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Masoud Ghorbani,1,2,* Shahram Teimourian,3,* Reza Farzad,4 Nabiollah Namvar Asl4 1Research and Development Department, Pasteur Institute of Iran, Tehran, Iran; 2Department of Biochemistry, University of Ottawa, Ottawa, ON, Canada; 3Department of Medical Genetics, Iran University of Medical Sciences, Tehran, Iran; 4Department of Animal Science, Pasteur Institute of Iran, Research and Production Complex, Karaj, Iran*These authors contributed equally to this work Background and objectives: The objective of this experiment was to study the effect of CL 316,243 (CL) (a highly selective ß3-adrenergic receptor agonist) on cellular changes occurring in retroperitoneal white adipose tissue (RWAT) of lean and obese rats. Methods: Ten-month-old lean and obese Zucker rats were implanted subcutaneously with osmotic mini-pumps, infusing either saline or CL (1 mg/kg body weight/day) for 4 weeks. Results: There was no effect of CL on food intake. However, the resting metabolic rate in lean and obese rats increased by 55% and 96% per rat, respectively. Total RWAT weight decreased in both lean and obese rats under influence of CL treatment by 65% and 38%, respectively. Total body weight and body fat were lower in CL treated rats. Detection of uncoupling protein 1(UCP1) in RWAT was confirmed qualitatively by both immunohistochemistry and immunofluorescence using a rabbit anti rat UCP1 antibody which showed the appearance of a marked increase of this protein in the adipose tissue. Stained semi-thin sections (0.5 µm) also demonstrated abundant nuclei in multilocular adipocytes, in endothelial cells associated with the vasculature, and in interstitial cells. In CL-treated obese rats, a clustering of several multilocular cells around the periphery of a white adipocyte was seen. Conclusion: These results indicate that treatment of both lean and obese Zucker rats with CL induces extensive remodeling of RWAT that includes shrinkage of white adipose tissue, appearance of abundant multilocular cells in RWAT together with the appearance of a marked increase of UCP, preferentially in lean rats. Keywords: brown adipose tissue, cellularity of adipose tissue, obesity, thermogenesis, uncoupling protein, Zucker rats

Mehdi Hajmohammadi,1 Seyed Davar Siadat,2 Masoud Ghorbani,3,4,* Mehdi Shafiee Ardestani,5,* Shahram Teimourian,6 Vahid Asgari,3 Reza Ahangari Cohan,3 Mostafa Hajmohammadi,5 Akram Hajmohammadi,7 Ramezan Behzadi,8 Saied Rajab Nezhad,9 Nabiollah Namvar Asl10 1Department of Research and Biotechnology, 2Department of Microbiology, 3Department of Virology, Pasteur Institute of Iran, Tehran Iran; 4Department of Virology, University of Ottawa, Ottawa, ON, Canada; 5Department of Radiopharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 6Department of Medical Genetics, Iran University of Medical Sciences, Tehran, 7Faculty of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, 8Laboratory Animal Management of North Research Center, Pasteur Institute of Iran, 9Department of Research and Development, Alhavi Pharmaceutical, Tehran, 10Pasteur Institute of Iran, Department of Animal Sciences, Karaj, Iran *These authors contributed equally to this work Abstract: In recent years, many experiments have been conducted for the production and evaluation of anticancer glycoconjugated vaccines in developed countries and many achievements have been accomplished with Globo H derivatives. In the current experiment, a new chemically designed triplicate version of (Globo H)3–diethylenetriamine pentaacetic acid (DTPA)–KLH antigen was synthesized and characterized. Immunization with (Globo H)3-DTPA-KLH, a hexasaccharide that is a member of a family of antigenic carbohydrates that are highly expressed in various types of cancers conjugated with DTPA and KLH protein, induced a high level of antibody titer along with an elevated level of IL-4 in mice. Treatment of tumors with the collected sera from immunized mice decreased the tumor size in nude mice as well. None of the immunized mice illustrated any sign of tumor growth after injection of MCF-7 cells compared to the control animals. These findings, based on the newly presented structure of the Globo H antigen, lend exciting and promising evidence for clinical advancement in the development of a therapeutic vaccine in the future. Keywords: (Globo H)3-DTPA-KLH, glycoconjugate vaccines, breast cancer

Abstract Objective To investigate whether daily diet provides adequate selenium intake in healthy men and women living in Tehran, Iran. Method Serum level of selenium was determined in 184 healthy individuals of both genders. The samples were divided into two age groups, adults and children, for analysis. The serum level of selenium was determined using hydride generation and flame atomic absorption spectroscopy. Results The mean and standard deviation of serum selenium levels in children (1–16 years) was 84.3 ± 11 μg/l and there was no significant difference between genders in this group. In adults (older than 16 years) the mean serum selenium level was 100.6 ± 13 SD μg/l; among women the mean was 93.9 ± 14 SD μg/l and among men it was 102.2 ± 12 SD μg/l. The mean selenium level in men was higher than in women and data analysis showed a significant difference between them (p < 0.005). There was also a positive correlation between higher selenium serum concentration and age in men (P < 0.001). Daily intake of selenium in men and women was calculated to be 67 μg and 62.1 μg respectively. Conclusion Our results show that the serum concentration of selenium in an Iranian population is similar to other nationalities in the Middle East, particularly Saudi Arabia.

