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1.
Vitamin D Effects on Bone Homeostasis and Cardiovascular System in Patients with Chronic Kidney Disease and Renal Transplant Recipients.
Cianciolo, G, Cappuccilli, M, Tondolo, F, Gasperoni, L, Zappulo, F, Barbuto, S, Iacovella, F, Conte, D, Capelli, I, La Manna, G
Nutrients. 2021;(5)
Abstract
Poor vitamin D status is common in patients with impaired renal function and represents one main component of the complex scenario of chronic kidney disease-mineral and bone disorder (CKD-MBD). Therapeutic and dietary efforts to limit the consequences of uremia-associated vitamin D deficiency are a current hot topic for researchers and clinicians in the nephrology area. Evidence indicates that the low levels of vitamin D in patients with CKD stage above 4 (GFR < 15 mL/min) have a multifactorial origin, mainly related to uremic malnutrition, namely impaired gastrointestinal absorption, dietary restrictions (low-protein and low-phosphate diets), and proteinuria. This condition is further worsened by the compromised response of CKD patients to high-dose cholecalciferol supplementation due to the defective activation of renal hydroxylation of vitamin D. Currently, the literature lacks large and interventional studies on the so-called non-calcemic activities of vitamin D and, above all, the modulation of renal and cardiovascular functions and immune response. Here, we review the current state of the art of the benefits of supplementation with native vitamin D in various clinical settings of nephrological interest: CKD, dialysis, and renal transplant, with a special focus on the effects on bone homeostasis and cardiovascular outcomes.
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2.
Assessing statin effects on cardiovascular pathways in HIV using a novel proteomics approach: Analysis of data from INTREPID, a randomized controlled trial.
Toribio, M, Fitch, KV, Stone, L, Zanni, MV, Lo, J, de Filippi, C, Sponseller, CA, Lee, H, Grundberg, I, Thompson, MA, et al
EBioMedicine. 2018;:58-66
Abstract
BACKGROUND People with HIV (PWH) demonstrate increased cardiovascular disease (CVD), due in part to increased immune activation, inflammation, and endothelial dysfunction. METHODS In a randomized trial (INTREPID), 252 HIV-infected participants with dyslipidemia and no history of coronary artery disease were randomized (1:1) to pitavastatin 4 mg vs. pravastatin 40 mg for 52 weeks. Using a proteomic discovery approach, 92 proteins biomarkers were assessed using Proximity Extension Assay technology to determine the effects of statins on key atherosclerosis and CVD pathways among PWH. 225 participants had specimens available for biomarker analysis pre- and post-baseline. FINDINGS The mean age was 49.5 ± 8.0 (mean ± SD), LDL-C 155 ± 25 mg/dl and CD4 count 620 ± 243 cell/mm3. Among all participants, three proteins significantly decreased: tissue factor pathway inhibitor [TFPI; t-statistic = -6.38, FDR p-value<0.0001], paraoxonase 3 [PON3; t-statistic = -4.64, FDR p-value = 0.0003], and LDL-receptor [LDLR; t-statistic = -4.45, FDR p-value = 0.0004]; and two proteins significantly increased galectin-4 [Gal-4; t-statistic = 3.50, FDR p-value = 0.01] and insulin-like growth factor binding protein 2 [IGFBP-2; t-statistic = 3.21, FDR p-value = 0.03]. The change in TFPI was significantly different between the pitavastatin and pravastatin groups. Among all participants, change in TFPI related to the change in LDL-C (r = 0.43, P < 0.0001) and change in Lp-PLA2 (r = 0.29, P < 0.0001). INTERPRETATION Using a proteomics approach, we demonstrated that statins led to a significant reduction in the levels of TFPI, PON3, and LDLR and an increase in Gal-4 and IGFBP-2, key proteins involved in coagulation, redox signaling, oxidative stress, and glucose metabolism. Pitavastatin led to a greater reduction in TFPI than pravastatin. These data highlight potential novel mechanisms of statin effects among PWH. FUND This work was supported by an investigator-initiated grant to S.K.G. from KOWA Pharmaceuticals America, Inc. and the National Institutes of Health [P30 DK040561; Nutrition Obesity Research Center at Harvard]. M.T. was support by National Institutes of Health [5KL2TR001100-05; Harvard Catalyst KL2 grant].
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3.
Vitamin D: not just the bone. Evidence for beneficial pleiotropic extraskeletal effects.
