خيارات البحث
النتائج 1 - 7 من 7
BPA modulates the WDR5/TET2 complex to regulate ERβ expression in eutopic endometrium and drives the development of endometriosis
2021
Xue, Wen | Yao, Xiong | Ting, Geng | Ling, Jin | Huimin, Liu | Yuan, Qiao | Chun, Zhou | Ming, Zhang | Yuanzhen, Zhang
Overexpression of estrogen receptor β (ERβ) in endometrium contributes to endometriosis (EM) pathogenesis. Trimethylation of the H3 lysine (K) 4 (H3K4me3) in promoters is strongly correlated with gene expression. This study aimed to explore the effects of bisphenol A (BPA) exposure on EM development from the perspective of the regulation of ERβ expression in eutopic endometrium via the H3K4me3-related epigenetic pathway. A mouse EM model was established to investigate the effects of BPA. Immortalized human normal endometrial stromal cells (iESCs) were cultured and treated with BPA to explore the underlying mechanism. Eutopic endometria from patients with or without EM were collected and analyzed. Results showed that BPA elevated ERβ expression in mouse eutopic endometrium and promoted lesion growth. BPA also promoted WD repeat domain 5 (WDR5) expression and upregulated H3K4me3 levels in the ERβ promoter and Exon 1. Further research indicated that WDR5 interacted with tet methylcytosine dioxygenase 2 (TET2), while BPA exposure enhanced the interaction between these two proteins, promoted the recruitment of the WDR5/TET2 complex to the ERβ promoter and Exon 1, and inhibited DNA methylation of CpG islands. The WDR5/TET2 interaction was essential for BPA-induced ERβ overexpression. Enhanced WDR5/TET2 interaction was also observed in eutopic endometria from EM patients. Further results showed that BPA upregulated WDR5 expression through the G protein-coupled estrogen receptor (GPER)-mediated PI3K/mTOR signaling pathway. In conclusion, our study suggests that BPA exposure promotes EM development by upregulating ERβ expression in eutopic endometrium via the WDR5/TET2-mediated epigenetic pathway.
اظهر المزيد [+] اقل [-]The interaction effects of FEN1 rs174538 polymorphism and polycyclic aromatic hydrocarbon exposure on damage in exon 19 and 21 of EGFR gene in coke oven workers
2021
Chen, Siqin | He, Yuefeng | Yan, Maosheng | Zhou, Yun | He, Qinghua | Tan, Jingwen | Yang, Binyao
Polycyclic aromatic hydrocarbon (PAH) exposure and genetic susceptibility were conductive to genotoxic effects including gene damage, which can increase mutational probability. We aimed to explore the dose-effect associations of PAH exposure with damage of exons of epidermal growth factor receptor (EGFR) and breast cancer susceptibility gene 1 (BRCA1), as well as their associations whether modified by Flap endonuclease 1 (FEN1) genotype. Two hundred eighty-eight coke oven male workers were recruited, and we detected the concentration of 1-hydroxypyrene (1-OH-pyr) as PAH exposure biomarker in urine and examined base modification in exons of EGFR and BRCA1 respectively, and genotyped FEN1 rs174538 polymorphism in plasma. We found that the damage indexes of exon 19 and 21 of EGFR (EGFR-19 and EGFR-21) were both significantly associated with increased urinary 1-OH-pyr (both Pₜᵣₑₙd < 0.001). The levels of urinary 1-OH-pyr were both significantly associated with increased EGFR-19 and EGFR-21 in both smokers and nonsmokers (both P < 0.001). Additionally, we observed that the urinary 1-OH-pyr concentrations were linearly associated with both EGFR-19 and EGFR-21 only in rs174538 GA+AA genotype carriers (both P < 0.001). Moreover, FEN1rs rs174538 showed modifying effects on the associations of urinary 1-OH-pyr with EGFR-19 and EGFR-21 (both Pᵢₙₜₑᵣₐcₜᵢₒₙ < 0.05). Our findings revealed the linear dose-effect association between exon damage of EGFR and PAH exposure and highlight differences in genetic contributions to exon damage and have the potential to identify at-risk subpopulations who are susceptible to adverse health effects induced by PAH exposure.