Breast cancer (BC) is the second most common malignancy worldwide. ADGRL4, as a modulator of angiogenesis, undergoes various epigenetic modifications affecting its biological functions. In this study, we aimed to assess ADGRL4 promoter methylation status and its expression levels in primary breast tumors and to evaluate its potency as a plausible prognostic biomarker in BC. Furthermore, we evaluated the effect of melatonin on ADGRL4 expression and viability of BC cells in vitro. One hundred breast tumor tissue samples and adjacent non-tumor tissues were collected, followed by DNA isolation, bisulfite conversion, qRT-PCR, qMSP assay, and immunoblotting. In addition, four BC cell lines were treated with melatonin and subjected to ADGRL4 expression analysis and apoptosis assay. We found a significant correlation between ADGRL4 expression levels and HER2 status and stage of disease (P < 0.05). We observed a substantial attenuation in ADGRL4 promoter methylation in tumor samples compared to marginal non-tumor samples. A significantly lower expression of ADGRL4 was detected in two BC cell lines in the presence of melatonin. MCF-7 and BT474 melatonin-treated cell lines showed a significantly higher number of apoptotic cells than non-treated cells (P < 0.0001). Based on the receiver operating characteristic (ROC) curve analysis, ADGRL4 expression and ADGRL4 promoter methylation status showed moderate prognostic value. We found that melatonin has anti-cancer effects on BC cells. In addition, ADGRL4 expression can potentially be used as a prognostic biomarker in BC., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Among the myriad of nanoparticles, silica nanoparticles (SiO 2 NPs) have gained significant attention since they are extensively produced and used across several kinds of industries. Because of its widespread usage, there has been increasing concern about the potential health effects. This study aims to evaluate the effects of SiO 2 NPs on Interleukin-6 (IL-6) gene expression in human lung epithelial cell lines (A549). In this study, A549 cells were exposed to SiO 2 NPs at concentrations of 0, 1, 10, 50, 100, and 200 µg/mL for 24 and 48 h. The IL-6 gene expression was assessed using Real-Time RT-PCR. Additionally, the impact of SiO 2 NPs on the viability of A549 cells was determined by MTT assay. Statistical analysis was performed using GraphPad Prism software 8.0. MTT assay results indicated a concentration-dependent impact on cell survival. After 24 h, survival decreased from 80 to 68% (1-100 µg/mL), rising to 77% at higher concentrations. After 48 h, survival dropped from 97 to 80%, decreasing to 90% at higher concentrations. RT-PCR showed a dose-response relationship in cellular toxicity up to 10 µg/mL. At higher concentrations, there was increased IL-6 gene expression, mitigating SiO 2 NP-induced cytotoxic effects. The study shows that the viability and proliferation of A549 cells are impacted by different SiO 2 NPs concentrations. There may be a potential correlation between IL-6 gene expression reduction and a mechanism linked to cellular toxicity. However, at higher concentrations, an unknown mechanism increases IL-6 gene expression, reducing SiO 2 NPs' cytotoxic effects. These effects are concentration-dependent and not influenced by exposure times. Further investigation is recommended to determine this mechanism's nature and implications, particularly in cancer research., (© 2024. The Author(s).)

Occupational health must be strictly considered in industries particularly in nanoparticle factories where workers were exposed to different types of chemicals. We measured the serum levels of inflammatory cytokines in workers who developed skin lesions after exposure to silver and silica nanoparticles. Using a questionnaire in this cross-sectional study, we identified 110 workers in nanoparticle industries who were exposed to silver and silica nanoparticles. We also included 40 healthy subjects as controls from the administrative department of the same factories who were not exposed to nanoparticles. Peripheral blood samples used to measure the mRNA levels of inflammatory cytokines by qRT-PCR. In comparison with the control group, the workers who developed skin lesions had significantly higher levels of interleukin IL4, IL6, IL8, and TNF-α, particularly after two or three decades of exposure to silver and silica nanoparticles. Participants who were exposed to silver had higher levels of IL6 and IL8 compared with those who were exposed to silica. Necessary measures must be considered to protect workers in nanoparticle industries against the potential toxic effects of these compounds. Our network pharmacology study suggests corresponding biochemical pathways for these disorders., (© 2024. The Author(s).)

Aim: MicroRNAs can be regarded as biomarkers for gastric cancer (GC) diagnosis in the early stages. This study assesses the expression levels of miR-362-3p, miR-362-5p and miR-363-5p as potential biomarkers for GC. Materials & methods: The expression levels of the miRNAs in 90 pairs of GC and adjacent normal tissue samples were analyzed by quantitative real-time reverse transcription PCR (qRT-PCR) and some bioinformatics tools were utilized for analyzing the target genes and possible molecular pathways in which these miRNAs participate. Results & conclusion: There was a significant overexpression of the miRNAs in GC cells and an outstanding correlation between their overexpression with some clinicopathological features of the patients.

The stem cells' ability to divide asymmetrically to produce differentiating and self-renewing daughter cells is crucial to maintain tissue homeostasis and development. Stem cell maintenance and differentiation rely on their regulatory microenvironment termed 'niches'. The mechanisms of the signal transduction pathways initiated from the niche, regulation of stem cell maintenance and differentiation were quite challenging to study. The knowledge gained from the study of Drosophila melanogaster testis and ovary helped develop our understanding of stem cell/niche interactions and signal pathways related to the regulatory mechanisms in maintaining homeostasis of adult tissue. In this review, we discuss the role of signaling pathways in Drosophila gonadal stem cell regeneration, competition, differentiation, dedifferentiation, proliferation, and fate determination. Furthermore, we present the current knowledge on how these signaling pathways are implicated in cancer, and how they contribute as potential candidates for effective cancer treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Autophagy is a significant catabolic procedure that increases in stressful conditions. This mechanism is mostly triggered after damage to the organelles, the presence of unnatural proteins, and nutrient recycling in reaction to these stresses. One of the key points in this article is that cleaning and preserving damaged organelles and accumulated molecules through autophagy in normal cells helps prevent cancer. Since dysfunction of autophagy is associated with various diseases, including cancer, it has a dual function in tumor suppression and expansion. It has newly become clear that the regulation of autophagy can be used for the treatment of breast cancer, which has a promising effect of increasing the efficiency of anticancer treatment in a tissue- and cell-type-specific manner by affecting the fundamental molecular mechanisms. Regulation of autophagy and its function in tumorigenesis is a vital part of modern anticancer techniques. This study discusses the current advances related to the mechanisms that describe essential modulators of autophagy involved in the metastasis of cancers and the development of new breast cancer treatments., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Lung adenocarcinoma is one of the leading causes of cancer-related mortality globally. Various treatment approaches and drugs had little influence on overall survival; thus, new drugs and treatment strategies are needed. Drug repositioning (repurposing) seems a favorable approach considering that developing new drugs needs much more time and costs. We performed a meta-analysis on 6 microarray datasets to obtain the main genes with significantly altered expression in lung adenocarcinoma. Following that, we found major gene clusters and hub genes. We assessed their enrichment in biological pathways to get insight into the underlying biological process involved in lung adenocarcinoma pathogenesis. The L1000 database was explored for drug perturbations that might reverse the expression of differentially expressed genes in lung adenocarcinoma. We evaluated the potential drug combinations that interact the most with hub genes and hence have the most potential to reverse the disease process. A total of 2148 differentially expressed genes were identified. Six main gene clusters and 27 significant hub genes mainly involved in cell cycle regulation have been identified. By assessing the interaction between 3 drugs and hub genes and information gained from previous clinical investigations, we suggested the three possible repurposed drug combinations, Vorinostat - Dorsomorphin, PP-110 - Dorsomorphin, and Puromycin - Vorinostat with a high chance of success in clinical trials.

