The Intrinsic Virtues of EGCG, an Extremely Good Cell Guardian, on Prevention and Treatment of Diabesity Complications

The pandemic proportion of diabesity—a combination of obesity and diabetes—sets a worldwide health issue. Experimental and clinical studies have progressively reinforced the pioneering epidemiological observation of an inverse relationship between consumption of polyphenol-rich nutraceutical agents and mortality from cardiovascular and metabolic diseases. With chemical identification of epigallocatechin-3-gallate (EGCG) as the most abundant catechin of green tea, a number of cellular and molecular mechanisms underlying the activities of this unique catechin have been proposed. Favorable effects of EGCG have been initially attributed to its scavenging effects on free radicals, inhibition of ROS-generating mechanisms and upregulation of antioxidant enzymes. Biologic actions of EGCG are concentration-dependent and under certain conditions EGCG may exert pro-oxidant activities, including generation of free radicals. The discovery of 67-kDa laminin as potential EGCG membrane target has broaden the likelihood that EGCG may function not only because of its highly reactive nature, but also via receptor-mediated activation of multiple signaling pathways involved in cell proliferation, angiogenesis and apoptosis. Finally, by acting as epigenetic modulator of DNA methylation and chromatin remodeling, EGCG may alter gene expression and modify miRNA activities. Despite unceasing research providing detailed insights, ECGC composite activities are still not completely understood. This review summarizes the most recent evidence on molecular mechanisms by which EGCG may activate signal transduction pathways, regulate transcription factors or promote epigenetic changes that may contribute to prevent pathologic processes involved in diabesity and its cardiovascular complications.

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Mechanisms for food polyphenols to ameliorate insulin resistance and endothelial dysfunction: therapeutic implications for diabetes and its cardiovascular complications

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00377.2013 ◽

2013 ◽

Vol 305 (6) ◽

pp. E679-E686 ◽

Cited By ~ 56

Author(s):

Kashif M. Munir ◽

Sruti Chandrasekaran ◽

Feng Gao ◽

Michael J. Quon

Keyword(s):

Insulin Resistance ◽

Endothelial Dysfunction ◽

Functional Foods ◽

Molecular Mechanisms ◽

Metabolic Diseases ◽

Clinical Medicine ◽

Cardiovascular Complications ◽

Therapeutic Implications ◽

Obesity And Diabetes ◽

Cardiovascular Morbidity And Mortality

The rising epidemic of diabetes is a pressing issue in clinical medicine worldwide from both healthcare and economic perspectives. This is fueled by overwhelming increases in the incidence and prevalence of obesity. Obesity and diabetes are characterized by both insulin resistance and endothelial dysfunction that lead to substantial increases in cardiovascular morbidity and mortality. Reciprocal relationships between insulin resistance and endothelial dysfunction tightly link metabolic diseases including obesity and diabetes with their cardiovascular complications. Therefore, therapeutic approaches that target either insulin resistance or endothelial dysfunction alone are likely to simultaneously improve both metabolic and cardiovascular pathophysiology and disease outcomes. Moreover, combination therapies with agents targeting distinct mechanisms are likely to have additive or synergistic benefits. Conventional therapies for diabetes and its cardiovascular complications that are both safe and effective are insufficient to meet rising demand. Large, robust, epidemiologic studies demonstrate beneficial metabolic and cardiovascular health effects for many functional foods containing various polyphenols. However, precise molecular mechanisms of action for food polyphenols are largely unknown. Moreover, translation of these insights into effective clinical therapies has not been fully realized. Nevertheless, some functional foods are likely sources for safe and effective therapies and preventative strategies for metabolic diseases and their cardiovascular complications. In this review, we emphasize recent progress in elucidating molecular, cellular, and physiological actions of polyphenols from green tea (EGCG), cocoa (ECG), and citrus fruits (hesperedin) that are related to improving metabolic and cardiovascular pathophysiology. We also discuss a rigorous comprehensive approach to studying functional foods that is essential for developing novel, effective, and safe medications derived from functional foods that will complement existing conventional drugs.

