Epigenetic regulatory mechanism of macrophage polarization in diabetic wound healing (Review).

Diabetic wounds represent a significant complication of diabetes and present a substantial challenge to global public health. Macrophages are crucial effector cells that play a pivotal role in the pathogenesis of diabetic wounds, through their polarization into distinct functional phenotypes. The field of epigenetics has emerged as a rapidly advancing research area, as this phenomenon has the potential to markedly affect gene expression, cellular differentiation, tissue development and susceptibility to disease. Understanding epigenetic mechanisms is crucial to further exploring disease pathogenesis. A growing body of scientific evidence has highlighted the pivotal role of epigenetics in the regulation of macrophage phenotypes. Various epigenetic mechanisms, such as DNA methylation, histone modification and non­coding RNAs, are involved in the modulation of macrophage phenotype differentiation in response to the various environmental stimuli present in diabetic wounds. The present review provided an overview of the various changes that take place in macrophage phenotypes and functions within diabetic wounds and discussed the emerging role of epigenetic modifications in terms of regulating macrophage plasticity in diabetic wounds. It is hoped that this synthesis of information will facilitate the elucidation of diabetic wound pathogenesis and the identification of potential therapeutic targets.

Isolated bovine pancreatic islets as an alternate in vitro model for diabetes research.

Background & objectives Isolation of functional pancreatic islets for diabetes research and clinical islet transplantation stands as a big challenge despite the advancements in the field. In this context, the non-availability of human/animal tissues is one of the major impediments to islet-based research, which has tremendous scope for translation. The current study explores the feasibility of using the bovine pancreas as an alternative source to isolate pancreatic islets and assess its functionality for in vitro studies. Methods The bovine pancreas was collected from a registered slaughterhouse and transported in an ice-cold medium - Hank's Balanced Salt Solution (HBSS) to the laboratory. Islets were isolated by sequential collagenase digestion followed by a two-step filtration and purification by density gradient separation method. After isolation, islets were identified with dithizone staining and the islet function was assayed in vitro for assessing the dynamic insulin secretory function by monitoring the glucose-stimulated insulin secretion (GSIS), in response to low and high glucose. Staining techniques were also used to understand the cytoarchitecture of the bovine pancreas. Results The islet yield was 157±23 islets per gram of pancreas and was viable. The cold ischaemia time was reduced to 60-75 min. The islets released insulin with glucose stimulation. The insulin release was observed more with high glucose (28 mM) than with low glucose (2.8 mM). Dithizone staining confirmed the presence of islets after isolation and the size of islets ranged from 50 to 600 µm size. The mantled islets (islets with acinar tissue) were also noted with the pure islets in culture. Hematoxylin and eosin (H&E) and aldehyde- fuchsin showed islets interspersed in the acinar tissue of the bovine pancreas. Special stain defined the islets better than regular staining. Fluorescent and diaminobenzidine (DAB) staining with insulin, glucagon and somatostatin revealed the arrangement of the cells in each islet. The beta cells were majorly found in the islet core with alpha cells interspersed with the delta cells in the periphery. Interpretation & conclusions The isolation procedure described in this study yielded viable islets for in vitro studies which showed a differential response to glucose challenge, confirming their viability. We provide a simple and reproducible method for small-scale isolation of functional islets from the bovine pancreas. This model proffers the beginner a hands-on in islet experiments and helps to re-iterate the process that could be extrapolated to other pancreatic tissues as well as to expand on diabetes research.

Decoding the diabetic bone paradox: How AGEs sabotage skeletal integrity.

Diabetes patients often suffer from fractures despite normal or high bone mineral density, a phenomenon known as the diabetic bone paradox. Gao et al.1 identify AGEs as disrupting bone quality and compromising skeletal integrity in diabetic bone disease.

Integrated stress response activator halofuginone protects mice from diabetes-like phenotypes.

