Publications by authors named "Shekoufeh Mirinejad"

9 Publications

  • Page 1 of 1

Association of a Novel Gene Polymorphism with Susceptibility to Schizophrenia and Breast Cancer: A Case-Control Study.

Iran J Public Health 2021 Feb;50(2):397-406

Department of Biology, Faculty of Science, Isfahan University, Isfahan, Iran.

Background: gene is found to play essential roles in regulating different aspects of cell proliferation and development of the nervous system. We aimed to determine if rs12407427 T/C polymorphism could affect susceptibility to schizophrenia (SZN) and breast cancer (BC), the two genetically correlated diseases.

Methods: The current case-control study was performed from Aug 2018 to Dec 2018. Briefly, 159 female pathologically confirmed BC cases referring to Alzahra Hospital, Isfahan, Iran, and 102 psychologically confirmed SZN patients (60 males and 42 females) admitted to Baharan Hospital, Zahedan, Iran, were enrolled. Using the salting-out method, genomic DNA was extracted, and variants were genotyped using allele-specific amplification refractory mutation system polymerase chain reaction (ARMS-PCR) method.

Results: The results revealed a significant association between the rs12407427 codominant CT (0.001), CC (0.0001), dominant CT+CC, and recessive CC (0.001) genotypes with the risk of developing SZN. Significant correlations were also found regarding rs12407427 and BC susceptibility in different inheritance models, including over-dominant CT (0.026), dominant CT+CC (0.001), recessive CC (0.009), and codominant CT and CC (0.001) genotypes. The over-presence of the C allele was also correlated with an increased risk for SZN (0.0001) and BC (0.0001). Finally, computational analysis predicted that T/C variation in this polymorphism could change the binding sites in proteins involved in splicing.

Conclusion: rs12407427 T/C as a de novo variant might be a novel genetic biomarker for SZN and/or BC susceptibility in a sample of the Iranian population.
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http://dx.doi.org/10.18502/ijph.v50i2.5359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956084PMC
February 2021

SNPs in the 3'-untranslated region of confer risk of type 2 diabetes mellitus in a south-east Iranian population: Evidences from case-control and bioinformatics studies.

J Diabetes Metab Disord 2020 Dec 21;19(2):979-988. Epub 2020 Jul 21.

Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran.

Background: Type 2 diabetes mellitus (T2DM) is a heterogenic disease with increasing incidence. The gene encodes an islet zinc transporter (ZnT8), and its variants have been associated with glucose and pro-insulin levels. This study was aimed to examine the effects of a missense variant (rs13266634 C/T), and two 3'UTR variants (rs2466294 C/G and rs2466293 T/C) in gene on T2DM risk in a south-east Iranian population.

Methods: In this experiment, 450 patients diagnosed with T2DM and 453 healthy subjects from the same geographic area were enrolled. Genotypes were amplified using the ARMS-PCR method. analyses were performed to determine the effects of the variants on the local structure of mRNA, splicing patterns, and potential miRNA-gene interactions as well.

Results: Significant differences were noticed between cases and controls regarding the genotypic and allelic distribution of the studied variants. As regards rs2466293 and rs2466294 variants, enhanced risk of T2DM was found under allelic, dominant, recessive, and codominant models (OR > 1). Besides, different genetic models of rs13266634 were associated with decreased risk of T2DM (OR < 1). Bioinformatics analyses indicated that the rs2466293 variant might influence the binding of some miRNAs, while the G-allele of rs2466294 decreased the stability of

Conclusions: In our population, both SNPs in the 3'-untranslated region of increased the risk of T2DM, while the rs13266634 variant showed a protective association against T2DM susceptibility. Investigating the effects of other variants in this gene or other ZnTs can further indicate such associations in subjects from the same ethnicity.
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http://dx.doi.org/10.1007/s40200-020-00590-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843856PMC
December 2020

Functional miR143/145 Cluster Variants and Haplotypes Are Associated with Chronic Kidney Disease: a Preliminary Case-Control Study and Computational Analyses.

Appl Biochem Biotechnol 2021 Jan 23. Epub 2021 Jan 23.

Nephrology Department, Faculty of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran.