اظهر المزيد [+] اقل [-]Alteration in antioxidant status in slow and fast alleles of EPHX1 gene polymorphisms among wood workers
2021
Occupational wood dust exposure may be associated with various health effects, especially in wood industry. These effects may be due to inducing oxidative stress which is related to inflammations. Biochemical assessment of antioxidant enzyme activities illustrated role of oxidative stress (OS) on its depletion. Super oxide dismutase, glutathione peroxidase (GPx) and catalase (CAT) were analyzed in 50 exposed workers and 50 control subjects. Also, macrophage inflammatory protein-2 was assessed among these workers as it was produced upon dust exposure. Microsomal epoxide hydrolase (EPHX1) enzyme shared in the protective mechanism against wood dust oxidative stress. It plays a dual role in the metabolism of environmental pollutants, detoxification, and bioactivation. Gene polymorphisms of EPHX1 may be associated with variations in enzyme activity. Polymorphisms in exons 3 and 4 have resulted in either decreased (slow conjugating allele) or increased (fast conjugating allele) activity in vitro. We aimed to evaluate the associations between EPHX1 polymorphisms and change in antioxidant status (SOD, CAT, and GPx) among wood dust exposed workers. EPHX1 genotyping in exon 3 and exon 4 polymorphisms was carried out by PCR-RFLP. Our result shows a significant reduction in enzymatic antioxidants (SOD, CAT, and GPx) levels with significant rise in MIP-2 levels in worker group. Also, there are significant variations in SOD, CAT, and GPx levels as well as in MIP-2 in different genotypes of EPHX polymorphisms in exon 3 or 4 (specially in Hist-Hist genotypes in both exons). We can conclude an alteration in antioxidant status in both slow and fast allele of EPHX gene polymorphisms with release of MIP-2 protein in wood workers.
اظهر المزيد [+] اقل [-]Ecology and population structure of some indigenous geese breeds and the impact of four GH and Pit-1 SNPs on their body weights
2021
Abdel Moniem, Hebatallah | Yusuf, Mohamed Sayed | Chen, Guohong
This study aims to determine the genetic correlation using nine microsatellite markers to reconstruct the history of some indigenous geese populations, along with the use of four single nucleotides polymorphisms (SNPs) to investigate their correlation with the geese body weight. Microsatellite markers are mainly used to provide updated information on changes in the population structure of geese breeds. The eight goose populations reported 24% private alleles specific for each population. Expected heterozygosity (He) ranged from 0.46 to 0.70. Three breeds were reported highly polymorphic. Inbreeding coefficient (Fis) revealed that three breeds were in a minimum level of extinction danger, while one breed was in a potential endangered situation. Phylogenetic tree, principal component analysis (PCA), and self-organizing map (SOM) were constructed using MATLAB to study the population distribution and relationship among these breeds. Four SNPs were detected, two SNPs at GH gene exon (C123T and C158T), and two SNPs at Pit-1 gene exons (G161A and T282G). Four SNP loci were reported to have a significant effect on geese body weight. They were CT genotype for C123T locus, TT genotype for C158T locus, GG genotype for G161A locus, and GG genotype for T282G locus.
اظهر المزيد [+] اقل [-]Correlation of MSH2 exonic deletions and protein downregulation with breast cancer biomarkers and outcome in Pakistani women/patients
2021
Malik, Saima Shakil | Mubarik, Sumaira | Aftab, Ayesha | Khan, Ranjha | Masood, Nosheen | Asif, Muhammad | Raja Bano,
Mismatch repair (MMR) pathway is one of the underlying mechanisms of predisposition to breast cancer (BC). The present study explored the association of MSH2 exonic deletions, respective survival analysis, protein structure prediction, transcription profiling, and expression analysis with BC risk. Genotyping analysis of 493 BC cases and 387 controls confirmed the association of two MSH2 exonic deletions, i.e., exon 3 (OR:6.4, CI = 3.4–12.1) and 9 (OR:7.8, CI = 4.1–14.8) with BC risk. In order to confirm the phenotypic–genotypic relationship, we have performed MSH2 transcriptomic (p < 0.05) and protein expression analysis (OR:30, CI = 4–230) which further confirmed its downregulation/loss in BC biopsy samples highlighting potential role in the onset of breast carcinogenesis. Additionally, we have presented that MSH2 mutations can alter the expression profile of other BC associated biomarkers like ER, PR, CK–7, GATA–3, and E–cadherin. Subsequently, the effect of exonic deletions on secondary structure of protein has shown missing of beta and alpha helices in their protein products via in-silico analysis. However, loss of exon 3 results in the altered core protein structure leading to dysfunction protein, possible cause of BC development. No association of MSH2 exonic deletions with survival statistics was observed conceivably due to the shorter follow-up time. Thus, our results at genetic, transcriptomic, and proteomic levels confirmed the downregulated MSH2, emphasizing its potential contribution in MMR mechanisms for breast tumorigenesis. In conclusion, MSH2 deficiency may cause breast cancer development and progression.
