Trained immunity and diabetic vascular disease

Abstract Trained immunity is a recently described phenomenon whereby innate immune cells undergo functional reprogramming in response to microbial products, vaccines, or other stimuli, leading them to mount a sensitized nonspecific response to subsequent stimulation. While it is essential for the host response to pathogens, many diseases are the product of excessive or chronic inflammation. Atherosclerosis is a disease characterized by chronic low-grade inflammation of the arterial wall leading to plaque formation, where macrophages are the most abundant cell regulating plaque progression and stability. Recent studies have revealed a role for endogenous compounds related to atherosclerosis in the induction of trained immunity, which can enhance the expression of genes implicated in atherosclerosis and associated cardiovascular disease. Accelerated atherosclerosis remains the principal cause of morbidity and premature mortality in patients with diabetes, and the burden of vascular complications is greatly enhanced by prior periods of inadequate control of blood glucose. Recent findings suggest that long-term changes in bone marrow myeloid progenitors, similar to those induced by microbial products or high cholesterol diets in mice, may help to explain the chronic inflammatory state driving atherosclerosis and cardiovascular risk that exists for patients with diabetes despite improved metabolic control. From an immunometabolic perspective, we speculate that changes supporting the trained macrophage phenotype, such as up-regulation of glycolysis, indicate that a high glucose environment could enhance the pro-inflammatory consequences of trained immunity thereby contributing to the accelerated progression of atherosclerosis in patients with diabetes.

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LTB4-Driven Inflammation and Increased Expression of ALOX5/ACE2 During Severe COVID-19 in Individuals with Diabetes

10.2337/figshare.14770662 ◽

2021 ◽

Author(s):

Icaro Bonyek-Silva ◽

Antônio Fernando Araújo Machado ◽

Thiago Cerqueira-Silva ◽

Sara Nunes ◽

Márcio Rivison Silva Cruz ◽

...

Keyword(s):

Intensive Care ◽

Mononuclear Cells ◽

Serum Levels ◽

Low Grade ◽

Receptor System ◽

Peripheral Blood Mononuclear ◽

Early Markers ◽

Patients With Diabetes ◽

Care Assistance ◽

Low Grade Inflammation

Diabetes is a known risk factor for severe COVID-19, the disease caused by the new coronavirus SARS-CoV-2. However, there is a lack of knowledge about the mechanisms involved in the evolution of COVID-19 in individuals with diabetes. Therefore, we aimed to evaluate whether the chronic low-grade inflammation of diabetes could play a role in the development of severe COVID-19. We collected clinical data and blood samples of hospitalized patients for COVID-19, with diabetes and without diabetes. Plasma samples were used to measure inflammatory mediators and peripheral blood mononuclear cells, for gene expression analysis of SARS-CoV-2 main receptor system (ACE2/TMPRSS2) and main molecule of LTB4 pathway (ALOX5). We found that diabetes activates LTB4 pathway, and during COVID-19, it increases ACE2/TMPRSS2 as well as ALOX5 expression. Diabetes was also associated with COVID-19-related disorders, such as reduced SpO2/FiO2 and PaO2/FiO2 levels, and increased disease duration. In addition, the expression of ACE2 and ALOX5 are positively correlated, with increased expression in COVID-19 patients with diabetes requiring intensive care assistance. We confirmed these molecular results at the protein level, where plasma LTB4 is significantly increased in individuals with diabetes. Besides, IL-6 serum levels are increased only in individuals with diabetes requiring intensive care assistance. Together, these results indicate that LTB4 and IL-6 systemic levels, as well as, ACE2/ALOX5 blood expression could be early markers of severe COVID-19 in individuals with diabetes.

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Mood Disorders, Accelerated Aging, and Inflammation: Is the Link Hidden in Telomeres?

Cells ◽

10.3390/cells8010052 ◽

2019 ◽

Vol 8 (1) ◽

pp. 52 ◽

Cited By ~ 10

Author(s):

Alessio Squassina ◽

Claudia Pisanu ◽

Roberta Vanni

Keyword(s):

Mood Disorders ◽

Accelerated Aging ◽

Cellular Level ◽

Low Grade ◽

Telomere Attrition ◽

Excess Morbidity ◽

Increased Risk ◽

Bidirectional Association ◽

Inflammatory State ◽

Low Grade Inflammation

Mood disorders are associated with an increased risk of aging-related diseases, which greatly contribute to the excess morbidity and mortality observed in affected individuals. Clinical and molecular findings also suggest that mood disorders might be characterized by a permanent state of low-grade inflammation. At the cellular level, aging translates into telomeres shortening. Intriguingly, inflammation and telomere shortening show a bidirectional association: a pro-inflammatory state seems to contribute to aging and telomere dysfunction, and telomere attrition is able to induce low-grade inflammation. Several independent studies have reported shorter telomere length and increased levels of circulating inflammatory cytokines in mood disorders, suggesting a complex interplay between altered inflammatory–immune responses and telomere dynamics in the etiopathogenesis of these disorders. In this review, we critically discuss studies investigating the role of telomere attrition and inflammation in the pathogenesis and course of mood disorders, and in pharmacological treatments with psychotropic medications.

