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Bone marrow-derived mesenchymal stem cells (BM-MSCs) have demonstrated potential in treating diabetic cardiomyopathy. However, patients with diabetes are on multiple drugs and there is a lack of understanding of how transplanted stem cells would respond in presence of such drugs. Metformin is an AMP kinase (AMPK) activator, the widest used antidiabetic drug. In this study, we investigated the effect of metformin on the efficacy of stem cell therapy in a diabetic cardiomyopathy animal model using streptozotocin (STZ) in male Wistar rats. To comprehend the effect of metformin on the efficacy of BM-MSCs, we transplanted BM-MSCs (1 million cells/rat) with or without metformin. Our data demonstrate that transplantation of BM-MSCs prevented cardiac fibrosis and promoted angiogenesis in diabetic hearts. However, metformin supplementation downregulated BM-MSC-mediated cardioprotection. Interestingly, both BM-MSCs and metformin treatment individually improved cardiac function with no synergistic effect of metformin supplementation along with BM-MSCs. Investigating the mechanisms of loss of efficacy of BM-MSCs in the presence of metformin, we found that metformin treatment impairs homing of implanted BM-MSCs in the heart and leads to poor survival of transplanted cells. Furthermore, our data demonstrate that metformin-mediated activation of AMPK is responsible for poor homing and survival of BM-MSCs in the diabetic heart. Hence, the current study confirms that a conflict arises between metformin and BM-MSCs for treating diabetic cardiomyopathy. Approximately 10% of the world population is diabetic to which metformin is prescribed very commonly. Hence, future cell replacement therapies in combination with AMPK inhibitors may be more effective for patients with diabetes.NEW & NOTEWORTHY Metformin treatment reduces the efficacy of mesenchymal stem cell therapy for cardiac repair during diabetic cardiomyopathy. Stem cell therapy in diabetics may be more effective in combination with AMPK inhibitors.

Allogeneic mesenchymal stem cells (MSCs) from young and healthy donors are immunoprivileged and have the potential to treat numerous degenerative diseases. However, recent reviews of clinical trials report poor long-term survival of transplanted cells in the recipient that turned down the enthusiasm regarding MSC therapies. Increasing evidence now confirm that though initially immunoprivileged, MSCs eventually become immunogenic after transplantation in the ischemic or hypoxic environment of diseased tissues and are rejected by the host immune system. We performed in vitro (in rat and human cells) and in vivo (in a rat model) investigations to understand the mechanisms of the immune switch in the phenotype of MSCs. The immunoprivilege of MSCs is preserved by the absence of cell surface immune antigen, major histocompatibility complex II (MHC-II) molecule. We found that the ATPase subunit of 19S proteasome "Sug1" regulates MHC-II biosynthesis in MSCs. Exposure to hypoxia upregulates Sug1 in MSCs and its binding to class II transactivator (CIITA), a coactivator of MHC-II transcription. Sug1 binding to CIITA in hypoxic MSCs promotes the acetylation and K63 ubiquitination of CIITA leading to its activation and translocation to the nucleus, and ultimately MHC-II upregulation. In both rat and human MSCs, knocking down Sug1 inactivated MHC-II and preserved immunoprivilege even following hypoxia. In a rat model of myocardial infarction, transplantation of Sug1-knockdown MSCs in ischemic heart preserved immunoprivilege and improved the survival of transplanted cells. Therefore, the current study provides novel mechanisms of post-transplantation loss of immunoprivilege of MSCs. This study may help in facilitating better planning for future clinical trials.

Objective: We aimed to investigate the association between university students' dietary patterns, their demographics and lifestyle in a cross-sectional study in Qatar. Participants: 370 students in eight universities in Qatar enrolled between February 2017 and February 2018. Methods: Based on a structured questionnaire, dietary patterns were identified using principal component analysis, and their associations with student characteristics were assessed using logistic regression. Results: Four dietary patterns were identified. The 'fast food' pattern was associated with being younger and male (p-values ≤ 0.1). The 'traditional diet' pattern was associated with not skipping meals or eating when bored (p-values = 0.1). The 'healthy diet' pattern was associated with regular exercise and having time to eat healthy foods (p-values ≤ 0.01). The 'protein shake' pattern was associated with being male and engaging in more vigorous physical activity (p-values ≤ 0.01). Conclusions: Our findings provide a roadmap for the prioritization of population-specific interventions in university students within Qatar and the region.

