Antioxidant therapy against TGF-ß/SMAD pathway involved in organ fibrosis.

Fibrosis refers to excessive build-up of scar tissue and extracellular matrix components in different organs. In recent years, it has been revealed that different cytokines and chemokines, especially Transforming growth factor beta (TGF-ß) is involved in the pathogenesis of fibrosis. It has been shown that TGF-ß is upregulated in fibrotic tissues, and contributes to fibrosis by mediating pathways that are related to matrix preservation and fibroblasts differentiation. There is no doubt that antioxidants protect against different inflammatory conditions by reversing the effects of nitrogen, oxygen and sulfur-based reactive elements. Oxidative stress has a direct impact on chronic inflammation, and as results, prolonged inflammation ultimately results in fibrosis. Different types of antioxidants, in the forms of vitamins, natural compounds or synthetic ones, have been proven to be beneficial in the protection against fibrotic conditions both in vitro and in vivo. In this study, we reviewed the role of different compounds with antioxidant activity in induction or inhibition of TGF-ß/SMAD signalling pathway, with regard to different fibrotic conditions such as gastro-intestinal fibrosis, cardiac fibrosis, pulmonary fibrosis, skin fibrosis, renal fibrosis and also some rare cases of fibrosis, both in animal models and cell lines.

CRISPR/Cas9 gene editing: a novel strategy for fighting drug resistance in respiratory disorders.

Respiratory disorders are among the conditions that affect the respiratory system. The healthcare sector faces challenges due to the emergence of drug resistance to prescribed medications for these illnesses. However, there is a technology called CRISPR/Cas9, which uses RNA to guide DNA targeting. This technology has revolutionized our ability to manipulate and visualize the genome, leading to advancements in research and treatment development. It can effectively reverse epigenetic alterations that contribute to drug resistance. Some studies focused on health have shown that targeting genes using CRISPR/Cas9 can be challenging when it comes to reducing drug resistance in patients with respiratory disorders. Nevertheless, it is important to acknowledge the limitations of this technology, such as off-target effects, immune system reactions to Cas9, and challenges associated with delivery methods. Despite these limitations, this review aims to provide knowledge about CRISPR/Cas9 genome editing tools and explore how they can help overcome resistance in patients with respiratory disorders. Additionally, this study discusses concerns related to applications of CRISPR and provides an overview of successful clinical trial studies.

Impact of miRNAs in the pathoetiology of recurrent implantation failure.

Recurrent implantation failure (RIF) is a condition with a multifactorial basis. Recent research has focused on the role of genetic factors in the pathophysiology of RIF. Of particular note, miRNAs have been found to contribute to the pathogenesis of RIF. Several miRNA polymorphisms have been investigated in this context. Moreover, dysregulation of expression of a number of miRNAs, including miR-374a-5p, miR-145-5p, miR-30b-5p, miR-196b-5p, miR-22, miR-181 and miR-145 has been found in RIF. This review concentrates on the role of miRNAs in RIF to help in identification of the molecular basis for this condition and design of more effective methods for management of RIF, especially in a personalized manner that relies on the expression profiles of miRNAs in the peripheral blood or endometrium.

Impacts of non-coding RNAs in the pathogenesis of varicocele.

Two classes of non-coding RNAs, namely lncRNAs and miRNAs have been reported to be involved in the pathogenesis of varicocele. MIR210HG, MLLT4-AS1, gadd7, and SLC7A11-AS1 are among lncRNAs whose expression has been changed in patients with varicocele in association with the sperm quality. Animal studies have also suggested contribution of NONRATG001060, NONRATG002949, NONRATG013271, NONRATG027523 and NONRATG023747 lncRNAs in this pathology. Meanwhile, expression of some miRNAs, such as miR-210-3p, miR-21, miR-34a, miR-122a, miR-181a, miR-34c and miR-192a has been altered in this condition. Some of these transcripts have the potential to predict the sperm quality. We summarize the impacts of lncRNAs and miRNAs in the pathogenesis of varicocele.

