Suicidal Erythrocyte Death in Metabolic Syndrome

Eryptosis is a coordinated, programmed cell death culminating with the disposal of cells without disruption of the cell membrane and the release of endocellular oxidative and pro-inflammatory milieu. While providing a convenient form of death for erythrocytes, dysregulated eryptosis may result in a series of detrimental and harmful pathological consequences highly related to the endothelial dysfunction (ED). Metabolic syndrome (MetS) is described as a cluster of cardiometabolic factors (hyperglycemia, dyslipidemia, hypertension and obesity) that increases the risk of cardiovascular complications such as those related to diabetes and atherosclerosis. In the light of the crucial role exerted by the eryptotic process in the ED, the focus of the present review is to report and discuss the involvement of eryptosis within MetS, where vascular complications are utterly relevant. Current knowledge on the mechanisms leading to eryptosis in MetS-related conditions (hyperglycemia, dyslipidemia, hypertension and obesity) will be analyzed. Moreover, clinical evidence supporting or proposing a role for eryptosis in the ED, associated to MetS cardiovascular complications, will be discussed.

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Endothelial Dysfunction in Diabetes Mellitus: Possible Involvement of Endoplasmic Reticulum Stress?

Experimental Diabetes Research ◽

10.1155/2012/481840 ◽

2012 ◽

Vol 2012 ◽

pp. 1-14 ◽

Cited By ~ 56

Author(s):

Basma Basha ◽

Samson Mathews Samuel ◽

Chris R. Triggle ◽

Hong Ding

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Clinical Trials ◽

Endoplasmic Reticulum ◽

Endothelial Dysfunction ◽

Er Stress ◽

Vascular Complications ◽

Cardiovascular Complications ◽

Therapeutic Agents ◽

Recent Past

The vascular complications of diabetes mellitus impose a huge burden on the management of this disease. The higher incidence of cardiovascular complications and the unfavorable prognosis among diabetic individuals who develop such complications have been correlated to the hyperglycemia-induced oxidative stress and associated endothelial dysfunction. Although antioxidants may be considered as effective therapeutic agents to relieve oxidative stress and protect the endothelium, recent clinical trials involving these agents have shown limited therapeutic efficacy in this regard. In the recent past experimental evidence suggest that endoplasmic reticulum (ER) stress in the endothelial cells might be an important contributor to diabetes-related vascular complications. The current paper contemplates the possibility of the involvement of ER stress in endothelial dysfunction and diabetes-associated vascular complications.

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circRNAs Signature as Potential Diagnostic and Prognostic Biomarker for Diabetes Mellitus and Related Cardiovascular Complications

Cells ◽

10.3390/cells9030659 ◽

2020 ◽

Vol 9 (3) ◽

pp. 659 ◽

Cited By ~ 9

Author(s):

Mohamed Zaiou

Keyword(s):

Diabetes Mellitus ◽

Rna Binding ◽

Rna Binding Proteins ◽

Current Knowledge ◽

Vascular Complications ◽

Cardiovascular Complications ◽

Future Research ◽

Circular Rnas ◽

Obesity Hypertension ◽

Based Medicine

Circular RNAs (circRNAs) belong to the ever-growing class of naturally occurring noncoding RNAs (ncRNAs) molecules. Unlike linear RNA, circRNAs are covalently closed transcripts mostly generated from precursor-mRNA by a non-canonical event called back-splicing. They are highly stable, evolutionarily conserved, and widely distributed in eukaryotes. Some circRNAs are believed to fulfill a variety of functions inside the cell mainly by acting as microRNAs (miRNAs) or RNA-binding proteins (RBPs) sponges. Furthermore, mounting evidence suggests that the misregulation of circRNAs is among the first alterations in various metabolic disorders including obesity, hypertension, and cardiovascular diseases. More recent research has revealed that circRNAs also play a substantial role in the pathogenesis of diabetes mellitus (DM) and related vascular complications. These findings have added a new layer of complexity to our understanding of DM and underscored the need to reexamine the molecular pathways that lead to this disorder in the context of epigenetics and circRNA regulatory mechanisms. Here, I review current knowledge about circRNAs dysregulation in diabetes and describe their potential role as innovative biomarkers to predict diabetes-related cardiovascular (CV) events. Finally, I discuss some of the actual limitations to the promise of these RNA transcripts as emerging therapeutics and provide recommendations for future research on circRNA-based medicine.

