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Alzheimer's, Parkinson's, and Huntington's are some of the most common neurological disorders, which affect millions of people worldwide. Although there have been many treatments for these diseases, there are still no effective treatments to treat or completely stop these disorders. Perhaps the lack of proper treatment for these diseases can be related to various reasons, but the poor results related to recent clinical research also prompted doctors to look for new treatment approaches. In this regard, various researchers from all over the world have provided many new treatments, one of which is CRISPR/Cas9. Today, the CRISPR/Cas9 system is mostly used for genetic modifications in various species. In addition, by using the abilities available in the CRISPR/Cas9 system, researchers can either remove or modify DNA sequences, which in this way can establish a suitable and useful treatment method for the treatment of genetic diseases that have undergone mutations. We conducted a non-systematic review of articles and study results from various databases, including PubMed, Medline, Web of Science, and Scopus, in recent years. and have investigated new treatment methods in neurodegenerative diseases with a focus on Alzheimer's disease. Then, in the following sections, the treatment methods were classified into three groups: anti-tau, anti-amyloid, and anti-APOE regimens. Finally, we discussed various applications of the CRISPR/Cas-9 system in Alzheimer's disease. Today, using CRISPR/Cas-9 technology, scientists create Alzheimer's disease models that have a more realistic phenotype and reveal the processes of pathogenesis; following the screening of defective genes, they establish treatments for this disease., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Osteoporosis, a systemic skeletal disease, is characterized by a quantitative and qualitative, and progressive decrease in bone mass, which is related to inflammation. Since a cytokine storm is triggered in Coronavirus disease 2019 (COVID-19), this study aims to evaluate pro-inflammatory cytokines (TNF-α, IL-1β), Receptor activator of nuclear factor-κB ligand (RANKL)/serum osteoprotegerin (OPG) ratio, and their relationship in mild and severe COVID-19., Methods: This study was performed on 48 adult patients (18 mild, 18 severe COVID-19, and 12 healthy subjects as a control group). Serum OPG, RANKL, TNF-α, IL-1β, 25-OH vitamin D, and ALKp were measured by ELISA and colorimetric assay., Results: COVID-19 patients had a significant increase in RANKL, and RANKL/OPG in mild and severe form (p < 0.001) while OPG decreased significantly in severe form compared to healthy controls (p < 0.05). Inflammatory cytokines (TNF-α and IL-1β) increased in both groups of patients whereas Alkaline phosphatase (ALKp) increased only in severe patients (p < 0.001). Both groups had 25-OH vitamin D deficiency in comparison to healthy ones (p < 0.001). Pearson's correlation coefficient was performed to determine the relationship between RANKL, OPG, ALKp, and 25-OH vitamin D with TNF-α and IL-1β in mild and severe COVID-19, which was statistically significant., Conclusion: Serum RANKL/OPG ratio was elevated in COVID-19 individuals and is assumed to be a risk factor for BMD reduction and osteoporosis in these patients. Correlations between IL-1β, TNF-α, ALKp, 25-OH vitamin D, OPG, RANKL, and RANKL/OPG ratio offered the potential role of these proinflammatory markers in the mechanism of osteoporosis in COVID-19 patients., (© 2024. The Author(s).)

Objective: The purpose of this study was to examine the effects of 10 weeks of high-intensity interval training (HIIT) and HIIT combined with circuit resistance training (HCRT) on selected measures of physical fitness, the expression of miR-9, -15a, -34a, -145, and - 155 as well as metabolic risk factors including lipid profiles and insulin resistance in middle-aged overweight/obese women., Methods: Twenty-seven overweight/obese women aged 35-50 yrs. were randomized to HIIT (n = 14) or HCRT (n = 13) groups. The HIIT group performed running exercises (5 reps x 4 min per session) with active recovery between repetitions for 10 weeks with 5 weekly sessions. The HCRT group performed 10 weeks of HIIT and resistance training with 3 weekly HIIT sessions and 2 weekly HCRT sessions. Anthropometric measures (e.g., body mass), selected components of physical fitness (cardiovascular fitness, muscle strength), levels of miRNAs (miR-9, -15a, -34a, -145, and - 155), lipid profiles (total cholesterol; TC, Triglycerides; TG, low-density lipoprotein cholesterol; LDL-C and high-density lipoprotein cholesterol; HDL-C), and insulin resistance; HOMA-IR index, were measured at baseline and week 10., Results: An ANOVA analysis indicated no significant group by time interactions (p > 0.05) for all anthropometric measures, and maximum oxygen consumption (VO 2max ). A significant group by time interaction, however, was found for the one-repetition maximum (IRM; p < 0.001, ES= 0.751 , moderate). A post-hoc test indicated an increase in the pre-to-post mean 1RM for HCRT (p = 0.001, ES = 1.83, large). There was a significant group by time interaction for miR-155 (p = 0.05, ES = 0.014, trivial). Levels for miR-155 underwent pre-to-post HIIT increases (p = 0.045, ES = 1.232, large). Moreover, there were also significant group by time interactions for TC (p = 0.035, ES = 0.187, trivial), TG (p < 0.001, ES = 0.586, small), LDL-C (p = 0.029, ES = 0.200, small) and HDL-C (p = 0.009, ES = 0.273, small). Post-hoc tests indicated pre-post HCRT decreases for TC (p = 0.001, ES = 1.44, large) and HDL-C (p = 0.001, ES = 1.407, large). HIIT caused pre-to-post decreases in TG (p = 0.001, ES = 0.599, small), and LDL-C (p = 0.001, ES = 0.926, moderate)., Conclusions: Both training regimes did not improve cardiovascular fitness. But, HCRT improved lower/upper limb muscle strength, and HIIT resulted in an increase in miR-155 expression in peripheral blood mononuclear cells. Furthermore, HIIT and HCRT each improved selected metabolic risk factors including lipid profiles and glucose and insulin metabolism in overweight/obese middle-aged women., Trial Registration: OSF, October, 4th 2023. Registration DOI: https://doi.org/10.17605/OSF.IO/UZ92E . osf.io/tc5ky . "Retrospectively registered"., (© 2024. The Author(s).)

