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Introduction: The process of vascular calcification has severe clinical consequences in a number of diseases, including diabetes, atherosclerosis, and end-stage renal disease. In the present study, we investigated the effect of policosanol (Poli), genistein (Gen), and vitamin D (VitD) separately and in association to evaluate the possible synergistic action on inorganic phosphate (Pi)-induced calcification of vascular smooth muscle cells (VSMCs). Methods: Primary human VSMCs were cultured with either growth medium or growth medium supplemented with calcium and phosphorus (calcification medium) in combination with Poli, Gen, and VitD. Alizarin Red staining, mineralization, and the protein expression of RUNX2 and superoxide dismutase-2 (SOD2) were investigated. Results: All three substances tested were effective at reducing osteogenic differentiation of VSMCs in a dose-dependent manner. Poli+Gen, Poli+VitD, Gen+VitD treatment induced a greater inhibition of calcification and RUNX2 expression compared to single compounds treatments. Moreover, the association of Poli+Gen+VitD (Reduplaxin®) was more effective at inhibiting VSMCs mineralization and preventing the increase in RUNX2 expression induced by calcification medium but not modified SOD2 expression. Conclusions: The association of Pol, Gen, and VitD (Reduplaxin®) has an additive inhibitory effect on the calcification process of VSMCs induced in vitro by a pro-calcifying medium.

BackgroundCurrent guidelines for nonalcoholic fatty liver disease (NAFLD) recommend high volumes and/or intensities of physical activity (PA), the achievement of which generally requires participation in supervised exercise training programs that however are difficult to implement in routine clinical practice. Conversely, counselling interventions may be more suitable, but result in only modest increases in moderate-to-vigorous-intensity PA (MVPA). This study assessed whether a counseling intervention for increasing PA and decreasing sedentary time (SED-time) is effective in improving NAFLD markers in people with type 2 diabetes.MethodsThree-hundred physically inactive and sedentary patients were randomized 1:1 to receive one-month theoretical and practical counseling once-a-year (intervention group) or standard care (control group) for 3 years. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltranspeptidase (γGT) levels were measured and fatty liver index (FLI), hepatic steatosis index (HSI), and visceral adiposity index (VAI) were calculated. Total PA volume, light-intensity PA (LPA), moderate-to-vigorous-intensity PA (MVPA), and SED-time were objectively measured by an accelerometer.ResultsThroughout the 3-year period, NAFLD markers did not change in the control group, whereas ALT, γGT, FLI, and HSI decreased in the intervention group, with significant between-group differences, despite modest MVPA increases, which however were associated with larger decrements in SED-time and reciprocal increments in LPA. Mean changes in NAFLD markers varied according to quartiles of (and correlated with) changes in MVPA (all markers) and SED-time, LPA, and PA volume (ALT, γGT, and HSI). Mean changes in MVPA or PA volume were independent predictors of changes in NAFLD markers. When included in the models, change in cardiorespiratory fitness and lower body muscle strength were independently associated with some NAFLD markers.ConclusionA behavior change involving all domains of PA lifestyle, even if insufficient to achieve the recommended MVPA target, may provide beneficial effects on NAFLD markers in people with type 2 diabetes.

The adipose organ adapts and responds to internal and environmental stimuli by remodeling both its cellular and extracellular components. Under conditions of energy surplus, the subcutaneous white adipose tissue (WAT) is capable of expanding through the enlargement of existing adipocytes (hypertrophy), followed by de novo adipogenesis (hyperplasia), which is impaired in hypertrophic obesity. However, an impaired hyperplastic response may result from various defects in adipogenesis, leading to different WAT features and metabolic consequences, as discussed here by reviewing the results of the studies in animal models with either overexpression or knockdown of the main molecular regulators of the two steps of the adipogenesis process. Moreover, impaired WAT remodeling with aging has been associated with various age-related conditions and reduced lifespan expectancy. Here, we delve into the latest advancements in comprehending the molecular and cellular processes underlying age-related changes in WAT function, their involvement in common aging pathologies, and their potential as therapeutic targets to influence both the health of elderly people and longevity. Overall, this review aims to encourage research on the mechanisms of WAT maladaptation common to conditions of both excessive and insufficient fat tissue. The goal is to devise adipocyte-targeted therapies that are effective against both obesity- and age-related disorders.

The (pro)renin receptor ((P)RR), a versatile protein found in various organs, including the kidney, is implicated in cardiometabolic conditions like diabetes, hypertension, and dyslipidemia, potentially contributing to organ damage. Importantly, changes in (pro)renin/(P)RR system localization during renal injury, a critical information base, remain unexplored. This study investigates the expression and topographic localization of the full length (FL)-(P)RR, its ligands (renin and prorenin), and its target cyclooxygenase-2 and found that they are upregulated in three distinct animal models of renal injury. The protein expression of these targets, initially confined to specific tubular renal cell types in control animals, increases in renal injury models, extending to glomerular cells. (P)RR gene expression correlates with protein changes in a genetic model of focal and segmental glomerulosclerosis. However, in diabetic and high-fat-fed mice, (P)RR mRNA levels contradict FL-(P)RR immunoreactivity. Research on diabetic mice kidneys and human podocytes exposed to diabetic glucose levels suggests that this inconsistency may result from disrupted intracellular (P)RR processing, likely due to increased Munc18-1 interacting protein 3. It follows that changes in FL-(P)RR cellular content mechanisms are specific to renal disease etiology, emphasizing the need for consideration in future studies exploring this receptor’s involvement in renal damage of different origins.

