The effects of vitamins and dietary pattern on epigenetic modification of non-communicable diseases.

Background: Non-communicable diseases (NCDs) have received more attention because of high prevalence and mortality rate. Besides genetic and environmental factors, the epigenetic abnormality is also involved in the pathogenesis of NCDs. Methylation of DNA, chromatin remodeling, modification of histone, and long non-coding RNAs are the main components of epigenetic phenomena. Methodology: In this review paper, the mechanistic role of vitamins and dietary patterns on epigenetic modification was discussed. All papers indexed in scientific databases, including PubMed, Scopus, Embase, Google Scholar, and Elsevier were searched during 2000 - 2021 using, vitamins, diet, epigenetic repression, histones, methylation, acetylation, and NCDs as keywords. Results: The components of healthy dietary patterns like Mediterranean and dietary approaches to stop hypertension diets have a beneficial effect on epigenetic hemostasis. Both quality and quantity of dietary components influence epigenetic phenomena. A diet with calorie deficiency in protein content and methyl-donor agents in a long time, with a high level of fat, disrupts epigenetic hemostasis and finally, causes genome instability. Also, soluble and insoluble vitamins have an obvious role in epigenetic modifications. Most vitamins interact directly with methylation, acetylation, and phosphorylation pathways of histone and DNA. However, numerous indirect functions related to the cell cycle stability and genome integrity have been recognized. Conclusion: Considering the crucial role of a healthy diet in epigenetic homeostasis, adherence to a healthy dietary pattern containing enough levels of vitamin and avoiding the western diet seems to be necessary. Having a healthy diet and consuming the recommended dietary level of vitamins can also contribute to epigenetic stability.

Sensitive and convenient detection of miRNA-145 using a gold nanoparticle-HCR coupled system: computational and in vitro validations.

Multiple sclerosis (MS) remains a challenging disease that requires timely diagnosis. Therefore, an ultrasensitive optical biosensor based on hybridization chain reaction (HCR) was developed to detect microRNA-145 (miRNA-145) as an MS biomarker. To construct such a sensor, HCR occurred between specific hairpin probes, as MB1 contains a poly-cytosine nucleotide loop and MB2 has a poly-guanine nucleotide sticky end. By introducing miR-145 as a target sequence, long-range dsDNA polymers are formed. Then, positively charged gold nanoparticles (AuNPs) were incubated with the HCR product, which adsorbed onto the dsDNA polymers due to electrostatic adsorption. This resulted in the precipitation of the AuNPs. By incubating different concentrations of miR-145 with AuNPs, the changes in the UV-vis spectrum of the supernatant were analyzed. The proposed biosensor showed a great ability to detect miR-145 in a wide linear range from 1 pM-1 nM with an excellent detection limit (LOD) of 0.519 nM. Furthermore, the developed biosensor indicated considerable selectivity in discriminating between miR-145 and mismatched sequences. It shows high selectivity in differentiating targets. Interestingly, the proposed method was also able to detect miRNA-145 in the diluted serum samples. In conclusion, this sensing platform exhibits high selectivity and specificity for the detection of circulating microRNAs, which holds great promise for translation to routine clinical applications.

The contributing factors of resistance or sensitivity to epigenetic drugs in the treatment of AML.

Drug resistance is the drug-effectiveness reduction in treatment and is a serious problem in oncology and infections. In oncology, drug resistance is a complicated process resulting from enhancing the function of a pump that transports drugs out of tumor cells, or acquiring mutations in drug target. Surprisingly, most drugs are very effective in the early stages, but the response to the drug wears off over time and resistance eventually develops. Drug resistance is caused by genetic and epigenetic changes that affect cancer cells and the tumor environment. The study of inherited changes in the phenotype without changes in the DNA sequence is called epigenetics. Because of reversible changes in epigenetics, they are an attractive target for therapy. Some of these epigenetic drugs are effective in treating cancers like acute myeloid leukemia (AML), which is characterized by the accumulation and proliferation of immature hematopoietic cells in the blood and bone marrow. In this article, we outlined the various contributing factors involved in resistance or sensitivity to epigenetic drugs in the treatment of AML.

PPAR-gamma agonists: Potential modulators of autophagy in obesity.

