Epstein-Barr virus-encoded BART9 and BART15 miRNAs are elevated in exosomes of cerebrospinal fluid from relapsing-remitting multiple sclerosis patients.

Epstein-Barr virus (EBV) infection is approved as the main environmental trigger of multiple sclerosis (MS). In this path, we quantified ebv-miR-BART9-3p and ebv-miR-BART15 in exosomes of cerebrospinal fluid (CSF) of untreated relapsing-remitting MS (RRMS) patients in comparison with the control group. Interestingly, patients displayed significant upregulation of ebv-miR-BART9-3p (18.4-fold) and ebv-miR-BART15 (3.1-fold) expression in CSF exosomes. Moreover, the expression levels of hsa-miR-21-5p and hsa-miR-146a-5p were found to be significantly elevated in the CSF samples obtained from the patient group compared to those obtained from the HC group. The levels of Interferon-gamma (IFN-γ), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-17 (IL-17), interleukin-23 (IL-23), transforming growth factor beta (TGF-ß), and tumor necrosis factor-alpha (TNF-α) were observed to be significantly elevated in the serum and CSF exosomes of the patients. The highest increase was observed in TGF-ß (8.5-fold), followed by IL-23 (3.9-fold) in CSF exosomes. These findings are in agreement with the association between EBV infection and inflammatory cytokines induction. Furthermore, the ratios of TGF-ß: TNF-α and TGF-ß: IFN-γ attained values of 4 to 16.4 and 1.3 to 3.6, respectively, in the CSF exosomes of the patients, in comparison to those of the control group. These findings show EBV activity in RRMS patients is different from that of healthy ones. Elevation of ebv-miR-BART9-3p, ebv-miR-BART15, and inflammatory cytokines expression in CSF exosomes in RRMS patients provides a substantial link between EBV activity and the onset of the disease, as well as the transition from EBV infection to MS.

Evaluation of T helper17 as skeletal homeostasis factor in peripheral blood mononuclear cells and T helper cells of end-stage renal disease cases with impaired parathyroid hormone.

BACKGROUND: Chronic renal failure is mainly connected with high and low parathyroid hormone (PTH) levels and immunological impairments. The present study aimed to evaluate T helper 17 (Th17) cells as a crucial modulator of the immune system and skeletal homeostasis in hemodialysis patients with impaired intact PTH (iPTH). METHODS: In this research, blood samples were taken from ESRD patients with high (> 300 pg/mL), normal (150-300 pg/mL), and low (< 150 pg/mL) serum intact parathyroid hormone (iPTH( levels (n = 30 in each group). The frequency of Th17 (CD4+ IL17+) cells was evaluated by flow cytometry in each group. The expression levels of Th17 cell-related master transcription factors, cytokines in peripheral blood mononuclear cells (PBMC), and Th cells, and the level of the mentioned cytokines were determined in the supernatant of PBMCs. RESULTS: The number of Th17 cells remarkably increased in subjects with high iPTH against low and normal iPTH. Also, RORÉ£t and STAT3 levels were significantly higher in high iPTH ESRD patients than in other groups in the expression of mRNA and protein levels. These findings are confirmed by evaluating the IL-17 and IL-23 in the supernatant of cultured PBMCs and isolated Th cells. CONCLUSION: Our findings indicated that increased serum PTH levels in hemodialysis cases may be involved in increasing the differentiation of CD4 + cells to Th17 cells in PBMC.

The integrative panel of fatty acid desaturase-2 (FADS2) rs174583 gene polymorphism and dietary indices (DQI-I and HEI) affects cardiovascular risk factors among obese individuals.