The hypoxia-inducible factor-1α (HIF-1α), a key player in the adaptive regulation of energy metabolism, and the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2), a critical regulator of glucose consumption, are the main drivers of the metabolic rewiring in cancer cells. The use of glycolysis rather than oxidative phosphorylation, even in the presence of oxygen (i.e., Warburg effect or aerobic glycolysis), is a major metabolic hallmark of cancer. Aerobic glycolysis is also important for the immune system, which is involved in both metabolic disorders development and tumorigenesis. More recently, metabolic changes resembling the Warburg effect have been described in diabetes mellitus (DM). Scientists from different disciplines are looking for ways to interfere with these cellular metabolic rearrangements and reverse the pathological processes underlying their disease of interest. As cancer is overtaking cardiovascular disease as the leading cause of excess death in DM, and biological links between DM and cancer are incompletely understood, cellular glucose metabolism may be a promising field to explore in search of connections between cardiometabolic and cancer diseases. In this mini-review, we present the state-of-the-art on the role of the Warburg effect, HIF-1α, and PKM2 in cancer, inflammation, and DM to encourage multidisciplinary research to advance fundamental understanding in biology and pathways implicated in the link between DM and cancer.

Modern lifestyle changes, especially the consumption of a diet high in salt, sugar, and fat, have contributed to the increasing incidence and prevalence of chronic metabolic diseases such as diabetes, obesity, and gout. Changing lifestyles continuously shape the gut microbiota which is closely related to the occurrence and development of metabolic diseases due to its specificity of composition and structural diversity. A large number of pathogenic bacteria such as Yersinia, Salmonella, Shigella, and pathogenic E. coli in the gut utilize the type III secretion system (T3SS) to help them resist host defenses and cause disease. Although the T3SS is critical for the virulence of many important human pathogens, its relationship with metabolic diseases remains unknown. This article reviews the structure and function of the T3SS, the disruption of intestinal barrier integrity by the T3SS, the changes in intestinal flora containing the T3SS in metabolic diseases, the possible mechanisms of the T3SS affecting metabolic diseases, and the application of the T3SS in the treatment of metabolic diseases. The aim is to provide insights into metabolic diseases targeting the T3SS, thereby serving as a valuable reference for future research on disease diagnosis, prevention, and treatment. [ABSTRACT FROM AUTHOR]

Setting up a sports club in Romania takes more than a coach and a gym or field, it is a complicated and elaborated system that needs to follow certain legal steps and a minimum marketing plan. Usually information about the ”how to” is not available on the government institutions and is scattered in bits and pieces on various blogs and websites, and it gets so complex that most people call for help an legal attorney. The following essay will take you into the fine details that make a difference between a success and failure, of a sports club in Romania. The paper work and legal steps that are necessary in founding a sports club, the human resources that are needed, the way you can attract sponsors or make legal contracts for members or staff.

Background: One of the most common microvascular complications of diabetes is diabetic kidney disease (DKD). The Huajuxiaoji formula (HJXJ) has shown clinical efficacy for DKD; however, its regulatory mechanisms against DKD remain elusive. We investigated NLRP3 inflammasome and the mechanisms of HJXJ by which HJXJ alleviates DKD. Methods: Phenyl sulfate (PS) was used to establish DKD models. HJXJ was administered to mice through intragastric or made into a pharmaceutical serum for the cell cultures. Biological indicator levels in mouse blood and urine were analyzed, and kidney tissues were used for HE, Masson, and PAS staining. ELISA and western blotting were used to detect inflammatory cytokines and protein levels, respectively. Reactive oxygen species (ROS) production and pyroptosis were evaluated using flow cytometry. Lentiviral vector‐mediated overexpression of NLRP3 was performed to determine whether NLRP3 participates in the antipyroptotic effect of HJXJ. Results: HJXJ significantly reduced the severity of the injury and, in a dose‐dependent manner, decreased the levels of biological markers including creatinine, blood urea nitrogen, urine protein, and endotoxin, as well as inflammatory cytokines such as interleukin (IL)‐1β, IL‐18, tumor necrosis factor‐α, and IL‐6 in DKD mice. Treatment with HJXJ reversed the downregulation of podocin, nephrin, ZO‐1, and occludin and upregulated ROS, NLRP3, Caspase‐1 P20, and GSDMD‐N induced by PS. Moreover, the upregulation of NLRP3 expression increased the number of cells positive for pyroptosis. HJXJ suppressed pyroptosis and inflammasome activation by inhibiting NLRP3 expression. Conclusions: Generally, HJXJ has the potential to reduce DKD injury and exerts anti‐DKD effects by inhibiting the NLRP3‐mediated NLRP3 inflammasome activation and pyroptosis in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Abstract Background Type 1 and 2 diabetes confer an increased risk of pancreatic cancer (PaC) of similar magnitude, suggesting a common mechanism. The recent finding that PaC incidence increases linearly with increasing fasting glucose levels supports a central role for hyperglycaemia, which is known to cause carbonyl stress and advanced glycation end-product (AGE) accumulation through increased glycolytic activity and non-enzymatic reactions. This study investigated the impact of hyperglycaemia on invasive tumour development and the underlying mechanisms involved. Methods Pdx1-Cre;LSL-Kras G12D/+ mice were interbred with mitosis luciferase reporter mice, rendered diabetic with streptozotocin and treated or not with carnosinol (FL-926-16), a selective scavenger of reactive carbonyl species (RCS) and, as such, an inhibitor of AGE formation. Mice were monitored for tumour development by in vivo bioluminescence imaging. At the end of the study, pancreatic tissue was collected for histology/immunohistochemistry and molecular analyses. Mechanistic studies were performed in pancreatic ductal adenocarcinoma cell lines challenged with high glucose, glycolysis- and glycoxidation-derived RCS, their protein adducts AGEs and sera from diabetic patients. Results Cumulative incidence of invasive PaC at 22 weeks of age was 75% in untreated diabetic vs 25% in FL-926-16-gtreated diabetic and 8.3% in non-diabetic mice. FL-926-16 treatment suppressed systemic and pancreatic carbonyl stress, extracellular signal-regulated kinases (ERK) 1/2 activation, and nuclear translocation of Yes-associated protein (YAP) in pancreas. In vitro, RCS scavenging and AGE elimination completely inhibited cell proliferation stimulated by high glucose, and YAP proved essential in mediating the effects of both glucose-derived RCS and their protein adducts AGEs. However, RCS and AGEs induced YAP activity through distinct pathways, causing reduction of Large Tumour Suppressor Kinase 1 and activation of the Epidermal Growth Factor Receptor/ERK signalling pathway, respectively. Conclusions An RCS scavenger and AGE inhibitor prevented the accelerating effect of diabetes on PainINs progression to invasive PaC, showing that hyperglycaemia promotes PaC mainly through increased carbonyl stress. In vitro experiments demonstrated that both circulating RCS/AGEs and tumour cell-derived carbonyl stress generated by excess glucose metabolism induce proliferation by YAP activation, hence providing a molecular mechanism underlying the link between diabetes and PaC (and cancer in general).

