scholarly journals Senescence and Type 2 Diabetic Cardiomyopathy: How Young Can You Die of Old Age?

2021 ◽  
Vol 12 ◽  
Author(s):  
Sian M. Henson ◽  
Dunja Aksentijevic
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Strong Predictor ◽  
Metabolic Stress ◽  
Cell Types ◽  
Chronic Inflammatory Disease ◽  
Therapeutic Interventions ◽  
Low Grade ◽  
Adaptive Mechanisms ◽  
Myocardial Structure

Inflammation is well understood to be a physiological process of ageing however it also underlies many chronic diseases, including conditions without an obvious pathogenic inflammatory element. Recent findings have unequivocally identified type 2 diabetes (T2D) as a chronic inflammatory disease characterized by inflammation and immune senescence. Immunosenescence is a hallmark of the prolonged low-grade systemic inflammation, in particular associated with metabolic syndrome and can be a cause as well as a consequence of T2D. Diabetes is a risk factor for cardiovascular mortality and remodelling and with particular changes to myocardial structure, function, metabolism and energetics collectively resulting in diabetic cardiomyopathy. Both cardiomyocytes and immune cells undergo metabolic remodelling in T2D and as a result become trapped in a vicious cycle of lost metabolic flexibility, thus losing their key adaptive mechanisms to dynamic changes in O2 and nutrient availability. Immunosenescence driven by metabolic stress may be both the cause and key contributing factor to cardiac dysfunction in diabetic cardiomyopathy by inducing metabolic perturbations that can lead to impaired energetics, a strong predictor of cardiac mortality. Here we review our current understanding of the cross-talk between inflammaging and cardiomyocytes in T2D cardiomyopathy. We discuss potential mechanisms of metabolic convergence between cell types which, we hypothesize, might tip the balance between resolution of the inflammation versus adverse cardiac metabolic remodelling in T2D cardiomyopathy. A better understanding of the multiple biological paradigms leading to T2D cardiomyopathy including the immunosenescence associated with inflammaging will provide a powerful target for successful therapeutic interventions.

scholarly journals Role of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 706 ◽  
Author(s):  
Justin Hou Ming Yung ◽  
Adria Giacca
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acids ◽  
Free Fatty Acids ◽  
Chronic Inflammatory Disease ◽  
Low Grade ◽  
Global Epidemic ◽  
Progressive Development ◽  
Cell Dysfunction

Obesity has been described as a global epidemic and is a low-grade chronic inflammatory disease that arises as a consequence of energy imbalance. Obesity increases the risk of type 2 diabetes (T2D), by mechanisms that are not entirely clarified. Elevated circulating pro-inflammatory cytokines and free fatty acids (FFA) during obesity cause insulin resistance and ß-cell dysfunction, the two main features of T2D, which are both aggravated with the progressive development of hyperglycemia. The inflammatory kinase c-jun N-terminal kinase (JNK) responds to various cellular stress signals activated by cytokines, free fatty acids and hyperglycemia, and is a key mediator in the transition between obesity and T2D. Specifically, JNK mediates both insulin resistance and ß-cell dysfunction, and is therefore a potential target for T2D therapy.

scholarly journals Lipid Chaperones and Metabolic Inflammation

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Masato Furuhashi ◽  
Shutaro Ishimura ◽  
Hideki Ota ◽  
Tetsuji Miura
Keyword(s):  
Large Body ◽  
Metabolic Stress ◽  
Fatty Acid Binding Proteins ◽  
Low Grade ◽  
Oxygen Species ◽  
Fatty Acid Binding ◽  
Metabolic Inflammation ◽  
The Past ◽  
Inflammatory State

Over the past decade, a large body of evidence has emerged demonstrating an integration of metabolic and immune response pathways. It is now clear that obesity and associated disorders such as insulin resistance and type 2 diabetes are associated with a metabolically driven, low-grade, chronic inflammatory state, referred to as “metaflammation.” Several inflammatory cytokines as well as lipids and metabolic stress pathways can activate metaflammation, which targets metabolically critical organs and tissues including adipocytes and macrophages to adversely affect systemic homeostasis. On the other hand, inside the cell, fatty acid-binding proteins (FABPs), a family of lipid chaperones, as well as endoplasmic reticulum (ER) stress, and reactive oxygen species derived from mitochondria play significant roles in promotion of metabolically triggered inflammation. Here, we discuss the molecular and cellular basis of the roles of FABPs, especially FABP4 and FABP5, in metaflammation and related diseases including obesity, diabetes, and atherosclerosis.