BACKGROUND: Recent studies have shown that dietary intakes and gene variants have a critical role in the obesity related comorbidities. This study aimed to evaluate the effects of the interactions between Fatty acid desaturase 2 (FADS2) gene rs174583 polymorphism and two dietary indices on cardiometabolic risk factors. METHODS: This cross-sectional study was carried out on 347 obese adults aged 20-50 years old in Tabriz, Iran. Healthy eating index (HEI) and Diet quality index-international (DQI-I) were evaluated by a validated semi-quantitative 147-item Food frequency questionnaire (FFQ). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine FADS2 gene variants. Multivariate analysis of covariance (MANCOVA) was used to identify gene-diet interactions on metabolic parameters. RESULTS: Waist circumference (WC) and serum triglyceride (TG) levels were significantly higher among carriers of TT genotype of FADS2 gene (P < 0.05). In addition, the interactions between FADS2 gene rs174583 polymorphism and DQI-I had significant effects on weight (P interaction = 0.01), fat mass (P interaction = 0.04), fat free mass (P interaction = 0.03), and Body mass index (BMI) (P interaction = 0.02); the highest level of these parameters belonged to TT carriers. Similarly, the interactions between FADS2 gene variants and HEI had significant effects on insulin (P interaction < 0.001), Homeostasis model assessment of insulin resistance (HOMA-IR) (P interaction < 0.001), Quantitative insulin check index (QUICKI) (P interaction = 0.001), and alpha Melanocyte stimulating hormone (α-MSH) (P interaction = 0.03). CONCLUSION: In this study, for the first time, we reported the effects of gene-diet interactions on metabolic traits. Compliance with dietary indices (DQI-I and HEI) ameliorated the adverse effects of gene variants on metabolic risk factors, especially in heterogeneous genotypes. Further prospective cohort studies are needed to confirm these results.

Expression pattern of miR-193a, miR122, miR155, miR-15a, and miR146a in peripheral blood mononuclear cells of children with obesity and their relation to some metabolic and inflammatory biomarkers.

BACKGROUND: The widespread presence of childhood obesity has increased considerably over three decades. The present study was designed to investigate expression patterns of miR-146a, miR-155, miR-15a, miR-193a, and miR-122 in peripheral blood mononuclear cells (PBMCs) in children who are obese along with their association with metabolic and inflammatory biomarkers. METHODS: Ninety test subjects were admitted. The profile of blood pressure, resting energy expenditure (REE), anthropometric measures, body composition, dietary intakes, physical activity levels, insulin, and lipid profile, fasting blood glucose (FBG), high-sensitivity C-reactive protein (hs-CRP), and pubertal stage have been measured. Total RNA (including small RNAs) was extracted from PBMCs. The expression levels of miRNAs were measured by stem-loop RT-qPCR. RESULTS: The miR-155a expression level was significantly lower in obese children, children with high hs-CRP, and children with high-fat mass. Obese girls had significantly higher PBMC levels of miR-122. MiR-155a had a significant negative association with fasting insulin, HOMA-IR, and hs-CRP. There were significant positive associations between miR-193a and miR-122 expression levels and fasting insulin, HOMA-IR, and TG. MiR-15a was positively correlated with fasting insulin and HOMA-IR. Children with metabolic syndrome, insulin resistance, and high-fat mass had higher PBMC levels of miR-122 and miR-193a. Higher miR-193a and miR-122 levels were also detected in PBMCs of children with fast REE, compared to those with slow REE, and the subjects with high hs-CRP, respectively. CONCLUSION: lower level of miR-155 expression in obese subjects and significant associations unfolds the need for more studies to detect the possible underlying mechanisms.

Paediatric pre-B acute lymphoblastic leukaemia-derived exosomes regulate immune function in human T cells.