Environmental safeguards promote innovative construction technologies for sustainable pavements. On these premises, this study investigated four hot mix asphalt (HMA) mixtures—i.e., A, B, C, and D—for the railway sub-ballast layer with 0%, 10%, 20%, and 30% reclaimed asphalt pavement (RAP) by total aggregate mass and a rejuvenator additive, varying the bitumen content between 3.5% and 5.0%. Both Marshall and gyratory compactor design methods have been performed, matching the stability, indirect tensile strength, and volumetric properties of each mixture. Dynamic stiffness and fatigue resistance tests provided mechanical performances. Laboratory results highlighted that the RAP and the rejuvenator additive increase the mechanical properties of the mixtures. In addition, the comparative analysis of production costs revealed up to 20% savings as the RAP content increased, and the life cycle impact analysis (LCIA) proved a reduction of the environmental impacts (up to 2% for resource use-fossils, up to 7% for climate change, and up to 13% for water use). The experimental results confirm that HMA containing RAP has mechanical performances higher than the reference mixture with only virgin raw materials. These findings could contribute to waste management and reduce the environmental and economic costs, since the use of RAP in the sub-ballast is not, so far, provided in the Italian specifications for railway construction.

Oxidative stress and hypoxia-inducible factors (HIFs) have been implicated in the pathogenesis of diabetic cardiovascular and renal diseases. Reactive oxygen species (ROS) mediate physiological and pathophysiological processes, being involved in the modulation of cell signaling, differentiation, and survival, but also in cyto- and genotoxic damage. As master regulators of glycolytic metabolism and oxygen homeostasis, HIFs have been largely studied for their role in cell survival in hypoxic conditions. However, in addition to hypoxia, other stimuli can regulate HIFs stability and transcriptional activity, even in normoxic conditions. Among these, a regulatory role of ROS and their byproducts on HIFs, particularly the HIF-1α isoform, has received growing attention in recent years. On the other hand, HIF-1α and HIF-2α exert mutually antagonistic effects on oxidative damage. In diabetes, redox-mediated HIF-1α deregulation contributes to the onset and progression of cardiovascular and renal complications, and recent findings suggest that deranged HIF signaling induced by hyperglycemia and other cellular stressors associated with metabolic disorders may cause mitochondrial dysfunction, oxidative stress, and inflammation. Understanding the mechanisms of mutual regulation between HIFs and redox factors and the specific contribution of the two main isoforms of HIF-α is fundamental to identify new therapeutic targets for vascular complications of diabetes.

