Cellular and Molecular Mechanisms of Impaired Angiogenesis and Delayed Wound Healing in Type 2 Diabetes: Amelioration Using siRNA-Pluronic Acid-Based Technology

2017 ◽  
pp. 45-55
Author(s):  
Milad S. Bitar
Keyword(s):  
Type 2 Diabetes ◽  
Wound Healing ◽  
Molecular Mechanisms ◽  
Delayed Wound Healing ◽  
Impaired Angiogenesis

Abstract 169: Type 2 Diabetes-Induced Hematopoietic Stem Cell Oxidant Stress Attenuates the Differentiation, Skews M1/M2 Specification of Monocytes/Macrophages and Delays Wound Healing in db/db Mice

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Jinglian Yan ◽  
Guodong Tie ◽  
Shouying Wang ◽  
Louis Messina
Keyword(s):  
Type 2 Diabetes ◽  
Wound Healing ◽  
Wound Closure ◽  
Oxidant Stress ◽  
M2 Macrophage ◽  
Delayed Wound Healing ◽  
Hematopoietic Stem ◽  
M1 Macrophage ◽  
M2 Phenotype

Rationale After recruitment to wounds, monocytes differentiate into macrophages which play a central role in all stages of wound healing. Wound healing is significantly delayed in type 2 diabetes and it is related to macrophage specification into M1/M2 phenotype, but the mechanism remains unknown. Objective This study tested the hypothesis that type 2 diabetes induces hematopoietic stem cells (HSCs) oxidant stress that reduces their differentiation towards monocytes and skews the specification of M1/M2 phenotype, thereby causing delayed wound healing. Methods and Results HSCs were sorted from bone marrow of WT and db/db type 2 diabetic mice. DCF staining showed significant oxidant accumulation in HSCs from db/db mice which was reversed by the antioxidant, N-acetylcysteine (NAC). Bone marrow monocyte concentration (FACS analysis of cell surface markers f4/80, cd14 and cd115) was significantly lower in db/db mice than in WT mice. NAC also reversed the reduced differentiation towards monocyte. Wound closure rate was significantly delayed in db/db mice. Macrophages were isolated from wounds and their concentration and M1/M2 phenotype were quantified by flow cytometry. During the inflammatory phase of wound healing, macrophage concentration was decreased and the proportion of M1 macrophage was lower in db/db mice than in WT mice. During new tissue formation phase , macrophage concentration was decreased and the proportion of M2 macrophage was lower, but M1 macrophage was higher in db/db mice than in WT mice. During tissue remodeling phase , macrophage concentration was increased and M1 macrophage remained higher in db/db mice, but no difference was observed in the proportion of M2 macrophage. The reduced differentiation of HSCs towards monocytes and the delayed wound closure phenotype of db/db mice could be transferred to WT mice by transplanting db/db HSCs into lethally irradiated WT mice. Conclusion Type 2 diabetes-induced HSC oxidant stress impairs HSC differentiation towards monocytes, skews the M1/M2 specification of macrophages and thereby accounts for the delayed wound healing. Type 2 diabetes-induced HSC oxidant stress may be a heretofore unrecognized critical regulator of dysinflammation in type 2 diabetes.

scholarly journals Therapies for the Treatment of Cardiovascular Disease Associated with Type 2 Diabetes and Dyslipidemia

2021 ◽  
Vol 22 (2) ◽  
pp. 660
Author(s):  
María Aguilar-Ballester ◽  
Gema Hurtado-Genovés ◽  
Alida Taberner-Cortés ◽  
Andrea Herrero-Cervera ◽  
Sergio Martínez-Hervás ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Molecular Mechanisms ◽  
Foam Cell ◽  
Leukocyte Adhesion ◽  
Experimental Studies ◽  
Lipid Lowering ◽  
Foam Cell Formation ◽  
Relevant Parameter

