Bioinformatic Prediction and Introducing of Some Targeting MicroRNAs of Sirt1 and Bcl2 Genes in Model of Parkinson's Disease

Abstract Background: Oxidative Stress and mitochondrial dysfunction leading to apoptotic death of neurons play key role in the pathogenesis of the Parkinson's disease. On the other hand، misregulation of microRNAs can cause several neurodegenerative diseases. Sirt1 and Bcl2 as two key genes, regulate pathogenic processes in neurodegenerative diseases such as mitochondrial dyfunction, oxidative stress and apoptosis. Materials and Methods: To investigate the role of microRNAs in model of Parkinson's disease, miRWalk 2.0 and TargetScan (v7) databases were served to predict microRNA-target interactions. Results: Possible targeting effects of different microRNAs on Bcl2 and Sirt1 genes in Rat organism were analyzed. Merging data from databases has shown that rno-miR-449a, rno-miR-182, rno-miR-211, rno-miR-34b, rno-miR-34c, rno-miR-448, rno-miR-466b and rno-miR-96 with strong possibility can inhibit expression of Bcl2 gene. Also, rno-miR-181, rno-miR-211, rno-miR-27a, rno-miR-449a, rno-miR-34c, rno-miR-30, rno-miR-200a and rno-miR-448can inhibit Sirt1 gene with high possibility. Conclusion: According to the findings, it can be predicted that regarding to high interaction scores of rno-miR-211, rno-miR-34c and rno-miR-448 and 449awith Bcl2 and Sirt1 genes in above-mentioned databases, these microRNAs probably can have critical role in disease process. Thus, these microRNAs can be introduced as appropriate candidates for investigations in in vitro model of Parkinson's disease

Hippo signaling pathway: A comprehensive gene expression profile analysis in breast cancer

Breast cancer (BC) is the most frequently diagnosed malignancy in women and a major public health concern. The Hippo pathway is an evolutionarily conserved signaling pathway that serves as a key regulator for a wide variety of biological processes. Hippo signaling has been shown to have both oncogenic and tumor-suppressive functions in various cancers. Core components of the Hippo pathway consist of various kinases and downstream effectors such as YAP/TAZ. In the current report, differential expression of Hippo pathway elements as well as the correlation of Hippo pathway mRNAs with various clinicopathologic characteristics, including molecular subtypes, receptor status, and methylation status, has been investigated in BC using METABRIC and TCGA datasets. In this review, we note deregulation of several Hippo signaling elements in BC patients. Moreover, we see examples of negative correlations between methylation of Hippo genes and mRNA expression. The expression of Hippo genes significantly varies between different receptor subgroups. Because of the clear associations between mRNA expression and methylation status, DNA methylation may be one of the mechanisms that regulate the Hippo pathway in BC cells. Differential expression of Hippo genes among various BC molecular subtypes suggests that Hippo signaling may function differently in different subtypes of BC. Our data also highlights an interesting link between Hippo components\u27 transcription and ER negativity in BC. In conclusion, substantial deregulation of Hippo signaling components suggests an important role of these genes in breast cancer

Notch signaling pathway: a comprehensive prognostic and gene expression profile analysis in breast cancer

Breast cancer is a complex disease exhibiting a great degree of heterogeneity due to different molecular subtypes. Notch signaling regulates the differentiation of breast epithelial cells during normal development and plays a crucial role in breast cancer progression through the abnormal expression of the Notch up-and down-stream effectors. To date, there are only a few patient-centered clinical studies using datasets characterizing the role of Notch signaling pathway regulators in breast cancer; thus, we investigate the role and functionality of these factors in different subtypes using publicly available databases containing records from large studies. High-throughput genomic data and clinical information extracted from TCGA were analyzed. We performed Kaplan-Meier survival and differential gene expression analyses using the HALLMARK_NOTCH_SIGNALING gene set. To determine if epigenetic regulation of the Notch regulators contributes to their expression, we analyzed methylation levels of these factors using the TCGA HumanMethylation450 Array data. Notch receptors and ligands expression is generally associated with the tumor subtype, grade, and stage. Furthermore, we showed gene expression levels of most Notch factors were associated with DNA methylation rate. Modulating the expression levels of Notch receptors and effectors can be a potential therapeutic approach for breast cancer. As we outline herein, elucidating the novel prognostic and regulatory roles of Notch implicate this pathway as an essential mediator controlling breast cancer progression

