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This exposition reveals the effect of glucose as a molecular crowder on the solvent environment in proximity of the protein surface in putative folded (Ubiquitin) and intrinsically disordered (dimeric Amyloid beta) states. Atomistic simulations reveal markedly higher structural perturbation in the disordered systems due to crowding effects, while the folded state retains overall structural fidelity. Key hydrophobic contacts in the disordered dimer are lost. However, glucose induced crowding results in elevated hydration on surfaces of both protein systems. Despite evident differences in their structural responses, the hydration layer of both the folded and disordered states display a distinct enhancement in lifetimes of mean residence and rotational relaxation under the hyperglycemic conditions. The results are crucial in the light of emergent co-solvent induced biological phenomena in crowded media.

Aim To evaluate the long-term clinical effect of continuous subcutaneous insulin infusion (CSII) in adult type 1 diabetes mellitus (T1DM) patients in a regional public healthcare system real-world scenario. Methods All adult T1DM patients on CSII for ≥10 years subjected to follow-up in the regional Castilla-La Mancha Public Health Service were included. The primary efficacy outcome was the variation in HbA1c during follow-up. Direct patient data were compiled through the web-based Spanish national registry on CSII therapy. Results A total of 69 T1DM adult patients were treated with insulin pumps for ≥10 years in our region. The mean age was 45.0 ± 10.5 years, with a T1DM duration of 13.9 ± 8.5 years. The mean duration of CSII therapy was 11.4 ± 2.1 years. The main indications for treatment were high glucose variability (39%), problematic hypoglycemia (26%), and HbA1c > 53 mmol/mol (7%) on multiple daily injections (20%). Sensor-augmented pump therapy was used by 31% of the patients. Glycosylated hemoglobin did not change during follow-up (58 ± 11 mmol/mol vs. 58 ± 11 mmol/mol; 7.5 ± 1.0 vs. 7.5 ± 1.0; p = 0.66). However, the percentage of patients with at least one episode of severe hypoglycemia during the last year and unnoticed hypoglycemia decreased from 36% to 7% (p = 0.006) and from 38% to 32% (p Conclusions The reduction of severe hypoglycemia without deterioration of glycemic control can be sustained over long-term CSII therapy.

The inhibition of high glucose on the proliferation and differentiation of osteoblast in alveolar bone are well documented. However, a comprehensive study focused on the molecular mechanisms is still unknown. Recent studies have revealed that caspase-1 participates in the pathological processes of hepatic injury, cancers and diabetes related complications. However, the relationship between pyroptosis and proliferation and differentiation of osteoblasts has not been investigated. This study aimed to explore the possible pyroptosis participating in the inhibition of high glucose on the proliferation and differentiation of osteoblast in alveolar bone. The diabetes model was constructed both in vitro and in vivo to detect the expression of pyroptosis related factors. These results show that high glucose inhibits proliferation and differentiation of osteoblast in alveolar bone through pyroptosis pathway. Furthermore, caspase-1 inhibitor was co-administered with high glucose in ME3T3-E1 cells, which shows that caspase-1 inhibitor could repress effect of high glucose on the proliferation and differentiation of osteoblast. In conclusion, High glucose could activate the pyroptosis through the caspase-1/GSDMD/IL-1β pathway to inhibit the proliferation and differentiation of osteoblast in alveolar bone, which provides a theoretical basis for clinical treatment of alveolar bone disease in diabetic patients.

The aim of this work was to realize 1,2,4-butantriol (BT) production from sugarcane bagasse hydrolysates by microbial fermentation, and obtain co-production of BT and ethanol. Candida glycerinogenes UG21 was utilized to reduce the effect of osmolality resulting from high glucose concentration and furfural in hydrolysates on cell growth of BT-producing strains, and produced 54.1 g/L ethanol from glucose. After ethanol recovering, xylose containing stillage was obtained and used for BT production. 1.3 g/L BT was generated by a BT-producing strain. By the deletion of the crr gene and process optimization, BT titer reached 4.9 g/L. Meanwhile, the efficient utilization of sugarcane bagasse was achieved by a two-stage fermentation for co-production of BT and ethanol. This study provided a novel strategy for BT production from sugarcane bagasse, and demonstrated the potential for making full use of sugarcane bagasse hydrolysates to co-production value-added products.

Diabetes leads to markedly accelerated rates of many associated macrovascular complications like hypertension and atherosclerosis, and microvascular complications like nephropathy and retinopathy. High glucose, the hallmark of diabetes, drives changes in vascular and inflammatory cells that promote the development of these complications. Understanding the molecular processes involved in the development of diabetes and its debilitating complications can lead to much needed newer clinical therapies. Recently, long-noncoding RNAs (lncRNAs) have been shown to be important in the biology of vascular cells and there is growing evidence that lncRNAs are also involved in the cell biology relevant to diabetic vascular complications. In this review, we provide an overview of lncRNAs that function in vascular cells, and those that have been linked to diabetic complications.