Background: Current guidelines for nonalcoholic fatty liver disease (NAFLD) recommend high volumes and/or intensities of physical activity (PA), the achievement of which generally requires participation in supervised exercise training programs that however are difficult to implement in routine clinical practice. Conversely, counselling interventions may be more suitable, but result in only modest increases in moderate-to-vigorous-intensity PA (MVPA). This study assessed whether a counseling intervention for increasing PA and decreasing sedentary time (SED-time) is effective in improving NAFLD markers in people with type 2 diabetes. Methods: Three-hundred physically inactive and sedentary patients were randomized 1:1 to receive one-month theoretical and practical counseling once-a-year (intervention group) or standard care (control group) for 3 years. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltranspeptidase (γGT) levels were measured and fatty liver index (FLI), hepatic steatosis index (HSI), and visceral adiposity index (VAI) were calculated. Total PA volume, light-intensity PA (LPA), moderate-to-vigorous-intensity PA (MVPA), and SED-time were objectively measured by an accelerometer. Results: Throughout the 3-year period, NAFLD markers did not change in the control group, whereas ALT, γGT, FLI, and HSI decreased in the intervention group, with significant between-group differences, despite modest MVPA increases, which however were associated with larger decrements in SED-time and reciprocal increments in LPA. Mean changes in NAFLD markers varied according to quartiles of (and correlated with) changes in MVPA (all markers) and SED-time, LPA, and PA volume (ALT, γGT, and HSI). Mean changes in MVPA or PA volume were independent predictors of changes in NAFLD markers. When included in the models, change in cardiorespiratory fitness and lower body muscle strength were independently associated with some NAFLD markers. Conclusion: A behavior change involving all domains of PA lifestyle, even if insufficient to achieve the recommended MVPA target, may provide beneficial effects on NAFLD markers in people with type 2 diabetes. [ABSTRACT FROM AUTHOR]

The adipose organ adapts and responds to internal and environmental stimuli by remodeling both its cellular and extracellular components. Under conditions of energy surplus, the subcutaneous white adipose tissue (WAT) is capable of expanding through the enlargement of existing adipocytes (hypertrophy), followed by de novo adipogenesis (hyperplasia), which is impaired in hypertrophic obesity. However, an impaired hyperplastic response may result from various defects in adipogenesis, leading to different WAT features and metabolic consequences, as discussed here by reviewing the results of the studies in animal models with either overexpression or knockdown of the main molecular regulators of the two steps of the adipogenesis process. Moreover, impaired WAT remodeling with aging has been associated with various age-related conditions and reduced lifespan expectancy. Here, we delve into the latest advancements in comprehending the molecular and cellular processes underlying age-related changes in WAT function, their involvement in common aging pathologies, and their potential as therapeutic targets to influence both the health of elderly people and longevity. Overall, this review aims to encourage research on the mechanisms of WAT maladaptation common to conditions of both excessive and insufficient fat tissue. The goal is to devise adipocyte-targeted therapies that are effective against both obesity- and age-related disorders. [ABSTRACT FROM AUTHOR]

Early structural anomalies identification allows to hold maintenance activities that avoid loss of both economic resources and human life. This is extremely important for crucial infrastructures like railway bridges. This paper illustrates the structural health monitoring approach applied to a simply supported prestressed concrete railway bridge. In the framework of long-term monitoring, both static quantities (displacements, strains, and rotations) and environmental measurements (temperatures) have been recorded. Machine learning techniques, Extreme Gradient boosting machine and Multi-Layer Perceptron, have been exploited to build regression correlation models associated with the undamaged structural condition after adequate pre-processing operations. In this way, alarm thresholds based on the expected residuals between the predicted structural quantities and the measured ones, have been defined. The thresholds turned out to be able to catch early-stage anomalies not pointed out by traditional damage thresholds based on the design values. The proposed damage index is chosen as the moving median of the residuals, allowing a significant reduction of false alarms. The used correlation models and the obtained results represent a starting point for the generalization of this approach to the bridges belonging to the same static typology. [ABSTRACT FROM AUTHOR]

In recent decades, relevant environmental and economic reasons have driven an increasing interest in using a large amount of recycled aggregate in replacement of natural ones to produce mortar and concrete. The present study aims to investigate the effect of substituting 100% of natural sand with recycled aggregate on fresh properties, mechanical properties, and the durability of a thixotropic and a self-leveling mortar. Recycled aggregate was characterized using X-ray diffractometry and energy-dispersive X-ray spectroscopy. Its morphology was investigated using scanning electron microscopy and automated morphological imaging. Recycled aggregate mortars showed a moderate decline in initial workability, as well as higher shrinkage and porosity than the control ones. The compressive strength of self-leveling mortars produced with recycled aggregate was only 6% lower than mortars produced with natural sand. The gap increased to 40% in the case of thixotropic mortars. The self-leveling recycled aggregate mortar showed equivalent resistance to freeze–thaw cycles and better sulfate resistance than the control one. The thixotropic recycled aggregate mortar showed comparable sulphate resistance and only slightly lower resistance to freeze–thaw cycles than the control one. Their capacity to relief stresses, due to hydraulic pressures and the formation of expansive products, arises from their higher porosity. Thermal stability of the prepared mortars, after a curing period of 90 days, up to 700 °C, was also investigated. A significant decrease in ultrasonic pulse velocity is observed in the 200–400 °C interval for all the mortars, due to the dehydration–dehydroxylation of calcium silicate hydrate. The overall decline in the strength of both the recycled aggregate mortars was comparable to the control ones. The results reported in the present investigation suggest that the selection of high-quality recycled aggregate helps to obtain good-quality mortars when a large amount of natural sand is replaced.