Background: Resveratrol (RSV) has a wide range of diabetic cardioprotective effects. It is currently recognized as a dietary supplement.Aim of Study: To investigate the impact of RSV on the molecular expression pattern of AMP-activated protein kinase (AMPK) and the glycogen synthase kinase-3(3 serine 9 (GSK-3(3S9) in diabetic cardiomyopathy.Methods: We investigated this point using three groups of Wistar albino rats; control group, diabetic cardiomyopathy rats (DCM) and diabetics treated with RSV (DM-RSV) for 20 weeks. Echocardiography was performed at base line, and every 4 weeks. At the end of the study, Ex-vivo assessment of myocardial contractility was performed. The molecular changes in the cardiac tissues were evaluated in all groups for assessment of the silent information regulator (SIRT1), GSK-3(3S9 and the AMPK levels. Histological assessment was done for all cardiac tissues. Apoptosis was assessed by measuring the modulation in the Bax/Bcl2 ratio and poly (ADP-ribose) polymerase-1 (PARP1) levels, trying to explore the RSV underlying mechanism of action.Results: Marked deterioration in the cardiac functions was detected in the diabetic non treated group. The decreased levels of SIRT1, AMPK and GSK-3(3S9 that was associated with increased apoptotic markers, may be the cause of dete-riorated cardiac functions. Assessment of the myocardial functions showed improvement in the diabetic RSV treated group. RSV aimed to normalize the hyperglycemic state and the disturbed molecular pattern associated with diabetes.Conclusion: Prolonged RSV administration protects the diabetic hearts. This could be explained by the interplay between SIRT1, AMPK and the GSK-3(3S9 levels.

ObjectiveTo describe the epidemiology of herpes simplex virus type 1 (HSV-1) in Europe.MethodsWe systematically reviewed HSV-1 related publications, conducted various meta-analyses and meta-regressions, assessed pooled mean seroprevalence, and estimated pooled mean proportions of HSV-1 viral detection in clinically diagnosed genital ulcer disease (GUD) and in genital herpes.ResultsWe extracted, from 142 relevant records, 179 overall (622 stratified) seroprevalence measures, 4 overall proportions of HSV-1 in GUD and 64 overall (162 stratified) proportions of HSV-1 in genital herpes. Pooled mean seroprevalence was 67.4% (95% CI 65.5% to 69.3%) with 32.5% (95% CI 29.4% to 35.7%) of children and 74.4% (95% CI 72.8% to 76.0%) of adults infected. Pooled seroprevalence increased steadily with age, being lowest in those aged 50 years (82.9%, 95% CI 78.8% to 86.6%). Pooled seroprevalence decreased yearly by 0.99-fold (95% CI 0.99 to 1.00). Pooled mean proportion of HSV-1 detection was 13.6% (95% CI 4.1% to 27.1%) in GUD, 34.1% (95% CI 31.7% to 36.5%) in genital herpes and 49.3% (95% CI 42.2% to 56.4%) in first episode genital herpes. Pooled proportion of HSV-1 detection in genital herpes increased yearly by 1.01-fold (95% CI 1.00 to 1.02), with higher detection in women (42.0%, 95% CI 37.4% to 46.7%) than men (24.1%, 95% CI 19.8% to 28.6%).ConclusionsHSV-1 epidemiology is transitioning away from its historical pattern of oral acquisition in childhood. Every year, seroprevalence is declining by 1% and the proportion of HSV-1 in genital herpes is increasing by 1%. As many as two-thirds of children are reaching sexual debut unexposed, and at risk of HSV-1 genital acquisition in adulthood.