MiR-143/145 cluster is a novel transcriptional target of many signaling pathways, with variations within this cluster contributed to the risk of multiple diseases. To date, no data regarding the link between miR143/145 cluster polymorphisms and the risk of developing chronic kidney disease (CKD) has been reported. Hence, we aimed to examine such association in a population of Iranian ancestry. In this preliminary study, 276 CKD patients and 300 unrelated age and sex-matched healthy controls were recruited. Genotyping was performed by PCR-RFLP and allele-specific-PCR methods. Computational analyses were performed to predict the potential effects of the variants. Our findings indicated that rs41291957, rs12659504, and rs353292 polymorphisms were positively associated with CKD, while rs4705342 and rs4705343 polymorphisms demonstrated a significant negative association with the disease. Moreover, a significant association was observed between CC + TC and TT genotypes and CKD stages. We found that AACTT, AATTC, AATTT, GATTC, GATTT, and GGCTT haplotypes significantly enhanced the risk of CKD compared with the GACTT haplotype. Computational analysis showed that rs353292, rs4705342, and rs4705343 might alter the binding of the transcription factors in this gene cluster. We found that miR-143/145 cluster polymorphisms were associated with CKD risk in a sample of the Iranian population. Replicated studies on different ethnicities are necessary to investigate the association between these promoter variants and clinical outcomes.
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http://dx.doi.org/10.1007/s12010-021-03489-wDOI Listing
January 2021

Impact of Proliferator-Activated Receptor γ Gene Polymorphisms on Risk of Schizophrenia: A Case-Control Study and Computational Analyses.

Iran J Psychiatry 2020 Oct;15(4):286-296

Department of Psychiatry, Zahedan University of Medical Sciences, Zahedan, Iran.

Schizophrenia (SCZ) is a common psychiatric disorder characterized by a complex mode of inheritance. Peroxisome proliferator-activated receptor-γ (PPARG) mainly regulates lipid and glucose metabolisms while it is constitutively expressed in rat primary microglial cultures. This preliminary study was aimed to investigate the relationship of two polymorphisms in the gene, rs1801282 C/G, and rs3856806 C/T, to the risk of SCZ in the southeast Iranian population. A total of 300 participants (150 patients with SCZ and 150 healthy controls) were enrolled. Genotyping was done using the amplification refractory mutation system polymerase chain reaction (ARMS-PCR) technique. Computational analyses were carried out to predict the potential effects of the studied polymorphisms. A significant link was found between genotypes of rs1801282 and SCZ susceptibility. The G allele of rs1801282 in CG and GG form of the codominant model increased the risk of SCZ by 2.49 and 2.64 folds, respectively. With regards to rs3856806, enhanced risk of SCZ was also observed under different inheritance models except for the overdominant model. Also, the T allele of rs3856806 enhanced the risk of SCZ by 3.19 fold. Computational analyses predicted that rs1801282 polymorphism might alter the secondary structure of -mRNA and protein function. At the same time, the other variant created the binding sites for some enhancer and silencer motifs. Our findings showed that rs1821282 and rs3856806 polymorphisms associate with SCZ susceptibility. Replication studies in different ethnicities with a larger population are needed to validate our findings.
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http://dx.doi.org/10.18502/ijps.v15i4.4294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610076PMC
October 2020

Hydro-alcoholic Extract of C. Koch Reduces the Expression of Cell Death-Associated Genes while Inducing DNA Damage in HeLa Cervical Cancer Cells.

Iran J Med Sci 2020 Sep;45(5):359-367

Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran.

Background: C. Koch hydroalcoholic extract (AWHE) is proven to induce cell death. Previous studies suggested that AWHE is an effective inhibitor against the proliferation of prostate cancer cells. The present study aimed to evaluate possible alterations of cell death-associated genes and determine the growth inhibitory activity of AWHE on HeLa cervical cancer cells.

Methods: The antiproliferative activity of AWHE was tested using the tetrazolium dye-based colorimetric assay (MTT assay). The mRNA levels of Vascular endothelial growth factor (), , and Breast Cancer Susceptibility gene 1 () were measured using the real-time Polymerase Chain Reaction method. The in-cell levels of phosphorylated H2AX were determined using the in-cell ELISA method. The data were analyzed using the non-parametric ANOVA and . P<0.05 was considered statistically significant.