scholarly journals Novel Combinatorial Approaches to Tackle the Immunosuppressive Microenvironment of Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1145
Author(s):  
Erin G. Shackleton ◽  
Haleema Yoosuf Ali ◽  
Masood Khan ◽  
Graham A. Pockley ◽  
Stephanie E. McArdle
Keyword(s):  
Prostate Cancer ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Therapy Resistance ◽  
Immune Checkpoint Blockade ◽  
Therapeutic Interventions ◽  
Th2 Cells ◽  
Low Grade ◽  
Castration Resistance

Prostate cancer (PCa) is the second-most common cancer in men worldwide and treatment options for patients with advanced or aggressive prostate cancer or recurrent disease continue to be of limited success and are rarely curative. Despite immune checkpoint blockade (ICB) efficacy in some melanoma, lung, kidney and breast cancers, immunotherapy efforts have been remarkably unsuccessful in PCa. One hypothesis behind this lack of efficacy is the generation of a distinctly immunosuppressive prostate tumor microenvironment (TME) by regulatory T cells, MDSCs, and type 2 macrophages which have been implicated in a variety of pathological conditions including solid cancers. In PCa, Tregs and MDSCs are attracted to TME by low-grade chronic inflammatory signals, while tissue-resident type 2 macrophages are induced by cytokines such as IL4, IL10, IL13, transforming growth factor beta (TGFβ) or prostaglandin E2 (PGE2) produced by Th2 cells. These then drive tumor progression, therapy resistance and the generation of castration resistance, ultimately conferring a poor prognosis. The biology of MDSC and Treg is highly complex and the development, proliferation, maturation or function can each be pharmacologically mediated to counteract the immunosuppressive effects of these cells. Herein, we present a critical review of Treg, MDSC and M2 involvement in PCa progression but also investigate a newly recognized type of immune suppression induced by the chronic stimulation of the sympathetic adrenergic signaling pathway and propose targeted strategies to be used in a combinatorial modality with immunotherapy interventions such as ICB, Sipuleucel-T or antitumor vaccines for an enhanced anti-PCa tumor immune response. We conclude that a strategic sequence of therapeutic interventions in combination with additional holistic measures will be necessary to achieve maximum benefit for PCa patients.

scholarly journals Eosinophils Reduce Chronic Inflammation in Adipose Tissue by Secreting Th2 Cytokines and Promoting M2 Macrophages Polarization

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Yi Zhang ◽  
Peng Yang ◽  
Ran Cui ◽  
Manna Zhang ◽  
Hong Li ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Liver Diseases ◽  
Chronic Inflammatory Disease ◽  
Interleukin 4 ◽  
Alternative Activation ◽  
Low Grade ◽  
Th2 Cytokines ◽  
Macrophages Polarization

Obesity is now recognized as a low-grade, chronic inflammatory disease that is linked to a myriad of disorders including cardiovascular diseases, type 2 diabetes, and liver diseases. Recently it is found that eosinophils accelerate alternative activation macrophage (AAM) polarization by secreting Th2 type cytokines such as interleukin-4 and interleukin-13, thereby reducing metainflammation in adipose tissue. In this review, we focused on the role of eosinophils in regulating metabolic homeostasis and obesity.

scholarly journals Metaflammation, NLRP3 Inflammasome Obesity and Metabolic Disease

2011 ◽  
Vol 3 (3) ◽  
pp. 168
Author(s):  
Anna Meiliana ◽  
Andi Wijaya
Keyword(s):  
Metabolic Disease ◽  
Type 2 Diabetes ◽  
Nlrp3 Inflammasome ◽  
Metabolic Diseases ◽  
Inflammatory Responses ◽  
Metabolic Stress ◽  
Nutrient Sensing ◽  
Low Grade ◽  
Wide Range

