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genetic variant in a BaP-activated super-enhancer increases prostate cancer risk by promoting AhR-mediated FAM227A expression

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Journal of Biomedical Research 2024年第2期38卷 149-162,I0001-I0010页

作者： Lulu Fan Hao Wang Shuai Ben Yifei Cheng Silu Chen Zhutao Ding Lingyan Zhao Shuwei Li Meilin Wang Gong Cheng Department of Environmental Genomics Jiangsu Key Laboratory of Cancer BiomarkersPrevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineSchool of Public HealthNanjing Medical UniversityNanjingJiangsu 211166China Department of genetic toxicology the Key Laboratory of Modern Toxicology of Ministry of EducationCenter for Global HealthSchool of Public HealthNanjing Medical UniversityNanjingJiangsu 211166China Department of Urology the First Affiliated Hospital of Nanjing Medical UniversityJiangsu Province HospitalNanjingJiangsu 210029China

genetic variants in super-enhancers(SEs)are increasingly implicated as a disease risk-driving *** studies have reported an associations between benzo[a]pyrene(BaP)exposure and some malignant tumor ***,it is unclear whether BaP is involved in the effect of genetic variants in SEs on prostate cancer risk,nor the associated intrinsic molecular *** the current study,by using logistic regression analysis,we found that rs5750581T>C in 22q-SE was significantly associated with prostate cancer risk(odds ratio=1.26,P=7.61×10^(-5)).We also have found that the rs6001092T>G,in a high linkage disequilibrium with rs5750581T>C(r^(2)=0.98),is located in a regulatory aryl hydrocarbon receptor(AhR)motif and may interact with the FAM227A promoter in further bioinformatics *** then performed a series of functional and BaP acute exposure experiments to assess biological function of the genetic variant and the target ***,the rs6001092-G allele strengthened the transcription factor binding affinity to AhR,thereby upregulating FAM227A,especially upon exposure to BaP,which induced the malignant phenotypes of prostate *** current study highlights that AhR acts as an environmental sensor of BaP and is involved in the SE-mediated prostate cancer risk,which may provide new insights into the etiology of prostate cancer associated with the inherited SE variants under environmental carcinogen stressors.

关键词： super-enhancer prostate cancer genetic variants AhR BaP FAM227A

UM15 reinforces a lymphocyte-mimicking nanotrap for precise HIV-1 inhibition

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Nano Research 2023年第7期16卷 9906-9920页

作者： Jinbang Zhang Zhengyang Li Jiaxin Li Hui Li Junwei Che Te Zhao Pengfei Zou Jingwan Han Yang Yang Meiyan Yang Yuli Wang Wei Gong Haihua Xiao Zhiping Li Lin Li Chunsheng Gao State key laboratory of toxicology and Medical Countermeasure Beijing Institute of Pharmacology and ToxicologyBeijing 100039China Pharmaceutical College Henan UniversityKaifeng 475001China State Key laboratory of Pathogen and Biosecurity Beijing Institute of Microbiology and EpidemiologyBeijing 100071China School of Public Health and Health Management Gannan Medical UniversityGanzhou 341000China Institute of Chemistry Chinese Academy of SciencesBeijing 100190China

Even the potential of T cell-mimicking nanotrap for long term viral control due to its overcoming of human immunodeficiency virus(HIV)genetic diversity and viral resistance,the robust HIV inhibition was not expected because these nanotraps displayed no obvious advantages compared with the infinite host ***,a glycoprotein 120(gp120)-targeting polypeptide UM15 reinforced lymphocyte-mimicking nanotrap was constructed,and its improved HIV-1 inhibiting efficacy was *** to the results,the constructed nanotraps exhibited evident escaping ability from uptake of the mononuclear phagocyte system and highly improved binding ability with gp120 *** constructed nanotraps neutralized all tested HIV-1 pseudo typed viruses with IC80 of 21.0μg/mL,and inhibited both X4-tropic and R5-tropic HIV-1 with IC80 of 34.4 and 20.6μg/mL,*** 40%of gp120 was observed to be shed from pseudo virus,and above 40%bystander T cells were prevented from gp120-induced death by the constructed *** safety of the constructed nanotraps was confirmed both in vitro and in ***,the constructed nanotraps could specifically neutralize free HIV-1,selectively bind with gp120 expressing HIV-1 infected cells,cause gp120 shedding,inhibit gp120-induced bystander T cell killing on the premise of safety,and were considered as promising therapeutic agents for precise inhibition of HIV.