Background: Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in various biological processes, including cancer development and progression. This study aimed to investigate the expression differences of the BRAF-activated non-coding RNA (BANCR) gene in GC tissues compared to adjacent normal tissues. The potential diagnostic significance of BANCR in GC was explored, with the aim of improving diagnostic and therapeutic approaches for this global health burden., Materials and Methods: Tissue samples from 100 gastric cancer (GC) patients were collected, and BANCR expression was analyzed using quantitative real-time PCR. Correlations between BANCR expression and clinicopathological features were assessed, and its biomarker potential was evaluated., Results: In individuals diagnosed with GC, the expression of BANCR was notably elevated in tumor tissues compared to adjacent normal tissues ( P < 0.0001). However, the analysis of gene expression data did not demonstrate any statistically significant correlation between elevated BANCR expression and clinicopathological features. According to the ROC analysis, BANCR demonstrated an AUC of 0.6733 ( P < 0.0001), with a sensitivity of 73% and a specificity of 45%. However, further evaluation is required to determine its potential as a biomarker (CI 95% = 0.5992 to 0.7473)., Conclusions: The observed upregulation of BANCR in GC tissues implies its potential involvement as an oncogenic lncRNA in GC patients. Furthermore, BANCR may serve as a promising biomarker for identification and treatment of GC., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Advanced Biomedical Research.)

Rheumatoid arthritis (RA) is a systemic and chronic inflammatory disease categorized by continuous synovitis in the joints and systemic inflammatory responses that can cause lifelong disability. The major cause of RA is the dysregulation of the immune response. The development of RA disease includes multiplex association of several interleukins and cells, which leads to synovial cell growth, cartilage and bone damage. The primary stage of RA disease is related to the modification of both the innate and adaptive immune systems, which leads to the formation of autoantibodies. This process results in many damaged molecules and epitope spreading. Both the innate (e.g., dendritic cells, macrophages, and neutrophils) and acquired immune cells (e.g., T and B lymphocytes) will increase and continue the chronic inflammatory condition in the next stages of the RA disease. In recent years, non-coding RNAs have been proved as significant controllers of biological functions, especially immune cell expansion and reactions. Non-coding RNAs were primarily containing microRNA (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA). Various studies confirmed non-coding RNAs as hopeful markers for diagnosing and curing RA. This review will describe and cover existing knowledge about RA pathogenesis, which might be favorable for discovering possible ncRNA markers for RA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Gastric cancer is the fourth leading cause of cancer-related mortality and one of the most commonly diagnosed malignancies worldwide. Gastric adenocarcinoma (GAC) accounts for the majority of gastric cancer cases. Circular RNAs (circRNAs) have been shown to be associated with carcinogenesis and cancer progression. This research aims to investigate GAC-associated circRNAs and the underlying mechanisms of circRNA-miRNA-mRNA networks in the development and progression of GAC. Differentially expressed miRNAs and mRNAs (DEMs and DEGs) were identified in Gene Expression Omnibus (GEO) microarray datasets using the R package Limma. A microarray meta-analysis was performed to identify potential GAC-associated circRNAs with high statistical power, resulting in 13 up-regulated and 19 down-regulated circRNAs. CircRNA-miRNA-mRNA networks were constructed by combining predicted and experimentally validated databases and considering differentially expressed miRNAs and mRNAs. The constructed ceRNA networks revealed the potential regulatory effect of hsa&#95;circ&#95;0002019 and hsa&#95;circ&#95;0074736 on key survival-related genes. The expression levels of these two circRNAs were measured in plasma samples from GAC patients and healthy controls using SYBR Green-based real-time PCR. Axon guidance, cellular senescence, AGE-RAGE signaling pathway in diabetic complications, and AMPK signaling pathway were among the major significant (P-value <0.05) enriched pathways of "main mRNAs" in the constructed ceRNA networks. In conclusion, we identified strongly correlated circRNAs and their likely mechanisms of action in GAC, which may improve the knowledge of regulatory networks underlying GAC formation and contribute to developing better strategies for early diagnosis, prognosis, and treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: Chronic wounds are debilitating complications of diabetes mellitus. The present study was conducted to investigate the effect of the hair follicle stem cells (HFSCs) by polycaprolactone scaffold on the healing of incisional cutaneous wounds on streptozotocin-induced diabetic male rats., Methods: The wound model was obtained by a biopsy punch of the skin of the animals' back. The animals were randomly divided into five groups as follows: (1) Sham (nondiabetic, not treated), (2) Control (diabetic, not treated), (3) Scaffold (diabetic, treated with polycaprolactone nanofiber scaffold), (4) HFSCs (diabetic, treated with HFSCs), and (5) Scaffold + HFSCs (diabetic, treated with combination of Scaffold and HFSCs). The wounds were photographed in the course of the treatment and their healing rate was assessed. The samples were collected from the wound sites 7, 14, and 28 d after their development. Angiogenesis was surveyed by examining messenger RNA expression and the protein synthesis levels of vascular endothelial growth factor receptor 2 (VEGFR2) and platelet/endothelial cell adhesion molecule-1/cluster of differentiation 31. The histological changes were investigated using hematoxylin and eosin and Masson's trichrome staining. Furthermore, the wound breaking strength was measured on the 28th day by tensiometry., Results: The application of the VEGFR2 as a substrate promotes the expression of CD31 in HFSCs and Scaffold + HFSCs groups compared to controls (P < 0.0001). HFSCs and scaffold also rescue the diabetes-induced dysfunction as assessed based on the parameters, such as viability, proliferation, colony formation, cellular adhesion, and chemotactic migration. HFSCs augment the levels of VEGFR2 and promote the restoration of the wound healing in diabetic groups. Furthermore, the maximum biomechanical stress significantly increased in the experimental diabetic groups (Scaffold: 1.38 ± 0.09, HFSCs: 2.13 ± 0.8, Scaffold + HFSCs: 2.38 ± 0.11) compared to the diabetes control group (1.16 ± 0.12). Using of HFSCs and scaffold on diabetic wounds leads to an accelerated wound closure, notably., Conclusions: Thus, the current data showed that HFSCs and scaffold form excellent biomaterial in the treatment of diabetic wounds., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Multiple Sclerosis (MS) is a multifactorial, neurodegenerative, and inflammatory demyelination disease with incomplete remyelination in the CNS. It would be more informative to reveal the underlying molecular mechanisms of MS. Molecular mechanisms involving epigenetic changes play a pivotal role in this disease. Epigenetic changes impact gene expression without altering the underlying DNA sequence. The main epigenetic modifications that play a key role in the regulation of gene expression principally include DNA methylation, histone modifications, and microRNA- associated post-transcriptional gene silencing. In this review, we summarize the dynamics of epigenetic changes and their relation to environmental risk factors in MS pathogenesis. Studies suggest that epigenetic changes have a role in the development of MS and environmental risk factors, such as vitamin D, smoking, and Epstein-Barr virus infection seem to influence the development and susceptibility to MS. Investigating epigenetic and environmental factors can provide new opportunities for the molecular basis of the diseases, which shows complicated pathogenesis. Epigenetic research has the potential to complete our understanding of MS initiation and progression. Increased understanding of MS molecular pathways leads to new insights into potential MS therapies. However, there is a need for in vivo evaluation of the role of epigenetic factors in MS therapy. It would be more valuable to indicate the role of various epigenetic factors in MS., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Nosocomial infections (NIs) have been defined as infections ocuurring shortly after hospitalization or discharging from the hospital. It is associated with increased morbidities and mortalities. Proteus mirabilis considered as the hospital-acquired pathogen. The purpose of this study was to investigate the effect of Lactobacillus acidophilus-derived biosurfactant on P. mirabilis biofilm formation and flhDC/rsmA expression level (P. mirabilis standard strain ATCC 7002 and urinary infection isolated P. mirabilis strains). One of the potential strategies for the prevention of nosocomial infections is the use of probiotics. L. acidophilus was selected as a probiotic strain to produce biosurfactants. A biosurfactant reduces the adhesion of strains to microtiter plate and glass slide surfaces due to the reduction of surface tension. By using Real time PCR quantitation method we showed that biosurfactant significantly reduced rsmA expression whereas increased flhDC expression in P. mirabilis isolates. Several properties of P. mirabilis cells (biofilm formation, adhesion, and gene expression) were changed after L. acidophilus- derived biosurfactant treatment. In this study we showed that biosurfacant treatment can pave the way for a possible control of biofilm development. Based on our findings, we suggest that the prepared biosurfactant may interfere with adhesion of P. mirabilis to catheters and other devices., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Growing evidence supports that changes in the methylation state of Inflammatory Bowel Disease (IBD)-associated genes could significantly alter levels of gene expression, potentially contributing to disease onset and progression. We supposed that alterations in DNA methylation status at promoter region within the suppressor of cytokine signaling 3 (SOCS3) gene in intestinal tissues may be involved in the susceptibility to Crohn's Disease (CD)., Methods: DNA methylation status in the promoter region of the human SOCS3 gene of intestinal tissues from 15 patients with CD and 15 age- and sex-matched healthy controls were profiled using the real-time Quantitative Multiplex Methylation Specific PCR (QM-MSP) assay., Results: Based on methylation assay data profiling, we found that patients with CD showed a higher degree of methylation of the SOCS3 gene promoter region than did the healthy controls (unmethylated DNA in CD vs. healthy controls; 0.00048±0.0011 vs. 0.07±0.142, p<0.000)., Conclusion: The data presented here demonstrate that aberrant methylation of the CpG islands within promoter regions of SOCS3 gene in colonic mucosa of CD was associated with mucosal inflammatory status, providing insights into the involvement of methylation could contribute to the initiation of the inflammatory process and development of CD., Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest., (Copyright© 2022 Avicenna Research Institute.)