Caprio, M, Infante, M, Calanchini, M, Mammi, C, Fabbri, A
Eating and weight disorders : EWD. 2017;(1):27-41
Abstract
Vitamin D is a fat-soluble vitamin and a steroid hormone that plays a central role in maintaining calcium-phosphorus and bone homeostasis in close interaction with parathyroid hormone, acting on its classical target tissues, namely, bone, kidney, intestine, and parathyroid glands. However, vitamin D endocrine system regulates several genes (about 3 % of the human genome) involved in cell differentiation, cell-cycle control, and cell function and exerts noncalcemic/pleiotropic effects on extraskeletal target tissues, such as immune and cardiovascular system, pancreatic endocrine cells, muscle, and adipose tissue. Several studies have demonstrated the role of vitamin D supplementation in the prevention/treatment of various autoimmune diseases and improvement of glucose metabolism, muscle, and adipose tissue function. Hence, this review aims to elucidate the effects of vitamin D on extraskeletal target tissues and to investigate the potential therapeutic benefit of vitamin D supplementation among a broad group of pathological conditions, especially with regard to metabolic and autoimmune diseases. In addition, we focused on the best daily intakes and serum levels of vitamin D required for extraskeletal benefits which, even if still controversial, appear to be higher than those widely accepted for skeletal effects.
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4.
Extrarenal roles of the with-no-lysine[K] kinases (WNKs).
Siew, K, O'Shaughnessy, KM
Clinical and experimental pharmacology & physiology. 2013;(12):885-94
Abstract
Identified over a decade ago, the with-no-lysine[K] kinases (WNKs) have been the subsequent focus of intense research into the renal handling of Na(+) , Cl(-) and K(+) and several rare monogenetic diseases. However, the potential extrarenal roles for WNKs have been less well explored. Thiazides and Gordon syndrome are known to have effects on bone mineral density, Ca(2+) and PO4 (3-) homeostasis, which were originally assumed to be an indirect effect through the kidney. However, current data suggest a complex and direct role for WNKs in the physiology of bone. The WNKs also modulate systemic blood pressure at several levels, including the vascular resistance vessels, where they cause vasoconstriction by altering the abundance of the transient receptor potential canonical channel 3 and/or phosphorylation of the Na(+) -K(+) -2Cl(-) cotransporter 1 in vascular smooth muscle cells. The WNKs and many of the cation-coupled Cl(-) cotransporters they regulate are highly expressed in the central nervous system and recent work suggests that WNK dysfunction may have a role in the development of autism, schizophrenia and hereditary sensory and autonomic neuropathy Type 2. Finally, the WNK-sterile 20 kinase signalling axis represents an evolutionarily ancient mechanism for maintaining osmotic homeostasis, but a rapidly expanding body of evidence also shows a role in immunity and cellular regulation.
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5.
[Melatonin: its role in the system of neurohumoral regulation in man. Part 2].
Baksheev, VI, Kolomoets, NM
Klinicheskaia meditsina. 2011;(2):8-13
Abstract
Part 2 of this review concerns the application of melatonin (Mt) to the treatment of aged patients with cardiovascular diseases and other pathology with reference to its genoprotective and anticarcinogenic action. Effects of Mt on the cardiovascular system are underlain by its antioxidative, vasodilating, and sedative activities, the ability to regulate the heart rate and inhibit platelet aggregation. Certain authors report negative correlation between Mt production and blood cholesterol level. Mt was shown to protect from cardiac lesions associated with ischemia and reperfusion. Mt inhibits carcinogenesis and is active at systemic, tissue, cellular and subcellular levels. At the systemic level, Mt decreases hormonal production, stimulates immune activity, and prevents the development of metabolic syndrome. It inhibits cell proliferation and promotes apoptosis of tumour cells but suppresses it the nervous tissue. Mt activates telomerase. It decreases expression of oncogens and interferes with the action of mutagens and clastogens at the genetic level. Extensive studies of Mt protective action in nervous diseases are underway with special reference to spinal cord, brain, neuron and glial cell lesions; experimental cerebral stroke, Parkinson's and Alzheimer's diseases. Similar studies concern the role of Mt in the protection against ionizing radiation, the development of renal pathology, and ophthalmology (glaucoma, cataract). Mt is shown to influence practically all organ systems by inhibiting mutagenesis and maintaining correlation between circadian rhythms of different biological processes throughout human evolution.
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6.
Sympathetic overstimulation during critical illness: adverse effects of adrenergic stress.
