Effects of oleoylethanolamide supplementation on the expression of lipid metabolism-related genes and serum NRG4 levels in patients with non-alcoholic fatty liver disease: A randomized controlled trial.

BACKGROUND: This study investigated the effects of oleoylethanolamide (OEA) supplementation on the expression levels of SIRT1, AMPK, PGC-1α, PPAR-γ, CEBP-α and CEBP-ß genes and serum neuregulin 4 (NRG4) levels in patients with non-alcoholic fatty liver diseases (NAFLD). METHODS: Sixty obese patients with NAFLD were equally allocated into either OEA or placebo group for 12 weeks. The mRNA expression levels of genes were determined using the reverse transcription polymerase chain reaction (RT-PCR) technique. Serum NRG4 level was also assessed using an enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: At the endpoint, mRNA expression levels of SIRT1(p = 0.001), PGC-1α (p = 0.011) and AMPK (p = 0.019) were significantly higher in the OEA group compared to placebo group. However, no significant differences were observed in the expression levels of PPAR-γ, CEBP-α and CEBP-ß between the two groups. Serum NRG4 levels significantly increased in the OEA group compared with the placebo group after controlling for confounders (p = 0.027). In the OEA group, significant relationships were found between percent of changes in the expression levels of the SIRT1, AMPK and PGC-1α as well as serum NRG4 level with percent of changes in some anthropometric measures. Moreover, in the intervention group, percent of changes in high-density lipoprotein cholesterol was positively correlated with percent of changes in the expression levels of the SIRT1 and AMPK. While, percent of changes in triglyceride was inversely correlated with percent of changes in the expression levels of SIRT1. CONCLUSION: OEA could beneficially affect expression levels of some lipid metabolism-related genes and serum NRG4 level. "REGISTERED UNDER IRANIAN REGISTRY OF CLINICAL TRIALS IDENTIFIER NO: IRCT20090609002017N32".

Human cardiac organoids: A recent revolution in disease modeling and regenerative medicine.

Three-dimensional (3D) myocardial tissues for studying human heart biology, physiology and pharmacology have recently received lots of attention. Organoids as 3D mini-organs are created from multiple cell types (i.e. induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESCs)) with other supporting co-cultured cells such as endothelial cells or fibroblasts. Cardiac organoid culture technologies are bringing about significant advances in organ research and allows for the establishment of tissue regeneration and disease modeling. The present review provides an overview of the recent advances in human cardiac organoid platforms in disease biology and for cardiovascular regenerative medicine.

Implantable smart hyperthermia nanofibers for cancer therapy: Challenges and opportunities.

Nanofibers (NFs) with practical drug-loading capacities, high stability, and controllable release have caught the attention of investigators due to their potential applications in on-demand drug delivery devices. Developing novel and efficient multidisciplinary management of locoregional cancer treatment through the design of smart NF-based systems integrated with combined chemotherapy and hyperthermia could provide stronger therapeutic advantages. On the other hand, implanting directly at the tumor area is a remarkable benefit of hyperthermia NF-based drug delivery approaches. Hence, implantable smart hyperthermia NFs might be very hopeful for tumor treatment in the future and provide new avenues for developing highly efficient localized drug delivery systems. Indeed, features of the smart NFs lead to the construction of a reversibly flexible nanostructure that enables hyperthermia and facile switchable release of antitumor agents to eradicate cancer cells. Accordingly, this study covers recent updates on applications of implantable smart hyperthermia NFs regarding their current scope and future outlook. This article is categorized under: Implantable Materials and Surgical Technologies > Nanomaterials and Implants.

The Roles of Signaling Pathways in Cardiac Regeneration.

In recent years, knowledge of cardiac regeneration mechanisms has dramatically expanded. Regeneration can replace lost parts of organs, common among animal species. The heart is commonly considered an organ with terminal development, which has no reparability potential during post-natal life. However, some intrinsic regeneration capacity has been reported for cardiac muscle, which opens novel avenues in cardiovascular disease treatment. Different endogenous mechanisms have been studied for cardiac repairing and regeneration in recent decades. Survival, proliferation, inflammation, angiogenesis, cell-cell communication, cardiomyogenesis, and anti-aging pathways are the most important mechanisms that have been studied in this regard. Several in vitro and animal model studies focused on proliferation induction for cardiac regeneration reported promising results. These studies have mainly focused on promoting proliferation signaling pathways and demonstrated various signaling pathways such as Wnt, PI3K/Akt, IGF- 1, TGF-ß, Hippo, and VEGF signaling cardiac regeneration. Therefore, in this review, we intend to discuss the connection between different critical signaling pathways in cardiac repair and regeneration.

MiR-622 acts as a tumor suppressor to induce cell apoptosis and inhibit metastasis in human prostate cancer.

