Microbes inhabiting the intestinal tract of humans represent a site for xenobiotic metabolism.The gut microbiome,the collection of microorganisms in the gastrointestinal tract,can alter the metabolic outcome of pharma...Microbes inhabiting the intestinal tract of humans represent a site for xenobiotic metabolism.The gut microbiome,the collection of microorganisms in the gastrointestinal tract,can alter the metabolic outcome of pharmaceuticals,environmental toxicants,and heavy metals,thereby changing their pharmacokinetics.Direct chemical modification of xenobiotics by the gut microbiome,either through the intestinal tract or re-entering the gut via enterohepatic circulation,can lead to increased metabolism or bioactivation,depending on the enzymatic activity within the microbial niche.Unique enzymes encoded within the microbiome include those that reverse the modifications imparted by host detoxification pathways.Additionally,the microbiome can limit xenobiotic absorption in the small intestine by increasing the expression of cell-cell adhesion proteins,supporting the protective mucosal layer,and/or directly sequestering chemicals.Lastly,host gene expression is regulated by the microbiome,including CYP450s,multi-drug resistance proteins,and the transcription factors that regulate them.While the microbiome affects the host and pharmacokinetics of the xenobiotic,xenobiotics can also influence the viability and metabolism of the microbiome.Our understanding of the complex interconnectedness between host,microbiome,and metabolism will advance with new modeling systems,technology development and refinement,and mechanistic studies focused on the contribution of human and microbial metabolism.展开更多
Drug metabolism is an orchestrated process in which drugs are metabolized and disposed through a series of specialized enzymes and transporters.Alterations in the expression and/or activity of these enzymes and transp...Drug metabolism is an orchestrated process in which drugs are metabolized and disposed through a series of specialized enzymes and transporters.Alterations in the expression and/or activity of these enzymes and transporters can affect the bioavailability(pharmacokinetics,or PK)and therapeutic efficacy(pharmacodynamics,or PD)of drugs.Recent studies have suggested that the long non-coding RNAs(IncRNAs)are highly relevant to drug metabolism and drug resistance,including chemoresistance in cancers,through the regulation of drug metabolism and disposition related genes.This review summarizes the regulation of enzymes,transporters,or regulatory proteins involved in drug metabolism by IncRNAs,with a particular emphasis on drug metabolism and chemo-resistance in cancer patients.The perspective strategies to integrate multi-dimensional pharmacogenomics data for future in-depth analysis of drug metabolism related IncRNAs are also proposed.Understanding the role of IncRNAs in drug metabolism will not only facilitate the identification of novel regulatory mechanisms,but also enable the discovery of IncRNA-based biomarkers and drug targets to personalize and improve the therapeutic outcome of patients,including cancer patients.展开更多
The nuclear receptors pregnane X receptor(PXR) and constitutive androstane receptor(CAR) were cloned and/or established as xenobiotic receptors in 1998.Due to their activities in the transcriptional regulation of phas...The nuclear receptors pregnane X receptor(PXR) and constitutive androstane receptor(CAR) were cloned and/or established as xenobiotic receptors in 1998.Due to their activities in the transcriptional regulation of phase I and phase II enzymes as well as drug transporters,PXR and CAR have been defined as the master regulators of xenobiotic responses.The discovery of PXR and CAR provides the essential molecular basis by which drugs and other xenobiotic compounds regulate the expression of xenobiotic enzymes and transporters.This article is intended to provide a historical overview on the discovery of PXR and CAR as xenobiotic receptors.展开更多
Mutations in genes encoding key players in oncogenic signaling pathways trigger specific downstream gene expression profiles in the respective tumor cell populations.While regulation of genes related to cell growth,su...Mutations in genes encoding key players in oncogenic signaling pathways trigger specific downstream gene expression profiles in the respective tumor cell populations.While regulation of genes related to cell growth,survival,and death has been extensively studied,much less is known on the regulation of drug-metabolizing enzymes(DMEs)by oncogenic signaling.Here,a comprehensive review of the available literature is presented summarizing the impact of the most relevant genetic alterations in human and rodent liver tumors on the expression of DMEs with a focus on phasesⅠandⅡof xenobiotic metabolism.Comparably few data are available with respect to DME regulation by p53-dependent signaling,telomerase expression or altered chromatin remodeling.By contrast,DME regulation by constitutive activation of oncogenic signaling via the RAS/RAF/mitogen-activated protein kinase(MAPK)cascade or via the canonical WNT/β-catenin signaling pathway has been analyzed in greater depth,demonstrating mostly positive-regulatory effects of WNT/β-catenin signaling and negativeregulatory effects of MAPK signaling.Mechanistic studies have revealed molecular interactions between oncogenic signaling and nuclear xeno-sensing receptors which underlie the observed alterations in DME expression in liver tumors.Observations of altered DME expression and inducibility in liver tumors with a specific gene expression profile may impact pharmacological treatment options.展开更多
