP3 A activity were measured by calculating the kinetic parameters of 4-OH and 1'-OH-midazolam hydroxylation, marker reactions for CYP3 A enzymes.RESULTS The m RNA and protein expression of CYP3 A1 increased significantly in mild cholestasis(P < 0.01). At variance, m RNA and protein expression of CYP3 A2 didn't change in mild cholestasis, whereas the expression and activity of both CYP3 A1 and CYP3 A2 decreased dramatically when cholestasis became severe. Consistently with these observations, the nuclear expression of both PXR and CAR, which was measured because they both translocate into the cell nucleus after their activation, virtually disappeared in the late stage of cholestatic injury, after an initial increase. These results indicate that early-and late-stage cholestasis affects CYP3 Amediated drug metabolism differently, probably as consequence of the different activation of PXR and CAR.CONCLUSION Early-and late-stage cholestasis affects CYP3 Amediated drug metabolism differently. PXR and CAR might be targeted therapeutically to promote CYP3 Amediated liver detoxification.
文摘Bacterial translocation(BT) has been impeccably implicated as a driving factor in the pathogenesis of a spectrum of chronic liver diseases(CLD). Scientific evidence accumulated over the last four decades has implied that the disease pathologies in CLD and BT are connected as a loop in the gut-liver axis and exacerbate each other. Pregnane X receptor(PXR) is a ligandactivated transcription factor and nuclear receptor that is expressed ubiquitously along the gut-liver-axis. PXR has been intricately associated with the regulation of various mechanisms attributed in causing BT. The importance of PXR as the mechanistic linker molecule in the gutliver axis and its role in regulating bacterial interactions with the host in CLD has not been explored. Pub Med was used to perform an extensive literature search using the keywords PXR and bacterial translocation, PXR and chronic liver disease including cirrhosis. In an adequate expression state, PXR acts as a sensor for bile acid dysregulation and bacterial derived metabolites, and in response shapes the immune profile beneficial to the host. Activation of PXR could be therapeutic in CLD as it counter-regulates endotoxin mediated inflammation and maintains the integrity of intestinal epithelium. This review mainly focuses PXR function and its regulation in BT in the context of chronic liver diseases.
基金supported by National Natural Science Funding of China(No.31170333)the Natural Sci-ence Foundation of Yunnan Province(No.2009CC019)+1 种基金the West Light Foundation of the Chinese Academy of Sciences(No.2908025712W1)a fund(No.540806321211)of State Key Laboratory of Phytochemistry and Plant Resources in West China,Germplasm Bank of Wild Species and CAS Innovation Program of Kunming Institute of Botany.
文摘The whole plants of Ypsilandra thibetica have been analyzed as part of a systematic study on saponin constituents of medicinal plants.This has resulted in the isolation of two new bisdesmosidic furostanol saponins,named ypsilandroside P(1)and ypsilandroside Q(2),and one new pregnane glycoside,named ypsilandroside R(3),together with nine known steroidal glycosides.Their structures were elucidated on the basis of extensive spectroscopic analysis,including that of 2D NMR data,and the results of acidic hydrolysis.Ypsilandroside P(1)was cytotoxicity against two human tumor cell lines.
文摘A novel pregnane glycoside, biondianoside E, was isolated from the roots of Biondia chinensis. By the spectroscopic and chemical methods, this structure was elucidated as 3B, 5B, 14B, 205, 21-pentahydroxypregnane 3-O-B-D-glucopyranosyl-(1-4)-B-D-cymaropyranoside .
基金supported by the National Natulal Science Foundation of China(NSFC)(39969005).
文摘A new minor pregnane glycoside was isolated from the fermented leaves of Agave americana. Its structure was elucidated as (20S)-5a-pregnane-3? 20-diol 20-O--D-glucopyrano- side (1) by spectral methods.
