Significant heightened methylation levels of RUNX3 gene promoter in patients with systemic lupus erythematosus.

OBJECTIVE: Researchers are actively investigating new diagnostic and prognostic biomarkers that offer improved sensitivity and specificity for systemic lupus erythematosus (SLE). One area of interest is DNA methylation changes. Previous studies have shown a connection between the RUNX3 gene dysfunction and SLE. In this study, the focus was on examining the methylation level of the RUNX3 promoter in peripheral blood mononuclear cells (PBMCs) of SLE patients and healthy individuals. METHODS: A total of 80 individuals diagnosed with SLE from Iran, along with 77 healthy individuals, were included. The methylation levels of the RUNX3 gene in the extracted DNA were evaluated using the MethyQESD method. To determine the diagnostic effectiveness of the RUNX3 promoter methylation level, a receiver operating characteristic (ROC) curve was generated. RESULTS: The methylation of the RUNX3 promoter was found to be significantly higher in patients with SLE compared to healthy individuals (p < .001). This difference in methylation levels was observed between SLE patients and healthy individuals and between SLE patients with renal involvement and those without renal involvement (86.29 ± 10.30 vs 40.28 ± 24.21, p < .001). ROC analyses revealed that the methylation level of the RUNX3 promoter had a diagnostic power of 0.769 [95% CI (0.681-0.814)] for SLE. Additionally, there was a positive correlation between the RUNX3 methylation level and levels of creatinine and C4. CONCLUSION: The findings of this study emphasize the potential use of RUNX3 methylation levels in PBMCs of SLE patients as biomarkers for diagnosing the disease, predicting renal damage, and assessing disease activity.

TUSC3 Methylation in Peripheral Blood Cells as a Biomarker for Diagnosis of Colorectal Cancer.

Background: Several case-control studies have suggested that global and loci-specific deoxyribonucleic acid (DNA) methylation in peripheral blood mononuclear cells (PBMCs) of DNA might be potential biomarkers of cancer diagnosis and prognosis. In this study, for the first time, we intended to assess the diagnostic power of the methylation level of tumor suppressor candidate 3 (TUSC3) gene promoter in patients with colorectal cancer (CRC). Materials and Methods: In the current study, we quantitatively assessed the promoter methylation level of TUSC3 in PBMCs of 70 CRC cases and 75 non-cancerous subjects via methylation quantification of endonuclease-resistant DNA (MethyQESD) method. Results: The methylation level of the TUSC3 was meaningfully higher in CRC cases than in non-CRC subjects (43.55 ± 21.80% vs. 16.07 ± 13.63%, respectively; P < 0.001). The sensitivity and specificity of this gene for the detection of CRC were 88.6% and 76.0%, respectively. The receiver operating characteristic (ROC) curve examination discovered an area under the curve (AUC) of 0.880, representing a very high accuracy of the TUSC3 methylation marker in distinguishing CRC subjects from healthy individuals. However, there was no substantial diversity in methylation level between various CRC stages (P: 0.088). Conclusion: For CRC screening, PBMCs are a reliable source for DNA methylation analysis and TUSC3 promoter methylation can be utilized as a hopeful biomarker for early and non-invasive diagnosis of CRC.

Significant hypomethylation of MMP9 gene promoter in patients with systemic lupus erythematosus.

OBJECTIVE: Scholars are exploring novel diagnostic and prognostic biomarkers with higher sensitivity and specificity for systemic lupus erythematosus (SLE). In this regard, DNA methylation alterations have aroused attention. The association between the dysfunction of MMP9 and TNFAIP3 genes and SLE has been previously demonstrated. Therefore, in this study, we investigated the methylation level of MMP9 and TNFAIP3 promoters in peripheral blood mononuclear cells (PBMCs) of SLE patients and healthy controls. METHODS: Eighty Iranian SLE patients and 77 healthy individuals were enrolled. The methylation quantification endonuclease-resistant DNA (MethyQESD) method was used to assess methylation levels of MMP9 and TNFAIP3 in extracted DNA of PBMCs. To quantify the diagnostic utility of the promoter methylation level of these genes, the receiver operating characteristic (ROC) curve was constructed. RESULTS: MMP9 promoter was significantly hypomethylated in SLE patients compared with healthy people (p < 0.001), while there was no significant difference in terms of TNFAIP3 promoter methylation levels (p = 0.167). Also, this differential MMP9 methylation was observed in patients with renal involvement and patients without renal involvement (42.07 ± 25.73 vs 56.74 ± 29.71, p = 0.007). ROC analyses indicated that the diagnostic power of the MMP9 promoter methylation level for SLE was 0.839 [95% CI (0.781-0.911)]. Moreover, MMP9 methylation level was negatively correlated with creatinine and anti-dsDNA concentration and positively correlated with C3 and C4 levels. CONCLUSION: The results of this study highlight the application of MMP9 methylation level in PBMCs of SLE patients as a diagnostic biomarker.