The wastewater discharged from tanneries lack biodegradability due to the presence of recalcitrant compounds at significant concentration. The focal theme of the present investigation was to use chemo-autotrophic acti...The wastewater discharged from tanneries lack biodegradability due to the presence of recalcitrant compounds at significant concentration. The focal theme of the present investigation was to use chemo-autotrophic activated carbon oxidation(CAACO) reactor, an immobilized cell reactor using chemoautotrophs for the treatment of tannery wastewater. The treatment scheme comprised of anaerobic treatment, sand filtration, and CAACO reactor, which remove COD, BOD, TOC, VFA and sulphides respectively by 86%, 95%, 81%, 71% and 100%. Rice bran mesoporous activated carbon prepared indigenously and was used for immobilization of chemoautotrophs. The degradation of xenobiotic compounds by CAACO was confirmed through HPLC and FT-IR techniques.展开更多
Vitamin K(VK), which was originally identified as a cofactor involved in the production of functional coagulation factors in the liver, has been shown to be involved in various aspects of physiological and pathologica...Vitamin K(VK), which was originally identified as a cofactor involved in the production of functional coagulation factors in the liver, has been shown to be involved in various aspects of physiological and pathological events, including bone metabolism, cardiovascular diseases and tumor biology. The mechanisms and roles of VK are gradually becoming clear. Several novel enzymes involved in the VK cycle were identified and have been shown to be linked to tumorigenesis. The VKs have been shown to suppress liver cancer cell growth through multiple signaling pathways via the transcription factors and protein kinases. A VK2 analog was applied to the chemoprevention of hepatocellular carcinoma(HCC) recurrence after curative therapy and was shown to have beneficial effects, both in the suppression of HCC recurrence and in patient survival. Although a large scale randomized control study failed to demonstrate the suppression of HCC recurrence, a meta-analysis suggested a beneficial effect on the long-term survival of HCC patients. However, the beneficial effects of VK administration alone were not sufficient to prevent or treat HCC in clinical settings. Thus its combination with other anti-cancer reagents and the development of more potent novel VK derivatives are the focus of ongoing research which seeks to achieve satisfactory therapeutic effects against HCC.展开更多
The susceptibility of individuals to obesity has been reported in many developed countries with predisposition of humans to obesity associated with high calorie diets and unhealthy lifestyles. Obesity may closely be i...The susceptibility of individuals to obesity has been reported in many developed countries with predisposition of humans to obesity associated with high calorie diets and unhealthy lifestyles. Obesity may closely be involved in cell suicide in various organ diseases with the importance of accelerated aging that requires early intervention with drug therapy to prevent diseases such as non alcoholic fatty liver disease (NAFLD) that has increased in children and reached to approx. 40% of the global population. Obesity is induced by various diets and lifestyle factors such as stress, anxiety and depression which are important to consider with the global increase in obesity and are possibly linked to the rise in individuals with brain disorders that involve neurodegeneration. Xenobiotics such as the endocrine disruptor chemicals that have increased in the environment in various developed countries lead to various chronic endocrine diseases as populations divert towards unhealthy diets and lifestyles with induction of NAFLD and obesity. The amount and nature of food intake that improves and increases liver lipid and xenobiotic metabolism in obese individuals have become important to decrease the risk for increased adiposity in man. High fibre or protein diets that contain leucine may improve liver glucose, lipid and xenobiotic metabolism and require further investigation with xenobiotics such as endocrine disruptors involved in appetite dysregulation and metabolic disorders in developed countries. The use of anti-obese drugs that reduce food intake and improve hypercholesterolemia and cardiovascular disease has been assessed in obesity with drug therapy closely involved either in the prevention or induction of NAFLD and obesity in man.展开更多
Sepsis is an infection-induced systemic inflammatory syndrome.The immune response in sepsis is characterized by the activation of both proinflammatory and anti-inflammatory pathways.When sepsis occurs,the expression a...Sepsis is an infection-induced systemic inflammatory syndrome.The immune response in sepsis is characterized by the activation of both proinflammatory and anti-inflammatory pathways.When sepsis occurs,the expression and activity of many inflammatory cytokines are markedly affected.Xenobiotic receptors are chemical-sensing transcription factors that play essential roles in the transcriptional regulation of drug-metabolizing enzymes(DMEs).Xenobiotic receptors mediate the functional crosstalk between sepsis and drug metabolism because the inflammatory cytokines released during sepsis can affect the expression and activity of xenobiotic receptors and thus impact the expression and activity of DMEs.Xenobiotic receptors in turn may affect the clinical outcomes of sepsis.Thisreview focuses on the sepsis-induced inflammatory response and xenobiotic receptors such as pregnane X receptor(PXR),aryl hydrocarbon receptor(AHR),glucocorticoid receptor(GR),and constitutive androstane receptor(CAR),DMEs such as CYP1A,CYP2B6,CYP2C9,and CYP3A4,and drug transporters such as p-glycoprotein(P-gp),and multidrug resistance-associated protein(MRPs)that are affected by sepsis.Understanding the xenobiotic receptor-mediated effect of sepsis on drug metabolism will help to improve the safe use of drugs in sepsis patients and the development of new xenobiotic receptor-based therapeutic strategies for sepsis.展开更多