Growing evidence indicating the critical modulator roles of microRNAs (miRNAs) involved in prostate cancer (PCa) metastasis that holds great promise as therapeutic targets. Herein, we transfected the miR-622 mimic into PC3 cells and evaluated the effects of this interference on these tumour cells' growth and the expression of specific metastatic genes. Transfecting of miR-622 mimic and inhibitor, negative control (NC) inhibitor and NC was established using Lipofectamine 2000. The mRNA levels of miR-622 and metastatic genes were evaluated using the qRT-PCR and Western blot. Cytotoxic effects of miR-622 were assessed by MTT. Apoptosis was detected using an ELISA cell death assay kit. miR-622 is down-regulated in PC3 cells. As expected, cell viability effects after transfection were described as miR-622 inhibitor >NC and NC inhibitor >miR-622 mimic (p < .01). Importantly, we showed that transfected miR-622 mimic could enhance the apoptosis of PC3 cells, while transfected miR-622 inhibitor could decrease cell apoptosis (p < .01). Furthermore, miR-622 overexpression could increase significantly down-regulated the MMP2, MMP9, CXCR-4, c-Myc and K-Ras expression levels. Findings demonstrate a novel mechanism by which miR-622 modulates PCa cells' metastasis by targeting metastatic genes. These data confirm the tumour-suppressive function of miR-622 in PCa cells by enhancing apoptosis and reducing metastasis.

Will stem cells from fat and growth factors from blood bring new hope to female patients with reproductive disorders?

Female reproductive system disorders (FRSD) with or without infertility are prevalent women's health problems with a variety of treatment approaches including surgery and hormone therapy. It currently considering to sub-branch of regenerative medicine including stem cells or growth factors injection-based delivery treatment might be improved female reproductive health life. The most common products used for these patients treatment are autologous cell or platelet-based products from patients, including platelet-rich plasma, plasma rich in growth factor, platelet-rich fibrin, and stromal vascular fraction. In this review, we discuss each of the above products used in treatment of FRSD and critically evaluate the clinical outcome.

Steroid-depleted endometriosis serum improves oocyte maturation in IVM systems.

In vitro maturation (IVM) is a novel approach to overcome the adverse effects of human in vitro fertilization (IVF). The aim of the present study is to evaluate the effect of total and steroid-depleted serum obtained from patients with endometriosis on IVM outcome as supplementation for this system. To this purpose, patients with endometriosis were selected according to in/excluding criteria. Germinal vesicles (GVs) and cumulus cells were treated with 10% of each serum. The expression levels of stearoyl CoA desaturase 1 (SCD 1) and cyclooxygenase-2 (COX-2) genes were evaluated by RT-qPCR. Gas-liquid chromatography and flow cytometry were performed to analyze fatty acids composition and apoptosis. The mRNA expression levels of SCD1 (2.47 fold) and COX-2 (6.4 fold), and also the synthesis of oleate, linoleate, and arachidonate were increased (1.19, 1.06, and 2.37 folds, respectively) in cumulus cells treated with steroid-depleted serum (p < .05). The synthesis of palmitate, palmitoleate, and stearate (0.995, 0.67, and 0.7 folds, respectively) and also the rate of apoptosis were significantly decreased in these cells (p < .05). Moreover, GVs cultured in steroid-depleted group showed a significantly higher rate of maturation (p < .001). Overall, our findings imply a new insight into the expansion of IVM system in oocytes development.

Role of Butyrate, a Gut Microbiota Derived Metabolite, in Cardiovascular Diseases: A comprehensive narrative review.

Cardiovascular diseases (CVD) are major causes of death worldwide. Recently, new roles for intestinal microbiota in pathology and treatment of CVD have been proposed. Butyrate, a bacterial metabolite, is synthesized in the gut and performs most of its functions in there. However, researchers have discovered that butyrate could enter to portal vein and interact with various organs. Butyrate exhibits a broad range of pharmacological activities, including microbiome modulator, anti-inflammatory, anti-obesity, metabolic pathways regulator, anti-angiogenesis, and antioxidant. In this article we review evidence supporting a potentially therapeutic role for butyrate in CVD and the mechanisms and pathways involved in the cardio-protective effects of butyrate from the gut and circulation to the nervous system. In summary, although butyrate exhibits a wide variety of biological activities in different pathways including energy homeostasis, glucose and lipid metabolism, inflammation, oxidative stress, neural signaling, and epigenetic modulation in experimental settings, it remains unclear whether these findings are clinically relevant and whether the molecular pathways are activated by butyrate in humans.

Effects of saffron supplementation on glycemia and inflammation in patients with type 2 diabetes mellitus: A randomized double-blind, placebo-controlled clinical trial study.