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Pathological Neuroinflammatory Conversion of Reactive Astrocytes Is Induced by Microglia and Involves Chromatin Remodeling

Frontiers in Pharmacology ◽

10.3389/fphar.2021.689346 ◽

2021 ◽

Vol 12 ◽

Author(s):

Alejandro Villarreal ◽

Camila Vidos ◽

Matías Monteverde Busso ◽

María Belén Cieri ◽

Alberto Javier Ramos

Keyword(s):

Chromatin Remodeling ◽

Molecular Mechanisms ◽

Reactive Astrocytes ◽

Pharmacological Intervention ◽

Temporary Increase ◽

Epigenetic Changes ◽

Cns Injury ◽

Gain Of Function ◽

Pathological Remodeling

Following brain injury or in neurodegenerative diseases, astrocytes become reactive and may suffer pathological remodeling, features of which are the loss of their homeostatic functions and a pro-inflammatory gain of function that facilitates neurodegeneration. Pharmacological intervention to modulate this astroglial response and neuroinflammation is an interesting new therapeutic research strategy, but it still requires a deeper understanding of the underlying cellular and molecular mechanisms of the phenomenon. Based on the known microglial–astroglial interaction, the prominent role of the nuclear factor kappa B (NF-κB) pathway in mediating astroglial pathological pro-inflammatory gain of function, and its ability to recruit chromatin-remodeling enzymes, we first explored the microglial role in the initiation of astroglial pro-inflammatory conversion and then monitored the progression of epigenetic changes in the astrocytic chromatin. Different configurations of primary glial culture were used to modulate microglia–astrocyte crosstalk while inducing pro-inflammatory gain of function by lipopolysaccharide (LPS) exposure. In vivo, brain ischemia by cortical devascularization (pial disruption) was performed to verify the presence of epigenetic marks in reactive astrocytes. Our results showed that 1) microglia is required to initiate the pathological conversion of astrocytes by triggering the NF-κB signaling pathway; 2) this interaction is mediated by soluble factors and induces stable astroglial phenotypic changes; 3) the pathological conversion promotes chromatin remodeling with stable increase in H3K9K14ac, temporary increase in H3K27ac, and temporary reduction in heterochromatin mark H3K9me3; and 4) in vivo reactive astrocytes show increased H3K27ac mark in the neuroinflammatory milieu from the ischemic penumbra. Our findings indicate that astroglial pathological pro-inflammatory gain of function is associated with profound changes in the configuration of astrocytic chromatin, which in turn are initiated by microglia-derived cues. These results open a new avenue in the study of potential pharmacological interventions that modify the initiation and stabilization of astroglial pathological remodeling, which would be useful in acute and chronic CNS injury. Epigenetic changes represent a plausible pharmacological target to interfere with the stabilization of the pathological astroglial phenotype.

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Hydrogen Therapy in Cardiovascular and Metabolic Diseases: from Bench to Bedside

Cellular Physiology and Biochemistry ◽

10.1159/000489737 ◽

2018 ◽

Vol 47 (1) ◽

pp. 1-10 ◽

Cited By ~ 16

Author(s):

Yaxing Zhang ◽

Sihua Tan ◽

Jingting Xu ◽

Tinghuai Wang

Keyword(s):

Molecular Mechanisms ◽

Ventricular Remodeling ◽

Metabolic Diseases ◽

Therapeutic Potential ◽

Chemical Properties ◽

Obesity And Diabetes ◽

Gas Molecules ◽

Heart Injury ◽

Physical And Chemical ◽

And Chemical Properties

Hydrogen (H2) is colorless, odorless, and the lightest of gas molecules. Studies in the past ten years have indicated that H2 is extremely important in regulating the homeostasis of the cardiovascular system and metabolic activity. Delivery of H2 by various strategies improves cardiometabolic diseases, including atherosclerosis, vascular injury, ischemic or hypertrophic ventricular remodeling, intermittent hypoxia- or heart transplantation-induced heart injury, obesity and diabetes in animal models or in clinical trials. The purpose of this review is to summarize the physical and chemical properties of H2, and then, the functions of H2 with an emphasis on the therapeutic potential and molecular mechanisms involved in the diseases above. We hope this review will provide the future outlook of H2-based therapies for cardiometabolic disease.

