Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies (i.e., re...Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies (i.e., resection, liver transplantation, percutaneous ablation). Treatments with palliative intent include chemoembolization and systemic therapy. Among systemic treatments, the small-molecule multikinase inhibitor sorafenib has been the only systemic treatment available for advanced HCC over 10 years. More recently, other smallmolecule multikinase inhibitors (e.g., regorafenib, lenvatinib, cabozantinib) have been approved for HCC treatment. The promising immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab) are still under investigation in Europe while in the US nivolumab has already been approved by FDA in sorafenib refractory or resistant patients. Other molecules, such as the selective CDK4/6inhibitors (e.g., palbociclib, ribociclib), are in earlier stages of clinical development, and the c- MET inhibitor tivantinib did not show positive results in a phase III study. However, even if the introduction of targeted agents has led to great advances in patient response and survival with an acceptable toxicity profile, a remarkable inter-individual heterogeneity in therapy outcome persists and constitutes a significant problem in disease management. Thus, the identification of biomarkers that predict which patients will benefit from a specific intervention could significantly affect decision-making and therapy planning. Germ-line variants have been suggested to play an important role in determining outcomes of HCC systemic therapy in terms of both toxicity and treatment efficacy. Particularly, a number of studies have focused on the role of genetic polymorphisms impacting the drug metabolic pathway and membrane translocation as well as the drug mechanism of action as predictive/prognostic markers of HCC treatment. The aim of this review is to summarize and critically discuss the pharmacogenetic literatu展开更多
AIM:To evaluate the association between genetic polymorphisms in CYP2E1, ALDH2 and ADH1B and the risk of esophageal squamous cell carcinoma (ESCC) in a high risk area of Gansu Province, in Chinese males. METHODS: A ca...AIM:To evaluate the association between genetic polymorphisms in CYP2E1, ALDH2 and ADH1B and the risk of esophageal squamous cell carcinoma (ESCC) in a high risk area of Gansu Province, in Chinese males. METHODS: A case-control study was conducted to investigate the genetic polymorphisms of these enzymes (CYP2E1 *c1/*c2, ALDH2 *1/*2 and ADH1B *1/*1 genotypes). A total of 80 esophageal cancer cases and 480 controls were recruited. RESULTS: Compared with controls, cases had a greater prevalence of heavier alcohol consumption (53.8% vs 16.2%) and a higher proportion of alcohol drinkers with > 30 drink-years (28.8% vs 13.5%). Heavier alcohol consumption and alcohol drinking with > 30 drink- years increased the risk of ESCC, with ORs (95% CI) of 3.20 (1.32-9.65) and 1.68 (0.96-3.21). CYP2E1 (*c1/*c1), ALDH2 (*1/*2) and ADH1B (*1/*1) genotype frequencies were higher among patients with squamous cell carcinomas, at a level close to statistical significance (P = 0.014; P = 0.094; P = 0.0001 respectively). There were synergistic interactions among alcohol drinking and ALDH2, ADH1B and CYP2E1 genotypes. The risk of the ESCC in moderate-to-heavy drinkers with an inactive ALDH2 encoded by ALDH2 *1/*2 as well as ADH1B encoded by ADH1B *1/*1 and CYP2E1 encoded by CYP2E1 *c1/*c1 was higher than that in the never/rare-to-light drinkers with an active ALDH2 (*1/*1 genotype) as well as ADH1B (*1/*2 + *2/*2) and CYP2E1 (*c1/*c2 + *c2/*c2) genotypes, with a statistically significant difference; ORs (95% CI) of 8.58 (3.28-22.68), 27.12 (8.52-70.19) and 7.64 (2.82-11.31) respectively. The risk of the ESCC in moderate-to-heavy drinkers with ALDH2 (*1/*2) combined the ADH1B (*1/*1) genotype or ALDH2 (*1/*2) combined the CYP2E1 (*c1/*c1) genotype leads to synergistic interactions, higher than drinkers with ALDH2 (*1/*1) + ADH1B (*1/*2 + *2/*2), ALDH2 (*1/*1) + CYP2E1 (*c1/*c2 + *c2/*c2) respectively , ORs (95% CI) of 7.46 (3.28-18.32) and 6.82 (1.44-9.76) respectively. Individuals with the ADH1B combined the CYP2E1 genotype showed no syn展开更多
