1,721,003 research outputs found
Effects of Diabetes-Induced Hyperglycemia in the Heart: Biochemical and Structural Alterations
No full textHyperglycemia (HG) plays a major role in the development of diabetes mellitus (DM) and its complications. HG induces numerous maladaptations at the cellular level and moreover it is an independent risk factor to worsen cardiac performance and cell survival. The heart is a major target organ for damage with hyperglycemia. Alterations as a result of HG can lead to the development of a diabetic cardiomyopathy, resulting in changes to cardiac structure and function. Mechanisms damaging the heart are similar to those that damage the vasculature, but are more widespread in the myocardium. Four major pathways are implicated in HG-induced cardiac and vascular damage, including increases in advanced glycation end products (AGEs), enhanced hexosamine and polyol flux, and activation of classical isoforms of protein kinase C (PKC). These changes lead to abnormalities such as increased ventricular stiffness, cardiac fibrosis, derangement in cellular calcium ion homeostasis, and reduced myocyte contractility, resulting in heart failure (HF) over time. These pathways reflect upon a single HG-induced process of overproduction of superoxide by the mitochondrial electron-transport chain, which is responsible for the changes occurring in the heart. This chapter discusses the HG-induced pathways, focusing on their effects on the structure of the diabetic heart, as well as examining the downstream signaling whereby oxidative stress leads to myocardial fibrosis and impaired contractile function. In addition, this review highlights the role of endothelin-1 (ET-1) in endothelial dysfunction and the effects of humoral factors, angiotensin II and transforming growth factor-β, in evoking multiple signaling pathways in cardiac fibroblasts or fibrosis that leads to cardiac remodelling. How these signaling pathways mediated by HG contribute to the pathophysiological alterations in the heart is also discussed in this review
Regulation of Na+/K+-ATPase Activity in the Nervous System
No full textThe Na+/K+-ATPase or sodium pump (NKA) is a membrane-anchored protein responsible for creating and maintaining the Na+ and K+ gradients across the plasma membrane of animal cells by using ATP hydrolysis to move three Na+ out of the cell and two K+ into the cell. In the nervous system, NKA activity is essential for the proper functioning of neurons and glial cells and for the driving of diverse brain processes. Regulation of NKA activity in the brain is achieved through multitude of complex mechanisms. The purpose of this chapter is to present an overview of mechanisms through which neurotransmitters such as glutamate, dopamine, and serotonin regulate NKA activity in neurons and glial cells. Here, the focus is on the signaling pathways and protein kinases that mediate neurotransmitter effects on the NKA activity. In addition, the chapter considers the regulation of neuronal and glial NKA activity by its direct interacting partners, that is, a diverse plasma membrane, synapse associated, cytoskeleton, and signaling cytoplasmic proteins that form complexes with NKA in the brain. Such complexes not only regulate NKA activity but also enable the pump to function as a signal transducer in the brain. In view of important physiological role that NKA plays in the brain, the perturbed regulation of NKA activity in neurons and glial cells and its association with the onset and progress of nervous system disorders is also addressed
The Myocardial Creatine Kinase System in the Normal, Ischaemic and Failing Heart
No full textThe creatine kinase (CK) system is the final step in cardiac energy metabolism providing a direct link between energy production in the mitochondria and energy utilising ATPases. It acts as an energy storage and transport mechanism and maintains favourable local ATP/ADP ratios, thereby supporting further energy production and high levels of free energy from ATP hydrolysis. Down-regulation of CK activity and myocardial creatine levels is a universal finding in chronic heart failure, and the degree of impairment has been shown to be an excellent prognostic indicator in patients. However, it is unclear whether these changes represent epiphenomenon or contribute to disease pathophysiology. This chapter focuses on attempts over the past 20 years to address this question using genetic loss-of-function models in the mouse. Findings from these models have been equivocal and at times contradictory, however, recent evidence suggests that loss of creatine or CK is not detrimental in surgical models of chronic heart failure, providing the clearest evidence to date that such changes do not contribute to dysfunction. Despite this conclusion, over-expression of CK in mouse heart has been found to protect against heart failure and improve survival. In the setting of ischaemia-reperfusion injury, loss of creatine or CK impairs functional recovery and augmentation of either is cardioprotective. We are therefore entering an exciting new era of research in this field aimed at understanding the benefits of CK system augmentation and identifying new mechanisms to achieve this without genetic modification for possible future clinical translation
