scholarly journals Catechol-Containing Compounds are a Broad Class of Protein Aggregation Inhibitors: II. Rosmarinic Acid Potently Detoxifies Amylin Amyloid and Ameliorates Diabetic Pathology in HIP Rats

2020 ◽  
Author(s):  
Ling Wu ◽  
Paul Velander ◽  
Anne M. Brown ◽  
Yao Wang ◽  
Dongmin Liu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Protein Aggregation ◽  
Rosmarinic Acid ◽  
Protein Misfolding ◽  
Broad Class ◽  
Diabetic Patients ◽  
Aggregation Inhibitors ◽  
Misfolding Diseases

AbstractProtein aggregation is associated with a large number of human protein misfolding diseases, yet FDA-approved drugs are currently not available. Amylin amyloid and plaque depositions in the pancreas are hallmark features of type 2 diabetes. Moreover, these amyloid deposits are implicated in the pathogenesis of diabetic complications such as neurodegeneration. We recently discovered that catechols and redox-related quinones/ anthraquinones represent a broad class of protein aggregation inhibitors. Further screening of a targeted library of natural compounds in complementary medicine that were enriched with catechol-containing compounds identified rosmarinic acid as a potent inhibitor of amylin aggregation (estimated inhibitory concentration IC50 = 200-300 nM). Structure-function relationship analysis of rosmarinic acid showed the additive effects of two catechol-containing components of the RA molecule. We further showed that RA does not reverse fibrillation back to monomeric amylin, but lead to non-toxic, remodeled protein aggregates. Rosmarinic acid has significant ex vivo efficacy in reducing human amylin oligomer levels in HIP rat sera as well as in sera from diabetic patients. In vivo efficacy studies of rosmarinic acid treatment with the diabetic HIP rat model demonstrated significant reduction in amyloid islet deposition and strong mitigation of diabetic pathology. Our work provides new in vitro molecular mechanisms and in vivo efficacy insights for a model nutraceutical agent against type 2 diabetes and other aging-related protein misfolding diseases.

scholarly journals Synergy in Polymicrobial Infections in a Mouse Model of Type 2 Diabetes

2005 ◽  
Vol 73 (9) ◽  
pp. 6055-6063 ◽  
Author(s):  
Matthew D. Mastropaolo ◽  
Nicholas P. Evans ◽  
Meghan K. Byrnes ◽  
Ann M. Stevens ◽  
John L. Robertson ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
White Blood Cells ◽  
In Vivo Model ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
E Coli ◽  
Polymicrobial Infections ◽  
Young Mice

ABSTRACT Human diabetics frequently suffer delayed wound healing, increased susceptibility to localized and systemic infections, and limb amputations as a consequence of the disease. Lower-limb infections in diabetic patients are most often polymicrobial, involving mixtures of aerobic, facultative anaerobic, and anaerobic bacteria. The purpose of this study is to determine if these organisms contribute to synergy in polymicrobial infections by using diabetic mice as an in vivo model. The model was the obese diabetic mouse strain BKS.Cg-m +/+ Lepr db /J, a model of human type 2 diabetes. Young (5- to 6-week-old) prediabetic mice and aged (23- to 24-week-old) diabetic mice were compared. The mice were injected subcutaneously with mixed cultures containing Escherichia coli, Bacteroides fragilis, and Clostridium perfringens. Progression of the infection (usually abscess formation) was monitored by examining mice for bacterial populations and numbers of white blood cells at 1, 8, and 22 days postinfection. Synergy in the mixed infections was defined as a statistically significant increase in the number of bacteria at the site of injection when coinfected with a second bacterium, compared to when the bacterium was inoculated alone. E. coli provided strong synergy to B. fragilis but not to C. perfringens. C. perfringens and B. fragilis provided moderate synergy to each other but only in young mice. B. fragilis was anergistic (antagonistic) to E. coli in coinfections in young mice at 22 days postinfection. When age-matched nondiabetic mice (C57BLKS/J) were used as controls, the diabetic mice exhibited 5 to 35 times the number of CFU as did the nondiabetic mice, indicating that diabetes was a significant factor in the severity of the polymicrobial infections.

scholarly journals Thermodynamic and kinetic design principles for protein aggregation inhibitors