关键词： nanotrap lymphocyte membrane UM15 human immunodeficiency virus-1(HIV-1) glycoprotein 120(gp120)

genetic variants in TP53 and MDM2 associated with male infertility in Chinese population

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Asian Journal of Andrology 2012年第5期14卷 691-694页

作者： Cong Huang Wei Liu Gui-Xiang Ji Ai-Hua Gu Jian-Hua Qu Ling Song Xin-Ru Wang State Key laboratory of Reproductive Medicine Institute of ToxicologyNanjing Medical UniversityNanjing 210029China Key laboratory of Modern toxicology of Ministry of Education School of Public HealthNanjing Medical UniversityNanjing 210029China Nanjing Institute of Environmental Sciences/Key laboratory of Pesticide Environmental Assessment and Pollution Control Ministry of Environmental ProtectionNanjing 210042China School of Public Health Nantong UniversityNantong 226019China

The TP53, a transcriptional regulator and tumor suppressor, is functionally important in spermatogenesis. MDM2 is a key regulator of the p53 pathway and modulates p53 activity. Both proteins have been functionally linked to germ cell apoptosis, which may affect human infertility, but very little is known on how common polymorphisms in these genes may influence germ cell apoptosis and the risk of male infertility. Thus, this study was designed to test whether three previously described polymorphisms 72Arg〉Pro （rs1042522） and the Ex2＋ 19C〉T （rs2287498） in TP53, and the 5＇ untranslated region （5＇ UTR） 309T〉G （rs937283） in MDM2, are associated with idiopathic male infertility in a Chinese population. The three polymorphisms were genotyped using OpenArray assay in a hospital-based case-control study, including 580 infertile patients and 580 fertile controls. Our analyses revealed that TP53 Ex2-1-19C〉T and MDM2 309T〉G polymorphisms are associated with male infertility. Furthermore, we detected a nearly statistically significant additive interaction between TP53 rs2287498 and MDM2 rs937283 for the development of male infertility （Pinteraction--O-055）- In summary, this study found preliminary evidence, demonstrating that genetic variants in genes of the TP53 pathway are risk factors for male infertility.

关键词： apoptosis male infertility MDM2 polymorphisms TP53

Theaflavin-3,3'-digallate might affect leptin-deficient nonalcoholic fatty liver disease via lipid metabolism regulated by Fads1/Pparδ/Fabp4 axis and gut microbiota

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Theaflavin-3,3'-digallate might affect leptin-deficient nona...

Bladder cancer epidemiology and genetic susceptibility

中国毒理学会第十次全国毒理学大会

作者： Cheng Zhou Wenji Zhang Luyun Zhang Fan Wu Yan Wang Susu Yu Xinyue Peng Wenli Cheng Min Li Xiaoying Pan Zhenrui Huang Wenjuan Zhang Department of toxicology School of Medicine Jinan University Key laboratory of Crop genetic Improvement Guangdong Academy of Agricultural Sciences