BACKGROUND: Increasing prevalence of obesity gives rise to many problems associated with multiple morbidities, such as diabetes, hypertension, heart disease, sleep apnea and cancer. The mechanism of obesity is very complex, thus its link to various disease is poorly understood. This review highlights important concepts in our understanding of the pathogenesis of obesity and related complications.CONTENT: Many studies have tried to explore the exciting and puzzling links between metabolic homeostasis and inflammatory responses. A form of subclinical, low-grade systemic inflammation is known to be associated with both obesity and chronic disease. This, later called as "metaflammation", refers to metabolically triggered inflammation. The nutrient-sensing pathway and the immune response coordination are facilitated by these molecular sites in order to maintain homeostasis under diverse metabolic and immune conditions. Recent studies have found that the NLRP3 inflammasome during metabolic stress forms a tie linking TXNIP, oxidative stress, and IL-1β production. This provides new opportunities for research and therapy for the disease often described as the next global pandemic: type 2 diabetes mellitus (T2DM).SUMMARY: The crucial role of metaflammation in many complications of obesity shown by the unexpected overlap between inflammatory and metabolic sensors and their downstream tissue responses. Then great interest arose to explore the pathways that integrate nutrient and pathogen sensing, give more understanding in the mechanisms of insulin resistance type 2 diabetes, and other chronic metabolic pathologies. A family of intracellular sensors called NLR family is a critical component of the innate immune system. They can form multiprotein complexes, called inflammasome which is capable of responding to a wide range of stimuli including both microbial and self molecules by activating the cysteine protease caspase-1, leading to processing and secretion of the proinflammatory cytokines IL-1β and IL-18, which play crucial roles in host defense. Inflammasome dysregulation has been linked to some autoinflammatory and metabolic diseases. These provide opportunities to continue to improve our understanding of the nature of metaflammation in the hope of modifying it to prevent and treat diseasese.KEYWORDS: Inflammation, metaflammation, inflammasome, metabolic disease, obesity

scholarly journals Antihyperglycemic drugs that improve cardiovascular outcomes and a model of diabetic cardiomyopathy

2019 ◽  
pp. 18-22
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Disease Process ◽  
Therapeutic Interventions ◽  
Second Line ◽  
Cardiovascular Outcome Trials ◽  
Short Period ◽  
Historical Importance ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Recent cardiovascular outcome trials (CVOTs) have transformed the landscape for the management of type 2 diabetes mellitus. In a remarkably short period of time, national and international guidelines have been overhauled to reflect the remarkable cardiovascular benefits of sodium/glucose linked transporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor analogues (GLP-1RA) in mitigating cardiovascular risk. Both SGLT2is and GLP-1RAs remain second-line to metformin, reflecting the historical importance of this biguanide antihyperglycemic. In this review, these three very different antihyperglycemics are discussed in the light of CVOT data and of the preclinical data revealing remarkable pleiotropic signaling effects of these drugs. A model of diabetic cardiomyopathy is discussed, and the points of contact that these therapeutic interventions have upon this model may of help in understanding how each can be best targeted in this complex pathophysiological disease process.

Inflammageing in the cardiovascular system: mechanisms, emerging targets, and novel therapeutic strategies

2020 ◽  
Vol 134 (17) ◽  
pp. 2243-2262
Author(s):  
Danlin Liu ◽  
Gavin Richardson ◽  
Fehmi M. Benli ◽  
Catherine Park ◽  
João V. de Souza ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Cardiovascular System ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Molecular Targets ◽  
Therapeutic Interventions ◽  
Low Grade ◽  
Cardiovascular Research ◽  
Inflammatory Processes ◽  
Ach Receptors

Abstract In the elderly population, pathological inflammation has been associated with ageing-associated diseases. The term ‘inflammageing’, which was used for the first time by Franceschi and co-workers in 2000, is associated with the chronic, low-grade, subclinical inflammatory processes coupled to biological ageing. The source of these inflammatory processes is debated. The senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammageing. The SASP is characterised by the release of inflammatory cytokines, elevated activation of the NLRP3 inflammasome, altered regulation of acetylcholine (ACh) nicotinic receptors, and abnormal NAD+ metabolism. Therefore, SASP may be ‘druggable’ by small molecule therapeutics targeting those emerging molecular targets. It has been shown that inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and adverse cardiac remodelling. Therefore, the pathomechanism involving SASP activation via the NLRP3 inflammasome; modulation of NLRP3 via α7 nicotinic ACh receptors; and modulation by senolytics targeting other proteins have gained a lot of interest within cardiovascular research and drug development communities. In this review, which offers a unique view from both clinical and preclinical target-based drug discovery perspectives, we have focused on cardiovascular inflammageing and its molecular mechanisms. We have outlined the mechanistic links between inflammageing, SASP, interleukin (IL)-1β, NLRP3 inflammasome, nicotinic ACh receptors, and molecular targets of senolytic drugs in the context of cardiovascular diseases. We have addressed the ‘druggability’ of NLRP3 and nicotinic α7 receptors by small molecules, as these proteins represent novel and exciting targets for therapeutic interventions targeting inflammageing in the cardiovascular system and beyond.