BACKGROUND: New evidence indicates that overproduction of pro-inflammatory cytokines is responsible for the development of diabetes difficulties. Some herbals such as saffron, may control inflammation and improve the hyperglycemic states in diabetic patients. Therefore, this investigation aimed to assess the effects of saffron supplementation on fasting glucose and inflammatory markers levels in patients with type2 diabetes mellitus (T2DM). METHODS: In this randomized double-blind, placebo-controlled clinical trial, 60 T2DM patients were randomly assigned into two groups as saffron and placebo (n = 30) receiving 100 mg/day saffron powder or starch capsules (1 capsule) for a duration of 8 weeks. Fasting blood sample was collected at baseline and at the end of the intervention. Fasting blood glucose (FBG) was immediately analyzed by the auto-analyzer. The serum level of Interleukin -6 (IL-6), Tumor necrosis factor-alpha (TNF-α), and Interleukin-10 (IL-10) were measured using ELISA assay by laboratory kits. Also, Real-time quantitative reverse transcription (RT-PCR) assay measured the expression level of TNF-α, IL-6, and IL-10 at the mRNA level. RESULTS: Saffron supplementation significantly decreased the FBG levels within 8 weeks compared to placebo (130.93 ± 21.21 vs 135.13 ± 23.03 mg/dl, P = 0.012). Moreover, the serum level of TNF-α notably reduced in the saffron group compared to the placebo group (114.40 ± 24.28 vs 140.90 ± 25.49 pg/ml, P < 0.001). Also, saffron supplementation significantly down-regulated the expressions of TNF-α (P = 0.035) and IL-6 mRNA levels (P = 0.014). CONCLUSION: In our study, it was indicated that saffron modulates glucose levels as well as inflammation status in T2DM patients through decreasing the expressions levels of some inflammatory mediators. Also, further investigations are necessary to confirm the positive effects of saffron as a complementary therapy for T2DM patients.

Effects of oral butyrate and inulin supplementation on inflammation-induced pyroptosis pathway in type 2 diabetes: A randomized, double-blind, placebo-controlled trial.

PURPOSE: Pyroptosis, a form of inflammatory programmed cell death, is activated in diabetic patients. This study was conducted to investigate the effects of daily consumption of sodium butyrate (NaBut) and high-performance (HP) inulin supplementation, individually or in combination, on the expression of pyroptosis-related genes, microRNA (miR) 146a-5p, miR-9-5p and biomarkers of oxidative stress in patients with type 2 diabetes (T2DM). METHODS: In this study, we conducted a randomized, double-blinded, placebo-controlled clinical involving sixty patients with type 2 diabetes. Participants received 600 mg/d of NaBut (group A), 10 g/d of HP inulin (group B), 600 mg/d of NaBut + 10 g/d of HP inulin (group C) or placebo (group D) for 45 consecutive days. We assessed the pyroptosis-related genes mRNA expression in peripheral blood mononuclear cells (PBMCs), as well as the plasmatic levels of miR-146a and miR-9 before and after the intervention. Moreover, blood samples of the patients at baseline and following the intervention were tested for total antioxidant capacity (TAC), superoxide dismutase (SOD) and catalase levels using enzyme-linked immunosorbent assay (ELISA). This study was registered on the Iranian Registry of Clinical Trials website (identifier: IRCT201605262017N29; https://www.irct.ir/). RESULTS: Following butyrate supplementation, the relative expression levels of TLR2/4, NF-κB1, Caspase-1, NLRP3, IL-1ß & IL-18 were significantly downregulated (p < 0.05). Furthermore, butyrate and concomitant use of butyrate and inulin caused a significant increase in the fold change of miR-146a and miR-9 compared with the placebo group (p < 0.05). Interestingly, the changes in total antioxidant capacity (p = 0.047) and superoxide dismutase (p = 0.006) were significantly increased after butyrate and concomitant use of butyrate and inulin supplement, respectively. CONCLUSION: In summary, the change in expression level of miR-146a-5p and miR-9-5p due to butyrate supplementation may have a pivotal role in alleviating of diabetes via inhibiting pyroptosis by targeting TLR2 and NF-κB1. These microRNAs might be considered as potential therapeutic targets in the treatment of type 2 diabetes but further researches is required to prove the link.

MicroRNAs in cancer cell death pathways: Apoptosis and necroptosis.