Exosomes derived from solid tumour cells are involved in immune suppression, angiogenesis and metastasis; however, the role of leukaemia-derived exosomes has less been investigated. Hence, changes in immune response-related genes and human T cells apoptosis co-incubated with exosomes isolated from patients' pre-B cell acute lymphoblastic leukaemia were evaluated in this in vitro study. Vein blood sample was obtained from each newly diagnosed acute lymphoblastic leukaemia (ALL) patient prior any therapy. ALL serum exosomes were isolated by ultrafiltration and characterized using Western blotting and transmission electron microscopy. Exosomes were then co-incubated with T lymphocytes and the gene expressions, as well as functions of human T cells were quantified by qRT-PCR. Apoptosis and caspase-3 and caspase-9 protein expression were also evaluated by flowcytometry and Western blotting analysis, respectively. Exosomes isolated from ALL patients affected T lymphocytes and elevated the apoptosis. Moreover, these exosomes altered the T cells profile into regulatory type by increasing the expression of FOXP3 and Tregs-related cytokines, including TGF-B and IL-10. The expression level of Th17-related transcription factors (RoRγt) and interleukins (IL-17 and IL-23) decreased after this treatment. According to our findings, exosomes derived from ALL patients' sera carry immunosuppressive molecules, indicating the possible effect of exosomes as liquid biomarkers for cancer staging.

Interplay between fatty acid desaturase2 (FADS2) rs174583 genetic variant and dietary antioxidant capacity: cardio-metabolic risk factors in obese individuals.

OBJECTIVE: Polymorphisms of the fatty acid desaturase (FADS) gene cluster have been associated with obesity and its-related consequences. This cross-sectional study aimed to investigate whether the adherence to dietary non-enzymatic antioxidant capacity (NEAC), reflecting the antioxidant potential of the whole diet, modifies the association of FADS2 rs174583 polymorphism with cardio-metabolic risk factors in obese adults. METHODS: The present study included 347 healthy obese adults (aged 20-50 years). Dietary NEAC was assessed by a validated food frequency questionnaire with 147 items and estimated through total radical-trapping antioxidant parameters (TRAP), oxygen radical absorbance capacity (ORAC), and ferric reducing ability of plasma (FRAP) with the use of published databases. FADS2 rs174583 polymorphism was characterized using PCR-RFLP. ANCOVA multivariate interaction model was used to analyze gene-diet interactions. RESULTS: after adjustment for the confounding variables (age, physical activity, SES and WC), this study showed significant interactions between rs174583 polymorphism and adherence to dietary ORAC on the serum cholesterol (P Interaction = 0.029), LDL-C (P Interaction = 0.025) and HDL-C levels (P Interaction = 0.049) among the male group; minor allele carriers who had the highest adherence to the NEAC (ORAC) showed a better metabolic profile (lower TG and LDL-C and higher HDL-C) (P < 0.05). Among women, the dietary ORAC-rs174583 interactions were statistically significant for the serum insulin concentration (P Interaction = 0.020), QUICKI (P Interaction = 0.023) and HOMA-IR (P Interaction = 0.017); the highest QUICKI and the lowest HOMA-IR and serum insulin levels were observed in the CC homozygote carriers with the moderate compliance with the dietary ORAC (P < 0.05). In addition, the dietary TRAP modified the association between FADS2 variant and change in LDL-C levels (P Interaction = 0.037); the homozygous wild-type (CC) women who placed in the top tertile of TRAP had significantly the lowest LDL-C levels than those in the second tertile (P < 0.05). CONCLUSION: These data indicate that the FADS2 rs174583 polymorphism interacts with the dietary NEAC to influence cardio-metabolic risk factors in obese subjects. Replication in prospective cohort studies among other populations is required to confirm the results of our study.

In vitro exosomal transfer of Nrf2 led to the oxaliplatin resistance in human colorectal cancer LS174T cells.