Carbonyl stress is a condition characterized by an increase in the steady-state levels of reactive carbonyl species (RCS) that leads to accumulation of their irreversible covalent adducts with biological molecules. RCS are generated by the oxidative cleavage and cellular metabolism of lipids and sugars. In addition to causing damage directly, the RCS adducts, advanced glycation end-products (AGEs) and advanced lipoxidation end-products (ALEs), cause additional harm by eliciting chronic inflammation through receptor-mediated mechanisms. Hyperglycemia- and dyslipidemia-induced carbonyl stress plays a role in diabetic cardiovascular complications and diabetes-related cancer risk. Moreover, the increased dietary exposure to AGEs/ALEs could mediate the impact of the modern, highly processed diet on cardiometabolic and cancer risk. Finally, the transient carbonyl stress resulting from supraphysiological postprandial spikes in blood glucose and lipid levels may play a role in acute proinflammatory and proatherogenic changes occurring after a calorie dense meal. These findings underline the potential importance of carbonyl stress as a mediator of the cardiometabolic and cancer risk linked to today’s unhealthy diet. In this review, current knowledge in this field is discussed along with future research courses to offer new insights and open new avenues for therapeutic interventions to prevent diet-associated cardiometabolic disorders and cancer.

The (pro)renin receptor ((P)RR), a versatile protein found in various organs, including the kidney, is implicated in cardiometabolic conditions like diabetes, hypertension, and dyslipidemia, potentially contributing to organ damage. Importantly, changes in (pro)renin/(P)RR system localization during renal injury, a critical information base, remain unexplored. This study investigates the expression and topographic localization of the full length (FL)-(P)RR, its ligands (renin and prorenin), and its target cyclooxygenase-2 and found that they are upregulated in three distinct animal models of renal injury. The protein expression of these targets, initially confined to specific tubular renal cell types in control animals, increases in renal injury models, extending to glomerular cells. (P)RR gene expression correlates with protein changes in a genetic model of focal and segmental glomerulosclerosis. However, in diabetic and high-fat-fed mice, (P)RR mRNA levels contradict FL-(P)RR immunoreactivity. Research on diabetic mice kidneys and human podocytes exposed to diabetic glucose levels suggests that this inconsistency may result from disrupted intracellular (P)RR processing, likely due to increased Munc18-1 interacting protein 3. It follows that changes in FL-(P)RR cellular content mechanisms are specific to renal disease etiology, emphasizing the need for consideration in future studies exploring this receptor's involvement in renal damage of different origins. [ABSTRACT FROM AUTHOR]

Introduction: The process of vascular calcification has severe clinical consequences in a number of diseases, including diabetes, atherosclerosis, and end-stage renal disease. In the present study, we investigated the effect of policosanol (Poli), genistein (Gen), and vitamin D (VitD) separately and in association to evaluate the possible synergistic action on inorganic phosphate (Pi)-induced calcification of vascular smooth muscle cells (VSMCs). Methods: Primary human VSMCs were cultured with either growth medium or growth medium supplemented with calcium and phosphorus (calcification medium) in combination with Poli, Gen, and VitD. Alizarin Red staining, mineralization, and the protein expression of RUNX2 and superoxide dismutase-2 (SOD2) were investigated. Results: All three substances tested were effective at reducing osteogenic differentiation of VSMCs in a dose-dependent manner. Poli+Gen, Poli+VitD, Gen+VitD treatment induced a greater inhibition of calcification and RUNX2 expression compared to single compounds treatments. Moreover, the association of Poli+Gen+VitD (Reduplaxin®) was more effective at inhibiting VSMCs mineralization and preventing the increase in RUNX2 expression induced by calcification medium but not modified SOD2 expression. Conclusions: The association of Pol, Gen, and VitD (Reduplaxin®) has an additive inhibitory effect on the calcification process of VSMCs induced in vitro by a pro-calcifying medium. [ABSTRACT FROM AUTHOR]

Intracellular metabolism of excess glucose induces mitochondrial dysfunction and diversion of glycolytic intermediates into branch pathways, leading to cell injury and inflammation. Hyperglycemia-driven overproduction of mitochondrial superoxide was thought to be the initiator of these biochemical changes, but accumulating evidence indicates that mitochondrial superoxide generation is dispensable for diabetic complications development. Here we tested the hypothesis that hypoxia inducible factor (HIF)-1α and related bioenergetic changes (Warburg effect) play an initiating role in glucotoxicity. By using human endothelial cells and macrophages, we demonstrate that high glucose (HG) induces HIF-1α activity and a switch from oxidative metabolism to glycolysis and its principal branches. HIF1-α silencing, the carbonyl-trapping and anti-glycating agent ʟ-carnosine, and the glyoxalase-1 inducer trans-resveratrol reversed HG-induced bioenergetics/biochemical changes and endothelial-monocyte cell inflammation, pointing to methylglyoxal (MGO) as the non-hypoxic stimulus for HIF1-α induction. Consistently, MGO mimicked the effects of HG on HIF-1α induction and was able to induce a switch from oxidative metabolism to glycolysis. Mechanistically, methylglyoxal causes HIF1-α stabilization by inhibiting prolyl 4-hydroxylase domain 2 enzyme activity through post-translational glycation. These findings introduce a paradigm shift in the pathogenesis and prevention of diabetic complications by identifying HIF-1α as essential mediator of glucotoxicity, targetable with carbonyl-trapping agents and glyoxalase-1 inducers.