Background: Multiple sclerosis (MS) is a complex autoimmune disease that affects the central nervous system, causing inflammation, demyelination, and neurodegeneration. Understanding the dysregulation of Tregs, dynamic cells involved in autoimmunity, is crucial in comprehending diseases like MS. However, the role of lymphocyte-activation gene 3 (Lag-3) in MS remains unclear., Methods: In this study, we explore the potential of exosomes derived from human umbilical cord mesenchymal stem cells (hUMSCs-Exs) as an immune modulator in experimental autoimmune encephalomyelitis (EAE), a model for MS., Results: Using flow cytometry, our research findings indicate that groups receiving treatment with hUMSC-Exs revealed a significant increase in Lag-3 expression on Foxp3 + CD4 + T cells. Furthermore, cell proliferation conducted on spleen tissue samples from EAE mice using the CFSE method exposed to hUMSC-Exs yielded relevant results., Conclusions: These results suggest that hUMSCs-Exs could be a promising anti-inflammatory agent to regulate T-cell responses in EAE and other autoimmune diseases. However, further research is necessary to fully understand the underlying mechanisms and Lag-3's precise role in these conditions., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Single-cell technology (SCT), which enables the examination of the fundamental units comprising biological organs, tissues, and cells, has emerged as a powerful tool, particularly in the field of biology, with a profound impact on stem cell research. This innovative technology opens new pathways for acquiring cell-specific data and gaining insights into the molecular pathways governing organ function and biology. SCT is not only frequently used to explore rare and diverse cell types, including stem cells, but it also unveils the intricacies of cellular diversity and dynamics. This perspective, crucial for advancing stem cell research, facilitates non-invasive analyses of molecular dynamics and cellular functions over time. Despite numerous investigations into potential stem cell therapies for genetic disorders, degenerative conditions, and severe injuries, the number of approved stem cell-based treatments remains limited. This limitation is attributed to the various heterogeneities present among stem cell sources, hindering their widespread clinical utilization. Furthermore, stem cell research is intimately connected with cutting-edge technologies, such as microfluidic organoids, CRISPR technology, and cell/tissue engineering. Each strategy developed to overcome the constraints of stem cell research has the potential to significantly impact advanced stem cell therapies. Drawing from the advantages and progress achieved through SCT-based approaches, this study aims to provide an overview of the advancements and concepts associated with the utilization of SCT in stem cell research and its related fields., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: Diabetes mellitus [DM], is a multifaceted metabolic disease, which has become a worldwide threat to human wellness. Over the past decades, an enormous amount of attention has been devoted to understanding how microRNAs [miRNAs], a class of small non-coding RNA regulators of gene expression at the post-transcriptional level, are tied to DM pathology. It has been demonstrated that miRNAs control insulin synthesis, secretion, and activity. This review aims to provide an evaluation of the use of miR-143 and miR-145 as biomarkers for the diagnosis and prognosis of diabetes., Methods: The use of miR-143 and miR-145 as biomarkers for the diagnosis and prognosis of diabetes has been studied, and research that examined this link was sought after in the literature. In addition, we will discuss the cellular and molecular pathways of insulin secretion regulation by miR-143/145 expression and finally their role in diabetes., Results: In the current review, we emphasize recent findings on the miR-143/145 expression profiles as novel DM biomarkers in clinical studies and animal models and highlight recent discoveries on the complex regulatory effect and functional role of miR-143/145 expression in DM., Conclusion: A novel clinical treatment that alters the expression and activity of miR-143/miR-145 may be able to return cells to their natural state of glucose homeostasis, demonstrating the value of using comprehensive miRNA profiles to predict the beginning of diabetes., Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-023-01317-y., Competing Interests: Conflict of interestThe authors declare that there are no conflicts of interest regarding the publication of this article., (© The Author(s), under exclusive licence to Tehran University of Medical Sciences 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Introduction: A growing body of evidence indicated that Alantolactone (ALT) promotes Reactive Oxygen Species (ROS) generation exclusively in cancer cells. Therefore, the aim of this study was to investigate the effect of ALT on the molecular mechanism of oxeiptosis, as a novel cell death pathway due to the high levels of intracellular ROS in ovarian cancer., Methods: MTT assay was used to evaluate the effect of ALT on SKOV3 cell viability. mRNA and protein expression levels of Nrf2 (nuclear factor erythroid 2-related factor 2), KEAP1 (Kelch-like ECH-associated protein 1), PGAM5 (phosphoglycerate mutase family member 5), AIFM1 (Mitochondrial Apoptosis-Inducing Factor), Glutathione synthetase (GSS) and glutathione peroxidase (GPX) were analyzed by real time PCR and western blotting methods respectively., Results: Our findings showed that ALT inhibits the proliferation of skov3 cells in a time and dose dependent manner and IC50 was 32 μM at 24h.A significant down-regulation of Nrf2, GSH and GPX mRNA levels was seen in skov3 cells incubated with 32 and 64 μM of ALT in comparison with control group, while, mRNA expression levels of PGAM5 and KEAP1 were increased.Western blot analysis showed that ALT significantly decreases protein levels of Nrf2 and increases PGAM5 and KEAP1.ALT dephosphorylated PS116-AIFM1 and total AIFM1 protein level was elevated., Conclusion: Our results provided evidence that ALT could be a potential option for ovarian cancer treatment by ROS-mediated oxeiptosis., Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper., (© 2023 The Authors.)

Purpose: The slow coronary flow (SCF) phenomenon is considered a coronary artery disorder. Because of the critical function of peroxisome proliferator-activated receptors (PPARs) in regulating the oxidative stress and inflammatory reactions in cardiovascular disease, The aim of the current study was to investigate the expression of the genes for uncoupling proteins 1 and 2 (UCP1 and UCP2), peroxisome proliferator-activated receptors and (PPAR- PPAR-), and PPAR- in SCF patients., Methods: In this case-control study, coronary angiography examination was used to analyze 35 individuals with SCF and 35 subjects with normal coronary flow (NCF). SCF was diagnosed using the TIMI (thrombolysis in myocardial infarction frame count) method. The SCF phenomenon is thought to be the TIMI > 27. In the peripheral blood mononuclear cells (PBMCs), the messenger ribonucleic acid (mRNA) expression levels of the PPAR-, PPAR-, UCP1, and UCP2 genes were evaluated., Results: UCP1 and UCP2 expression levels were significantly higher in the SCF group compared to the NCF group (P = 0.034 and P0.001, respectively). The PPAR- and PPAR- levels were found to be significantly lower in the SCF group compared to the NCF group (P = 0.015, P0.001, respectively). According to the results of the logistic regression analysis, high UCP1 and UCP2 levels and low PPAR- and PPAR- levels are each independent predictors of the SCF phenomenon., Conclusion: This research provided evidence about the potential role of PPAR-α, PPAR-γ, UCP1, and UCP2 as biomarkers in SCF. More investigations are suggested to assess the functions of these factors in SCF patients mechanistically., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

COVID-19 can induce lung inflammation, and inflammatory factors play an essential role in its pathogenesis. This inflammation can be controlled to a great extent by microRNAs(miRs). This study evaluated miR-146a-5p expression levels in the serum of patients with COVID-19 and their association with the expression of interleukin (IL)-18 and receptor activator of nuclear factor kappa-Β ligand (RANKL) genes, and lung damage. patients with COVID-19 were divided into two groups: mild and severe phases. The severe phase is defined as having a positive polymerase chain reaction (PCR) for SARS-CoV2, and acute pulmonary symptoms. The subjects' demographic, clinical, and paraclinical characteristics were collected according to a pre-prepared checklist. Total RNA was isolated from all samples using the Trizol kit to assess gene expression. The extracted product was then evaluated for the expression of miR-146a and the target genes (i.e., IL-18 and RANKL) using real-time PCR. The miR-146a gene's mean expression in mild and severe patients was 0.73 and 1.89, respectively, and this difference was statistically significant between the two groups. Also, the mean Expression of the IL-18 gene, 1.37±0.38 in the mild and 2.83±0.58 in the severe groups of the disease, demonstrated a significant difference between the two groups. In contrast, the expression levels of the RANKL gene did not show a significant difference between the two groups. Therefore, it may be hypothesized that altered levels of miR-146a may contribute to the severe COVID-19 that is more commonly observed in smokers, but further research is required.

Genome-wide studies related to neurological disorders and neurodegenerative diseases have pointed to the role of epigenetic changes such as DNA methylation, histone modification, and noncoding RNAs. DNA methylation machinery controls the dynamic regulation of methylation patterns in discrete brain regions., Objective: This review aims to describe the role of DNA methylation in inhibiting and progressing neurological and neurodegenerative disorders and therapeutic approaches ., Methods: A Systematic search of PubMed, Web of Science, and Cochrane Library was conducted for all qualified studies from 2000 to 2022., Results: For the current need of time, we have focused on the DNA methylation role in neurological and neurodegenerative diseases and the expression of genes involved in neurodegeneration such as Alzheimer's, Depression, and Rett Syndrome. Finally, it appears that the various epigenetic changes do not occur separately and that DNA methylation and histone modification changes occur side by side and affect each other. We focused on the role of modification of DNA methylation in several genes associated with depression (NR3C1, NR3C2, CRHR1, SLC6A4, BDNF, and FKBP5), Rett syndrome (MECP2), Alzheimer's, depression (APP, BACE1, BIN1 or ANK1) and Parkinson's disease (SNCA), as well as the co-occurring modifications to histones and expression of non-coding RNAs. Understanding these epigenetic changes and their interactions will lead to better treatment strategies., Conclusion: This review captures the state of understanding of the epigenetics of neurological and neurodegenerative diseases. With new epigenetic mechanisms and targets undoubtedly on the horizon, pharmacological modulation and regulation of epigenetic processes in the brain holds great promise for therapy., (© 2022 The Authors.)