Chemotherapy resistance is a serious pitfall in the treatment of colon cancers (CCs). Previous studies have found that exosomes (Exo) play a pivotal role in tumor drug resistance via the transfer of proteins and genetic materials to the acceptor cells. To date, the mechanisms orchestrating Exo-derived resistance in cancer cells have been the center of attention. Herein, we aimed to evaluate the role of exosomal nuclear factor erythroid 2-related factor 2 (Nrf2) on oxaliplatin (1-OHP) resistance in human colorectal cancer LS174T cells in vitro. To this end, exosomal-Nrf2-mediated 1-OHP resistance was examined using different assays. Exo was isolated from resistant LS174T cells (LS174T/R) and added to the culture medium of sensitive LS174T cells (LS174T/S). According to our data, LS174T/S cells successfully adsorbed PKH26-Exo driven from LS174T/R cells. Western blotting showed an increased Nrf2 level in Exo isolated from LS174T/R cells compared to LS174T/S cell-derived Exo (p < .05). The incubation of LS174T/S cells with LS174T/R-derived Exo increased half-maximal inhibitory concentration values in response to treatment with 1-OHP (p < .05). Besides this, the apoptotic changes were diminished in LS174T/S cells after incubation with LS174T/R-derived Exo. Of note, the exposure of LS174T/S cells to LS174T/R cell-derived Exo increased the expression of Nrf2 and P-glycoprotein (P-gp) compared to the nontreated LS174T/S cells (p < .05). In line with these changes, lower intracellular Rhodamin 123 content was detected in Exo-treated cells compared to the nontreated LS174T/S cells. Exo increased migration and clonogenic capacity of LS174T/S cells after incubation with Exo-derived from resistant cells. Of note, inhibition of Nrf2 with a specific blocker, brusatol, blunted these effects. Taken together, Exo-mediated transfer of Nrf2 is involved in the development of oxaliplatin resistance in CC cells by upregulating P-gp.

Altered Th17/Treg ratio as a possible mechanism in pathogenesis of idiopathic membranous nephropathy.

Idiopathic membranous nephropathy (IMN) as a single organ autoimmune disease is a main cause of nephrotic syndrome in adults which is determined through autoantibodies to podocytes proteins. Th17/regulatory T (Treg) balance has emerged as a prominent factor in the regulation of autoimmunity. In this study, we evaluated the balance of Th17 and Treg cells, expression level of related master transcription factors, cytokines and microRNAs in mononuclear cells of peripheral blood of 30 patients with IMN and 30 healthy individuals before treatment. No significant variation was observed in Th17 cell frequency, retinoic acid receptor-related orphan nuclear receptor γt (RORÉ£t), signal transducer and Activator of transcription 3(STAT3), IL-17, and IL-23, while IL-21, IL-4, and IL-10 had significant increase in mRNA expression and protein level of peripheral blood mononuclear cells in IMN cases. Reduction in the percentage of Treg cells was also accompanied with significantly decreased expression of Forkhead box P3(FOXP3) and Transforming growth factor beta(TGF-ß) in IMN patients compared to the control group. Our study revealed that Th17 cells themselves might not be engaged in the pathogenesis of newly diagnosed patients with IMN; however, decreased T reg cells and increased ratio of Th17/Treg lymphocytes might display a role in the pathogenesis of IMN before treatment.

Unraveling the Effect of Breast Cancer Patients' Plasma on the Targeting Ability of Folic Acid-Modified Chitosan Nanoparticles.