DNA methylation alterations in systemic lupus erythematosus: A systematic review of case-control studies.

BACKGROUND: Traditionally, the diagnosis and monitoring of disease activity in systemic lupus erythematosus (SLE) are contingent upon clinical manifestations and serological markers. However, researchers are struggling to find biomarkers with higher sensitivity and specificity. DNA methylation has been the most studied epigenetic feature in SLE. So, in this study, we performed a systematic review of studies about DNA methylation alterations in SLE patients compared to healthy controls. METHODS: By searching PubMed, Scopus, and Google Scholar up to July 2022, all case-control studies in which DNA methylation of specific genes was assessed by a non-high-throughput technique and passed the quality of bias assessment were included. RESULTS: In total, 44 eligible studies underwent a data extraction process. In all, 3471 SLE patients and 1028 healthy individuals were included. Among the studies that reported the patients' gender (n = 2853), 89.41% were female and 10.59% were male. Forty studies have been conducted on adult patients. The number of works on fractionated and unfractionated blood cells was almost equal. In this regard, 22 studies were conducted on whole blood or peripheral blood mononuclear cells and two studies on unfractionated white blood cells. Sorted blood cells were biological sources in 20 studies. The most investigated gene was IFI44L. Sensitivity, specificity, and diagnostic power of methylation levels were only reported for IFI44L in five studies. The most employed methylation profiling method was bisulfite sequencing polymerase chain reaction. The correlation between methylation patterns and clinical parameters was explored in 22 studies, which of them 16 publications displayed a remarkable association between DNA methylation status and clinical indices. CONCLUSIONS: The methylation status of some genes especially IFI44L, FOXP3, and MX1 has been suggested as promising SLE biomarkers. However, given the conflicting findings between studies because of potential confounders such as different sample types, methylation profiling methods, and ethnicity as well as shared DNA methylation patterns of SLE and other autoimmune diseases, DNA methylation biomarkers are currently not reliable diagnostic biomarkers and do not represent surrogate markers of SLE disease activity. Future investigations on a larger scale with the discarding of limitations of previous studies would probably lead to a consensus.

Hypermethylation of MGMT Gene Promoter in Peripheral Blood Mononuclear Cells as a Noninvasive Biomarker for Colorectal Cancer Diagnosis.

Background: Early colorectal cancer (CRC) diagnosis can drastically reduce CRC-related morbidity and mortality. In this regard, increasing attention is now being directed to DNA-based tests, especially the evaluation of methylation levels, to prioritize high-risk suspected persons for colonoscopy examination. Therefore, we aimed to assess the accuracy of MGMT gene promoter methylation levels in peripheral blood mononuclear cells (PBMCs) for distinguishing CRC patients from healthy people. Materials and Methods: For this study, a total of seventy individuals with CRC and 75 healthy individuals from Iran were included. The methylation level of MGMT in the DNA isolated from PBMCs was evaluated using the methylation quantification endonuclease-resistant DNA technique. To assess the diagnostic capability of the MGMT promoter methylation level, a receiver operating characteristic (ROC) curve was generated. Results: The mean promoter methylation level of MGMT in the CRC and control groups was, respectively, 27.83 ± 22.80 vs. 12.36 ± 14.48. The average percentage of methylation of the MGMT promoter between the CRC and control groups was significantly different (P < 0.001). Also, the MGMT promoter was more hypermethylated in female patients than in males. ROC analyses indicated that the diagnostic power of the MGMT promoter methylation level for CRC was 0.754, with a sensitivity of 81.43% and a specificity of 75.71%, indicating a good biomarker for CRC diagnosis. Conclusion: Methylation evaluation of MGMT in PBMCs could be utilized as a diagnostic biomarker with high accuracy for prioritizing suspected CRC patients before colonoscopy.