Role of circular RNA/miRNA axes in the pathophysiology of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a disorder resulted from interactions between genetic and environmental factors. Based on the importance of epigenetic factors in the pathoetiology of PCOS, the current review focused on identification of circular RNAs (circRNAs) that are involved in PCOS through acting as molecular sponges for microRNAs (miRNAs). The literature search led to identification of circ_0043533/miR-1179, circ_0030018/miR-136, circ_FURIN/miR-423-5p, circ-FURIN/miR-195-5p, circ_0043532/miR-182, circ_RANBP9/miR-136-5p, circRHBG/miR-515-5p, circMTO1/miR-320b, circASPH/miR-375, circPSMC3/miR-296-3p, circLDLR/miR-1294, circPUM1/miR-760, and hsa_circ_0118530/miR-136 as molecular axes contributing to the pathogenesis of PCOS. To set the stage for future research on the role of the ceRNA network in PCOS, in-silico analyses were performed using miRWalk, miRNet, and miRDIP databases. miRWalk identified 80 genes regulated by 5 miRNAs, miRNet revealed 6449 circRNAs potentially controlling 11 miRNAs, and miRDIP identified 11 miRNAs associated with 35 human pathways. These targets can be used in the treatment options, design of personalized medicine and prediction of prognosis of PCOS.

Expression assay of calcium signaling related lncRNAs in autism.

BACKGROUND: Calcium signaling has essential roles in the neurodevelopmental processes and pathophysiology of related disorders for instance autism spectrum disorder (ASD). METHODS AND RESULTS: We compared expression of SLC1A1, SLC25A12, RYR2 and ATP2B2, as well as related long non-coding RNAs, namely LINC01231, lnc-SLC25A12, lnc-MTR-1 and LINC00606 in the peripheral blood of patients with ASD with healthy children. Expression of SLC1A1 was lower in ASD samples compared with control samples (Expression ratio (95% CI) 0.24 (0.08-0.77), adjusted P value = 0.01). Contrary, expression of LINC01231 was higher in cases compared with control samples (Expression ratio (95% CI) 25.52 (4.19-154), adjusted P value = 0.0006) and in male cases compared with healthy males (Expression ratio (95% CI) 28.24 (1.91-418), adjusted P value = 0.0009). RYR2 was significantly over-expressed in ASD children compared with control samples (Expression ratio (95% CI) 4.5 (1.16-17.4), adjusted P value = 0.029). Then, we depicted ROC curves for SLC1A1, LINC01231, RYR2 and lnc-SLC25A12 transcripts showing diagnostic power of 0.68, 0.75, 0.67 and 0.59, respectively. CONCLUSION: To sum up, the current study displays possible role of calcium related genes and lncRNAs in the development of ASD.

A novel homozygote nonsense variant of MSH4 leads to primary ovarian insufficiency and non-obstructive azoospermia.

BACKGROUND: Both non-obstructive azoospermia (NOA) and primary ovarian insufficiency (POI) are pathological conditions characterized by premature and frequently complete gametogenesis failure. Considering that the conserved meiosis I steps are the same between oogenesis and spermatogenesis, inherited defects in meiosis I may result in common causes for both POI and NOA. The present research is a retrospective investigation on an Iranian family with four siblings of both genders who were affected by primary gonadal failure. METHODS: Proband, an individual with NOA, was subjected to clinical examination, hormonal assessment, and genetic consultation. After reviewing the medical history of other infertile members of the family, patients with NOA went through genetic investigations including karyotyping and assessment of Y chromosome microdeletions, followed by Whole exome sequencing (WES) on the proband. After analyzing WES data, the candidate variant was validated using Sanger sequencing and traced in the family. RESULTS: WES analysis of the proband uncovered a novel homozygote nonsense variant, namely c.118C>T in MSH4. This variant resulted in the occurrence of a premature stop codon in residue 40 of MSH4. Notably, the variant was absent in all public exome databases and in the exome data of 400 fertile Iranian individuals. Additionally, the variant was found to co-segregate with infertility in the family. It was also observed that all affected members had homozygous mutations, while their parents were heterozygous and the fertile sister had no mutant allele, corresponding to autosomal recessive inheritance. In addition, we conducted a review of variants reported so far in MSH4, as well as available clinical features related to these variants. The results show that the testicular sperm retrieval and ovarian stimulation cycles have not been successful yet. CONCLUSION: Overall, the results of this study indicate that the identification of pathogenic variants in this gene will be beneficial in selecting proper therapeutic strategies. Also, the findings of this study demonstrate that clinicians should obtain the history of other family members of the opposite sex when diagnosing for POI and/or NOA.

