Vitamins and Hormones最新文献

Exposure to neurotoxic and heavy metals (Pb²⁺, As³⁺, Mn²⁺, Cd²⁺, etc) has increased over time and has shown to negatively affect brain health. Heavy metals can cross the blood brain barrier (BBB) in various ways including receptor or carrier-mediated transport, passive diffusion, or transport via gaps in the endothelial cells of the brain. In high concentrations, these metals have been shown to cause structural and functional impairment to the BBB, by inducing oxidative stress, ion dyshomeostasis, tight junction (TJ) loss, astrocyte/pericyte damage and interference of gap junctions. The structural and functional impairment of the BBB results in increased BBB permeability, which ultimately leads to accumulation of these heavy metals in the brain and their subsequent toxicity. As a result of these effects, heavy metals are correlated with various neurological disorders. The pathological effects of these heavy metals can be effectively mitigated via chelation. In addition, it is possible to treat the associated disorders by counteracting the molecular mechanisms associated with the brain and BBB impairment.

Advanced glycation end products (AGEs) are a heterogeneous group of potentially harmful molecules that can form as a result of a non-enzymatic reaction between reducing sugars and proteins, lipids, or nucleic acids. The total body pool of AGEs reflects endogenously produced AGEs as well as exogeneous AGEs that come from sources such as diet and the environment. Engagement of AGEs with their cellular receptor, the receptor for advanced glycation end products (RAGE), which is expressed on the surface of various cell types, converts a brief pulse of cellular activation to sustained cellular dysfunction and tissue destruction. The AGEs/RAGE interaction triggers a cascade of intracellular signaling pathways such as mitogen-activated protein kinase/extracellular signal-regulated kinase, phosphoinositide 3-kinases, transforming growth factor beta, c-Jun N-terminal kinases (JNK), and nuclear factor kappa B, which leads to the production of pro-inflammatory cytokines, chemokines, adhesion molecules, and oxidative stress. All these events contribute to the progression of several chronic diseases. This chapter will provide a comprehensive understanding of the dynamic roles of AGEs in health and disease which is crucial to develop interventions that prevent and mitigate the deleterious effects of AGEs accumulation.

Insulin resistance is a central hallmark that connects the metabolic syndrome and diabetes to the resultant formation of advanced glycation end products (AGEs), which further results in the complications of diabetes, including diabetic nephropathy. Several factors play an important role as an inducer to diabetic nephropathy, and AGEs elicit their harmful effects via interacting with the receptor for AGEs Receptor for AGEs, by induction of pro-inflammatory cytokines, oxidative stress, endoplasmic reticulum stress and fibrosis in the kidney tissues leading to the loss of renal function. Insulin resistance results in the activation of other alternate pathways governed by insulin, which results in the hypertrophy of the renal cells and tissue remodeling. Apart from the glucose uptake and disposal, insulin dependent PI3K and Akt also upregulate the expression of endothelial nitric oxide synthase, that results in increasing the bioavailability of nitric oxide in the vascular endothelium, which further results in tissue fibrosis. Considering the global prevalence of diabetic nephropathy, and the impact of protein glycation, various inhibitors and treatment avenues are being developed, to prevent the progression of diabetic complications. In this chapter, we discuss the role of glycation in insulin resistance and further its impact on the kidney.

The blood-brain barrier (BBB) predominantly regulates insulin transport into and levels within the brain. The BBB is also an important site of insulin binding and mediator of insulin receptor (INSR) signaling. The insulin transporter is separate from the INSR, highlighting the important, unique role of each protein in this structure. After a brief introduction on the structure of insulin and the INSR, we discuss the importance of insulin interactions at the BBB, the properties of the insulin transporter and the role of the BBB insulin transporter in various physiological conditions. We go on to further describe insulin BBB signaling and the impact not only within brain endothelial cells but also the cascade into other cell types within the brain. We close with future considerations to advance our knowledge about the importance of insulin at the BBB.

Waterhouse-Friderichsen syndrome is a rare but potentially fatal disorder of the adrenal gland characterized by bilateral adrenal hemorrhage. It is classically a result of meningococcal sepsis and presents acutely with features of shock, petechial rashes, abdominal pain, and non-specific symptoms such as headache, fatigue, and vomiting. Treatment consists of fluid resuscitation, corticosteroid replacement, and possibly surgery. The prognosis is poor despite treatment. This chapter will review the etiology, pathogenesis, clinical features, and management of the disease.

Chronic diabetes leads to various complications including diabetic kidney disease (DKD). DKD is a major microvascular complication and the leading cause of morbidity and mortality in diabetic patients. Varying degrees of proteinuria and reduced glomerular filtration rate are the cardinal clinical manifestations of DKD that eventually progress into end-stage renal disease. Histopathologically, DKD is characterized by renal hypertrophy, mesangial expansion, podocyte injury, glomerulosclerosis, and tubulointerstitial fibrosis, ultimately leading to renal replacement therapy. Amongst the many mechanisms, hyperglycemia contributes to the pathogenesis of DKD via a mechanism known as non-enzymatic glycation (NEG). NEG is the irreversible conjugation of reducing sugars onto a free amino group of proteins by a series of events, resulting in the formation of initial Schiff's base and an Amadori product and to a variety of advanced glycation end products (AGEs). AGEs interact with cognate receptors and evoke aberrant signaling cascades that execute adverse events such as oxidative stress, inflammation, phenotypic switch, complement activation, and cell death in different kidney cells. Elevated levels of AGEs and their receptors were associated with clinical and morphological manifestations of DKD. In this chapter, we discussed the mechanism of AGEs accumulation, AGEs-induced cellular and molecular events in the kidney and their impact on the pathogenesis of DKD. We have also reflected upon the possible options to curtail the AGEs accumulation and approaches to prevent AGEs mediated adverse renal outcomes.