Expression of ERBB gene family in females with breast cancer and its correlation with clinicopathological characteristics of the disease.

BACKGROUND: Breast cancer (BC) is the most prevalent and fatal cancer in women. Given that there are very few studies investigating the overexpression of four members of ERBB genes, we decided to investigate the correlation between these four genes with clinicopathological characteristics in breast cancer cases. METHODS: Tumoural tissue of 50 patients with sporadic invasive ductal BC was recruited. Also, control samples were provided from adjacent non-cancerous tissues (ANCTs) of the same patients. The expression of four ERBB genes was evaluated by real-time PCR and its correlation with clinicopathological characteristics was assessed. RESULTS: Only ERBB2 (HER2) was overexpressed in tumoural tissue compared with ANCTs. Our data showed a significant relationship between ERBB1 overexpression with triple-negative tumors, ER, and PR negativity (P < 0.05). Also, ERBB2 overexpression indicated a significant correlation with several pathological characteristics such as age < 50, tumor size larger than 2 cm, early and advanced stages, negative involved lymph nodes, luminal B, triple-negative, ERBB2-enrich, estrogen receptor (ER) and progesterone receptor (PR) negative tumors, Ki-67 mutation more than 15%, and finally HER2/neu immunohistochemistry (IHC) positive and intermediate (P < 0.05). Moreover, this study demonstrated that ERBB4 overexpression had a significant correlation with tumor size smaller than 2 cm, grade I and II tumors (early-stage tumors), luminal A, ER and PR positive tumors, HER-2/neu IHC intermediate, and tumors that had a Ki-67 mutation lower than 15% (P < 0.05). Besides, our analysis showed a significant correlation between the expression of ERBB1 with ERBB2 and ERBB3 with ERBB4 (P < 0.05). CONCLUSIONS: Our findings showed a significant relationship between unfavorable clinicopathological characteristics with ERBB1 and ERBB2 overexpression, but overexpression of ERBB4 was correlated with favorable outcomes.

Association of a miRNA-binding site polymorphism in IL-16 gene with disease risk and clinical characteristics of rheumatoid arthritis and systemic lupus erythematosus.

INTRODUCTION: /objectives. Single nucleotide polymorphisms (SNPs) located at the 3'-UTR region of the target genes of microRNAs (miRNAs) can dysregulate their expression via disrupting the binding site of miRNAs. Interleukin-16 (IL-16) is involved in the pathogenesis of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In the current study, we assessed the possible association between rs1131445 polymorphism in IL-16 gene with risk and clinical characteristics of RA and SLE in the Iranian population. METHODS: In this case-control study, 120 patients with RA, 120 patients with SLE, and 120 unrelated healthy subjects were collected to estimate rs1131445 (T > C) polymorphism in IL-16 gene using real-time PCR high-resolution melting (HRM) method. RESULTS: Our results demonstrated considerable associations between TC genotype and C allele of rs1131445 with enhanced risk of RA (ORfor TC genotype = 3.01; 95%CI [1.667-5.526], P < 0.001; ORfor C allele = 1.96; 95%CI [1.314-2.941], P < 0.001). Besides, there was a marginal association between CC genotype and increased risk of RA (P: 0.031). However, there was an insignificant correlation between genotypes and allele frequencies of rs1131445 with incidence risk of SLE (P > 0.05). Moreover, stratification analysis indicated that the C allele in rs1131445 was linked with disease activity-associated laboratory parameters such as CRP and ESR in both RA and SLE patients, as well as the higher incidence of neurological symptoms in SLE subjects (P < 0.05). CONCLUSION: These results proposed a significant association between IL-16 polymorphism and augmented risk of RA and clinical characteristics of RA and SLE.

Phenotype and genotype spectrum of variants in guanine nucleotide exchange factor genes in a broad cohort of Iranian patients.