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Insulin and the Lung: Connecting Asthma and Metabolic Syndrome

Journal of Allergy ◽

10.1155/2013/627384 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 24

Author(s):

Suchita Singh ◽

Y. S. Prakash ◽

Allan Linneberg ◽

Anurag Agrawal

Keyword(s):

Metabolic Syndrome ◽

Clinical Evidence ◽

Current Knowledge ◽

Signaling Cascades ◽

Airway Diseases ◽

Lung Structure ◽

Smooth Muscle Proliferation ◽

And Function ◽

Cellular Components ◽

Insight Into

Obesity, metabolic syndrome, and asthma are all rapidly increasing globally. Substantial emerging evidence suggests that these three conditions are epidemiologically and mechanistically linked. Since the link between obesity and asthma appears to extend beyond mechanical pulmonary disadvantage, molecular understanding is necessary. Insulin resistance is a strong, independent risk factor for asthma development, but it is unknown whether a direct effect of insulin on the lung is involved. This review summarizes current knowledge regarding the effect of insulin on cellular components of the lung and highlights the molecular consequences of insulin-related metabolic signaling cascades that could adversely affect lung structure and function. Examples include airway smooth muscle proliferation and contractility and regulatory signaling networks that are associated with asthma. These aspects of insulin signaling provide mechanistic insight into the clinical evidence for the links between obesity, metabolic syndrome, and airway diseases, setting the stage for novel therapeutic avenues targeting these conditions.

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Can Metformin Exert as an Active Drug on Endothelial Dysfunction in Diabetic Subjects?

Biomedicines ◽

10.3390/biomedicines9010003 ◽

2020 ◽

Vol 9 (1) ◽

pp. 3

Author(s):

Teresa Salvatore ◽

Pia Clara Pafundi ◽

Raffaele Galiero ◽

Luca Rinaldi ◽

Alfredo Caturano ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Clinical Evidence ◽

Polyol Pathway ◽

Cardiovascular Complications ◽

Diabetic Patients ◽

Beneficial Effects ◽

Kinase C ◽

First Choice ◽

Glycation End Products

Cardiovascular mortality is a major cause of death among in type 2 diabetes (T2DM). Endothelial dysfunction (ED) is a well-known important risk factor for the development of diabetes cardiovascular complications. Therefore, the prevention of diabetic macroangiopathies by preserving endothelial function represents a major therapeutic concern for all National Health Systems. Several complex mechanisms support ED in diabetic patients, frequently cross-talking each other: uncoupling of eNOS with impaired endothelium-dependent vascular response, increased ROS production, mitochondrial dysfunction, activation of polyol pathway, generation of advanced glycation end-products (AGEs), activation of protein kinase C (PKC), endothelial inflammation, endothelial apoptosis and senescence, and dysregulation of microRNAs (miRNAs). Metformin is a milestone in T2DM treatment. To date, according to most recent EASD/ADA guidelines, it still represents the first-choice drug in these patients. Intriguingly, several extraglycemic effects of metformin have been recently observed, among which large preclinical and clinical evidence support metformin’s efficacy against ED in T2DM. Metformin seems effective thanks to its favorable action on all the aforementioned pathophysiological ED mechanisms. AMPK pharmacological activation plays a key role, with metformin inhibiting inflammation and improving ED. Therefore, aim of this review is to assess metformin’s beneficial effects on endothelial dysfunction in T2DM, which could preempt development of atherosclerosis.