The formation of protein corona (PC) around nanoparticles (NPs) has been reported inside biological conditions. This effect can alter delivery capacity toward the targeted tissues. Here, we synthesized folic acid-modified chitosan NPs (FA-CS NPs) using different concentrations of folic acid (5, 10, and 20%). FA-CS NPs were exposed to plasmas of breast cancer patients and healthy donors to evaluate the possibility of PC formation. We also monitored uptake efficiency in in vitro conditions after incubation with human breast cancer cell line MDA-MB-231 and monocyte/macrophage-like Raw264.7 cells. Data showed that the formation of PC around FA-CS NPs can change physicochemical properties coincided with the rise in NP size and negative surface charge. SDS-PAGE electrophoresis revealed differences in the type and content rate of plasma proteins attached to NP surface in a personalized manner. Based on MTT data, the formation of PC around NPs did not exert cytotoxic effects on MDA-MB-231 cells while this phenomenon reduced uptake rate. Fluorescence imaging and flow cytometry analyses revealed reduced cellular internalization rate in NPs exposed to patients' plasma compared to the control group. In contrast to breast MDA-MB-231 cells, Raw264.7 cells efficiently adsorbed the bare and PC-coated NPs from both sources, indicating the involvement of ligand-receptor-dependent and independent cellular engulfment. These data showed that the PC formed on the FA-CS NPs is entirely different in breast cancer patients and healthy counterparts. PC derived from patients' plasma almost abolishes the targeting efficiency of FA-CS NPs even in different mechanisms, while this behavior was not shown in the control group. Surprisingly, Raw264.7 cells strongly adsorbed the PC-coated NPs, especially when these particles were in the presence of patients' sera. It is strongly suggested that the formation of PC around can affect delivering capacity of FA-CS NPs to cancer cells. It seems that the PC-coated FA-CS NPs can be used as an efficient delivery strategy for the transfer of specific biomolecules in immune system disorders.

Clinical application of immune checkpoints in targeted immunotherapy of prostate cancer.

Immunotherapy is considered as an effective method for cancer treatment owing to the induction of specific and long-lasting anti-cancer effects. Immunotherapeutic strategies have shown significant success in human malignancies, particularly in prostate cancer (PCa), a major global health issue regarding its high metastatic rates. In fact, the first cancer vaccine approved by FDA was Provenge, which has been successfully used for treatment of PCa. Despite the remarkable success of cancer immunotherapy in PCa, many of the developed immunotherapy methods show poor therapeutic outcomes. Immunosuppression in tumor microenvironment (TME) induced by non-functional T cells (CD4+ and CD8+), tolerogenic dendritic cells (DCs), and regulatory T cells, has been reported to be the main obstacle to the effectiveness of anti-tumor immune responses induced by an immunotherapy method. The present review particularly focuses on the latest findings of the immune checkpoints (ICPs), including CTLA-4, PD-1, PD-L1, LAG-3, OX40, B7-H3, 4-1BB, VISTA, TIM-3, and ICOS; these checkpoints are able to have immune modulatory effects on the TME of PCa. This paper further discusses different approaches in ICPs targeting therapy and summarizes the latest advances in the clinical application of ICP-targeted therapy as monotherapy or in combination with other cancer therapy modalities in PCa.

Corneal endothelium tissue engineering: An evolution of signaling molecules, cells, and scaffolds toward 3D bioprinting and cell sheets.

Cornea is an avascular and transparent tissue that focuses light on retina. Cornea is supported by the corneal-endothelial layer through regulation of hydration homeostasis. Restoring vision in patients afflicted with corneal endothelium dysfunction-mediated blindness most often requires corneal transplantation (CT), which faces considerable constrictions due to donor limitations. An emerging alternative to CT is corneal endothelium tissue engineering (CETE), which involves utilizing scaffold-based methods and scaffold-free strategies. The innovative scaffold-free method is cell sheet engineering, which typically generates cell layers surrounded by an intact extracellular matrix, exhibiting tunable release from the stimuli-responsive surface. In some studies, scaffold-based or scaffold-free technologies have been reported to achieve promising outcomes. However, yet some issues exist in translating CETE from bench to clinical practice. In this review, we compare different corneal endothelium regeneration methods and elaborate on the application of multiple cell types (stem cells, corneal endothelial cells, and endothelial precursors), signaling molecules (growth factors, cytokines, chemical compounds, and small RNAs), and natural and synthetic scaffolds for CETE. Furthermore, we discuss the importance of three-dimensional bioprinting strategies and simulation of Descemet's membrane by biomimetic topography. Finally, we dissected the recent advances, applications, and prospects of cell sheet engineering for CETE.

Cocaine and amphetamine-regulated transcript prepropeptide gene (CARTPT) polymorphism interacts with Diet Quality Index-International (DQI-I) and Healthy Eating Index (HEI) to affect hypothalamic hormones and cardio-metabolic risk factors among obese individuals.

