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Inflammasomes are large intracellular multi-protein signalling complexes that are formed in the cytosolic compartment as an inflammatory immune response to endogenous danger signals. The formation of the inflammasome enables activation of an inflammatory protease caspase-1, pyroptosis initiation with the subsequent cleaving of the pro-inflammatory cytokines interleukin (IL)-1β and proIL-18 to produce active forms. The inflammasome complex consists of a Nod-like receptor (NLR), the adapter apoptosis-associated speck-like (ASC) protein, and Caspase-1. Dysregulation of NLRP3 inflammasome activation is involved tumor pathogenesis, although its role in cancer development and progression remains controversial due to the inconsistent findings described. In this review, we summarize the current knowledge on the contribution of the NLRP3 inflammasome on potential cancer promotion and therapy.

Purpose: Endothelial dysfunction is a known comorbidity in women with polycystic ovary syndrome (PCOS). The aim was to assess if supervised, moderate intensity exercise could potentially impact markers of endothelial disruption; endothelial cell derived microparticles (EMP). Methods: The current study investigated the effects of a supervised 8-week moderate intensity exercise programme on EMP in women with PCOS (n = 11) and control women free from any known disease (n = 10). EMP were enumerated via specific antibody (CD105, CD106) labeling and flow cytometry. Results: CD105+MP significantly reduced in women with PCOS from pre to post-exercise programme, with CD105+ MP reducing from 2114 CD105+ MP per μl platelet free plasma (PFP) to 424 CD105+ MP per μl PFP (p = 0.025). Control women showed no significant change in CD105+ MP (p = 0.25) after completing the same exercise programme. CD106+ MP showed no change in either PCOS (p = 0.95) or control groups (p = 0.99). No significant correlations existed with the changes in EMP compared to body composition changes as a result of exercise. Conclusion: Supervised, moderate intensity exercise independent of substantial weight loss reduced circulating CD105+ MP, likely reflecting an improvement in endothelial function in women with PCOS compared to healthy control women. Additionally, EMP may be a useful marker for physical improvement in exercise programmes for clinical populations.

Objective: Soy and cocoa have been suggested to be beneficial for diabetes. The aim of this study was to identify the effects of soy protein, isoflavones, and cocoa on glycemic control parameters. Research design and methods: The study was a parallel, double-blind, placebo-controlled study where patients with diet or metformin controlled type 2 diabetes were randomized to, casein soy protein with or without isoflavones (SPI, SP), and with or without cocoa (SPIC, SPC) arms for an 8 week period. Glycemic control and cardiovascular risk factors were assessed prior to and after the completion of the dietary intervention. Sixty participants completed the study. Results: Soy protein improved HbA1c compared to casein (p < 0.05). The addition of isoflavones improved indices of insulin resistance and LDL [delta QUICKIE (SPI: −0.12 ± 0.04 vs. SP: 0.03 ± 0.06, p = 0.03); delta LDL (−0.27 ± 0.41 vs. 0.22 ± 0.43, p = 0.02); percentage change in HOMA (31.02 ± 54.75 vs. −14.42 ± 27.07, p = 0.02); percentage change in QUICKIE (−3.89 ± 7.07 vs. 6.11 ± 10.54, p = 0.01)]. However, the addition of cocoa provided no benefit with or without isoflavones. Summary: Soy protein had intrinsic activity on glycemic control compared to casein. Isoflavones improved both insulin resistance and LDL, but cocoa did not have added benefit on these indices. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01754662.

Aim: Strict glycaemic control has been associated with an increased mortality rate in subjects with type 2 diabetes (T2DM). Here we examined platelet function immediately and 24 hours following induced hypoglycaemia in people with type 2 diabetes compared to healthy age-matched controls. Methods: Hyperinsulinaemic clamps reduced blood glucose to 2.8 mmol/L (50 mg/dl) for 1 hour. Sampling at baseline; euglycaemia 5 mmol/L (90 mg/dl); hypoglycaemia; and at 24 post clamp were undertaken. Platelet function was measured by whole blood flow cytometry. Results: 10 subjects with T2DM and 8 controls were recruited. Platelets from people with T2DM showed reduced sensitivity to prostacyclin (PGI2, 1 nM) following hypoglycaemia. The ability of PGI2 to inhibit platelet activation was significantly impaired at 24 hours compared to baseline in the T2DM group. Here, inhibition of fibrinogen binding was 29.5% (10.3–43.8) compared to 50.8% (36.8–61.1), (P < 0.05), while inhibition of P-selectin expression was 32% (16.1–47.6) vs. 54.4% (42.5–67.5) (P < 0.05). No significant changes in platelet function were noted in controls. Conclusion: Induced hypoglycaemia in T2DM enhances platelet hyperactivity through impaired sensitivity to prostacyclin at 24 hours.

The endoplasmic reticulum (ER) is critical in protein processing and particularly in ensuring that proteins undergo their correct folding to exert their functionality. What is becoming increasingly clear is that the ER may undergo increasing stress brought about by nutrient deprivation, hypoxia, oxidized lipids, point mutations in secreted proteins, cellular differentiation or significant deviation from metabolic set points, and loss of Ca2+ homeostasis, with detrimental effects on ER-resident calcium-dependent chaperones, alone or in combination. This results in the unfolded protein response (UPR) that is a repair mechanism to limit the formation of newly damaged proteins until ER homeostasis is restored, though may result in increased cell death. ER stress has been shown to be implicated in a variety of diseases. Statins are well-known cholesterol-lowering drugs and have been extensively reported to possess beneficial cholesterol-independent effects in a variety of human diseases. This review focuses on the concept of ER stress, the underlying molecular mechanisms and their relationship to the pathophysiology and, finally, the role of statins in moderating ER stress and UPR.

Lifestyle modification is the cornerstone of diabetes prevention and treatment. Weight loss through caloric restriction (CR) is effective in improving glycemic control, though it is difficult for patients to follow in practice, and remains critical to achieve optimal glucose homeostasis. In this review, we look at what is known about the molecular pathways involved in CR-induced insulin sensitivity and improved insulin resistance.