Allogeneic mesenchymal stem cells (MSCs) from young and healthy donors are reported to hold the potential to treat several immunological and degenerative disorders. However, recent data from animal studies and clinical trials demonstrate that immunogenicity and poor survival of transplanted MSCs impaired the efficacy of cells for regenerative applications. It is reported that initially immunoprivileged under in vitro conditions, MSCs are targeted by the host immune system after transplantation in the ischemic tissues in vivo. We performed in vitro (in MSCs) and in vivo (in the rat model of myocardial infarction [MI]) studies to elucidate the mechanisms responsible for the change in the immunophenotype of MSCs from immunoprivileged to immunogenic under ischemic conditions. We have recently reported that a soluble factor prostaglandin E2 (PGE2) preserves the immunoprivilege of allogeneic MSCs. In the current study, we found that PGE2 levels, which were elevated during normoxia, decreased in MSCs following exposure to hypoxia. Further, we found that proteasome-mediated degradation of cyclooxygenase-2 (COX2, rate-limiting enzyme in PGE2 biosynthesis) in hypoxic MSCs is responsible for PGE2 decrease and loss of immunoprivilege of MSCs. While investigating the mechanisms of COX2 degradation in hypoxic MSCs, we found that in normoxic MSCs, COP9 signalosome subunit 5 (CSN5) binds to COX2 and prevents its degradation by the proteasome. However, exposure to hypoxia leads to a decrease in CSN5 levels and its binding to COX2, rendering COX2 protein susceptible to proteasome-mediated degradation. This subsequently causes PGE2 downregulation and loss of immunoprivilege of MSCs. Maintaining COX2 levels in MSCs preserves immunoprivilege in vitro and improves the survival of transplanted MSCs in a rat model of MI. These data provide novel mechanistic evidence that PGE2 is downregulated in hypoxic MSCs which is responsible for the post-transplantation rejection of allogeneic MSCs. Therefore, our data suggest that the new strategies that target CSN5-COX2 signaling may improve survival and utility of transplanted allogeneic MSCs in the ischemic heart.

Wnt/β-catenin signaling pathway plays a crucial role in diabetic cardiomyopathy (DCM), thus we aimed at investigating the effect of one therapeutic approach with resveratrol (RSV) given systemically and combined treatment of RSV with mesenchymal stem cells (MSCs) that was either RSV-preconditioned or not on Wnt/β-catenin signaling pathway in streptozotocin-induced DCM, and to evaluate effects of RSV preconditioning on MSCs therapeutic potential. The rats were divided into control (C, n = 8), diabetic (DM, n = 8), diabetic treated with systemic RSV (DM-RSV, n = 8), diabetic treated with RSV and nonconditioned MSCs (DM-RSV-MSCs, n = 8), diabetic treated with RSV and RSV-incubated with MSCs (DM-RSV-MSCc, n = 8) and diabetic treated with RSV-conditioned MSCs (DM-MSCc, n = 8). Echocardiography (Echo) showed significant improvement of cardiac functions in all groups treated with RSV either systemic or added in culture media. Data of ejection fraction (EF%) of DM-RSV-MSCc (81.50; interquartile range [IQR], 80.00-83.00) was comparable to both DM-RSV-MSCs (77.50; IQR, 71.50-79.00), and DM-MSCc (71.50; IQR, 70.00-74.50). Histological examination of the left ventricles was performed for all groups. DM group revealed significant myocardial hypertrophy, apoptosis, interstitial fibrosis, and microvascular affection. All treated groups were associated, in variable degrees, with attenuation of cardiac hypertrophy and fibrosis, decreased area% for cardiac immunostaining of secreted frizzled-related protein (sFRP2) and Wnt/β-catenin and improvement of the microvasculature. In conclusion, MSCs pretreated with resveratrol for 7 days showed increased 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and combined use of RSV (systemically and in culture media) significantly could improve cardiac remodeling capacity of MSCs via attenuation of sFRP2-mediated fibrosis and the downstream Wnt/β-catenin pathway.