BACKGROUND: Epidemiologic studies show that cocaine- and amphetamine-regulated transcript prepropeptide (CARTPT) gene polymorphism modifies diet-obesity relationships. However, the interaction between CARTPT gene polymorphism and diet quality indices have not been investigated yet. The current study was aimed to evaluate the interaction between major dietary indices including Diet Quality Index-International (DQI-I) and Healthy Eating Index (HEI)-2015 and CARTPT gene rs2239670 variants among apparently healthy obese Iranians. METHODS: This cross-sectional study was carried out by employing 288 apparently healthy obese adults aged 20-50 years with a BMI of 30-40 kg/m2. Diet quality was evaluated by Diet Quality Index-International (DQI-I) and Healthy Eating Index-2015 (HEI-2015) using a 132-items semi-quantitative validated food frequency questionnaire. The CARTPT gene rs2239670 polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Blood concentrations of glycemic markers, lipid profile, α-melanocyte stimulating hormone (MSH) and agouti-related peptide (AgRP) were also measured. ANCOVA multivariate interaction model was used to analyze gene-diet interactions. RESULTS: The significant interactions were identified between CARTPT gene polymorphism and HEI, affecting BMR (PInteraction = 0.003), serum glucose (PInteraction = 0.009) and high density lipoprotein cholesterol HDL concentrations (PInteraction = 0.03) after adjusting for the effects of sex and age. Also we found gene-diet interaction between CARTPT genotypes and DQI-I in terms of fat mass (FM; PInteraction = 0.02), waist circumference (WC; PInteraction < 0.001), body mass index (BMI; PInteraction < 0.001), basal metabolic rate (BMR, PInteraction < 0.001), serum fasting glucose (PInteraction < 0.01) and AgRP (PInteraction = 0.05) in individuals even after adjusting for potential confounders. CONCLUSION: Current study showed the effects of interaction between CARTPT genotype with adherence to HEI and DQI-I scores on obesity-related anthropometric and metabolic risk-factors.

Interleukin-17 mRNA expression and serum levels in Behçet's disease.

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.

The oncogenic roles of bacterial infections in development of cancer.

Initiation of cancer is interconnected with different factors like infections. It has been estimated that infections, particularly viruses, participate in about 20% of all cancers. Bacteria as the most common infectious agents are also reported to be emerging players in the establishment of malignant cells. Microbial infections are able to modulate host cell transformation for promoting malignant features through the production of carcinogenic metabolites participating in inflammation responses, disruption of cell metabolism, and integrity and also genomic or epigenetic manipulations. It seems that the best example of the role of bacteria in cancer promotion is Helicobacter pylori infection, which is related to gastric cancer. World Health Organization (WHO) describes bacterium as class I carcinogens. Several bacterial infections have been reported in association with prevalent cancers. In this review, we will summarize the role of known bacterial infections in the initiation of the main common cancers, which show high mortality in the world. Examining the microbiomes in cancer patients is important and necessary to better understand the pathogenesis of this disease and also to plan therapeutic interventions.

Dietary quality indices modifies the effects of melanocortin-4 receptor (MC4R) rs17782313 polymorphism on cardio-metabolic risk factors and hypothalamic hormones in obese adults.