Association Between RORA Polymorphisms and Obesity.

RORα is a transcription factor encoded by RORA gene. This protein is involved in several metabolic conditions, including obesity. We assessed association between two polymorphisms within this gene (namely rs11639084 and rs4774388) and severe obesity in Iranian population. Both SNPs were associated with obesity in all models (P < 0.0001) except for over-dominant model. T allele of rs11639084 was associated with this trait with OR (95% CI) of 16.85 (13.11-21.67) and was considered as the risk allele. Allelic model best fit the data, since the AIC value for this model was the highest (AIC = 28.82). In the co-dominant model, TT genotype was associated with obesity with OR (95% CI) of 301.6 (137.4-662.1). This genotype was shown to be the risk genotype in the recessive model when compared with TC+CC (OR (95% CI) = 60.54 (30.35-120.7)). The C allele of rs4774388 was shown to be the risk allele with OR (95% CI) of 4.61 (3.72-5.71). In the recessive model, the CC genotype was associated with the mentioned trait with OR (95% CI) of 9.92 (6.62-14.8). This model best fit the data (AIC = 37.08). Cumulatively, the current study suggests contribution of RORα to the pathogenesis of obesity.

Association Between rs217727 and rs2839698 H19 Polymorphisms and Obesity.

Obesity is a worldwide health problem with an increasing trend. This condition has a significant genetic background. H19 lncRNA has been shown to protect from dietary obesity through decreasing levels of monoallelic genes in brown fat. In the current study, we aimed to find the association between two possibly functional H19 polymorphisms, namely rs217727 and rs2839698 and obesity in Iranian population. These polymorphisms have been shown to affect risk of some obesity-related conditions in different populations. The study included 414 obese cases and 392 controls. Notably, both rs2839698 and rs217727 were associated with obesity in the allelic model as well as all supposed inheritance models. In addition, after adjustment for gender, all P values remained significant. For rs2839698, the OR (95% CI) for T allele vs. C allele was 3.29 (2.67-4.05) (P-value < 0.0001). In the co-dominant model, both TT and CT genotypes were found to confer risk of obesity compared with CC genotype (OR (95% CI)= 14.02 (8.39-23.43) and 9.45 (6.36-14.04), respectively). Similarly, combination of TT and CT genotypes had an OR (95% CI) = 10.32 (7.03-15.17) when compared with CC genotype. For rs217727, the T allele was found to exert a protective effect (OR (95% CI) = 0.6 (0.48-0.75)). Moreover, in the co-dominant model, OR (95% CI) values for TT and TC genotypes vs. CC genotype were 0.23 (0.11-0.46) and 0.65 (0.49-0.87), respectively. Taken together, H19 polymorphisms may affect risk of obesity in Iranian population. It is necessary to conduct functional studies to confirm a causal relationship between the rs217727 and rs2839698 polymorphisms and obesity.

In Silico Prediction of Functional SNPs Interrupting Antioxidant Defense Genes in Relation to COVID-19 Progression.

The excessive production of reactive oxygen species and weakening of antioxidant defense system play a pivotal role in the pathogenesis of different diseases. Extensive differences observed among individuals in terms of affliction with cancer, cardiovascular disorders, diabetes, bacterial, and viral infections, as well as response to treatments can be partly due to their genomic variations. In this work, we attempted to predict the effect of SNPs of the key genes of antioxidant defense system on their structure, function, and expression in relation to COVID-19 pathogenesis using in silico tools. In addition, the effect of SNPs on the target site binding efficiency of SNPs was investigated as a factor with potential to change drug response or susceptibility to COVID-19. According to the predicted results, only six missense SNPs with minor allele frequency (MAF) ≥ 0.1 in the coding region of genes GPX7, GPX8, TXNRD2, GLRX5, and GLRX were able to strongly affect their structure and function. Our results predicted that 39 SNPs with MAF ≥ 0.1 led to the generation or destruction of miRNA-binding sites on target antioxidant genes from GPX, PRDX, GLRX, TXN, and SOD families. The results obtained from comparing the expression profiles of mild vs. severe COVID-19 patients using GEO2R demonstrated a significant change in the expression of approximately 250 miRNAs. The binding efficiency of 21 of these miRNAs was changed due to the elimination or generation of target sites in these genes. Altogether, this study reveals the fundamental role of the SNPs of antioxidant defense genes in COVID-19 progression and susceptibility of individuals to this virus. In addition, different responses of COVID-19 patients to antioxidant defense system enhancement drugs may be due to presence of these SNPs in different individuals.