Objective Theaflavin-3, 3′-digallate(TF3), a kind of polyphenol compound extracted from black tea, has been reported to produce an effect on hypoglycemic and anti-lipid deposition in vitro. In this study, the function and novel mechanism of TF3 were investigated in protecting NAFLD in vivo. Materials and Methods C57BL/6J mice were the control group with saline(WT), and ob/ob mice were randomized into five groups, including the model group with saline(ob/ob), the positive group with polyene phosphatidyl choline of 3000 μL/kg(ob/ob + PPC), low TF3 group with the dose of 5 mg/kg(ob/ob + L-TF3), middle TF3 group with the dose of 10 mg/kg(ob/ob + M-TF3) and high TF3 group with the dose of 20 mg/kg(ob/ob + H-TF3). The intraperitoneal injection administration was performed every day for 4 weeks. The serum and tissue samples were obtained at the end of the experiment. Then the biochemical and histological analyses, transcriptome sequencing and 16S rRNA sequencing were performed further. Results TF3 treatment prevented body weight and waistline gain, reduced lipid accumulation, and alleviated liver function injury, as well as decreased serum lipid levels and TG levels in livers in ob/ob mice, with no side effects. Furthermore, the transcriptome sequencing of liver tissue showed that TF3 treatment corrected the expression profile of livers in ob/ob mice compared with that of the model group. It was interesting to note that TF3 might regulate lipid metabolism via the Fads1/Pparδ/Fabp4 axis. In addition, 16S rRNA sequencing demonstrated that TF3 increased the abundance of PrevotellaceaeCG-001, norankuminococcaceae, and GCA-900066575 and significantly decreased that of Parvibacter. Conclusion The effects of TF3 on NAFLD might be related to lipid metabolism regulated by the Fads1/PPARδ/Fabp4 axis and gut microbiota, as a promising candidate for the prevention and therapy of NAFLD.

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来源： cnki会议评论

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The Journal of Biomedical Research 2013年第3期27卷 170-178页

作者： Haiyan Chu Meilin Wang Zhengdong Zhang Department of Environmental Genomics Jiangsu Key Laboratory of Cancer BiomarkersPrevention and TreatmentCancer CenterNanjing Medical University Department of genetic toxicology the Key Laboratory of Modern Toxicology of Ministry of EducationSchool of Public HealthNanjing Medical University

Bladder cancer is the most common malignancy of the urinary system. The incidence of bladder cancer of men is higher than that of women （approximately 4：1）. Here, we summarize the bladder cancer-related risk factors, in- cluding environmental and genetic factors. In recent years, although the mortality rate induced by bladder cancer has been stable or decreased gradually, the public health effect may be pronounced. The well-established risk fac- tors for bladder cancer are cigarette smoking and occupational exposure. genetic factors also play important roles in the susceptibility to bladder cancer. A recent study demonstrated that hereditary non-polyposis colorectal cancer is associated with increased risk of bladder cancer. Since 2008, genome-wide association study （GWAS） has been used to identify the susceptibility loci for bladder cancer. Further gene-gene or gene-environment interaction stud- ies need to be conducted to provide more information for the etiology of bladder cancer.

关键词： bladder cancer molecular epidemiology risk factors genetic susceptibility

Evaluation of the Genotoxicity of Chlorpyrifos in Common Indus Valley Toad, <i>Bufo stomaticus</i>Using Alkaline Single-Cell Gel Electrophoresis (Comet) Assay

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Agricultural Sciences 2014年第4期5卷 376-382页

作者： Muhammad Ismail Qaiser Mahmood Khan Rahat Ali Tayyaba Ali Ameena Mobeen Department of Zoology Wildlife and Fisheries Government College University Faisalabad Faisalabad Pakistan Environmental toxicology laboratory National Institute for Biotechnology and Genetic Engineering (NIBGE) Faisalabad Pakistan