The integrated stress response (ISR) is a vital signaling pathway initiated by four kinases, PERK, GCN2, HRI and PKR, that ensure cellular resilience and protect cells from challenges. Here, we investigated whether increasing ISR signaling could rescue diabetes-like phenotypes in a mouse model of diet-induced obesity (DIO). We show that the orally available and clinically approved GCN2 activator halofuginone (HF) can activate the ISR in mouse tissues. We found that daily oral administration of HF increases glucose tolerance whilst reducing weight gain, insulin resistance, and serum insulin in DIO mice. Conversely, the ISR inhibitor GSK2656157, used at low doses to optimize its selectivity, aggravates glucose intolerance in DIO mice. Whilst loss of function mutations in mice and humans have revealed that PERK is the essential ISR kinase that protects from diabetes, our work demonstrates the therapeutic value of increasing ISR signaling by activating the related kinase GCN2 to reduce diabetes phenotypes in a DIO mouse model.

OxInflammation Affects Transdifferentiation to Myofibroblasts, Prolonging Wound Healing in Diabetes: A Systematic Review.

Skin wounds, primarily in association with type I diabetes mellitus, are a public health problem generating significant health impacts. Therefore, identifying the main pathways/mechanisms involved in differentiating fibroblasts into myofibroblasts is fundamental to guide research into effective treatments. Adopting the PRISMA guidelines, this study aimed to verify the main pathways/mechanisms using diabetic murine models and analyze the advances and limitations of this area. The Medline (PubMed), Scopus, and Web of Science platforms were used for the search. The studies included were limited to those that used diabetic murine models with excisional wounds. Bias analysis and methodological quality assessments were undertaken using the SYRCLE bias risk tool. Eighteen studies were selected. The systematic review results confirm that diabetes impairs the transformation of fibroblasts into myofibroblasts by affecting the expression of several growth factors, most notably transforming growth factor beta (TGF-beta) and NLRP3. Diabetes also compromises pathways such as the SMAD, c-Jun N-terminal kinase, protein kinase C, and nuclear factor kappa beta activating caspase pathways, leading to cell death. Furthermore, diabetes renders the wound environment highly pro-oxidant and inflammatory, which is known as OxInflammation. As a consequence of this OxInflammation, delays in the collagenization process occur. The protocol details for this systematic review were registered with PROSPERO: CRD42021267776.

Receptors and Signaling Pathways Controlling Beta-Cell Function and Survival as Targets for Anti-Diabetic Therapeutic Strategies.

Preserving the function and survival of pancreatic beta-cells, in order to achieve long-term glycemic control and prevent complications, is an essential feature for an innovative drug to have clinical value in the treatment of diabetes. Innovative research is developing therapeutic strategies to prevent pathogenic mechanisms and protect beta-cells from the deleterious effects of inflammation and/or chronic hyperglycemia over time. A better understanding of receptors and signaling pathways, and of how they interact with each other in beta-cells, remains crucial and is a prerequisite for any strategy to develop therapeutic tools aimed at modulating beta-cell function and/or mass. Here, we present a comprehensive review of our knowledge on membrane and intracellular receptors and signaling pathways as targets of interest to protect beta-cells from dysfunction and apoptotic death, which opens or could open the way to the development of innovative therapies for diabetes.

Research progress of brain organoids in the field of diabetes.

Human embryonic stem cells and human induced pluripotent stem cells may be used to create 3D tissues called brain organoids. They duplicate the physiological and pathological characteristics of human brain tissue more faithfully in terms of both structure and function, and they more precisely resemble the morphology and cellular structure of the human embryonic brain. This makes them valuable models for both drug screening and in vitro studies on the development of the human brain and associated disorders. The technical breakthroughs enabled by brain organoids have a significant impact on the research of different brain regions, brain development and sickness, the connections between the brain and other tissues and organs, and brain evolution. This article discusses the development of brain organoids, their use in diabetes research, and their progress.

As condições clínicas de mulheres com diabetes tipo 2: avaliando para prevenir agravos / The clinical conditions of women with type 2 Diabetes: evaluating to prevent worsening / Lascondiciones clínicas de las mujeres con Diabetes Tipo 2: evaluación para prevenir empeoramientos