A concise review on the role of MIR100HG in human disorders.

MIR100HG is a long non-coding RNA (lncRNA) encoded by a locus on chr11:122,028,203-122,556,721. This gene can regulate cell proliferation, apoptosis, cell cycle transition and cell differentiation. MIR100HG was firstly identified through a transcriptome analysis and found to regulate differentiation of human neural stem cells. It is functionally related with a number of signalling pathways such as TGF-ß, Wnt, Hippo and ERK/MAPK signalling pathways. Dysregulation of MIR100HG has been detected in a diversity of cancers in association with clinical outcomes. Moreover, it has a role in the pathophysiology of dilated cardiomyopathy, intervertebral disk degeneration and pulmonary fibrosis. The current study summarizes the role of these lncRNAs in human disorders.

Expression of cAMP and oxidative phosphorylation-related lncRNAs in non-functioning pituitary adenomas.

Non-functioning pituitary adenomas (NFPAs) are benign lesions in the pituitary gland with important morbidities. In this study, based on a bioinformatics analysis to identify the genes and pathways that display significant differences between tumour tissues of NFPA patients and normal pituitary tissues, we selected lncRNAs related to cAMP and oxidative phosphorylation pathways, namely DNAH17-AS1, LINC00706 and SLC25A5-AS1. Then, we aimed to investigate by means of RT-qPCR, the expression of these lncRNAs along with two other lncRNAs, namely CADM3-AS1 and MIR7-3HG in NFPA samples compared to that in healthy tissues adjacent to the tumours. Transcripts of DNAH17-AS1, LINC00706 and MIR7-3HG were lower in NFPA samples compared with controls (Expression ratios (95% CI) = 0.43 (0.23-0.78), 0.58 (0.35-0.96) and 0.58 (0.35-0.96); p-values = 0.009, 0.025 and 0.036, respectively). AUC values of ROC curves of DNAH17-AS1, LINC00706 and MIR7-3HG were 0.62, 0.61 and 0.62, respectively. Expression of CADM3-AS1 was associated with the gender of patients in a way that it was lower in female patients (p-value = 0.04). The level of SLC25A5-AS1 was lower in subjects with disease duration lower than 1 year (p-value = 0.048). We showed dysregulation of three lncRNAs in NFPA tissues and potentiates these lncRNAs as important regulators of pathogenic events in these tumours.

Upregulation of MAPKAPK5-AS1, PXN-AS1 and URB1-AS1 lncRNAs in non-functioning pituitary adenoma.

Long non-coding RNAs (lncRNAs) have been shown to be dysregulated in a variety of malignant and non-malignant lesions including non-functioning pituitary adenomas (NFPAs). In the current experimental study, we have selected six lncRNAs, namely MAPKAPK5-AS1, NUTM2B-AS1, ST7-AS1, LIFR-AS1, PXN-AS1 and URB1-AS1 to assess their expression in a cohort of Iranian patients with NFPA. MAPKAPK5-AS1, PXN-AS1 and URB1-AS1 were shown to be over-expressed in NFPA tissues compared with control samples (Expression ratios (95% CI) = 10 (3.94-25.36), 11.22 (4.3-28.8) and 9.33 (4.12-21.12); p values < 0.0001, respectively). The depicted ROC curves showed the AUC values of 0.73, 0.80 and 0.73 for MAPKAPK5-AS1, PXN-AS1 and URB1-AS1, respectively. Relative expression level of PXN-AS1 was associated with tumour subtype (p value = 0.49). Besides, relative expression levels of MAPKAPK5-AS1 and LIFR-AS1 were associated with gender of patients (p values = 0.043 and 0.01, respectively). Cumulatively, the current study indicates the possible role of MAPKAPK5-AS1, PXN-AS1 and URB1-AS1 lncRNAs in the pathogenesis of NFPAs.