Modified level of miR-376a is associated with Parkinson's disease

Parkinson's disease (PD) is a frequent progressive neurodegenerative disorder. Impaired mitochondrial function is a major feature of sporadic PD. Some susceptibility or causative genes detected in PD are strongly associated with mitochondrial dysfunction including PGC1α, TFAM and GSK3β. microRNAs (miRNAs) are non‐coding RNAs whose altered levels are proven in disparate PD models and human brains. Therefore, the aim of this study was to detect modulations of miRs upstream of PGC1α, TFAM and GSK3β in association with PD onset and progress. In this study, a total of 33 PD subjects and 25 healthy volunteers were recruited. Candidate miRNA (miR‐376a) was selected through target prediction tools and literature survey. Chronic and acute in vitro PD models were created by MPP+‐intoxicated SHSY5Y cells. The levels of miR‐376a and aforementioned genes were assessed by RT‐qPCR. The expression of target genes was decreased in chronic model while there were dramatically up‐regulated levels of those genes in acute model of PD. miR‐376a was strongly altered in both acute and chronic PD models as well as PBMCs of PD patients. Our results also showed overexpression of PGC1α, and TFAM in PBMCs is inversely correlated with down‐regulation of miR‐376a, suggesting that miR‐376a possibly has an impact on PD pathogenesis through regulation of these genes which are involved in mitochondrial function. miR‐376a expression in PD‐derived PBMCs was also correlated with disease severity and may serve as a potential biomarker for PD diagnosis. This is the first study showing altered levels of miR‐376a in PD models and PBMCs, suggesting the probable role of this miRNA in PD pathogenesis. The present study also proposed TFAM and PGC1α as target genes of miR‐376a for the first time, through which it possibly can exert its impact on PD pathogenesis.Peer reviewe

Upregulation of miR‐9 and miR‐193b over human Th17 cell differentiation

Abstract Background Th17 cells are a newly discovered subset of CD4+ T cells known as key participants in various immune responses and inflammatory conditions including autoimmune diseases. Mi(cro)RNAs are a family of non‐coding RNAs that regulate numerous critical immune functions. Immuno‐miRNAs modulate cell biological processes in T cells, such as differentiation and function of Th17 cells. The aim of the present study is to investigate the expression of miR‐9‐5p, miR‐193b‐3p, and autoimmunity‐related genes during human Th17 cells differentiation. Methods Human naïve CD4+ T cells were purified from peripheral blood mononuclear cells (PBMCs) by magnetic cell sorting system (MACS) and their purity was checked by flow‐cytometric analysis. Naïve CD4+ T cells were cultured under Th17‐polarizing condition for 6 days. IL‐ 17 secretion was determined by means of enzyme‐linked immunosorbent assay (ELISA). Next, the expression levels of miRNAs and putative targets genes were assessed by qRT‐PCR at different time points of differentiation. Results Our result showed dramatic downregulation of TCF7, MAP3K1, ENTPD1, and NT5E genes during human Th17 differentiation. Polarization also had a significant inducible effect on the expression of miR‐9 and miR‐193b over differentiation of human Th17 cells. According to our results, miR‐9‐5p and miR‐193b‐3p may contribute to Th17 differentiation probably by inhibiting the expression of negative regulators of Th17 differentiation. Conclusion This study confirmed deregulation of TCF7, MAP3K1, ENTPD1, and NT5E genes in Th17 differentiation process and introduced miR‐9 and miR‐193b as Th17 cell‐associated miRNAs, making them good candidates for further investigations

Cancer stem cell-mediated drug resistance: A comprehensive gene expression profile analysis in breast cancer

Breast cancer is the most frequently diagnosed malignancy in women and a major public health concern. In the current report, differential expression of the breast cancer resistance promoting genes with a focus on breast cancer stem cell related elements as well as the correlation of their mRNAs with various clinicopathologic characteristics, including molecular subtypes, tumor grade/stage, and methylation status, have been investigated using METABRIC and TCGA datasets. To achieve this goal, we downloaded gene expression data of breast cancer patients from TCGA and METABRIC. Then, statistical analyses were used to assess the correlation between the expression levels of stem cell related drug resistant genes and methylation status, tumor grades, various molecular subtypes, and some cancer hallmark gene sets such as immune evasion, metastasis, and angiogenesis. According to the results of this study, a number of stem cell related drug resistant genes are deregulated in breast cancer patients. Furthermore, we observe negative correlations between methylation of resistance genes and mRNA expression. There is a significant difference in the expression of resistance-promoting genes between different molecular subtypes. As mRNA expression and DNA methylation are clearly related, DNA methylation might be a mechanism that regulates these genes in breast cancer cells. As indicated by the differential expression of resistance-promoting genes among various breast cancer molecular subtypes, these genes may function differently in different subtypes of breast cancer. In conclusion, significant deregulation of resistance-promoting factors indicates that these genes may play a significant role in the development of breast cancer