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Intestinal Fructose and Glucose Metabolism in Health and Disease

Nutrients ◽

10.3390/nu12010094 ◽

2019 ◽

Vol 12 (1) ◽

pp. 94 ◽

Cited By ~ 7

Author(s):

Beatriz Merino ◽

Cristina M. Fernández-Díaz ◽

Irene Cózar-Castellano ◽

German Perdomo

Keyword(s):

Glucose Metabolism ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Metabolic Diseases ◽

Sugar Metabolism ◽

Sugar Consumption ◽

Cellular Mechanisms ◽

Obesity And Diabetes ◽

Health And Disease ◽

Dietary Sugars

The worldwide epidemics of obesity and diabetes have been linked to increased sugar consumption in humans. Here, we review fructose and glucose metabolism, as well as potential molecular mechanisms by which excessive sugar consumption is associated to metabolic diseases and insulin resistance in humans. To this end, we focus on understanding molecular and cellular mechanisms of fructose and glucose transport and sensing in the intestine, the intracellular signaling effects of dietary sugar metabolism, and its impact on glucose homeostasis in health and disease. Finally, the peripheral and central effects of dietary sugars on the gut–brain axis will be reviewed.

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Molecular Insulin Actions Are Sexually Dimorphic in Lipid Metabolism

Frontiers in Endocrinology ◽

10.3389/fendo.2021.690484 ◽

2021 ◽

Vol 12 ◽

Author(s):

Rosa Isela Ortiz-Huidobro ◽

Myrian Velasco ◽

Carlos Larqué ◽

Rene Escalona ◽

Marcia Hiriart

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Sexual Dimorphism ◽

Energy Homeostasis ◽

Molecular Mechanisms ◽

Metabolic Diseases ◽

Critical Role ◽

Metabolic Dysfunction ◽

Anabolic Hormone ◽

Obesity And Diabetes

The increment in energy-dense food and low physical activity has contributed to the current obesity pandemic, which is more prevalent in women than in men. Insulin is an anabolic hormone that regulates the metabolism of lipids, carbohydrates, and proteins in adipose tissue, liver, and skeletal muscle. During obesity, nutrient storage capacity is dysregulated due to a reduced insulin action on its target organs, producing insulin resistance, an early marker of metabolic dysfunction. Insulin resistance in adipose tissue is central in metabolic diseases due to the critical role that this tissue plays in energy homeostasis. We focused on sexual dimorphism on the molecular mechanisms of insulin actions and their relationship with the physiology and pathophysiology of adipose tissue. Until recently, most of the physiological and pharmacological studies were done in males without considering sexual dimorphism, which is relevant. There is ample clinical and epidemiological evidence of its contribution to the establishment and progression of metabolic diseases. Sexual dimorphism is a critical and often overlooked factor that should be considered in design of sex-targeted therapeutic strategies and public health policies to address obesity and diabetes.

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Metabolic Diseases and Down Syndrome: How Are They Linked Together?

Biomedicines ◽

10.3390/biomedicines9020221 ◽

2021 ◽

Vol 9 (2) ◽

pp. 221

Author(s):

Manon Moreau ◽

Soukaina Benhaddou ◽

Rodolphe Dard ◽

Stefania Tolu ◽

Rim Hamzé ◽

...