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Dietary Pattern and Macronutrients Profile on the Variation of Inflammatory Biomarkers: Scientific Update

Cardiology Research and Practice ◽

10.1155/2018/4762575 ◽

2018 ◽

Vol 2018 ◽

pp. 1-18 ◽

Cited By ~ 6

Author(s):

Brenda Kelly Souza Silveira ◽

Thatianne Moreira Silva Oliveira ◽

Patrícia Amaro Andrade ◽

Helen Hermana Miranda Hermsdorff ◽

Carla de Oliveira Barbosa Rosa ◽

...

Keyword(s):

Dietary Pattern ◽

Saturated Fat ◽

Inflammatory Biomarkers ◽

Low Grade ◽

Omega 3 ◽

Cross Sectional ◽

Positive Effects ◽

Inflammatory State ◽

Fat Diets ◽

Low Grade Inflammation

It is known that the dietary pattern and macronutrients profile may influence the expression and secretion of inflammatory biomarkers, and the low-grade inflammation is associated with the manifestation of noncommunicable chronic diseases. Therefore, this review aimed to present and discuss the role of dietary patterns and macronutrients on the variation of inflammatory markers related to NCD risk. Scientific evidences within the last five years based on clinical trials, case-controls, cohorts, and cross-sectional studies indicate that normocaloric, carbohydrate-moderated, low-glycemic index, protein-moderated, monounsaturated and polyunsaturated fatty acid-rich, omega-3, and low-saturated fat diets display positive effects on the inflammatory state, both in healthy individuals and in those with cardiovascular risk, although the second group seems to benefit more from changes in the dietary profile.

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Physical activity, exercise and low-grade systemic inflammation

Proceedings of The Nutrition Society ◽

10.1017/s0029665110001928 ◽

2010 ◽

Vol 69 (3) ◽

pp. 400-406 ◽

Cited By ~ 43

Author(s):

Julia Wärnberg ◽

Karen Cunningham ◽

Javier Romeo ◽

Ascension Marcos

Keyword(s):

Physical Activity ◽

Type Ii Diabetes ◽

The Body ◽

Low Grade ◽

Type Ii ◽

Active Lifestyle ◽

Physically Active ◽

Inflammatory State ◽

Physical Activity And Exercise ◽

Low Grade Inflammation

Prospective studies have shown that chronic low-grade inflammation may contribute to the pathogenesis of the most common chronic diseases and in particular CVD. Obesity has repeatedly been associated with moderately raised levels of inflammation, and this observation has led to the view that obesity is characterised by a state of chronic low-grade inflammation. There is now great interest in elucidating how physical activity and exercise modulate inflammation. This review summarises the current research addressing the influence of physical activity and exercise in mitigating the risks of obesity and diseases such as type-II diabetes and CVD, through its action on the low-grade inflammatory state. Most research on this topic hypothesised that the association between physical activity and inflammatory markers is independent of fatness, but very few studies have proven this. Given that physical activity and obesity are often inversely related, it is not clear as to whether the anti-inflammatory health benefits of a physically active lifestyle are due to exercise per se or result from favourable changes in the body composition.

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Lack of Association betweenTLR4Genetic Polymorphisms and Diabetic Nephropathy in a Chinese Population

BioMed Research International ◽

10.1155/2014/704167 ◽

2014 ◽

Vol 2014 ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

Danfeng Peng ◽

Jie Wang ◽

Jiemin Pan ◽

Rong Zhang ◽

Shanshan Tang ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Chinese Population ◽

Diabetic Patients ◽

Low Grade ◽

Nucleotide Polymorphisms ◽

Type 2 Diabetic Patients ◽

Single Nucleotide ◽

Patients With Diabetes ◽

Low Grade Inflammation

Objective. Toll-like receptor 4 (TLR4) plays a central role in innate immunity. Activation of innate immune response and subsequent chronic low-grade inflammation are thought to be involved in the pathogenesis of diabetic nephropathy. In this study, we aimed to investigate whetherTLR4variants are associated with diabetic nephropathy in the Chinese population.Methods. Seven tagging single nucleotide polymorphisms (SNPs) ofTLR4based on HapMap Chinese data were genotyped in 1,455 Chinese type 2 diabetic patients. Of these patients, 622 were diagnosed with diabetic nephropathy and 833 were patients with diabetes for over 5 years but without diabetic nephropathy.Results. None of the SNPs and haplotypes showed significant association to diabetic nephropathy in our study. No association between the SNPs and quantitative traits was observed either.Conclusion. We concluded that common variants withinTLR4genes were not associated with diabetic nephropathy in the Chinese type 2 diabetes patients.