To protect tissues and the organism from disease, potentially harmful cells are removed through programmed cell death processes, including apoptosis and necroptosis. These types of cell death are critically controlled by microRNAs (miRNAs). MiRNAs are short RNA molecules that target and inhibit expression of many cellular regulators, including those controlling programmed cell death via the intrinsic (Bcl-2 and Mcl-1), extrinsic (TRAIL and Fas), p53-and endoplasmic reticulum (ER) stress-induced apoptotic pathways, as well as the necroptosis cell death pathway. In this review, we discuss the current knowledge of apoptosis and necroptosis pathways and how these are impaired in cancer cells. We focus on how miRNAs disrupt apoptosis and necroptosis, thereby critically contributing to malignancy. Understanding which and how miRNAs and their targets affect cell death pathways could open up novel therapeutic opportunities for cancer patients. Indeed, restoration of pro-apoptotic tumor suppressor miRNAs (apoptomiRs) or inhibition of oncogenic miRNAs (oncomiRs) represent strategies that are currently being trialed or are already applied as miRNA-based cancer therapies. Therefore, better understanding the cancer type-specific expression of apoptomiRs and oncomiRs and their underlying mechanisms in cell death pathways will not only advance our knowledge, but also continue to provide new opportunities to treat cancer.

Evaluation of ovarian cancer risk in granulosa cells treated with steroid-depleted endometriosis serum: Role of NF-κB/RelA and AKT.

BACKGROUND: Despite at the beginning known as a benign disease, endometriosis is defined as a risk factor for developing ovarian carcinoma. The effect of endometriosis on ovarian malignancy is known but its role in granulosa cell tumor is still unclear. METHODS AND MATERIALS: In this study, serum samples were collected from patients with endometriosis and divided into whole and steroid-depleted groups. Desertification was performed according to the charcoal-dextran protocol and sera were added to the culture media of granulosa cells retrieved from tubal or male factor infertile women. Quantitative real-time polymerase chain reaction and flow cytometry were performed to determine the expression level of inflammatory and apoptotic genes and apoptosis level of granulosa cells. The total concentration of lipid was measured using gas chromatography method in the granulosa cells. RESULTS: Results revealed that the expression of AKT and NF-κB/RelA gene was significantly higher in the granulosa cells treated with steroid-depleted serum obtained from patients with distrificated endometriosis (DE) compared with the control group (9.39- and 7.9-folds, respectively; p < 0.0001). In the DE group, the declined pattern of expression was observed for the genes related to apoptosis. The synthesis of saturated fatty acids was significantly decreased; however, unsaturated fatty acids showed increased levels in the DE group. CONCLUSION: The effect of steroids on endometriosis is contradictory. The level of cortisol and sex hormones could be affected by endometriosis, causing alterations of the disease progression. Reduced level of steroid hormones in patients with endometriosis may be considered as a critical risk factor for granulosa cell tumor.

Endometriosis: Perspective, lights, and shadows of etiology.

Endometriosis refers to the growth of ectopic endometrial tissue outside the uterine cavity. About 10-15% of female in reproductive age suffer from endometriosis. Several etiologies - such as oxidative stress, inflammatory factors and cytokines, genetic etiology, and hormone role - have been reported for endometriosis. Indeed, oxidative stress leads to abnormalities by the production of ROS and RNS. The mechanism of endometriosis genesis is a complicated process that concerns the alterations in cellular immunity. Also, endometriosis is a hormonal response that illustrates stimulation in steroid hormone production. Genetic polymolymorphisms and epigenetic factors are also important in endometriosis initiation and progression. This review paper presents the role of oxidative stress, reactive oxygen species (ROS), and antioxidants and inflammatory, genetic, and epigenetic factors involved in the initiation and progression of the endometriosis.

Steroid-depleted polycystic ovarian syndrome serum promotes in vitro oocyte maturation and embryo development.

In vitro maturation (IVM) of immature oocytes obtained from patients with polycystic ovarian syndrome (PCOS) is considered as a novel strategy in order to reduce clinical side effects and cost of in vitro fertilization (IVF) technique. The aim of this study was to evaluate the effects of PCOS whole and steroid-depleted serums on in vitro oocyte maturation indices. Patients with PCOS were selected according to the Rotterdam criteria. Cumulus-oocyte complexes and blood serums were collected and pooled. Cumulus cells and immature oocytes were treated with 10% whole or steroid-depleted serums. Stearoyl-CoA desaturase-1 (SCD1) and cyclooxygenase-2 (COX2) expression levels in cumulus cells were evaluated by quantitative PCR. Fatty acid composition of cumulus cells was analyzed using gas-liquid chromatography. Polar body observation was considered as the oocyte maturation index. Oleate (1.28-fold, p = .006), SCD1 expression (450-fold, p = .001), and COX2 expression (35-fold, p = .02) in cumulus cell, as well as oocyte maturation (p < .001) and in vitro embryo development (p < .05) were significantly higher in treatment with steroid-depleted serum compared to that of whole serum. Steroid depletion of PCOS serum improved its capacity to increase success rate of oocyte maturation, intra-cytoplasmic sperm injection and early embryo development.