Background: Plasma elevated levels of branched chain amino acids (BCAA) and aromatic amino acids (AAA) have been associated with obesity and insulin resistance, but their relationship to stimulated insulin resistance (IR) in PCOS and in response to exercise is unknown. Indeed, it is unknown whether the mechanism of IR in PCOS is mediated through changes in the metabolome.Methods: Twelve women with polycystic ovary syndrome (PCOS) and ten age and body mass index matched controls completed an 8 week supervised exercise program at 60% maximal oxygen consumption. Before and after the exercise program, all participants underwent maximal IR stimulation with intralipid infusions followed by insulin sensitivity (IS) measurement by hyperinsulinaemic euglycaemic clamps. Amino acid profiles and metabolites were taken at baseline and at maximal insulin resistance stimulation before and after the exercise program.Results: At baseline, PCOS subjects showed increased leucine/isoleucine, glutamate, methionine, ornithine, phenylalanine, tyrosine and proline (p < 0.05) that, following exercise, did not differ from controls. While compering within the groups, no significant changes in the amino acid levels before and after exercise were observed. Exercise improved VO2 max (p < 0.01) but did not alter weight. Amino acid profiles were unaffected by an acute increase in IR induced by the lipid infusion. IS was lower in PCOS (p < 0.001) and was further decreased by the lipid infusion in both PCOS and controls. Although, exercise improved IS in both PCOS and in controls, the IS remained compromised in PCOS.Conclusion: The baseline amino acid profile in PCOS reflected that seen in obese subjects and differed to controls. After exercise, and despite no change in weight in either group, there were no differences in the amino acid profile between PCOS and controls. This shows that exercise may normalize the amino acid metabolome, irrespective of weight.ISRCTN number: ISRCTN42448814

Objective The aim of this study was to develop a simple phenotypic algorithm that can capture the underlying clinical and hormonal abnormalities to help in the diagnosis and risk stratification of polycystic ovary syndrome (PCOS). Methods The study consisted of 111 women with PCOS fulfilling the Rotterdam diagnostic criteria and 67 women without PCOS. A Firth's penalized logistic regression model was used for independent variable section. Model optimism, discrimination and calibration were assessed using bootstrapping, area under the curve (AUC) and Hosmer‐Lemeshow statistics, respectively. The prognostic index (PI) and risk score for developing PCOS were calculated using independent variables from the regression model. Results Firth penalized logistic regression model with backward selection identified four independent predictors of PCOS namely free androgen index [β 0.30 (0.12), P = 0.008], 17‐OHP [β = 0.20 (0.01), P = 0.026], anti‐mullerian hormone [AMH; β = 0.04 (0.01) P < 0.0001] and waist circumference [β = 0.08 (0.02), P < 0.0001]. The model estimates indicated high internal validity (minimal optimism on 1000‐fold bootstrapping), good discrimination ability (bias corrected c‐statistic = 0.90) and good calibration (Hosmer‐Lemeshow χ2 = 3.7865). PCOS women with a high‐risk score (q1 + q2 + q3 vs q4) presented with a worse metabolic profile characterized by a higher 2‐hour glucose (P = 0.01), insulin (P = 0.0003), triglycerides (P = 0.0005), C‐reactive protein (P < 0.0001) and low HDL‐cholesterol (P = 0.02) as compared to those with lower risk score for PCOS. Conclusions We propose a simple four‐variable model, which captures the underlying clinical and hormonal abnormalities in PCOS and can be used for diagnosis and metabolic risk stratification in women with PCOS.

Objective This study aimed to explore the effects of ambient temperature and relative humidity on insulin pharmacodynamics in adults with type 1 diabetes. Research Design A 3‐way, cross‐over, randomised study was performed in adults with type 1 diabetes mellitus (n=10). The pharmacodynamics profile of a single dose of short‐acting insulin (insulin lispro) was investigated under three environmental conditions: i) temperature: 15°C and humidity: 10%, ii) temperature: 30°C and humidity: 10%, and iii) temperature: 30°C and humidity: 60%, controlled in an environmental chamber. Euglycaemic glucose clamp technique ensured a constant blood glucose of 100 mg/dl (5.5 mmol/l). The following pharmacodynamic endpoints were calculated: maximum glucose infusion rate (GIRmax), time to GIRmax (tGIRmax), total area under the curve (AUC) for GIR from 0‐6 hours (AUCGIR.0–6h), and partial AUCs (AUCGIR.0‐1h, AUCGIR.0‐2h and AUCGIR.2‐6h). Results Higher temperature (30oC) under 10% fixed humidity resulted in a greater GIRmax (p=0.04), a later tGIR.max (p=0.049) compared to lower temperature (15oC). Humidity did not affect any pharmacodynamic parameter. When the combined effects of temperature and humidity were explored, tGIR.max (p=0.008) occurred earlier with a lower late insulin pharmacodynamic effect (AUCGIR.2‐6h, p=0.017) at temperature 15oC and humidity 10% compared to temperature 30oC and humidity 60%. Conclusions High ambient temperature resulted in greater insulin peak effect compared to low ambient temperature, with the contribution of high relative humidity only apparent at high ambient temperature. This suggests that patients with type 1 diabetes mellitus entering higher environmental temperatures with or without high humidity could experience more hypoglycaemic events.