BACKGROUND: Although the Melanocortin-4 Receptor (MC4R) gene rs17782313 C/T has been consistently related to obesity risk, the interaction between MC4R polymorphism and diet quality indices on cardio-metabolic risk factors has not yet investigated. Therefore we aimed to test this hypothesis. METHODS: This cross-sectional study recruited 188 (96 males and 92 females) healthy obese adults aged 20-50 years. Diet quality indices including Healthy Eating Index-2015 (HEI-2015) and Diet Quality Index-International (DQI-I) were constructed using data from a validated food frequency questionnaire. MC4R s17782313 were genotyped by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). The interaction between MC4R polymorphism and diet quality indices was tested by Analysis of covariance (ANCOVA) multivariate interaction model. RESULTS: There were significant gene-diet interactions between rs17782313 and HEI-2015 (P Interaction < 0.05) in modulating low-density lipoprotein cholesterol (LDL-C) levels among female group; rare allele heterozygotes of rs17782313 had highest mean of LDL-C concentration when placed in second tertile of HEI (P < 0.05). Moreover, rs17782313 and both indices (HEI and DQI-I) had significant interaction on serum glucose concentrations, systolic and diastolic blood pressure (SBP, DBP) in males (P Interaction < 0.05); when adherence to these indices was low, the obesity risk allele was associated with serum glucose concentrations, SBP and DBP. These gene-diet interactions remained significant even after adjustment for potential confounders. CONCLUSION: Our study showed that MC4R rs17782313 interacts with adherence to the dietary quality indices (HEI and DQI-I) to influence several cardio-metabolic risk factors in obese male and females. Further large prospective studies are warranted to confirm our findings.

The interaction between dietary Non-Enzymatic Antioxidant Capacity (NEAC) with variants of Melanocortin-4 receptor (MC4R) 18q21.23-rs17782313 locus on hypothalamic hormones and cardio-metabolic risk factors in obese individuals from Iran.

Background: In the current study, we aimed to evaluate the interaction between dietary Non-Enzymatic Antioxidant Capacity (NEAC) and rs17782313 polymorphism on hypothalamic hormones and cardio-metabolic risk factors. Methods: A total of 287 subjects (aged 20-50 years, 147 males and 140 females) enrolled in the cross-sectional study. Dietary NEAC was assessed using databases of NEAC measurements compiled from outcomes for three different analyses: oxygen radical absorbance capacity (ORAC), ferric reducing-antioxidant power (FRAP), and total radical-trapping antioxidant parameter (TRAP) and genotyping for the near MC4R rs17782313 was carried out by Polymerase chain reaction-restriction fragments length polymorphism (PCR-RFLP) method. Results: The significant interactions were found between adherence to the dietary NEAC and MC4R rs17782313 in relation to high-density lipoprotein-cholesterol (HDL-C), glucose, α-melanocyte stimulating hormone (α-MSH), insulin and quantitative insulin sensitivity check index (QUICKI) (P Interaction = 0.03, 0.01, 0.04, 0.04 and 0.04, respectively). In homozygous subjects for the minor allele, the serum insulin level and QUICKI in participants with the highest adherence to TRAP were significantly higher than those with the lowest adherence (p < 0.001). There was a significant inverse association between high ORAC score and risk of metabolic syndrome even after adjusting for potential confounders (OR: 0.33; 95%CI:0.13-0.81) and also a significant inverse association between high NEAC (ORAC, FRAP and TRAP assays) score and high triglyceride (TG) level was found in obese adults. Conclusion: In conclusion, our study found for the first time that the NEAC significantly interacts with the rs17782313 genotypes to influence several metabolic risk factors in obesity.

Exosomes: from carcinogenesis and metastasis to diagnosis and treatment of gastric cancer.

Exosomes represent an important group of extracellular vesicles with a defined size between 40 and 150 nm and cup-shaped construction which have a pivotal role in elimination of intracellular debris and intercellular signaling networks. A line of evidence revealed the impact of different types of exosomes in initiation, progression, and metastasis of gastric cancer (GC). These bioactive vesicles mediate tumor and stromal communication network through modulation of cell signaling for carcinogenesis and pre-metastatic niche formation in distant organs. Exosomes contain various cargos including DNAs (mitochondrial and genomic), proteins, transposable elements, and RNAs (coding and noncoding) with different compositions related to functional status of origin cells. In this review, we summarize the main roles of key exosomal cargos in induction of exosome-mediated signaling in cancer cells. Body fluids are employed frequently as the source of exosomes released by tumor cells with a potential role in early diagnosis of GC and chemoresistance. These vesicles as non-toxic and non-immunogenic carriers are also found to be applied for novel drug delivery systems.