Dünser, MW, Hasibeder, WR
Journal of intensive care medicine. 2009;(5):293-316
Abstract
The term ''adrenergic'' originates from ''adrenaline'' and describes hormones or drugs whose effects are similar to those of epinephrine. Adrenergic stress is mediated by stimulation of adrenergic receptors and activation of post-receptor pathways. Critical illness is a potent stimulus of the sympathetic nervous system. It is undisputable that the adrenergic-driven ''fight-flight response'' is a physiologically meaningful reaction allowing humans to survive during evolution. However, in critical illness an overshooting stimulation of the sympathetic nervous system may well exceed in time and scope its beneficial effects. Comparable to the overwhelming immune response during sepsis, adrenergic stress in critical illness may get out of control and cause adverse effects. Several organ systems may be affected. The heart seems to be most susceptible to sympathetic overstimulation. Detrimental effects include impaired diastolic function, tachycardia and tachyarrhythmia, myocardial ischemia, stunning, apoptosis and necrosis. Adverse catecholamine effects have been observed in other organs such as the lungs (pulmonary edema, elevated pulmonary arterial pressures), the coagulation (hypercoagulability, thrombus formation), gastrointestinal (hypoperfusion, inhibition of peristalsis), endocrinologic (decreased prolactin, thyroid and growth hormone secretion) and immune systems (immunomodulation, stimulation of bacterial growth), and metabolism (increase in cell energy expenditure, hyperglycemia, catabolism, lipolysis, hyperlactatemia, electrolyte changes), bone marrow (anemia), and skeletal muscles (apoptosis). Potential therapeutic options to reduce excessive adrenergic stress comprise temperature and heart rate control, adequate use of sedative/analgesic drugs, and aiming for reasonable cardiovascular targets, adequate fluid therapy, use of levosimendan, hydrocortisone or supplementary arginine vasopressin.
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7.
Reduction in trunk fat predicts cardiovascular exercise training-related reductions in C-reactive protein.
Vieira, VJ, Hu, L, Valentine, RJ, McAuley, E, Evans, EM, Baynard, T, Woods, JA
Brain, behavior, and immunity. 2009;(4):485-91
Abstract
C-reactive protein (CRP) is an independent risk factor for cardiovascular disease. We sought to determine (1) if 10 months of cardiovascular exercise training (Cardio) reduces CRP in a group of older adults, (2) if such a reduction is related to improvements in trunk fat, fitness, and/or psychosocial variables, and (3) if the effect of Cardio on CRP differs between men and women. Community-dwelling residents (n=127; 60-83 yrs) were randomized to a Flex group (n=61) where they participated in 2-75 min supervised sessions per wk during which they performed non-cardiovascular flexibility and balance exercises or a Cardio group (n=66) where they participated in three supervised sessions per wk during which they performed cardiovascular exercises for approximately 45-60 min at 60-70% maximal oxygen uptake. The main outcome measures were serum CRP, cardiovascular fitness, total and central adiposity, and self-reported psychosocial function. Cardio experienced a reduction in CRP (-0.5mg/L), as well as improvements in fitness (+7%) and total (-1.5%) and central (i.e., trunk) (-2.5%) adiposity. These relationships were not modified by sex. Regression analyses indicated that only the reduction in trunk fat was significantly related to the reduction in CRP. Ten months of cardiovascular exercise training reduced CRP in previously sedentary older adults and this effect was partially mediated by a reduction in trunk fat.
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8.
Anthrax toxin: pathologic effects on the cardiovascular system.
Golden, HB, Watson, LE, Lal, H, Verma, SK, Foster, DM, Kuo, SR, Sharma, A, Frankel, A, Dostal, DE
Frontiers in bioscience (Landmark edition). 2009;(6):2335-57
Abstract
Anthrax is a disease caused by infection with spores from the bacteria Bacillus anthracis. After entering the body, the spores germinate into bacteria and secrete a toxin that causes local edema and, in systemic infections, cardiovascular collapse and death. The toxin is a tripartite polypeptide, consisting of protective antigen (PA), lethal factor (LF) and edema factor (EF), which have key roles in the bacterial pathogenesis and disease progression. PA facilitates transfer of LF and EF to the cytosol. Lethal toxin is a zinc metalloproteinase, which has the capacity to inactivate mitogen-activated protein (MAP) kinase kinase (MEK) and stimulates the release of sepsis-related cytokines tumor necrosis factor-alpha and interleukin-1beta. Edema factor is a calmodulin (CaM)-dependent adenylate cyclase, which increases levels of cyclic AMP, causing impaired neutrophil function and disruption of water balance that ultimately results in massive tissue edema. Together, the toxins effectively inhibit host innate and adaptive immune responses, allowing the bacteria to grow unrestrained and overwhelming any resistance. Clinically, inhalational anthrax presents in a biphasic pattern with initial nonspecific "flu-like" symptoms nausea and vomiting 1 to 4 days after exposure, followed by severe illness with dyspnea, high fever and circulatory shock. The latter symptoms represent a terminal stage and treatment is often ineffective when started at that time. Key indicators of early anthrax cardiovascular-related pathogenesis include mediastinal widening in association with pleural effusion and edema. In this review, we describe the current understanding of anthrax toxins on cellular function in the context of cardiovascular function and discuss potential therapeutic strategies.