Keyword(s):

Down Syndrome ◽

Life Expectancy ◽

Drug Targets ◽

Molecular Mechanisms ◽

Metabolic Diseases ◽

Genetic Disorder ◽

Cognitive Disorders ◽

Positive Outcome ◽

Chromosome 21 ◽

Obesity And Diabetes

Down syndrome is a genetic disorder caused by the presence of a third copy of chromosome 21, associated with intellectual disabilities. Down syndrome is associated with anomalies of both the nervous and endocrine systems. Over the past decades, dramatic advances in Down syndrome research and treatment have helped to extend the life expectancy of these patients. Improved life expectancy is obviously a positive outcome, but it is accompanied with the need to address previously overlooked complications and comorbidities of Down syndrome, including obesity and diabetes, in order to improve the quality of life of Down syndrome patients. In this focused review, we describe the associations between Down syndrome and comorbidities, obesity and diabetes, and we discuss the understanding of proposed mechanisms for the association of Down syndrome with metabolic disorders. Drawing molecular mechanisms through which Type 1 diabetes and Type 2 diabetes could be linked to Down syndrome could allow identification of novel drug targets and provide therapeutic solutions to limit the development of metabolic and cognitive disorders.

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Astrocytes in health and disease

Orvosi Hetilap ◽

10.1556/oh.2007.27892 ◽

2007 ◽

Vol 148 (15) ◽

pp. 697-702 ◽

Cited By ~ 2

Author(s):

Marianna Murányi ◽

Zsombor Lacza

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Free Radicals ◽

Molecular Mechanisms ◽

Neuronal Dysfunction ◽

Supporting Cells ◽

Neuronal Synapses ◽

Health And Disease ◽

Novel Targets ◽

Therapeutic Tools

It is now known that astrocytes are not merely supporting cells but they also play an important role in neuronal funcions. Astrocytes tightly ensheat neuronal synapses and regulate the excitation of neurons by uptaking neurotransmitters; reglulate the cerebral blood flow, cerebral fluid volume and extracellular concentrations of ions. They also supply fuel in the form of lactate and provide free radical scavangers such as glutathione for active neurons. These facts indicate that impaired function of astrocytes may lead to neuronal dysfunction. After brain injury (stroke, trauma or tumors) astrocytes are swollen and release active molecules such as glutamate or free radicals resulting in neuronal dysfunction. Thus, investigation of the molecular mechanisms of astrocyte function may reveal novel targets for the development of therapeutic tools in neuronal diseases.

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Periodontal Pathogens and Neuropsychiatric Health

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200110161105 ◽

2020 ◽

Vol 20 (15) ◽

pp. 1353-1397 ◽

Cited By ~ 3

Author(s):

Abhishek Wadhawan ◽

Mark A. Reynolds ◽

Hina Makkar ◽

Alison J. Scott ◽

Eileen Potocki ◽

...

Keyword(s):

Molecular Mechanisms ◽

Metabolic Diseases ◽

Low Grade ◽

Periodontal Pathogens ◽

Synergistic Interactions ◽

Brain Vasculature ◽

Micro Rnas ◽

Clinical Conditions ◽

Low Grade Inflammation ◽

Neuropsychiatric Illness

Increasing evidence incriminates low-grade inflammation in cardiovascular, metabolic diseases, and neuropsychiatric clinical conditions, all important causes of morbidity and mortality. One of the upstream and modifiable precipitants and perpetrators of inflammation is chronic periodontitis, a polymicrobial infection with Porphyromonas gingivalis (P. gingivalis) playing a central role in the disease pathogenesis. We review the association between P. gingivalis and cardiovascular, metabolic, and neuropsychiatric illness, and the molecular mechanisms potentially implicated in immune upregulation as well as downregulation induced by the pathogen. In addition to inflammation, translocation of the pathogens to the coronary and peripheral arteries, including brain vasculature, and gut and liver vasculature has important pathophysiological consequences. Distant effects via translocation rely on virulence factors of P. gingivalis such as gingipains, on its synergistic interactions with other pathogens, and on its capability to manipulate the immune system via several mechanisms, including its capacity to induce production of immune-downregulating micro-RNAs. Possible targets for intervention and drug development to manage distal consequences of infection with P. gingivalis are also reviewed.