The role of microRNA (miR)200c-3p in regulating ACE2 gene expression in viral and bacterial respiratory diseases has been established. Since ACE2 reduces the acute inflammatory effects in lung diseases and acts as a coronavirus receptor to invade the lung cells, this study investigates the relationship between miR-200c-3p and ACE2 expression in COVID -19 patients. In this study, COVID-19 patients were divided into two groups: mild phase (PCR-positive and mild symptoms) and severe phase (PCR-positive with acute pulmonary symptoms and inflammation). Then, the subjects' demographic, clinical, and paraclinical characteristics were recorded using a prepared checklist. Total RNA was isolated from all samples according to the Trizol kit protocol to evaluate gene expression. Subsequently, the extracted product was analysed for miR-200c expression and ACE2 target gene expression by real-time PCR. The results of the checklist data showed that smoking, cough, and the factors ESR and HCT were statistically significant between the two groups of patients in the mild and acute phases. Also, the mean expression of the miR-200c gene in the mild and acute patients was 1.87±0.70 and 1.87±0.62, respectively, which was not statistically significant. Still, the mean expression of the ACE2 gene, which was 3.96±0.76 and 3.28±0.52 in the mild and acute disease groups, respectively, showed a significant difference between the two groups. This study showed that the expression levels of ACE2 were significantly reduced in people with severe inflammation compared to people with mild inflammation.

Background and Aims: Atherosclerosis as a chronic inflammatory disorder of the arterial wall is the main leading cause of the cardiovascular disease (CVD). Caspase-dependent pyroptosis plays a pivotal role in the pathogenesis of CVD. Selenium (Se) is an important component of the antioxidant defense and plays a crucial role in cardiovascular health. This study aimed to investigate the effects of daily consumption of sodium selenite and Se-enriched yeast on the expression of pyroptosis-related genes, and biomarkers of oxidative stress in patients with atherosclerosis., Methods and Results: In this randomized, double-blinded, placebo-controlled clinical trial, 60 patients with atherosclerosis were recruited. Participants received 200 μg/day of sodium selenite, Se-enriched yeast, or placebo for 8 following weeks. The pyroptosis-related genes' mRNA expression in peripheral blood mononuclear cells (PBMCs) was assessed before and after the intervention. Also, the levels of superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO), and glutathione peroxidases (GPX) were measured at baseline and following the intervention. Following sodium selenite and Se-enriched yeast supplementation, the relative expression levels of TLR4, ASC, NLRP3, and NF-κB1 were significantly downregulated (p < 0.05). Furthermore, the changes in GPX were significantly increased after selenite and yeast supplementation (p < 0.05). Also, selenite and yeast consumption caused a statistically significant decrease in the change of MDA level (p < 0.05)., Conclusion: In summary, these findings showed that Se supplementation may reduce inflammation through down-regulation of some pro-inflammatory genes, improving antioxidant defenses in atherosclerosis patients. Further research is required to come to a definite conclusion of selenium supplementation on the CVD risk. This study was registered on the Iranian Registry of Clinical Trials website (identifier: RCT20110123005670N28; https://www.irct.ir/)., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aim: To investigate effects of anti-TNF biologic drugs on uveitis severity (comparing visual acuity logMAR levels) in Behçet patients., Methods: Three databases PubMed, Scopus, and the Web of Science were searched for qualified papers focusing on the anti-TNF-α factors treatment in Behçet's disease (BD)-associated uveitis. Studies that were designed pre and post anti-TNF drug treatment, were selected. After determining the search strategy for this study, the relevant data were extracted., Results: The initial search was performed in the target databases and a total of about 1458 articles were found. Fifteen articles were selected for systematic review and only 12 of them had inclusion criteria for Meta-analysis (with visual acuity data). The mean dose of prednisolone before and after biological treatments was reported in 5 studies (28.56 and 7.56 mg/kg, respectively). Also, the preliminary results indicate a significant reduction in visual acuity logMAR levels (MD=-1.5 IU/L, 95%CI: -2.1, -0.01)., Conclusion: Biological drugs significantly reduce the dose of prednisolone and affect visual acuity values., (International Journal of Ophthalmology Press.)

Background and Purpose: Ovarian cancer is one of the leading causes of cancer mortality in women. Despite the increase in cases of this cancer, the current therapeutic strategy is not effective. This study aimed to investigate the effect of cisplatin (Cis) with alantolactone (ALT) and ZnO nanoparticles (ZnONPs) in inducing apoptosis in SKOV3 ovarian cancer cells line., Experimental Approach: To evaluate the viability of SKOV3 cells and determine the IC 50 of Cis, ALT, and ZnONPs, MTT assay was used. Real-time PCR and western blotting were used to evaluate the expression levels of genes (XIAP, cyclin D1, Bcl-2, Bax, and MDM2) and proteins (XIAP, cyclin D1, Bcl-2, Bax), respectively. Also, cellular ROS levels were assessed by fluorimetry., Findings / Results: Our results showed that ALT and ZnONPs significantly increased the response to Cis in SKOV3 cells compared to the control and this response is remarkably increased in the triple combination (ALT-Cis-ZnONPs). The expression of XIAP, cyclin D1, and Bcl-2 genes and proteins in the groups treated with ALT, Cis, and ZnONPs as a single agent, double and triple combination were significantly reduced compared to the control, while Bax was generally shown an increase. Also, the level of intracellular ROS is higher in the treatment groups than in the control group and the highest increase was observed in the triple combination., Conclusion and Implications: Taken together, our data demonstrated the potential therapeutic approach of using ALT and ZnONPs that may enhance the apoptotic effects of Cis on the SKOV3 cells., Competing Interests: All authors declared no conflict of interest in this study., (Copyright: © 2022 Research in Pharmaceutical Sciences.)

Competing Interests: Conflict of interest: The authors declare no conflict of interest.

Coronavirus disease 2019 (COVID-19) has rapidly developed as a global health emergency. Respiratory diseases are significant causes of morbidity and mortality in these patients with a spectrum of different diseases, from asymptomatic subclinical infection to the progression of severe pneumonia and subsequent acute respiratory distress syndrome. Individuals with cardiovascular disease are more likely to become infected with SARS-CoV-2 and develop severe symptoms. Hence, patients with underlying cardiovascular disease mortality rate are over three times. Furthermore, note that patients with a history of cardiovascular disease are more likely to have higher cardiac biomarkers, especially cardiac troponins, than infected patients, especially those with severe disease, making these patients more susceptible to cardiac damage caused by SARS-2-CoV. Biomarkers are important in decision-making to facilitate the efficient allocation of resources. Viral replication in the heart muscle can lead to a cascade of inflammatory processes that lead to fibrosis and, ultimately, cardiac necrosis. Elevated troponin may indicate damage to the heart muscle and may predict death. After the first Chinese analysis, increased cardiac troponin value was observed in a significant proportion of patients, suggesting that myocardial damage is a possible pathogenic mechanism leading to severe disease and death. However, the prognostic performance of troponin and whether its value is affected by different comorbidities present in COVID-19 patients are not known. This review aimed to assess the diagnostic value of troponin to offer insight into pathophysiological mechanisms and reported new assessment methods, including new biosensors for troponin in patients with COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rasmi, Mosa, Alipour, Heidari, Javanmard, Golchin and Gholizadeh-Ghaleh Aziz.)

Mesenchymal stem cells (MSCs), as one of the leading cell-based therapy, have provided a strong link between clinical investigation and basic research. MSCs have been successfully employed in treating graft versus host disease (GvHD), autoimmune disease, and several other diseases, particularly with high immune activity. Recently, MSCs have attracted attention to treating untreatable viral infections such as severe coronavirus disease 2019 (COVID-19). Given that the Toll-like receptors (TLRs) are directly able to detect internal and external hazard signals, and their stimulation has an intense effect on the ability to grow, differentiate, migrate, and maintain MSCs, it seems stimulation of these receptors can have a direct impact on the interaction of MSCs and immune cells, altering the ability to modify immune system responses. Hence, this mini-review focused on TLRs' critical roles in the polarization of MSCs for developing MSC-based therapy in viral infections. Consequently, according to the literature review, a polarization process, mediated by TLRs concerning anti-inflammatory and proinflammatory phenotype, may be considered for MSC-therapy against viral infections., Competing Interests: Conflict of interestThe authors declare that they have no conflicts of interest., (© The Author(s), under exclusive licence to Springer-Verlag London Ltd. part of Springer Nature 2021.)