The hepatic endoplasmic reticulum(ER)-anchored cytochromes P450(P450s)are mixedfunction oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic...The hepatic endoplasmic reticulum(ER)-anchored cytochromes P450(P450s)are mixedfunction oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic and environmental relevance.P450 ER-content and hence function is regulated by their coordinated hemoprotein syntheses and proteolytic turnover.Such P450 proteolytic turnover occurs through a process known as ER-associated degradation(ERAD)that involves ubiquitindependent proteasomal degradation(UPD)and/or autophagic-lysosomal degradation(ALD).Herein,on the basis of available literature reports and our own recent findings of in vitro as well as in vivo experimental studies,we discuss the therapeutic and pathophysiological implications of altered P450 ERAD and its plausible clinical relevance.We specifically(i)describe the P450 ERAD-machinery and how it may be repurposed for the generation of antigenic P450 peptides involved in P450 autoantibodypathogenesis in drug-induced acute hypersensitivity reactions and liver injury,or viral hepatitis;(ⅱ)discuss the relevance of accelerated or disrupted P450-ERAD to the pharmacological and/or toxicological effects of clinically relevant P450 drug substrates;and(ⅲ)detail the pathophysiological consequences of disrupted P450 ERAD,contributing to non-alcoholic fatty liver disease(NAFLD)/non-alcoholic steatohepatitis(NASH)under certain synergistic cellular conditions.展开更多
Clopidogrel in association with aspirine is considered state of the art of medical treatment for acute coronary syndrome by reducing the risk of new ischemic events.Concomitant treatment with proton pump inhibitors in...Clopidogrel in association with aspirine is considered state of the art of medical treatment for acute coronary syndrome by reducing the risk of new ischemic events.Concomitant treatment with proton pump inhibitors in order to prevent gastrointestinal side effects is recommended by clinical guidelines.Clopidogrel needs metabolic activation predominantly by the hepatic cytochrome P450 isoenzyme Cytochrome 2C19(CYP2C19) and proton pump inhibitors(PPIs) are extensively metabolized by the CYP2C19 isoenzyme as well.Several pharmacodynamic studies investigating a potential clopidogrel-PPI interaction found a significant decrease of the clopidogrel platelet antiaggregation effect for omeprazole,but not for pantoprazole.Initial clinical cohort studies in 2009 reported an increased risk for adverse cardiovascular events,when under clopidogrel and PPI treatment at the same time.These observations led the United States Food and Drug Administration and the European Medecines Agency to discourage the combination of clopidogrel and PPI(especially omeprazole) in the same year.In contrast,more recent retrospective cohort studies including propensity score matching and the only existing randomized trial have not shown any difference concerning adverse cardiovascular events when concomitantly on clopidogrel and PPI or only on clopidogrel.Three meta-analyses report an inverse correlation between clopidogrel-PPI interaction and study quality,with high and moderate quality studies not reporting any association,rising concern about unmeasured confounders biasing the low quality studies.Thus,no definite evidence exists for an effect on mortality.Because PPI induced risk reduction clearly overweighs the possible adverse cardiovascular risk in patients with high risk of gastrointestinal bleeding,combination of clopidogrel with the less CYP2C19 inhibiting pantoprazole should be recommended.展开更多
Microbes can cause or accelerate metal corrosion,leading to huge losses in corrosion damages each year.Geobacter sulfurreducens is a representative electroactive bacterium in many soils,sediments,and wastew-ater syste...Microbes can cause or accelerate metal corrosion,leading to huge losses in corrosion damages each year.Geobacter sulfurreducens is a representative electroactive bacterium in many soils,sediments,and wastew-ater systems.It has been confirmed to directly extract electrons from elemental metals.However,little is known about the effect of electron shuttles in G.sulfurreducens corrosion on stainless steel.In this study,we report that exogenous flavins promote iron-to-microbe electron transfer,accelerating micro-bial corrosion.G.sulfurreducens caused 1.3 times deeper pits and increased electron uptake(with 2 times increase of i_(corr))from stainless steel when riboflavin was added to the culture medium.OmcS-deficient mutant data suggest that G.sulfurreducens utilizes riboflavin as a bound-cofactor in outer membrane c-type cytochromes.The finding that,in the presence of microbes,riboflavin can substantially accelerate corrosion highlights the role of flavin redox cycling for enhanced iron-to-microbe electron transfer by G.sulfurreducens and provides new insights in microbial corrosion.展开更多