文摘Human pregnane X receptor (PXR) is of vital importance in pharmaceutical and exogenous compound metabolism within the body. This provides strong motivation for investigating this orphan receptor’s activation by various pharmaceuticals, xenobiotics, and endocrine disrupting chemicals (EDCs). A nanomechanical transducer is developed to study xenobiotic and EDC interactions with the bioreceptor PXR’s ligand binding domain (LBD). The combination of immobilized LBD PXR with a nanostructured microcantilever (MC) platform allows for the sensitive, label-free study of ligand interaction with the receptor. PXR shows real-time, reversible responses when exposed to a specific pharmaceutical, EDCs, and xenobiotic ligands. Three EDCs binding interactions are tested, which include phthalic acid, nonylphenol, and bisphenol A, with PXR. PXR LBD was exposed to rifampicin, a potent PXR activator, with various injection and recovery times to study their interaction. A two protein array of PXR and estrogen receptor ? (ER-?) directly compares the nanomechanical responses of these receptors with rifampicin on a single platform.
文摘To search for pharmacologically active constituents of folk medicine, a new pregnane, 2α,3α,15β-trihydroxy-20(S)-tigloyl-pregnane (compound 1), and nine known compounds, geranylgeraniol (compound 2), β-daucosterol (compound 3), 6-hydroxystigmast-4oen-3-one (compound 4), sitoindoside Ⅰ (compound 5), sitoindoside Ⅱ (compound 6), β-sitosterol (compound 7), kaempferol (compound 8), quercetin (compound 9), and rutin (compound 10), were isolated from the ethanol extract of whole plants of Munronia delavayi Franch using chromatographic methods. The structures of compounds 1-10 were elucidated on the basis of spectral data.
基金Foundation of Doctors of Southwest University for Nationalities(26701001)
文摘Objective To study the chemical constituents from the stems of Marsdenia tenacissima.Methods The chemical constituents were isolated by various column chromatography and their structures were identified by spectral and chemical analysis.Results Two pregnane glycosides were isolated from the stems of M.tenacissima and identified as 3-O-β-D-glucopyranosyl-(1→4)-6-deoxy-3-O-methyl-β-D-allopyranosyl-(1→4)-β-D-oleandropyranosyl-11α-O- tigloyltenacigenin B,named as tenacigenoside I(1)and 3-O-β-D-glucopyranosyl-(1→4)-6-deoxy-3-O-methyl-β-D- allopyranosyl-(1→4)-β-D-oleandropyranosyl-11α,12β-di-O-acetyltenacigenin B,named as tenacigenoside K(2).Conclusion Compound 1 is a new compound,1H-NMR and 13C-NMR data of compound 2 are reported for the first time.
基金This study was supported by a grant from the National Natural Science Foundation of China (No. 30771778).
文摘During the last decade, much progress has been made in exploring the mechanisms of alterations elicited by foreign compounds in xeno- and endobiotic metabolism regulated by the human nuclear pregnane X receptor (PXR). PXR, identified as a human nuclear receptor in 1998 and generally regarded as a sensor activated by exogenous and endogenous chemicals, regulates a large number of enzymes and transporters involved in the response of mammals to their chemical environment.
基金This work was supported by the USA National Center for Com-plementary and Integrative Health Grant R21AT011088(to X.Ma)in part by Grant U54AT008909(to M.F.Paine)+1 种基金in part by the USA National Institute of Allergy and Infectious Diseases Grant R01AI131983(to X.Ma)National Institute of Diabetes and Digestive and Kidney Diseases Grant R01DK126875(to X.Ma).
文摘Background and aims:The herbal supplement Gancao,also known as licorice,belongs to the genus Glycyrrhiza and has been used worldwide for its hepatoprotective effect.Recent studies have raised concerns about potential herb-drug interactions associated with Gancao via pregnane X receptor(PXR)-mediated induction of hepatic cytochrome P4503A4(CYP3A4).The current work aimed to determine the phytochemicals in Gancao that activate PXR and induce CYP3A4.Methods:DPX2 cells were used for cell-based PXR reporter assays.The phytochemicals in Gancao extract were identified using a metabolomics approach.The effects of PXR activators identified from in vitro studies were further investigated in PXR-and CYP3A4-humanized mouse models.Results:Gancao was verified to be a PXR-activating herb.Two major phytochemicals in Gancao,gly-cyrrhizin(GZ)and glycyrrhetinic acid(GA),did not activate PXR in the cell-based reporter assays.However,glabridin was shown to activate PXR in a dose-dependent manner.In vivo studies confirmed that GZ is not a PXR activator and glabridin is a weak PXR activator.Although GA did not active PXR in vitro,it induced CYP3A4 expression in a PXR-dependent manner in the PXR-and CYP3A4-humanized mice.