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Nucleated Cell Death by a Single Hole Generated by C5b-9

10.1101/2020.12.02.408690 ◽

2020 ◽

Author(s):

Anil K. Chauhan

Keyword(s):

Cell Death ◽

Cell Membrane ◽

Current Knowledge ◽

Membrane Attack Complex ◽

Therapeutic Interventions ◽

Membrane Pore ◽

Single Hole ◽

Bacterial Cell Death ◽

Current Paradigm ◽

Lipid Micelles

AbstractCell death is essential for tissue regeneration and removal of pathogenic cells. Immunological cell death is caused by membrane attack complex (MAC) or bacterial perforins. A complete understanding of nucleated cell death or bacterial cell death by MAC is essential for therapeutic interventions. The mechanism of MAC mediated cell death in nucleated cell is controversial. We know show that MAC causes cell death in nucleated cells by creating a large single hole in the membrane. Our results are contrary to the current paradigm that states “MAC kills nucleated cell by multiple hits”. MAC deposition on the cell membrane also trigger clustering of membrane rafts, which will have relevant consequences for enhanced cell signaling.Significance StatementProteins of late complement pathway that form membrane attack complex, cause death of undesirable nucleated cells such as lymphocytes. The structure of these proteins and their similarity to bacterial cytolysins has been studied. How C9 pore forming protein assemble with rest of C5b-8 on nucleated cell membrane remains controversial. We thus examined and now show the structures formed by these proteins on nucleated cell membranes. Formation of MAC occurs during complement activation during infection and autoimmunity. Largely, our current knowledge of the membrane pore formation is gained using ghost cells, lipid micelles, and erythrocytes. Understanding of how MAC kills nucleated cells will enhance our ability to design new therapies for selective killing of pathogens.

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Mediterranean diet, endothelial function and vascular inflammatory markers

Public Health Nutrition ◽

10.1017/s1368980007668529 ◽

2006 ◽

Vol 9 (8A) ◽

pp. 1073-1076 ◽

Cited By ~ 58

Author(s):

Katherine Esposito ◽

Miryam Ciotola ◽

Dario Giugliano

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Endothelial Dysfunction ◽

Low Grade ◽

The Metabolic Syndrome ◽

Inflammatory State ◽

Triggering Factor ◽

Inflammatory Milieu ◽

Visceral Adipose

AbstractObjectivesTo discuss present knowledge about the relation between adipose tissue, inflammation and the Mediterranean-style diet.DesignReview of the literature and personal perspectives.Setting and resultsRecent studies indicate that adipose tissue is an endocrine organ producing numerous proteins, collectively referred to as adipokines, with broad biological activity, which play an important autocrine role in obesity-associated complications. Adipose tissue in general and visceral fat in particular are thought to be key regulators of inflammation which is heavily involved in the onset and development of atherothrombotic disease. Moreover, chronic inflammation may also represent a triggering factor in the origin of the metabolic syndrome and type 2 diabetes mellitus. An increased release of proinflammatory adipokines from the visceral adipose tissue, associated with a reduced secretion of anti-inflammatory adipokines and cytokines, could determine a low-grade chronic inflammatory state which might play a role in the future development of the metabolic syndrome, diabetes and atherosclerosis through both insulin resistance and endothelial dysfunction. Interventions aimed at decreasing weight loss and improving adherence to a Mediterranean-style diet in people with obesity or metabolic syndrome decrease the inflammatory milieu and ameliorate both insulin resistance and endothelial dysfunction.ConclusionsAppropriate dietary patterns, as those associated with the eating model of Mediterranean-type diets, represent therapeutic strategies to reduce inflammation and the associated metabolic and cardiovascular risk.