Cytochromes P450(CYPs)play a prominent role in catalyzing phase I xenobiotic biotransformation and account for about 75%of the total metabolism of commercially available drugs,including chemotherapeutics.The gene expr...Cytochromes P450(CYPs)play a prominent role in catalyzing phase I xenobiotic biotransformation and account for about 75%of the total metabolism of commercially available drugs,including chemotherapeutics.The gene expression and enzyme activity of CYPs are variable between individuals,which subsequently leads to different patterns of susceptibility to carcinogenesis by genotoxic xenobiotics,as well as differences in the efficacy and toxicity of clinically used drugs.This research aimed to examine the presence of the CYP2B6*9 polymorphism and its possible association with the incidence of B-CLL in Egyptian patients,as well as the clinical outcome after receiving cyclophosphamide chemotherapy.DNA was isolated from whole blood samples of 100 de novo B-CLL cases and also from 100 sex-and age-matched healthy individuals.The presence of the CYP2B6*9(G516T)polymorphism was examined by PCR-based allele specific amplification(ASA).Patients were further indicated for receiving chemotherapy,and then they were followed up.The CYP2B6*9 variant indicated a statistically significant higher risk of B-CLL under different genetic models,comprising allelic(T-allele vs.G-allele,OR=4.8,p<0.001)and dominant(GT+TT vs.GG,OR=5.4,p<0.001)models.Following cyclophosphamide chemotherapy,we found that the patients with variant genotypes(GT+TT)were less likely to achieve remission compared to those with the wild-type genotype(GG),with a response percentage of(37.5%vs.83%,respectively).In conclusion,our findings showed that the CYP2B6*9(G516T)polymorphism is associated with B-CLL susceptibility among Egyptian patients.This variant greatly affected the clinical outcome and can serve as a good therapeutic marker in predicting response to cyclophosphamide treatment.展开更多
Electroactive microorganisms(EAMs)could utilize extracellular electron transfer(EET)pathways to exchange electrons and energy with their external surroundings.Conductive cytochrome proteins and nanowires play crucial ...Electroactive microorganisms(EAMs)could utilize extracellular electron transfer(EET)pathways to exchange electrons and energy with their external surroundings.Conductive cytochrome proteins and nanowires play crucial roles in controlling electron transfer rate from cytosol to extracellular electrode.Many previous studies elucidated how the c-type cytochrome proteins and conductive nanowires are synthesized,assembled,and engineered to manipulate the EET rate,and quantified the kinetic processes of electron generation and EET.Here,we firstly overview the electron transfer pathways of EAMs and quantify the kinetic parameters that dictating intracellular electron production and EET.Secondly,we systematically review the structure,conductivity mechanisms,and engineering strategies to manipulate conductive cytochromes and nanowire in EAMs.Lastly,we outlook potential directions for future research in cytochromes and conductive nanowires for enhanced electron transfer.This article reviews the quantitative kinetics of intracellular electron production and EET,and the contribution of engineered c-type cytochromes and conductive nanowire in enhancing the EET rate,which lay the foundation for enhancing electron transfer capacity of EAMs.展开更多
Physicians are often faced with the fact that the duration of anesthesia varies in different patients, which significantly complicates the process of surgical intervention and may confront the surgeon with an unforese...Physicians are often faced with the fact that the duration of anesthesia varies in different patients, which significantly complicates the process of surgical intervention and may confront the surgeon with an unforeseen situation. Recently, publications have appeared in the literature on the effects of various, including exotic products on anesthesia. There are also many conflicting statements about the effect of camel milk (CM) on the duration of anesthesia. Some data show that CM prolongs anesthesia, while