Meta-analysis of Cytochrome P4501A1 MspI Gene Polymorphism and Childhood Acute Leukemia

Objective To investigate the relationship between cytochrome P4501A1 （CYPIA1） Msp I gene polymorphism and childhood acute leukemia （AL）. Methods Relevant literature was extensively searched and screened by Pubmed and Wanfang Database, Chinese Science Journal Database and Chinese Journal Net. Various data consolidation, combined OR values and their 95% CI were tested by RevMan 4.2; Funnel plots were used for the bias analysis. Results Six related literatures were found to meet the requirements. According to heterogeneity results, there was no significant difference in homozygous types（P〉0.05）, while there was significant difference in two others types （P all〈0.05）. For wild CYPIAIMspl homozygous for the reference group, Combined OR of heterozygous mutation, homozygous, heterozygous ＋ homozygous mutation in AL and control groups were 1.18, 0.96, and 1.10 respectively. Subgroup analysis： Z values of CYP1A1Mspl homozygous, heterozygous ＋ homozygous in the acute lymphoblastic leukemia （ALL） and the control group were 0.10 and 0.76 respectively, Z values in non-acute lymphoblastic leukemia and control group were 0.74 and 0.75. Conclusion There is no correlation between CYP1A1Mspl gene polymorphism and the susceptibility of childhood AL.

The benzo(a) pyrene-induced mRNA expression of aromatic hydrocarbon receptor and cytochrome P4501A1 genes in rat liver

Objective To study the benzo(a)pyrene(B[a]P)-induced mRNA expression of aromatic hydrocarbon receptor(AHR)and cytochrome P4501A1(CYP1A1)genes in rat liver.Methods Rats were injected intraperitoneally with 5,10 and 15mg/kg of B[a]P.The total RNAs were extracted from rat livers by RNA purification kit,and the mRNA expression of AHR and CYP1A1 genes was determined by reverse transcription polymerase chain reaction(RT-PCR).β-actin was used as the internal control.The mRNA expression of both AHR and CYP1A1 genes was measured at indicated time points(24,48 and 72h)after B[a]P treatment at three different concentrations(5,10 and 15mg/kg).Results The mRNA expression of AHR gene increased in a time-dependent manner at the concentration of 10mg/kg but not at 5 and 15mg/kg of B[a]P.The mRNA expression of CYP1A1 gene differed significantly at 48h and 24h in rat livers treated with 10 and 15mg/kg dosage of B[a]P.The mRNA expression of AHR and CYP1A1 genes increased with B[a]P treatment in a concentration-dependent manner.The time-dependent increase in mRNA expression was shown by AHR but not by CYP1A1 gene with B[a]P(10mg/kg)treatment.Conclusion This study demonstrates that toxic B[a]P increases the mRNA expression of both AHR and CYP1A1 genes in vivo,suggesting that B[a]P may play a role in cancer genesis by this way.

Sensing cytochrome P4501A1 activity by a resorufin-based isoform-specific fluorescent probe

Cytochrome P4501 A1(CYP1A1),a heme-containing monooxygenase,is of particular importance for human health because of its vital roles in the metabolic activation of pro-carcinogenic compounds to the carcinogens.Deciphering the relevance of CYP1A1 to human diseases and screening of CYP1A1 modulators require reliable tool(s)for probing this key enzyme in complex biological matrices.Herein,a practical and ultrasensitive fluorescence-based assay for real-time sensing CYP1A1 activities in biological systems has been developed,via designing an isoform-specific fluorogenic sensor for CYP1A1(CHPO).The newly developed fluorogenic substrate for CYP1A1 has been carefully investigated in terms of specificity,sensitivity,precision,quantitative linear range and the anti-interference ability.The excellent selectivity,strong anti-interference ability and fast response kinetics,making the practicability of CHPObased CYP1A1 activity assay is better than that of most reported CYP1A1 activity assays.Furthermore,CHPO has been successfully used for imaging CYP1A1 activities in living cells and human tissues,as well as for high-throughput screening of CYP1A1 inhibitors using tissue preparations as enzyme sources.Collectively,this study provided a practical fluorogenic sensor for real-time sensing CYP1A1 in complex biological systems,which would strongly facilitate the investigations on the relevance of CYP1A1 to human diseases and promote high-throughput screening of CYP1A1 modulators for biomedical applications.