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Ginger and Heart Health: From Mechanisms to Therapeutics

Current Molecular Pharmacology ◽

10.2174/1874467213666201209105005 ◽

2020 ◽

Vol 13 ◽

Author(s):

Sajad Fakhri ◽

Jayanta Kumar Patra ◽

Swagat Kumar Das ◽

Gitishree Das ◽

Mohammad Bagher Majnooni ◽

...

Keyword(s):

Side Effects ◽

Molecular Mechanisms ◽

Biological Activities ◽

Health Benefits ◽

Herbal Medicines ◽

Cardiovascular Complications ◽

National Database ◽

Heart Health ◽

Natural Entities ◽

Cardioprotective Effects

Background: As a major cause of morbidity and mortality, cardiovascular diseases (CVDs) are globally increasing. In spite of recent development in the management of cardiovascular complications, CVDs have remained a medical challenge. Numerous conventional drugs are used to play cardioprotective roles; however, they are associated with several side effects. Considering the rich phytochemistry and fewer side effects of herbal medicines, they have gained particular attention to develop novel herbal drugs with cardioprotective potentials. Amongst natural entities, ginger is an extensively used and well-known functional food and condiment, possessing plentiful bioactivities, like antiinflammatory, antioxidant, and antimicrobial properties in several disorders management. Objective: The current review deliberated phytochemical properties as well as the ginger/ginger constituents' biological activities and health benefits in several diseases, with particular attention to cardiovascular complications. Methods: A comprehensive research was conducted using multiple databases, including Scopus, PubMed, Medline, Web of Science, national database (Irandoc and SID), and related articles in terms of the health benefits and cardioprotective effects of ginger/ginger constituents. These data were collected from inception until August 2019. Results: In recent years, several herbal medicines were used to develop new drugs with more potency and also minor side effects. Amongst natural entities, ginger is an extensively used traditional medicine in several diseases. The crude extract, along with related pungent active constituents, is mostly attributed to heart health. The cardioprotective effects of ginger are contributed to its cardiotonic, antihypertensive, anti-hyperlipidemia, and anti-platelet effects. The signaling pathways and molecular mechanisms of ginger regarding its cardioprotective effects are also clarified. Conclusion: This study revealed the biological activities, health benefits, and cardioprotective properties of ginger/ginger constituents along with related mechanisms of action, which gave new insights to show new avenue in the treatment of CVDs.

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Genome-Wide Mapping of Histone H3 Lysine 4 Trimethylation (H3K4me3) and Its Involvement in Fatty Acid Biosynthesis in Sunflower Developing Seeds

Plants ◽

10.3390/plants10040706 ◽

2021 ◽

Vol 10 (4) ◽

pp. 706

Author(s):

Antonio J. Moreno-Pérez ◽

Raquel Martins-Noguerol ◽

Cristina DeAndrés-Gil ◽

Mónica Venegas-Calerón ◽

Rosario Sánchez ◽

...

Keyword(s):

Fatty Acid ◽

Chromatin Remodeling ◽

Molecular Mechanisms ◽

Acid Metabolism ◽

Fatty Acid Biosynthesis ◽

Acid Synthesis ◽

Sunflower Seeds ◽

Acid Biosynthesis ◽

Functional Regions ◽

Genome Wide

Histone modifications are of paramount importance during plant development. Investigating chromatin remodeling in developing oilseeds sheds light on the molecular mechanisms controlling fatty acid metabolism and facilitates the identification of new functional regions in oil crop genomes. The present study characterizes the epigenetic modifications H3K4me3 in relationship with the expression of fatty acid-related genes and transcription factors in developing sunflower seeds. Two master transcriptional regulators identified in this analysis, VIV1 (homologous to Arabidopsis ABI3) and FUS3, cooperate in the regulation of WRINKLED 1, a transcriptional factor regulating glycolysis, and fatty acid synthesis in developing oilseeds.

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