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Dietary AGEs as Exogenous Boosters of Inflammation

Nutrients ◽

10.3390/nu13082802 ◽

2021 ◽

Vol 13 (8) ◽

pp. 2802

Author(s):

Ma. Eugenia Garay-Sevilla ◽

Armando Rojas ◽

Manuel Portero-Otin ◽

Jaime Uribarri

Keyword(s):

Dietary Intake ◽

Thermal Processing ◽

Experimental Models ◽

The Body ◽

Low Grade ◽

Glycation End Products ◽

Inflammatory State ◽

Low Grade Inflammation ◽

Oxidative State ◽

Small Clinical Trials

Most chronic modern non-transmissible diseases seem to begin as the result of low-grade inflammation extending over prolonged periods of time. The importance of diet as a source of many pro-inflammatory compounds that could create and sustain such a low-grade inflammatory state cannot be ignored, particularly since we are constantly exposed to them during the day. The focus of this review is on specific components of the diet associated with inflammation, specifically advanced glycation end products (AGEs) that form during thermal processing of food. AGEs are also generated in the body in normal physiology and are widely recognized as increased in diabetes, but many people are unaware of the potential importance of exogenous AGEs ingested in food. We review experimental models, epidemiologic data, and small clinical trials that suggest an important association between dietary intake of these compounds and development of an inflammatory and pro-oxidative state that is conducive to chronic diseases. We compare dietary intake of AGEs with other widely known dietary patterns, such as the Mediterranean and the Dietary Approaches to Stop Hypertension (DASH) diets, as well as the Dietary Inflammation Index (DII). Finally, we delineate in detail the pathophysiological mechanisms induced by dietary AGEs, both direct (i.e., non-receptor-mediated) and indirect (receptor-mediated).

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The role of adipose tissue immune cells in obesity and low-grade inflammation

Journal of Endocrinology ◽

10.1530/joe-14-0283 ◽

2014 ◽

Vol 222 (3) ◽

pp. R113-R127 ◽

Cited By ~ 260

Author(s):

Milos Mraz ◽

Martin Haluzik

Keyword(s):

Diabetes Mellitus ◽

Adipose Tissue ◽

Immune Cells ◽

Vascular Complications ◽

Cellular Component ◽

Low Grade ◽

Induced Changes ◽

Low Grade Inflammation

Adipose tissue (AT) lies at the crossroad of nutrition, metabolism, and immunity; AT inflammation was proposed as a central mechanism connecting obesity with its metabolic and vascular complications. Resident immune cells constitute the second largest AT cellular component after adipocytes and as such play important roles in the maintenance of AT homeostasis. Obesity-induced changes in their number and activity result in the activation of local and later systemic inflammatory response, marking the transition from simple adiposity to diseases such as type 2 diabetes mellitus, arterial hypertension, and ischemic heart disease. This review has focused on the various subsets of immune cells in AT and their role in the development of AT inflammation and obesity-induced insulin resistance.

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Splenectomy Exacerbates the Hypercoagulable State and Causes Significant Organ Dysfunction in Patients with Hemoglobin E/β-Thalassemia.

Blood ◽

10.1182/blood.v114.22.2014.2014 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2014-2014

Author(s):

Vichai Atichartakarn ◽

Suporn Chuncharunee ◽

Napaporn Archararit ◽

Umaporn Udomsubpayakul ◽

Atiporn Ingsathit ◽

...

Keyword(s):

Conflicts Of Interest ◽

Laboratory Data ◽

Clinical Manifestations ◽

Hypercoagulable State ◽

P Value ◽

Low Grade ◽

Hemoglobin E ◽

Inflammatory State ◽

Pulmonary Arterial ◽

Low Grade Inflammation

Abstract Abstract 2014 Poster Board I-1036 Introduction: Clinical manifestations of blood hypercoagulability, such as pulmonary arterial hypertension (PAH) and ischemic stroke, are well known in patients with thalassemia. We herein present evidence that the hypercoagulable state in β-Thalassemia disease patients is to a significant extent the result of prior splenectomy. Patients and Methods: One hundred and ten clinically stable hemoglobin E/β-Thalassemia outpatients, on no medication aside from folic acid and who received no blood transfusion in the preceding 4 weeks were studied. All gave written informed consent, and study protocol was approved by the institution ethics committee on studies in humans (#0774/2548). Echocardiogram was used to estimate systolic PA pressure (SPAP). Clinical features and laboratory data were stratified according to the presence or absence of the spleen, and statistical analysis was done by STATA version 10 (Stata Corp, Texas), considering a P value <0.05 as statistically significant. Results: Of the 110 patients, 61 were asplenic and females comprised 51% in both groups. Selected statistically significant results are shown in the table. Conclusions: In comparison with non-splenectomized hemoglobin E/β-Thalassemia patients, asplenic ones have higher SPAP, more severe hemolysis, more liver impairment and chronic iron overload, significant chronic low grade inflammation, and evidence of coagulation activation. Splenectomy should be more judiciously applied than heretofore, and if performed, measures to blunt or prevent a subsequent hypercoagulable and inflammatory state, which could lead to PAH should be initiated. Disclosures: No relevant conflicts of interest to declare.