Deoxynivalenol (DON) is a Fusarium toxin, to which humans are frequently exposed via diet. Although the elderly are speculated to be sensitive to the toxic effects of DON as a result of age-related conditions, disease and altered DON metabolism, there is lack of available data on DON biomarkers in this age group. This study characterised urinary DON concentrations and its metabolites in elderly aged ≥65years (n = 20) residing in Hull, UK. Morning urinary specimens were collected over two consecutive days together with food records to assess dietary intake over a 24h-period prior to each urinary collection. Free DON (un-metabolised), total DON (sum of free DON and DON-glucuronides or DON-GlcA) and de-epoxy deoxynivalenol (DOM-1) were analysed using a validated LC-MS/MS methodology. Total DON above the limit of quantification 0.25 ng/mL was detected in the urine from 90% of elderly men and women on both days. Mean total DON concentrations on day 1 were not different from those on day 2 (elderly men, day 1: 22.2 ± 26.3 ng/mg creatinine (creat), day 2: 28.0 ± 34.4 ng/mg creat, p = 0.95; elderly women, day 1: 22.4 ± 14.6 ng/mg creat, day 2: 29.1 ± 22.8 ng/mg creat, p = 0.58). Free DON and DON-GlcA were detected in 60-70% and 90% of total urine samples, respectively. DOM-1 was absent from all samples; the LoQ for DOM-1 was 0.50 ng/mL. Estimated dietary intake of DON suggested that 10% of the elderly exceeded the maximum provisional tolerable daily intake for DON. In this single-site, UK-based cohort, elderly were frequently exposed to DON, although mean total DON concentrations were reported at moderate levels. Future larger studies are required to investigate DON exposure in elderly from different regions of the UK, but also from different counties worldwide.

Diabetes mellitus is the most prevalent metabolic disorder worldwide. Glycemic control is the main focus of antidiabetic therapy. However, there are data suggesting that some antidiabetic drugs may have intrinsic beneficial renal effects and protect against the development and progression of albuminuria, thus minimizing the risk of diabetic nephropathy. These pharmacological agents can suppress upstream molecular pathways involved in the pathophysiology of diabetes-induced renal dysfunction such as oxidative stress, inflammatory responses, and apoptosis. In this narrative review, the pathophysiology of albuminuria in patients with diabetic nephropathy is discussed. Furthermore, the renoprotective effects of antidiabetic drugs, focusing on albuminuria, are reviewed.

The toll-like receptors (TLRs) are a class of transmembrane-spanning receptors that are sentinels of both innate and adaptive immunity. Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are the most commonly prescribed therapeutic agents for treating hypercholesterolemia globally. However, statin therapy appears to have pleiotropic effects including attenuation of chronic low-grade inflammation and modulation of TLR activity. Statins through abolition of TLR4 expression and regulation of the TLR4/Myd88/NF-κB signaling pathway may slow the progression of atherosclerosis and other inflammatory diseases. In this review, we have focused on the impact and mechanism of action of statins on cardiovascular and non-cardiovascular diseases.

The prevalence of type 2 diabetes mellitus (T2DM) is increasing rapidly with its associated morbidity and mortality. Many pathophysiological pathways such as oxidative stress, inflammatory responses, adipokines, obesity-induced insulin resistance, improper insulin signaling, and beta cell apoptosis are associated with the development of T2DM. There is increasing evidence of the role of mitochondrial dysfunction in the onset of T2DM, particularly in relation to the development of diabetic complications. Here, the role of mitochondrial dysfunction in T2DM is reviewed together with its modulation by antidiabetic therapeutic agents, an effect that may be independent of their hypoglycemic effect.

Background The global pandemic of obesity and the metabolic syndrome are leading causes of mortality and morbidity. Bariatric surgery leads to sustained weight loss and improves obesity-associated morbidity including remission of type 2 diabetes. MicroRNAs are small, endogenous RNAs that regulate gene expression post-transcriptionally, controlling most of the human transcriptome and contributing to the regulation of systemic metabolism. This preliminary, longitudinal, repeat sampling study, in which subjects acted as their own control, aimed to assess the temporal effect of bariatric surgery on circulating microRNA expression profiles. Methods We used Exiqon’s optimized circulating microRNA panel (comprising 179 validated miRNAs) and miRCURY locked nucleic acid plasma/serum Polymerase Chain Reaction (PCR) to assess circulating microRNA expression. The microRNAome was determined for Roux-en-Y gastric bypass (RYGB) patients examined preoperatively and at 1 month, 3 months, 6 months, 9 months and 12 months postoperatively. Data was analysed using multivariate and univariate statistics. Results Compared to the preoperative circulating microRNA expression profile, RYGB altered the circulating microRNAome in a time dependent manner and the expression of 48 circulating microRNAs were significantly different. Importantly, these latter microRNAs are associated with pathways involved in regulation and rescue from metabolic dysfunction and correlated with BMI, the percentage of excess weight loss and fasting blood glucose levels. Conclusions The results of this pilot study show that RYGB fundamentally alters microRNA expression in circulation with a time-dependent progressive departure in profile from the preoperative baseline and indicate that microRNAs are potentially novel biomarkers for the benefits of bariatric surgery. Electronic supplementary material The online version of this article (10.1186/s40608-018-0199-z) contains supplementary material, which is available to authorized users.

Objective: Soy phytoestrogens are suggested to impair thyroid function but the effects of pharmacological doses of soy phytoestrogens are unknown; therefore, this study was performed to determine the effect of high dose soy phytoestrogens (66 mg) on thyroid function in subclinical hypothyroidism. Design and setting: Randomized, double-blind, crossover study. Participants: Forty four patients with subclinical hypothyroidism. Intervention: Participants were randomly allocated to either 66 mg phytoestrogen with 30 g soy protein (active) or 0 mg phytoestrogen with 30 g soy protein (placebo) supplementation for 8 weeks, washed out for 8 weeks and then crossed over for another 8 week period. Main outcome measures: The primary outcome was progression to overt hypothyroidism with the secondary outcome measures were changes in thyroid function tests. Results: Two patients in this trial progressed into overt hypothyroidism after high dose phytoestrogen supplementation. TSH, free thyroxine and triiodothyronine did not differ between groups. Conclusion: A pharmacological dose of 66 mg of soy phytoestrogens did not increase the overt thyroid failure rate or alter thyroid function tests in patients with subclinical hypothyroidism.