Results: Based on the MTT assay, The half-maximal inhibitory concentration and 81.99 µg/mL, respectively. The mRNA levels of increased after 12 and 24 hours of treatment (P<0.001), while the mRNA levels of significantly decreased after 12 hours (P=0.003) and 24 hours (P=0.001). expression was increased in the HeLa cells after 6 and 12 hours (P<0.001) whereas γ-H2AX levels significantly increased after 24 and 48 hours of treatment (P<0.001).

Conclusion: AWHE possesses growth inhibitory activity by altering the expression of cell death-associated genes. Using extracts from herbal plants may provide alternative strategies to be deployed in the fight against cancer.
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http://dx.doi.org/10.30476/ijms.2020.72657.0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519407PMC
September 2020

Relationship between gene polymorphisms and schizophrenia susceptibility: a case-control study and analyses.

Int J Neurosci 2020 Oct 8:1-10. Epub 2020 Oct 8.

Department of Psychiatry, Zahedan University of Medical Sciences, Zahedan, Iran.

Purpose: Converging evidence has recently established the significance of γ-aminobutyric acid neurotransmitter (GABA) system in the development of schizophrenia (SCZ). We aimed to determine the association of two markers of the GABA receptor β subunit gene (), rs12187676 G/C and rs1816072 T/C, with the risk of SCZ in Iranian population.

Materials And Methods: In this case-control study, 190 patients with SCZ and 200 healthy controls were recruited from December 2018 to February 2020. Genotyping was done using the Tetra-ARMS-PCR technique. analyses were performed to determine the potential effects of the variants.

Results: The C allele and genotypes of codominant CC vs.TT and CT vs.TT, dominant TT vs. TC + CC, recessive TT + TC vs. CC of rs1816072 polymorphism, as well as codominant CC vs. GG and recessive GG + GC vs. CC genetic models of rs12187676 polymorphism were significantly associated with SCZ susceptibility. Compared to the TC/GC model, we have found that the TC/CC combination significantly increased the risk of SCZ by 4.32 fold while the TT/GG combination conferred a protective role against SCZ. Haplotypes analysis indicated that polymorphisms are in weak linkage disequilibrium with each other (LD = 0.1). However, bioinformatics analyses predicted that these polymorphisms do not have significant effects on the secondary structure and the splicing of -mRNA.

Conclusions: We found that intronic polymorphisms were associated with SCZ risk in a sample of the Iranian population. These findings provided proof of concept for the involvement of the GABAergic neurotransmission system in SCZ development. These observations should be validated across other ethnicities and clinical subtypes.
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http://dx.doi.org/10.1080/00207454.2020.1830087DOI Listing
October 2020

Relationship between Single Nucleotide Polymorphisms of and Schizophrenia Susceptibility: A Preliminary Case-Control Study and Bioinformatics Analysis.

Int J Mol Cell Med 2020 10;9(2):154-164. Epub 2020 Aug 10.

Department of Psychiatry, Zahedan University of Medical Sciences, Zahedan, Iran.

Grainyhead-like (GRHL) transcription factors were recently linked to the etiology of neural tube defects (NTDs). Overlapping patterns in the variation of schizophrenia (SCZ) incidence with that of NTDs suggests the presence of common etiological risk factors. This preliminary study was designed to examine the relationship between two missense variants of gene (rs2486668C/G and rs545809A/T) and SCZ susceptibility among Iranians. Three hundred ninety subjects (192 patients confirmed with SCZ, and 198 healthy controls) were enrolled and genotyped. Statistical and bioinformatics analyzes were performed to determine the effects of the variants. analyzes were performed to determine the effects of the variants on the secondary structure of prediction of silencer motifs for each variation. Statistically significant differences were observed between the studied groups under codominant AA, dominant AT+AA, and recessive AA genetic contrast models for rs545809A/T. The presence of the A allele of rs545809A/T enhanced SCZ risk by 2.33 fold. In contrast, rs2486668C/G was not linked to SCZ susceptibility (P > 0.05). Bioinformatics analysis revealed that both missense SNPs caused substantial changes in the secondary structure of -mRNA. Screening of the flanking sequences of rs545809A/T predicted silencer motifs for this SNP. Our results demonstrated that the rs545809A/T of gene could affect the risk of SCZ in Iranian populations. Replication studies are warranted to confirm these results.
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http://dx.doi.org/10.22088/IJMCM.BUMS.9.2.154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489109PMC
August 2020

Induction of apoptosis and modulation of homologous recombination DNA repair pathway in prostate cancer cells by the combination of AZD2461 and valproic acid.