BACKGROUND: Guanine nucleotide exchange factors (GEFs) play pivotal roles in neuronal cell functions by exchanging GDP to GTP nucleotide and activation of GTPases. We aimed to determine the genotype and phenotype spectrum of GEF mutations by collecting data from a large Iranian cohort with intellectual disability (ID) and/or developmental delay (DD). METHODS: We collected data from nine families with 20 patients extracted from Iranian cohort of 640 families with ID and/or DD. Next-generation sequencing (NGS) was used to identify the causing variants in recruited families. We also compared our clinical and molecular findings with previously reported patients carrying mutations in these GEF genes in the literature published until mid-2021. RESULTS: We identified disease-causing variants in eight GEF genes including ALS2, IQSEC2, MADD, RAB3GAP1, RAB3GAP2, TRIO, ITSN1, and DENND2A. The major clinical manifestations in 203 previously reported cases along with our 20 patients with disease causing variants in eight GEF genes were as follow; speech disorder (85.2%), ID (81.6%), DD (81.1%), inability to walk (71.3%), facial dysmorphisms features (52.4%), abnormalities in skull morphology (55.6%), hypotonia and muscle weakness (47%), and brain MRI abnormalities (43.4%). CONCLUSION: Our study provides new insights into the genotype and phenotype spectrum of mutations in GEF genes.

Characterizing Genotypes and Phenotypes Associated with Dysfunction of Channel-Encoding Genes in a Cohort of Patients with Intellectual Disability.

BACKGROUND: Ion channel dysfunction in the brain can lead to impairment of neuronal membranes and generate several neurological diseases, especially neurodevelopmental disorders. METHODS: In this study, we set out to delineate the genotype and phenotype spectrums of 14 Iranian patients from 7 families with intellectual disability (ID) and/or developmental delay (DD) in whom genetic mutations were identified by next-generation sequencing (NGS) in 7 channel-encoding genes: KCNJ10, KCNQ3, KCNK6, CACNA1C, CACNA1G, SCN8A, and GRIN2B. Moreover, the data of 340 previously fully reported ID and/or DD cases with a mutation in any of these seven genes were combined with our patients to clarify the genotype and phenotype spectrum in this group. RESULTS: In total, the most common phenotypes in 354 cases with ID/DD in whom mutation in any of these 7 channel-encoding genes was identified were as follows: ID (77.4%), seizure (69.8%), DD (59.8%), behavioral abnormality (29.9%), hypotonia (21.7%), speech disorder (21.5%), gait disturbance (20.9%), and ataxia (20.3%). Electroencephalography abnormality (33.9%) was the major brain imaging abnormality. CONCLUSION: The results of this study broaden the molecular spectrum of channel pathogenic variants associated with different clinical presentations in individuals with ID and/or DD.

PBMCs: a new source of diagnostic and prognostic biomarkers.

There are various types of molecular biomarkers that are derived from distinct starting materials. Although many indirect biomarkers are found in blood, their detection remains a challenging issue because of the high degree of fragmentation, minute quantity and a vast amount of non-specific background. The present review points out the sensitivity and specificity of peripheral blood mononuclear cells (PBMCs) as an intact source of biomarkers in a variety of diseases. Multiple recent studies that have used PBMCs as a source of biomarkers reveal the alteration of mRNAs/microRNAs (miRNAs) signature and methylation profile in many kinds of disorders; for instance, dysregulation of mRNAs/miRNAs in schizophrenia, diabetes and different types of cancers and change in the methylation status of LINE-1 in neoplasms. In conclusion with a strong probability, PBMCs mimic conditions of some tissues which are in contact with them like the tumour cells, hence providing a non-invasive and suitable source of biomarkers.

Association of Three Functional Polymorphisms in the NLRP3 Gene with Susceptibility to Rheumatoid Arthritis in the Iranian Population.

BACKGROUND: Rheumatoid arthritis (RA) is a complex systemic autoimmune disorder with multifactorial nature. Numerous previous studies have shown that several genes are involved in the pathogenesis and increased risk of RA. The Nod-like receptor pyrin domain containing 3 (NLRP3) is involved in the regulation of innate immunity and its upregulation has previously been reported in RA. OBJECTIVE: To evaluate the correlation between 3 functional polymorphisms of NLRP3 and its gene expression and RA risk. METHOD: One hundred and fourteen patients with RA and 120 healthy participants were recruited to this case-control study. Genotyping of rs4612666 (intronic variant), rs10754558 (3UTR variant), and rs6672995 (downstream variant) were performed applying the real­time polymerase chain reaction high­resolution melting (HRM) method. RESULTS: Based on logistic regression analysis, subjects with CC genotype and C allele in rs4612666 had increased risk of RA (OR for CC genotype= 3.10; 95%CI [1.78-8.26]/ OR for C allele= 2.00; 95%CI [1.45-3.10]). Furthermore, in the patient groups, there was a significant relationship between the concentration of C-reactive protein (CRP) and rs4612666 and rs10754558 polymorphism (p < 0.05). Besides, our results revealed no significant association between the genotype and allele frequency of rs10754558 and rs6672995 and the risk of RA (P> 0.05). CONCLUSION: Our findings propose a significant association between rs4612666 polymorphism and increased risk of RA in the Iranian population. Moreover, rs4612666 and rs10754558 were correlated with disease activity.

