Apoptosis may contribute to a significant proportion of neuron death following acute brain ischemia (ABI), but the underlying mechanisms are still not fully understood. Brain ischemia may lead to ...stroke, which is one of the main causes of long-term morbidity and mortality in both developed and developing countries. Therefore, stroke prevention and treatment is clinically important. There are two important separate areas of the brain during ABI: the ischemic core and the ischemic penumbra. The ischemic core of the brain experiences a sudden reduction of blood flow, just minutes after ischemic attack with irreversible injury and subsequent cell death. On the other hand, apoptosis within the ischemic penumbra may occur after several hours or days, while necrosis starts in the first hours after the onset of ABI in the ischemic core. ABI is characterized by key molecular events that initiate apoptosis in many cells, such as overproduction of free radicals, Ca2+ overload and excitotoxicity. These changes in cellular homeostasis may trigger either necrosis or apoptosis, which often depends on cell type, cell age, and location in the brain. Apoptosis results in DNA fragmentation, degradation of cytoskeletal and nuclear proteins, cross-linking of proteins, formation of apoptotic bodies, expression of ligands for phagocytic cell receptors and finally uptake by phagocytic cells. This review focuses on recent findings based on animal and human studies regarding the apoptotic mechanisms of neuronal death following ABI and the development of potential neuroprotective agents that reduce morbidity. The effects of statins on stroke prevention and treatment as well as on apoptotic mediators are also considered.
Metabolic syndrome (MetS) is a leading public health and clinical challenge worldwide. MetS represents a group of interrelated risk factors that predict cardiovascular diseases (CVD) and diabetes ...mellitus (DM). Its prevalence ranges between 10 and 84%, depending on the geographic region, urban or rural environment, individual demographic characteristics of the population studied (sex, age, racial and ethnic origin), as well as the criteria used to define MetS. Persons with MetS have higher mortality rate when compared with people without MetS, primarily caused by progressive atherosclerosis, accelerated by pro-inflammatory and pro-coagulation components of MetS. Considering the high prevalence of metabolic disorders (glucose metabolism disorder, hypertension, dyslipidaemia, obesity etc.), preventive healthcare should focus on changing lifestyle in order to reduce obesity and increase physical activity. This narrative review considers the available evidence from clinical and experimental studies dealing with MetS, and current treatment options for patients with insulin resistance and MetS.
The peptide hormone leptin regulates food intake, body mass, and reproductive function and plays a role in fetal growth, proinflammatory immune responses, angiogenesis and lipolysis. Leptin is a ...product of the obese (
) gene and, following synthesis and secretion from fat cells in white adipose tissue, binds to and activates its cognate receptor, the leptin receptor (LEP-R). LEP-R distribution facilitates leptin's pleiotropic effects, playing a crucial role in regulating body mass
a negative feedback mechanism between adipose tissue and the hypothalamus. Leptin resistance is characterized by reduced satiety, over-consumption of nutrients, and increased total body mass. Often this leads to obesity, which reduces the effectiveness of using exogenous leptin as a therapeutic agent. Thus, combining leptin therapies with leptin sensitizers may help overcome such resistance and, consequently, obesity. This review examines recent data obtained from human and animal studies related to leptin, its role in obesity, and its usefulness in obesity treatment.
The Role of miRNAs in Metabolic Diseases Macvanin, Mirjana; Obradovic, Milan; Zafirovic, Sonja ...
Current medicinal chemistry,
01/2023, Letnik:
30, Številka:
17
Journal Article
Recenzirano
Metabolic diseases such as obesity, diabetes, dyslipidemia, and insulin resistance are characterized by glucose and lipid metabolism alterations and represent a global health problem. Many studies ...have established the crucial role of micro-ribonucleic acids (miRNAs) in controlling metabolic processes in various tissues. miRNAs are single- stranded, highly conserved non-coding RNAs containing 20-24 oligonucleotides that are expressed in a tissue-specific manner. miRNAs mainly interact through base pairing with 3' untranslated regions of target gene mRNAs to promote inhibition of their translation. miRNAs regulate the expression of as many as 30% of the human genes and have a role in crucial physiological processes such as human growth and development, cell proliferation, apoptosis, and metabolism. The number of miRNA molecules with a confirmed role in the pathogenesis of metabolic diseases is quickly expanding due to the availability of high-throughput methodologies for their identification. In this review, we present recent findings regarding the role of miRNAs as endocrine signaling molecules involved in the regulation of insulin production and fat metabolism. We discuss the potential of extracellular miRNAs present in biological fluids miRNAs as biomarkers for the prediction of diabetes and MetS. We also give an updated overview of therapeutic interventions based on antisense oligonucleotides and the CRISPR/Cas9 editing platform for manipulating levels of miRNAs involved in metabolic disorders.