Chronic Low Grade Inflammation in Type 2 Diabetes—Activation of the Inflammasomes by Circulating Metabolites

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 1726-P
Author(s):  
MARIE MONLUN ◽  
VINCENT RIGALLEAU ◽  
LAURENCE BLANCO ◽  
KAMEL MOHAMMEDI ◽  
PATRICK BLANCO
Keyword(s):  
Type 2 Diabetes ◽  
Low Grade ◽  
Low Grade Inflammation

2217-PUB: Type 2 Diabetes Is a Strong Predictor for LDL Cholesterol Target Achievement in Patients with Peripheral Artery Disease

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 2217-PUB
Author(s):  
SIMON STERNBAUER ◽  
ALEXANDER VONBANK ◽  
CHRISTINE HEINZLE ◽  
DANIELA ZANOLIN-PURIN ◽  
JÖRN F. DOPHEIDE ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Peripheral Artery Disease ◽  
Ldl Cholesterol ◽  
Strong Predictor ◽  
Peripheral Artery ◽  
Artery Disease

Exercise and Stevia Rebaudiana (R) Extracts Attenuate Diabetic Cardiomyopathy in Type 2 Diabetic Rats: Possible Underlying Mechanisms

2020 ◽  
Vol 20 (7) ◽  
pp. 1117-1132
Author(s):  
Abdelaziz M. Hussein ◽  
Elsayed A. Eid ◽  
Ismaeel Bin-Jaliah ◽  
Medhat Taha ◽  
Lashin S. Lashin
Keyword(s):  
Oxidative Stress ◽  
Blood Glucose ◽  
Diabetic Cardiomyopathy ◽  
Caspase 3 ◽  
Stevia Rebaudiana ◽  
Diabetic Rats ◽  
Control Group ◽  
Underlying Mechanisms ◽  
Type 2 Diabetic

Background and Aims: In the current work, we studied the effects of exercise and stevia rebaudiana (R) extracts on diabetic cardiomyopathy (DCM) in type 2 diabetic rats and their possible underlying mechanisms. Methods: : Thirty-two male Sprague Dawley rats were randomly allocated into 4 equal groups; a) normal control group, b) DM group, type 2 diabetic rats received 2 ml oral saline daily for 4 weeks, c) DM+ Exercise, type 2 diabetic rats were treated with exercise for 4 weeks and d) DM+ stevia R extracts: type 2 diabetic rats received methanolic stevia R extracts. By the end of the experiment, serum blood glucose, HOMA-IR, insulin and cardiac enzymes (LDH, CK-MB), cardiac histopathology, oxidative stress markers (MDA, GSH and CAT), myocardial fibrosis by Masson trichrome, the expression of p53, caspase-3, α-SMA and tyrosine hydroxylase (TH) by immunostaining in myocardial tissues were measured. Results: T2DM caused a significant increase in blood glucose, HOMA-IR index, serum CK-MB and LDH, myocardial damage and fibrosis, myocardial MDA, myocardial α-SMA, p53, caspase-3, Nrf2 and TH density with a significant decrease in serum insulin and myocardial GSH and CAT (p< 0.05). On the other hand, treatment with either exercise or stevia R extracts significantly improved all studied parameters (p< 0.05). Moreover, the effects of stevia R was more significant than exercise (p< 0.05). Conclusion: Both exercise and methanolic stevia R extracts showed cardioprotective effects against DCM and Stevia R offered more cardioprotective than exercise. This cardioprotective effect of these lines of treatment might be due to attenuation of oxidative stress, apoptosis, sympathetic nerve density and fibrosis and upregulation of the antioxidant transcription factor, Nrf2.

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