Autophagy pathways are involved in the pathogenesis of some obesity related health problems. As obesity is a nutrient sufficiency condition, autophagy process can be altered in obesity through AMP activated protein kinase (AMPK) inhibition. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) as the main modulator of adipogenesis process can be effective in the regulation of obesity related phenotypes. As well, it has been revealed that PPAR-gamma and its agonists can regulate autophagy in different normal or cancer cells. However, their effects on autophagy modulation in obesity have been investigated in the limited number of studies. In the current comprehensive mechanistic review, we aimed to investigate the possible mechanisms of action of PPAR-gamma on the process of autophagy in obesity through narrating the effects of PPAR-gamma on autophagy in the non-obesity conditions. Moreover, mode of action of PPAR-gamma agonists on autophagy related implications comprehensively reviewed in the various studies. Understanding the different effects of PPAR-gamma agonists on autophagy in obesity can help to develop a new approach to management of obesity.

CML derived exosomes promote tumor favorable functional performance in T cells.

BACKGROUND: Leukemic cells facilitate the creation of the tumor-favorable microenvironment in the bone marrow niche using their secreted factors. There are not comprehensive details about immunosuppressive properties of chronic myelogenous leukemia-derived exosomes in the bone marrow stromal and immune compartment. We explained here that K562-derived exosomes could affect the gene expression, cytokine secretion, nitric oxide (NO) production, and redox potential of human primary cord blood-derived T cells (CB T cells). METHODS: Human primary cord blood-derived T cells were treated with K562-derived exosomes. We evaluated the expression variation of some critical genes activated in suppressor T cells. The alterations of some inflammatory and anti-inflammatory cytokines levels were assessed using ELISA assay and real-time PCR. Finally, NO production and intracellular ROS level in CB T cells were evaluated using Greiss assay and flow cytometry, respectively. RESULTS: Our results showed the over-expression of the genes involved in inhibitory T cells, including NQO1, PD1, and FoxP3. In contrast, genes involved in T cell activation such as CD3d and NFATc3 have been reduced significantly. Also, the expression of interleukin 10 (IL-10) and interleukin 6 (IL-6) mRNAs were significantly up-regulated in these cells upon exosome treatment. In addition, secretion of the interleukin 10, interleukin 6, and interleukin 17 (IL-17) proteins increased in T cells exposed to K562-derived exosomes. Finally, K562-derived exosomes induce significant changes in the NO production and intracellular ROS levels in CB T cells. CONCLUSIONS: These results demonstrate that K562-derived exosomes stimulate the immunosuppressive properties in CB-derived T cells by inducing anti-inflammatory cytokines such as IL-10, reducting ROS levels, and arising of NO synthesis in these cells. Moreover, considering the elevation of FOXP3, IL-6, and IL-17 levels in these cells, exosomes secreted by CML cells may induce the fates of T cells toward tumor favorable T cells instead of conventional activated T cells.

MicroRNA-22 in female malignancies: Focusing on breast, cervical, and ovarian cancers.

MicroRNAs (miRNAs), a novelty-defined class of regulatory genes, have revolutionized principles of classical bimolecular. These RNAs regulate the expression of a gene through inhibition of translational initiation or targeting mRNAs for degradation. MiRNAs act in several biological operations, including proliferation, differentiation, and cell death, and their expression is often abnormal in human diseases such as cancer. In recent years, miR-22 has attracted much attention from researchers. Its expression is downregulated in female malignancies such as breast, cervical, and ovarian cancers, exhibiting that miR-22 plays a tumor-suppressive function in these cancers. Also, different reports exist about the involvement of miR-22 in non-tumor diseases. In the present review, we report the results of performed studies on the potential roles of miR-22 in female malignancies with a focus on breast, cervical, and ovarian cancers. Also, we summary its predicted target genes in various cancers. In conclusion, it is effective for researchers to understand the role of miR-22 in different cellular operations.

MiR-330-3p and miR-485-5p as biomarkers for glioblastoma: An integrated bioinformatics and experimental study.