other scientists argue the exact opposite: CM shortens the effect of the anesthetic. We decided to shed light on these studies by analyzing the effect of CM consumption on the effectiveness of local anesthesia in different patients. This article highlights the significant changes that occur in anesthesia due to the patients’ diet. To achieve the set goal, we sort the twenty patients underwent local anesthesia into groups depending on the habit of using CM. The first, control, group consisted of practically healthy patients who did not use CM throughout their lives, and the second group had the habit of regularly taking CM. In both groups, local anesthesia was first performed without pre-drink CM. For the second time, participants in the control and experimental groups were asked to drink CM before the anesthesia procedure. Both in the control and experimental groups, patients drank CM one hour before local anesthesia. A significant correlation was found between the use of CM and the duration of anesthesia in both groups. Consumption of CM had a different effect on the duration of local anesthesia in the experimental and control groups. When milk was consumed before the use of analgesics in these two different groups, it changed exactly the opposite: for those who usually drink milk, it was shortened, and for those who did not drink it daily, lengthened. Thus, we found that the differences in the statements of scientists about the CM impact on anesthesia are based on the fact of different effects of CM in it展开更多
Cytochrome P4501A (the CYP1A1 and CYP1A2 enzymes) are regulated through the aryl hydrocarbon receptor (AhR)-dependent signal transduction pathway and are generally known as enzymes which metabolize anthropogenic xenob...Cytochrome P4501A (the CYP1A1 and CYP1A2 enzymes) are regulated through the aryl hydrocarbon receptor (AhR)-dependent signal transduction pathway and are generally known as enzymes which metabolize anthropogenic xenobiotics such as dioxin to carcinogenic and mutagenic compounds. However, recently the facts of CYP1A activation under physiological conditions or under action of non-dioxin-like compounds appear. In the present study we show that genistein, herbimycin A and geldanamycin (the protein-tyrosine kinase inhibitors) affect in vivo to CYP1A1 activity, the CYP1A1 mRNA level and the CYP1A1 protein level. These data provide insight into the role of protein kinases in CYP1A regulation may facilitate the understanding of CYP1A regulation.展开更多
OBJECTIVE:To observe the effects of moxibustion at bilateral Feishu(BL13)and Xinshu(BL15)combined with benazepril on myocardial cells apoptosis index,the expression levels of apoptosis-related proteins cytochrome c(Cy...OBJECTIVE:To observe the effects of moxibustion at bilateral Feishu(BL13)and Xinshu(BL15)combined with benazepril on myocardial cells apoptosis index,the expression levels of apoptosis-related proteins cytochrome c(Cyt-C)and apoptosis-inducing factor(AIF)in chronic heart failure(CHF)rats.METHODS:Sixty-five rats were randomly divided into normal group(n=10)and model-I group(n=55).After modeling,CHF rats in model-I group were divided into model group,moxibustion group,benazepril group,moxibustion plus benazepril group(abbreviated as aibei group,the same below),10 rats in each group.Echocardiogram index was examined by echocardiography.Hemodynamic indices were measured by rat cardiac function meter.Serum B-type brain natriuretic peptide(BNP)was detected by enzymelinked immunosorbent assay.Myocardial cells apoptosis index was detected by terminal-deoxynucleoitidyl transferase mediated nick end labeling staining.Pathological changes of myocardial tissues were observed by hematoxylin and eosin staining.The expression levels of Cyt-C and AIF in myocardial tissues were detected by Western blot.RESULTS:Compared with normal group,ejection fraction and left ventricular diameter shortening rate in model-Ⅰgroup were significantly reduced,myocardial cells of rats in model group exhibited unclear transverse striations,cells swellings and vacuoles,cardiac functions were deteriorated,serum BNP level,myocardial cells apoptosis index,and the expression levels of Cyt-C and AIF were significantly increased.Compared with model group,myocardial cells of rats in moxibustion group,benazepril group,and aibei group were dyed more evenly,muscle fibers were arranged relatively neatly,cardiac functions were improved,serum BNP level,myocardial cells apoptosis index,and the expression levels of Cyt-C and AIF were significantly decreased.Compared with aibei group,cardiac functions were worsened,myocardial cells apoptosis index,and the expression levels of Cyt-C and AIF were increased.CONCLUSION:Moxibustion at bilateral Feishu(BL13)and Xinshu(B展开更多