Introduction: The aim of this study was to evaluate the methylation status of TNF-α and SOCS3 promoters in patients with BD and compare them with a healthy group. Method: This was a case-control study, in which 47 subjects with BD and 61 individuals as the control participated. Blood samples were collected from all the participants. Then, PBMCs were isolated using the Ficoll method and methylation of considered sites was investigated using the qMS-PCR technique after DNA extraction by the rapid genomic DNA extraction method and its analysis with Nano-drop. Results: The methylation and expression of TNF-α showed that the methylation level significantly declined in the patient in comparison with the healthy ( p  < 0.05). Moreover, the results on the mean expression showed that it significantly increased in the patient group, as compared with the healthy group ( p  < 0.05). In addition, the expression of the SOCS3 gene was not significantly different between the patients and healthy subjects while the level of SOCS3 methylation was significantly higher in the patient group than that in the healthy group ( p  < 0.05). Discussion: The present study revealed that the gene expression of TNF-alpha increased in BD patients, suggesting that TNF-alpha likely has a role in the pathogenesis of BD.

BCL2 and BAX genes are a group of signalling inducer and inhibitor genes playing a key role in the process of cellular physiological death (apoptosis). These genes, through the JAK/STAT signalling pathway, affect different cytokines on cell function and subsequently lead to the pathophysiology of diseases, especially autoimmune diseases. In addition, altering the methylation of genes can affect their expression. Since the aetiology and pathology of Behcet's disease is not fully understood, the aim of this study was to determine the methylation pattern of BCL2 and BAX genes in patients with Behcet's disease and compare it with those of control group. This was a case-control study on 51 patients with Behcet and 61 control subjects. Blood samples were received from all subjects. Subsequently, the peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll method and the methylation of the sites was investigated using quantitative methylation specific PCR (qMS-PCR) technique after extraction of DNA by salting out method and its examination with Nano drop. The results of methylation and expression of Bax gene suggest that the methylation level in the patient group significantly increased compared to the healthy individuals (p-value < .05). Furthermore, the results related to Bax gene expression revealed that the mean of gene expression in the patient group has decreased compared to the healthy group, and this decrease was statistically significant (p-value < .05). The rate of expression and methylation of Bcl2 did not indicate any change in the two patient and healthy groups. Given the results of this study, it can be guessed that perhaps DNA methylation is involved in certain conditions of the disease and it may result in regulation of the expression of the involved genes such as Bax gene, in the pathogenesis of the disease., (© 2020 John Wiley & Sons Ltd.)

Background: Obesity has reached an alarming rate worldwide. Promoting thermogenesis via increasing the function of brown adipose tissue (BAT) or white adipose tissue (WAT) browning has been proposed as a new protective approach against obesity. The goal of this study was to evaluate the effects of Royal Jelly (RJ) and tocotrienol rich fraction (TRF) on BAT activation and WAT browning during calorie restriction diet (CRD) in obesity model., Methods: In this experimental study, 50 obese Wistar rats were randomly divided into 5 groups and then received one of the following treatments for a period of 8-week: High-fat diet (HFD), CRD, RJ + CRD, TRF + CRD, and RJ + TRF + CRD. Effects of RJ and TRF, individually and in combination on body weight and the expression of key thermoregulatory genes in WAT and BAT were examined by quantitative real-time (qRT-PCR). Also, morphological alterations were assessed by hematoxylin and eosin staining., Results: RJ (- 67.21 g ±4.84 g) and RJ + TRF (- 73.29 g ±4.51 g) significantly reduced weight gain relative to the CRD group (- 40.70 g ±6.50 g, P  < 0.001). In comparison with the CRD group, RJ and RJ + TRF remarkably enhanced the uncoupling protein1 (UCP1) expression in WAT (5.81, 4.72 fold, P  < 0.001) and BAT (4.99, 4.75 fold, P  < 0.001). The expression of PR domain containing 16 (PRDM 16) , cAMP response element-binding protein1 (CREB1) , P38 mitogen-activated protein kinases (P38MAPK), and Bone morphogenetic protein8B (BMP8B) have significantly increased following RJ and RJ + TRF treatments ( P  < 0.001). However , the expression levels of CCAAT/enhancer-binding protein beta (CEBPβ) and Bone morphogenetic protein7 ( BMP7) did not remarkably change. Multilocular beige cells in WAT and compacted dense adipocytes were also observed in BAT of RJ and RJ + TRF received groups. TRF showed no substantial effects on the expression of the mentioned thermoregulatory genes and brown fat-like phenotype., Conclusion: Our results suggest that, Royal Jelly promotes thermogenesis and browning of WAT, contributing to an increase in energy expenditure. Thus, Royal Jelly may give rise to a novel dietary choice to attenuate obesity., Competing Interests: Competing interestsThe authors have declared no conflict of interest., (© The Author(s) 2020.)

Background: IL-6 mRNA expression is significantly high in many autoimmune diseases such as Behçet's disease; this is often related with more aggressive phenotypes. Nevertheless, the essential molecular process for its high expression has not been completely realized. The aim of this study was undertaken to estimate the gene copy number variation and promoter methylation to IL-6's high expression., Methods: This study was performed on 51 patients and 61 healthy controls. Initially, DNA and RNA were extracted from all specimens. Promoter methylation levels of IL-6 were evaluated by MeDIP-qPCR technique. Also, IL-6 gene expression was measured by Real-time PCR. After that, we evaluated the relationship between gene expression and methylation, as well as their relationship with clinical specification., Results: As we expected, the expression level of IL-6 gene increased significantly in the patient group compared to the healthy subjects. Also, the relative promoter methylation level of the IL-6 mRNA was significantly lower in patient group compared to healthy group (p<0.001)., Discussion: We disclosed that the promoter hypomethylation may be considered as one of the main defects for IL-6 mRNA high expression in patients with Behçet's disease., (Copyright © 2018. Publicado por Elsevier España, S.L.U.)

Behçet's disease (BD) was considered a T-helper 1 (Th1)-mediated autoimmune disease, but with the introduction of Th17 cells, their role in the pathogenesis of BD was also addressed. Despite studies on IL-17 in BD, the prognostic value of this cytokine in BD is unclear. The aim of this study is to determine the IL-17 mRNA expression rate and serum levels in patients with BD and its correlation with clinical manifestations and activity of BD. Forty-six BD patients in the active phase of the disease and 70 healthy controls were recruited in this study. BD activity was measured by Behçet's disease current activity form (BDCAF), Iranian Behçet's disease dynamic activity measure (IBDDAM) and total inflammatory activity index (TIAI). The IL-17 mRNA expression and serum levels were significantly higher in the BD patients compared with the healthy controls. These parameters in the BD patients aged <25 at disease onset, positive pathergy test, and positive HLA-B5 and HA-B51 were significantly higher than the healthy controls (P < 0.05). The IL-17 serum level in the patients with active uveitis was lower than the patients with in-active uveitis. There was no association between other clinical manifestations of BD and these parameters. No significant correlation was found between BDCAF and IBDDAM with IL-17 mRNA expression and serum levels. However, TIAI had a significant and negative correlation with the serum levels of IL-17., 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 © 2020 Elsevier Ltd. All rights reserved.)

The aim of this study was to evaluate the effect of prolonged dietary nitrate supplementation on the gonadotropin level, testicular histology and morphometry, expression of miR-34b and p53 mRNA, and spermatogenesis in streptozotocin-induced diabetic male rats., Methods: Fifty male Wistar rats were divided into 5 groups: Control (C), control + nitrate (CN), diabetes (D), diabetes + insulin (DI), and diabetes + nitrate (DN). Diabetes was induced using 45 mg kg -1 of streptozotocin intraperitoneally. Rats in the CN and DN groups were administered sodium nitrate in drinking water (100 mg L -1 ). NPH insulin (2-4 U d -1 ) was injected subcutaneously in the DI group for 2 months. Nitrate and insulin supplementation was started one month after confirmation of diabetes., Results: Nitrate supplementation in the DN group significantly increased the body weight (p < 0.05), sperm parameters (p < 0.001), indices of spermatogenesis (p < 0.001), and testis histopathology as well as decreased the blood glucose level (p < 0.001) compared to the untreated diabetic group, although it had no significant effect on testicular parameters, LH and FSH levels. Nitrate administration in the DN group also decreased miR-34b (p < 0.001) and p53 mRNA (p < 0.001) expression, and increased serum insulin and NOx levels compared to the untreated diabetic rats., Conclusions: Chronic nitrate supplementation in streptozotocin-induced diabetic rats improved fertility parameters, which may be associated with increased miR-34b and decreased p53 mRNA.