Glioblastoma Multiforme (GBM) is the most common, invasive, and malignant primary brain tumor with a poor prognosis and a median survival of 12-15 months. This study tried to identify the most significant miRNA biomarkers in both tissue and serum samples of GBM. GSE25632 was employed from gene expression omnibus and using WGCNA package, association of miRNA networks and clinical data was explored and brown and green modules identified as the most relevant modules. Independently, Limma package was utilized to identify differentially expressed miRNAs (DEMs) in GSE25632 by cutoff logFC > 2 and P.value < 0.05. By merging the results of Limma and WGCNA, the miRNAs that were in brown and green modules and had mentioned cutoff were selected as hub miRNAs. Performing enrichment analysis, Pathways in cancer, Prostate cancer, Glioma, p53 signaling pathway, and Focal adhesion were identified as the most important signaling pathways. Based on miRNA- target genes, has-mir-330-3p and has-mir-485-5p were identified as core miRNAs. The expression level of core miRNAs was validated by GSE90604, GSE42657, and GSE93850. We evaluated the expression level of common target genes of two detected core genes based on GSE77043, GSE42656, GSE22891, GSE15824, and GSE122498. The ability of detected miRNAs to discriminate GBM from healthy controls was assessed by area under the curve (AUC) using the ROC curve analysis. Based on TCGA database, we tested the prognostic significance of miRNAs using overall survival analysis. We evaluated the expression level of the miRNAs in tissue of 83 GBM patients and also non-tumoral adjacent (as control) tissues. We used serum samples of 34 GBM patients to evaluate the expression levels of the hub miRNAs compare to the controls. Our results showed that has-mir-330-3p and has-mir-485-5p could be potential biomarkers in GBM.

The Engaged Role of Tumor Microenvironment in Cancer Metabolism: Focusing on Cancer-Associated Fibroblast and Exosome Mediators.

Metabolic reprogramming is a significant property of various cancer cells, which most commonly arises from the Tumor Microenvironment (TME). The events of metabolic pathways include the Warburg effect, shifting in Krebs cycle metabolites, and the rate of oxidative phosphorylation, potentially providing energy and structural requirements for the development and invasiveness of cancer cells. TME and tumor metabolism shifting have a close relationship through bidirectional signaling pathways between stromal and tumor cells. Cancer- Associated Fibroblasts (CAFs), as the most dominant cells of TME, play a crucial role in the aberrant metabolism of cancer. Furthermore, the stated relationship can affect survival, progression, and metastasis in cancer development. Recently, exosomes are considered one of the most prominent factors in cellular communications considering effective content and bidirectional mediatory effect between tumor and stromal cells. In this regard, CAF-Derived Exosomes (CDE) exhibit an efficient obligation to induce metabolic reprogramming for promoting growth and metastasis of cancer cells. The understanding of cancer metabolism, including factors related to TME, could lead to the discovery of a potential biomarker for diagnostic and therapeutic approaches in cancer management. This review focuses on the association between metabolic reprogramming and engaged microenvironmental, factors such as CAFs, and the associated derived exosomes.

Effects of Royal Jelly and Tocotrienol Rich Fraction in obesity treatment of calorie-restricted obese rats: a focus on white fat browning properties and thermogenic capacity.

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 (CEBPß) 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.

Emerging molecular functions of microRNA-124: Cancer pathology and therapeutic implications.

MicroRNAs are characterized as small, single-stranded, non-coding RNA molecules that bind to their target mRNA to prevent protein synthesis. MicroRNAs regulate various normal processes; however, they are aberrantly regulated in many cancers. They control the expression of various genes, including cancer-related genes. This causes microRNAs to be considered as a good target for further investigations for designing novel therapeutic strategies. Since miR124 is known for some time already, it has a tumor-suppressing role in various cancers. Numerous studies indicate its definite roles in malignant processes such as epithelial-to-mesenchymal transition, cell cycle arrest, metastasis, cancer stem cell formation and induction of apoptosis. However, some studies have indicated a dual role for miR-124 in oncogenic processes like autophagy and multi-drug resistance. In this article, we will review recent researches on the biological functions and clinical implications of miR-124. Subsequently, we will discuss future perspectives in terms of the roles of this miRNA in cancers.

Effect of pomegranate seed oil supplementation on the GLUT-4 gene expression and glycemic control in obese people with type 2 diabetes: A randomized controlled clinical trial.

Abnormality in glucose transporter type 4 (GLUT-4) function and insulin secretion are the main causes of type 2 diabetes mellitus (T2DM). Due to adverse effects of antidiabetic drugs, nowadays, nutraceuticals have been of much interest to investigators. The aim of the present study was to determine the effect of pomegranate seed oil (PSO) on the GLUT-4 gene expression and glycemic control in obese people with T2DM. This randomized clinical trial was conducted on 52 obese type 2 diabetic patients for 8 weeks in Tabriz, Iran, in 2018. Patients were divided into the intervention group (n = 26; who consumed daily three capsules containing 1 g PSO) and the placebo group (n = 26; the same amounts paraffin). GLUT-4 gene expression and glycemic indices were evaluated by standard methods. GLUT-4 gene expression was increased significantly in the PSO group. Within-group changes in fasting blood sugar (FBS) and quantitative insulin sensitivity check index were significant in the PSO group. After adjusting the age, gender, and baseline values, FBS was significantly decreased. Insulin concentration, HbA1C, HOMA-IR, and HOMA-ß did not manifest significant changes. PSO increased the GLUT-4 gene expression in diabetic patients without any side effects. However, future clinical studies are needed to confirm the obtained results.