基金This work was supported by the US National Institute of Allergy and Infectious Diseases(R01AI131983)in part by the National Institute of Diabetes and Digestive and Kidney Diseases(DK090305).
文摘The pregnane X receptor(PXR)is a ligand activated nuclear receptor that is highly expressed in the liver and regulates many cellular functions including drug metabolism,endobiotic metabolism,oxidative stress response,apoptosis,inflammation,cell proliferation and regeneration.PXR activation promotes drug-induced liver injury(DILI)through its ability to increase the expression of phaseⅠand phaseⅡdrug metabolizing enzymes.The PXR also increases lipid synthesis and fatty acid uptake into the liver,leading to lipid accumulation and steatosis.In recent years,PXR has been explored as an important target in DILI and liver diseases.This review will highlight the roles of PXR in modulating DILI.PXR polymorphisms that have been associated with DILI will also be discussed.
基金supported by grants from the Czech Science Foundation 17-06841S to Petr PavekEFSA-CDN(No.CZ.02.1.01/0.0/0.0/16_019/0000841,Czech Republic)co-funded by ERDF to Tomas Smutny.
文摘Pregnane X receptor(PXR)is the major regulator of xenobiotic metabolism.PXR itself is controlled by various signaling molecules including glucocorticoids.Moreover,negative feed-back regulation has been proposed at the transcriptional level.We examined the involvement of the 3’-untranslated region(3’-UTR)of NR1I2 mRNA and microRNAs in PXR-and glucocorticoid receptor(GR)-mediated regulation of NR1I2 gene expression.PXR ligands were found to significantly downregulate NR1I2 mRNA expression in a set of 14 human hepatocyte cultures.Similarly,PXR was downregulated by PCN in the C57/BL6 mice liver.In mechanistic studies with the full-length 3’-UTR cloned into luciferase reporter or expression vectors,we showed that the 3’-UTR reduces PXR expression.From the miRNAs tested,miR-18a-5p inhibited both NR 112 expression and CYP3A4 gene induction.Importantly,we observed significant upregulation of miR-18a-5p expression 6 h after treatment with the PXR ligand rifampicin,which indicates a putative mechanism underlying NR1I2 negative feed-back regulation in hepatic cells.Additionally,glucocorticoids upregulated NR1I2 expression not only through the promoter region but also via 3’-UTR regulation,which likely involves downregulation of miR-18a-5p.We conclude that miR-18a-5p is involved in the down-regulation of NR1I2expression by its ligands and in the upregulation of NR1I2 mRNA expression by glucocorticoids in hepatic cells.
基金This study was funded by the National Natural Science Foun-dation of China(Grant Nos.81772972,81672731,81572703,81572451)Natural Science Foundation of Guangdong Prov-ince(Grant Nos.2021A1515010776,2015A030313449)+1 种基金Science and Technology Planning Project of Guangdong Province“Public Research and Capacity Building”Special Project Fund(Grant No.2014A020212285)Department of Education,Guangdong Government under the Toptier University Development Scheme for Research and Control of Infectious Diseases(Grant Nos.2016026,2015060,2015089).