基金the European Union’s Horizon 2020 Research and Innovation Programme,No.668353
文摘Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies (i.e., resection, liver transplantation, percutaneous ablation). Treatments with palliative intent include chemoembolization and systemic therapy. Among systemic treatments, the small-molecule multikinase inhibitor sorafenib has been the only systemic treatment available for advanced HCC over 10 years. More recently, other smallmolecule multikinase inhibitors (e.g., regorafenib, lenvatinib, cabozantinib) have been approved for HCC treatment. The promising immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab) are still under investigation in Europe while in the US nivolumab has already been approved by FDA in sorafenib refractory or resistant patients. Other molecules, such as the selective CDK4/6inhibitors (e.g., palbociclib, ribociclib), are in earlier stages of clinical development, and the c- MET inhibitor tivantinib did not show positive results in a phase III study. However, even if the introduction of targeted agents has led to great advances in patient response and survival with an acceptable toxicity profile, a remarkable inter-individual heterogeneity in therapy outcome persists and constitutes a significant problem in disease management. Thus, the identification of biomarkers that predict which patients will benefit from a specific intervention could significantly affect decision-making and therapy planning. Germ-line variants have been suggested to play an important role in determining outcomes of HCC systemic therapy in terms of both toxicity and treatment efficacy. Particularly, a number of studies have focused on the role of genetic polymorphisms impacting the drug metabolic pathway and membrane translocation as well as the drug mechanism of action as predictive/prognostic markers of HCC treatment. The aim of this review is to summarize and critically discuss the pharmacogenetic literatu
文摘AIM:To evaluate the association between genetic polymorphisms in CYP2E1, ALDH2 and ADH1B and the risk of esophageal squamous cell carcinoma (ESCC) in a high risk area of Gansu Province, in Chinese males. METHODS: A case-control study was conducted to investigate the genetic polymorphisms of these enzymes (CYP2E1 *c1/*c2, ALDH2 *1/*2 and ADH1B *1/*1 genotypes). A total of 80 esophageal cancer cases and 480 controls were recruited. RESULTS: Compared with controls, cases had a greater prevalence of heavier alcohol consumption (53.8% vs 16.2%) and a higher proportion of alcohol drinkers with > 30 drink-years (28.8% vs 13.5%). Heavier alcohol consumption and alcohol drinking with > 30 drink- years increased the risk of ESCC, with ORs (95% CI) of 3.20 (1.32-9.65) and 1.68 (0.96-3.21). CYP2E1 (*c1/*c1), ALDH2 (*1/*2) and ADH1B (*1/*1) genotype frequencies were higher among patients with squamous cell carcinomas, at a level close to statistical significance (P = 0.014; P = 0.094; P = 0.0001 respectively). There were synergistic interactions among alcohol drinking and ALDH2, ADH1B and CYP2E1 genotypes. The risk of the ESCC in moderate-to-heavy drinkers with an inactive ALDH2 encoded by ALDH2 *1/*2 as well as ADH1B encoded by ADH1B *1/*1 and CYP2E1 encoded by CYP2E1 *c1/*c1 was higher than that in the never/rare-to-light drinkers with an active ALDH2 (*1/*1 genotype) as well as ADH1B (*1/*2 + *2/*2) and CYP2E1 (*c1/*c2 + *c2/*c2) genotypes, with a statistically significant difference; ORs (95% CI) of 8.58 (3.28-22.68), 27.12 (8.52-70.19) and 7.64 (2.82-11.31) respectively. The risk of the ESCC in moderate-to-heavy drinkers with ALDH2 (*1/*2) combined the ADH1B (*1/*1) genotype or ALDH2 (*1/*2) combined the CYP2E1 (*c1/*c1) genotype leads to synergistic interactions, higher than drinkers with ALDH2 (*1/*1) + ADH1B (*1/*2 + *2/*2), ALDH2 (*1/*1) + CYP2E1 (*c1/*c2 + *c2/*c2) respectively , ORs (95% CI) of 7.46 (3.28-18.32) and 6.82 (1.44-9.76) respectively. Individuals with the ADH1B combined the CYP2E1 genotype showed no syn
基金supported by NIDDK Center Grant DK26743supported by NIH Grants GM44037 and DK26506(USA)to Maria Almira Correia.