Introdução:O diabetes mellitus é uma doença metabólica caracterizada pelo controle inadequado dos níveis de glicose no sangue, principalmente um estado crônico de hiperglicemia, causado por diferentes processos patogênicos, levando a complicaçõesdosistema nervoso do diabético queincluem axonopatias, doenças neurodegenerativas, doenças neurovasculares e comprometimento cognitivo geral.Objetivo:Avaliar as complicações clínicas da diabetes tipo 2 em mulheres. Metodologia:Tratou-se de um transversal, do tipo prevalência. Foram usados dois grupos de mulheres, onde todas as mulheres estavam com diagnóstico de diabetes Tipo 2 e idade de 40 e 60 anos, comotratamentooral -G1e com tratamentocominsulinoterapia ­G2,ambosfornecidospelarede pública Para comparação das variáveis estudadas foi utilizado o método de Mann-Whitney, adotando-se o nível de significância menor que 5% (p, valor ,0,05). Resultados:Aproporçãode pessoas com diabetes no Piauí, com consulta e hemoglobina glicada solicitada no primeiro quadrimestre de 2021, 2022, 2023, foi de18, 16 e 34 percentuais,respectivamenteeem Boa Hora nos mesmos quadrimestres foi 36, 39, 56 percentuais, respectivamente.Osprocedimentoshospitalares-por local de residência -Piauí foi de um total de 1.193e em Boa Hora 24. O grupo de mulheres estudadas mostrou uma diferença significativa para a glicemia em jejum e a Hemoglobina glicada quando comparados os grupos G1 e G2. Quase 100% da amostra estava obesa (IMC > 25), não fumava e não praticava atividade física.Conclusões:Concluiu-se que a as pacientes tiveram um agravamento do adoecimento ao longo dos anos com aumento de medicação. A ausência das boas práticas de promoção de saúde, atividade física e alimentação, podem ter contribuídocom o agravamento. Outrossim há necessidade urgente de uma intervenção para mudança de hábitos na população para que a medicalização seja diminuída para a promoção da saúde (AU).

Introduction: Diabetes mellitus is a metabolic disease characterized by inadequate control of blood glucose levels, mainly a chronic state of hyperglycemia, caused by different pathogenic processes, leading to complications of the nervous system including axonopathies, neurodegenerative diseases,neurovascular diseases and general cognitive impairment.Objective: To evaluate the clinical complications of type 2 diabetes in women.Methodology: This was a cross-sectional, prevalence study.Two groupsof women were used, where all women were diagnosed with Type 2 diabetes and aged between 40 and 60 years, with oral treatment -G1 and treatment with insulin therapy -G2, both provided by the public network .To compare the variables studied, the Mann-Whitney method was used, adopting a significance level of less than 5% (p, value 0.05).Results:The proportion of people with diabetes in Piauí, with consultation and glycated hemoglobin requested in the first four months of 2021, 2022, 2023, was 18, 16 and34 percentages, respectively and in Boa Hora in the same four months it was 36, 39, 56percentages, respectively.SUS hospital procedures -by place of residence -Piauí was a total of 1,193 and in Boa Hora 24. The group of women studied showed a significant difference in fasting blood glucose and glycated hemoglobin when comparing groups G1 and G2.Almost 100% of the sample was obese (BMI > 25), did not smoke and did not practice physical activity.Conclusions: It was concluded that the patients' illness worsened over the years with increased medication.The absence of good health promotion practices, physical activity and nutrition may have contributed to the worsening.Furthermore, there is an urgent need for intervention to change habits in the population so that medicalization is reduced to promote health (AU).

Introducción: La diabetes mellitus ecaracterizada por un control inadecuado de los niveles de glucosa en sangre, principalmente un estado crónico de hiperglucemia, causado por diferentes procesos patogénicos, derivando en complicaciones del sistema nervioso incluyendo axonopatías, enfermedades neurodegenerativas, enfermedades neurovasculares y deterioro cognitivo general.Objetivo: Evaluar las complicaciones clínicas de la diabetes tipo 2 en mujeres.Metodología: Se trata de un estudio transversal de prevalencia.Se utilizaron dos grupos de mujeres, donde todas fueron diagnosticadas con diabetes tipo 2 y con edades entre 40 y 60 años, con tratamiento oral -G1 y tratamiento con insulinoterapia -G2, ambos prestados por la red pública.Para comparar las variables estudiadas se utilizó el método de Mann-Whitney, adoptando un nivel de significancia inferior al 5% (p, valor 0,05).Resultados:La proporción de personas con diabetes en Piauí, con consulta y hemoglobina glucosilada solicitada en los primeros cuatro meses de 2021, 2022, 2023, fuede 18, 16 y 34 porcentajes, respectivamente y en Boa Hora en los mismos cuatro meses fue de 36 , 39, 56 porcentajes, respectivamente.Los procedimientos hospitalarios del SUS -por lugar de residencia -en Piauí fueron en total 1.193 y en Boa Hora 24. El grupo de mujeres estudiado presentó diferencia significativa en la glucemia en ayunas y en la hemoglobina glucosilada al comparar los grupos G1 y G2.Casi el 100% de la muestra era obesa (IMC > 25), no fumaba y no practicaba actividad física.Conclusiones:Se concluyó que la enfermedad de los pacientes empeoró con el paso de los años con el aumento de la medicación.La ausencia de buenas prácticas de promoción de la salud, actividad física y nutrición puede haber contribuido al empeoramiento.Además, es urgente intervenir para cambiar los hábitos de la población para promover la salud (AU).