Cardiovascular disease (CVD) is a major cause of death globally. Addressing cardiovascular risk factors, particularly dyslipidemia, represents the most robust clinical strategy towards reducing the CVD burden. Statins inhibit 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and represent the main therapeutic approach for lowering cholesterol and reducing plaque formation/rupture. The protective effects of statins extend beyond lowering cholesterol. MicroRNAs (miRNAs or miRs), small noncoding regulatory RNAs, likely mediate the positive pleiotropic effects of statins via modulation of lipid metabolism, enhancement of endothelial function, inhibition of inflammation, improvement of plaque stability, and immune regulation. miRNAs are implicated in statin-related interindividual variations in therapeutic response, directly via HMG-CoA reductase, or indirectly through targeting cytochrome P450 3A (CYP3A) functionality and proprotein convertase subtilisin/kexin type9 (PCSK9) biology.

Curcumin, a natural polyphenolic and yellow pigment obtained from the spice turmeric, has strong antioxidative, anti-inflammatory, and antibacterial properties. Due to these properties, curcumin has been used as a remedy for the prevention and treatment of skin aging and disorders such as psoriasis, infection, acne, skin inflammation, and skin cancer. Curcumin has protective effects against skin damage caused by chronic ultraviolet B radiation. One of the challenges in maximizing the therapeutic potential of curcumin is its low bioavailability, limited aqueous solubility, and chemical instability. In this regard, the present review is focused on recent studies concerning the use of curcumin for the treatment of skin diseases, as well as offering new and efficient strategies to optimize its pharmacokinetic profile and increase its bioavailability.

Curcumin is a bioactive phytochemical that modulates several physiological and cellular processes leading to therapeutic effects against different diseases. Sirtuins are highly conserved nicotine adenine dinucleotide-dependent proteins that regulate the activity of target enzymes and transcription factors by deacetylation. Curcumin possesses both antioxidant and anti-inflammatory properties and has been shown to increase sirtuin-1 (SIRT1) by activating small molecules. Upregulation of SIRT1 by curcumin has been reported to confer protective effects against a range of neurological disorders including glutamate excitotoxicity, β-amyloid-induced cell death in cortical neurons, cerebral ischemic damage, and stroke. Activation of AMPK and SIRT1 by curcumin has also been noted to mediate the protective effects of curcumin against ischemia/reperfusion injury, cardiac fibrosis, diabetes, and lipid metabolism abnormalities. These protective effects of SIRT1 activation are partly mediated by the deacetylation of p53 and reduction of apoptosis. In this review, we summarize the role of SIRT1 in mediating the pharmacological effects of curcumin in several diseases.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are therapeutic agents that have been used recently to reduce tubular absorption of glucose, leading to enhanced glycosuria, resulting in the reduction of blood glucose and improved diabetes control. Recent data suggest that SGLT2 inhibitors have antioxidant properties that may be key to the reduction in cardiovascular death found in clinical trials. Oxidative stress is involved in the development and progression of atherosclerosis, as well as underlying diabetes complications, and may result from either increased free-radical production, a reduction in antioxidative capacity, or a combination of both. In this report, we have reviewed the recent evidence of the impact that SGLT2 inhibition may have on improved oxidative stress by either amelioration of free-radical generation or potentiation of cellular antioxidative capacity, and its importance in the prevention of cardiovascular and diabetes complications.

Despite significant advances in treatment modalities, millions of cancer-related deaths continue to occur annually, often as a consequence of developing resistance against the range of available chemotherapeutic drugs. Furthermore, available anti-cancer chemotherapeutic agents show limited efficacy, often have severe side effects, and are expensive. Thus, the discovery of pharmacological agents that do not have these disadvantages is necessary. Curcumin, a polyphenolic compound derived from turmeric (Curcumin longa L.), is one such agent that has been widely studied for its anti-inflammatory and/or anti-cancer effects. Curcumin exerts its anti-cancer effect by suppressing the initiation, progression, and metastasis of a variety of cancers and appears to inhibit carcinogenesis by affecting two main processes: angiogenesis and tumor growth. These anti-cancer effects are largely mediated via negative regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other oncogenic molecules. The PI3K/AKT pathway is commonly activated in cancer initiation and progression. Considered to be the key signaling pathway, the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathway therefore represents a key target for cancer therapeutics. In the current review, we focus upon curcumin's targeting of PI3K/AKT in different malignancies to effect inhibition of cancer development and progression.

ObjectiveThe aim of this study is to evaluate the effect of growth hormone therapy (rGH) on mitochondrial function on peripheral muscle and to correlate with exercise capacity in subjects with severe adult growth hormone deficiency (GHD).DesignSix months, double-blind, randomized, crossover, placebo-controlled trial of subcutaneous rGH in 17 patients with GHD.MeasurementsQuadriceps muscle biopsies were obtained at baseline, 3 months, and 6 months to measure succinate dehydrogenase (SDH) to assess mitochondrial activity. Exercise capacity was measured with cardiopulmonary exercise testing. Lipids, glycemic parameters, and body fat levels were also measured.ResultsSerum insulin-like growth factor 1 (IGF1) levels reduced fat mass by 3.2% (p

Heart failure is a major public health concern and one of the most common reasons for a cardiac hospital admission. Heart failure may be classified as having a reduced or preserved ejection fraction and its severity is based on the symptom score. Given the aging population, it is predicted that admissions with heart failure will increase. Whilst pharmacological therapy has improved the associated morbidity and mortality, there is a need for additional therapies to improve the clinical outcome as the death rate remains high. Curcumin is a natural product derived from turmeric that appears to have cardiovascular benefit through a number of mechanisms. In this review, we have assessed the mechanisms by which curcumin may exert its effects in different models of heart failure and show that it has promise as a complementary treatment in heart failure.

Background/Aim: Perfluorinated alkyl acids (PFAAs) are used widely as surfactants in household and industrial applications such as textile treatments and food packaging, and can be persistent and b...