Alterations of epigenetic landscape in Down syndrome carrying pregnancies: A systematic review of case-control studies.

OBJECTIVE: Great attention is currently paid to both the pathogenetic mechanisms and non-invasive prenatal diagnosis (NIPD) of Down syndrome (DS). It has been posited that dysregulation of epigenetic signatures including DNA methylation and microRNAs (miRNAs) crucially contribute to the pathomechanism of DS. Therefore, we aimed to perform a systematic review of case-control publications that have examined the differences in epigenetic landscape between pregnancies bearing euploid fetuses and those affected with DS to provide a focused insight into the pathophysiology of DS and also novel biomarkers for NIPD of DS. STUDY DESIGN: Pertinent keywords were utilized to search into PubMed, Scopus, and Google Scholar. We enrolled studies that have compared the pattern of miRNAs expression profile or DNA methylation between pregnant women who carries DS fetuses and those with euploid fetuses. RESULTS: An assessment of 599 articles resulted in, finally, 18 eligible studies (12 miRNAs and 6 DNA methylation). The most investigated miRNAs were those that are encoded by genes on chromosome 21 and more hypermethylation regions in DS fetuses than euploids with nearly evenly distribution on all chromosomes were found. Distinct mechanisms with potential therapeutic purposes have been put forward for the involvement of epigenetic perturbations in the etiopathogenesis of DS. CONCLUSION: There is a disagreement in the recruiting of epigenetic biomarkers for NIPD of DS. This heterogeneity in results of the qualified publications emanates from confounding factors such as differences in demographic data of participants, analytical platforms, and study design. Hence, before harnessing epigenetic signatures for NIPD of DS, more experiments are required.

The global prevalence of familial multiple sclerosis: an updated systematic review and meta-analysis.

BACKGROUND: Considering that many recent studies have reported the prevalence of familial multiple sclerosis (FMS), we performed an updated meta-analysis of the worldwide prevalence of FMS by the addition of recent publications. METHODS: A search in PubMed, Scopus, the ISI Web of Science, and Google Scholar was undertaken up to 20 December 2020. The inclusion criteria were based on the CoCoPop approach (condition, context, and population). Meta-analysis of the qualified studies was conducted by comprehensive meta-analysis ver. 2 software. RESULTS: The pooled prevalence of MS in relatives of 16,179 FMS cases was estimated to be 11.8% (95% CI: 10.7-13) based on a random-effects model. The pooled mean age of disease onset in adult probands was calculated to be 28.7 years (95% CI: 27.2 ± 30.2). Regarding 13 studies that reported the data of FMS in pediatrics (n = 877) and adults (n = 6636), the FMS prevalence in pediatrics and adults was 15.5% (95% CI: 13.8-17.4) and 10.8% (95% CI: 8.1-14.2), respectively. The prevalence of FMS in affected males (n = 5243) and females (n = 11,503) was calculated to be 13.7% (95% CI: 10.1-18.2) and 15.4% (95% CI: 10.3-22.4), respectively. The odds ratio of male/female in FMS cases was not statistically significant (OR = 0.9; 95% CI: 0.6-1.2, P = 0.55). Subgroup analysis demonstrated a significant difference in the prevalence of FMS between the geographical areas (P = 0.007). The meta-regression model indicated that the prevalence of FMS is lower with higher latitude and higher MS prevalence (P < 0.001). In contrast, meta-regression based on prevalence day was not statistically significant (P = 0.29). CONCLUSIONS: The prevalence of FMS is higher in the pediatric group than that of adults, distinct between geographical areas, and diminishes with the increment of MS prevalence and latitude. Also, the symptoms initiate relatively at younger ages in the FMS cases. Interestingly, our analysis unveiled that FMS is not more prevalent in men than women and the risk of MS development in relatives is not higher when the affected proband is male.