Resveratrol (RSV), a polyphenolic compound and naturally occurring phytoalexin, has been reported to exert cardio-protective effects in several animal studies. However, the outcome of initial clinical trials with RSV was less effective compared to pre-clinical studies. Therefore, RSV treatment protocols need to be optimized. In this study we evaluated prophylactic versus therapeutic effect of resveratrol (RSV) in mitigating doxorubicin (Dox)-induced cardiac toxicity in rats. To investigate prophylactic effects, RSV was supplemented for 2 weeks along with Dox administration. After 2 weeks, Dox treatment was stopped and RSV was continued for another 4 weeks. To study therapeutic effects, RSV treatment was initiated after 2 weeks of Dox administration and continued for 4 weeks. Both prophylactic and therapeutic use of RSV mitigated Dox induced deterioration of cardiac function as assessed by echocardiography. Also RSV treatment (prophylactic and therapeutic) prevented Dox induced myocardial damage as measured by cardiac enzymes (LDH and CK-MB) in serum. Which was associated with decrease in Dox induced myocardial apoptosis and fibrosis. Interestingly our study also reveals that prophylactic use of RSV was more effective than its therapeutic use in mitigating Dox induced apoptosis and fibrosis in the myocardium. Therefore, prophylactic use of resveratrol may be projected as a possible future adjuvant therapy to minimize cardiotoxic side effects of doxorubicin in cancer patients.

The role of vascular endothelial growth factor (VEGF) and erythropoietin (EPO) in mediating hypoxic preconditioning under the acute intermittent hypoxic condition (AIH) was investigated in this study. Male Wistar rats were randomly assigned and kept in normoxic conditions, (Nx) or in AIH conditions and subjected to brief cycles hypoxia/reoxygenation. Hearts were isolated, perfused, and subjected to in vitro global ischemia followed by reperfusion. During and at the end of reperfusion, left ventricular developed pressure (LVDP); LV end diastolic pressure (LVEDP); rate pressure product (RPP); peak left ventricular pressure rise (ΔP/Δt max ) and heart rate (HR) were measured. Hearts subjected to AIH displayed a significant higher LVDP (P < .001), RPP (P < .001), and ΔP/Δt max (P < .001). Expression of VEGF and EPO were significantly increased at 3, 8, and 24 hours after AIH. Hypoxic training could provide a new approach to enhance endogenous cardioprotective mechanisms.

Introduction Doxorubicin (DOX) is a well-known anticancer drug. However its clinical use has been limited due to cardiotoxic effects. One of the major concerns with DOX therapy is its toxicity in patients who are frail, particularly diabetics. Several studies suggest that mesenchymal stem cells (MSCs) have the potential to restore cardiac function after DOX-induced injury. However, limited data are available on the effects of MSC therapy on DOX-induced cardiac dysfunction in diabetics. Our objective was to test the efficacy of bone marrow-derived (BM-MSCs) and adipose-derived MSCs (AT-MSCs) from age-matched humans in a non-immune compromised rat model. Methods Diabetes mellitus was induced in rats by streptozotocin injection (STZ, 65 mg/kg b.w, i.p.). Diabetic rats were treated with DOX (doxorubicin hydrochloride, 2.5 mg/kg b.w, i.p) 3 times/wk for 2 weeks (DOX group); or with DOX+ GFP labelled BM-MSCs (2x106cells, i.v.) or with DOX + GFP labelled AT-MSCs (2x106cells, i.v.). Echocardiography and Langendorff perfusion analyses were carried out to determine the heart function. Immunostaining and western blot analysis of the heart tissue was carried out for CD31 and to assess inflammation and fibrosis. Statistical analysis was carried out using SPSS and data are expressed as mean ± SD. Results Glucose levels in the STZ treated groups were significantly greater than control group. After 4 weeks of intravenous injection, the presence of injected MSCs in the heart was confirmed through fluorescent microscopy and real time PCR for ALU transcripts. Both BM-MSCs and AT-MSCs injection prevented DOX-induced deterioration of %FS, LVDP, dp/dt max and rate pressure product. Staining for CD31 showed a significant increase in the number of capillaries in BM-MSCs and AT-MSCs treated animals in comparison to DOX treated group. Assessment of the inflammation and fibrosis revealed a marked reduction in the DOX-induced increase in immune cell infiltration, collagen deposition and αSMA in the BM-MSCs and AT-MSCs groups. Conclusions In conclusion BM-MSCs and AT-MSCs were equally effective in mitigating DOX-induced cardiac damage by promoting angiogenesis, decreasing the infiltration of immune cells and collagen deposition.