2020 ◽  
Author(s):  
Thomas C. T. Michaels ◽  
Andela Šarić ◽  
Georg Meisl ◽  
Gabriella T. Heller ◽  
Samo Curk ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Protein Misfolding ◽  
Complex Problem ◽  
Binding Rate ◽  
Potent Inhibition ◽  
Aggregation Inhibitors ◽  
Aggregation Inhibition ◽  
General Physical ◽  
Misfolding Diseases ◽  
Physical Laws

AbstractUnderstanding the mechanism of action of compounds capable of inhibiting protein aggregation is critical to the development of potential ther-apeutics against protein misfolding diseases. A fundamental challenge for progress is the range of possible target species and the disparate timescales involved, since the aggregating proteins are simultaneously the reactants, products, intermediates and catalysts of the reaction. It is a complex problem, therefore, to choose the states of the aggregating proteins that should be bound by the compounds to achieve the most potent inhibition. We present here a comprehensive kinetic theory of protein aggregation inhibition which reveals the fundamental thermodynamic and kinetic signatures characterising effective inhibitors by identifying quantitative relationships between the aggregation and binding rate constants. These results provide general physical laws to guide the design and optimisation of protein aggregation inhibitors.

scholarly journals Lipotoxic Stress Induces Pancreaticβ-Cell Apoptosis through Modulation of Bcl-2 Proteins by the Ubiquitin-Proteasome System

2015 ◽  
Vol 2015 ◽  
pp. 1-16 ◽  
Author(s):  
Sara A. Litwak ◽  
Jibran A. Wali ◽  
Evan G. Pappas ◽  
Hamdi Saadi ◽  
William J. Stanley ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Death ◽  
Er Stress ◽  
Ubiquitin Proteasome System ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Ubiquitin Proteasome

Pancreaticβ-cell loss induced by saturated free fatty acids (FFAs) is believed to contribute to type 2 diabetes. Previous studies have shown induction of endoplasmic reticulum (ER) stress, increased ubiquitinated proteins, and deregulation of the Bcl-2 family in the pancreas of type 2 diabetic patients. However, the precise mechanism ofβ-cell death remains unknown. In the present study we demonstrate that the FFA palmitate blocks the ubiquitin-proteasome system (UPS) and causes apoptosis through induction of ER stress and deregulation of Bcl-2 proteins. We found that palmitate and the proteasome inhibitor MG132 induced ER stress inβ-cells, resulting in decreased expression of the prosurvival proteins Bcl-2, Mcl-1, and Bcl-XL, and upregulation of the prodeath BH3-only protein PUMA. On the other hand, pharmacological activation of the UPS by sulforaphane ameliorated ER stress, upregulated prosurvival Bcl-2 proteins, and protectedβ-cells from FFA-induced cell death. Furthermore, transgenic overexpression of Bcl-2 protected islets from FFA-induced cell deathin vitroand improved glucose-induced insulin secretionin vivo. Together our results suggest that targeting the UPS and Bcl-2 protein expression may be a valuable strategy to preventβ-cell demise in type 2 diabetes.

scholarly journals Inhaled Insulin Forms Toxic Pulmonary Amyloid Aggregates

Endocrinology ◽  
2010 ◽  
Vol 151 (10) ◽  
pp. 4717-4724 ◽  
Author(s):  
Cristian A. Lasagna-Reeves ◽  
Audra L. Clos ◽  
Terumi Midoro-Hiriuti ◽  
Randall M. Goldblum ◽  
George R. Jackson ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Protein Misfolding ◽  
Diabetic Patients ◽  
Amyloid Formation ◽  
Pulmonary Tissue ◽  
Inhaled Insulin ◽  
Parkinson’S Diseases ◽  
Pulmonary Air Flow

It is well known that interfaces, such as polar-nonpolar or liquid-air, play a key role in triggering protein aggregation in vitro, in particular the aggregation of peptides and proteins with the predisposition of misfolding and aggregation. Here we show that the interface present in the lungs predisposes the lungs to form aggregation of inhaled insulin. Insulin inhalers were introduced, and a large number of diabetic patients have used them. Although inhalers were safe and effective, decreases in pulmonary capacity have been reported in response to inhaled insulin. We hypothesize that the lung air-tissue interface provides a template for the aggregation of inhaled insulin. Our studies were designed to investigate the harmful potential that inhaled insulin has in pulmonary tissue in vivo, through an amyloid formation mechanism. Our data demonstrate that inhaled insulin rapidly forms amyloid in the lungs causing a significant reduction in pulmonary air flow. Our studies exemplify the importance that interfaces play in protein aggregation in vivo, illustrating the potential aggregation of inhaled proteins and the formation of amyloid deposits in the lungs. These insulin deposits resemble the amyloid structures implicated in protein misfolding disorders, such as Alzheimer’s and Parkinson’s diseases, and could as well be deleterious in nature.