Background: Familial Mediterranean fever (FMF) is common in Azari-Turkish people, one of the biggest ethnic groups in Iran. In this study, we sought to investigate the mutation spectrum of the MEFV gene and any genotype-phenotype correlations., Methods and Materials: 400 unrelated Azari-Turkish FMF patients were analyzed in this study. Mutations in exons 2, 3, 5, and 10 of the MEFV gene were investigated using direct Sanger sequencing, and their correlations with the clinical features of the patients were analyzed., Results: At least one mutation was detected in 248 (62%) patients. The most common mutations were M694V (26.25%) and E148Q (24.75%), respectively. Abdominal pain (65.2%) and fever 204 (51%) were the most frequent clinical problems in all subjects. The analysis recognized a novel missense mutation in the coding region of the MEFV gene, named P313H, which is the first report of a new mutation in exon 2 of the MEFV gene in an Azari-Turkish family., Conclusion: Genotype-phenotype correlations obtained from this study would be helpful in the diagnosis and management of FMF patients in clinical situations. This novel missense mutation may provide useful evidence for further studies of FMF pathogenesis., (© 2019 John Wiley & Sons Ltd/University College London.)

Forkhead box P3 (Foxp3) gene is an important means in the Treg cells function, in both maintenances of immune tolerance and regulation of response. Epigenetic modifications of the foxp3 gene at its regulatory regions control the chromatin accessibility for the transcription factors and other transcriptional regulators in order to control Foxp3 expression. In addition, the methylation status of CpG islands within the Foxp3 promoter and regulatory elements regulate the expression of Foxp3. This study was performed to assess the role of the foxp3 gene in patients with Behçet's syndrome (BS). Venous blood samples were collected from all participants and peripheral blood mononuclear cells (PBMC) were extracted through Ficoll-Hypaque method. Genomic DNA was randomly sheared by sonication and immunoprecipitated with a monoclonal antibody. The status methylation of the foxp3 gene was estimated in 108 blood samples of active BS patients and healthy individuals (controls); using methylation DNA immunoprecipitation (MeDIP) technique. Expression analysis was carried out; using Real-time PCR. The expression of foxp3 gene in the patients' group (mean±SD: 1.79±1.12) was significantly lower than the healthy group (mean±SD: 2.73±1.33) (p<001). Also, the methylation levels of Foxp3 promoter showed that its level in patients (mean±SD: 2.3±1.16) was higher than the healthy group (mean±SD: 1.85±0.59). However, this increase was not statistically significant (p>0.05). Also, these results indicated that increasing the amount of methylation of the foxp3 gene by reducing its expression leads to an increase and intensifying of the disease. The decrease in Foxp3 expression is possibly associated with hypermethylation of the gene, and it can be considered as a risk factor for BS. Future studies may be needed to identify the capability of specific DNA methylation alterations in this syndrome.

Aim: Behcet's disease (BD) is a vasculitis. Lines of evidence suggest miRNAs as diagnostic and prognostic markers in autoimmune diseases. This study was designed to investigate the potential role of miR-21, miR-146b and miR-326 as biomarkers for diagnosis, predicting organs involvement and measuring BD activity. Patients & methods: In this cross-sectional study, the study groups consisted of 46 BD patients and 70 age- and sex-matched healthy volunteers. The expression rates of three miRNAs were determined by quantitative real-time PCR. Results: Our results demonstrated significantly lower expression of miR-21 and miR-146b and higher expression of miR-326 in BD patients. MiR-21 expression rate in patients with severe eye involvement and miR-326 expression rate in patients with uveitis and severe eye involvement were increased. Conclusion: MiR-326 expression rate can be used as a biomarker for prediction of uveitis and severe eye involvement in patients with BD.

Behçet's disease (BD) is a multisystem inflammatory disease with unknown etiology. Although evidence about the pathogenesis of BD is growing, the actual cause of this disease is unclear. Both genetic and epigenetic factors are claimed to play significant roles in BD. Epigenetic factors such as age, gender, smoking as well as exogenous factors like diet, infection, stress are related to the onset and clinical manifestations of BD. DNA methylation refers to a major epigenetic element which influences gene activities with catalyzing DNA using a set of DNA methyltransferases (Dnmts). DNA methylation status of many genes in patients with BD is different from that of healthy people. For example, cytoskeletal gene, Human Leukocyte Antigen (HLA) loci, Long interspersed nuclear element (LINE-1), and Arthrobacter luteus (Alu) repetitive sequences are different in the DNA methylation status in patients with BD and healthy controls. In this paper we reviewed, according to previous studies, the mechanisms of epigenetic, the epigenetic factors involved in the BD, and especially the effect of DNA methylation in the Behcet's disease. Future studies are needed to identify the capability of specific DNA methylation alterations in BD in order to predict disease manifestations, medical course, and response to treatment.

Akkermansia muciniphila bacterium is one of the inhabitant gut microbiota involving in the energy homeostasis and inhibition of the inflammations. The present study was designed to evaluate the effects of Oleoylethanolamide (OEA) supplementation on the abundance of A. muciniphila and the dietary intakes in obese people. In this randomized, double-blind, controlled clinical trial, 60 eligible obese people were selected and divided randomly into two groups including OEA group (received two capsules containing 125 mg of OEA daily) and placebo group (received two capsules containing 125 mg of starch daily). The treatment lasted for 8 weeks. Dietary intakes were evaluated according to the three -day food record and, were analyzed by the Nutritionist 4 software. In order to evaluate the changes in the abundance of A. muciniphila bacterium, faeces samples were collected at baseline and at the end of study. The targeting of the 16S rRNA gene in A. muciniphila was measured by the quantitative real-time PCR analysis. For OEA group, the energy and carbohydrate intakes decreased significantly after adjusting for baseline values and confounder factors; (p = 0.035), the amount of carbohydrate was reported as 422.25 (SD = 103.11) gr and 368.44 (SD = 99.08) gr; (p = 0.042)), before and after the treatment, respectively. The abundance of A. muciniphila bacterium increased significantly in OEA group compared to placebo group (p < 0.001). Considering the accumulating evidence identified OEA as a novel, safe, and efficacious pharmaceutical agent increasing the abundance of A. muciniphila bacterium and modifying the energy balance, therefore it is suggested to use its supplement for treatment of the obese people. However, future studies are needed to confirm the positive results obtained in this study., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: Behçet's disease (BD) is a chronic multi-factorial inflammatory disease with the important role of genetic in activation of its inflammatory response. Interleukin (IL)-33 is a member of the IL-1 family of cytokines that affects innate and adaptive immune systems to promote inflammatory responses. In the current study, we investigated the association of IL-33 gene rs1342326 polymorphism and expression levels of this gene in peripheral blood mononuclear cells (PBMCs) with the susceptibility to BD in Azari population of Iran., Methods: We recruited 44 patients with BD and 61 age and sex-matched healthy controls in this cross-sectional study. The existence of rs1342326 T/G IL-33 gene single nucleotide polymorphism was investigated using Tetra-Amplification Refractory Mutation System (Tetra-ARMS)-PCR. Allele and genotype distributions were evaluated among groups using chi-square or Fisher's test. Moreover, the mRNA levels of IL-33 in PBMCs were assessed through the Real-time PCR., Results: Patients with BD exhibited a significantly higher prevalence of the T/G genotype of rs1342326 polymorphism compared with the control group. Moreover, the expression level of IL-33 in PBMCs was significantly higher in the BD group compared to the healthy controls. Interestingly, the rs1342326 T/G polymorphism was associated with higher IL-33 expression in patients with BD. There was no association between the clinical manifestation of BD and disease activity with rs1342326 polymorphism and IL-33 expression., Conclusions: Our study implies that rs1342326 T/G polymorphism of the IL-33 gene may contribute to the genetic susceptibility to BD in part through regulation of the IL-33 expression., (Copyright © 2018. Published by Elsevier B.V.)