Aims: To determine if clotting, platelet and endothelial function were affected by simulated short haul commercial air flight conditions (SF) in participants with type 2 diabetes (T2DM) compared to controls. Methods: 10 participants with T2DM (7 females, 3 males) and 10 controls (3 females, 7 males) completed the study. Participants were randomized to either spend 2 hours in an environmental chamber at sea level conditions (temperature: 23oC, oxygen concentration 21%, humidity 45%), or subject to a simulated 2-hour simulated flight (SF: temperature: 23oC, oxygen concentration 15%, humidity 15%), and crossed over 7 days later. Main outcome measures: clot formation and clot lysis parameters, functional platelet activation markers and endothelial function measured by reactive hyperaemia index (RHI) by EndoPAT and serum microparticles. Results: Comparing baseline with simulated flight conditions, clot maximal absorption was increased in controls (0.375±0.05 v 0.39±0.05, p

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and is potentially treatable, though there are few therapeutic agents available. Artichoke leaf extract (ALE) has shown potential as a hepatoprotective agent. This study sought to determine if ALE had therapeutic utility in patients with established NAFLD. In this randomized double-blind placebo-controlled parallel-group trial, 100 subjects with ultrasound-diagnosed NAFLD were randomized to either ALE 600 mg daily or placebo for a 2-month period. NAFLD response was assessed by liver ultrasound and serological markers including the aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio and AST to platelet ratio index (APRI) score. Ninety patients completed the study (49 ALE and 41 placebo) with no side effects reported. ALE treatment compared with placebo: Doppler sonography showed increased hepatic vein flow (p

ObjectivesThis meta-analysis of randomised placebo-controlled clinical trials aimed to assess the effect of fenofibrate on apolipoprotein C-III (apo C-III), a key regulator of triglyceride metabolism.Materials and methodsRandomised placebo-controlled trials investigating the impact of fenofibrate treatment on apo C-III levels were searched in PubMed-Medline, Scopus, Web of Science and Google Scholar databases from inception to 18 August 2017. Quantitative data synthesis was determined by a random-effects model and generic inverse variance method. Sensitivity analysis was conducted using the leave-one-out method. A weighted random-effects meta-regression was performed to evaluate glycaemic parameter confounders.ResultsMeta-analysis of 10 clinical trials involving 477 subjects showed fenofibrate therapy decreased apo C-III levels (weighted mean difference (WMD) −4.78 mg/dL, 95% CI −6.95 to –2.61, p266.87%). Subgroup analysis showed that fenofibrate reduced plasma apo C-III concentrations in subgroups of trials with treatment durations of either 200 mg/day (p=0.006), with no significant difference between the subgroups.ConclusionThis meta-analysis found that fenofibrate therapy significantly decreases apo C-III levels, an effect evident with both short-term treatment and doses less than 200 mg/day.

Objective: Fibrinogen is a key mediator of thrombosis and it has been implicated in the pathogenesis of atherosclerosis. Because metformin has shown a potential protective effect on different atherothrombotic risk factors, we assessed in this meta-analysis its effect on plasma fibrinogen concentrations. Methods: A systematic review and meta-analysis was carried out to identify randomized placebo-controlled trials evaluating the effect of metformin administration on fibrinogen levels. The search included PubMed-Medline, Scopus, ISI Web of Knowledge and Google Scholar databases (by June 2, 2017) and quality of studies was performed according to Cochrane criteria. Quantitative data synthesis was conducted using a random-effects model and sensitivity analysis by the leave-one-out method. Meta-regression analysis was performed to assess the modifiers of treatment response. Results: Meta-analysis of data from 9 randomized placebo-controlled clinical trials with 2302 patients comprising 10 treatment arms did not suggest a significant change in plasma fibrinogen concentrations following metformin therapy (WMD: -0.25 g/L, 95% CI: -0.53, 0.04, p = 0.092). The effect size was robust in the leave-one-out sensitivity analysis and remained non-significant after omission of each single study from the meta-analysis. Conclusion: No significant effect of metformin on plasma fibrinogen concentrations was demonstrated in the current meta-analysis.

Polycystic ovary syndrome (PCOS) is a chronic endocrine disorder that affects women of reproductive age and is associated with infertility, hyperandrogenism, hirsutism, metabolic disorders including type 2 diabetes mellitus, and psychologic issues. Approximately 80% of PCOS patients are overweight or obese, particularly abdominal obesity. Although PCOS is an independent factor, obesity exaggerates all the reproductive, metabolic, and psychologic features related to PCOS. The underlying insulin resistance that is greater in PCOS for any given body mass index (BMI) compared with BMI-matched controls likely mediates this. Weight loss is the cornerstone for treatment in obese PCOS patients. A modest weight loss of less than 10% has been shown to improve ovulation, infertility, androgen levels, insulin resistance, and dyslipidemia in women with PCOS. Lifestyle modification (diet and exercise) is the first treatment step, followed by medical, and, potentially, surgical treatment. Pharmacologic therapy has proved disappointing in treating obesity associated with PCOS, because only orlistat is currently available. In women with PCOS, orlistat has shown to reduce both total testosterone levels and insulin resistance by inducing weight loss; however, its associated gastrointestinal side effects limit its value. Although metformin improves insulin resistance in PCOS, its effect on weight is controversial. Future medical therapy may involve glucagon-like peptide-1 analogues that reduce weight, and data suggest a concomitant improvement in menstrual cycles, ovulation rate, hyperandrogenism, and insulin sensitivity. Bariatric surgery in morbidly obese PCOS patients is effective, leading to marked weight reduction with improvement in hyperandrogenemia, insulin resistance, and hirsutism, with subsequent improvement in menstrual cycles and ovulation.

Background Impaired fasting glucose (IFG), prediabetes, has a conversion to diabetes of 10% yearly, contributing to the prevalence of diabetes of 16.7% in Qatar. This high prevalence of diabetes will translate into serious vascular complications with considerable individual early mortality.Methods The Qatar Biobank is an ambitious national project that is collecting the demographic and biological data on an unselected Qatari population that currently has data from 1100 women aged 18-84 years. Data extraction of all women between the aged 18 to 40 years (inclusive) was undertaken by the Qatar Bio bank that identified 750 women in total. The number of women with and without impaired fasting glucose (IFG: plasma glucose 5.5-6.9 mmol/l; ADA diagnostic criteria) was determined and their demographic details compared. Bio statistical analysis was undertaken using SPSS. Results The prevalence of IFG was found to be 8.3% (62/750 women). Patients with IFG had a higher cardiovascular risk profile with a higher waist hip ratio (P