Objective There is scarce information regarding the performance of a specific, structured education program addressed to patients with type 1 diabetes (T1D) using continuous subcutaneous insulin infusion (CSII) including both routine use of the therapy and patient experience evaluation. We aimed to assess the routine use of CSII and patient's experience and satisfaction regarding a specific structured patient self-management education and care program. Methods A retrospective, observational, cross-sectional study collecting CSII routine use downloaded data. Patient experience and satisfaction were evaluated using an anonymous online survey covering different aspects of CSII self-management education and care program. Results 380 T1D subjects were included (aged 45.3 ± 12.17 years, 62.1% women, diabetes duration 27.8 ± 10.3 years, 9.7 ± 4.7 years on CSII, HbA1c 7.7 + 1.0%; 61.0 ± 7.9 mmol/mol). Participants with HbA1c ≤ 7.5% (58 mmol/mol, n = 178) did more SMBGs per day (4.4 ± 2.1 vs. 3.9 ± 1.9); used more boluses (5.0 ± 1.8 vs. 4.5 ± 2.0); the percentage of insulin given as bolus was higher (50.1 ± 12.8 vs. 44.9 ± 13.2%); the night bolus wizard (BW) high glucose target was lower (125.9 ± 4.4 vs. 130.5 ± 12.8 mg/dl) and time on CSII therapy was shorter (8.9 ± 4.6 vs. 10.3 ± 4.6 years. p Conclusions The analysis of routine clinical use of CSII by T1D patients demonstrates that glucose control may be associated with some pump usage and adherence parameters. The overall user experience and satisfaction with our CSII self-management education and care program was remarkably favorable.

Recent study has showed that Ginsenoside Rg1, the mian active compound of Panax ginseng, could ameliorate oxidative stress and myocardial apoptosis in diabetes mellitus. However, the roles and mechanisms of Rg1 in proliferative diabetic retinopathy (PDR) are still unclear. In the present study, we aimed to investigate the effects of Rg1 on mesenchymal activation of high-glucose (HG) cultured müller cells. High glucose conditions up-regulate MMP-2, MMP-9 and down-regulate TIMP-2, and promote mesenchymal activation in Müller cells. And Rg1 inhibits the HG-induced mesenchymal activation and HG-increased MMP-2 and MMP-9 and HG-decreased TIMP-2 in Müller cells. HG up-regulates Zeb1 and lncRNA RP11-982M15.8, and down-regulates miR-2113, and Rg1 inhibits these effects of HG. Both inhibition of miR-2113 and over-expression of RP11-982M15.8 significantly restored the HG induced mesenchymal activasion. Taken together, our findings suggested that Rg1 inhibited HG-induced mesenchymal activation and fibrosis via regulating miR-2113/RP11-982M15.8/Zeb1 pathway.

Systemic changes during diabetes such as high glucose, dyslipidemia, hormonal changes and low grade inflammation, are believed to induce structural and functional changes in the cardiomyocyte associated with the development of diabetic cardiomyopathy. One of the hallmarks of the diabetic heart is increased oxidative stress. NADPH-oxidases (NOXs) are important ROS-producing enzymes in the cardiomyocyte mediating both adaptive and maladaptive changes in the heart. NOXs have been suggested as a therapeutic target for several diabetic complications, but their role in diabetic cardiomyopathy is far from elucidated. In this review we aim to provide an overview of the current knowledge regarding the understanding of how NOXs influences cardiac adaptive and maladaptive processes in a "diabetic milieu". This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.

The excessive proliferation and migration of vascular smooth muscle cells (VSMCs) are important steps in atherosclerosis. The present study aimed to investigate whether the high glucose-induced changes of VSCMs are mediated by miR-145 and the potential molecular mechanism involved. We found that loss of miR-145 accompanied with increased proliferation and migration was observed in cultured human VSMCs exposed to high glucose. Exogenous overexpression of miR-145 effectively suppressed the high glucose-induced excessive proliferation and migration of VSMCs. Furthermore, we identified ROCK1 as a downstream target gene product of miR-145, and ROCK1 partially rescues the effects of miR-145 on high glucose-induced VSMC proliferation and migration. Taken together, our results suggested a protective role of miR-145 in high glucose-treated VSMCs by suppressing ROCK1, which might provide a therapeutic target for diabetic atherosclerosis.