Optical discrimination of pathological red blood cells.

Fast diagnostic methods are crucial to reduce the burden on healthcare systems. Currently, detection of diabetes complications such as neuropathy requires time-consuming approaches to observe the correlated red blood cells (RBCs) morphological changes. To tackle this issue, an optical analysis of RBCs in air was conducted in the 250-2500 nm range. The distinct oscillations present in the scattered and direct transmittance spectra have been analyzed with both Mie theory and anomalous diffraction approximation. The results provide information about the swelling at the ends of RBCs and directly relate the optical data to RBCs morphology and deformability. Both models agree on a reduction in the size and deformability of RBCs in diabetic patients, thus opening the way to diabetes diagnosis and disease progression assessment.

Unveiling impaired vascular function and cellular heterogeneity in diabetic donor-derived vascular organoids.

Vascular organoids (VOs), derived from induced pluripotent stem cells (iPSCs), hold promise as in vitro disease models and drug screening platforms. However, their ability to faithfully recapitulate human vascular disease and cellular composition remains unclear. In this study, we demonstrate that VOs derived from iPSCs of donors with diabetes (DB-VOs) exhibit impaired vascular function compared to non-diabetic VOs (ND-VOs). DB-VOs display elevated levels of reactive oxygen species (ROS), heightened mitochondrial content and activity, increased proinflammatory cytokines, and reduced blood perfusion recovery in vivo. Through comprehensive single-cell RNA sequencing, we uncover molecular and functional differences, as well as signaling networks, between vascular cell types and clusters within DB-VOs. Our analysis identifies major vascular cell types (endothelial cells [ECs], pericytes, and vascular smooth muscle cells) within VOs, highlighting the dichotomy between ECs and mural cells. We also demonstrate the potential need for additional inductions using organ-specific differentiation factors to promote organ-specific identity in VOs. Furthermore, we observe basal heterogeneity within VOs and significant differences between DB-VOs and ND-VOs. Notably, we identify a subpopulation of ECs specific to DB-VOs, showing overrepresentation in the ROS pathway and underrepresentation in the angiogenesis hallmark, indicating signs of aberrant angiogenesis in diabetes. Our findings underscore the potential of VOs for modeling diabetic vasculopathy, emphasize the importance of investigating cellular heterogeneity within VOs for disease modeling and drug discovery, and provide evidence of GAP43 (neuromodulin) expression in ECs, particularly in DB-VOs, with implications for vascular development and disease.

Pathology of Diabetes-Induced Immune Dysfunction.

Diabetes is associated with numerous comorbidities, one of which is increased vulnerability to infections. This review will focus on how diabetes mellitus (DM) affects the immune system and its various components, leading to the impaired proliferation of immune cells and the induction of senescence. We will explore how the pathology of diabetes-induced immune dysfunction may have similarities to the pathways of "inflammaging", a persistent low-grade inflammation common in the elderly. Inflammaging may increase the likelihood of conditions such as rheumatoid arthritis (RA) and periodontitis at a younger age. Diabetes affects bone marrow composition and cellular senescence, and in combination with advanced age also affects lymphopoiesis by increasing myeloid differentiation and reducing lymphoid differentiation. Consequently, this leads to a reduced immune system response in both the innate and adaptive phases, resulting in higher infection rates, reduced vaccine response, and increased immune cells' senescence in diabetics. We will also explore how some diabetes drugs induce immune senescence despite their benefits on glycemic control.