Plant organ primordia develop successively at the shoot apical meristem (SAM). In Arabidopsis, primordia formed early in development differentiate into vegetative leaves, whereas those formed later generate inflorescence branches and flowers. TERMINAL FLOWER 1 (TFL1), a negative regulator of transcription, acts in the SAM to delay flowering and to maintain inflorescence meristem indeterminacy. We used confocal microscopy, time-resolved transcript profiling and reverse genetics to elucidate this dual role of TFL1. We found that TFL1 accumulates dynamically in the SAM reflecting its dual function. Moreover, TFL1 represses two major sets of genes. One set includes genes that promote flowering, expression of which increases earlier in tfl1 mutants. The other set is spatially misexpressed in tfll inflorescence meristems. The misexpression of these two gene sets in tfl1 mutants depends upon FD transcription factor, with which TFL1 interacts. Furthermore, the MADS-box gene SEPALLATA 4, which is upregulated in tfl1, contributes both to the floral transition and shoot determinacy defects of tfl1 mutants. Thus, we delineate the dual function of TFL1 in shoot development in terms of its dynamic spatial distribution and different modes of gene repression. [ABSTRACT FROM AUTHOR]

Twenty years have passed since Brownlee and colleagues proposed a single unifying mechanism for diabetic complications, introducing a turning point in this field of research. For the first time, reactive oxygen species (ROS) were identified as the causal link between hyperglycemia and four seemingly independent pathways that are involved in the pathogenesis of diabetes-associated vascular disease. Before and after this milestone in diabetes research, hundreds of articles describe a role for ROS, but the failure of clinical trials to demonstrate antioxidant benefits and some recent experimental studies showing that ROS are dispensable for the pathogenesis of diabetic complications call for time to reflect. This twenty-year journey focuses on the most relevant literature regarding the main sources of ROS generation in diabetes and their role in the pathogenesis of cell dysfunction and diabetic complications. To identify future research directions, this review discusses the evidence in favor and against oxidative stress as an initial event in the cellular biochemical abnormalities induced by hyperglycemia. It also explores possible alternative mechanisms, including carbonyl stress and the Warburg effect, linking glucose and lipid excess, mitochondrial dysfunction, and the activation of alternative pathways of glucose metabolism leading to vascular cell injury and inflammation.

Aims: To investigate the relationship between changes in physical fitness and cardiovascular risk factors and scores in patients with type 2 diabetes receiving either a behavioural counselling intervention to increase moderate‐to‐vigorous‐intensity physical activity (MVPA) and decrease sedentary‐time (SED‐time) or standard care. Materials and Methods: This is a pre‐specified ancillary analysis of the Italian Diabetes and Exercise Study_2, a 3‐year randomized clinical trial in which 300 physically inactive and sedentary patients were randomized 1:1 to receive either a one‐month theoretical and practical counselling each year or standard care. Mean changes from baseline throughout the 3‐year period in MVPA, SED‐time, cardiorespiratory fitness (VO2max), muscle strength, flexibility, cardiovascular risk factors and scores were calculated for study completers (n = 267) and considered irrespective of study arm. Results: Haemoglobin (Hb) A1c and coronary heart disease (CHD) risk scores decreased with quartiles of VO2max and lower body muscle strength changes. Multivariable linear regression analysis showed that increases in VO2max independently predicted decreases in HbA1c, blood glucose, diastolic blood pressure (BP), CHD and total stroke 10‐year risk and increases in HDL cholesterol, whereas increases in lower body muscle strength independently predicted decreases in body mass index (BMI), waist circumference, triglycerides, systolic BP, CHD and fatal stroke 10‐year risk. These associations remained after including changes in BMI, waist circumference, fat mass and fat‐free mass, or MVPA and SED‐time as covariates. Conclusions: Improvement in physical fitness predicts favourable changes in cardiometabolic risk profile, independent of changes not only in (central) adiposity or body composition but also in MVPA and SED‐time. Trial Registration: ClinicalTrials.gov; NCT01600937; URL https://clinicaltrials.gov/ct2/show/NCT01600937. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) ranks seventh as a cause of death worldwide. Chronic complications, including cardiovascular, renal, and eye disease, as well as DM-associated non-alcoholic fatty liver disease (NAFLD) account for most of the morbidity and premature mortality in DM. Despite continuous improvements in the management of late complications of DM, significant gaps remain. Therefore, searching for additional strategies to prevent these serious DM-related conditions is of the utmost importance. DM is characterized by a state of low-grade chronic inflammation, which is critical in the progression of complications. Recent clinical trials indicate that targeting the prototypic pro-inflammatory cytokine interleukin-1β (IL-1 β) improves the outcomes of cardiovascular disease, which is the first cause of death in DM patients. Together with IL-18, IL-1β is processed and secreted by the inflammasomes, a class of multiprotein complexes that coordinate inflammatory responses. Several DM-related metabolic factors, including reactive oxygen species, glyco/lipoxidation end products, and cholesterol crystals, have been involved in the pathogenesis of diabetic kidney disease, and diabetic retinopathy, and in the promoting effect of DM on the onset and progression of atherosclerosis and NAFLD. These metabolic factors are also well-established danger signals capable of regulating inflammasome activity. In addition to presenting the current state of knowledge, this review discusses how the mechanistic understanding of inflammasome regulation by metabolic danger signals may hopefully lead to novel therapeutic strategies targeting inflammation for a more effective treatment of diabetic complications.