Glutathione S-transferases（GSTs） from Liposcelis bostrychophila Badonnel and L.entomophila（Enderlein）（Psocoptera：Liposcelididae） were purified by glutathione-agarose affinity chromatography,and characterized su...Glutathione S-transferases（GSTs） from Liposcelis bostrychophila Badonnel and L.entomophila（Enderlein）（Psocoptera：Liposcelididae） were purified by glutathione-agarose affinity chromatography,and characterized subsequently by their Michaelis-Menten kinetics toward the artificial substrates 1-chloro-2,4-dinitrobenzene（CDNB） and reduced glutathione（GSH）,respectively.The specific activity of the purified GST toward CDNB was 2.3-fold higher in L.bostrychophila than in L.entomophila.Though the specific activities of purified enzymes varied between the two species,the purification yields were similar.SDS-PAGE revealed one band at 23 kDa for both the species.GSTs of L.entomophila exhibited higher Michaelis-Menten constants（Km） but lower maximal velocity（Vmax） values than those of L.bostrychophila.The optimum pH for CDNB conjugation of L.bostrychophila and L.entomophila GSTs was 7.0 and 7.5,and optimum temperature was 35 and 40°C,respectively.Inhibition kinetics showed that cibacron blue,curcumin,bromosulfalein,ethacrynic acid,and carbosulfan had excellent inhibitory effects on GSTs in both species,but the inhibitory effects of beta-cypermethrin,fenpropathrin,tetraethylthiuram disulfide,and diethyl maleate were not significant.展开更多
High-throughput next generation sequencing (NGS) is a shotgun approach applied in a parallel fashion by which the genome is fragmented and sequenced through small pieces and then analyzed either by aligning to a known...High-throughput next generation sequencing (NGS) is a shotgun approach applied in a parallel fashion by which the genome is fragmented and sequenced through small pieces and then analyzed either by aligning to a known reference genome or by de novo assembly without reference genome.This technology has led researchers to conduct an explosion of sequencing related projects in multidisciplinary fields of science.However,due to the limitations of sequencing-based chemistry,length of sequencing reads and the complexity of genes,it is difficult to determine the sequences of some portions of the human genome,leaving gaps in genomic data that frustrate further analysis.Particularly,some complex genes are difficult to be accurately sequenced or mapped because they contain high GC-content and/or low complexity regions,and complicated pseudogenes,such as the genes encoding xenobiotic metabolizing enzymes and transporters (XMETs).The genetic variants in XMET genes are critical to predicate interindividual variability in drug efficacy,drug safety and susceptibility to environmental toxicity.We summarized and discussed challenges,wet-lab methods,and bioinformatics algorithms in sequencing "complex" XMET genes,which may provide insightful information in the application of NGS technology for implementation in toxicogenomics and pharmacogenomics.展开更多
AIM To analyze the association between oncohematological diseases and GSTT1 /GSTM1 /CYP1A1 polymorphisms, dietary habits and smoking, in an argentine hospitalbased case-control study.METHODS This hospital-based case-c...AIM To analyze the association between oncohematological diseases and GSTT1 /GSTM1 /CYP1A1 polymorphisms, dietary habits and smoking, in an argentine hospitalbased case-control study.METHODS This hospital-based case-control study involved 125 patients with oncohematological diseases and 310 control subjects. A questionnaire was used to obtain sociodemographic data and information about habits. Blood samples were collected, and DNA was extracted using salting out methods. Deletions in GSTT1 and GSTM1 (null genotypes) were addressed by PCR. CYP1A1 MspI polymorphism was detected by PCR-RFLP. Odds ratio(OR) and 95%CI were calculated to estimate the association between each variable studied and oncohematological disease.RESULTS Women showed lower risk of disease compared to men(OR 0.52, 95%CI: 0.34-0.82, P = 0.003). Higher levels of education(> 12 years) were significantly associated with an increased risk, compared to complete primary school or less(OR 3.68, 95%CI: 1.82-7.40, P < 0.001 adjusted for age and sex). With respect to tobacco, none of the smoking categories showed association with oncohematological diseases. Regarding dietary habits, consumption of grilled/barbecued meat 3 or more times per month showed significant association with an increased risk of disease(OR 1.72, 95%CI: 1.08-2.75, P = 0.02). Daily consumption of coffee also was associated with an increased risk(OR 1.77, 95%CI: 1.03-3.03, P = 0.03). Results for GSTT1, GSTM1 and CYP1A1 polymorphisms showed no significant association with oncohematological diseases. When analyzing the interaction between polymorphisms and tobacco smoking or dietary habits, no statistically significant associations that modify disease risk were found. CONCLUSION We reported an increased risk of oncohematological diseases associated with meat and coffee intake. We did not find significant associations between genetic polymorphisms and blood cancer.展开更多