Fundamentals of cross-seeding of amyloid proteins: an introduction

2019 ◽  
Vol 7 (46) ◽  
pp. 7267-7282 ◽  
Author(s):  
Baiping Ren ◽  
Yanxian Zhang ◽  
Mingzhen Zhang ◽  
Yonglan Liu ◽  
Dong Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Protein Misfolding ◽  
Protein Aggregates ◽  
Misfolded Protein ◽  
Amyloid Proteins ◽  
Misfolding Diseases

Misfolded protein aggregates formed by the same (homologous) or different (heterologous/cross) sequences are the pathological hallmarks of many protein misfolding diseases (PMDs) including Alzheimer's disease (AD) and type 2 diabetes (T2D).

Dual amyloid cross-seeding reveals steric zipper-facilitated fibrillization and pathological links between protein misfolding diseases

2021 ◽  
Vol 9 (15) ◽  
pp. 3300-3316
Author(s):  
Yanxian Zhang ◽  
Mingzhen Zhang ◽  
Yonglan Liu ◽  
Dong Zhang ◽  
Yijing Tang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Alzheimer Type ◽  
Amyloid Peptides ◽  
Misfolding Diseases ◽  
Amyloid Diseases

In vitro cross-interactions between three different amyloid peptides of GNNQQNY, Aβ, and hIAPP demonstrate the pathological links between three different amyloid diseases of Alzheimer, type 2 diabetes, and Prion diseases.

scholarly journals Natural Hydrogen Sulfide Donors from Allium sp. as a Nutraceutical Approach in Type 2 Diabetes Prevention and Therapy

Nutrients ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1581 ◽  
Author(s):  
Melino ◽  
Leo ◽  
Papajani
Keyword(s):  
Type 2 Diabetes ◽  
Medicinal Plants ◽  
Dietary Therapy ◽  
Diabetic Patients ◽  
Organosulfur Compounds ◽  
Type 2 Dm ◽  
Peripheral Arterial Diseases

Type 2 diabetes mellitus (DM) is a socially relevant chronic disease with high prevalence worldwide. DM may lead to several vascular, macrovascular, and microvascular complications (cerebrovascular, coronary artery, and peripheral arterial diseases, retinopathy, neuropathy, and nephropathy), often accelerating the progression of atherosclerosis. Dietary therapy is generally considered to be the first step in the treatment of diabetic patients. Among the current therapeutic options, such as insulin therapy and hypoglycemic drugs, in recent years, attention has been shifting to the effects and properties—that are still not completely known—of medicinal plants as valid and inexpensive therapeutic supports with limited side effects. In this review, we report the relevant effects of medicinal plants and nutraceuticals in diabetes. In particular, we paid attention to the organosulfur compounds (OSCs) present in plant extracts that due to their antioxidant, hypoglycemic, anti-inflammatory, and immunomodulatory effects, can contribute as cardioprotective agents in type 2 DM. OSCs derived from garlic (Allium sp.), due to their properties, can represent a valuable support to the diet in type 2 DM, as outlined in this manuscript based on both in vitro and in vivo studies. Moreover, a relevant characteristic of garlic OSCs is their ability to produce the gasotransmitter H2S, and many of their effects can be explained by this property. Indeed, in recent years, several studies have demonstrated the relevant effects of endogenous and exogenous H2S in human DM, including by in vitro and in vivo experiments and clinical trials; therefore, here, we summarize the effects and the underlying molecular mechanisms of H2S and natural H2S donors.

scholarly journals In Vivo Investigation of Cardiac benefits of Sodium Glucose Cotransporter Inhibition using the Zebrafish Model

2020 ◽  
Author(s):  
Asma Essa ◽  
Noura Aldous ◽  
Fatiha Benslimane ◽  
Huseyin Yalcin
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Diabetic Patients ◽  
Zebrafish Embryos ◽  
Cardiac Markers ◽  
Zebrafish Model ◽  
Sodium Glucose Cotransporter ◽  
Predominant Expression