Ameliorating and refining islet organoids to illuminate treatment and pathogenesis of diabetes mellitus.

Diabetes mellitus, a significant global public health challenge, severely impacts human health worldwide. The organoid, an innovative in vitro three-dimensional (3D) culture model, closely mimics tissues or organs in vivo. Insulin-secreting islet organoid, derived from stem cells induced in vitro with 3D structures, has emerged as a potential alternative for islet transplantation and as a possible disease model that mirrors the human body's in vivo environment, eliminating species difference. This technology has gained considerable attention for its potential in diabetes treatment. Despite advances, the process of stem cell differentiation into islet organoid and its cultivation demonstrates deficiencies, prompting ongoing efforts to develop more efficient differentiation protocols and 3D biomimetic materials. At present, the constructed islet organoid exhibit limitations in their composition, structure, and functionality when compared to natural islets. Consequently, further research is imperative to achieve a multi-tissue system composition and improved insulin secretion functionality in islet organoid, while addressing transplantation-related safety concerns, such as tumorigenicity, immune rejection, infection, and thrombosis. This review delves into the methodologies and strategies for constructing the islet organoid, its application in diabetes treatment, and the pivotal scientific challenges within organoid research, offering fresh perspectives for a deeper understanding of diabetes pathogenesis and the development of therapeutic interventions.

Multi-omics analysis of diabetic pig lungs reveals molecular derangements underlying pulmonary complications of diabetes mellitus.

Growing evidence shows that the lung is an organ prone to injury by diabetes mellitus. However, the molecular mechanisms of these pulmonary complications have not yet been characterized comprehensively. To systematically study the effects of insulin deficiency and hyperglycaemia on the lung, we combined proteomics and lipidomics with quantitative histomorphological analyses to compare lung tissue samples from a clinically relevant pig model for mutant INS gene-induced diabetes of youth (MIDY) with samples from wild-type littermate controls. Among others, the level of pulmonary surfactant-associated protein A (SFTPA1), a biomarker of lung injury, was moderately elevated. Furthermore, key proteins related to humoral immune response and extracellular matrix organization were significantly altered in abundance. Importantly, a lipoxygenase pathway was dysregulated as indicated by 2.5-fold reduction of polyunsaturated fatty acid lipoxygenase ALOX15 levels, associated with corresponding changes in the levels of lipids influenced by this enzyme. Our multi-omics study points to an involvement of reduced ALOX15 levels and an associated lack of eicosanoid switching as mechanisms contributing to a proinflammatory milieu in the lungs of subjects with diabetes mellitus.

MicroRNA-29-mediated cross-talk between metabolic organs in the pathogenesis of diabetes mellitus and its complications: A narrative review.

Diabetes mellitus (DM) is a heterogeneous group of disorders characterized by hyperglycemia. Microribonucleic acids (microRNAs) are noncoding RNA molecules synthesized in the nucleus, modified, and exported to the extracellular environment to bind to their complementary target sequences. It regulates protein synthesis in the targeted cells by inhibiting translation or triggering the degradation of the target messenger. MicroRNA-29 is one of noncoding RNA that can be secreted by adipose tissue, hepatocytes, islet cells, and brain cells. The expression level of the microRNA-29 family in several metabolic organs is regulated by body weight, blood concentrations of inflammatory mediators, serum glucose levels, and smoking habits. Several experimental studies have demonstrated the effect of microRNA-29 on the expression of target genes involved in glucose metabolism, insulin synthesis and secretion, islet cell survival, and proliferation. These findings shed new light on the role of microRNA-29 in the pathogenesis of diabetes and its complications, which plays a vital role in developing appropriate therapies. Different molecular pathways have been proposed to explain how microRNA-29 promotes the development of diabetes and its complications. However, to the best of our knowledge, no published review article has summarized the molecular mechanism of microRNA-29-mediated initiation of DM and its complications. Therefore, this narrative review aims to summarize the role of microRNA-29-mediated cross-talk between metabolic organs in the pathogenesis of diabetes and its complications.

Bone morphogenetic protein 10, a rising star in the field of diabetes and cardiovascular disease.