Lina H.M Ahmed1, Youssra Dakroury1, Soha R. Dargham1, Aishah Latif2, Stephen Atkin1, Amal Robay1, Omar M. Chidiac1, Charbel Abi Khalil1 1 Weill Cornell Medicine Qatar, 2Antidoping Laboratory Qatar. Introduction: Vitamin D deficiency is a major issue worldwide and particularly in countries in the Middle East where full coverage of the body is a normal cultural practice. Epidemiology studies have suggested that vitamin D deficiency is associated with the development of diabetes where those levels are lower than normal subjects. However, the role of vitamin D in the development of diabetes complications is unclear. We hypothesized that vitamin D3 levels (25OHD3) and its active form 1,25 dihydroxyvitaminD3 (1,25OHD3) would differ between subjects with and without diabetes due to full coverage of the body being the determining factor. Methods: 499 Qatari subjects were recruited of whom 274 (54.9%) had type 2 diabetes and 222 (44.5%) did not. We used the Mann-Whitney test to compare the levels of both vitamin D outcomes, 25OHD3 and 1,25OHD3, their data were not normally distributed. First we compared the 25OHD3 and its active form 1,25OHD3 between diabetes and non diabetes subjects. Among those who were diabetic, we then correlated the 25OHD3 and 1,25OHD3 with diabetes complications (Table). 25OHD3 and 1,25OHD3 were measured by LC-MS/MS analysis. Results: Patients with diabetes were significantly more deficient in both 25OHD3 (p-value = 0.001) and 1,25OHD3 (p-value

Deoxynivalenol (DON), the mycotoxin produced mainly by Fusarium graminearum and found in contaminated cereal-based foodstuff, has been consistently detected in body fluids in adults. Available data in children and adolescents are scarce. This study assessed urinary DON concentrations in children aged 3–9 years (n = 40) and adolescents aged 10–17 years (n = 39) in the UK. Morning urine samples were collected over two consecutive days and analysed for free DON (un-metabolised form), DON-glucuronides (DON-GlcA), deepoxy deoxynivalenol (DOM-1), and total DON (sum of free DON, DON-GlcA, and DOM-1). Total DON was detected in the urine of >95% of children and adolescents on both days. Mean total DON concentrations (ng/mg creatinine) were 41.6 and 21.0 for children and adolescents, respectively. The greatest total DON levels were obtained in female children on both days (214 and 219 ng/mg creatinine on days 1 and 2, respectively). Free DON and DON-GlcA were detected in most urine specimens, whereas DOM-1 was not present in any sample. Estimation of dietary DON exposure suggested that 33–63% of children and 5–46% of adolescents exceeded current guidance regarding the maximum provisional tolerable daily intake (PMTDI) for DON. Although moderate mean urinary DON concentrations were shown, the high detection frequency of urinary DON, the maximum biomarker concentrations, and estimated dietary DON exposure are concerning.

The aim of this systematic review and meta-analysis was to determine and clarify the impact of curcuminoids on serum lipid levels.Randomized controlled trials (RCTs) investigating the effects of curcuminoids on plasma lipids were searched in PubMed-Medline, Scopus, Web of Science databases (from inception to April 3A meta-analysis of 20 RCTs with 1427 participants suggested a significant decrease in plasma concentrations of triglycerides (WMD: -21.36 mg/dL, 95% CI: -32.18, -10.53, p0.001), and an elevation in plasma HDL-C levels (WMD: 1.42 mg/dL, 95% CI: 0.03, 2.81, p = 0.046), while plasma levels of LDL-C (WMD: -5.82 mg/dL, 95% CI: -15.80, 4.16, p = 0.253) and total cholesterol (WMD: -9.57 mg/dL, 95% CI: -20.89, 1.75, p = 0.098) were not altered. The effects of curcuminoids on lipids were not found to be dependent on the duration of supplementation.This meta-analysis has shown that curcuminoid therapy significantly reduces plasma triglycerides and increases HDL-C levels.

UNLABELLED: ORAI and stromal interaction molecule (STIM) are store-operated channel molecules that play essential roles in human physiology through a coupling mechanism of internal Ca(2+) store to Ca(2+) influx. However, the roles of ORAI and STIM in vascular endothelial cells under diabetic conditions remain unknown. Here, we investigated expression and signalling pathways of ORAI and STIM regulated by high glucose or hyperglycaemia using in vitro cell models, in vivo diabetic mice and tissues from patients. We found that ORAI1-3 and STIM1-2 were ubiquitously expressed in human vasculatures. Their expression was upregulated by chronic treatment with high glucose (HG, 25 mM D-glucose), which was accompanied by enhanced store-operated Ca(2+) influx in vascular endothelial cells. The increased expression was also observed in the aortae from genetically modified Akita diabetic mice (C57BL/6-Ins2(Akita)/J) and streptozocin-induced diabetic mice, and aortae from diabetic patients. HG-induced upregulation of ORAI and STIM genes was prevented by the calcineurin inhibitor cyclosporin A and NFATc3 siRNA. Additionally, in vivo treatment with the nuclear factor of activated T cells (NFAT) inhibitor A-285222 prevented the gene upregulation in Akita mice. However, HG had no direct effects on ORAI1-3 currents and the channel activation process through cytosolic STIM1 movement in the cells co-expressing STIM1-EYFP/ORAIs. We concluded that upregulation of STIM/ORAI through Ca(2+)-calcineurin-NFAT pathway is a novel mechanism causing abnormal Ca(2+) homeostasis and endothelial dysfunction under hyperglycaemia. KEY MESSAGE: ORAI1-3 and STIM1-2 are ubiquitously expressed in vasculatures and upregulated by high glucose. Increased expression is confirmed in Akita (Ins2(Akita)/J) and STZ diabetic mice and patients. Upregulation mechanism is mediated by Ca(2+)/calcineurin/NFATc3 signalling. High glucose has no direct effects on ORAI1-3 channel activity and channel activation process.