Background: Colorectal cancer is one of the most deadliest malignancies worldwide. Due to the dearth of appropriate biomarkers, the diagnosis of this mortal disease is usually deferred, in its turn, culminating in the failure of prevention. By the same token, proper biomarkers are at play in determining the quality of prognosis. In other words, the survival rate is contingent upon the regulation of such biomarkers., Materials and Methods: The information regarding expression (GSE41258, and GSE31905), methylation (GSE101764), and miRNA (dbDEMC) were downloaded. MEXPRESS and GEPIA confirmed the validated differentially expressed/methylated genes using TCGA data. Taking advantage of the correlation plots and receiver-operating-characteristic (ROC) curves, expression and methylation profiles were compared. The interactions between validated differentially expressed genes and differentially expressed miRNA were recognized and visualized by miRTarBase and Cytoscape, respectively. Then, the protein-protein interaction (PPI) network and hub genes were established via STRING and Cytohubba plugin. Utilizing R packages (DOSE, Enrichplot, and clusterProfiler) and DAVID database, the Functional Enrichment analysis and the detection of KEGG pathways were performed. Ultimately, in order to recognize the prognostic value of found biomarkers, they were evaluated through drawing survival plots for CRC patients., Results: In this research, we found an expression profile (with 13 novel genes), a methylation profile (with two novel genes), and a miRNA profile with diagnostic value. Concerning diagnosis, the expression profile was evaluated more powerful in comparison with the methylation profile. Furthermore, a prognosis-related expression profile was detected., Conclusion: In addition to diagnostic- and prognostic-applicability, the discerned profiles can assist in targeted therapy and current therapeutic strategies., Competing Interests: The authors have declared that no competing interests exist.

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide, which has a high mortality rate and poor treatment outcomes with yet unknown molecular basis. It seems that gene expression plays a pivotal role in the pathogenesis of the disease. Circular RNAs (circRNAs) can interact with microRNAs (miRNAs) to regulate gene expression in various malignancies by acting as competitive endogenous RNAs (ceRNAs). However, the potential pathogenesis roles of the ceRNA network among circRNA/miRNA/mRNA in HCC are unclear. In this study, first, the HCC circRNA expression data were obtained from three Gene Expression Omnibus microarray datasets (GSE164803, GSE94508, GSE97332), and the differentially expressed circRNAs (DECs) were identified using R limma package. Also, the liver hepatocellular carcinoma (LIHC) miRNA and mRNA sequence data were retrieved from TCGA and differentially expressed miRNAs (DEMIs) and mRNAs (DEGs) were determined using the R DESeq2 package. Second, CSCD website was used to uncover the binding sites of miRNAs on DECs. The DECs' potential target miRNAs were revealed by conducting an intersection between predicted miRNAs from CSCD and downregulated DEMIs. Third, candidate genes were uncovered by intersecting targeted genes predicted by miRWalk and targetscan online tools with upregulated DEGs. The ceRNA network was then built using the Cytoscape software. The functional enrichment and the overall survival time of these potential targeted genes were analyzed, and a PPI network was constructed in the STRING database. Network visualization was performed by Cytoscape, and ten hub genes were detected using the CytoHubba plugin tool. Four DECs (hsa&#95;circ&#95;0000520, hsa&#95;circ&#95;0008616, hsa&#95;circ&#95;0070934, hsa&#95;circ&#95;0004315) were obtained and six miRNAs (hsa-miR-542-5p, hsa-miR-326, hsa-miR-511-5p, hsa-miR-195-5p, hsa-miR-214-3p, and hsa-miR-424-5p) which are regulated by the above DECs were identified. Then 543 overlapped genes regulated by six miRNAs mentioned above were predicted. Functional enrichment analysis showed that these genes are mostly associated with regulatory pathways in cancer. Ten hub genes (TTK, AURKB, KIF20A, KIF23, CEP55, CDC6, DTL, NCAPG, CENPF, PLK4) have been screened from the PPI network of the 204 survival-related genes. KIF20A, NCAPG, TTK, PLK4, and CDC6 were selected for the highest significance p-values. At the end, a circRNA-miRNA-mRNA regulatory axis was established for five final selected hub genes. This study implies the potential pathogenesis of the obtained network and proposes that the two DECs (has&#95;circ&#95;0070934 and has&#95;circ&#95;0004315) may be important prognostic markers for HCC., (© 2022. The Author(s).)