文摘The hepatic endoplasmic reticulum(ER)-anchored cytochromes P450(P450s)are mixedfunction oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic and environmental relevance.P450 ER-content and hence function is regulated by their coordinated hemoprotein syntheses and proteolytic turnover.Such P450 proteolytic turnover occurs through a process known as ER-associated degradation(ERAD)that involves ubiquitindependent proteasomal degradation(UPD)and/or autophagic-lysosomal degradation(ALD).Herein,on the basis of available literature reports and our own recent findings of in vitro as well as in vivo experimental studies,we discuss the therapeutic and pathophysiological implications of altered P450 ERAD and its plausible clinical relevance.We specifically(i)describe the P450 ERAD-machinery and how it may be repurposed for the generation of antigenic P450 peptides involved in P450 autoantibodypathogenesis in drug-induced acute hypersensitivity reactions and liver injury,or viral hepatitis;(ⅱ)discuss the relevance of accelerated or disrupted P450-ERAD to the pharmacological and/or toxicological effects of clinically relevant P450 drug substrates;and(ⅲ)detail the pathophysiological consequences of disrupted P450 ERAD,contributing to non-alcoholic fatty liver disease(NAFLD)/non-alcoholic steatohepatitis(NASH)under certain synergistic cellular conditions.
文摘Clopidogrel in association with aspirine is considered state of the art of medical treatment for acute coronary syndrome by reducing the risk of new ischemic events.Concomitant treatment with proton pump inhibitors in order to prevent gastrointestinal side effects is recommended by clinical guidelines.Clopidogrel needs metabolic activation predominantly by the hepatic cytochrome P450 isoenzyme Cytochrome 2C19(CYP2C19) and proton pump inhibitors(PPIs) are extensively metabolized by the CYP2C19 isoenzyme as well.Several pharmacodynamic studies investigating a potential clopidogrel-PPI interaction found a significant decrease of the clopidogrel platelet antiaggregation effect for omeprazole,but not for pantoprazole.Initial clinical cohort studies in 2009 reported an increased risk for adverse cardiovascular events,when under clopidogrel and PPI treatment at the same time.These observations led the United States Food and Drug Administration and the European Medecines Agency to discourage the combination of clopidogrel and PPI(especially omeprazole) in the same year.In contrast,more recent retrospective cohort studies including propensity score matching and the only existing randomized trial have not shown any difference concerning adverse cardiovascular events when concomitantly on clopidogrel and PPI or only on clopidogrel.Three meta-analyses report an inverse correlation between clopidogrel-PPI interaction and study quality,with high and moderate quality studies not reporting any association,rising concern about unmeasured confounders biasing the low quality studies.Thus,no definite evidence exists for an effect on mortality.Because PPI induced risk reduction clearly overweighs the possible adverse cardiovascular risk in patients with high risk of gastrointestinal bleeding,combination of clopidogrel with the less CYP2C19 inhibiting pantoprazole should be recommended.
基金supported by the National Natural Science Foundation of China(Nos.52101078,U2006219)the National Key Research and Development Program of China(No.2020YFA0907300)+1 种基金the Fundamental Research Funds for the Central Universities of the Ministry of Education of China(Nos.N2102009,N2002019)Liaoning Revitalization Talents Program(No.XLYC1907158).
文摘Microbes can cause or accelerate metal corrosion,leading to huge losses in corrosion damages each year.Geobacter sulfurreducens is a representative electroactive bacterium in many soils,sediments,and wastew-ater systems.It has been confirmed to directly extract electrons from elemental metals.However,little is known about the effect of electron shuttles in G.sulfurreducens corrosion on stainless steel.In this study,we report that exogenous flavins promote iron-to-microbe electron transfer,accelerating micro-bial corrosion.G.sulfurreducens caused 1.3 times deeper pits and increased electron uptake(with 2 times increase of i_(corr))from stainless steel when riboflavin was added to the culture medium.OmcS-deficient mutant data suggest that G.sulfurreducens utilizes riboflavin as a bound-cofactor in outer membrane c-type cytochromes.The finding that,in the presence of microbes,riboflavin can substantially accelerate corrosion highlights the role of flavin redox cycling for enhanced iron-to-microbe electron transfer by G.sulfurreducens and provides new insights in microbial corrosion.