Chlorpyrifos is a commonly used pesticide of organophosphate group, which causes toxicological effects in non-target organisms especially fish and frogs. In the present study, the genotoxicity of sublethal concentrations of chlorpyrifos was observed in the erythrocytes of common Indus valley toad, Bufo stomaticus, using the Alkaline Single-Cell Gel Electrophoresis (Comet) assay. In the first step, acute toxicity of chlorpyrifos was evaluated by exposing the tadpoles to high concentrations of the pesticide. The acute LC50 value of chlorpyrifos, calculated by Trimmed Spearman-Karber (TSK) in static bioassay, was found to be 930.0 μg/L. On the basis of acute LC50 value, the tadpoles were exposed to three sublethal concentrations (155, 233 and 465 μg/L) of chlorpyrifos for 96 h. Blood cells were collected at every 24 h interval and were subjected to the Alkaline Single-Cell Gel Electrophoresis assay. The observed DNA damage was concentration and time-dependent, and those levels of DNA damage in between the tested concentrations and times were significantly different (p < 0.05). The tadpoles exposed to different concentrations of chlorpyrifos also showed different morphological abnormalities. It was concluded that chlorpyrifos is a genotoxic pesticide causing DNA damage in Bufo stomaticus.

关键词： Pesticide Chlorpyrifos Tadpoles DNA Damage Comet Assay

Synthesis of haptens and production of antibodies to bisphenol A

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Frontiers of Agricultural Science and Engineering 2017年第3期4卷 366-372页

作者： Xiya ZHANG Xiaoyun DONG Sijun ZHAO Yuebin KE Kai WEN Suxia ZHANG Zhanhui WANG Jianzhong SHEN Beijing Advanced Innovation Center for Food Nutrition and Human Health/College of Veterinary Medicine China Agricultural University Beijing Key laboratory of Detection Technology for Animal-Derived Food Safety Department for Safety Supervision of Animal Products China Animal Health and Epidemiology Center Department of genetic toxicology Shenzhen Center for Disease Control and Prevention Beijing laboratory for Food Quality and Safety/National Reference laboratory for Veterinary Drug Residues

Three immunizing haptens of bisphenol A(BPA), including two new haptens, were used to produce highly sensitive and specific polyclonal antibodies. The spacer arms of haptens for coupling to the protein carrier were located at different positions in BPA, and different length spacer arms were tested. Highly sensitive polyclonal antibodies were obtained and characterized using indirect competitive enzyme-linked immunosorbent assay(ic ELISA). Under optimized conditions, the half maximal inhibitory concentration(IC50) value of the best polyclonal antibody was 2.1 mg·L^(-1), based on coating heterogeneous antigens, and this optimal polyclonal antibody was highly sensitive toward BPA and displayed negligible crossreactivity with bisphenol B and bisphenol E. A sensitive ic ELISA method utilizing the polyclonal antibody was developed for the determination of BPA in milk. In spiked samples(5, 10 and 20 mg·L^(-1)), the recovery ranged from 80% to 102% with a coefficient of variation(CV) value below 15.8%. The limit of detection of ic ELISA was1.95 mg·L^(-1). These results indicate that the ic ELISA method is suitable for the detection of BPA in milk.

关键词： bisphenol A cross-reactivity hapten indirect competitive ELISA polyclonal antibody

Cannabinoid CB1 receptors are expressed in a subset of dopamine neurons and underlie cannabinoid modulation of DA release and DA-related behavior in mice

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中国药理学与毒理学杂志 2023年第7期37卷 535-536页

作者： HAN Xiao WU Ning XI Zhengxiong LI Jin Beijing Key laboratory of Neuropsychopharmacology State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and Toxicology Addiction Biology Unit Molecular Targets and Medications Discovery Branch Intramural Research Program National Institute on Drug Abuse