Three functional variants in the NLRP3 gene are associated with susceptibility and clinical characteristics of systemic lupus erythematosus.

OBJECTIVE: Nod-like receptor pyrin domain containing 3 (NLRP3) gene encodes an intracellular receptor whose dysregulation in systemic lupus erythematosus (SLE) has been reported in multiple studies. Activation of NLRP3 inflammasome leads to the induction of inflammatory response via cleaving and producing of specific cytokines. In the present study, we assessed the possible association between three functional polymorphisms in this gene and SLE risk in the Iranian population. These variants include two gain of function (rs4612666 and rs10754558) and one loss of function (rs6672995) which are correlated with modulation of expression of NLRP3. METHODS: A case-control study involving 110 SLE patients and 116 control subjects was undertaken to estimate the frequency of rs4612666, rs10754558, and rs6672995 genotypes using real-time PCR high resolution melting method (HRM). RESULTS: Our findings revealed significant associations between GG genotype and G allele of rs10754558 with increased risk of SLE (OR for GG genotype= 2.82; 95%CI [1.45-5.46]/OR for G allele= 1.97; 95%CI [1.36-2.87]). Although, no significant associations were recognized between allele and genotype frequencies of rs4612666 and rs6672995 polymorphisms with SLE risk (P > 0.05). Also, our analysis revealed that the C allele in rs4612666 and G allele in rs10754558 was correlated with the severity of disease activity (P < 0.001). Moreover, these common variants were associated with lower age of onset and some clinical symptoms in the patient group, such as skin manifestation, neurological symptom and, renal involvement (P < 0.05). CONCLUSION: This study demonstrates a substantial association between NLRP3 polymorphisms with increased risk, clinical symptoms, and the severity of disease activity of SLE.

Association of rs3135500 and rs3135499 Polymorphisms in the MicroRNA-binding Site of Nucleotide-binding Oligomerization Domain 2 (NOD2) Gene with Susceptibility to Rheumatoid Arthritis.

The nucleotide-binding oligomerization domain 2 (NOD2) is the key regulator of inflammatory responses and has been involved in the pathogenesis of rheumatoid arthritis (RA). Laboratory and in silico evaluations have demonstrated that some polymorphisms in 3'UTR of NOD2 gene could influence the secondary structure of this region and similarly thermodynamic features of hybridization site and finally deregulate the expression of NOD2. In the current study, for the first time, we evaluated the possible association between single nucleotide polymorphisms (SNPs) rs3135500 and rs3135499 in the NOD2 gene with RA risk in the Iranian population. One hundred and fifteen patients with RA and 120 healthy subjects were recruited in this case-control study. Genotyping of rs3135500 and rs3135499 polymorphisms were accomplished using the real­time polymerase chain reaction high resolution melting (HRM) method. We found a substantial association of AA and AG genotypes in rs3135500 with the risk of RA (AA vs GG; OR=5.547; 95%CI [2.564-11.999]; p<0.001 and AG vs GG; OR=2.179; 95%CI [1.145-4.147]; p=0.017). Moreover, in the patient group, there was a significant relationship between the increased concentration of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) with rs3135500 (A allele) (p<0.05). However, there were no important associations between rs3135499 with the risk of RA (p>0.05). However, we found a noteworthy association of the C allele in rs3135499 with an increased level of CRP in patients (p>0.05). Our findings propose a considerable association between NOD2 polymorphisms with increased risk of RA and disease activity.

Modulations of obesity-related microRNAs after exercise intervention: a systematic review and bioinformatics analysis.

Obesity is one of the prevalent health-threatening conditions; however, it is preventable by lifestyle interventions such as exercise. The molecular mechanisms underlying physiological adaptation to physical activity are not fully understood. It has been documented that both intracellular and extracellular (circulating) microRNAs (miRNAs) are involved in both obesogenic and exercise adaptation mechanisms. We aimed to conduct a systematic review of publications that examined the effect of exercise on the expression of miRNAs in individuals with obesity. In addition, bioinformatics analysis was performed on most repetitive miRNAs. PubMed, Scopus, and Google Scholar were searched with relevant keywords. We only included studies that utilized exercise as a modality for the health management of human subjects with obesity to evaluate the changes in expression of obesity-related miRNAs. Through checking of 211 retrieved articles, we reached 12 eligible studies. Some studies reported a statistically significant correlation between the change of miRNAs and clinical parameters such as body mass index and fasting glucose. In silico analysis of most repetitive miRNAs i.e. miR-126, miR-21, miR-146a, miR-221, and miR-223 resulted in the molecular signaling pathways that potentially involve in cellular adaption to exercise in people with obesity. miRNAs partake in health-related benefits of physical activity on obesity-associated cellular and molecular phenomena. However, our understanding of the exact mechanism is still in its infancy. Consistently, the clinicians waiting for the result of more integrated experiments to develop a miRNAs panel as a predictive biomarker of exercise in patients with obesity.