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Targeting Endothelial Dysfunction in Vascular Complications Associated with Diabetes

International Journal of Vascular Medicine ◽

10.1155/2012/750126 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 7

Author(s):

Arpeeta Sharma ◽

Pascal N. Bernatchez ◽

Judy B. de Haan

Keyword(s):

Endothelial Dysfunction ◽

Vascular Complications ◽

Cardiovascular Complications ◽

Vascular Protection ◽

Mortality And Morbidity ◽

Improved Outcomes ◽

Overwhelming Evidence ◽

Novel Strategy ◽

Endogenous Antioxidant ◽

Key Events

Cardiovascular complications associated with diabetes remain a significant health issue in westernized societies. Overwhelming evidence from clinical and laboratory investigations have demonstrated that these cardiovascular complications are initiated by a dysfunctional vascular endothelium. Indeed, endothelial dysfunction is one of the key events that occur during diabetes, leading to the acceleration of cardiovascular mortality and morbidity. In a diabetic milieu, endothelial dysfunction occurs as a result of attenuated production of endothelial derived nitric oxide (EDNO) and augmented levels of reactive oxygen species (ROS). Thus, in this review, we discuss novel therapeutic targets that either upregulate EDNO production or increase antioxidant enzyme capacity in an effort to limit oxidative stress and restore endothelial function. In particular, endogenous signaling molecules that positively modulate EDNO synthesis and mimetics of endogenous antioxidant enzymes will be highlighted. Consequently, manipulation of these unique targets, either alone or in combination, may represent a novel strategy to confer vascular protection, with the ultimate goal of improved outcomes for diabetes-associated vascular complications.

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Chronic dietary n-3 PUFA intervention improves dyslipidaemia and subsequent cardiovascular complications in the JCR:LA-cp rat model of the metabolic syndrome

British Journal Of Nutrition ◽

10.1017/s0007114510005453 ◽

2011 ◽

Vol 105 (11) ◽

pp. 1572-1582 ◽

Cited By ~ 34

Author(s):

Jing Lu ◽

Faye Borthwick ◽

Zahra Hassanali ◽

Ye Wang ◽

Rabban Mangat ◽

...

Keyword(s):

Metabolic Syndrome ◽

Adipose Tissue ◽

Fatty Acid Synthase ◽

Regulatory Element ◽

Vascular Complications ◽

Plasma Lipid ◽

Cardiovascular Complications ◽

Pufa Supplementation ◽

The Metabolic Syndrome ◽

Myocardial Lesions

There is increasing interest in the potential chronic beneficial effects of dietary n-3 PUFA on the metabolic syndrome (MetS) and associated cardiovascular complications. We have recently established that increased dietary n-3 PUFA has a profound acute benefit on fasting lipids and the postprandial pro-inflammatory response in the JCR:LA-cp rat, a model of the MetS. However, it is unclear to what extent chronic dietary n-3 PUFA intervention can modulate the progression of end-stage metabolic and vascular complications. The present study aimed to determine the chronic effects of dietary n-3 PUFA supplementation on fasting and non-fasting dyslipidaemia, insulin resistance and vascular complications in the JCR:LA-cp rodent model. JCR:LA-cp rats were fed an isoenergetic lipid-balanced diet supplemented with 5 % n-3 PUFA (w/w) of the total fat (fish oil-derived EPA/DHA) for 16 weeks. Fasting and non-fasting (postprandial) plasma lipid profile was assessed. Hepatic and adipose tissue was probed for the expression of lipogenic proteins (acyl-CoA carboxylase (ACC), fatty acid synthase (FAS) and sterol regulatory element-binding protein-1 (SREBP-1)), while the activity of Jun N-terminal kinase (JNK) was assessed via Western blot to target phosphorylated JNK protein in primary enterocytes. The frequency of myocardial lesions was assessed by haematoxylin and eosin staining. Increased dietary n-3 PUFA improved both the fasting and postprandial lipid profiles (TAG, cholesterol and apoB48) in the JCR:LA-cp rat, potentially via the down-regulation of the hepatic or adipose tissue expression of lipogenic enzymes (ACC, FAS and SREBP-1). Rats fed the 5 % n-3 PUFA diet had lower (58·2 %; P < 0·01) enterocytic phosphorylated JNK protein and secreted less cholesterol (30 %; P < 0·05) into mesenteric lymph compared with the control. The chronic metabolic benefits of dietary n-3 PUFA may underlie the potential to reduce vascular complications during the MetS, including the observed reduction in the frequency (approximately 80 %) of late-stage 3 myocardial lesions.