Diabetes represents a serious risk factor for the development of cardiovascular problems such as coronary heart disease, peripheral arterial disease, hypertension, stroke, cardiomyopathy, nephropathy and retinopathy. Identifying the pathogenesis of this increased risk provides a basis for secondary intervention to reduce morbidity and mortality in diabetic patients. Hyperglycemia and protein glycation, increased inflammation, a prothrombotic state and endothelial dysfunction have all been implicated as possible mechanisms for such complications. A linking element between many of these phenomena could possibly be, among other factors, increased production of reactive oxygen species. Vascular endothelial cells have several physiological actions that are essential for the normal function of the cardiovascular system. These include the production of nitric oxide (NO), which regulates vasodilatation, anticoagulation, leukocyte adhesion, smooth muscle proliferation and the antioxidative capacity of endothelial cells. However, under conditions of hyperglycemia, excessive amounts of superoxide radicals are produced inside vascular cells and this can interfere with NO production leading to the possible complications. This article aims at reviewing the links between reactive oxygen species, diabetes and vascular disease and whether or not antioxidants can alter the course of vascular complications in diabetic patients and animal models. A possible beneficial effect of antioxidants might present a new addition to the range of secondary preventive measures used in diabetic patients.

Cardiovascular disease (CVD) is among the most major causes of morbidity and mortality worldwide. Great progress has been made in the management of CVD which has been influenced by the use of experimental animal models. These models provided information at cellular and molecular levels and allowed the development of treatment strategies. CVD models have been developed in many species, including large animals (e.g. pigs and dogs) and small animals (e.g. rats and mice). Although, no model can solely reproduce clinical HF, simulations of heart failure (HF) are available to experimentally tackle certain queries not easily resolved in humans. Induced HF may also be produced experimentally through myocardial infarction (MI), pressure loading, or volume loading. Volume loading is useful to look at hormone and electrolyte disturbances, while pressure loading models is helpful to study ventricular hypertrophy, cellular imbalance and vascular changes in HF. Coronary heart disease is assessed in MI animal models. In this review we describe various experimental models used to study the pathophysiology of HF.

The hormone erythropoietin (EPO) has been demonstrated to have cardioprotective properties. The present study investigates the role of EPO to prevent heart failure following cancer treatment with doxorubicin [adriamycin (AD)]. Male Wistar rats (150 ± 10 g) were treated with saline (vehicle control group); with EPO, subcutaneously at 1,000 IU/kg body wt, three times per week for 4 wk (EPO group); with adriamycin, intraperitoneally at 2.5 mg/kg body wt, three times per week for 2 wk (AD group); and with adriamycin and EPO (EPO-AD group). Echocardiographic measurements showed that EPO-AD treatment prevented the AD-induced decline in cardiac function. Each of the hearts was then exposed to ischemia and reperfusion during Langendorff perfusion. The percentage of recovery after ischemia-reperfusion was significantly greater in EPO-AD than the AD-treated group for left ventricular developed pressure, maximal increase in pressure, and rate pressure product. The level of oxidative stress was significantly higher in AD (5 μM for 24 h)-exposed isolated cardiomyocytes; EPO (5 U/ml for 48 h) treatment prevented this. EPO treatment also decreased AD-induced cardiomyocyte apoptosis, which was associated with the decrease in the Bax-to-Bcl2 ratio and caspase-3 activation. Immunostaining of myocardial tissue for CD31 showed a significant decrease in the number of capillaries in AD-treated animals. EPO-AD treatment restored the number of capillaries. In conclusion, EPO treatment effectively prevented AD-induced heart failure. The protective effect of EPO was associated with a decreased level of oxidative stress and apoptosis in cardiomyocytes as well as improved myocardial angiogenesis.