اظهر المزيد [+] اقل [-]Estimation of genomic instability and mutation induction by graphene oxide nanoparticles in mice liver and brain tissues
2020
Mohamed, Hanan R. H. | Welson, Mary | Yaseen, Ahmed Essa | EL-Ghor, Akmal A.
The rapidly growing interest in using graphene-based nanoparticles in a wide range of applications increases human exposure and risk. However, very few studies have investigated the genotoxicity and mutagenicity of the widely used graphene oxide (GO) nanoparticles in vivo. Consequently, this study estimated the possible genotoxicity and mutagenicity of GO nanoparticles as well as possible oxidative stress induction in the mice liver and brain tissues. Nano-GO particles administration at the dose levels of 10, 20, or 40 mg/kg for one or five consecutive days significantly increased the DNA breakages in a dose-dependent manner that disrupts the genetic material and causes genomic instability. GO nanoparticles also induced mutations in the p53 (exons 6&7) and presenilin (exon 5) genes as well as increasing the expression of p53 protein. Positive p53 reaction in the liver (hepatic parenchyma) and brain (cerebrum, cerebellum, and hippocampus) sections showed significant increase of p53 immunostaining. Additionally, induction of oxidative stress was proven by the significant dose-dependent increases in the malondialdehyde level and reductions in both the level of reduced glutathione and activity of glutathione peroxidase observed in GO nanoparticles administered groups. Acute and subacute oral administration of GO nanoparticles induced genomic instability and mutagenicity by induction of oxidative stress in the mice liver and brain tissues.
اظهر المزيد [+] اقل [-]Lifestyle chemical carcinogens associated with mutations in cell cycle regulatory genes increases the susceptibility to gastric cancer risk
2018
Yadav, Ravi Prakash | Ghatak, Souvik | Chakraborty, Payel | Lalrohlui, Freda | Kannan, Ravi | Kumar, Rajeev | Pautu, Jeremy L. | Zomingthanga, John | Chenkual, Saia | Muthukumaran, Rajendra | Senthil Kumar, Nachimuthu
In the present study, we correlated the various lifestyle habits and their associated mutations in cell cycle (P21 and MDM2) and DNA damage repair (MLH1) genes to investigate their role in gastric cancer (GC). Multifactor dimensionality reduction (MDR) analysis revealed the two-factor model of oral snuff and smoked meat as the significant model for GC risk. The interaction analysis between identified mutations and the significant demographic factors predicted that oral snuff is significantly associated with P21 3′UTR mutations. A total of five mutations in P21 gene, including three novel mutations in intron 2 (36651738G > A, 36651804A > T, 36651825G > T), were identified. In MLH1 gene, two variants were identified viz. one in exon 8 (37053568A > G; 219I > V) and a novel 37088831C > G in intron 16. Flow cytometric analysis predicted DNA aneuploidy in 07 (17.5%) and diploidy in 33 (82.5%) tumor samples. The G2/M phase was significantly arrested in aneuploid gastric tumor samples whereas high S-phase fraction was observed in all the gastric tumor samples. This study demonstrated that environmental chemical carcinogens along with alteration in cell cycle regulatory (P21) and mismatch repair (MLH1) genes may be stimulating the susceptibility of GC by altering the DNA content level abnormally in tumors in the Mizo ethic population.
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