1,721,038 research outputs found
The role of p66Shc knockout in a murine model of diabetic ulcers and peripheral ischemia
Full text linkThis thesis studied the role of p66shc in a murine model of ulcers complicated with peripheral ischemia. This study showed that the knockout of p66Shc improved wound healing in the setting of diabetes and ischemia. Moreover, diabetes increases the expression of p66Shc.Questa tesi ha studiato il ruolo di p66Shc in un modello murino di ulcere diabetiche complicate da ischemia periferica. Questo studio ha dimostrato che il knockout di p66Shc migliora la guarigione delle ulcere nel contesto di diabete ed ischemia. Il diabete, inoltre, aumenta l'espressione di p66Shc
Exploring neutrophils as therapeutic targets in cardiometabolic diseases
No full textCurrent therapies for diabetes and atherosclerotic cardiovascular diseases (ACVDs) mainly target metabolic risk factors, but often fall short in addressing systemic inflammation, a key driver of disease onset and progression. Advances in our understanding of the biology of neutrophils, the cells that are principally involved in inflammatory situations, have highlighted their pivotal role in cardiometabolic diseases. Yet, neutrophils can reprogram their immune-metabolic functions based on the energetic substrates available, thus influencing both tissue homeostasis and the resolution of inflammation. In this review, we examine the effects of canonical therapies for cardiometabolic diseases on the key molecular pathways through which neutrophils respond to inflammatory stimuli. In addition, we explore potential synergies between these established therapeutic approaches and the anti-inflammatory therapies being evaluated for repurposing in the treatment of cardiometabolic diseases
Impaired haematopoietic stem / progenitor cell traffic and multi-organ damage in diabetes
Full text linkDuring antenatal development, haematopoietic stem/progenitor cells (HSPCs) arise from a specialized endothelium and migrate from the extraembryonic mesoderm to the foetal liver before establishing haematopoiesis in the bone marrow (BM). It is still debated whether, in adulthood, HSPCs display such ontologic overlap with vascular cells and capacity for endothelial differentiation. Yet, adult HSPCs retain a prominent migratory activity and traffic in the bloodstream to secondary lymphoid organs and all peripheral tissues, before eventually returning to the BM. While patrolling parenchymatous organs, HSPCs locate close to the vasculature, where they establish local haematopoietic islands and contribute to tissue homeostasis by paracrine signals. Solid evidence shows that diabetes mellitus jeopardizes the traffic of HSPCs from BM to the circulation and peripheral tissues, a condition called "mobilopathy". A reduction in the levels of circulating HSPCs is the most immediate and apparent consequence, which has been consistently observed in human diabetes, and is strongly associated with future risk for multi-organ damage, including micro- and macroangiopathy. But shortage of HSPCs in the blood is only the visible tip of the iceberg. Abnormal HSPC traffic results from a complex interplay among metabolism, innate immunity, and haematopoiesis. Notably, mobilopathy is mechanistically connected with diabetes-induced myelopoiesis. Impaired traffic of HSPCs and enhanced generation of pro-inflammatory cells synergize for tissue damage and impair resolution of inflammation. We herein summarize the current evidence that diabetes affects HSPC traffic, which are the causes and consequences of such alteration, and how it contributes to the overall disease burden
Strategies for Enhancing Progenitor Cell Mobilization and Function in Diabetes.
No full textBone marrow (BM) holds a pool of stem and progenitor cells whose role is not limited to hematopoiesis. Indeed, growing evidences showed that BM-derived progenitors could contribute to various extents to cardiovascular homeostasis. Notably, diabetic patients experience an intrinsic defect of the progenitor pool, whereas some recent works point directly to an intrinsic defect of the BM, resulting in defective mobilization and impaired functions of progenitors. These defects could have important pathophysiological roles in the development of diabetic complications. An integrated approach, which enhances mobilization of progenitors and improves their functions, could represent a novel method to improve cardiovascular repair by endogenous progenitors. Furthermore, potential clinical trials of cell therapy would gain benefit from stratagems that enhance the number and functions of progenitors prior to transplantation. In this review we discuss the strategies to stimulate the mobilization of progenitors in diabetes and the protocols to improve their functions
Restoring stem cell mobilization to promote vascular repair in diabetes.