Glycation is a protein post-translational modification that can occur on lysine and arginine residues as a result of a non-enzymatic process known as the Maillard reaction. This modification is irreversible, so the only way it can be removed is by protein degradation and replacement. Small reactive carbonyl species, glyoxal and methylglyoxal, are the primary glycating agents and are elevated in several conditions associated with an increased risk of cardiovascular disease, including diabetes, rheumatoid arthritis, smoking, and aging. Thus, how protein glycation impacts the cardiomyocyte is of particular interest, to both understand how these conditions increase the risk of cardiovascular disease and how glycation might be targeted therapeutically. Glycation can affect the cardiomyocyte through extracellular mechanisms, including RAGE-based signaling, glycation of the extracellular matrix that modifies the mechanical environment, and signaling from the vasculature. Intracellular glycation of the cardiomyocyte can impact calcium handling, protein quality control and cell death pathways, as well as the cytoskeleton, resulting in a blunted contractility. While reducing protein glycation and its impact on the heart has been an active area of drug development, multiple clinical trials have had mixed results and these compounds have not been translated to the clinic-highlighting the challenges of modulating myocyte glycation. Here we will review protein glycation and its effects on the cardiomyocyte, therapeutic attempts to reverse these, and offer insight as to the future of glycation studies and patient treatment.

Nonenzymatic glycation of proteins is accelerated in the context of elevated blood sugar levels in diabetes. Vitamin and mineral deficiencies are strongly linked to the onset and progression of diabetes. The antiglycation ability of various water- and fat-soluble vitamins, along with trace minerals like molybdenum (Mo), manganese (Mn), magnesium (Mg), chromium, etc., have been screened using Bovine Serum Albumin (BSA) as in vitro model. BSA was incubated with methylglyoxal (MGO) at 37 °C for 48 h, along with minerals and vitamins separately, along with controls and aminoguanidine (AG) as a standard to compare the efficacy of the minerals and vitamins. Further, their effects on renal cells' (HEK-293) antioxidant potential were examined. Antiglycation potential is measured by monitoring protein glycation markers, structural and functional modifications. Some minerals, Mo, Mn, and Mg, demonstrated comparable inhibition of protein-bound carbonyl content and ß-amyloid aggregation at maximal physiological concentrations. Mo and Mg protected the thiol group and free amino acids and preserved the antioxidant potential. Vitamin E, D, B1 and B3 revealed significant glycation inhibition and improved antioxidant potential in HEK-293 cells as assessed by estimating lipid peroxidation, SOD and glyoxalase activity. These results emphasize the glycation inhibitory potential of vitamins and minerals, indicating the use of these micronutrients in the prospect of the therapeutic outlook for diabetes management.

Without knowledge of the spatial [three-dimensional, (3D)] organization of an organ at the tissue and cellular levels, it is impossible to form a complete picture of its structure and function. At the same time, tissue components hidden in the thickness of the organ are the most difficult to study. The rapid development of computer technologies has contributed both to the development and implementation of new methods for studying 3D microstructures of organs, and the improvement of classical ones but the most complete picture can still be obtained only by recreating 3D models from serial histological sections. This fully applies to the important, but hidden in the thickness of the organ, and difficult to study 3D organization of the adrenal medulla. Only 3D reconstruction from serial sections makes it possible to identify all the main tissue components of the adrenal medulla simultaneously and with good resolution. Of particular importance to this method is the ability to reliably differentiate and study separately the 3D organization of the two main subpopulations of medulla endocrinocytes: adrenaline-storing (A-) cells and noradrenaline-storing (NA-) cells. In this chapter, we discuss the 3D organization of the adrenal medulla based on these original serial section 3D reconstructions and correlating them with data obtained by other methods.

Hemoglobin (Hb) is a hemeprotein found inside erythrocytes and is crucial in transporting oxygen and carbon dioxide in our bodies. In erythrocytes (Ery), the main energy source is glucose metabolized through glycolysis. However, a fraction of Hb can undergo glycation, in which a free amine group from the protein spontaneously binds to the carbonyl of glucose in the bloodstream, resulting in the formation of glycated hemoglobin (HbA1c), widely used as a marker for diabetes. Glycation leads to structural and conformational changes, compromising the function of proteins, and is intensified in the event of hyperglycemia. The main changes in Hb include structural alterations to the heme group, compromising its main function (oxygen transport). In addition, amyloid aggregates can form, which are strongly related to diabetic complications and neurodegenerative diseases. Therefore, this chapter discusses in vitro protocols for producing glycated Hb, as well as the main techniques and biophysical assays used to assess changes in the protein's structure before and after the glycation process. This more complete understanding of the effects of glycation on Hb is fundamental for understanding the complications associated with hyperglycemia and for developing more effective prevention and treatment strategies.