文摘Background and Aims:Hepatitis B virus(HBV)infection has been found to increase hepatocellular sensitivity to carcinogenic xenobiotics,by unknown mechanisms,in the generation of hepatocellular carcinoma.The pregnane X receptor(PXR)is a key regulator of the body’s defense against xenobiotics,including xenobiotic carcinogens and clinical drugs.In this study,we aimed to investigate the molecular mechanisms of HBV X protein(HBx)-PXR signaling in the synergistic effects of chemical carcinogens in HBV-associated hepatocarcinogenesis.Methods:The expression profile of PXR-cytochrome p4503A4(CYP3A4)signaling was determined by PCR,western blotting,and tissue microarray.Cell viability and aflatoxin B1(AFB1)cytotoxicity were measured using the cell counting kit-8 assay.Target gene expression was evaluated using transient transfection and real time-PCR.The genotoxicity of AFB1 was assessed in newborn mice with a single dose of AFB1.Results:HBx enhanced the hepatotoxicity of AFB1 by activating CYP3A4 and reducing glutathione Stransferase Mu 1(GSTM1)in cell lines.Activation of PXR by pregnenolone 16α-carbonitrile increased AFB1-induced liver tumor incidence by up-regulating oncogenic KRAS to enhance interleukin(IL)-11:IL-11 receptor subunit alpha-1(IL11RA-1)-mediated inflammation in an HBx transgenic model.Conclusions:Our finding regarding AFB1 toxicity enhancement by an HBx-PXR-CYP3A4/GSTM1-KRASIL11:IL11RA signaling axis provides a rational explanation for the synergistic effects of chemical carcinogens in HBV infection-associated hepatocarcinogenesis.
基金supported in part by grants from the National Natural Science Foundation of China(Grant Nos.:81973405,82122071,and 82030111)to Dan XuHui Wang,the National Key R&D Program of China(Grant No.:2020YFA0803900)to Hui Wangthe Hubei Provincial Natural Science Foundation Outstanding Youth Found,China(Grant No.:2022CFA083).
文摘The central nervous system is susceptible to the modulation of various neurophysiological processes by the cytochrome P450 enzyme(CYP),which plays a crucial role in the metabolism of neurosteroids.The antiepileptic drug phenytoin(PHT)has been observed to induce neuronal side effects in patients,which could be attributed to its induction of CYP expression and testosterone(TES)metabolism in the hippocampus.While pregnane X receptor(PXR)is widely known for its regulatory function of CYPs in the liver,we have discovered that the treatment of mice with pregnenolone 16α-carbonitrile(PCN),a PXR agonist,has differential effects on CYP expression in the liver and hippocampus.Specifically,the PCN treatment resulted in the induction of cytochrome P450,family 3,subfamily a,polypeptide 11(CYP3A11),and CYP2B10 expression in the liver,while suppressing their expression in the hippocampus.Functionally,the PCN treatment protected mice from PHT-induced hippocampal nerve injury,which was accompanied by the inhibition of TES metabolism in the hippocampus.Mechanistically,we found that the inhibition of hippocampal CYP expression and attenuation of PHT-induced neurotoxicity by PCN were glucocorticoid receptor dependent,rather than PXR independent,as demonstrated by genetic and pharmacological models.In conclusion,our study provides evidence that PCN can negatively regulate hippocampal CYP expression and attenuate PHT-induced hippocampal neurotoxicity independently of PXR.Our findings suggest that glucocorticoids may be a potential therapeutic strategy for managing the neuronal side effects of PHT.
基金The work was supported by the National Natural Science Foundation of China(Grant Nos.82073934 and 81872937)to J.Y.
文摘cis-Diamminedichloroplatinum(CDDP)is widely used for the treatment of various solid cancers.Here we reported that CDDP increased the expression and enzymatic activities of carboxylesterase 1(CES1)and carboxylesterase 2(CES2),along with the upregulation of pregnane X receptor(PXR)and the downregulation of differentiated embryonic chondrocyte-expressed gene 1(DEC1)in human hepatoma cells,primary mouse hepatocytes,mouse liver and intestine.The overexpression or knockdown of PXR alone upregulated or downregulated the CES1 and CES2 expression,respectively.The increases in CES1 and CES2 expression levels induced by CDDP abolished or enhanced by PXR knockdown or overexpression,implying that CDDP induces carboxylesterases through the activation of PXR.Likewise,the overexpression or knockdown of DEC1 alone significantly decreased or increased PXR and its targets.Moreover,the increases of PXR and its targets induced by CDDP were abolished or alleviated by the overexpression or knockdown of DEC1.The overexpression or knockdown of DEC1 affected the response of PXR to CDDP,but not vice versa,suggesting that CDDP increases carboxylesterases by upregulating PXR mediated by the decrease of DEC1.In addition,CDDP did not increase DEC1 mRNA degradation but suppressed DEC1 promoter reporter activity,indicating that it suppresses DEC1 transcriptionally.The combined use of CDDP and irinotecan had a synergistic effect on two cell lines,especially when CDDP was used first.
