Correlation of Single Nucleotide Polymorphisms of PRM1, PRM2, PYGO2, and DAZL Genes with Male Infertility in North West of Iran.

OBJECTIVE: Almost half of infertility is related to male factors. Although the effect of genetic factors on male infertility is identified, about 30%-50% still has no proven cause and is classified as idiopathic infertility. This study was performed to investigate the correlation of some single nucleotide polymorphisms of PYGO2, DAZL, PRM1, and PRM2 genes with male infertility in idiopathic cases among the Iranian population. MATERIAL AND METHODS: In this case-control study, 120 idiopathic azoospermia or severe oligospermia patients in the range of 25-45 years and 120 fertile men in the same age range were recruited as case and control groups, respectively. Eight different single nucleotide polymorphisms including PRM1 rs737008, PRM1 rs423668, PRM2 rs1646022, PRM2 rs11645592, PYGO2 rs141722381, PYGO2rs61758741, DAZL rs75931701, and DAZL rs188506466 were genotyped by using ampli ficat ion-r efrac tory mutation system polymerase chain reaction methods. Hardy-Weinberg was calculated by using online website. Statistical Package for Social Sciences software was applied for statistical analysis. P value <.05 was considered significant. Thirty percent of the samples were regenotyped to confirm the obtained results. RESULTS: The obtained results showed a significant correlation between PYGO2 rs141722381 in the heterozygote form (odds ratio: 2.803, 95% CI: 1.397-5.626). Heterozygote over-dominance was also observed in this variant (odds ratio: 2.637, 95%CI: 1.321-5.264). There was no significant association between other studied single nucleotide polymorphisms and male infertility. CONCLUSION: This study proposed a novel single nucleotide polymorphism as a predisposition of male infertility among the Iranian population, but more studies in larger populations are needed to confirm the results.

Association of Novel Single Nucleotide Polymorphisms of Genes Involved in Cell Functions with Male Infertility: A Study of Male Cases in Northwest Iran.

BACKGROUND: Infertility is a global health problem caused by various environmental and genetic factors. Male infertility accounts for 40-50% of all cases of infertility and approximately half of them are grouped as idiopathic with no definitive causes. Previous studies have suggested an association between some SNPs and infertility in men. In this study, an attempt was made to investigate the association of 7 different SNPs of 4 genes involved in common cell functions with male infertility. METHODS: MTHFR rs1801131 (T>G), MTHFR rs2274976 (G>A), FASLG rs80358238 (A>G), FASLG rs12079514 (A>C), GSTM1 rs1192077068 (G>A), BRCA2 rs4987117 (C>T), and BRCA2 rs11571833 (A>T) were genotyped in 120 infertile men with idiopathic azoospermia or severe oligospermia and 120 proven fertile controls using ARMS-PCR methods. Next, 30% of SNPs were regenotyped to confirm the results. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using SPSS statistical software to evaluate the strength of association. The p<0.05 were considered statistically significant. RESULTS: Statistical analysis revealed significant association between MTHFR rs-2274976 AA variant (OR: 10.00, CI: 3.203-31.225), FASLG rs12079514 AC variant (OR: 0.412, CI: 0.212-0.800), and BRCA2 rs11571833 TT variant OR: 6.233, CI: 3.211-12.101) with male infertility, but there was no significant difference between case and control groups in MTHFR rs1801131 (p= 0.111), GSTM1 rs1192077068 (p=0.272), BRCA2 rs4987117 (p=0.221), and FASLG rs80358238 (p=0.161). CONCLUSION: Our findings suggested that some novel polymorphisms including MTHFR rs2274976, FASLG rs12079514, and BRCA2 rs11571833 might be the possible predisposing risk factors for male infertility in cases with idiopathic azoospermia.

The conundrum of dietary antioxidants in cancer chemotherapy.

Although chemotherapy succeeds in reducing tumor burden, the efficacy is limited due to acquired drug resistance and often irreparable side effects. Studies show that antioxidants may influence the response to chemotherapy and its side effects, although their use remains controversial. The evidence shows that some chemo-drugs induce oxidative stress and lead to normal tissue apoptosis and the entry of cancer cells to a dormant G0 state. Through the suppression of oxidative stress, antioxidants could protect normal cells and bring the tumor out of dormancy so as to expose it to chemotherapies. This review is focused on the redox biology of cancer/normal cells and association of reactive oxygen species with drug resistance, cancer dormancy, and side effects. To this end, evidence from cellular, animal, and clinical studies is provided to better understand the conundrum of dietary antioxidants in cancer chemotherapy.

Functional expression and impact of testis-specific gene antigen 10 in breast cancer: a combined in vitro and in silico analysis.