Cardiovascular disease (CVD) is the leading cause of death worldwide and is the clinical manifestation of the atherosclerosis. Elevated LDL-cholesterol levels are the first line of therapy but the increasing prevalence in type 2 diabetes mellitus (T2DM) has positioned the cardiometabolic risk as the most relevant parameter for treatment. Therefore, the control of this risk, characterized by dyslipidemia, hypertension, obesity, and insulin resistance, has become a major goal in many experimental and clinical studies in the context of CVD. In the present review, we summarized experimental studies and clinical trials of recent anti-diabetic and lipid-lowering therapies targeted to reduce CVD. Specifically, incretin-based therapies, sodium-glucose co-transporter 2 inhibitors, and proprotein convertase subtilisin kexin 9 inactivating therapies are described. Moreover, the novel molecular mechanisms explaining the CVD protection of the drugs reviewed here indicate major effects on vascular cells, inflammatory cells, and cardiomyocytes, beyond their expected anti-diabetic and lipid-lowering control. The revealed key mechanism is a prevention of acute cardiovascular events by restraining atherosclerosis at early stages, with decreased leukocyte adhesion, recruitment, and foam cell formation, and increased plaque stability and diminished necrotic core in advanced plaques. These emergent cardiometabolic therapies have a promising future to reduce CVD burden.

scholarly journals Molecular mechanisms and the vital roles of resistin, TLR 4, and NF-κB in treating type 2 diabetic complications

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Venkataiah Gudise ◽  
Bimalendu Chowdhury
Keyword(s):  
Type 2 Diabetes ◽  
Effective Treatment ◽  
Diabetic Complications ◽  
Molecular Mechanisms ◽  
Cellular Proliferation ◽  
Vascular Complications ◽  
Diabetic Patients ◽  
Rapid Progression ◽  
Main Body

Abstract Background Type 2 diabetes in obese (≥ 25 and ≥ 30 kg/m2) patients is the foremost cause of cardiovascular complications like stroke, osteoarthritis, cancers (endometrial, breast, ovarian, liver, kidney, colon, and prostate), and vascular complications like diabetic neuropathy, diabetic and retinopathy, and diabetic nephropathy. It is recognized as a global burden disorder with high prevalence in middle-income nations which might lead to a double burden on health care professionals. Hence, this review emphasizes on understanding the complexity and vital signaling tracts involved in diabetic complications for effective treatment. Main body Type 2 diabetes in overweight patients induces the creation of specific ROS that further leads to changes in cellular proliferation, hypothalamus, and fringe. The resistin, TLR4, and NF-κB signalings are mainly involved in the progression of central and fringe changes such as insulin resistance and inflammation in diabetic patients. The overexpression of these signals might lead to the rapid progression of diabetic vascular complications induced by the release of proinflammatory cytokines, chemokines, interleukins, and cyclooxygenase-mediated chemicals. Until now, there has been no curative treatment for diabetes. Therefore, to effectively treat complications of type 2 diabetes, the researchers need to concentrate on the molecular mechanisms and important signaling tracts involved. Conclusion In this review, we suggested the molecular mechanism of STZ-HFD induced type 2 diabetes and the vital roles of resistin, TLR4, and NF-κB signalings in central, fringe changes, and development diabetic complications for its effective treatment. Graphical abstract

scholarly journals Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1236
Author(s):  
Jesús Burillo ◽  
Patricia Marqués ◽  
Beatriz Jiménez ◽  
Carlos González-Blanco ◽  
Manuel Benito ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Progressive Disease

Type 2 diabetes mellitus is a progressive disease that is characterized by the appearance of insulin resistance. The term insulin resistance is very wide and could affect different proteins involved in insulin signaling, as well as other mechanisms. In this review, we have analyzed the main molecular mechanisms that could be involved in the connection between type 2 diabetes and neurodegeneration, in general, and more specifically with the appearance of Alzheimer’s disease. We have studied, in more detail, the different processes involved, such as inflammation, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction.

scholarly journals High Energy Intake Induced Overexpression of Transcription Factors and Its Regulatory Genes Involved in Acceleration of Hepatic Lipogenesis: A Rat Model for Type 2 Diabetes