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The beneficial role of anti-inflammatory dietary ingredients in attenuating markers of chronic low-grade inflammation in aging

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2015-0017 ◽

2015 ◽

Vol 23 (2) ◽

Cited By ~ 7

Author(s):

Kiran S. Panickar ◽

Dennis E. Jewell

Keyword(s):

Scientific Data ◽

Bioactive Molecules ◽

Low Grade ◽

Reactive Protein ◽

General Decline ◽

Inflammatory State ◽

Anti Inflammatory ◽

Factor Α ◽

Low Grade Inflammation

AbstractAging in humans is associated with chronic low-grade inflammation (systemic), and this condition is sometimes referred to as “inflammaging”. In general, canines also age similarly to humans, and such aging is associated with a decline in mobility, joint problems, weakened muscles and bones, reduced lean body mass, cancer, increased dermatological problems, decline in cognitive ability, reduced energy, decreased immune function, decreased renal function, and urinary incontinence. Each of these conditions is also associated with an increase in pro-inflammatory cytokines. An inflammatory state characterized by an increase in pro-inflammatory markers including but not restricted to tumor necrosis factor-α, interleukin-6, IL-1β, and C-reactive protein (CRP) is believed to contribute to or worsen a general decline in biological mechanisms responsible for physical function with aging. Nutritional management of inflammation in aging dogs is important in maintaining health. In particular, natural botanicals have bioactive components that appear to have robust anti-inflammatory effects and, when included in the diet, may contribute to a reduction in inflammation. While there are scientific data to support the anti-inflammatory effects and the efficacy of such bioactive molecules from botanicals, the clinical data are limited and more studies are needed to validate the efficacy of these ingredients. This review will summarize the role of dietary ingredients in reducing inflammatory molecules as well as review the evidence available to support the role of diet and nutrition in reducing chronic low-grade systemic inflammation in animal and human studies with a special reference to canines, where possible.

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Dicarbonyl stress, protein glycation and the unfolded protein response

Glycoconjugate Journal ◽

10.1007/s10719-021-09980-0 ◽

2021 ◽

Author(s):

Naila Rabbani ◽

Mingzhan Xue ◽

Paul J. Thornalley

Keyword(s):

Insulin Resistance ◽

Unfolded Protein Response ◽

Vascular Complications ◽

Protein Glycation ◽

Low Grade ◽

Unfolded Protein ◽

Obesity And Diabetes ◽

The Unfolded Protein Response ◽

Protein Response ◽

Low Grade Inflammation

AbstractThe reactive dicarbonyl metabolite, methylglyoxal (MG), is increased in obesity and diabetes and is implicated in the development of insulin resistance, type 2 diabetes mellitus and vascular complications of diabetes. Dicarbonyl stress is the metabolic state of abnormal high MG concentration. MG is an arginine-directed glycating agent and precursor of the major advanced glycation endproduct, arginine-derived hydroimidazolone MG-H1. MG-H1 is often formed on protein surfaces and an uncharged hydrophobic residue, inducing protein structural distortion and misfolding. Recent studies indicate that dicarbonyl stress in human endothelial cells and fibroblasts in vitro induced a proteomic response consistent with activation of the unfolded protein response (UPR). The response included: increased abundance of heat shock proteins and ubiquitin ligases catalysing the removal of proteins with unshielded surface hydrophobic patches and formation of polyubiquitinated chains to encapsulate misfolded proteins; and increased low grade inflammation. Activation of the UPR is implicated in insulin resistance. An effective strategy to counter increased MG is inducing increased expression of glyoxalase-1 (Glo1). An optimized inducer of Glo1 expression, trans-resveratrol and hesperetin combination, normalized increased MG concentration, corrected insulin resistance and decreased low grade inflammation in overweight and obese subjects. We propose that dicarbonyl stress, through increased formation of MG-glycated proteins, may be an important physiological stimulus of the UPR and Glo1 inducers may provide a route to effective suppression and therapy. With further investigation and validation, this may provide key new insight into physiological activators of the UPR and association with dicarbonyl stress.

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