文摘Cytochromes P450(CYPs)play a prominent role in catalyzing phase I xenobiotic biotransformation and account for about 75%of the total metabolism of commercially available drugs,including chemotherapeutics.The gene expression and enzyme activity of CYPs are variable between individuals,which subsequently leads to different patterns of susceptibility to carcinogenesis by genotoxic xenobiotics,as well as differences in the efficacy and toxicity of clinically used drugs.This research aimed to examine the presence of the CYP2B6*9 polymorphism and its possible association with the incidence of B-CLL in Egyptian patients,as well as the clinical outcome after receiving cyclophosphamide chemotherapy.DNA was isolated from whole blood samples of 100 de novo B-CLL cases and also from 100 sex-and age-matched healthy individuals.The presence of the CYP2B6*9(G516T)polymorphism was examined by PCR-based allele specific amplification(ASA).Patients were further indicated for receiving chemotherapy,and then they were followed up.The CYP2B6*9 variant indicated a statistically significant higher risk of B-CLL under different genetic models,comprising allelic(T-allele vs.G-allele,OR=4.8,p<0.001)and dominant(GT+TT vs.GG,OR=5.4,p<0.001)models.Following cyclophosphamide chemotherapy,we found that the patients with variant genotypes(GT+TT)were less likely to achieve remission compared to those with the wild-type genotype(GG),with a response percentage of(37.5%vs.83%,respectively).In conclusion,our findings showed that the CYP2B6*9(G516T)polymorphism is associated with B-CLL susceptibility among Egyptian patients.This variant greatly affected the clinical outcome and can serve as a good therapeutic marker in predicting response to cyclophosphamide treatment.
基金National Key Research and Development Program of China,Grant/Award Number:2018YFA0901300National Natural Science Foundation of China,Grant/Award Numbers:22378305,32071411,32001034,21621004Tianjin Science and Technology Plan Project,Grant/Award Number:20JCQNJC00830。
文摘Electroactive microorganisms(EAMs)could utilize extracellular electron transfer(EET)pathways to exchange electrons and energy with their external surroundings.Conductive cytochrome proteins and nanowires play crucial roles in controlling electron transfer rate from cytosol to extracellular electrode.Many previous studies elucidated how the c-type cytochrome proteins and conductive nanowires are synthesized,assembled,and engineered to manipulate the EET rate,and quantified the kinetic processes of electron generation and EET.Here,we firstly overview the electron transfer pathways of EAMs and quantify the kinetic parameters that dictating intracellular electron production and EET.Secondly,we systematically review the structure,conductivity mechanisms,and engineering strategies to manipulate conductive cytochromes and nanowire in EAMs.Lastly,we outlook potential directions for future research in cytochromes and conductive nanowires for enhanced electron transfer.This article reviews the quantitative kinetics of intracellular electron production and EET,and the contribution of engineered c-type cytochromes and conductive nanowire in enhancing the EET rate,which lay the foundation for enhancing electron transfer capacity of EAMs.