The endothelium consists of a monolayer of Endothelial Cells (ECs) which form the inner cellular lining of veins, arteries, capillaries and lymphatic vessels. ECs interact with the blood and lymph. ...The endothelium fulfils functions such as vasodilatation, regulation of adhesion, infiltration of leukocytes, inhibition of platelet adhesion, vessel remodeling and lipoprotein metabolism. ECs synthesize and release compounds such as Nitric Oxide (NO), metabolites of arachidonic acid, Reactive Oxygen Species (ROS) and enzymes that degrade the extracellular matrix. Endothelial dysfunction represents a phenotype prone to atherogenesis and may be used as a marker of atherosclerotic risk. Such dysfunction includes impaired synthesis and availability of NO and an imbalance in the relative contribution of endothelialderived relaxing factors and contracting factors such as endothelin-1 and angiotensin. This dysfunction appears before the earliest anatomic evidence of atherosclerosis and could be an important initial step in further development of atherosclerosis. Endothelial dysfunction was historically treated with vitamin C supplementation and L-arginine supplementation. Short term improvement of the expression of adhesion molecule and endothelial function during antioxidant therapy has been observed. Statins are used in the treatment of hyperlipidaemia, a risk factor for cardiovascular disease. Future studies should focus on identifying the mechanisms involved in the beneficial effects of statins on the endothelium. This may help develop drugs specifically aimed at endothelial dysfunction.
Abstract
Atherosclerosis is a life-long illness that begins with risk factors, which in turn contribute to the development of subclinical disease, followed by the establishment of overt ...cardiovascular disease (CVD). Thrombotic-occlusive complications of atherosclerosis are among the most widespread and costly health problems. Oxidized low-density lipoprotein (OxLDL) plays an important role in atherogenesis by promoting an inflammatory environment and lipid deposition in the arterial wall. As cardiovascular events occur in individuals without common risk factors, there is a need for additional tools that may help in CVD risk assessment and management. The use of biomarkers has improved diagnostic, therapeutic and prognostic outcome in cardiovascular medicine. This review elaborates on the value of circulating OxLDL as a biomarker of CVD. Three enzyme-linked immunosorbent assays (4E6, DLH3 and E06) using murine monoclonal antibodies for determination of OxLDL blood levels have been developed. However, none of these assays are currently approved for routine clinical practice. We identified studies investigating OxLDL in CVD (measured by 4E6, DLH3 or E06 assay) by searching the PubMed database. Circulating OxLDL was found to be associated with all stages of atherosclerosis, from early atherogenesis to hypertension, coronary and peripheral arterial disease, acute coronary syndromes and ischemic cerebral infarction. The results of studies investigating the usefulness of OxLDL for CVD prediction were also summarized. Furthermore, OxLDL was found to be associated with pathologic conditions linked to CVD, including diabetes mellitus, obesity and metabolic syndrome (MetS). In addition, we have addressed the mechanisms by which OxLDL promotes atherogenesis, and the effects of antiatherogenic treatments on circulating OxLDL. Finally, we highlight the evidence suggesting that lipoprotein (a) Lp(a) is the preferential carrier of oxidized phospholipids (OxPL) in human plasma. A strong association between OxPL/apoB level (representing the content of OxPL on apolipoprotein B-100 particles, measured by E06 assay) and Lp(a) has been determined.
Small, dense low density lipoprotein (sdLDL) represents an emerging cardiovascular risk factor, since these particles can be associated with cardiovascular disease (CVD) independently of established ...risk factors, including plasma lipids. Obese subjects frequently have atherogenic dyslipidaemia, including elevated sdLDL levels, in addition to elevated triglycerides (TG), very low density lipoprotein (VLDL) and apolipoprotein-B, as well as decreased high density lipoprotein cholesterol (HDL-C) levels. Obesity-related co-morbidities, such as metabolic syndrome (MetS) are also characterized by dyslipidaemia. Therefore, agents that favourably modulate LDL subclasses may be of clinical value in these subjects. Statins are the lipid-lowering drug of choice. Also, anti-obesity and lipid lowering drugs other than statins could be useful in these patients. However, the effects of anti-obesity drugs on CVD risk factors remain unclear. We review the clinical significance of sdLDL in being overweight and obesity, as well as the efficacy of anti-obesity drugs on LDL subfractions in these individuals; a short comment on HDL subclasses is also included. Our literature search was based on PubMed and Scopus listings. Further research is required to fully explore both the significance of sdLDL and the efficacy of anti-obesity drugs on LDL subfractions in being overweight, obesity and MetS. Improving the lipoprotein profile in these patients may represent an efficient approach for reducing cardiovascular risk.
Reactive species are highly-reactive enzymatically, or non-enzymatically produced compounds with important roles in physiological and pathophysiological cellular processes. Although reactive species ...represent an extensively researched topic in biomedical sciences, many aspects of their roles and functions remain unclear. This review aims to systematically summarize findings regarding the biochemical characteristics of various types of reactive species and specify the localization and mechanisms of their production in cells. In addition, we discuss the specific roles of free radicals in cellular physiology, focusing on the current lines of research that aim to identify the reactive oxygen species-initiated cascades of reactions resulting in adaptive or pathological cellular responses. Finally, we present recent findings regarding the therapeutic modulations of intracellular levels of reactive oxygen species, which may have substantial significance in developing novel agents for treating several diseases.
The pathogenesis of acute brain ischemia (ABI) is highly complex and involves multiple mechanisms including free radical generation. Imbalance between the cellular production of free radicals and the ...ability of cells to defend against them is referred to as oxidative stress. Oxidative stress is one of the mechanisms contributing to neuronal damage, potentially induced through the ABI. Through interactions with a large number of molecules, reactive oxygen species may irreversibly destroy or alter the function of the cellular lipids, proteins, and nucleic acids and initiate cell signaling pathways after cerebral ischemia. Future investigations should focus on the understanding of oxidative stress mechanisms and neuroprotection in order to discover new treatment targets.
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