Recent years, widespread long non-coding RNAs (lncRNAs) were identified and known as regulator of gene expression. Diabetic gastroparesis (DGP) is one of the most common chronic complications of diabetes mellitus. There was no research reported the role of lncRNAs in DGP. In this study, we firstly established a rat model of DGP by STZ injection. Then, we detected the expression of MALAT1 and found that expression of MALAT1 was up-regulated in rat model of DGP, comparing to the control group (P .01). Furthermore, we revealed that MALAT1 expression was increased in the samples from diabetic patients with DGP symptoms, in comparison with the control. In addition, we demonstrated that the inhibition of MALAT1 increased the expression of α-SMA and SM myosin heavy chains, reduced the cell viability, inhibited the potential of cell migration and induced cell apoptosis in human gastric smooth muscle cells (SMCs). Ultimately, we found that the regulation of MALAT1 expression modulated the function of high-glucose stimulation in human gastric SMCs. Therefore, our study firstly indicated that MALAT1 was up-regulated in DGP and played an important role in the pathogenesis of DGP.

Glucagon-like peptide-1 (GLP-1) is a potent therapeutic agent for the treatment of diabetes and has been proven to protect pancreatic β-cells from glucotoxicity; however, its mechanisms of action are not entirely understood. Autophagy is a dynamic lysosomal degradation process that can protect organisms against metabolic stress. Studies have shown that autophagy plays a protective role in the survival of pancreatic β-cells under high glucose conditions. In the present study, we explored the role of autophagy in GLP-1-induced protection of pancreatic β-cells exposed to high glucose. We demonstrated that the GLP-1 analogue liraglutide increased autophagy in rat INS-1 β-cells, and inhibition of autophagy abated the anti-apoptosis effect of liraglutide under high glucose conditions. Our results also showed that activation of 5'-AMP-activated protein kinase (AMPK) reduced liraglutide-induced autophagy enhancement and inhibited liraglutide-induced protection of INS-1 β-cells from high glucose. These data suggest that GLP-1 may protect β-cells from glucotoxicity through promoting autophagy by the modulation of AMPK. Deeper insight into the molecular mechanisms linking autophagy and GLP-1-induced β-cell protection may reveal novel therapeutic targets to preserve β-cell mass.

Background In patients with COVID 19, with or without history of diabetes, having hyperglycemia is an important factor in mortality; approximately 45.2% of patients with this disease have elevated blood glucose levels. Glucose variability (GV) has also been shown to be an independent predictor of mortality in critically ill patients. A patient is considered uncontrolled if he/she has a value above 36%. Objective: To determine whether GV is a prognostic factor for mortality in patients with COVID-19 admitted to the Intensive Care Unit (ICU) Methods All patients with positive PCR for COVID-19, who were admitted to the ICU of the Guatemalan Institute of Social Security during the months of May and June 2021, were subjected to glycosylated hemoglobin and periodic serum glucose samples to calculate the GV, using the coefficient of variation of glucose. Results To determine the normality of the sample, the Kolmogorov-Smirnov statistic was used, after that, it was determined which variables to include in the statistical model, Student's t-test was used for quantitative variables and chi-square for categorical variables. The following variables were included in the final model: Sex, History of diabetes, Glycosylated Hemoglobin, and GV (p=

Senescence marker protein 30 (SMP30) is an aging-related protein that participates in the regulation of tissue damage under various pathological conditions. However, the role of SMP30 in mediating high glucose (HG)-induced injury of retinal ganglion cells (RGCs) has not been fully determined. We found that SMP30 expression declined during HG stimulation in RGCs. Cellular functional studies showed that the up-regulation of SMP30 dramatically prohibited HG-evoked apoptosis, oxidative stress and inflammatory response in RGCs. Mechanism research reported that SMP30 overexpression led to the enhancement of nuclear factor erythroid 2-related factor (Nrf2) activation in HG-stimulated RGCs. Moreover, SMP30 overexpression enhanced the phosphorylation of Akt and glucogen synthase kinase-3β (GSK-3β), and the suppression of Akt markedly abolished SMP30-mediated Nrf2 activation in HG-stimulated RGCs. Additionally, the suppression of Nrf2 substantially reversed SMP30-overexpression-induced anti-HG injury effects in RGCs. Overall, these findings suggest that SMP30 protects against HG injury of RGCs by potentiating Nrf2 through regulation of the Akt/GSK-3β pathway. Our work underscores that SMP30/Akt/GSK-3β/Nrf2 may exert a vital role in mediating the injury of RGCs during diabetic retinopathy.