EXCLI J 2019 8;18:485-498. Epub 2019 Jul 8.

Department of Clinical Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

Cancer therapies using defects in homologous recombination (HR) DNA repair pathway of tumor cells are not yet approved to be applicable in patients with malignancies other than BRCA1/2-mutated tumors. This study was designed to determine the efficacy of combination therapy of a histone deacetylase inhibitor, valproic acid (VPA) and a novel PARP inhibitor AZD2461 in both PC-3 (PTEN-mutated) and DU145 (PTEN-unmutated) prostate cancer cell lines. The Trypan blue dye exclusion assay and the tetrazolium-based colorimetric (MTT) assay were performed to measure the cytotoxicity while combination effects were assessed based on Chou-Talalay's principles. Flow-cytometric assay determined the type of cell death. The real-time PCR analysis was used to evaluate the alterations in mRNA levels of HR-related genes while their protein levels were measured using the ELISA method. γ-H2AX levels were determined as a marker of DNA damage. We observed a synergistic relationship between VPA and AZD2461 in all affected fractions of PC-3 cells (CI<0.9), but not in DU145 cells (CI>1.1). Annexin-V staining analysis revealed a significant induction of apoptosis when PC-3 cells were treated with VPA+AZD2461 (). Both mRNA and protein levels of and were significantly decreased in PC-3 cells co-treated with VPA+AZD2461 while enhanced H2AX phosphorylation was found in PC-3 cells after 12 and 24 hours of co-treatment (). Our findings established a preclinical rationale for selective targeting of HR repair pathways by a combination of VPA and AZD2461 as a mechanism for reducing the HR pathway sufficiency in -mutated prostate cancer cells.
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http://dx.doi.org/10.17179/excli2019-1098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694702PMC
July 2019

Mild antagonistic effect of Valproic acid in combination with AZD2461 in MCF-7 breast cancer cells.

Med J Islam Repub Iran 2019 10;33:29. Epub 2019 Apr 10.

Student Research committee, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

Breast cancer (BC) is a complex disease, but current treatments are not efficient enough considering increased relapse and decreased survival rate among patients. Poly (ADP-ribose) polymerase inhibitors are recently developed anticancer agents which target cells with defects in homologous recombination (HR) pathway. This study wishes to assess whether the combination of AZD2461 as a newly developed PARP1 inhibitor and valproic acid (VPA), a histone deacetylase inhibitor could effectively reduce the growth of MCF-7 cells with no fundamental DNA repair defect. Both trypan blue dye exclusion assay and MTT viability test were used to evaluate cell death. γ-H2AX levels, as a marker of DNA repair, were measured using in cell ELISA method. The Student's t-test and non-parametric analysis of variance (ANOVA) were applied for our data analyses where p-value <0.05 was considered statistically significant. As calculated by CompuSyn software, IC50 values for VPA and AZD2461 were 4.89 mM and 42.83 µM respectively following 48 hours treatment. Also, the trypan blue exclusion assay results showed a concentration- and time-dependent decrease when MCF-7 cells were treated with both agents (p<0.05). Combination analysis showed a mild antagonism (CI>1.1) while γ-H2AX levels found not to be significantly increased in MCF-7 cells co-treated with VPA+AZD2461 compared to each agent alone (p=0.29). Our findings revealed that the combination of VPA and AZD2461 could decrease cell viability of MCF-7 cells, but it was not able to significantly increase unrepaired DNA damage sites. The mechanism responsible for drugs combination was not of synergism or addition. Determining the type of involved cell death mechanisms might be followed in further studies.
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http://dx.doi.org/10.34171/mjiri.33.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662678PMC
April 2019