基金The work was supported by Foundation from Guangdong Province Science and Technology Department(Grant number:2012A080202013 and 2009A030100002)National Natural Science Foundations of China(Grant number:81202961)the National Major Projects for science and technology development from Science and Technology Ministry of China(Grant No.2012ZX09506001-004).
文摘The intestinal uptake of paclitaxel is hampered by trans-membrane efflux transporters such as P-glycoprotein(P-gp),and paclitaxel is mainly metabolized by cytochrome P4503A4(CYP3A4)presented in the liver.Our previous results demonstrated that flavonoids extracted from Taxus yunnanensis could improve the oral absorption of paclitaxel.The current study was purposed to investigate the effects of the flavonoid extracts on P-gp and CYP3A4 in vitro.The expression and activity of P-gp were detected by western blotting and intracellular rhodamine 123 accumulation assay in Caco-2 cells treated with the flavonoids extract.The expression of CYP3A4 was investigated by western blotting in mouse primary hepatocytes and the activity of CYP3A4 was detected by LC-MS/MS method using rat liver microsomes.Our results showed that the flavonoid extracts from T.yunnanensis could inhibit P-gp activity and concurrently decrease the expression and activity of CYP3A4.In conclusion,activity of P-gp and CYP3A4 could be inhibited by flavonoids extracted from T.yunnanensis which might be potential candidates for development of oral formulation of paclitaxel.
基金the National Natural Science Foundation of China NO.29972017, the Foundation of Ministry of Education of China for Doctoral Prog
文摘A pregnane glycoside and a lignan glycoside were isolated from the aerial parts of Rubus amabilis. Their structures were elucidated as 3-O-beta-D-glucopyranosyl-3 beta.15 alpha-dihydroxypregn-5-en-20-one and (-)-secoisolariciresinol-O-alpha-L-rhamnopyranoside using spectroscopic and chemical methods.
基金Supported by Grant Agency of Charles University,No.Progres Q40/05Specific University Research,No.SVV-2016-260287+1 种基金Czech Science Foundation(GA CR)No.303/12/G163
文摘AIM To investigate the effect of resveratrol on biliary secretion of cholephilic compounds in healthy and bile duct-obstructed rats. METHODS Resveratrol(RSV) or saline were administered to rats by daily oral gavage for 28 d after sham operation or reversible bile duct obstruction(BDO). Bile was collected 24 h after the last gavage during an intravenous bolus dose of the Mdr1/Mrp2 substrate azithromycin. Bile acids,glutathione and azithromycin were measured in bile to quantify their level of biliary secretion. Liver expression of enzymes and transporters relevant for bile production and biliary secretion of major bile constituents and drugs were analyzed at the m RNA and protein levels using q RT-PCR and Western blot analysis,respectively. The TR-FRET PXR Competitive Binding Assay kit was used to determine the agonism of RSV at the pregnane X receptor. RESULTS RSV increased bile flow in sham-operated rats due to increased biliary secretion of bile acids(BA) and glutathione. This effect was accompanied by the induction of the hepatic rate-limiting transporters for bile acids and glutathione,Bsep and Mrp2,respectively. RSV also induced Cyp7 a1,an enzyme that is crucial for bile acid synthesis; Mrp4,a transporter important for BA secretion from hepatocytes to blood; and Mdr1,the major apical transporter for xenobiotics. The findings were supported by increased biliary secretion of azithromycin. The TR-FRET PXR competitive binding assay confirmed RSV as a weak agonist of the human nuclear receptor PXR,which is a transcriptional regulator of Mdr1/Mrp2. RSV demonstrated significant hepatoprotective properties against BDO-induced cirrhosis. RSV also reduced bile flow in BDO rats without any corresponding change in the levels of the transporters and enzymes involved in RSV-mediated hepatoprotection. CONCLUSION Resveratrol administration for 28 d has a distinct effect on bile flow and biliary secretion of cholephilic compounds in healthy and bile duct-obstructed rats.