Early research suggested that bone morphogenetic protein 10 (BMP10) is primarily involved in cardiac development and congenital heart disease processes. BMP10 is a newly identified cardiac-specific protein. In recent years, reports have emphasized the effects of BMP10 on myocardial apoptosis, fibrosis and immune response, as well as its synergistic effects with BMP9 in vascular endothelium and role in endothelial dysfunction. We believe that concentrating on this aspect of the study will enhance our knowledge of the pathogenesis of diabetes and the cardiovascular field. However, there have been no reports of any reviews discussing the role of BMP10 in diabetes and cardiovascular disease. In addition, the exact pathogenesis of diabetic cardiomyopathy is not fully understood, including myocardial energy metabolism disorders, microvascular changes, abnormal apoptosis of cardiomyocytes, collagen structural changes and myocardial fibrosis, all of which cause cardiac function impairment directly or indirectly and interact with one another. This review summarizes the research results of BMP10 in cardiac development, endothelial function and cardiovascular disease in an effort to generate new ideas for future research into diabetic cardiomyopathy.

A Comprehensive Review on the Significance of Cysteine in Various Metabolic Disorders; Particularly CVD, Diabetes, Renal Dysfunction, and Ischemic Stroke.

Metabolic disorders have long been a challenge for medical professionals and are a leading cause of mortality in adults. Diabetes, cardiovascular disorders (CVD), renal dysfunction, and ischemic stroke are the most prevalent ailments contributing to a high mortality rate worldwide. Reactive oxygen species are one of the leading factors that act as a fundamental root cause of metabolic syndrome. All of these disorders have their respective treatments, which, to some degree, sabotage the pathological worsening of the disease and an inevitable death. However, they pose a perilous health hazard to humankind. Cysteine, a functional amino acid shows promise for the prevention and treatment of metabolic disorders, such as CVD, Diabetes mellitus, renal dysfunction, and ischemic stroke. In this review, we explored whether cysteine can eradicate reactive oxygen species and subsequently prevent and treat these diseases.

Effector function and neutrophil cell death in the severity of sepsis with diabetes mellitus.

Sepsis, a life-threatening condition resulting from immune dysregulation, is typically triggered by bacterial infections and commonly coexists with diabetes mellitus. Neutrophils are the first responders to infection and require regulated activation to control pathogen and damage-associated molecular patterns. Dysregulation of neutrophil activation leads to uncontrolled inflammatory responses, often observed in both sepsis and diabetes patients. Neutrophil dysregulation, characterized by effector dysfunction and inadequate cell death processes, can serve as a biomarker for assessing sepsis severity, particularly in diabetic patients. This review provides information on the relationship between effector function, neutrophil cell death, and the severity of sepsis in individuals with diabetes mellitus, aiming to shed light on the mechanisms underlying sepsis progression. Topics covered in the review include an overview of effector function of neutrophil cells, mechanisms of neutrophil cell death, and dysregulation of effectors and neutrophil cell death processes in sepsis severity with diabetes mellitus.

The Elevated Inflammatory Status of Neutrophils Is Related to In-Hospital Complications in Patients with Acute Coronary Syndrome and Has Important Prognosis Value for Diabetic Patients.

Despite neutrophil involvement in inflammation and tissue repair, little is understood about their inflammatory status in acute coronary syndrome (ACS) patients with poor outcomes. Hence, we investigated the potential correlation between neutrophil inflammatory markers and the prognosis of ACS patients with/without diabetes and explored whether neutrophils demonstrate a unique inflammatory phenotype in patients experiencing an adverse in-hospital outcome. The study enrolled 229 ACS patients with or without diabetes. Poor evolution was defined as either death, left ventricular ejection fraction (LVEF) <40%, Killip Class 3/4, ventricular arrhythmias, or mechanical complications. Univariate and multivariate analyses were employed to identify clinical and paraclinical factors associated with in-hospital outcomes. Neutrophils isolated from fresh blood were investigated using qPCR, Western blot, enzymatic assay, and immunofluorescence. Poor evolution post-myocardial infarction (MI) was associated with increased number, activity, and inflammatory status of neutrophils, as indicated by significant increase of Erythrocyte Sedimentation Rate (ESR), C-reactive protein (CRP), fibrinogen, interleukin-1ß (IL-1ß), and, interleukin-6 (IL-6). Among the patients with complicated evolution, neutrophil activity had an important prognosis value for diabetics. Neutrophils from patients with unfavorable evolution revealed a pro-inflammatory phenotype with increased expression of CCL3, IL-1ß, interleukin-18 (IL-18), S100A9, intracellular cell adhesion molecule-1 (ICAM-1), matrix metalloprotease (MMP-9), of molecules essential in reactive oxygen species (ROS) production p22phox and Nox2, and increased capacity to form neutrophil extracellular traps. Inflammation is associated with adverse short-term prognosis in acute ACS, and inflammatory biomarkers exhibit greater specificity in predicting short-term outcomes in diabetics. Moreover, neutrophils from patients with unfavorable evolution exhibit distinct inflammatory patterns, suggesting that alterations in the innate immune response in this subgroup may exert detrimental effects on disease progression.