Type 2 diabetes mellitus (T2DM) affects >16% of adults in Qatar. Newly emerging class of antidiabetic drugs, focused on SGLT inhibition were observed to reduce CVDs risks in diabetic patients. Up to date, the mechanism contributing to the CV benefits remains unrevealed. Zebrafish embryos were injected with different morpholinos to knockdown SGLT genes and study their effects on cardiac parameters. SGLT1 inhibition caused the most severe effects on zebrafish embryos with survival rate ~10 %. It also caused tube-like structured heats with edema, affecting significantly the cardiac output and diameter, and increased cardiac markers expressions. Analysis acquired correlates with literature data of SGLT1 predominant expression in heart tissues.

scholarly journals Interleukin-6 autoantibodies are involved in the pathogenesis of a subset of type 2 diabetes

2009 ◽  
Vol 204 (3) ◽  
pp. 265-273 ◽  
Author(s):  
K Fosgerau ◽  
P Galle ◽  
T Hansen ◽  
A Albrechtsen ◽  
C de Lemos Rieper ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Interleukin 6 ◽  
Plasma Levels ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Type 2 Diabetic

AbstractInterleukin-6 (IL6) is critically involved in inflammation and metabolism. About 1% of people produce IL6 autoantibodies (aAb-IL6) that impair IL6 signaling in vivo. We tested the hypothesis that the prevalence of such aAb-IL6 is increased in type 2 diabetic patients and that aAb-IL6 plays a direct role in causing hyperglycemia. In humans, the prevalence of circulating high-affinity neutralizing aAb-IL6 was 2.5% in the type 2 diabetic patients and 1% in the controls (odds ratio 2.5, 95% confidence interval 1.2–4.9, P=0.01). To test for the role of aAb-IL6 in causing hyperglycemia, such aAb-IL6 were induced in mice by a validated vaccination procedure. Mice with plasma levels of aAb-IL6 similar to the 2.5% type 2 diabetic patients developed obesity and impaired glucose tolerance (area under the curve (AUC) glucose, 2056±62 vs 1793±62, P=0.05) as compared with sham-vaccinated mice, when challenged with a high-fat diet. Mice with very high plasma levels of aAb-IL6 developed elevated fasting plasma glucose (mM, 4.8±0.4 vs 3.3±0.1, P<0.001) and impaired glucose tolerance (AUC glucose, 1340±38 vs 916±25, P<0.001) as compared with sham-control mice on normal chow. In conclusion, the prevalence of plasma aAb-IL6 at levels known to impair IL6 signaling in vivo is increased 2.5-fold in people with type 2 diabetes. In mice, matching levels of aAb-IL6 cause obesity and hyperglycemia. These data suggest that a small subset of type 2 diabetes may in part evolve from an autoimmune attack against IL6.

scholarly journals Downregulation of Erythrocyte miR-210 Induces Endothelial Dysfunction in Type 2 Diabetes

2021 ◽  
Author(s):  
Zhichao Zhou ◽  
Aida Collado ◽  
Changyan Sun ◽  
Yahor Tratsiakovich ◽  
Ali Mahdi ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Ex Vivo ◽  
Tyrosine Phosphatase ◽  
Protective Role ◽  
Diabetic Patients

Red blood cells (RBCs) act as mediators of vascular injury in type 2 diabetes mellitus (T2DM). miR-210 plays a protective role in cardiovascular homeostasis and is decreased in whole blood of T2DM mice. We hypothesized that downregulation of RBC miR-210 induces endothelial dysfunction in T2DM. RBCs were co-incubated with arteries and endothelial cells <i>ex vivo</i> and transfused <i>in vivo</i> to identify the role of miR-210 and its target protein tyrosine phosphatase 1B (PTP1B) in endothelial dysfunction. RBCs from patients with T2DM (T2DM RBC) and diabetic rodents induced endothelial dysfunction <i>ex vivo</i> and <i>in vivo</i>. miR-210 levels were lower in human T2DM RBC than in RBCs from healthy subjects (H RBC). Transfection of miR-210 in human T2DM RBC rescued endothelial function, whereas miR-210 inhibition in H RBC or RBCs from miR-210 knockout mice impaired endothelial function. Human T2DM RBC decreased miR-210 expression in endothelial cells. miR-210 expression in carotid artery plaques was lower in T2DM patients than in non-diabetic patients. Endothelial dysfunction induced by downregulated RBC miR-210 involved PTP1B and reactive oxygen species. miR-210 mimic attenuated endothelial dysfunction induced by RBCs via downregulating vascular PTP1B and oxidative stress in diabetic mice <i>in vivo</i>. These data reveal that the downregulation of RBC miR-210 is a novel mechanism driving the development of endothelial dysfunction in T2DM.

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