Sarcopenia and noncoding RNAs: A comprehensive review.

Sarcopenia is an elderly disease and is related to frailty and loss of muscle mass (atrophy) of older adults. The exact molecular mechanisms contributing to the pathogenesis of disease are yet to be discovered. In recent years, the role of noncoding RNAs in the pathogenesis of almost every kind of malignant and nonmalignant conditions is pinpointed. Regarding their regulatory function, there have been an increased number of studies on the role of noncoding RNAs in the progress of sarcopenia. In this manuscript, we review the role of microRNAs and long noncoding RNAs in development and progression of disease. We also discuss their potential as therapeutic targets in this condition.

Identification of key differentially expressed genes in SARS-CoV-2 using RNA-seq analysis with a systems biology approach.

COVID-19 is associated with dysregulation of several genes and signaling pathways. Based on the importance of expression profiling in identification of the pathogenesis of COVID-19 and proposing novel therapies for this disorder, we have employed an in silico approach to find differentially expressed genes between COVID-19 patients and healthy controls and their relevance with cellular functions and signaling pathways. We obtained 630 DEmRNAs, including 486 down-regulated DEGs (such as CCL3 and RSAD2) and 144 up-regulated DEGs (such as RHO and IQCA1L), and 15 DElncRNAs, including 9 down-regulated DElncRNAs (such as PELATON and LINC01506) and 6 up-regulated DElncRNAs (such as AJUBA-DT and FALEC). The PPI network of DEGs showed the presence of a number immune-related genes such as those coding for HLA molecules and interferon regulatory factors. Taken together, these results highlight the importance of immune-related genes and pathways in the pathogenesis of COVID-19 and suggest novel targets for treatment of this disorder.

Impact of COVID-19 and vaccination on first and second trimester screening results.

COVID-19 has been shown to affect pregnant women. Since pregnant women are at risk of this infection, vaccination against COVID-19 has been suggested as an imperative way to diminish rate of COVID-19 in this population. In the current observational study, we have collected data of first and second trimester screening (FTS and STS) from pregnant women who were infected with SARS-CoV-2 and/or vaccinated against COVID-19 during their pregnancy, and compared this data with a group of control pregnant women. The cohort included 4612 and 2426 women referred for FTS and STS, respectively. There was no significant difference in median values of Pregnancy-associated plasma protein A (PAPP-A) and human chorionic gonadotropin-beta subunit (ßHCG) between infected women and controls. Moreover, these levels were not different between "Infected + vaccinated" and "Only vaccinated" groups. However, median values of PAPP-A and ßHCG were higher in "Infected + vaccinated" and "Only vaccinated" groups compared with "Infected" and "Control" groups (P < 0.001). Median values of unconjugated Estriol (uE3) and ßHCG markers were not different between "Only vaccinated" and "Control" groups, yet both markers were elevated in "Infected" and "Infected + vaccinated" groups compared with other groups. AFP values were higher in "Infected" group (P = 0.012). However, multiple of the median (MoM) and risk of open spina bifida (OSB) were not affected. Finally, median of calculated risk of trisomy 18 was lower in "Infected" and "Vaccinated" groups compared with controls (P = 0.007). Moreover, AstraZeneca and Sinopharm vaccines were associated with elevation of the calculated risk values of trisomy 21 and trisomy 18 (P < 0.001). While Sinopharm did not affect nuchal translucency (NT) and NT MoM (P = 0.13), AstraZeneca and Barakat increased and decreased these values, respectively (P values = 0.0027 and 0.015, respectively). Taken together, COVID-19 during pregnancy might be associated with some adverse obstetric outcomes. Besides, vaccination against this infection might affect the results of STS or FTS.

Non-coding RNA profile for natural killer cell activity.