Pregnane and Xenobiotic Receptor (PXR; or Steroid and Xenobiotic Receptor, SXR), a new member of the nuclear receptor superfamily, is thought to modulate a network of genes that are involved in xenobiotic metabolism a...Pregnane and Xenobiotic Receptor (PXR; or Steroid and Xenobiotic Receptor, SXR), a new member of the nuclear receptor superfamily, is thought to modulate a network of genes that are involved in xenobiotic metabolism and elimination. To further explore the role of PXR in body’s homeostatic mechanisms, we for the first time, report successful prokary- otic expression and purification of full-length PXR and preparation of polyclonal antibody against the whole protein. The full-length cDNA encoding a 434 amino acids protein was sub-cloned into prokaryotic expression vector, pET-30b and transformed into E. coli BL21(DE3) cells for efficient over expression. The inclusion body fraction, containing the expressed recombinant protein, was purified first by solubilizing in sarcosine extraction buffer and then by affinity column chromatography using Ni-NTA His-Bind matrix. The efficacy of anti-PXR antibody was confirmed by immunocytology, Western blot analysis, EMSA and immunohistochemistry. The antibody obtained was capable of detecting human and mouse PXR with high specificity and sensitivity. Immunofluorescence staining of COS-1 cells transfected with human or mouse PXR showed a clear nuclear localization. Results from immunohistochemistry showed that level of PXR in liver sections is immunologically detectable in the nuclei. Similar to exogenously transfected PXR, Western blot analysis of cell extract from HepG2 and COLO320DM cells revealed a major protein band for endogenous PXR having the expected molecular weight of 50 kDa. Relevance of other immunodetectable bands with reference to PXR isoforms and current testimony are evaluated. Advantages of antibody raised against full-length PXR protein for functional characterization of receptor is discussed and its application for clinical purposes is envisaged.展开更多
Objective: Since the ban of antibiotics as growth promoting feed additives in the EU in 2006 research in alternatives has gained importance. Phytogenic feed additives represent a heterogenous class of different plant ...Objective: Since the ban of antibiotics as growth promoting feed additives in the EU in 2006 research in alternatives has gained importance. Phytogenic feed additives represent a heterogenous class of different plant derived substances that are discussed to improve the health of farm animals by direct and indirect antioxidant effects and by influencing microbial eubiosis in the gastrointestinal tract. Consequently our study aimed to investigate the influence of broccoli extract and the essential oils of tur- meric, oregano, thyme and rosemary, as selected individual additives, on intestinal and faecal microflora, on xenobiotic enzymes, and on the antioxidant system of piglets. Methods: 48 four weeks old male weaned piglets were assigned to 6 groups of 8. The piglets were housed individually in stainless steel pens with slatted floor. The control group (Con) was fed a diet without an additive for 4 weeks. The diet of group BE contained 0.15 g/kg sulforaphane in form of a broccoli extract. 535, 282, 373 and 476 mg/kg of the essential oils of turmeric (Cuo), oregano (Oo), thyme (To) and rosemary (Ro) were added to the diets of the remaining 4 groups to stan-dardise supplementation to 150 mg/kg of the oils’ key terpene compounds ar-turmerone, carvacrol, thymol and 1,8-cineole. The composition of bacterial microflora was examined by cultivating samples of jejeunal and colonic mucosa and of faeces under specific conditions. The mRNA expression of xenobiotic and antioxidant enzymes was determined by reversing transcrip- tase real time detection PCR (RT-PCR). Total antioxidant status was assayed using the Trolox Equivalent Antioxidant Capacity (TEAC), and lipid peroxidation was determined by measuring thiobarbioturic acid reactive substances (TBA- RS). Results: Compared to Con piglets all additives positively influenced weight gain and feed conversion in week 1. Over the whole trial period no significant differences in performance parameters existed between the experimental groups. Compared to group Con performance of 展开更多
Surfactants are the major active ingredients of laundry detergents. Therefore, special attention should be focused on the treatment and disposal of laundry wastewater. The aim of this study was to characterise the was...Surfactants are the major active ingredients of laundry detergents. Therefore, special attention should be focused on the treatment and disposal of laundry wastewater. The aim of this study was to characterise the wastewater from a commercial laundry over 30 days. Physicochemical analyses were performed, monitoring the content of nitrogen, phosphate, heavy metals, linear alkylbenzene sulphonate (LAS), volatile organic acids and alcohols. The pH was approximately 5.6 and the COD approximately 4800 mg·L-1. The average concentrations of sulphate, sulphide, N-ammoniacal organic nitrogen compounds and heavy metals were below the maximum limit, in accordance with local and national environmental legislation, and the average total suspended solids was 0.08 g·L-1. Among the metals analysed, iron was observed with the highest concentrations (0.037 mg·L-1 and 0.72 mg·L-1). Phosphate was detected in 93% of samples (94.65 mg·L-1 average). LAS was detected in all samples (12.24 mg·L-1 to 1023.7 mg·L-1). Thirty-three different xenobiotic organic compounds were identified in the laundry wastewater with the qualitative screening. The major groups of the compounds were fragrances, preservatives, solvents and some surfactants. Although the characterisation indicated low values for many parameters, this does not eliminate the need for specific treatment before its disposal at the sewage system.展开更多