文摘Physicians are often faced with the fact that the duration of anesthesia varies in different patients, which significantly complicates the process of surgical intervention and may confront the surgeon with an unforeseen situation. Recently, publications have appeared in the literature on the effects of various, including exotic products on anesthesia. There are also many conflicting statements about the effect of camel milk (CM) on the duration of anesthesia. Some data show that CM prolongs anesthesia, while other scientists argue the exact opposite: CM shortens the effect of the anesthetic. We decided to shed light on these studies by analyzing the effect of CM consumption on the effectiveness of local anesthesia in different patients. This article highlights the significant changes that occur in anesthesia due to the patients’ diet. To achieve the set goal, we sort the twenty patients underwent local anesthesia into groups depending on the habit of using CM. The first, control, group consisted of practically healthy patients who did not use CM throughout their lives, and the second group had the habit of regularly taking CM. In both groups, local anesthesia was first performed without pre-drink CM. For the second time, participants in the control and experimental groups were asked to drink CM before the anesthesia procedure. Both in the control and experimental groups, patients drank CM one hour before local anesthesia. A significant correlation was found between the use of CM and the duration of anesthesia in both groups. Consumption of CM had a different effect on the duration of local anesthesia in the experimental and control groups. When milk was consumed before the use of analgesics in these two different groups, it changed exactly the opposite: for those who usually drink milk, it was shortened, and for those who did not drink it daily, lengthened. Thus, we found that the differences in the statements of scientists about the CM impact on anesthesia are based on the fact of different effects of CM in it
文摘Cytochrome P4501A (the CYP1A1 and CYP1A2 enzymes) are regulated through the aryl hydrocarbon receptor (AhR)-dependent signal transduction pathway and are generally known as enzymes which metabolize anthropogenic xenobiotics such as dioxin to carcinogenic and mutagenic compounds. However, recently the facts of CYP1A activation under physiological conditions or under action of non-dioxin-like compounds appear. In the present study we show that genistein, herbimycin A and geldanamycin (the protein-tyrosine kinase inhibitors) affect in vivo to CYP1A1 activity, the CYP1A1 mRNA level and the CYP1A1 protein level. These data provide insight into the role of protein kinases in CYP1A regulation may facilitate the understanding of CYP1A regulation.
基金Supported by National Natural Science Foundation of China:Mechanism of Protective Effects of Moxibustion on Regulating m TOR Signaling Pathway and Inhibiting Autophagy in Rats(No.81574084)Key Research and Development Program of Anhui Province:Mechanism and Clinical Application of Moxibustion in that Treatment of Chronic Heart Failure(No.202004j07020045)+1 种基金Open Fund Project of Key Laboratory of Xin’an Medical Education Ministry:Effect of Moxibustion on Myocardial Cell Energy Metabolism in Chronic Heart Failure Patients Based on Xin’an Physician’s Theory of Strengthening the Foundation and Cultivating the Original(No.2020xayx07)Key Natural Science Projects of Anhui Provincial Education Department:Mechanism of Moxibustion Against CHF Fibrosis Based on mi R-21/PTEN/m TOR Signaling Pathway-mediated Regulation of Autophagy in Myocardial Cells by circ PAN3(No.KJ2021A0570)。
文摘OBJECTIVE:To observe the effects of moxibustion at bilateral Feishu(BL13)and Xinshu(BL15)combined with benazepril on myocardial cells apoptosis index,the expression levels of apoptosis-related proteins cytochrome c(Cyt-C)and apoptosis-inducing factor(AIF)in chronic heart failure(CHF)rats.METHODS:Sixty-five rats were randomly divided into normal group(n=10)and model-I group(n=55).After modeling,CHF rats in model-I group were divided into model group,moxibustion group,benazepril group,moxibustion plus benazepril group(abbreviated as aibei group,the same below),10 rats in each group.Echocardiogram index was examined by echocardiography.Hemodynamic indices were measured by rat cardiac function meter.Serum B-type brain natriuretic peptide(BNP)was detected by enzymelinked immunosorbent assay.Myocardial cells apoptosis index was detected by terminal-deoxynucleoitidyl transferase mediated nick end labeling staining.Pathological changes of myocardial tissues were observed by hematoxylin and eosin staining.The expression levels of Cyt-C and AIF in myocardial tissues were detected by Western blot.RESULTS:Compared with normal group,ejection fraction and left ventricular diameter shortening rate in model-Ⅰgroup were significantly reduced,myocardial cells of rats in model group exhibited unclear transverse striations,cells swellings and vacuoles,cardiac functions were deteriorated,serum BNP level,myocardial cells apoptosis index,and the expression levels of Cyt-C and AIF were significantly increased.Compared with model group,myocardial cells of rats in moxibustion group,benazepril group,and aibei group were dyed more evenly,muscle fibers were arranged relatively neatly,cardiac functions were improved,serum BNP level,myocardial cells apoptosis index,and the expression levels of Cyt-C and AIF were significantly decreased.Compared with aibei group,cardiac functions were worsened,myocardial cells apoptosis index,and the expression levels of Cyt-C and AIF were increased.CONCLUSION:Moxibustion at bilateral Feishu(BL13)and Xinshu(B