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Endothelial Dysfunction: An Intermediate Clinical Feature between Urolithiasis and Cardiovascular Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms23020912 ◽

2022 ◽

Vol 23 (2) ◽

pp. 912

Author(s):

Javier Saenz-Medina ◽

Mercedes Muñoz ◽

Claudia Rodriguez ◽

Ana Sanchez ◽

Cristina Contreras ◽

...

Keyword(s):

Oxidative Stress ◽

Cardiovascular Disease ◽

Cardiovascular Diseases ◽

Endothelial Dysfunction ◽

Disease Risk ◽

Current Knowledge ◽

Angiotensin Receptor Blockers ◽

Vascular Complications ◽

Risk Scores ◽

Clinical Feature

An epidemiological relationship between urolithiasis and cardiovascular diseases has extensively been reported. Endothelial dysfunction is an early pathogenic event in cardiovascular diseases and has been associated with oxidative stress and low chronic inflammation in hypertension, coronary heart disease, stroke or the vascular complications of diabetes and obesity. The aim of this study is to summarize the current knowledge about the pathogenic mechanisms of urolithiasis in relation to the development of endothelial dysfunction and cardiovascular morbidities. Methods: A non-systematic review has been performed mixing the terms “urolithiasis”, “kidney stone” or “nephrolithiasis” with “cardiovascular disease”, “myocardial infarction”, “stroke”, or “endothelial dysfunction”. Results: Patients with nephrolithiasis develop a higher incidence of cardiovascular disease with a relative risk estimated between 1.20 and 1.24 and also develop a higher vascular disease risk scores. Analyses of subgroups have rendered inconclusive results regarding gender or age. Endothelial dysfunction has also been strongly associated with urolithiasis in clinical studies, although no systemic serum markers of endothelial dysfunction, inflammation or oxidative stress could be clearly related. Analysis of urine composition of lithiasic patients also detected a higher expression of proteins related to cardiovascular disease. Experimental models of hyperoxaluria have also found elevation of serum endothelial dysfunction markers. Conclusions: Endothelial dysfunction has been strongly associated with urolithiasis and based on the experimental evidence, should be considered as an intermediate and changeable feature between urolithiasis and cardiovascular diseases. Oxidative stress, a key pathogenic factor in the development of endothelial dysfunction has been also pointed out as an important factor of lithogenesis. Special attention must be paid to cardiovascular morbidities associated with urolithiasis in order to take advantage of pleiotropic effects of statins, angiotensin receptor blockers and allopurinol.

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Gasdermins: pore-forming activities and beyond

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmaa016 ◽

2020 ◽

Vol 52 (5) ◽

pp. 467-474

Author(s):

Zengzhang Zheng ◽

Wanyan Deng ◽

Xiwen Lou ◽

Yang Bai ◽

Junhong Wang ◽

...

Keyword(s):

Cell Death ◽

Cell Membrane ◽

Domain Structure ◽

Expression Profile ◽

Inflammatory Mediators ◽

Inflammatory Cell ◽

Current Knowledge ◽

Membrane Integrity ◽

Spontaneous Mutations ◽

Cell Membrane Integrity

Abstract Gasdermins (GSDMs) belong to a protein superfamily that is found only in vertebrates and consists of GSDMA, GSDMB, GSDMC, GSDMD, DFNA5 (a.k.a. GSDME) and DFNB59 (a.k.a. Pejvakin (PJVK)) in humans. Except for DFNB59, all members of the GSDM superfamily contain a conserved two-domain structure (N-terminal and C-terminal domains) and share an autoinhibitory mechanism. When the N-terminal domain of these GSDMs is released, it possesses pore-forming activity that causes inflammatory death associated with the loss of cell membrane integrity and release of inflammatory mediators. It has also been found that spontaneous mutations occurring in the genes of GSDMs have been associated with the development of certain autoimmune disorders, as well as cancers. Here, we review the current knowledge of the expression profile and regulation of GSDMs and the important roles of this protein family in inflammatory cell death, tumorigenesis and other related diseases.

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