Obesity: Molecular Mechanisms, Epidemiology, Complications and Pharmacotherapy
No full textObesity is a common disorder affecting millions of people worldwide. The number of overweight and obese subjects, globally, is currently 2 billion and 800 million, respectively. Projected estimates show that the number of overweight citizens will approach 60% of the world’s population by the year 2030. Oxidative stress facilitates the development of obesity by stimulating pre-adipocyte differentiation and eventual adipose accumulation. Large deposits of fat release excessive quantities of adipocytokines, resulting in chronic inflammation. The obesity-induced chronic inflammation paves the way for a large variety of systemic complications including but not limited to diabetes mellitus, hyperlipidemia, atherosclerotic lesions, cardiovascular diseases tissue and malignancy. In addition, other obesity-inducers, such as increased insulin growth factor 1, insulin resistance, and increased tissue level of leptin and low concentration of adiponectin may lead to the development of tissue malignancy. Increased physical activity coupled with a healthy food intake is crucial to the management of obesity. Anti-obesity drugs such as sibutramine, qsymia (a combination of phentermine and topiramate), and orlistat have been used to treat obesity with variable degrees of efficacy. Bariatric surgery becomes a choice in severe cases when physical activity and pharmacotherapy fail. In the obese patient with diabetes mellitus, the choice of hypoglycemic agent is important. Metformin, and sodium glucose cotransporters 2 (SGLT2) inhibitors, a new set of antidiabetic drugs can significantly reduce body weight and improve cardiorenal function. SGLT2 inhibitors, thus belong to a class of potential drugs that can be used to treat obesity. In conclusion, obesity is a “deadly” condition that can predispose individuals to many life threatening health conditions
Dietary Micronutrient Supplements and Epigenetic Regulation in Obesity
No full textNutritional factors such as micronutrients play major physiological roles in maintaining good health in the population globally. Recent studies indicate that intake of dietary nutrients can also impact metabolism and epigenetics. Food additives may interact, causing epigenetic changes in histone deacetylation, DNA methylation, and chromatin-transforming factors, thereby regulating gene expression and controlling the cell phenotype. These changes may contribute to gene reprogramming during development, even though most phenotypic changes occur during the perinatal period. Modern lifestyle habits and metabolic disorders such as type 2 diabetes mellitus (T2DM), hypertension, atherosclerosis, obesity predisposition, and weight changes can result in the alteration of epigenetic styles, indicating the impact of certain diets, especially those with micronutrient deficiency, on human epigenetics throughout maturity and adulthood. Presently, the three important targets in epigenetic studies with regard to obesity include (1) a search for novel epigenetic biomarkers, (2) an understanding of the obesity-associated environmental factors and (3) identification of curative techniques based on either dietary or pharmacological proxies to regulate epigenetic marks. This review addresses many important aspects such as ascertaining the impact of dietary micronutrient supplements and their doses in modifying the epigenome, identifying those epigenetic marks that predispose people to nutritional exposures, evaluating the significance of obesity on epigenetic regulation, and describing genetic markers of weight-related issues
Cellular and Biochemical Mechanisms Driving the Susceptibility of Obese Subjects to Covid-19 Infection
No full textOverweight is a major global health problem currently affecting almost 2 billion people worldwide. An additional 800 million are obese. These figures showed that 40% of the global adult population aged 18 years, and over are overweight while 14% are obese. What is now worrying is that more than 40 million children worldwide, as young as 5 years of age are either overweight or obese. Individuals with a body mass index (BMI) of 25–29 kg/m2 are considered to be overweight while obesity is the term used when the BMI is 30 kg/m2 and over. Obesity is an imbalance between calorie intake and calorie expenditure. In general, obesity can be caused by excessive eating and reduced physical activity. Obesity is a major risk factor for non-communicable diseases