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that in most cases occurs sporadic (sALS). The disease is not curable, and its pathogenesis mechanisms are not well understood yet. Given the intricacy of underlying molecular interactions and heterogeneity of ALS, the discovery of molecules contributing to disease onset and progression will open a new avenue for advancement in early diagnosis and therapeutic intervention. Here we conducted a meta-analysis of 12 circulating miRNA profiling studies using the robust rank aggregation (RRA) method, followed by enrichment analysis and experimental verification. We identified miR-451a and let-7f-5p as meta-signature miRNAs whose targets are involved in critical pathogenic pathways underlying ALS, including 'FoxO signaling pathway', 'MAPK signaling pathway', and 'apoptosis'. A systematic review of 7 circulating gene profiling studies elucidated that 241 genes up-regulated in sALS circulation with concomitant being targets of the meta-signature miRNAs. Protein-protein interaction (PPI) network analysis of the candidate targets using MCODE algorithm revealed the main subcluster is involved in multiple cascades eventually leads apoptosis, including 'positive regulation of neuron apoptosis. Besides, we validated the meta-analysis results using RT-qPCR. Indeed, relative expression analysis verified let-7f-5p and miR-338-3p as significantly down-regulated and up-regulated biomarkers in the plasma of sALS patients, respectively. Receiver operating characteristic (ROC) analysis also highlighted the let-7f-5p and miR-338-3p potential as robustness plasma biomarkers for diagnosis and potential therapeutic targets of sALS disease., (© 2022. The Author(s).)

Gastric cancer (GC) is the leading cause of death and cancer mortality in the world, with poor survival for cases with higher stages of GC. During the past decade, GC stem cells (GCSCs), a group of cancer cells, have been the focus of significant research on cancer. GCSCs have the capability of selfrenewal and are identified to participate in GC development, invasion, chemoresistance, and tumor relapse. Research projects have indicated the main activities of noncoding RNAs in cellular pathways. Micro (mi)RNAs and lncRNAs play important functions in the modulation of different cellular pathways in the post-transcriptional form through their dysregulated expression in several cancers, including GC. In this paper, we highlight the impact of dysregulated expression of micro- and lncRNAs and their downstream transcripts on GCSCs. Data collection on the progression of GCSCs may be beneficial for the introduction of new insights to the GC treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Colorectal cancer (CRC) is one of the main causes of malignancy-related mortality worldwide. It was well-identified that microRNAs (miRNAs) decisively participate in cellular biological pathways; in a way that their deregulated expression causes CRC progression. miRNAs can control the translation and degradation of mRNAs by binding to various molecular targets involved in different biological processes, including growth, apoptosis, cell cycle, autophagy, angiogenesis, metastasis, etc. The functions of these dysregulated miRNAs may be either oncogenic or tumorsuppressive. Therefore, these miRNAs can be contributed to prognostic, diagnostic, and therapeutic approaches in CRC. In this study, we reviewed the tumor-suppressive and oncogenic functions of miRNAs in CRC and assessed their molecular activities in CRC development. However, further investigation for the involvement of dysregulated miRNAs in CRC progression is required., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Epigenetics is related to the various pathways that show long-term impacts on the gene expression patterns without alterations in nucleotide sequences. Over the last decade, epigenetics advanced significantly in the science of biology, oncology, innate immunity as well as pathogens and infectious diseases. In the present paper, we aimed to review the relationships between COVID-19 and epigenetic alterations of the infected cells. Coronavirus is one of the known infectious diseases that causes respiratory infection, such as pneumonia and coughing, while in animals, it causes diarrhea and upper respiratory disorders. This virus could be transmitted human to human or human to an animal through droplets. It translocates via membrane ACE-2 exopeptidase into the host cells. In conclusion, hypomethylation of angiotensin II converting enzyme (ACE II) possibly upregulates its expression, enhancing the possibility of SARS-CoV-2 infection., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Vulvovaginal candidiasis (VVC) is a vaginal mucosal infection that usually affects women in their reproductive age. When the signs of VVC persist on a daily basis or last for a long time and repeat at least three times per year, the disease is considered chronic and recurrent., Objective: The purpose of this study was to evaluate the frequency of HLA-DRB1 alleles in patients with recurrent vulvovaginal candidiasis (RVVC)., Study Design: 120 patients with RVVC and 136 age-matched healthy controls underwent low-resolution HLA-DRB typing performed using the polymerase chain reaction-sequence-specific primers (PCR-SSP) technique., Results: In the present work, we studied different genes that encode HLA-DRB (HLA-DRB1 / HLA-DRB3 / HLA-DRB4 / HLA-DRB5) and showed that HLA-DRB1×14, found in 25% of the patients. In the present study, the significant frequency of HLA-DRB1×10 in the control group suggests a resistant role of this allele to RVVC infections CONCLUSIONS: In the HLA-DRB region, the DRB1×14 allele showed a higher frequency in the patients with RVVC than in the controls. Moreover, the higher frequency of DRB1×10 observed in the controls than in the patients with RVVC. These results demonstrate the HLA-DRB1 alleles are in relation with both susceptibility and immunity factors in RVVC infection and possible susceptible role of HLA-DRB1×14., Competing Interests: Disclosure and conflict of interest All authors declare to have no conflicts of interest., (Copyright © 2021 SFMM. Published by Elsevier Masson SAS. All rights reserved.)

Introduction : Breast cancer (BC) is the most significant threat to women's life. To demonstrate its molecular mechanisms, which results in BC progression, it is crucial to develop approaches to enhance prognosis and survival in BC cases. Areas covered : In the current study, we aimed to highlight the updated data on the oncogenic and tumor suppressive roles of lncRNAs in the progression of various subtypes of BC by specifically putting importance on the functional characteristics, modulatory agents, therapeutic potential, future perspectives and challenges of lncRNAs in BC. We reviewed recent studies published between 2019 and 2020. Expert opinion : The latest investigations have demonstrated that the long non-coding RNAs (lncRNAs) participate in different BC molecular subtypes via different molecular mechanisms; however, the exact functional information of the lncRNAs has yet to be elucidated. The studied lncRNAs could be more applicable as therapeutic targets in BC treatment after pre-clinical and clinical studies.