The crucial role of ZEB2: From development to epithelial-to-mesenchymal transition and cancer complexity.

Zinc finger E-box binding homeobox 2 (ZEB2) is a DNA-binding transcription factor, which is mainly involved in epithelial-to-mesenchymal transition (EMT). EMT is a conserved process during which mature and adherent epithelial-like state is converted into a mobile mesenchymal state. Emerging data indicate that ZEB2 plays a pivotal role in EMT-induced processes such as development, differentiation, and malignant mechanisms, for example, drug resistance, cancer stem cell-like traits, apoptosis, survival, cell cycle arrest, tumor recurrence, and metastasis. In this regard, the understanding of mentioned subjects in the development of normal and cancerous cells could be helpful in cancer complexity of diagnosis and therapy. In this study, we review recent findings about the biological properties of ZEB2 in healthy and cancerous states to find new approaches for cancer treatment.

Gene expression of TWIST1 and ZBTB16 is regulated by methylation modifications during the osteoblastic differentiation of mesenchymal stem cells.

BACKGROUND: Osteoblastic differentiation of mesenchymal stem cells (MSCs) is the principal stage during the restoration and regeneration of bone tissue. Epigenetic modifications such as DNA methylation play a key role in the differentiation process of stem cells. In this study, the methylation status of the promoter region of ZBTB16 and Twist1 genes and their role in controlling osteoblastic differentiation in MSCs was investigated during the osteoblastic differentiation of MSCs. METHODS: The MSCs were cultured under standard conditions and differentiated into the osteoblasts. We had three treatment groups including 5-azacytidine (methylation inhibitor), metformin (Twist-inhibitor), and procaine (Wnt/ß-catenin inhibitor) and a non-treated group (control). Methylation level of DNA in the promoter regions was monitored by methylation specific-quantitative polymerase chain reaction (PCR). Also, the mRNA levels of key genes in osteoblastic differentiation were measured using real-time PCR. RESULTS: ZBTB16 gene expression was upregulated, and promoter methylation was decreased. For Twist1 messenger RNA (mRNA) level decreased and promoter methylation increased during osteoblastic differentiation of MSCs. 5-Azacytidine caused a significant reduction in methylation and increased the mRNA expression of ZBTB16 and Twist1. Metformin repressed the Twist1 expression, and therefore osteoblastic differentiation was increased. On the opposite side, procaine could block the WNT/ß-catenin signaling pathway, as a consequence the gene expression of key genes involved in osteoblastic differentiation was declined. CONCLUSION: We found that methylation of DNA in the promoter region of ZBTB16 and Twist1 genes might be one of the main mechanisms that controlling the gene expression during osteoblastic differentiation of MSCs. Also, we could find an association between regulation of Twist1 and ZBTB16 genes and osteoblastic differentiation in MSCs by showing the relation between their expression and some key genes involved in osteoblastic differentiation. In addition, we found a connection between the Twist1 expression level and osteoblastic differentiation by using a Twist-inhibitor (metformin).

Punicic acid: A potential compound of pomegranate seed oil in Type 2 diabetes mellitus management.

Diabetes is one of the most prevalent diseases in the worldwide. Type 2 diabetes mellitus (T2DM), the most common form of the disease, has become a serious threat to public health and is a growing burden on global economies. Due to the unexpected adverse effects of antidiabetic medicines, the use of nutraceuticals as a complementary therapy has drawn extensive attention by investigators. In this issue, a novel nutraceutical, Punicic acid (PA)-the main ingredient of pomegranate seed oil (PSO) that has potential therapeutic effects in T2DM-has been investigated. PA is a peroxisome proliferator-activated receptor gamma agonist, and unlike synthetic ligands, such as thiazolidinediones, it has no side effects. PA exerts antidiabetic effects via various mechanisms, such as reducing inflammatory cytokines, modulating glucose homeostasis, and antioxidant properties. In this review, we discussed the potential therapeutic effects of PSO and PA and represented the related mechanisms involved in the management of T2DM.