Introduction: Testis-specific gene antigen 10 (TSGA10) is a less-known gene, which is involved in the vague biological paths of different cancers. Here, we investigated the TSGA10 expression using different concentrations of glucose under hypoxia and also its interaction with the hypoxia-inducible factor 1 (HIF-1). Methods: The breast cancer MDA-MB-231 and MCF-7 cells were cultured with different concentrations of glucose (5.5, 11.0 and 25.0 mM) under normoxia/hypoxia for 24, 48, and 72 hours and examined for the HIF-1α expression and cell migration by Western blotting and scratch assays. The qPCR was employed to analyze the expression of TSGA10. Three-dimensional (3D) structure and the energy minimization of the interacting domain of TSGA10 were performed by MODELLER v9.17 and Swiss-PDB viewer v4.1.0/UCSF Chimera v1.11. The UCSF Chimera v1.13.1 and Hex 6.0 were used for the molecular docking simulation. The Cytoscape v3.7.1 and STRING v11.0 were used for protein-protein interaction (PPI) network analysis. The HIF-1a related hypoxia pathways were obtained from BioModels database and reconstructed in CellDesigner v4.4.2. Results: The increased expression of TSGA10 was found to be significantly associated with the reduced metastasis in the MDA-MB-231 cells, while an inverse relationship was seen between the TSGA10 mRNA level and cellular migration but not in the MCF-7 cells. The C-terminal domain of TSGA10 interacted with HIF-1α with high affinity, resulting in PPI network with 10 key nodes (HIF-1α, VEGFA, HSP90AA1, AKT1, ARNT, TP53, TSGA10, VHL, JUN, and EGFR). Conclusions: Collectively, TSGA10 functional expression alters under the hyper-/hypo-glycemia and hypoxia, which indicates its importance as a candidate bio-target for the cancer therapy.

Photo-modulation of zinc phthalocyanine-treated breast cancer cell line ZR-75-1 inhibited the normal tumor activity in vitro.

Regarding post-complication of convenient therapies against breast cancer, the emergence of effective approaches is essential. Photodynamic therapy is touted as a novel invasive therapeutic approach by the application of a photosensitizer promoted by laser irradiation. This study aimed to investigate the combined regime of low-level laser irradiation with zinc phthalocyanine in human breast cancer ZR-75-1 cell line. Cells were treated with 0.01 and 5 µg/ml of ZnPc for 24 h and exposed to radiation (70 mW) for 60 s. Cell viability was evaluated by MTT and flow cytometry. Cell migration capacity was monitored by scratch test, Transwell migration insert, and gelatin zymography. The function of MDR in treated cells was examined by Rhodamine 123 exclusion test. The level of GALNT11 was measured by ELISA. The expression of Bax and Bcl-2 genes was evaluated by real-time PCR. Laser irradiation and zinc phthalocyanine induced cell cytotoxicity in a dose-dependent manner. Flow cytometry analysis showed the induction of apoptotic and necrotic changes in treated cells. We found a reduction in migration rate and MMP-9 activity in cells undergoing the experimental procedure (p < 0.05). Immunofluorescence imaging revealed the intracellular accumulation of Rhodamine 123 coincided with a reduction in the level of GALNT11 in treated cells, showing the reduction of MDR activity and tumor cell resistance. Similar to flow cytometry assay, the reduction of Bcl-2 (approximately twofold) and upregulation of Bax genes were found in treated cells. Photodynamic therapy could be as an effective and alternative method for the treatment of breast cancer in a human.

Molecular machineries of pH dysregulation in tumor microenvironment: potential targets for cancer therapy.

Introduction: Cancer is an intricate disorder/dysfunction of cells that can be defined as a genetic heterogeneity in human disease. Therefore, it is characterized by several adaptive complex hallmarks. Among them, the pH dysregulation appears as a symbol of aberrant functions within the tumor microenvironment (TME). In comparison with normal tissues, in the solid tumors, we face with an irregular acidification and alkalinization of the extracellular and intracellular fluids. Methods: In this study, we comprehensively discussed the most recent reports on the hallmarks of solid tumors to provide deep insights upon the molecular machineries involved in the pH dysregulation of solid tumors and their impacts on the initiation and progression of cancer. Results: The dysregulation of pH in solid tumors is fundamentally related to the Warburg effect and hypoxia, leading to expression of a number of molecular machineries, including: NHE1, H+ pump V-ATPase, CA-9, CA-12, MCT-1, GLUT-1. Activation of proton exchangers and transporters (PETs) gives rise to formation of TME. This condition favors the cancer cells to evade from the anoikis and apoptosis, granting them aggressive and metastasis phenotype, as well as resistance to chemotherapy and radiation therapy. This review aimed to discuss the key molecular changes of tumor cells in terms of bio-energetics and cancer metabolism in relation with pH dysregulation. During this phenomenon, the intra- and extracellular metabolites are altered and/or disrupted. Such molecular alterations provide molecular hallmarks for direct targeting of the PETs by potent relevant inhibitors in combination with conventional cancer therapies as ultimate therapy against solid tumors. Conclusion: Taken all, along with other treatment strategies, targeting the key molecular machineries related to intra- and extracellular metabolisms within the TME is proposed as a novel strategy to inhibit or block PETs that are involved in the pH dysregulation of solid tumors.