Various tissues and cell types are the targets of vitamin D. However, the major targets of vitamin D in the immune system are monocytes/macrophages, dendritic cells (DCs), as well as B and T cells. Vitamin D plays an important role in the immune system modulation via regulating the expression of genes that generate pro-inflammatory mediators and inhibiting the proliferation of pro-inflammatory cells, both of which have been implicated in the pathophysiology of the inflammatory diseases. Recent studies have revealed the important relations between vitamin D and Behçet's disease (BD). Vitamin D function and its deficiency have been linked to a wide range of metabolic disorders including malignant, cardiovascular, infectious, neuromuscular, and autoimmune diseases. Here, we provide a brief analysis of the recent literature regarding immune-regulatory effects as well as clinical evidence of vitamin D influence on the molecular level in BD., (Copyright © 2019 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Impaired inflammatory immune cells have been implicated in the pathogenesis of Behcet's disease (BD). In the current study, we aimed to evaluate the frequency of T helper (Th) 17 and regulatory T (Treg) cells, cytokine secretion, the expression of transcription factors related to Th17 and Treg cells, and microRNAs (miRNAs) targeting these transcription factors in BD patients. Blood samples from 47 BD patients and 58 healthy subjects were drawn, and the peripheral blood mononuclear cells (PBMCs) were separated and isolated. The frequency of Th17 and Treg cells was assessed using flow cytometry. Transcription factors related to these cells and miRNAs targeting these transcription factors were quantified using real-time polymerase chain reaction. Finally, the levels of associated cytokines were measured using enzyme-linked immunosorbent assay. A significant reduction in the percentage of Treg cell frequency and the levels of interleukin (IL)-10 and forkhead box P3 messenger RNA (mRNA) expressions were observed. The proportion of Th17 cells was notably increased, which was accompanied by a increased levels of IL-17, IL-23, and retinoic acid-related orphan receptor ɣ (RORɣt) mRNA expressions in BD patients. The level of Th17-associated cytokines in the supernatant was found to be elevated in BD patients. T-cell-associated miRNA expression levels, miR-25, miR-106b, miR-326, and miR-93 were significantly upregulated, while miR-146a and miR-155 levels were lower in PBMCs of patients with BD when compared with the controls. The increase in the proportion of Th17 cells alongside the decrease in Treg cells are possibly the involving factors in the pathogenesis of BD. Therefore, the evaluation of immune cells and related miRNA profile may serve as both prognostic biomarker and therapeutic approach in treating patients with BD., (© 2018 Wiley Periodicals, Inc.)

Background: MicroRNAs (miRNAs) play critical roles in different pathological processes including cancer development and progression. To find novel molecular diagnostic and prognostic markers and promising therapeutic tools for gastric cancer (GC), we aimed to investigate the relationship of the expression levels of miR-28-5p or miR-200a-3p with the clinicopathological criteria and to explore their impacts on the progression of human GC., Materials and Methods: Quantitative RT-PCR was performed to analyze miR-28 and miR-200a expression in 60 GC and 60 non-GC tissue samples., Result: Our results revealed that the expressions of miR-200a and miR-28 were significantly downregulated in GC in comparison with non- GC tissues. Tumors with low miR-28 expression had larger tumor size, more advanced histological grade, and a higher incidence of lymph node and distal metastasis than the tumors with high miR-28 expressions. Furthermore, receiver operating characteristic (ROC) analyses demonstrate that the expression of miR-28 is a predictive biomarker allows predicting the histological grade, tumor size, and occurrence of nodal and distal metastases. We also found a significant inverse association between miR-200a expression and the rate of lymph node metastasis (p = 0.010, r = -0.334)., Conclusion: Our findings suggest that the miR-28 and miR-200a have tumor-suppressor functions and may be considered as potential biomarkers for gastric cancer diagnosis and prognosis., (Copyright© 2019, Galen Medical Journal.)

MicroRNAs (miRNAs) are uniquely regulated in healthy, inflamed, activated, cancerous, or other cells and tissues of a pathological state. Many studies confirm that immune dysregulation and autoimmune diseases with inflammation are correlated with various miRNA expression changes in targeted tissues and cells in innate or adaptive immunity. In this review, we will explain the history and classification of epigenetic changes. Next, we will describe the role of miRNAs changes, especially mir-326 in autoimmunity, autoinflammatory, and other pathological conditions. A systematic search of MEDLINE, Embase, and Cochrane Library was presented for all related studies from 1899 to 2017 with restrictions in the English language. In recent years, researchers have concentrated on mostly those roles of miRNA that are correlated with the inflammatory and anti-inflammatory process. Latest studies have proposed a fundamental pathogenic role in cancers and autoinflammatory diseases. Studies have described the role of microRNAs in autoimmunity and autoinflammatory diseases, cancers, and so on. The miRNA-326 expression plays a significant role in autoimmune and other types of diseases., (© 2018 Wiley Periodicals, Inc.)

Introduction: MicroRNAs (miRNAs) are involved in the pathogenesis of inflammatory diseases. MiR-146 and miR-155 emerged as key regulators of the immune response. This study designed to analyze the miR-146a and miR-155 expression in patients with Behcet's disease (BD) and investigated their association with the expression of tumor necrosis factor-alpha (TNF-α) and cytotoxic T lymphocyte associated antigen-4 (CTLA-4) genes., Methodology: In a case-control study, 47 Iranian Azeri BD patients and 61 age- and sex matched healthy controls recruited to the study. Peripheral blood mononuclear cells (PBMCs) were isolated from EDTA blood tubes by Ficoll density-gradient centrifugation. Genomic DNA samples of BD and healthy controls were extracted using the rapid genomic DNA extraction method from the peripheral blood collected in tubes containing EDTA. Total RNA was extracted from the PBMCs according to the TRIzol protocol. MiR-146a, miR-155, TNF-α and CTLA-4 expression were studied using real-time PCR., Results: MiR-155 and TNF-α expression was significantly increased, whilst CTLA-4 expression was significantly decreased in the PBMCs of BD patients. There was no significant difference in the miR-146a expression rate between BD patients and controls. A positive correlation between miR-155 and TNF-α expression and negative correlation between miR-155 and CTLA-4 expression were observed. No significant association was observed between the expression of miR-155, miR-146a, TNF-α and CTLA-4 genes with BD activity. MiR-155 and miR-146a expression rate were significantly higher in patients with uveitis and phlebitis, respectively., Discussion and Conclusion: The expression of miR-155 increased in BD and associated with upregulation of TNF-α and downregulation of CTLA-4 genes., (Copyright © 2018 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Introduction: Epigenetic discusses to inherited changes in mitosis and meiosis in the gene expression pattern which is independent of primary DNA sequence. Since, SOCS1 hyper-methylation can activate JAK / STAT signaling pathway and activation of this pathway can directly affect the impact of different cytokines on cell function and subsequently lead to pathophysiology of diseases, in particular autoimmune diseases that interact directly with the amount of cytokines and due to the fact that the cause and pathology of Behcet's disease (BD) have not ever been completely determined. So, the purpose of this study was to evaluate the methylation pattern of SOCS1 gene in patients with BD and compare them with healthy group., Methodology: This study was a case-control study in which 50 patients with BD and 60 subjects as healthy group participated. Blood samples were collected from all participants and then Peripheral Blood Mononuclear Cells (PBMCs) were isolated through Ficoll method. After extraction of DNA by Salting out method and its analysis with Nano-drop, the methylation level of SOCS1 was examined using qMS-PCR technique., Results: Findings about methylation and gene expression in SOCS1 gene showed that the level of SOCS1 methylation was increased in patient groups compared with healthy subjects (control group) which the increase was statistically significant (p-value<0.05). Also, the results of gene expression revealed that the fold change of SOCS1 gene expression was decreased in patient group compared with healthy subjects which the decrease was statistically significant (p-value<0.05)., Discussion and Conclusion: According to the results of this study, it can be suggested that the DNA methylation of SOCS1 gene is likely to affect the gene expression and thereby contribute to the pathogenesis of Behcet's disease., (Copyright © 2018. Published by Elsevier B.V.)