Detoxification Efforts in Longnose Dace (Rhinichthys cataractae) Exposed to Municipal and Agricultural Inputs

Ecological impacts of contaminants on population patterns in wild fish are impacted by many contaminants that readily enter aquatic systems. Responses to toxicants by individuals in lab studies generally do not predict population level consequences in natural systems. Trace levels of contaminants are present in all major rivers in southern Alberta, Canada, with concentrations higher down-stream of anthropogenic inputs like agricultural land-use and inputs of municipal wastewater effluents. Longnose dace (Rhinichthys cataractae) were used as a sentinel species to study field-based population-level responses to contaminants. We hypothesized that biomarker activity, triggered by contaminant exposure, should increase downstream of anthropogenic inputs in two southern Alberta rivers, with corresponding relations between biomarker activity and sex ratios, after accounting for age structure. Liver detoxification (ethoxyresorufin-O-deethylase activity = EROD) measured at reference and exposed sites on each river differed significantly in only the Bow River system. Sex ratios varied more downstream of anthropogenic inputs than upstream, but the direction of sex ratio bias was inconsistent and temporally dynamic. Sex ratios correlated with liver detoxification in only the Bow River. Taken together, these results suggest that contaminants alter sex ratios in long-nose dace, but that there is variation in anthropogenic stressors among rivers.

Single-cell RNA-seq unveils critical regulators of human FOXP3^+regulatory T cell stability

The heterogeneity and plasticity of T lymphocytes is critical for determining immune response outcomes.Functional regulatory T(Treg)cells are commonly characterized by stable FOXP3 expression and have reported to exhibit heterogeneous phenotypes under inflammatory conditions.However,the interplay between inflammation and Treg cell suppressive activity still remains elusive.Here,we utilized singlecell RNA sequencing to investigate how human Treg cells respond to the pro-inflammatory cytokine interleukin-6(IL-6).We observed that Treg cells divided into two subpopulations after IL-6 stimulation.TIGITàunstable Treg cells lost FOXP3 expression and gained an effector-like T cell phenotype,whereas TIGIT+Treg cells retained robust suppressive function.Single cell transcriptome analysis revealed a spectrum of cellular states of IL-6-stimulated Treg cells and how cytochrome P450 family 1 subfamily A member 1(CYP1A1)is a crucial regulator of Treg cell suppressive capability and stability.CYP1A1-deficient human Treg cells developed a Th17-like phenotype after IL-6 stimulation.Our findings implicate CYP1A1 as a previously unidentified regulator of Treg cells that may have target potential for clinical application for biotherapies.

Hepatoprotective and antioxidant effects of dietary Glycyrrhiza polysaccharide against TCDD-induced hepatic injury and RT-PCR quantification of AHR2,ARNT2,CYPIA mRNA in Jian Carp(Cyprinus carpio var.Jian)

To evaluate the protective effects of Glycyrrhiza polysaccharide（GPS） against 2,3,7,8-tetrachlorodibenzo-p-dioxin（TCDD）-induced hepatotoxicity in Jian carp,the fish were fed diets containing GPS at doses of 0.1,0.5 and 1.0 g/kg for 60 days before an intraperitoneal injection of 0.6 μg/kg TCDD at a volume of 0.05 mL/10 g body weight.At 72 hr post-injection,blood and liver samples were taken for biochemical analysis and the fish liver samples were used for the preparation of pathological slices.The results showed that increases in alanine aminotransferase（GPT）,aspartate aminotransferase（GOT）,lactate dehydrogenase（LDH）,and alkaline phosphatase（AKP） in serum induced by TCDD were significantly inhibited by pre-treatment with 1.0 g/kg GPS.Following the 1.0 g/kg GPS pre-treatment,total protein（TP）,albumin（Alb）,catalase（CAT）,glutathione peroxidase（GPx）,total antioxidant capacity（T-AOC） and superoxide dismutase（SOD） activities in liver tissue increased significantly,malondialdehyde（MDA） formation（P ＆lt; 0.05 or P ＆lt; 0.01） was significantly inhibited,and the expression of cytochrome P4501A（CYP1A）,aryl hydrocarbon receptor 2（AHR2） and aryl hydrocarbon receptor nuclear translocator 2（ARNT2） mRNA（P ＆lt; 0.05） was significantly enhanced.Histological observations on fish liver were obtained by preparing paraffin tissue sections via HE staining,and the results showed that histological changes were obviously reduced by 0.5 and 1.0 g/kg GPS.GPS significantly reduced liver tissue damage caused by TCDD.Overall,these results proved the hepatoprotective effect of GPS in protecting against fish liver injury induced by TCDD,and supported the use of GPS（1.0 g/kg） as a hepatoprotective and antioxidant agent in fish.