Background The bone-derived protein osteocalcin (OC), in its undercarboxylated (ucOC) form, has a beneficial effect on energy metabolism and may be a future therapeutic target for metabolic diseases. Increasing evidence suggests a link between ucOC and cardiovascular disease (CVD) development; however, the exact relationship is conflicting and unclear. Scope of review The aim of this review was to summarise the current research examining the interaction between OC and vascular dysfunction, the initiating stage in the development of atherosclerosis and CVD. Major conclusions In humans, the association between OC and vascular function is inconsistent. Several studies report that total OC (tOC) is associated with adverse function or beneficial function, whereas others report that tOC and ucOC has no effect on vascular function. The conflicting data are likely due to several methodological inconsistencies, in particular the lack of studies reporting circulating ucOC levels. In animal models, the direct administration of ucOC to isolated blood vessels ex vivo produced minimal changes in endothelial function, but importantly, no adverse responses. Finally, in human endothelial and vascular smooth muscle cells, ucOC treatment did not influence classical markers of cellular function, including endothelin-1, vascular adhesion molecule-1 and monocyte chemoattractant protein-1 after exposure to high glucose and inflammatory conditions. The lack of adverse effects in ex vivo and in vitro studies suggests that ucOC may be targeted as a future therapeutic for metabolic diseases, without the risk of detrimental effects in the vasculature. However, further studies are needed to confirm these findings and to investigate whether there is a direct beneficial influence of ucOC., Highlights • ucOC is implicated in the regulation of glucose homeostasis; but its role in the vasculature has been minimally reported. • Studies which examine the association between ucOC and vascular function in humans often report inconsistent outcomes. • In addition, ex vivo and in vitro studies have reported that ucOC likely does not directly regulate endothelial function. • ucOC may be targeted as a therapeutic treatment for metabolic diseases without a risk of adverse effects in the vasculature.

OBJECTIVES: Diabetic retinopathy (DR) is a complication of diabetes, caused by high blood glucose levels damaging to blood vessels in the retina. It can leading cause of blindness. Nobiletin is a polymethoxyflavone present in citrus fruit and peels, it has anti-cancer and anti-inflammatory effects. This study investigated the protective effects of nobiletin on retinal blood-retinal barrier (BRB) breakdown in high glucose-exposed human retinal endothelial cells and in db/db mouse eyes. METHODS: Human retinal microvascular endothelial cell (HRMVEC) were incubated in media exposed to 33 mM glucose in the absence and presence of 1–20 μM nobiletin up to 5 d. Antibodies ZO-1, MMP2, Bax and Bcl2 were used for western blot analysis. The in vivo animal model employed db/db mice orally administrated with 10 mg/kg of nobiletin. RESULTS: Non-toxic nobiletin declined the expression of ZO-1 which is retinal tight junction protein and Bcl2 expression in high glucose stimulation. when treated with nobiletin promoted the expression of ZO-1 and Bcl2 in HRMVEC cell. Also, of MMP2 and Bax was up-regulated by high glucose stimulation and nobiletin down-regulated high glucose induced expression of the MMP2 and Bax. In in vivo study, oral administration of 10 mg/kg nobiletin protected the retinal endothelial microvascular through recovering ZO-1 and Bcl2 expression as control. Also, nobiletin reduced tissue expressions of MMP2 and Bax. CONCLUSIONS: These results demonstrated that nobiletin may be a potent retinoprotective agent to prevent diabetes-associated microvascular abnormalities and BRB breakdown in retinal microvascular functions leading to retinal failure. FUNDING SOURCES: This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (2017R1A6A3A04011473).

Depressed Na+/K+-ATPase activity has long been reported to be involved in diabetic-related cardiomyocyte death and cardiac dysfunction. However, the nature of directly regulating Na+-K+-ATPase in diabetic-related myocardial diseases remains unknown. Hyperglycemia is believed as one of major factors responsible for diabetic-related myocardial apoptosis and dysfunction. In this study, whether inhibiting Na+-K+-ATPase by ouabain or activating Na+-K+-ATPase by DRm217 has functions on high glucose (HG) -induced myocardial injury was investigated. Here we found that addition of DRm217 or ouabain to HG-treated cells had opposite effects. DRm217 decreased but ouabain increased HG-induced cell injury and apoptosis. This was mediated by changing Na+-K+-ATPase activity and Na+-K+-ATPase cell surface expression. The inhibition of Na+-K+-ATPase endocytosis alleviated HG-induced ROS accumulation. Na+-K+-ATPase·c-Src dependent NADPH oxidase/ROS pathway was also involved in the effects of ouabain and DRm217 on HG-induced cell injury. These novel results may help us to understand the important role of the Na+-K+-ATPase in diabetic cardiovascular diseases.

Objective The purpose of the present study was to analyze the effects of glucose and shear stress on the morphology and density of endothelial cells, actin filamen, and the expression of VE-cadherin. Methods After confluency of endothelial cells (3–4 days), 22 mM of d -glucose was administered for 7 days. Endothelial cells were exposed to shear stress of 10 dyne/cm 2 for varied durations of 5, 8, 12, and 15 min. Morphology of ECs was observed using an inverted microscope before and after shear stress exposure. VE-cadherin and actin filament were analyzed immunohistochemically. Results Exposure to high glucose induces more shrinkage and the cell density decreased at 15 min. High glucose reduced actin filaments and the more globular ones, especially around the nuclei. There was a decline in VE-cadherin scores with significant differences between treatments with 5 mM and 22 mM of glucose. Conclusion Combination exposure of shear stress and high glucose changes morphology, reduces actin filament and VE-cadherin, of endothelial cells.