Regulation of DNA methylation machinery by epi-miRNAs in human cancer: emerging new targets in cancer therapy.

Disruption in DNA methylation processes can lead to alteration in gene expression and function that would ultimately result in malignant transformation. In this way, studies have shown that, in cancers, methylation-associated silencing inactivates tumor suppressor genes, as effectively as mutations. DNA methylation machinery is composed of several genes, including those with DNA methyltransferases activity, proteins that bind to methylated cytosine in the promoter region, and enzymes with demethylase activity. Based on a prominent body of evidence, DNA methylation machinery could be regulated by microRNAs (miRNAs) called epi-miRNAs. Numerous studies demonstrated that dysregulation in DNA methylation regulators like upstream epi-miRNAs is indispensable for carcinogenesis; consequently, the malignant capacity of these cells could be reversed by restoring of this regulatory system in cancer. Conceivably, recognition of these epi-miRNAs in cancer cells could not only reveal novel molecular entities in carcinogenesis, but also render promising targets for cancer therapy. In this review, at first, we have an overview of the methylation alteration in cancers, and the effect of this phenomenon in miRNAs expression and after that, we conduct an in-depth discussion about the regulation of DNA methylation regulators by epi-miRNAs in cancer cells.

microRNAs: key modulators of disease-modifying therapies in multiple sclerosis.

There is a high level of heterogeneity in symptom manifestations and response to disease-modifying therapies (DMTs) in multiple sclerosis (MS), an immune-based neurodegenerative disease with ever-increasing prevalence in recent decades. Because of unknown aspects of the etiopathology of MS and mechanism of action of DMTs, the reason for this variability is undetermined, and much remains to be understood. Traditionally, physicians consider switching to other DMTs based on the exacerbation of symptoms and/or change in the results of magnetic resonance imaging and biochemical factors. Therefore, identifying biological treatment response markers that help us recognizing non-responders rapidly and subsequently choosing another DMTs is necessary. microRNAs (miRNAs) are micromanagers of gene expression which have been profiled in different samples of MS patients, highlighting their role in pathogenetic of MS. Recent studies have investigated expression profiling of miRNAs after treatment with DMTs to clarify possible DMTs-mediated mechanism and obtaining response to therapy biomarkers. In this review, we will discuss the modulation of miRNAs by DMTs in cells and pathways involved in MS.

Genetically engineered mesenchymal stem cells: targeted delivery of immunomodulatory agents for tumor eradication.

Cancer immunotherapy emerged as a novel therapeutic option that employs enhanced or amended native immune system to create a robust response against malignant cells. The systemic therapies with immune-stimulating cytokines have resulted in substantial dose-limiting toxicities. Targeted cytokine immunotherapy is being explored to overcome the heterogeneity of malignant cells and tumor cell defense with a remarkable reduction of systemic side effects. Cell-based strategies, such as dendritic cells (DCs), fibroblasts or mesenchymal stem cells (MSCs) seek to minimize the numerous toxic side effects of systemic administration of cytokines for extended periods of time. The usual toxicities comprised of a vascular leak, hypotension, and respiratory insufficiency. Natural and strong tropism of MSCs toward malignant cells made them an ideal systemic delivery vehicle to direct the proposed therapeutic genes to the vicinity of a tumor where their expression could evoke an immune reaction against the tumor. Compared with other methods, the delivery of cytokines via engineered MSCs is safer and renders a more practical, and promising strategy. Large numbers of genes code for cytokines have been utilized to reengineer MSCs as therapeutic cells. This review highlights the recent findings on the cytokine gene therapy for human malignancies by focusing on MSCs application in cancer immunotherapy.