Beta-secretase (BACE1) and gamma-secretase activating protein (GSAP) are pivotal enzymes in the cleavage of amyloid precursor protein (APP). Beta-amyloid (Aß) formation is considered one of the main reasons for Alzheimer's disease (AD) pathology. In our preliminary study, a series of microRNAs (miRs) with possible interaction with BACE1 and/or GSAP was selected using computational analysis. Our results showed that miR-4422-5p had a reduced level in the serum of AD patients. In this study, the effect of miR-4422-5p using miR-4422-5p mimic and inhibitor on BACE1 and GSAP were investigated, and a probable novel early diagnostic marker for AD was introduced. The effect of miR-4422-5p interaction with BACE1 and GSAP was evaluated via in vitro experiments using dual-luciferase assays, western blotting, and Immunocytochemistry. Luciferase assay demonstrated that miR-4422-5p mimic suppresses BACE1 and GSAP expression by directly targeting the 3'UTR of BACE1 and GSAP mRNA in HEK293T cells. Also, western blotting and immunocytochemistry confirmed the regulatory role of miR-4422-5p mimic on BACE1 and GSAP genes. miR-4422-5p mimic significantly decreased BACE1 and GSAP protein expression in SH-SY5Y and A549 cells, respectively. Moreover, miR-4422-5p-inhibitor reversed the expression processes in both cell lines. Our data suggest that miR-4422-5p may be an important regulator of both BACE1 and GSAP genes and can represent a novel potential biomarker or therapeutic target in AD., (Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.)

Congenital factor XIII (FXIII) deficiency is an extremely rare bleeding disorder (RBD) with estimated prevalence of one per 2 million in the general population. The disorder causes different clinical manifestations such as intracranial hemorrhage (ICH), recurrent miscarriage, umbilical cord bleeding, etc. High incidence of the disorder might be due to founder effect. To assess founder effect, haplotype analysis is an important step. For this purpose, suitable and reliable genetic markers such as microsatellites (Hum FXIIIA01 and HumFXIIIA02) and single nucleotide polymorphisms (SNP) are suggested. In the present study we tried to describe evaluation of founder effect in patients with congenital FXIII deficiency via haplotype analysis using suitable genetic markers., (Copyright © 2020 Tehran University of Medical Sciences.)

Tuberculosis has been declared as a global emergency. Latent tuberculosis infection (LTBI) is a state in which host immunity cannot completely eradicate Mycobacterium tuberculosis . Cigarette smoke increases the risk of respiratory infections, such a TB, as it has adverse effects on respiratory immune function. In this cross-sectional study, which was performed from 2016 to 2017, 31 patients with newly diagnosed lung cancer, 63 Chronic obstructive pulmonary disease (COPD), 46 with problems in respiratory system, and 40 healthy subjects were studied. Demographic data of all subjects were recorded via a questionnaire. IGRAs (Interferon-γ release assays) were used to determine LTBI. We showed that smoking has significant odds ratio for COPD patients (OR: 4.58, 95% CI: 1.93-10.87). Also, the concordance of smoking with COPD (OR: 22, 95% CI: 2.7-179.2), lung cancer (OR: 10, 95% CI: 1.03-97), and other respiratory diseases (OR: 4.54, 95% CI: 1.93-10.87) is a significant risk factor for the presence of LTBI whereas the existence of LTBI in the study groups did not show any significant odds ratio. This study is the first to analyze the relationship between smoking in patients with respiratory diseases and LTBI susceptibility in Iran by IGRAs, which proposes cigarette smoking as a powerful risk factor for LTBI.

Background: Vulvovaginal candidiasis (VVC) is a vaginal mucosal infection that usually infects women in their reproductive age. When the signs of VVC persist on a daily basis or last for a long time and repeat at least three times per year, the disease is considered chronic and recurrent., Objectives: The purpose of this study was to determine the expression rate of 2 genes responsible for adhesion and virulence of candida in RVVC patients using Real-time PCR, and comparing them together and assess the presence or absence of ALS9-2 allele in these patients., Patients/methods: The vaginal discharge was collected from 120 women aged (22-55) attending lolagar hospital which were all diagnosed with RVVC and 120 age-matched healthy controls. The expression rate of ALS2 and ALS 9 genes was quantified using real-time PCR. PCR method was used for Identification of ALS9 gene alleles., Results: Results showed an increase in ALS2 gene expression and a decrease in ALS9 gene expression, comparing to basic level and standard sample. 42.5% (51 of total 120 samples) contained the small allele., Conclusions: The significant difference in expression rates of ALS2 and ALS9 genes indicates their different roles in making morphogenesis changes during the virulence of Candida albicans. Emergence of heterogeneous form and detection of ALS's short allele in invasive form of fungi proves the significant pathogenic role of this allele, specially when attached to mucosal tissue. Invasive and recurrent form of the disease can be accompanied by genetic-morphologic changes in fungi. Considering the form of this disease and the reduction in ALS9 gene expression, it can be concluded that this gene plays a significant role in attachment and initiation of the pathogenic phase., (Copyright © 2020. Published by Elsevier B.V.)

Background and Objective: Severe combined immunodeficiency disease (SCID) is a rare inherited severe immunodeficiency, in which functions of T cells and B cells are impaired. SCID is inherited either in X-linked recessive, or autosomal recessive forms, and is either radiosensitive or radioresistant. Artemis (DCLRE1C gene), DNA ligase IV, DNA-PKC, and Cernunnos/XLF proteins are regarded as NHEJ (Non-Homologous End-Joining) proteins that are involved in the repair process of double-strand DNA breaks and their mutations would lead to cellular radiosensitivity. Diagnostic radiosensitivity assays are important for the management of clinical BMT (Bone Marrow Transplantation) conditions, such as what conditioning agents and doses should be used., Materials and Methods: In this study, five SCID patients and healthy controls were examined. Skin fibroblasts were cultured. After X-irradiation, cells either underwent clonogenic assay or incubated to allow DNA repair and examined by the alkaline comet assay. Finally, DCLRE1C, RAG-1, and RAG-2 genes sequenced., Results: By clonogenic assay, three patients were detected as radiosensitive with possible mutations in NHEJ genes such as DCLRE1C gene. The percentage of DNA in the tail measured by comet assay, in all three patients, was significantly different from the two other patients and the control group (p-value < 0.05). By using Sanger sequencing, a mutation in DCLRE1C gene was detected in one of the radiosensitive patients and two mutations in RAG-1, and RAG-2 genes were detected in the two radioresistant patients., Conclusion: Our findings suggest that comet assay is a fast technique for the diagnosis of the radiosensitive form of SCID and is very suitable for the timely diagnosis of RS-SCID before BMT., Competing Interests: Declaration of competing interest The authors have no conflict of interest., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Diabetes is associated with numerous complications, such as diabetic skin wounds or ulcerations. The aim of this study was to evaluate experimentally the effectiveness of applying polycaprolactone (PCL)-gelatin scaffold, with or without rat CD93 hematopoietic stem cells (HSCs), in diabetic wound healing in a rat model. CD93 HSCs were aseptically isolated from rat bone marrow using fluorescent activated cell sorting (FACS) method and FACS-SORTER. A total of 25 Wistar rats were divided into five groups including Group I (sham, nondiabetic, and wound covered only with sterile dressing), II (control, diabetic rat), III (CD93 HSCs alone), IV (PCL-gelatin scaffold), and V (CD93 HSCs+PCL-gelatin scaffold). Animals were killed on Days 7, 14, or 28 posttreatment and histological sections were blindly evaluated by two expert pathologists. Death-associated protein kinase 1 (DAPK-1) gene and vesicular endothelial growth factors (VEGF) protein expression were evaluated using reverse transcription-polymerase chain reaction and western blot, respectively. The thickest and the thinnest epidermises microscopically were belonged to CD93+HSCs+scaffold and the control group, respectively. The growth rate of the epidermis and adnexal epithelia was the highest in both the cell and cell+scaffold groups. Evaluation of the protein expression level of VEGF indicated that the expression levels of this growth factor were the most on Day 7 posttreatment in sham, HSCs alone, and HSCs cell+scaffold groups. While the lowest expression levels of this growth factor was detected in the control and scaffold groups. The gene expression level of DAPK-1 on Day 7 posttreatment was higher than that of the Day 14 posttreatment in all groups. The highest and lowest gene expression levels of DAPK-1 belonged to control and sham groups, respectively. According to our findings, CD93 HSCs offer new prospects for the treatment of diabetic ulcers and concomitant application of these cells with PCL-gelatin nanofiber scaffold significantly improves diabetic wound treatment., (© 2019 Wiley Periodicals, Inc.)