Type 1 diabetes mellitus complicated with pregnancy, know as diabetic embryopathy, is the cause of neonatal malformations and low for gestational age neonates. With the use of the whole-embryo culture system, it has been demonstrated that high glucose causes embryo dysmorphogenesis, and that oxidative stress appears to be the main mechanism. In recent years, beneficial effect of omega-3 fatty acids has been demonstrated in various diabetic models, and in diabetic complications. Since diabetic embryopathy is mediated probably through membrane lipoperoxidation, This study was designed to find if omega-3 fatty acids could ameliorate the effect of high glucose over the dysmorphogenesis of whole rat embryo in culture. Postimplantational rat embryos were cultured in hyperglycemic media, with addition of alpha-linolenic acid, and morphologic and morphometric parameters were registered. Also, lipoperoxidation and fatty acids composition were measured in cultured embryos. Growth of embryos cultured in presence of glucose was very affected, whereas lipoperoxidation was increased, and it was found that Triton X-100 causes similar results than glucose. Addition of low micromolar doses of alpha-linolenic acid overcome the effect of high glucose or Triton X-100, but higher doses does not ameliorates the effects of the carbohydrate or the detergent. Paradoxically, there are not significant changes in fatty acids composition, although the U/S fatty acids ratio shows an increasing tendency by high glucose and a normalizing tendency by omega-3 fatty acids. In conclusion, glucose and Triton X-100 induces in vitro dysmorphogenesis in post-implantational rat embryos associated with increased lipoperoxidation; and this nocive effect could be ameliorated by low micromolar doses of ALA.

Senescence of vascular endothelial cells promotes endothelial dysfunction and contributes to the progression of cardiovascular diseases. It is imperative to explore effective methods to suppress endothelial senescence. Herein, we found flavonoids including quercetin, puerarin and troxerutin, which exist in normal diet and extracted from traditional herbs, delayed d -glucose-induced endothelial senescence and restored endothelial functions. In the process, d -glucose amplified endogenous reactive oxygen species (ROS) level and subsequently promoted NLRP3 inflammasome activation. However, these alterations were reversed by flavonoids. Meanwhile, clearance of ROS or interference of NLRP3 function by specific siRNA attenuated high glucose-induced senescence but advanced the anti-senescent impact of flavonoids. On the contrary, the preventive effect of flavonoids on senescence was disturbed once NLRP3 inflammasome was overactivated. Our studies suggest that flavonoids can inhibit high glucose-induced endothelial premature senescence by suppressing NLRP3 inflammasome activity, which may be a useful therapeutic strategy to alleviate endothelial senescence-related vascular diseases.

Zymomonas mobilis cells were immobilized with a novel Fe2O3-modified polyvinyl alcohol (PVA) matrix to perform continuous ethanol fermentation with very high efficiency. The key operating parameters, such as glucose feeding concentration, dilution rate, and cells loading were optimized to achieve high bioethanol production performance at a high dilution rate and high glucose utilization efficiency. The optimal conditions for ethanol fermentation with the modified PVA immobilized cells were determined as: cell loading, 40% (w/v); glucose feeding concentration, 125 g/L; hydraulic retention time (HRT), 2 h (or 0.5 h⿿1 dilution rate). The bioethanol productivity was nearly doubled (31.09 g/L/h) when the PVA-immobilized cells were modified with 1% (w/v) Fe2O3. The modified PVA-immobilized cells could be utilized for more than 20 days without losing their activity.

Metformin improved vascular function in obese type 2 diabetic patients. 8-oxoguanine glycosylase (OGG1), a main DNA glycosylase, was involved in vascular complications in diverse diseases. However, whether metformin suppressed endothelial ROS via OGG1 pathway was unclear. Human umbilical vein endothelial cells (HUVECs) were exposed to HG (high glucose) or HG with metformin. OGG1 and AMPfα levels were measured after metformin treatment while HG-caused ROS was measured by DHE prober. Diabetic mice were induced by daily intraperitoneal injections of streptozotocin (STZ). Metformin reduced Endothelial ROS caused by HG via upregulating OGG1. Additionally, OGG1 protein expression was dependent on its mRNA stability, which was reversed by genetic inhibition of AMPKα and Lin-28. The role of OGG1 on ROS stimulated by HG was partially dependent on NFKB/NOX4 pathway in HUVECs. These results suggested that metformin contacted HG-induced endothelial ROS via AMPKα/Lin-28/OGG1 pathway.