No full textDiabetes triggers endothelial dysfunction, which is linked to increased risk of cardiovascular diseases. Stem and progenitor cells from the bone marrow are involved in the maintenance of vascular integrity. Diabetic patients show a dysfunction of these cells, which might represent a novel pathophysiological mechanism of vascular disease. Specifically, stem and progenitor cells fail to egress from the bone marrow (BM) due to BM pathological alterations and unresponsiveness to mobilizing stimuli. In this review, we describe impaired stem cell mobilization in diabetes as a mechanism of failed vascular repair and we provide evidence that pharmacological strategies can restore mobilization. We discuss recent advances in the knowledge of aberrant organization of the diabetic BM and its implications for impaired mobilization. Finally, we describe in detail the pharmacological exploitation of the G-CSF/DPP-4(CD26)/SDF-1α axis as a novel strategy to improve mobilization and attain vascular repair in diabetes
Direct effects of DPP-4 inhibition on the vasculature. Reconciling basic evidence with lack of clinical evidence
No full textDiabetes is burdened by macrovascular and microvascular complications that collectively reduce life expectancy. As the ultimate goal of diabetes treatment is to prevent excess morbidity and mortality associated with its complications, the interest on cardiovascular effects of glucose lowering medications is high. Dipeptidyl peptidase-4 inhibitors (DPP-4i) lower blood glucose by protecting the incretin hormone glucagon-like peptide-1 (GLP-1) from enzymatic degradation, thereby restoring meal-stimulated insulin release. DPP-4 has several non-incretin substrates, including cytokines, chemokines, and neurohormones, which can exert favourable, but also unpredictable, vascular effects, once they are stabilized by DPP-4i. Choi et al. now provide additional evidence that DPP-4i counteracts vascular smooth muscle cell proliferation and migration, resulting in an attenuation of neointimal hyperplasia. Though several other in vitro, preclinical, and preliminary clinical studies on surrogate endpoints suggest that DPP-4i can exert similar direct vasculoprotective actions, results of placebo-controlled phase IV trials have so far shown no reduction cardiovascular endpoints by DPP-4i. In this commentary, we put DPP-4 pleiotropy and complexity into context, trying to reconcile why results from basic science have not yet translated into clinical evidence of cardiovascular protectio
Concise Review: Perspectives and Clinical Implications of Bone Marrow and Circulating Stem Cell Defects in Diabetes
No full textDiabetes mellitus is a complex systemic disease characterized by severe morbidity and excess mortality. The burden of its multiorgan complications relies on an imbalance between hyperglycemic cell damage and defective endogenous reparative mechanisms. Inflammation and abnormalities in several hematopoietic components are typically found in diabetes. The discovery that diabetes reduces circulating stem/progenitor cells and impairs their function has opened an entire new field of study where diabetology comes into contact with hematology and regenerative medicine. It is being progressively recognized that such rare circulating cell populations mirror finely regulated processes involved in hematopoiesis, immunosurveillance, and peripheral tissue homeostasis. From a clinical perspective, pauperization of circulating stem cells predicts adverse outcomes and death. Furthermore, studies in murine models and humans have identified the bone marrow (BM) as a previously neglected site of diabetic end-organ damage, characterized by microangiopathy, neuropathy, fat deposition, and inflammation. As a result, diabetes impairs the mobilization of BM stem/progenitor cells, a defect known as mobilopathy or myelokathexis, with negative consequences for physiologic hematopoiesis, immune regulation, and tissue regeneration. A better understanding of the molecular and cellular processes that govern the BM stem cell niche, cell mobilization, and kinetics in peripheral tissues may uncover new therapeutic strategies for patients with diabetes. This concise review summarizes the current knowledge on the interplay between the BM, circulating stem cells, and diabetes, and sets the stages for future developments in the field. Stem Cells 2016
Circulating Cellular Players in Vascular Calcification.
No full textVascular calcification is the deposition of calcium-phosphate salts in the form of hydroxyapatite within the arterial wall. This is a finely regulated process to such an extent that it shares some mechanisms with endochondral and membranous embryonic ossification. Current theories describe vascular calcification as the imbalance between mechanisms, which promote calcification and those that inhibit it. Canonical cellular players in this scenario include endothelial cells, resident vascular smooth muscle cells and immune cells. Nevertheless, the last decade has seen the rise of extraparietal cells as important players in vascular biology and also in the setting of ectopic calcification. After an overview of the mechanism involved in vascular calcification, we herein discuss the potential role of different populations of circulating calcifying cells
Angiogenic Abnormalities in Diabetes Mellitus: Mechanistic and Clinical Aspects
No full textDiabetes causes severe pathological changes to the microvasculature in many organs and tissues and is at the same time associated with an increased risk of coronary and peripheral macrovascular events. We herein review alterations in angiogenesis observed in human and experimental diabetes and how they contribute to diabetes onset and development of vascular complications
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