AIM: To evaluate the effects of frying oil and Houttuynia cordata Thunb (H. cordata), a vegetable traditionally consumed in Taiwan, on the xenobiotic-metabolizing enzyme system of rodents. METHODS: Forty-eight Sprague...AIM: To evaluate the effects of frying oil and Houttuynia cordata Thunb (H. cordata), a vegetable traditionally consumed in Taiwan, on the xenobiotic-metabolizing enzyme system of rodents. METHODS: Forty-eight Sprague-Dawley rats were fed with a diet containing 0%, 2% or 5% H. cordata powder and 15% fresh soybean oil or 24-h oxidized frying oil (OFO) for 28 d respectively. The level of microsomal protein, total cytochrome 450 content (CYP450) and enzyme activities including NADPH reductase, ethoxyresorufin 0-deethylase (EROD), pentoxyresorufin 0-dealkylase (PROD), aniline hydroxylase (ANH), aminopyrine demethylase (AMD), and quinone reductase (QR) were determined. QR represented phase Ⅱ enzymes, the rest of the enzymes tested represented phase Ⅰ enzymes. RESULTS: The oxidized frying oil feeding produced a significant increase in phase Ⅰ and Ⅱ enzyme systems, including the content of CYP450 and microsomal protein, and the activities of NADPH reductase, EROD, PROD, ANH, AMD and QR in rats (P<0.05). In addition, the activities of EROD, ANH and AMD decreased and QR increased after feeding with H. cordata in OFO-fed group (P<0.05). The feeding with 2% H. cordata diet showed the most significant effect. CONCLUSION: The OFO diet induces phases I and II enzyme activity, and the 2% H. cordata diet resulted in a better regulation of the xenobiotic-metabolizing enzyme system.展开更多
文摘Microbes inhabiting the intestinal tract of humans represent a site for xenobiotic metabolism.The gut microbiome,the collection of microorganisms in the gastrointestinal tract,can alter the metabolic outcome of pharmaceuticals,environmental toxicants,and heavy metals,thereby changing their pharmacokinetics.Direct chemical modification of xenobiotics by the gut microbiome,either through the intestinal tract or re-entering the gut via enterohepatic circulation,can lead to increased metabolism or bioactivation,depending on the enzymatic activity within the microbial niche.Unique enzymes encoded within the microbiome include those that reverse the modifications imparted by host detoxification pathways.Additionally,the microbiome can limit xenobiotic absorption in the small intestine by increasing the expression of cell-cell adhesion proteins,supporting the protective mucosal layer,and/or directly sequestering chemicals.Lastly,host gene expression is regulated by the microbiome,including CYP450s,multi-drug resistance proteins,and the transcription factors that regulate them.While the microbiome affects the host and pharmacokinetics of the xenobiotic,xenobiotics can also influence the viability and metabolism of the microbiome.Our understanding of the complex interconnectedness between host,microbiome,and metabolism will advance with new modeling systems,technology development and refinement,and mechanistic studies focused on the contribution of human and microbial metabolism.
基金supported in part by NIH grant ES030429(to W.X.)and CA222274(to D.Y.)supported in part by the Joseph Koslow Endowed Professorship from the University of Pittsburgh School of Pharmacy.
文摘Drug metabolism is an orchestrated process in which drugs are metabolized and disposed through a series of specialized enzymes and transporters.Alterations in the expression and/or activity of these enzymes and transporters can affect the bioavailability(pharmacokinetics,or PK)and therapeutic efficacy(pharmacodynamics,or PD)of drugs.Recent studies have suggested that the long non-coding RNAs(IncRNAs)are highly relevant to drug metabolism and drug resistance,including chemoresistance in cancers,through the regulation of drug metabolism and disposition related genes.This review summarizes the regulation of enzymes,transporters,or regulatory proteins involved in drug metabolism by IncRNAs,with a particular emphasis on drug metabolism and chemo-resistance in cancer patients.The perspective strategies to integrate multi-dimensional pharmacogenomics data for future in-depth analysis of drug metabolism related IncRNAs are also proposed.Understanding the role of IncRNAs in drug metabolism will not only facilitate the identification of novel regulatory mechanisms,but also enable the discovery of IncRNA-based biomarkers and drug targets to personalize and improve the therapeutic outcome of patients,including cancer patients.
基金supported in part by the Joseph Koslow Endowed Professorship from the University of Pittsburgh School of Pharmacy
文摘The nuclear receptors pregnane X receptor(PXR) and constitutive androstane receptor(CAR) were cloned and/or established as xenobiotic receptors in 1998.Due to their activities in the transcriptional regulation of phase I and phase II enzymes as well as drug transporters,PXR and CAR have been defined as the master regulators of xenobiotic responses.The discovery of PXR and CAR provides the essential molecular basis by which drugs and other xenobiotic compounds regulate the expression of xenobiotic enzymes and transporters.This article is intended to provide a historical overview on the discovery of PXR and CAR as xenobiotic receptors.
文摘Mutations in genes encoding key players in oncogenic signaling pathways trigger specific downstream gene expression profiles in the respective tumor cell populations.While regulation of genes related to cell growth,survival,and death has been extensively studied,much less is known on the regulation of drug-metabolizing enzymes(DMEs)by oncogenic signaling.Here,a comprehensive review of the available literature is presented summarizing the impact of the most relevant genetic alterations in human and rodent liver tumors on the expression of DMEs with a focus on phasesⅠandⅡof xenobiotic metabolism.Comparably few data are available with respect to DME regulation by p53-dependent signaling,telomerase expression or altered chromatin remodeling.By contrast,DME regulation by constitutive activation of oncogenic signaling via the RAS/RAF/mitogen-activated protein kinase(MAPK)cascade or via the canonical WNT/β-catenin signaling pathway has been analyzed in greater depth,demonstrating mostly positive-regulatory effects of WNT/β-catenin signaling and negativeregulatory effects of MAPK signaling.Mechanistic studies have revealed molecular interactions between oncogenic signaling and nuclear xeno-sensing receptors which underlie the observed alterations in DME expression in liver tumors.Observations of altered DME expression and inducibility in liver tumors with a specific gene expression profile may impact pharmacological treatment options.