Aims The objectives of this study were to explore physiological and pathological changes in the corneas of diabetic rats by intervening in the expression of silent information regulator 1 (Sirt1) and to investigate whether Sirt1 can regulate the activation of endoplasmic reticulum stress (ERS) while influencing corneal epithelial cell apoptosis under high glucose conditions. Materials and methods Using 8-week old Sprague-Dawley rats, we established a model of type 1 diabetes, with or without Sirt1 intervention. Clinical evaluation was performed once per week. Primary rat corneal epithelial cells (RCECs) were cultured by combining Sirt1 intervention under high glucose conditions. Generation of reactive oxygen species (ROS), apoptosis, and the expression of Sirt1 and ERS-related proteins were evaluated in rat corneal tissues and RCECs. Key findings During the intervention, clinical evaluation of the ocular surface, ROS generation, apoptosis, and protein expression of ERS-related proteins in corneal tissue and cultured RCECs were altered with Sirt1expression levels. Significance Sirt1 expression influences the pathological progression of diabetic keratopathy, plays an important role in regulating the ERS pathway, and decreases corneal epithelial cell apoptosis.

A comparative controlled study was carried out to evaluate the performance of Saccharomyces cerevisiae var. boulardii to act as brewer's yeast for potential probiotic beer production. The yeast performance on the beer wort (cell growth, sugar consumption and products production) was compared with the conventional top-fermentation Saccharomyces cerevisiae. To improve the yeast metabolism, changes were made in the malt concentration of the wort recipe and in the ramp mash temperature profile, emphasizing β-amylase activity to provide high glucose concentration in the wort. Next, metabolism close to conventional brewer's yeast was achieved. Saccharomyces cerevisiae var. boulardii survivability in the beer and after in vitro gastrointestinal transit was assessed as the indicative of potential probiotic properties in the beer. The yeast population did not decrease dramatically over the storage period, withstanding alive above the minimal dose prescribed to confer health benefit to the host. The present work shows an alternative method to produce potential probiotic wheat beer. However, Saccharomyces cerevisiae var. boulardii metabolism is still not completely understood, especially the metabolism on the wort sugar and the optimized conditions of the wort recipe and ramp mash temperature profile.

Introduction Epidemiological and preclinical studies have pointed out a correlation between hyperglycemia and increasing risk of heart failure. In cardiomyocytes, hyperglycemia has been shown to alter Ca2+ signaling via CaMKII a downstream effector of Epac2, a key player in Ca2+ mishandling. However the role of Epac2 in high-glucose (HG) mediated Ca2+ dysregulation is unclear. Objective To test the involvement of Epac2 in hyperglycemia-mediated cardiac Ca2+ mishandling. Method Ca2+ signaling was measured by confocal microscopy in Fluo-4 loaded ventricular cardiomyocytes isolated from C57BL6 and Epac2-KO mice and treated with different glucose concentrations. Results HG (500 mg/dL) enhanced the occurrence of Ca2+ sparks and pro-arrhythmic events in WT mice but not in Epac2 KO. This increase was prevented by Epac2 pharmacological inhibition (ESI-05 10 μM) (Ca2+ sparks frequency [#/s/100 μm]: 1.07 ± 0.39 for HG vs. 0.16 ± 0.06 for normal glucose [NG, 100 mg/dL], P Conclusion Our work shows an Epac2 O-GlcNAcylation by HG responsible for pro-arrhythmic SR Ca2+ leak in cardiomyocytes, a new mechanism that might be involved in diabetic cardiomyopathy.

Decomposition of soil organic matter (SOM) protected within aggregates can be accelerated via priming effect (PE) by the addition of fresh substrates. However, the knowledge of the sources of mineralization and PE in aggregate size classes is absent. We applied the three-source-partitioning isotopic (14C + δ13C) approach to determine how aggregate size classes affect the contribution of three C sources (substrate added, recent and old SOM) to CO2 efflux and PE depending on the amount of added primer. Soil from a field with 3 years of maize cropping (C4 plants) after long-term C3 vegetation was used to differentiate between recent C (C4 C; C; >3 years). Soil samples were separated into three aggregate size classes (>2 mm, 2–0.25 mm macroaggregates and The proportion of glucose mineralized to CO2 increased with decreasing aggregate size, but 14C incorporation into microbial biomass decreased, indicating higher C use efficiency in macroaggregates compared with microaggregates. The short-time PE was positive and was accompanied by a rapid reduction of dissolved organic C. After 49 days, the PE was higher in macro-versus microaggregates at both glucose levels. Positive PE induced by a low glucose level was observed only in large macroaggregates (>2 mm), but was observed in both macroaggregates (>0.25 mm) and microaggregates ( C than old C3 C in larger macroaggregates under a low glucose level. The relative contribution of recent C4 C to primed CO2 increased from macroaggregates (37.8%) to microaggregates (100%) after high glucose amendment. Therefore, increasing glucose addition stimulated the decomposition of old C3 C in macroaggregates, but not in microaggregates. This indicates that microaggregates protect SOM against decomposition better than macroaggregates, and consequently, microaggregates can be considered as a potential reservoir for long-term C sequestration. Concluding, aggregate size is crucial for SOM decomposition, and it determines the source of PE and thus the protection of sequestrated C. The effects of the added primer on C sources involved in PE depend on the aggregate size.