OBJECTIVE Cannabinoids modulate dopamine(DA) transmission and DA-related behavior,which has been thought to be mediated initially by activation of cannabinoid CB1 receptors(CB1Rs) on GABA neurons. However, the cellular and receptor mechanisms underlying cannabinoids′ psychoactive effects are not fully understood. The present study is to explore the possible expression character of CB1Rs and elucidated the underlying mechanism of them. METHODS We took advantage of RNAscope in situ hybridization(ISH)assays and triple-staining assays to detect the CB1Rexpressing neurons. We established an optical intracranial self-stimulation(OICSS) behavioral model by using optogenetics to study dopaminergic reinforcement *** and synthetic cannabinoids were used to study the function of CB1Rs. Conditional genetic depletion of CB1Rs and behavioral assay were performed to study the modulatory role of CB1Rs in DA-related *** We found that CB1Rs are also expressed in a subset of DA neurons and functionally underlie cannabinoid action in male and female mice. ISH assays demonstrated CB1 mRNA in tyrosine hydroxylase(TH)-positive DA neurons in the ventral tegmental area(VTA) and glutamate decarboxylase 1(GAD1)-positive GABA neurons. The CB1R expressing DA neurons were located mainly in the middle portion of the VTA with the number of CB1-TH colocalization progressively decreasing from the medial to the lateral VTA. Triple-staining assays indicated CB1R mRNA colocalization with both TH and vesicular glutamate transporter 2(VgluT2, a glutamate neuronal marker) in the medial VTA close to the midline of the brain. Optogenetic activation of this population of DA neurons was rewarding as assessed by OICSS.D9-tetrahydrocannabinol(D9-THC) or ACEA(a selective CB1R agonist) dose-dependently inhibited optical intracranial self-stimulation in DAT-Cre control mice, but not in conditional knockout mice with the CB1R gene absent in DA neurons. In addition, deletion of CB1Rs from

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Alternative polyadenylation-related genetic variants contribute to bladder cancer risk

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The Journal of Biomedical Research 2023年第6期37卷 405-417页

作者： Ting Liu Jingjing Gu Chuning Li Mengfan Guo Lin Yuan Qiang Lv Chao Qin Mulong Du Haiyan Chu Hanting Liu Zhengdong Zhang Department of Environmental Genomics Jiangsu Key Laboratory of Cancer BiomarkersPrevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineSchool of Public HealthNanjing Medical UniversityNanjingJiangsu 211166China Department of genetic toxicology the Key Laboratory of Modern Toxicology of Ministry of EducationCenter for Global HealthSchool of Public HealthNanjing Medical UniversityNanjingJiangsu 211166China Department of Urology Jiangsu Province Hospital of Traditional Chinese MedicineNanjingJiangsu 210029China Department of Urology the First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu 210029China

Aberrant alternative polyadenylation(APA)events play an important role in cancers,but little is known about whether APA-related genetic variants contribute to the susceptibility to bladder *** genome-wide association study performed APA quantitative trait loci(apaQTL)analyses in bladder cancer,and identified 17955 single nucleotide polymorphisms(SNPs).We found that gene symbols of APA affected by apaQTL-associated SNPs were closely correlated with cancer signaling pathways,high mutational burden,and immune *** analysis showed that apaQTL-associated SNPs rs34402449 C>A,rs2683524 C>T,and rs11540872 C>G were significantly associated with susceptibility to bladder cancer(rs34402449:OR=1.355,95%confidence interval[CI]:1.159-1.583,P=1.33×10^(−4);rs2683524:OR=1.378,95%CI:1.164-1.632,P=2.03×10^(−4);rs11540872:OR=1.472,95%CI:1.193-1.815,P=3.06×10^(−4)).Cumulative effect analysis showed that the number of risk genotypes and smoking status were significantly associated with an increased risk of bladder cancer(P_(trend)=2.87×10^(−12)).We found that PRR13,being demonstrated the most significant effect on cell proliferation in bladder cancer cell lines,was more highly expressed in bladder cancer tissues than in adjacent normal ***,the rs2683524 T allele was correlated with shorter 3′untranslated regions of PRR13 and increased PRR13 expression ***,our findings have provided informative apaQTL resources and insights into the regulatory mechanisms linking apaQTL-associated variants to bladder cancer risk.

关键词： alternative polyadenylation genetic variant bladder cancer PRR13 apaQTL