Hormone replacement therapy may be beneficial for cardiovascular disease risk (CVR) in post-menopausal women. Soy isoflavones may act as selective estrogen receptor modulators. The aim of this study was to evaluate whether soy isoflavones had an effect on CVR markers.The expected 10-year risk of cardiovascular disease and mortality were calculated as a secondary endpoint from a double blind randomised parallel study involving 200 women (mean age 55 years, Caucasian, Hull, UK, 2012) in the early menopause who were randomised to 15 g soy protein with 66 mg isoflavone (SPI) or 15 g soy protein alone (depleted of all isoflavones; SP) given as a snack bar between meals daily for 6 months. Age, diabetes, smoking, blood pressure and lipid profiles were used to calculate CVR using the Framingham CVR engine.SPI treatment resulted in a significant reduction in the metabolic parameters and systolic blood pressure compared to SP (p 0.01). There were no changes in fasting lipid profile and diastolic blood pressure with either treatment. At 6 months, changes in these parameters with SPI treatment were reflected in a calculated 27% (p 0.01) reduction in 10 year coronary heart disease risk, a 37% (p 0.01) reduction in myocardial infarction risk, a 24% (p 0.04) reduction in cardiovascular disease and 42% (p 0.02) reduction in cardiovascular disease death risk.Supplementation with soy protein with isoflavones for 6 months significantly improved CVR markers and calculated CVR at 6 months during early menopause compared to soy protein without isoflavones.ISRCTN34051237.

Background Evidence suggests that endocannabinoid system activation through the cannabinoid receptor 1 (CB1) is associated with enhanced liver injury, and CB1 antagonism may be beneficial. The aim of this study was to determine the impact of rimonabant (CB1 antagonist) on alanine aminotransferase (ALT), a hepatocellular injury marker, and a hepatic inflammatory cytokine profile. Methods Post hoc review of 2 studies involving 50 obese women with PCOS and well matched for weight, randomised to weight reducing therapy; rimonabant (20 mg od) or orlistat (120 mg tds), or to insulin sensitising therapy metformin, (500 mg tds), or pioglitazone (45 mg od). No subject had non-alcoholic fatty liver disease (NAFLD). Results Treatment with rimonabant for 12 weeks reduced both ALT and weight (p

Objective Anti-Mullerian hormone (AMH) is derived from the small antral follicles and an elevated level has been suggested to add value to the Rotterdam criteria for the diagnosis of PCOS in cases of diagnostic uncertainty. Therefore, the role of AMH in the classical phenotype of PCOS was defined within a Caucasian population. Design This was a cross sectional study. Patients 65 women without PCOS and 110 women with PCOS fulfilling all 3 diagnostic Rotterdam criteria. Measurements The main outcomes were the utility of serum AMH for the diagnosis of PCOS and its relationship to the metabolic parameters. Results AMH was increased in PCOS compared to controls (p

Polycystic ovary syndrome (PCOS) is associated with an increased risk of type 2 diabetes mellitus (T2DM) but its association with prediabetes and T2DM is unknown in Qatar. A cross sectional analysis of 3,017 Qatari subjects from the Qatar Biobank, identified 749 women aged 18–40 years, 720 of whom were assessed by the National Institute for Health (NIH) Guidelines for PCOS. Prediabetes (HbA1c 5.7–6.4% and/or impaired fasting glucose (IFG): fasting plasma glucose (FPG) 100–125 mg/dL (5.6–6.9 mmol/L)), and T2DM (fasting plasma glucose > 125 mg/dL (≥7 mmol/L), and/or HbA1c ≥ 6.5%) were determined. The prevalence of prediabetes was 10.6% and the prevalence of undiagnosed diabetes was found to be 4.0% in the total population. Overall, 12.1% of 720 women had PCOS, of whom FPG and HbA1c were available in 62 women with PCOS: 19.4% had prediabetes and 9.7% had diabetes. An adverse cardiovascular risk profile for IFG women compared to normal women was found. Women with PCOS alone had a similar adverse cardiovascular profile as those with IFG alone and T2DM. Thus, the risk of prediabetes and diabetes is increased in Qatari women with PCOS, with an adverse cardiovascular risk profile similar to that seen in prediabetes and T2DM.

Deoxynivalenol (DON) is produced by Fusarium graminearum and is one of the most commonly occurring trichothecenes. Vegetarians are alleged to be a high-risk group for DON exposure due to high intakes of cereals susceptible to the growth of the mycotoxin. This study provides the levels of DON and de-epoxi Deoxynivalenol (DOM-1) in urine analysed by liquid chromatography-mass spectrometry (LC-MS) in UK vegetarians. Over two consecutive days, morning urine samples were collected from 32 vegetarians and 31 UK adult volunteers, and associated food consumption 24 h prior to the sample was recorded. Statistically significant differences between the weight of the UK adults and vegetarians (t = 3.15. df = 61, p ≤ 0.005 two-tailed) were observed. The mean levels of DON in urine for adults on day 1 was 3.05 ng free DON/mg creatinine, and on day 2 was 2.98 ng free DON/mg creatinine. Even though high mean levels were observed, most adults were within the tolerable daily intake. However, for vegetarians, the mean level of urinary DON on day 1 was 6.69 ng free DON/mg creatinine, and on day 2 was 3.42 ng free DON/mg creatinine. These levels equate to up to 32% of vegetarians exceeding recommended tolerable daily intakes (TDI) of exposure (1 µg/kg b.w./day).