Mechanisms of spinophilin-dependent pancreas dysregulation in obesity.

Spinophilin is an F-actin binding and protein phosphatase 1 (PP1) targeting protein that acts as a scaffold of PP1 to its substrates. Spinophilin knockout (Spino-/-) mice have decreased fat mass, increased lean mass, and improved glucose tolerance, with no difference in feeding behaviors. Although spinophilin is enriched in neurons, its roles in nonneuronal tissues, such as ß cells of the pancreatic islets, are unclear. We have corroborated and expanded upon previous studies to determine that Spino-/- mice have decreased weight gain and improved glucose tolerance in two different models of obesity. We have identified multiple putative spinophilin-interacting proteins isolated from intact pancreas and observed increased interactions of spinophilin with exocrine, ribosomal, and cytoskeletal protein classes that normally act to mediate peptide hormone production, processing, and/or release in Leprdb/db and/or high-fat diet-fed (HFF) models of obesity. In addition, we have found that spinophilin interacts with proteins from similar classes in isolated islets, suggesting a role for spinophilin in the pancreatic islet. Consistent with a pancreatic ß cell type-specific role for spinophilin, using our recently described conditional spinophilin knockout mice, we found that loss of spinophilin specifically in pancreatic ß cells improved glucose tolerance without impacting body weight in chow-fed mice. Our data further support the role of spinophilin in mediating pathophysiological changes in body weight and whole body metabolism associated with obesity. Our data provide the first evidence that pancreatic spinophilin protein interactions are modulated by obesity and that loss of spinophilin specifically in pancreatic ß cells impacts whole body glucose tolerance.NEW & NOTEWORTHY To our knowledge, these data are the first to demonstrate that obesity impacts spinophilin protein interactions in the pancreas and identify spinophilin specifically in pancreatic ß cells as a modulator of whole body glucose tolerance.

Spilanthes filicaulis (Schumach. & Thonn.) C.D. Adams leaves protects against streptozotocin-induced diabetic nephropathy.

BACKGROUND AND OBJECTIVE: Diabetic neuropathy (DN) is a complex type of diabetes. The underlying cause of diabetic nephropathy remains unclear and may be due to a variety of pathological conditions resulting in kidney failure. This study examines the protective effect of the methanolic extract of Spilanthes filicaulis leaves (MESFL) in fructose-fed streptozotocin (STZ)-induced diabetic nephropathy and the associated pathway. METHODS: Twenty-five rats were equally divided randomly into five categories: Control (C), diabetic control, diabetic + metformin (100 mg/kg), diabetic + MESFL 150 mg/kg bw, and diabetic + MESFL 300 mg/kg bw. After 15 days, the rats were evaluated for fasting blood glucose (FBG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), urea, uric acid, serum creatinine, reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation (MDA). Gene expression levels of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP response element-binding (CREB), cFOS and the antiapoptotic protein Bcl-2 were examined. RESULTS: We observed that MESFL at 150 and 300 mg/kg bw significantly downregulated the protein expression of cAMP, PKA, CREB, and cFOS and upregulated the Bcl-2 gene, suggesting that the nephroprotective action of MESFL is due to the suppression of the cAMP/PKA/CREB/cFOS signaling pathway. In addition, MESFL increases SOD and CAT activities and GSH levels, reduces MDA levels, and reduces renal functional indices (ALP, urea, uric acid, and creatinine). CONCLUSION: Therefore, our results indicate that MESFL alleviates the development of diabetic nephropathy via suppression of the cAMP/PKA/CREB/cFOS pathways.