Biomedicines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 76 ◽  
Author(s):  
Suresh P. Khadke ◽  
Aniket A. Kuvalekar ◽  
Abhay M. Harsulkar ◽  
Nitin Mantri
Keyword(s):  
Type 2 Diabetes ◽  
Transcription Factors ◽  
Glucose Tolerance ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
High Energy ◽  
Tolerance Test ◽  
Diabetic Control ◽  
Ppar Γ

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by impaired insulin action and its secretion. The objectives of the present study were to establish an economical and efficient animal model, mimicking pathophysiology of human T2DM to understand probable molecular mechanisms in context with lipid metabolism. In the present study, male Wistar rats were randomly divided into three groups. Animals were fed with high fat diet (HFD) except healthy control (HC) for 12 weeks. After eight weeks, intra peritoneal glucose tolerance test was performed. After confirmation of glucose intolerance, diabetic control (DC) group was injected with streptozotocin (STZ) (35 mg/kg b.w., i.p.). HFD fed rats showed increase (p ≤ 0.001) in glucose tolerance and HOMA-IR as compared to HC. Diabetes rats showed abnormal (p ≤ 0.001) lipid profile as compared to HC. The hepatocyte expression of transcription factors SREBP-1c and NFκβ, and their target genes were found to be upregulated, while PPAR-γ, CPT1A and FABP expressions were downregulated as compared to the HC. A number of animal models have been raised for studying T2DM, but the study has been restricted to only the biochemical level. The model is validated at biochemical, molecular and histopathological levels, which can be used for screening new therapeutics for the effective management of T2DM.

Abstract 199: Type 2 Diabetes Impairs Wound Healing By DNMT1-dependent Reduction of Hematopoietic Stem Cell Differentiation towards Monocytes/Macrophages and Skewing of the M1/M2 Polarization

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Jinglian Yan ◽  
Guodong Tie ◽  
Lyne Khair ◽  
Elena Filippova ◽  
Louis Messina
Keyword(s):  
Type 2 Diabetes ◽  
Wound Healing ◽  
Epigenetic Modification ◽  
Stem Cell Differentiation ◽  
M1 Macrophages ◽  
Hematopoietic Stem ◽  
Impaired Wound Healing ◽  
Inflammatory Phase ◽  
M2 Polarization

Rationale: People with Type 2 Diabetes Mellitus (T2DM) have a 25x higher risk of limb loss than non-diabetics due in large part to impaired wound healing. The mechanisms that cause impaired wound healing remain incompletely characterized. Objective: We hypothesize that T2DM impairs wound healing by epigenetic modifications in hematopoietic stem cells (HSC) that reduce their differentiation towards monocytes/macrophages and disrupts the balance in M1/M2 polarization during the three phases of wound healing. Methods and Results: Wounds were created on the back of mice. Wound healing was significantly slower in diabetic db/db than in WT mice. During the early inflammatory phase, db/db wounds exhibited a significant decrease in total macrophages and M1 macrophages. Then, total macrophages and M2 macrophages were decreased, while M1 macrophages increased in tissue formation phase. In the late tissue remodeling phase, total macrophages and M1 macrophages were persistently increased. The impaired wound healing phenotype of db/db mice was recapitulated in WT recipients which were resconstituted with db/db HSCs, demonstrating that the impaired differentiation of HSCs towards macrophages as well as their M1/M2 polarization was due to a cell autonomous mechanism. Epigenetic studies indicated that DNMT1-dependent hypermethylation of Notch1, Pu.1 and KLF4 in T2D HSCs was responsible for the impaired differentiation towards monocytes/macrophages as well as the skewed M1/M2 polarization. Knockdown of DNMT1 in HSCs from db/db mice transplanted into lethally irradiated WT mice led to improved wound healing by an increase in macrophage infiltration as well as a normalization of the M1/M2 polarization. Conclusion: This study indicates that the dynamic changes of macrophage concentration and M1/M2 polarization in wound healing are regulated at the level of HSCs. Moreover, T2DM impairs wound healing by inducing DNMT1-dependent reduction of HSCs’ differentiation towards macrophages and their M1/M2 polarization. This novel finding indicates that inflammation is regulated at the level of HSCs, which creates new opportunities to develop epigenetic modification related therapies for T2DM and potentially other conditions that result from dysinflammation.

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