This article discusses a study that aimed to evaluate the presence of undiagnosed pelvic diseases in patients who underwent in vitro fertilization (IVF) and experienced recurrent implantation failure (RIF). The study used high-quality transvaginal sonography (TVS) performed by experts to assess the patients. The results showed that only 17% of patients had a normal pelvic scan after RIF, with a significant difference observed between the already known abnormal TVS group before IVF and the new diagnosis after RIF. The study suggests that expert TVS should be performed before the first embryo transfer and not just after RIF, as it could potentially lead to new diagnoses and improve the outcomes of IVF. [Extracted from the article]

The hypoxia-inducible factor-1a (HIF-1a), a key player in the adaptive regulation of energy metabolism, and the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2), a critical regulator of glucose consumption, are the main drivers of the metabolic rewiring in cancer cells. The use of glycolysis rather than oxidative phosphorylation, even in the presence of oxygen (i.e., Warburg effect or aerobic glycolysis), is a major metabolic hallmark of cancer. Aerobic glycolysis is also important for the immune system, which is involved in both metabolic disorders development and tumorigenesis. More recently, metabolic changes resembling the Warburg effect have been described in diabetes mellitus (DM). Scientists from different disciplines are looking for ways to interfere with these cellular metabolic rearrangements and reverse the pathological processes underlying their disease of interest. As cancer is overtaking cardiovascular disease as the leading cause of excess death in DM, and biological links between DM and cancer are incompletely understood, cellular glucose metabolism may be a promising field to explore in search of connections between cardiometabolic and cancer diseases. In this mini-review, we present the state-of-the-art on the role of the Warburg effect, HIF-1a, and PKM2 in cancer, inflammation, and DM to encourage multidisciplinary research to advance fundamental understanding in biology and pathways implicated in the link between DM and cancer. [ABSTRACT FROM AUTHOR]

Objective. Quantitative ultrasound (QUS) provides an estimate of bone mineral density (BMD) and also evaluates bone quality, which has been related to increased fracture risk in people with diabetes. This study aimed at assessing the correlates of calcaneal QUS parameters in diabetic subjects encompassing various degrees of micro and macrovascular complications and a wide-range of peripheral nerve function. Methods. Four hundred consecutive diabetic patients were examined by QUS to obtain values of broadband ultrasound attenuation (BUA), the speed of sound (SOS), quantitative ultrasound index (QUI), and BMD. Results. Among surrogate measures of complications, sensory and motor nerve amplitude and heart rate response to cough test and standing correlated with QUS parameters at univariate analysis, together with age, body mass index (BMI), waist circumference, lipid profile, and renal function. Multivariate analysis revealed that BUA, SOS, QUI, and BMD were independently associated with age, male gender, hemoglobin A1c, BMI (or fat, but not fat-free mass), and somatic and autonomic nerve function parameters. Conclusions. These data indicate that peripheral nerve dysfunction is associated with worse QUS parameters, possibly contributing to increased fracture risk in diabetes. The positive relation of QUS measures with adiposity needs further investigation. This trial is registered with ClinicalTrials.gov (NCT01600924).

The lack of BTK in X-linked agammaglobulinemia (XLA) patients does not affect monocytes and polymorphonuclear cells (PMN) phenotype and functions. In this study, we show that XLA patients had an increased frequency of the intermediate monocytes subset and that BTK-deficient monocytes and PMN had a normal expression of receptors involved in the activation and cellular responses. We demonstrate that BTK is not required for migration, phagocytosis and the production of reactive oxygen species (ROS) following engagement of FC gamma receptors (FcγR). XLA monocytes and PMN showed an efficient calcium (Ca2+)-independent activation of oxidative burst, suggesting that oxidative burst is less dependent by Ca2+ mobilization. The phagocytosis was functional and it remained unaltered also after Ca2+ chelation, confirming the independence of phagocytosis on Ca2+ mobilization. Intravenous immunoglobulin (IVIg) infusion exerted an anti-inflammatory effect by reducing the frequency of pro-inflammatory monocytes. In monocytes, the IVIg reduce the oxidative burst and phagocytosis even if these functions remained efficient.

The paper deals with an extension of standard Shewhart control charts witch provide independent runs of given length, or IR-charts, with the purpose of improving the performance of the former by allowing a faster detection of small and medium shifts in a process mean. The author purposely chooses to remain in the field of indipendent sample observations, which are much more frequently used in SPC compared to other types of charts due to their simplicity, and shows how careful choice of independent runs, formed by the same sample means used in a standard X-chart, can be adopted in order to reduce ARL values and, therefore, the expected time of detection of out-of-control situations. The result is obtained without the main drawback of dependent runs procedures as summarised in the Western Electric Company runs rules and others recalled in the paper, with lies in the fact that their "in-control" ARL is too low, thus providing a too short expected time before a false "out-of control" alarm occurs.