Purpose: Pancreatic adenocarcinoma has a high prevalence all over the world. Most of the therapeutic approaches failed as a result of tumor invasion and rapid metastasis. Several natural plants have been shown to have promising therapeutic effects. Thus, the aim of this study was to investigate the cytotoxic activity of Eryngium billardieri against PANC-1 cancer cell lines. Methods: Dimethylthiazole diphenyltetrazolium bromide assay (MTT assay) and flow cytometry were used to assess the cytotoxicity of E. billardieri extracts against PANC-1 cancer cell lines. Quantitative Polymerase Chain Reaction (qPCR) was conducted to investigate the expression levels of Bcl2- associated X protein (BAX) and cyclin D1. Results: The results of the MTT assay showed that E. billardieri extracts had cytotoxic effects on PANC- 1 cancer cell lines. Moreover, the findings from the gene expression confirmed the over expression of Bax, and under expression of cyclin D1 following treatment with dichloromethane (DCM) and n-hexane (n- hex) extracts in cancer cells (P < 0.05). Interestingly, the flow cytometry results showed that DCM and n- hex extracts of E. billardieri induced apoptosis in PANC- 1 cancer cell lines. Conclusion: The results of this study demonstrated that DCM and n- hex extracts of E. billardieri significantly induce apoptosis by increasing Bax and decreasing cyclin D1 mRNA expression. Therefore, E. billardieri may be regarded as a novel approach for treatment of pancreatic cancer as a result of its promising apoptotic and cytotoxic properties.

Interleukin-10 (IL-10), produced generally by monocyte, T helper type 2 (Th2), and regulatory T cells (Treg), plays a central role in controlling inflammatory responses and regulating the immune response of the IL-10 mRNA expression. It is significantly down-regulated in many autoimmune diseases such as Behçet's disease; this is mostly associated with more aggressive complications. Nevertheless, the essential molecular process for its low expression has not been completely realized. The aim of this project was attempted to estimate the gene expression, promoter methylation, and protein levels to IL-10's down-regulated expression. In this study, blood samples from 51 (4 missed) patients and 63 (2 missed) healthy controls were taken, with the mononuclear cells isolated by the Ficoll Protocol. DNA and RNA were then subsequently extracted. Promoter methylation levels were evaluated by MeDIP-qPCR. Following this, the extracted RNA was converted to cDNA using the RT-PCR method, with the expression of IL-10 later evaluated by Real-time PCR. And then, serum levels of IL-10 were measured using ELISA method. As we expected, the expression level of the IL-10 gene was seen to significantly decline in the patient group in comparison to the control. Also, the rate of promoter methylation was significantly higher in the IL-10 mRNA low expression group (patient group) compared to its high expression group (healthy group) (P < 0.001). We revealed that hypermethylation of promoter region was the principal defect for the IL-10 mRNA low expression in patients with Behçet's disease., (© 2018 Wiley Periodicals, Inc.)

Background: Emu oil (EO) with anti-inflammatory, antioxidative, and wound healing properties can be blended for preparing bioactive nanofibrous scaffold. Adipose tissue-derived stem cells (ADSCs) are promising candidates for tissue engineering, and preserving their stemness potential is vital for further therapeutic applications., Aim: The aim of this study was to fabricate EO-blended nanofiber and investigate its effect on proliferation, survival, and stemness preservation of ADSCs., Materials and Methods: Pure EO composition was characterized using a gas chromatograph mass spectrometer. EO-PCL-polyethylene glycol (PEG) nanofibers were successfully fabricated using an electrospinning technique and characterized by field emission scanning electron microscopy (FE-SEM) and fourier-transform infrared spectroscopy (FTIR). Cell viability and adhesion were measured using the MTT assay and FE-SEM. Finally, quantitative PCR (qPCR) was used to quantify the expression level of cell cycle regulated genes and pluripotency-associated transcription factors., Results: Findings showed that 20% (w/w) of EO is the optimum oil content in the electrospun solution to achieve good morphology and ultrafine fibers. The relatively high optical densities and FE-SEM images indicated that EO highly supported cell adhesion and proliferation on the matrices. In addition, EO-PCL-PEG electrospun nanofibrous mats significantly upregulated the expression levels of cell cycle regulated genes (Cyclin D1, pRb, and P53) and stemness markers (Nanog, OCT-4, Rex-1, and Sox-2) than PCL-PEG nanofiber and tissue culture polystyrene in 7 and 14 days of cell culture., Conclusion: These results demonstrate that the EO-blended nanofibrous mat can be used as a bioactive scaffold to support cell adhesion and proliferation while simultaneously maintaining the stemness of ADSCs.

In recent decades, mesenchymal stem cells originated from adipose tissue (adipose-derived stem cells, ASCs) have gained increased attention for production of cell-based therapeutics. Emu oil as a natural compound showed antioxidant effects in previous studies. The goal of this study was to investigate the effect of crude emu oil on the proliferation, cell cycle progression, stemness genes expression, and in vitro wound healing potential of ASCs. An emulsion of emu oil was prepared using egg lecithin and butylated hydroxytoluene to improve bioavailability and solubility of emu oil in the expansion medium. The ASCs were treated using a series of emu oil concentrations in emulsion form, diluted in expansion medium (0.03-3 mg/ml). The emu oil-free emulsion was used as control treatment. The results revealed that emu oil (1.25 mg/ml) in emulsion form significantly (p < 0.001) increased ASCs proliferation and colony formation. Additionally, emu oil caused upregulation of stemness marker genes (Sox2, Oct4, Nanog, and Nestin) (p < 0.05). The cell cycle analysis after emu oil treatments showed an increase in the population of ASCs in S-phase of the cell cycle. Besides, an accelerated in vitro scratch wound healing was observed in emu oil-treated ASCs. Emu oil enhanced proliferation, colony formation, stemness genes expression, and in vitro wound healing of ASCs. These findings suggest that emu oil treatment could maintain the stemness of ex vivo cultivated ASCs and enhance their regenerative potential.

Purpose: The worldwide prevalence of metabolic disorders such as diabetes is increasing rapidly. Currently, the complications of diabetes are the major health concern. The aim of this study was to investigate the effect of high performance (HP) inulin supplementation on glucose homeostasis via KLF5 mRNA expression in adults with type 2 diabetes. Methods: In the present clinical trial conducted for a duration of 6 weeks, 46 volunteers diabetic patients referring to diabetes clinic in Tabriz, Iran, were randomly assigned into intervention (n= 23, consuming 10 gr/d HP inulin) and control groups (n= 23, consuming 10 gr/ d starch). We assessed glycemic and anthropometric indices, blood lipids and plasmatic level of miR-375 as well as KLF5 mRNA expression before and after the intervention. Results: Findings indicated that inulin supplementation significantly decreased fasting plasma glucose (FPG) in comparison to the placebo group (P<0.001). Also Intra-group and between group results showed that inulin supplementation resulted in significant decrease in KLF5 mRNA expression in peripheral blood mononuclear cells (PBMCs) (Fold change: 0.61± 0.11; P-value= 0.001) and significant increase in plasmatic level of miR-375 (Fold change: 3.75± 0.70; P-value=0.004). Conclusion: Considering the improvements of FPG level in diabetic patients, it seems that HP inulin supplementation may be beneficial in controlling diabetes via the expression of some genes. However, further studies are needed to achieve concise conclusions.

Nanoparticle-based targeted drug delivery has the potential for rendering silibinin specifically at the favorite site using an external magnetic field. Also, it can circumvent the pitfalls of poor solubility. For this purpose, silibinin-loaded magnetic nanoparticles are fabricated, characterized and evaluated cytotoxicity and hTERT gene expression in A549 lung cancer cell line. silibinin-loaded PLGA-PEG-Fe 3 O 4 had dose- and time-dependent cytotoxicity than pure silibinin. Additionally, hTERT expression is more efficiently reduced with increasing concentrations of nanosilibinin than pure silibinin. The present study indicates that PLGA-PEG-Fe 3 O 4 nanoparticles, as an effective targeted carrier, can make a promising horizon in targeted lung cancer therapy.