This study examined the effect of delphinidin on high glucose-induced cell proliferation and collagen synthesis in mesangial cells. Glucose dose-dependently (5.6-25 mM) increased cell proliferation and collagen I and IV mRNA levels, whereas pretreatment with delphinidin (50 mM) prevented cell proliferation and the increased collagen mRNA levels induced by high glucose (25 mM). High glucose increased reactive oxygen species (ROS) generation, and this was suppressed by pretreating delphinidin or the antioxidant N-acetyl cysteine. NADPH oxidase (NOX) 1 was upregulated by high glucose, but pretreatment with delphinidin abrogated this upregulation. Increased mitochondrial superoxide by 25 mM glucose was also suppressed by delphinidin. The NOX inhibitor apocynin and mitochondriatargeted antioxidant Mito TEMPO inhibited ROS generation and cell proliferation induced by high glucose. Phosphorylation of extracellular signal regulated kinase (ERK) 1/2 was increased by high glucose, which was suppressed by delphinidin, apocynin or Mito TEMPO. Furthermore, PD98059 (an ERK1/2 inhibitor) prevented the high glucose-induced cell proliferation and increased collagen mRNA levels. Transforming growth factor (TGF)-beta protein levels were elevated by high glucose, and pretreatment with delphinidin or PD98059 prevented this augmentation. These results suggest that delphinidin prevents high glucose-induced cell proliferation and collagen synthesis by inhibition of NOX-1 and mitochondrial superoxide in mesangial cells. (C) 2016 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license.

The traditional computational model of the pancreatic islets of Langerhans is a lattice of β -cells connected with gap junctions. Numerous studies have investigated the behavior of networks of coupled β -cells and have shown that gap junctions synchronize bursting strongly. This simplistic architecture of islets, however, seems increasingly untenable at the face of recent experimental advances. In a microfluidics experiment on isolated islets, Rocheleau et al. (2004) showed a failure of penetration of excitation when one end received high glucose and other end was not excited sufficiently; this suggested that gap junctions may not be efficient at inducing synchrony throughout the islet. Recently, Stozer et al. (2013) have argued that the functional networks of β -cells in an islet are small world. Their results implicate the existence of a few long-range connections among cells in the network. The physiological reason underlying this claim is not well understood. These studies cast doubt on the original lattice model that largely predict an all-or-none synchrony among the cells. Here we have attempted to reconcile these observations in a unified framework. We assume that cells in the islet are coupled randomly to their nearest neighbors with some probability, p . We simulated detailed β -cell bursting in such islets. By varying p systematically we were led to network parameters similar to those obtained by Stozer et al. (2013). We find that the networks within islets break up into components giving rise to smaller isles within the super structure— isles-within-islets , as it were. This structure can also account for the partial excitation seen by Rocheleau et al. (2004). Our updated view of islet architecture thus explains the paradox how islets can have strongly synchronizing gap junctions, and be weakly coordinated at the same time.

To investigate the effect and action mechanism of resveratrol on the vascular endothelial cell by high glucose treatment. Primarily cultured human umbilical vein endothelial cells (HUVECs) were pretreated by resveratrol (0.2μmol/L) and holding for 6h, and then cultured in Dulbecco Modified Eagle Medium (DMEM) within 0.45mmol/L of palmimte acid and 32.8mmol/L of glucose, which is holding for 12h. The cells were collected to analyze the expression of E-selected element. Supernatant of cultured cells, induced by 100nmol/L insulin for 30min, was used to analyze the nitric oxide content. Compared with normal control cells, the secretion of nitric oxide is stimulated by insulin decrease, however, the expression of E-selected element increased in HUVEC. Resveratrol treatment increased the secretion of nitric oxide stimulated by insulin and decreased the expression of E-selected element and partly counteracts the impairment of high glucose and palmitate acid on the function of endothelial cells. Resveratrol can improve and protect the function of high glucose and fatty acid cultured endothelial cell, and therefore may be a promising medicine in the prevention or therapy of diabetic macrovascular diseases.

Glycogen, a glucose homopolymer with many glucose chains, is the primary blood-sugar reservoir in many organisms. It comprises β particles (∼20 nm) which can bind together to form large α particles with a rosette morphology. When dimethyl sulfoxide (DMSO) is added to glycogen from diabetic livers, α particles break apart to β particles (‘fragility’), possibly due to H-bond disruption; this is not seen in healthy livers. Glycogen α and β particles, and α-particle fragility, are observed in mammals and bacteria, and are examined here in the worm Caenorhabditis elegans, with glycogen from two C. elegans strains, cultured in normal and high-glucose conditions. There were mainly β particles, with some large α particles. Most particles were fragile in DMSO. Growing in a high-glucose medium results in more long chains and more fragility, consistent with previous observations in diabetic animal models. Why high glucose levels facilitate fragility is worthy of further investigation.