Environmental safeguards promote innovative construction technologies for sustainable pavements. On these premises, this study investigated four hot mix asphalt (HMA) mixtures—i.e., A, B, C, and D—for the railway sub-ballast layer with 0%, 10%, 20%, and 30% reclaimed asphalt pavement (RAP) by total aggregate mass and a rejuvenator additive, varying the bitumen content between 3.5% and 5.0%. Both Marshall and gyratory compactor design methods have been performed, matching the stability, indirect tensile strength, and volumetric properties of each mixture. Dynamic stiffness and fatigue resistance tests provided mechanical performances. Laboratory results highlighted that the RAP and the rejuvenator additive increase the mechanical properties of the mixtures. In addition, the comparative analysis of production costs revealed up to 20% savings as the RAP content increased, and the life cycle impact analysis (LCIA) proved a reduction of the environmental impacts (up to 2% for resource use-fossils, up to 7% for climate change, and up to 13% for water use). The experimental results confirm that HMA containing RAP has mechanical performances higher than the reference mixture with only virgin raw materials. These findings could contribute to waste management and reduce the environmental and economic costs, since the use of RAP in the sub-ballast is not, so far, provided in the Italian specifications for railway construction. [ABSTRACT FROM AUTHOR]

Player exploitation in esports refers to the practice of exploiting players for financial or other gain without providing fair compensation or benefits. This can include issues such as low wages lack of job security and poor working conditions. Examples of player exploitation in esports include signing players with long-term contracts with low wages and no benefits and the use of non-disclosure agreements. Agreement (NDA) prevents players from discussing their pay or working conditions. This situation makes it difficult for players to negotiate better contracts or speak out against abuse leaving teams if they are unhappy with their situation. Another example is the lack of proper training support and benefits for players such as healthcare and mental health. Many esports teams do not provide enough resources for players to improve their skills and maintain good physical condition. This can lead to fatigue and injuries which can seriously affect a player's career. Many esports players are young and the lack of access to these resources makes them vulnerable to exploitation. The esports industry is still relatively new and unregulated which can make it easy for companies and teams to exploit players. However, there are many organizations and advocacy groups working to improve working conditions and ensure fair treatment for sports athletes. Athlete exploitation in esports in general is a serious issue that needs to be addressed to ensure that athletes are treated fairly and have the resources they need to succeed in their careers. [ABSTRACT FROM AUTHOR]

Tom Brady, Cristiano Ronaldo, Lionel Messi, and others are household names, while Lee Faker Sang-Hyeok is less well-known. Although Kim Doinb Tae-sang and Luka Perkz Perkovi are still well known, they are also rising to the status of world-renowned athletes. The most popular computer video game in the world, League of Legends, has professional players like Faker Perks and Toinb. The League is one of the many ambitious and well-liked sporting events that make up the fast-growing esports category. Administrators operate in what is referred to as a global gray area. Esports is a lucrative corporate sponsorship option for athletes because of its enormous popularity (some events regularly draw tens of thousands of viewers), but it is also fluid and lacks defined standards. This article describes the global phenomenon of esports; provides an overview of the role and practice of esports; highlights why esports is considered an integral part of the evolving internet culture and introduces the reader to the structure of gaming more broadly. [ABSTRACT FROM AUTHOR]

Galectin-3 is expressed in various tissues, including the bone, where it is considered a marker of chondrogenic and osteogenic cell lineages. Galectin-3 protein was found to be increased in the differentiated chondrocytes of the metaphyseal plate cartilage, where it favors chondrocyte survival and cartilage matrix mineralization. It was also shown to be highly expressed in differentiating osteoblasts and osteoclasts, in concomitance with expression of osteogenic markers and Runt-related transcription factor 2 and with the appearance of a mature phenotype. Galectin-3 is expressed also by osteocytes, though its function in these cells has not been fully elucidated. The effects of galectin-3 on bone cells were also investigated in galectin-3 null mice, further supporting its role in all stages of bone biology, from development to remodeling. Galectin-3 was also shown to act as a receptor for advanced glycation endproducts, which have been implicated in age-dependent and diabetes-associated bone fragility. Moreover, its regulatory role in inflammatory bone and joint disorders entitles galectin-3 as a possible therapeutic target. Finally, galectin-3 capacity to commit mesenchymal stem cells to the osteoblastic lineage and to favor transdifferentiation of vascular smooth muscle cells into an osteoblast-like phenotype open a new area of interest in bone and vascular pathologies.

Oxidative stress and hypoxia-inducible factors (HIFs) have been implicated in the pathogenesis of diabetic cardiovascular and renal diseases. Reactive oxygen species (ROS) mediate physiological and pathophysiological processes, being involved in the modulation of cell signaling, differentiation, and survival, but also in cyto- and genotoxic damage. As master regulators of glycolytic metabolism and oxygen homeostasis, HIFs have been largely studied for their role in cell survival in hypoxic conditions. However, in addition to hypoxia, other stimuli can regulate HIFs stability and transcriptional activity, even in normoxic conditions. Among these, a regulatory role of ROS and their byproducts on HIFs, particularly the HIF-1α isoform, has received growing attention in recent years. On the other hand, HIF-1α and HIF-2α exert mutually antagonistic effects on oxidative damage. In diabetes, redox-mediated HIF-1α deregulation contributes to the onset and progression of cardiovascular and renal complications, and recent findings suggest that deranged HIF signaling induced by hyperglycemia and other cellular stressors associated with metabolic disorders may cause mitochondrial dysfunction, oxidative stress, and inflammation. Understanding the mechanisms of mutual regulation between HIFs and redox factors and the specific contribution of the two main isoforms of HIF-α is fundamental to identify new therapeutic targets for vascular complications of diabetes. [ABSTRACT FROM AUTHOR]