Dietary patterns interact with the variations of 18q21.23 rs17782313 locus on regulation of hypothalamic-pituitary axis hormones and cardio-metabolic risk factors in obesity.

BACKGROUND: Evidence shows the role of polymorphisms in rs17782313 MC4R gene with increased risk of obesity in Asians adult. In the current report, we investigated the interaction between rs17782313 MC4R gene and major dietary patterns on α-melanocyte stimulating hormone (α-MSH), Agouti-related peptide (AgRP), serum lipids and blood pressure among obese individuals. METHODS: This cross-sectional study was performed in 288 obese adults between 20 and 50 years of age. Anthropometric measurements and biochemical assays were conducted with standard methods. To evaluate appetite, the Visual Analogue Scale (VAS) was used. Dietary patterns were obtained by principal component analysis (PCA). Genotyping of rs17782313 was assessed by restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: Three major dietary patterns were extracted: Prudent Dietary Pattern (PDP), Legume Dietary Pattern (LDP) and Mixed Dietary Pattern (MDP). Higher PDP score was associated with reduced SBP and insulin concentration while highest MDP score was associated with lower TG concentration (P < 0.05). Significant interactions were observed between higher adherence to PDP and rs17782313 CC genotype on increased SBP (PInteraction = 0.04), serum insulin (PInteraction = 0.05) and AgRP (PInteraction = 0.03) and also between higher adherence to MDP and CC genotype of rs17782313 on reduced serum TG (P = 0.03). CONCLUSIONS: The findings of the current study showed that being on CC genotype of rs17782313 polymorphism made obese individuals more prone to have higher SBP, insulin and AgRP even in highest adherence to PDP. However, adherence to MDP could attenuate the risky effects of being on CC genotype of rs17782313 by reducing serum TG concentrations. LEVEL OF EVIDENCE: Level V, cross-sectional descriptive study.

Survivin modulatory role in autoimmune and autoinflammatory diseases.

Baculoviral IAP repeat containing 5 (BIRC5) gene encodes the important protein as survivin, a multifunctional protein, which is involved in cellular and molecular networks, progression of cell cycle, homeostasis, developmental morphogenesis, and apoptosis. The proximal BIRC5 promoter possesses specific binding sites for key transcription factors such as nuclear factor κB and signal transducer and activator of transcription 3. Upregulation of survivin exacerbates the autoimmune diseases (AIDs) including multiple sclerosis and myasthenia gravis by reducing the activity threshold of survivin-specific cytotoxic T cells. DNA damage along with upregulation or downregulation of survivin have been demonstrated in initiation and pathogenesis of cancers and AIDs. However, detailed mechanism of survivin function in pathogenesis of AIDs is not well understood. This review focuses on the structure, specificity, regulation, and function of survivin in physiologic conditions and pathogenesis of AIDs.

Tumor-derived exosomes: Implication in angiogenesis and antiangiogenesis cancer therapy.

Tumor cells utilize different strategies to communicate with neighboring tissues for facilitating tumor progression and invasion, one of these strategies has been shown to be the release of exosomes. Exosomes are small nanovesicles secreted by all kind of cells in the body, especially cancer cells, and mediate cell to cell communications. Exosomes play an important role in cancer invasiveness by harboring various cargoes that could accelerate angiogenesis. Here first, we will present an overview of exosomes, their biology, and their function in the body. Then, we will focus on exosomes derived from tumor cells as tumor angiogenesis mediators with a particular emphasis on the underlying mechanisms in various cancer origins. Also, exosomes derived from stem cells and tumor-associated macrophages will be discussed in this regard. Finally, we will discuss the novel therapeutic strategies of exosomes as drug delivery vehicles against angiogenesis.