文摘The wastewater discharged from tanneries lack biodegradability due to the presence of recalcitrant compounds at significant concentration. The focal theme of the present investigation was to use chemo-autotrophic activated carbon oxidation(CAACO) reactor, an immobilized cell reactor using chemoautotrophs for the treatment of tannery wastewater. The treatment scheme comprised of anaerobic treatment, sand filtration, and CAACO reactor, which remove COD, BOD, TOC, VFA and sulphides respectively by 86%, 95%, 81%, 71% and 100%. Rice bran mesoporous activated carbon prepared indigenously and was used for immobilization of chemoautotrophs. The degradation of xenobiotic compounds by CAACO was confirmed through HPLC and FT-IR techniques.
文摘Vitamin K(VK), which was originally identified as a cofactor involved in the production of functional coagulation factors in the liver, has been shown to be involved in various aspects of physiological and pathological events, including bone metabolism, cardiovascular diseases and tumor biology. The mechanisms and roles of VK are gradually becoming clear. Several novel enzymes involved in the VK cycle were identified and have been shown to be linked to tumorigenesis. The VKs have been shown to suppress liver cancer cell growth through multiple signaling pathways via the transcription factors and protein kinases. A VK2 analog was applied to the chemoprevention of hepatocellular carcinoma(HCC) recurrence after curative therapy and was shown to have beneficial effects, both in the suppression of HCC recurrence and in patient survival. Although a large scale randomized control study failed to demonstrate the suppression of HCC recurrence, a meta-analysis suggested a beneficial effect on the long-term survival of HCC patients. However, the beneficial effects of VK administration alone were not sufficient to prevent or treat HCC in clinical settings. Thus its combination with other anti-cancer reagents and the development of more potent novel VK derivatives are the focus of ongoing research which seeks to achieve satisfactory therapeutic effects against HCC.
文摘The susceptibility of individuals to obesity has been reported in many developed countries with predisposition of humans to obesity associated with high calorie diets and unhealthy lifestyles. Obesity may closely be involved in cell suicide in various organ diseases with the importance of accelerated aging that requires early intervention with drug therapy to prevent diseases such as non alcoholic fatty liver disease (NAFLD) that has increased in children and reached to approx. 40% of the global population. Obesity is induced by various diets and lifestyle factors such as stress, anxiety and depression which are important to consider with the global increase in obesity and are possibly linked to the rise in individuals with brain disorders that involve neurodegeneration. Xenobiotics such as the endocrine disruptor chemicals that have increased in the environment in various developed countries lead to various chronic endocrine diseases as populations divert towards unhealthy diets and lifestyles with induction of NAFLD and obesity. The amount and nature of food intake that improves and increases liver lipid and xenobiotic metabolism in obese individuals have become important to decrease the risk for increased adiposity in man. High fibre or protein diets that contain leucine may improve liver glucose, lipid and xenobiotic metabolism and require further investigation with xenobiotics such as endocrine disruptors involved in appetite dysregulation and metabolic disorders in developed countries. The use of anti-obese drugs that reduce food intake and improve hypercholesterolemia and cardiovascular disease has been assessed in obesity with drug therapy closely involved either in the prevention or induction of NAFLD and obesity in man.
基金supported by grants from the National Natural Science Foundation of China(8140130969and 8176130232)Hainan Provincial Science and Technology Major Project(ZDKJ201804,China).
文摘Sepsis is an infection-induced systemic inflammatory syndrome.The immune response in sepsis is characterized by the activation of both proinflammatory and anti-inflammatory pathways.When sepsis occurs,the expression and activity of many inflammatory cytokines are markedly affected.Xenobiotic receptors are chemical-sensing transcription factors that play essential roles in the transcriptional regulation of drug-metabolizing enzymes(DMEs).Xenobiotic receptors mediate the functional crosstalk between sepsis and drug metabolism because the inflammatory cytokines released during sepsis can affect the expression and activity of xenobiotic receptors and thus impact the expression and activity of DMEs.Xenobiotic receptors in turn may affect the clinical outcomes of sepsis.Thisreview focuses on the sepsis-induced inflammatory response and xenobiotic receptors such as pregnane X receptor(PXR),aryl hydrocarbon receptor(AHR),glucocorticoid receptor(GR),and constitutive androstane receptor(CAR),DMEs such as CYP1A,CYP2B6,CYP2C9,and CYP3A4,and drug transporters such as p-glycoprotein(P-gp),and multidrug resistance-associated protein(MRPs)that are affected by sepsis.Understanding the xenobiotic receptor-mediated effect of sepsis on drug metabolism will help to improve the safe use of drugs in sepsis patients and the development of new xenobiotic receptor-based therapeutic strategies for sepsis.
基金funded in part by the National Natural Sciences Foundation of China (30871631)the Specialized Research Fund for the Doctoral Program of Higher Education of China to Prof. Wang Jinjun(200806350009)+1 种基金the Doctoral Program of Southwest University of China (SWU109023)the Fundamental Research Funds for the Central Universities,China(XDJK2009C112)
文摘Glutathione S-transferases（GSTs） from Liposcelis bostrychophila Badonnel and L.entomophila（Enderlein）（Psocoptera：Liposcelididae） were purified by glutathione-agarose affinity chromatography,and characterized subsequently by their Michaelis-Menten kinetics toward the artificial substrates 1-chloro-2,4-dinitrobenzene（CDNB） and reduced glutathione（GSH）,respectively.The specific activity of the purified GST toward CDNB was 2.3-fold higher in L.bostrychophila than in L.entomophila.Though the specific activities of purified enzymes varied between the two species,the purification yields were similar.SDS-PAGE revealed one band at 23 kDa for both the species.GSTs of L.entomophila exhibited higher Michaelis-Menten constants（Km） but lower maximal velocity（Vmax） values than those of L.bostrychophila.The optimum pH for CDNB conjugation of L.bostrychophila and L.entomophila GSTs was 7.0 and 7.5,and optimum temperature was 35 and 40°C,respectively.Inhibition kinetics showed that cibacron blue,curcumin,bromosulfalein,ethacrynic acid,and carbosulfan had excellent inhibitory effects on GSTs in both species,but the inhibitory effects of beta-cypermethrin,fenpropathrin,tetraethylthiuram disulfide,and diethyl maleate were not significant.