Natural killer cells (NK cells) are a type of cytotoxic lymphocytes which are involved in innate immunity, alongside with assisting with adaptive immune response. Since they have cytotoxic effects, disruptions in their functionality and development leads to a variety of conditions, whether malignant or non-malignant. The profile and interaction of these non-coding RNAs and NK cells in different conditions is extensively studied, and it is now approved that if dysregulated, non-coding RNAs have detrimental effects on NK cell activity and can contribute to the pathogenesis of diverse disorders. In this review, we aim at a thorough inspection on the role of different non-coding RNAs on the activity and development of NK cells, in a broad spectrum of conditions, including blood-related disorders, viral infections, neurological diseases, gastrointestinal disorders, lung disorders, reproductive system conditions and other types of maladies, alongside with providing insight to the future non-coding RNA-NK cell studies.

A review on the role of NDRG1 in different cancers.

NDRG1 is a member of the α/ß hydrolase superfamily that resides in the cytoplasm and participates in the stress responses, hormone response, cell growth, and differentiation. Several studies have pointed to the importance of NDRG1 in the carcinogenesis. This gene has been found to be up-regulated in an array of cancer types such as bladder, esophageal squamous cell carcinoma, endometrial, lung and liver cancers, but being down-regulated in other types of cancers such as colorectal, gastric and ovarian cancers. The current study summarizes the evidence on the role of NDRG1 in the carcinogenic processes in different types of tissues.

Emerging functions and significance of circCDYL in human disorders.

Circular RNAs (circRNAs) are a group of non-coding transcripts in which a loop structure is shaped via a back splicing procedure. They have central roles in the regulation of gene expression. hsa_circ_0008285, alternatively named as circCDYL, is a circular RNA originated from the exon 4 of CDYL gene. It is produced by a back-splice incident and is mainly located in the cytoplasm. It has no internal ribosome entry site, open reading frame and intronic sequences. CircCDYL dysregulation has been reported in the malignant conditions including multiple myeloma, mantle cell lymphoma, breast cancer, non-small cell lung cancer, Wilms tumor, bladder cancer, colon cancer, and hepatocellular carcinoma. It also has an emerging role in the pathophysiology of non-malignant conditions including myocardial infarction, gestational diabetes mellitus, membranous nephropathy, and abdominal aortic aneurysm. In the current study, we summarize the emerging roles of circCDYL in malignant and non-malignant conditions.

Oleoylethanolamide protects mesenchymal stem/stromal cells (MSCs) from oxidative stress and reduces adipogenic related genes expression in adipose-derived MSCs undergoing adipocyte differentiation.

BACKGROUND: Human mesenchymal stem/stromal cells (hMSCs) are known for their pronounced therapeutic potential; however, they are still applied in limited clinical cases for several reasons. ROS-mediated oxidative stress is among the chief causes of post-transplantation apoptosis and death of hMSCs. It has been reported that a strategy to protect hMSCs against ROS is to pretreat them with antioxidants. Oleoylethanolamide (OEA) is a monounsaturated fatty acid derived from oleic acid and it has many protective properties, including anti-obesity, anti-inflammatory, and antioxidant effects. OEA is also used as a weight loss supplement; due to its high affinity for the PPAR-α receptor, OEA increases the fat metabolism rate. METHODS AND RESULTS: This study hence assessed the effects of OEA pretreatment on the in vitro survival rate and resistance of hMSCs under oxidative stress as well as the cellular and molecular events in the biology of stem/stromal cells affected by oxidative stress and free radicals. Considering the role of MSCs in adipogenesis and obesity, the expression of the main genes involved in adipogenesis was also addressed in this study. Results revealed that OEA increases the in vitro proliferation of MSCs and inhibits cell apoptosis by reducing the induction of oxidative stress. The results also indicated that OEA exerts its antioxidant properties by both activating the Nrf2/NQO-1/HO-1 signaling pathway and directly combating free radicals. Moreover, OEA can reduce adipogenesis through reducing the expression of PPARγ, leptin and CEBPA genes in hMSCs undergoing adipocyte differentiation. CONCLUSIONS: Thus, OEA protects hMSCs from oxidative stress and reduces adipogenic related genes expression and can be regarded as a therapeutic agent for this purpose.