such as diabetes mellitus, respiratory and liver dysfunctions, sleep apnea, chronic inflammation, compromised immune system, renal failure, cancer, musculoskeletal disorders, cardiovascular diseases and others. Obesity is also a major risk factor for coronavirus disease 19 (Covid-19), which can induce severe cases of pneumonia and sepsis or acute respiratory distress syndrome. In many cases, Covid-19 causes severe and long-lasting damage to the lungs and other vital organs of the body resulting in death. This review describes the cellular and biochemical mechanism(s) whereby obese patients become susceptible to Covid-19 infection. It also outlines how obesity on its own can affect the lungs, which in turn become more compromised in cases of Covid-19 disease resulting in the imminent death of the patient
Dysfunctional Circadian Rhythm Is Associated with Food Consumption, Obesity and Related Metabolic Diseases: Role of Ion Channels
No full textCircadian oscillators are the body’s biological clocks which exhibited in most of living organisms from bacteria to higher vertebrates. They are responsible for organizing a variety of biochemical and physiological cellular functions with a rhythmic period of a day cycle (24 h, circadian, repeat cycle in a day) even without any timing indicators. Any disruption in synchronization of circadian rhythm (chronodistruption) causes a wide range of complications which can be referred to as metabolic syndrome, obesity or type 2 diabetes mellitus (T2DM). Food intake can be stimulated because of its hedonic properties, although energy need is sufficiently provided. Addiction can be determined as excessive intake of either drug or food. Drug and food addiction shares some similar hedonic neuroadaptative properties in perception reward circuits. That could be as a result of childhood physical or psychological trauma by increasing neurotransmitter hypersensivity or dysregulation. Circadian clocks are key players of hormone synthesis and release, which cause cellular adaptations to the body environment. Ion channels are protein structured gate keepers located in the cell membrane, allowing charged ions to move across the membrane. They contribute and regulate many of cellular functions in the body. Ion channels act as an important player in circadian phases and also subsequent physiological functions by contributing in signaling pathway including homeostasis, gene expression, etc. Hence, this review focuses on the importance of chronobiology and its role on prevention of obesity, T2DM and regulation of the ion channels by circadian rhythm
Adipocytes Under Environmental Assault: Targets for Obesity?
No full textAbstract In the recent years, there has been a tremendous concern over the possible health threat posed by endocrine-disrupting chemicals (EDCs). These are mostly synthetic chemicals found in various materials such as organo-chlorinated
pesticides, industrial chemicals, plastics and plasticizers, fuels, heavy metals, additives or contaminants in food, and personal care products. These chemicals are present in the environment and are with widespread use. Human exposure to EDCs
occurs via ingestion of food, dust and water, via inhalation of gases and particles in the air, and through the skin. Data from several animal models, human clinical observations, and epidemiological studies converge to implicate their association
with altered reproductive function in males and females, increased incidence of breast cancer, abnormal growth patterns and neuro-developmental delays in children, disruption of adipocyte function, as well as changes in immune function. The
EDCs exert their insulting effects by interfering with hormone biosynthesis, metabolism, or action resulting in a deviation from normal homeostatic control or reproduction. The mechanisms of EDCs involve divergent pathways including (but not limited to) estrogenic, anti-androgenic, thyroid, peroxisome proliferator-activated receptor c, retinoid, and actions through other nuclear
receptors; steroidogenic enzymes; neurotransmitter receptors and systems; and many other pathways that are highly conserved in wildlife and humans. Emerging data from in vitro as well as in vivo models suggest new targets (i.e. adipocyte
differentiation and mechanisms involved in weight homeostasis) of abnormal programming by EDCs, and provide strong evidence to support the scientific term ‘obesogen’. The emerging idea of a link between EDCs and obesity expands the focus on obesity from intervention and treatment to include prevention and avoidance of these chemical modifiers. Because expansion of the adipocyte pool is critical for safely storing excess lipid, an understanding how these signaling axes can be altered by EDCs is critical in appreciating how environmental contaminants might contribute to the development of metabolic diseases
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