基金supported by the FDA Project(E0765001)the National Key Research and Development Program of China(2016YFC0902100 to Geng Chen)
文摘High-throughput next generation sequencing (NGS) is a shotgun approach applied in a parallel fashion by which the genome is fragmented and sequenced through small pieces and then analyzed either by aligning to a known reference genome or by de novo assembly without reference genome.This technology has led researchers to conduct an explosion of sequencing related projects in multidisciplinary fields of science.However,due to the limitations of sequencing-based chemistry,length of sequencing reads and the complexity of genes,it is difficult to determine the sequences of some portions of the human genome,leaving gaps in genomic data that frustrate further analysis.Particularly,some complex genes are difficult to be accurately sequenced or mapped because they contain high GC-content and/or low complexity regions,and complicated pseudogenes,such as the genes encoding xenobiotic metabolizing enzymes and transporters (XMETs).The genetic variants in XMET genes are critical to predicate interindividual variability in drug efficacy,drug safety and susceptibility to environmental toxicity.We summarized and discussed challenges,wet-lab methods,and bioinformatics algorithms in sequencing "complex" XMET genes,which may provide insightful information in the application of NGS technology for implementation in toxicogenomics and pharmacogenomics.
基金Supported by The "Consejo Nacional de Investigaciones Científicas y Técnicas"(PIP-634 to Richard S and Scholarship Grant to Cerliani MB)the "Instituto Nacional del Cáncer"(grant No.R.M.493:Asistencia financiera a proyectos de investigación en cáncer de origen nacional Ⅱ,to Pavicic W)
文摘AIM To analyze the association between oncohematological diseases and GSTT1 /GSTM1 /CYP1A1 polymorphisms, dietary habits and smoking, in an argentine hospitalbased case-control study.METHODS This hospital-based case-control study involved 125 patients with oncohematological diseases and 310 control subjects. A questionnaire was used to obtain sociodemographic data and information about habits. Blood samples were collected, and DNA was extracted using salting out methods. Deletions in GSTT1 and GSTM1 (null genotypes) were addressed by PCR. CYP1A1 MspI polymorphism was detected by PCR-RFLP. Odds ratio(OR) and 95%CI were calculated to estimate the association between each variable studied and oncohematological disease.RESULTS Women showed lower risk of disease compared to men(OR 0.52, 95%CI: 0.34-0.82, P = 0.003). Higher levels of education(> 12 years) were significantly associated with an increased risk, compared to complete primary school or less(OR 3.68, 95%CI: 1.82-7.40, P < 0.001 adjusted for age and sex). With respect to tobacco, none of the smoking categories showed association with oncohematological diseases. Regarding dietary habits, consumption of grilled/barbecued meat 3 or more times per month showed significant association with an increased risk of disease(OR 1.72, 95%CI: 1.08-2.75, P = 0.02). Daily consumption of coffee also was associated with an increased risk(OR 1.77, 95%CI: 1.03-3.03, P = 0.03). Results for GSTT1, GSTM1 and CYP1A1 polymorphisms showed no significant association with oncohematological diseases. When analyzing the interaction between polymorphisms and tobacco smoking or dietary habits, no statistically significant associations that modify disease risk were found. CONCLUSION We reported an increased risk of oncohematological diseases associated with meat and coffee intake. We did not find significant associations between genetic polymorphisms and blood cancer.
文摘Pregnane and Xenobiotic Receptor (PXR; or Steroid and Xenobiotic Receptor, SXR), a new member of the nuclear receptor superfamily, is thought to modulate a network of genes that are involved in xenobiotic metabolism and elimination. To further explore the role of PXR in body’s homeostatic mechanisms, we for the first time, report successful prokary- otic expression and purification of full-length PXR and preparation of polyclonal antibody against the whole protein. The full-length cDNA encoding a 434 amino acids protein was sub-cloned into prokaryotic expression vector, pET-30b and transformed into E. coli BL21(DE3) cells for efficient over expression. The inclusion body fraction, containing the expressed recombinant protein, was purified first by solubilizing in sarcosine extraction buffer and then by affinity column chromatography using Ni-NTA His-Bind matrix. The efficacy of anti-PXR antibody was confirmed by immunocytology, Western blot analysis, EMSA and immunohistochemistry. The antibody obtained was capable of detecting human and mouse PXR with high specificity and sensitivity. Immunofluorescence staining of COS-1 cells transfected with human or mouse PXR showed a clear nuclear localization. Results from immunohistochemistry showed that level of PXR in liver sections is immunologically detectable in the nuclei. Similar to exogenously transfected PXR, Western blot analysis of cell extract from HepG2 and COLO320DM cells revealed a major protein band for endogenous PXR having the expected molecular weight of 50 kDa. Relevance of other immunodetectable bands with reference to PXR isoforms and current testimony are evaluated. Advantages of antibody raised against full-length PXR protein for functional characterization of receptor is discussed and its application for clinical purposes is envisaged.