Duchenne muscular dystrophy is an X-linked recessive hereditary monogenic disorder caused by inability to produce dystrophin protein. In most patients, the expression of dystrophin lost due to disrupting mutations in open reading frame. Despite the efforts in a large number of different therapeutic approaches to date, the treatments available for DMD remain mitigative and supportive to improve the symptoms of the disease, rather than to be curative. The advent of CRISPR/Cas9 technology has revolutionized genome editing scope and considered as pioneer in effective genomic engineering. Deletions or excisions of intragenic DNA by CRISPR as well as a similar strategy with exon skipping at the DNA level induced by antisense oligonucleotides, are new and promising approaches in correcting DMD gene, which restore the expression of a truncated but functional dystrophin protein. Also, CRISPR/Cas9 technology can be used to treat DMD by removing duplicated exons, precise correction of causative mutation by HDR-based pathway and inducing the expression of compensatory proteins such as utrophin. In this study, we briefly explained the molecular genetics of DMD and a historical overview of DMD gene therapy. We in particular focused on CRISPR/Cas9-mediated therapeutic approaches that used to treat DMD., (© 2020 Chongqing Medical University. Production and hosting by Elsevier B.V.)

Angiogenesis and metastasis are two critical steps for cancer cells survival and migration. The microenvironment of tumor sphere induces new blood vessels formation for enhancing tumor mass. Preexisting capillaries and postcapillary venules in tumors bring about new blood vessels. ROBO1-ROBO4 are transmembrane receptors family which act as guidance molecules of the nervous system. The SLITs family is secreted glycoproteins that bind to these receptors. SLIT-ROBO signaling pathway plays an important role in neurogenesis and immune response. Linkage between ROBOs and their ligands (SLITs) induce chemorepllent signal for regulation of axon guidance and leukocyte cell migration, recent finding shows that it is also involved in endothelial cell migration and angiogenesis in various type of cancers. In this article we review recent finding of SLIT-ROBO pathway in angiogenesis and metastasis.

Aims: Fibrosis as the hallmark of adipose tissue dysfunction which is associated with insulin resistance and type 2 diabetes, results from deposition of excess extra cellular matrix components like collagen and increased cell death. Here we investigated the effect of antidiabetic drug, Metformin, on the factors that play role in fibrosis such as; integrin/ERK pathway, collagen VI, MMP2, MMP9, apoptosis markers including DAPK1, DAPK3, DAP, SIVA, necrosis markers including RIPK1, RIPK3, and MLKL in insulin resistant and hypertrophied adipocytes., Methods: 3T3-L1 adipocytes after differentiation to insulin resistant and hypertrophied cells, treated with Metformin, and the gene expression of aforementioned factors assayed by real time PCR. The protein expression of collagen VI and ERK assayed by western blotting., Key Findings: The expression of integrins changed from 0.5 to 6-fold in hypertrophied adipocyte versus adipocyte. Apoptosis and necrosis markers increased >1.5-fold in insulin resistant and hypertrophied adipocytes. Also ECM components and ERK activation increased >2-fold and 1.5-fold, respectively in insulin resistant and hypertrophied adipocytes. Metformin caused reduction of activity of integrin/ERK pathway in Metformin treated insulin resistant and hypertrophied adipocytes compared to untreated group. Metformin also reduced collagen VI in both gene and protein expression level, MMP2 and MMP9 in gene expression, and also the expression of apoptosis and necrosis gene., Significance: Metformin with reduction of ECM component as collagen VI, MMP2 and MMP9, integrin/ERK pathway, necrosis markers as RIPK1, RIPK3 and MLKL, and apoptosis markers including DAP, DAPK1, DAPK3 and SIVA effects on fibrosis in insulin resistant and hypertrophied adipocytes in vitro., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background Quantitative fluorescent polymerase chain reaction (QF-PCR) technique is a rapid prenatal aneuploidy detection method. This method can diagnose abnormality in chromosome 13, 18, 21, X and Y. Karyotyping is a technique in which, by the process of pairing and painting, all the chromosomes of an organism are displayed under a microscope. In the present study, a statistical comparison was made between karyotyping and QF-PCR for prenatal diagnosis. Methods A total of 270 samples were tested for QF-PCR and the results were compared with karyotyping. We also investigated heterozygosity of short tandem repeat (STR) markers by QF-PCR. Deoxyribonucleic acid (DNA) samples (n = 270) were extracted from amniotic fluid (AF) cells. After PCR amplifications, analysis was performed using GeneMarker. A Devyser QF-PCR kit containing 26 primers was used to estimate the observed heterozygosity of STR markers located on chromosome 13, 18, 21, X and Y. Results The results of karyotyping and QF-PCR were as follows: trisomy 13 (one case), trisomy 18 (five cases), trisomy 21 (five cases) and triploidy (one case). Chromosomal rearrangements and mosaicisms were not detected by QF-PCR but were detected by karyotyping. Maternal cell contamination (MCC) made the karyotyping fail but not the QF-PCR. Conclusion The QF-PCR method is especially important because it is fast, accurate, low cost and has a short turnaround time. This method will avoid ambiguity of karyotype results and parental anxiety. It will also shorten clinical management for high-risk families.