Objective The prevalence of polycystic ovary syndrome (PCOS) in the Qatari population is unknown and hence the estimated impact on the local population cannot be determined. The purpose of this study was to estimate the prevalence and metabolic features of PCOS among Qatari women. Design Cross sectional analysis. Patients 3,017 Qatari subjects volunteered to be phenotyped and genotyped for the Qatar Biobank from which all women between the ages of 18–40 years were identified (750). Measurements 720 women had testosterone and sex hormone binding globulin (SHBG) measurements. PCOS was diagnosed according the National Institute of Health (NIH) Guidelines of a raised androgen level (free androgen index >4.5 or a raised total testosterone) and menstrual irregularity after the exclusion of other conditions. Results All results are reported as mean value of PCOS versus control. 87 of 720 women fulfilled the NIH guidelines (12.1%) for PCOS specifically using a free androgen index greater than 4.5 or a total testosterone greater than 2.7nmol/l and menstrual irregularity. Subjects were heavier with a more metabolic profile of a greater systolic and diastolic blood pressure, higher levels of C reactive protein, insulin (p

Background Androsterone glucuronide (ADTG) concentrations have been suggested as a marker of the effects of androgens at the target tissue level. As the mechanism for hyperandrogenemia in obese and nonobese polycystic ovary syndrome (PCOS) may differ, this study compared the different androgen parameters in non-obese compared to obese women with PCOS, and in normal subjects. Methods Eleven non-obese and 14 obese women with PCOS were recruited and compared to 11 control women without PCOS. Total testosterone, dehydroepiandrosterone sulphate (DHEAS), ADTG, and androstenedione were analysed using gold standard tandem mass spectrometry, and the free androgen index (FAI) was calculated. Results Total testosterone, ADTG and androstendione levels did not differ between non-obese (body mass index (BMI) ≤25 kg/m2) and obese PCOS (BMI >25 kg/m2) but all were significantly higher than for controls (p

Objective Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes mellitus. There are also reports of an effect of these drugs in reducing inflammation through inhibition of tumor necrosis factor-α (TNF-α) that is an important mediator for several inflammatory processes. The present systematic review and meta-analysis were performed to evaluate the effect of DPP-4 inhibitors on circulating TNF-α levels in T2DM patients. Methods A systematic review and a meta-analysis were undertaken on all controlled trials of DPP-4 inhibitors that included measurement of TNF-α. The search included PubMed-Medline, Scopus, ISI Web of Knowledge and Google Scholar databases. Quantitative data synthesis was performed using a random-effects model, with standardized mean difference (SMD) and 95% confidence interval (CI) as summary statistics. Meta-regression and leave-one-out sensitivity analysis were performed to assess the modifiers of treatment response. Results Eight eligible articles (6 with sitagliptin and 2 with vildagliptin) comprising 9 treatment arms were selected for this meta-analysis. Meta-analysis suggested a significant reduction of circulating TNF-α concentrations following treatment with DPP-4 inhibitors (SMD: −1.84, 95% CI: −2.88, −0.80, p =0.001). The effect size was robust in the sensitivity analysis and not mainly driven by a single study. A subgroup analysis did not suggest any significant difference between the TNF-α-lowering activity of sitagliptin (SMD: −1.49, 95% CI: −2.89, −0.10) and vildagliptin (SMD: −2.80, 95% CI: −4.98, −0.61) (p=0.326). Conclusion This meta-analysis of the 8 available controlled trials showed that DPP-4 inhibition in patients with type 2 diabetes mellitus was associated with significant reductions in plasma TNF-α levels with no apparent difference between sitagliptin and vildagliptin.

Pollen grain and spore shells are natural microcapsules designed to protect the genetic material of the plant from external damage. The shell is made up of two layers, the inner layer (intine), made largely of cellulose, and the outer layer (exine), composed mainly of sporopollenin. The relative proportion of each varies according to the plant species. The structure of sporopollenin has not been fully characterised but different studies suggest the presence of conjugated phenols, which provide antioxidant properties to the microcapsule and UV (ultraviolet) protection to the material inside it. These microcapsule shells have many advantageous properties, such as homogeneity in size, resilience to both alkalis and acids, and the ability to withstand temperatures up to 250 °C. These hollow microcapsules have the ability to encapsulate and release actives in a controlled manner. Their mucoadhesion to intestinal tissues may contribute to the extended contact of the sporopollenin with the intestinal mucosa leading to an increased efficiency of delivery of nutraceuticals and drugs. The hollow microcapsules can be filled with a solution of the active or active in a liquid form by simply mixing both together, and in some cases operating a vacuum. The active payload can be released in the human body depending on pressure on the microcapsule, solubility and/or pH factors. Active release can be controlled by adding a coating on the shell, or co-encapsulation with the active inside the shell.

Unfortunately, the fifth author name was incorrectly published in the original publication. The correct name should read as 'Ozgur Demir'.

SummaryIntroduction Nonalcoholic fatty liver disease (NAFLD) has been linked to polycystic ovary syndrome (PCOS) and carries an increased risk of liver cirrhosis. Procollagen type 3 amino-terminal peptide (PIIINP) is an independent predictor of liver cirrhosis. Objective To assess whether 6-month treatment with GLP-1 analogue, liraglutide, improves markers of liver fibrosis. Design A case–control study comparing women with PCOS to age- and weight-matched controls. PCOS was diagnosed according to the Rotterdam criteria. All participants underwent liver function tests and liver ultrasound scan to assess for fatty infiltration. Serum marker for liver fibrosis, PIIINP, was measured at baseline and after 6-month treatment with liraglutide 1·8 mg od. Results Nineteen women with PCOS and 17 controls were recruited, age 32·8 ± 7·2 vs 33·5 ± 6·7 years and weight 100·9 ± 16·7 vs 99·3 ± 14·7 kg, respectively. At baseline, the PCOS group had higher testosterone 1·2 ± 0·3 vs 0·9 ± 0·3 nm (P = 0·01), HOMA-IR 5·1 ± 2·6 vs 3·5 ± 1·3 (P = 0·03), AST 22·4 ± 5·2 vs 18·8 ± 3·4 u/l (P = 0·04), PIIINP 4·4 ± 0·8 vs 3·5 ± 0·8 ug/ml (P = 0·01) and NAFLD seven (35%) vs none (P = 0·005), respectively. Twenty-five (69%) participants completed the study (13 PCOS, 12 controls). Following treatment, weight was reduced by 3·0 ± 4·2 kg (P = 0·01) and 3·8 ± 3·4 kg (P = 0·001), respectively. Similarly, HOMA-IR, hsCRP, triglycerides and urinary isoprostane significantly reduced in both groups. PIIINP significantly reduced the in PCOS group 4·4 ± 0·8 vs 3·7 ± 0·9 ug/ml (P