Nanoparticle (NP)-based combinational chemotherapy has been proposed as a potent approach for improving intracellular drug concentrations and attaining synergistic effects in colorectal cancer therapy. Here, two well-known herbal substances, Curcumin (Cur) and Chrysin (Chr), were co-encapsulated in PEGylated PLGA NPs and investigated their synergistic inhibitory effect against Caco-2 cancer cells. Characterization of nanoformulated drugs was determined using DLS, FTIR, TEM, and SEM. Drug release study was performed using dialysis method. MTT and real-time PCR assays were applied to evaluate the cytotoxic effects of free and nano-encapsulated drugs on expression level of hTERT in Caco-2 cells. The results showed that free drugs and nano-formulations exhibited a dose-dependent cytotoxicity against Caco-2 cells and especially, Cur-Chr-PLGA/PEG NPs had more synergistic antiproliferative effect and significantly arrested the growth of cancer cells than the other groups (P < 0.05). Real-time PCR results revealed that Cur, Chr, and combination of Cur-Chr in free and encapsulated forms inhibited hTERT gene expression. Also, it was found that Cur-Chr-PLGA/PEG NPs than free combination forms could further decline hTERT expression in all concentration (P < 0.05). In summary, our study represents the first report of nano-combinational application of the natural herbal substances with a one-step fabricated codelivery system for effective colorectal cancer combinational chemotherapy.

Studies on humans with diabetes mellitus showed that the crosstalk between the intestinal microbiota and the host has a key role in controlling the disease. The aim of this study was to evaluate the effects of sodium butyrate and high performance inulin supplementation simultaneously or singly on glycemic status, lipid profile, and glucagon-like peptide 1 level in adults with type 2 diabetes mellitus. Sixty patients were recruited for the study. The participants were randomly allocated, using randomized block procedure, to one of the four treatment groups (A, B, C, or D). Group A received sodium butyrate capsules, group B received inulin supplement powder, group C was exposed to the concomitant use of inulin and sodium butyrate, and group D consumed placebo for 45 consecutive days. Markers of glycemia, lipid profile, and glucagon-like peptide 1 were measured pre- and post-intervention. Dietary supplementation in groups A, B, and C significantly reduced diastolic blood pressure in comparison with the placebo group (p<0.05). Also, intra-group statistical analysis showed that only treatment with sodium butyrate + inulin (group C) significantly reduced fasting blood sugar (p=0.049) and waist to hip ratio (p=0.020). Waist circumference in groups B and C reduced significantly after the intervention (p=0.007 and p=0.011; respectively). The post hoc Tukey tests showed significant increase in glucagon-like peptide 1 concentration in groups A and C in comparison with group D (p<0.05). The results suggest that inulin supplementation may be useful to diabetic patients and these effects could be increased with butyrate supplement., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background Gastric carcinoma still remains the second most common cause of cancer mortality in the world. Chrysin, as a flavone, has showed cancer chemopreventive activity. The cellular and molecular mechanisms of chrysin in cancer cells have not been fully understood. Objective In this study, we investigate expression levels of let-7a, miR-9, mir-18a, miR-21, miR-22, miR-34a, miR-126 and mir-221 to describe the anti-cancer effects of chrysin. Materials and Methods The cytotoxic effects of chrysin were assessed using MTT assay. The effect of chrysin on the microRNAs expression was determined by qRT-PCR. Results The MTT results for different concentrations of chrysin at different times on the Gastric carcinoma cells showed that IC50 for chrysin was 68.24 µM after 24 h of treatment. Expression analysis identified that miR-18, miR-21 and miR-221 were down regulated whereas let-7a, miR-9, miR-22, miR-34a and miR-126 were up regulated in Gastric carcinoma cell line (p<0.05). Conclusion Treatment with chrysin can alter the miRNAs expression and these findings might be an explanation for molecular mechanism of chrysin effect on gastric cancer., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: 'Epigenetics' is specified as the inheritable changes in gene expression with no alterations in DNA sequences. Epigenetics is a rapidly overspreading scientific field, and the study of epigenetic regulation in chronic disease is emerging. This study aims to evaluate epigenetic changes including DNA methylation, histone modification, and non-coding RNAs (ncRNAs) in inflammatory disease, with focus on Behçet's disease. In this review, first we describe the history and classification of epigenetic changes, and then the role of epigenetic alterations in chronic diseases is explained., Methods: Systematic search of MEDLINE, Embase, and Cochrane Library was conducted for all comparative studies since 2000 to 2015 with the limitations of the English language., Results: For a notable period of time, researchers have mainly focused on the epigenetic pathways that are involved in the modulation of inflammatory and anti-inflammatory genes. Recent studies have proposed a central role for chronic inflammation in the pathogenesis of chronic disease, including Behçet's disease., Conclusion: Studies have been reported on the epigenetic of BD showed the role of alterations in the methylation level of IRS elements; histone modifications such as H3K4me27 and H3K4me3; up regulation of miR-182 and miR-3591-3p; down regulation of miR-155, miR-638 and miR-4488 in the pathogenesis of the disease., (Copyright © 2017. Published by Elsevier Masson SAS.)

Objective: Breast cancer is one of the most significant causes of female cancer death worldwide. Although several chemotherapeutics have been developed to treat this type of cancer, issues remain such as low survival rates and high reoccurrence after chemotherapy and radiotherapy. To explore a chemopreventive approach to enhancing breast cancer treatment efficacy, the antiproliferative effects of a combination of chrysin and silibinin, two herbal substances, in T47D breast cancer cells were assessed. Materials and Methods: Cytotoxicity of the agents singly and in combination was evaluated by MTT assay. Also, qRT-PCR was used to measure the expression levels of hTERT and cyclin D1 genes after 48 h treatment. Results: Cell viability assays revealed that chrysin or silibinin alone inhibited proliferation in a dose and time-dependent manner, and combining the drugs synergistically induced growth inhibition in the breast cancer cell line. The precise nature of this interaction was further analyzed by the median-effect method, where the combination indices (CI) were <1 for combination treatments, indicating synergism regarding T47D cell proliferation. qPCR results showed that the drug combination also synergistically down-regulated the mRNA levels of hTERT and cyclin D1 at all used concentrations compared with the drugs used alone after 48 h treatment (P ≤ 0.05). Conclusion: The data provide evidence that synergistic antiproliferative effects of Chrysin and Silibinin are linked to the down-regulation of cyclin D1 and hTERT genes, and suggest that their combination may have therapeutic value in treatment of breast cancer., (Creative Commons Attribution License)

Introduction: Inflammation has a crucial role in the progression of cardiovascular disease in diabetes. Tumour necrosis factor-α (TNF-α) as an inflammatory marker induces angiotensin II (Ang II) related hypertension pathway in diabetic patients. Gut modulation via prebiotics may ameliorate hypertension caused by inflammation. The aim of this study was to investigate the role of sodium butyrate (NaBut) and inulin supplements on inflammatory and oxidative stress parameters in type 2 diabetic patients. Methods: In this clinical trial, 60 overweight and obese diabetic patients were recruited and randomly allocated into four groups. The groups received, respectively, 600 mg/d NaBut (group A), 10 g/d inulin powder (group B), both inulin and NaBut (group C), or placebo (group D) for 45 consecutive days. Blood and stool samples were collected at baseline and after intervention. Quantitative real-time PCR analysis targeting the 16S rRNA gene of Akkermansia muciniphila was done. We assessed the TNF-α mRNA expression and the serum levels of the high sensitive C-reactive protein (hs-CRP) and malondialdehyde (MDA). Results: There was a significant increase in A. muciniphila percent change in inulin and butyrate supplemented groups ( P  < 0.05). Furthermore, significant decrease was seen in TNF-α mRNA expression in group A (fold change 0.88 ± 0.16, P < 0.05), group B (fold change 0.75 ± 0.18, P  < 0.05) and group C (fold change 0.91 ± 0.32, P  < 0.05). Also hs-CRP, MDA and diastolic blood pressure levels decreased significantly in these groups ( P  < 0.05). Conclusion: Intervention had significant effects on inflammatory and oxidative stress parameters and led to improvement of hypertension. However, further investigations are needed to make concise conclusions.