Integrins are cell attachment receptors that function in the communication between the intracellular and extracellular compartments. Integrins and extra cellular matrix (ECM) collaborate to regulate gene expression by extracellular signal-regulated kinases (ERKs). Integrins as regulators, have critical role in ECM remodeling. Fibrosis is the hallmark of obesity and insulin resistance originated by aberrant ECM remodeling. Therefore deciphering integrins' expression profile in cells at different conditions is worthy. The aim of this study is evaluation of integrins' gene expression profile changes in mouse 3T3-L1 preadipocytes, adipocytes, insulin resistant and hypertrophic adipocytes. For this purpose, we differentiated mouse 3T3-L1 preadipocytes to adipocytes, insulin resistant and hypertrophied adipocytes and assayed integrins' gene expression in four conditions by real time-PCR. Also the proteins expression changes of ERK and collagen VI assayed by Western blotting. Data analysis has shown that integrins' gene expression changes throughout adipocyte differentiation and pathological processes. The expressions of many integrins genes were significantly up- or down-regulated by >1.5-fold during differentiation, insulin resistant, and hypertrophic adipocytes. In addition to changes in the type of integrin, the integrins expression levels were different. Integrins, on the whole were more expressed in pathological processes relative to normal adipocytes. Also, phosphorylation of ERK 1,2 was increased >1.5-fold in differentiated, insulin resistant and hypertrophied adipocytes versus preadipocytes. Collagen VI only increased 2-fold in hypertrophied adipocytes. Examination of the total integrin gene family expression during adipocyte differentiation and pathological processes, leads to the identification of differential integrin gene expression. These results suggest that the type of integrin may not only play a role in adipocyte differentiation but also in pathological processes which may associate to increased ERK pathway activity in these conditions., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Mucopolysaccharidosis VI is a rare autosomal recessive disorder caused by the deficiency of enzyme Arylsulfatase B. The enzyme deficiency leads to the accumulation of dermatan sulfate in connective tissue which causes manifestations related to MPS VI. Up to now, three different disease causing variants are reported in Iranian patients. In this study, we scanned ARSB gene of 13 Iranian patients from 12 families in whom all parents were consanguineous and from the same ethnicity except one family that were not consanguineous but co-ethnic. We found six not previously reported disease causing variants. We extracted DNA from peripheral blood samples of patients that were previously confirmed as MPS VI by clinical, biochemical and enzymatic assays including berry-spot test and fluorimetry, followed by PCR and direct sequencing. Computational approaches were used to analyze novel variants in terms of their impact on the protein structure. 11 disease causing variants and 15 polymorphisms were found. Six disease causing variants were novel and five were previously reported of which three were in Iranian population. Four of patients, who were unrelated, two by two had the same disease causing variant and polymorphisms, which indicates a possible founder effect. Our study also implicates genotype-phenotype correlation. Computational structural modeling indicated these disease causing variants might affect structural stability and function of the protein. Data of this study confirms the existence of mutational heterogeneity in the ARSB between Iranian patients. Disease causing variants with high frequency can be used in the prenatal diagnosis and genetic counseling. Also, the existence of the same variants and polymorphisms in some of the unrelated patients indicates a possible founder effect.

Mendelian Susceptibility to Mycobacterial Disease (MSMD) is a rare syndrome with infections-among other complications-after Bacillus Calmette-Guerin (BCG) vaccination in children. We focused on the IL-12/IFN-γ pathway to identify new mutations in our patients. This study included 20 patients by vulnerability to mycobacteria and clinical manifestations of severe, recurrent infections. Blood samples were activated with BCG, BCG + IL-12 and BCG + IFN-γ. Cytokine levels were analyzed by ELISA. Measurements of IL-12Rβ1 and IL-12Rβ2 on the surface of peripheral blood mononuclear cells were performed by flow cytometry. To detect genetic defects, next-generation sequencing was performed by Thermo Fisher immunodeficiency panel. Flow cytometry analysis of 20 patients indicated reduction in IL-12R (β1/β2) expression in seven patients who showed incomplete production of IFN-γ by ELISA. In the patient with reduced IL-12 production, IFN-γR and IL-12R (β1/β2) expression levels were normal. Mutation analysis showed three previously reported mutations, two novel mutations in IL-12 R (β1/β2), and one previously reported mutation in IL-12., (© FEMS 2019.)

Common variable immunodeficiency (CVID), a clinically symptomatic primary immunodeficiency disease (PID), is characterized by hypogammaglobulinemia leading to recurrent infections and various complications. Recently, some defects in the signaling of TLRs have been identified in CVID patients which led us to investigate the expression of TLR4 and 9 negative regulatory molecules and their upregulation status following their activation. Using TaqMan real-time PCR, SOCS1, TNFAIP3, RFN216, and IRAK-M transcripts among peripheral blood mononuclear cells (PBMCs) were measured with/without TLR4 and 9 activations. TLR4 and 9 were activated by lipopolysaccharide (LPS) and unmethylated CpG-oligodeoxynucleotide (CpG-ODN), respectively. Production of IFN-α and TNF-α cytokines, as a part of the functional response of mentioned TLRs, was also measured using ELISA. Deficient transcripts of IRAK-M and TNFAIP3 in unstimulated PBMCs and lower production of TNF-α and IFN-α after treatments were observed. Upregulation of RFN216 and TNFAIP3 after TLR9 activation was abnormal compared to healthy individuals. Significant correlations were found between abnormal IRAK-M and TNFAIP3 transcripts, and lymphadenopathy and inflammatory scenarios in patients, respectively. It seems that the transcriptional status of some negative regulatory molecules is disturbed in CVID patients, and this could be caused by the underlying pathogenesis of CVID and could involve complications like autoimmunity and inflammatory responses.

Background: Extracellular vesicles (EVs) are a heterogeneous group of membrane-bound vesicles with complex cargoes including proteins, lipids, and nucleic acids. EVs have received significant attention due to their specific features including stability under harsh conditions and involvement in cell-to-cell communication. Circulating EVs and the molecules associated with them are important in the diagnosis and prognosis of cancers. MicroRNAs (miRNAs) are a group of small noncoding RNAs that have a role in regulating gene expression. Current literature shows that circulating miRNAs can be used as noninvasive biomarkers for early detection of cancers. The present study was set to investigate the potential role of serum exosomal miRNA expression levels in colorectal cancer (CRC) patients and evaluate their correlation with clinicopathologic features., Methods: Exosome-enriched fractions were isolated from the serum of 25 CRC patients and 13 age- and sex-matched healthy controls using a polymer-based precipitation method. During the pilot phase, real-time polymerase chain reaction (RT-PCR) was carried out on 12 CRC patients and eight healthy participants to evaluate the expression difference of 11 candidate miRNAs between CRC patients and tumor free subjects. Finally, the results were validated in a separate group, which was similar in size to the pilot group. The clinicopathologic data were also collected and the relationship between aberrant miRNA expression and clinicopathological parameters were investigated., Results: There were high expressions of exosomal miR-23a and miR-301a in serum samples of CRC patients compared to normal controls in training and validation phases; these differences were not significantly correlated with clinicopathologic features. Receiver operating characteristic curve analysis showed that miR-301a and miR-23a were able to discriminate CRC patients from normal subjects., Conclusion: The findings provide evidence on the roles of miR-301a and miR-23a in CRC development and their potential roles as noninvasive biomarkers for early detection of CRC.