Increasing research indicates that hyperglycemia plays a crucial role in the progression of diabetic nephropathy (DN); however, effective treatment for preventing or slowing DN progression are seriously lacking. Although salidroside (SAL) has been demonstrated to have a positive anti-diabetic effect, the cellular mechanisms remain unclear. FG-4592, a novel prolyl hydroxylase inhibitor, was used to regulate HIF-1α and HIF-2α expression. The present study aimed to explore the underlying mechanisms of SAL and FG-4592 on high glucose (HG)-induced rat glomerular endothelial cells (rGECs) injury. HG-cultured rGECs were used to induce a diabetic environment. An MTT assay, RT-qPCR, Western blot, flow cytometry, and immunofluorescent staining were performed to investigate the effects of SAL on HG-induced rGECs injury. FG-4592 and SAL protected rGECs against HG-induced injury by increasing cellular viability and reducing the cell apoptosis rate. SAL and FG-4592 downregulated PHD-2 expression and upregulated HIF-1α and HIF-2α expression. In conclusion, our findings suggest that SAL and FG-4592 ameliorate HG-induced rGEC injury by upregulating HIF expression, indicating that SAL and FG-4592 might be favorable for further DN-treatment.

α-Mangostin play crucial role in several cellular progress, including hyperglycemia-induced inhibition of cell growth and promotion of cell apoptosis. Increasing evidence displayed the important roles of lncRNAs and their potential as novel targets for drug development in human disease. However, there is rare study to comprehensively and systematically explore the role and underlying mechanism of lncRNAs in human umbilical vein endothelial cells (HUVECs) under hyperglycemia with or without α-Mangostin. In this study, we firstly found that α-Mangostin reduced the high glucose-induced inhibition of cell proliferation and migration potential of HUVECs. Then, we performed RNA-seq to dissect the expression profiles of lncRNAs in HUVECs treated with high glucose or high glucose supplemented with α-Mangostin. The results showed that the expression of H19 and HE4 was down-regulated by high glucose and further, α-Mangostin restored the high glucose-induced inhibition of H19 and HE4 expression. Further examination demonstrated that the modulation of the H19 and HE4 expression affected the function of α-Mangostin in hyperglycemia. In addition, H19 regulated HE4 expression via the modulation of the miR-140 expression. Finally, we showed that H19 exerted its function via the modulation of H19/miR-140/HE4 in hyperglycemia with α-Mangostin. In summary, this study is the first to comprehensively identify the lncRNAs/mRNAs network in hyperglycemia with or without α-Mangostin, highlighting a novel regulatory pathway in hyperglycemia with or without α-Mangostin and indicating the potential therapeutic role of α-Mangostin in diabetes mellitus.

Five novel phragmalin-type limonoids, carapanolides M–Q (1–5), together with two mexicanolide-type limonoids, carapanolides R–S (6–7), were isolated from the oil of Carapa guianensis AUBLET (Meliaceae) seeds, a traditional medicine in Brazil and Latin American countries. Their structures were elucidated on the basis of spectroscopic analyses using 1D and 2D NMR techniques and a single-crystal X-ray diffraction analysis. Compounds 1–7 along with 12 known limonoids, 8–19, isolated from the flower and seed oil of C. guianensis were assayed to determine their triglyceride metabolism-promoting activities in the high glucose-pretreated human hepatocellular carcinoma cell line, HepG2. Gedunin-type limonoid: 14 (% of control at 10 μM: 35.4±3.9), 13 (55.0±3.6 at 10 μM), and 18 (75.4±4.2 at 10 μM) significantly reduced TG levels in hepatocytes.

Pathological conditions are bound to affect the molecules on erythrocytes, and accordingly affect their functions. Chondroitin sulphate/dermatan sulphate (CS/DS), one of the classes of molecules found to be expressed in erythrocytes was previously observed by us to be either overexpressed in diabetic condition or undergo structural changes in hypercholesterolemic condition. Both of them had implications on their binding to extracellular matrix components (ECM). In the present work, we have explored the quantitative changes in erythrocyte glycosaminoglycans (GAGs) and their role in erythrocyte binding towards ECM components in the combined milieu of both diabetes and hypercholesterolemia (SFHD). Membrane cholesterol was significantly higher in SFHD group compared to control (SFC) and diabetic groups (SFD). Interestingly, there were no quantitative changes in CS/DS compared to SFC erythrocytes, but showed significantly increased cytoadherence to selected ECM components to various extents. Binding was partly dependent on CS/DS as digesting the chains resulted in relatively decreased cytoadherence. It also showed significantly increased binding to chondroitin sulphate and heparan sulphate. Thus, combined milieu of high glucose and high cholesterol can have more deleterious consequences than either of them independently.