文摘Objective: Since the ban of antibiotics as growth promoting feed additives in the EU in 2006 research in alternatives has gained importance. Phytogenic feed additives represent a heterogenous class of different plant derived substances that are discussed to improve the health of farm animals by direct and indirect antioxidant effects and by influencing microbial eubiosis in the gastrointestinal tract. Consequently our study aimed to investigate the influence of broccoli extract and the essential oils of tur- meric, oregano, thyme and rosemary, as selected individual additives, on intestinal and faecal microflora, on xenobiotic enzymes, and on the antioxidant system of piglets. Methods: 48 four weeks old male weaned piglets were assigned to 6 groups of 8. The piglets were housed individually in stainless steel pens with slatted floor. The control group (Con) was fed a diet without an additive for 4 weeks. The diet of group BE contained 0.15 g/kg sulforaphane in form of a broccoli extract. 535, 282, 373 and 476 mg/kg of the essential oils of turmeric (Cuo), oregano (Oo), thyme (To) and rosemary (Ro) were added to the diets of the remaining 4 groups to stan-dardise supplementation to 150 mg/kg of the oils’ key terpene compounds ar-turmerone, carvacrol, thymol and 1,8-cineole. The composition of bacterial microflora was examined by cultivating samples of jejeunal and colonic mucosa and of faeces under specific conditions. The mRNA expression of xenobiotic and antioxidant enzymes was determined by reversing transcrip- tase real time detection PCR (RT-PCR). Total antioxidant status was assayed using the Trolox Equivalent Antioxidant Capacity (TEAC), and lipid peroxidation was determined by measuring thiobarbioturic acid reactive substances (TBA- RS). Results: Compared to Con piglets all additives positively influenced weight gain and feed conversion in week 1. Over the whole trial period no significant differences in performance parameters existed between the experimental groups. Compared to group Con performance of
基金The authors gratefully acknowledge the Laboratório de Processos Biológicos-LPB/EESC/USP Sao Paulo,Research Foundation(FAPESP)(No 2010/11531-9)the National Council for Scientific and Technological Development for their financial support.
文摘Surfactants are the major active ingredients of laundry detergents. Therefore, special attention should be focused on the treatment and disposal of laundry wastewater. The aim of this study was to characterise the wastewater from a commercial laundry over 30 days. Physicochemical analyses were performed, monitoring the content of nitrogen, phosphate, heavy metals, linear alkylbenzene sulphonate (LAS), volatile organic acids and alcohols. The pH was approximately 5.6 and the COD approximately 4800 mg·L-1. The average concentrations of sulphate, sulphide, N-ammoniacal organic nitrogen compounds and heavy metals were below the maximum limit, in accordance with local and national environmental legislation, and the average total suspended solids was 0.08 g·L-1. Among the metals analysed, iron was observed with the highest concentrations (0.037 mg·L-1 and 0.72 mg·L-1). Phosphate was detected in 93% of samples (94.65 mg·L-1 average). LAS was detected in all samples (12.24 mg·L-1 to 1023.7 mg·L-1). Thirty-three different xenobiotic organic compounds were identified in the laundry wastewater with the qualitative screening. The major groups of the compounds were fragrances, preservatives, solvents and some surfactants. Although the characterisation indicated low values for many parameters, this does not eliminate the need for specific treatment before its disposal at the sewage system.
基金Supported by Grant From the National Science Council of Taiwan, No. NSC 90-2320-13-038-038
文摘AIM: To evaluate the effects of frying oil and Houttuynia cordata Thunb (H. cordata), a vegetable traditionally consumed in Taiwan, on the xenobiotic-metabolizing enzyme system of rodents. METHODS: Forty-eight Sprague-Dawley rats were fed with a diet containing 0%, 2% or 5% H. cordata powder and 15% fresh soybean oil or 24-h oxidized frying oil (OFO) for 28 d respectively. The level of microsomal protein, total cytochrome 450 content (CYP450) and enzyme activities including NADPH reductase, ethoxyresorufin 0-deethylase (EROD), pentoxyresorufin 0-dealkylase (PROD), aniline hydroxylase (ANH), aminopyrine demethylase (AMD), and quinone reductase (QR) were determined. QR represented phase Ⅱ enzymes, the rest of the enzymes tested represented phase Ⅰ enzymes. RESULTS: The oxidized frying oil feeding produced a significant increase in phase Ⅰ and Ⅱ enzyme systems, including the content of CYP450 and microsomal protein, and the activities of NADPH reductase, EROD, PROD, ANH, AMD and QR in rats (P<0.05). In addition, the activities of EROD, ANH and AMD decreased and QR increased after feeding with H. cordata in OFO-fed group (P<0.05). The feeding with 2% H. cordata diet showed the most significant effect. CONCLUSION: The OFO diet induces phases I and II enzyme activity, and the 2% H. cordata diet resulted in a better regulation of the xenobiotic-metabolizing enzyme system.
