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1.
Is Cardiac Diastolic Dysfunction a Part of Post-Menopausal Syndrome?
Maslov, PZ, Kim, JK, Argulian, E, Ahmadi, A, Narula, N, Singh, M, Bax, J, Narula, J
JACC. Heart failure. 2019;(3):192-203
Abstract
Post-menopausal women exhibit an exponential increase in the incidence of heart failure with preserved ejection fraction compared with men of the same age, which indicates a potential role of hormonal changes in subclinical and clinical diastolic dysfunction. This paper reviews the preclinical evidence that demonstrates the involvement of estrogen in many regulatory molecular pathways of cardiac diastolic function and the clinical data that investigates the effect of estrogen on diastolic function in post-menopausal women. Published reports show that estrogen deficiency influences both early diastolic relaxation via calcium homeostasis and the late diastolic compliance associated with cardiac hypertrophy and fibrosis. Because of the high risk of diastolic dysfunction and heart failure with preserved ejection fraction in post-menopausal women and the positive effects of estrogen on preserving cardiac function, further clinical studies are needed to clarify the role of endogenous estrogen or hormone replacement in mitigating the onset and progression of heart failure with preserved ejection fraction in women.
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2.
Disassociation of Vitamin D's Calcemic Activity and Non-calcemic Genomic Activity and Individual Responsiveness: A Randomized Controlled Double-Blind Clinical Trial.
Shirvani, A, Kalajian, TA, Song, A, Holick, MF
Scientific reports. 2019;(1):17685
Abstract
The aims of this randomized controlled double-blind clinical trial were to assess the impact of vitamin D supplementation on calcium metabolism and non-calcemic broad gene expression by relating them to the individual's responsiveness to varying doses of vitamin D3. Thirty healthy adults were randomized to receive 600, 4,000 or 10,000 IU/d of vitamin D3 for 6 months. Circulating parathyroid hormone (PTH), 25(OH)D, calcium and peripheral white blood cells broad gene expression were evaluated. We observed a dose-dependent increase in 25(OH)D concentrations, decreased PTH and no change in serum calcium. A plateau in PTH levels was achieved at 16 weeks in the 4000 and 10,000 IU/d groups. There was a dose-dependent 25(OH)D alteration in broad gene expression with 162, 320 and 1289 genes up- or down-regulated in their white blood cells, respectively. Our results clearly indicated that there is an individual's responsiveness on broad gene expression to varying doses of vitamin D3. Vitamin D3 supplementation at 10,000 IU/d produced genomic alterations several fold higher than 4,000 IU/d even without further changes in PTH levels. Our findings may help explain why there are some inconsistency in the results of different vitamin D's clinical trials.
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3.
Stochastic and deterministic approaches to modelling calcium release in cardiac myocytes at different spatial arrangements of ryanodine receptors.
Iaparov, BI, Moskvin, AS, Zahradník, I, Zahradníková, A
European biophysics journal : EBJ. 2019;(6):579-584
Abstract
Calcium release sites (CRSs) play a key role in excitation-contraction coupling of cardiac myocytes. Recent studies based on electron tomography and super-resolution imaging revealed that CRSs are not completely filled with ryanodine receptors (RyRs) and that the spatial arrangement of RyRs is neither uniform nor static. In this work, we studied the effect of spatial arrangement of RyRs on RyR activation using simulations based on Monte Carlo (MC) and mean-field (MF) approaches. Both approaches showed that activation of RyRs is sensitive to the arrangement of RyRs in the CRS. However, the MF simulations did not reproduce results of MC simulations for non-compact CRSs, suggesting that the approximations used in the MF approach are not suitable for simulation studies of RyRs arrangements observed experimentally. MC simulations revealed the importance of realistic spatial arrangement of RyRs for adequate modelling of calcium release in cardiac myocytes.
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4.
Effect of 16-weeks vitamin D replacement on calcium-phosphate homeostasis in overweight and obese adults.
Mesinovic, J, Mousa, A, Wilson, K, Scragg, R, Plebanski, M, de Courten, M, Scott, D, Naderpoor, N, de Courten, B
The Journal of steroid biochemistry and molecular biology. 2019;:169-175
Abstract
This randomised placebo-controlled trial aimed to determine the effect of 16-weeks cholecalciferol supplementation on calcium-phosphate homeostasis and bone mineral density (BMD) in overweight and obese adults. Fifty-four vitamin D-deficient (25OHD<50 nmol/L), overweight and obese adults (mean age 32 ± 8.5 years) were included in the trial. Participants were randomly assigned to receive either a bolus oral dose of 100,000 IU cholecalciferol followed by 4000 IU cholecalciferol/d or a matching placebo for 16 weeks. Before and after the intervention, serum calcium, phosphate, 25-hydroxyvitamin D [25(OH)D], intact parathyroid hormone (iPTH) and C-terminal plasma fibroblast growth factor-23 (cFGF-23) concentrations were measured. Whole-body BMD was assessed using dual-energy X-ray absorptiometry (DXA) and diet and sun exposure were assessed using self-administered questionnaires. There were no significant differences in baseline characteristics between the vitamin D and placebo group. After 16-weeks of vitamin D supplementation, mean changes in 25(OH)D concentration were higher in the vitamin D group (57 nmol/L 95% CI 49, 65) compared with placebo (2 nmol/L 95% CI -4, 8), P < 0.001. Additionally, iPTH concentrations declined in the vitamin D group (-1.19 pmol/L 95% CI -1.9, -0.47) compared with placebo (0.14 pmol/L 95% CI -0.49, 0.77), P = 0.006. There were no significant differences in calcium, phosphate, iPTH and cFGF-23 concentrations and whole-body BMD between vitamin D and placebo at follow-up. Inverse correlations were observed between mean change in serum iPTH and cFGF-23 in the vitamin D group only (r=-0.41, P = 0.029). In individuals with greater vitamin D deficiency at baseline (25(OH)D < 30 nmol/L), there was a significant increase in mean whole-body BMD (0.01 g/cm2, 95% CI 0.001, 0.025) however, the mean change in BMD was not different between vitamin D and placebo groups in this sub-group analysis. We conclude that cholecalciferol supplementation for 16 weeks increases serum 25(OH)D concentrations and reduces iPTH concentrations in overweight and obese, but otherwise healthy adults with vitamin D deficiency, and has no effect on calcium, phosphate and iFGF-23 concentrations and whole-body BMD.
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5.
A simple mechanochemical model for calcium signalling in embryonic epithelial cells.
Kaouri, K, Maini, PK, Skourides, PA, Christodoulou, N, Chapman, SJ
Journal of mathematical biology. 2019;(7):2059-2092
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Abstract
Calcium signalling is one of the most important mechanisms of information propagation in the body. In embryogenesis the interplay between calcium signalling and mechanical forces is critical to the healthy development of an embryo but poorly understood. Several types of embryonic cells exhibit calcium-induced contractions and many experiments indicate that calcium signals and contractions are coupled via a two-way mechanochemical feedback mechanism. We present a new analysis of experimental data that supports the existence of this coupling during apical constriction. We then propose a simple mechanochemical model, building on early models that couple calcium dynamics to the cell mechanics and we replace the hypothetical bistable calcium release with modern, experimentally validated calcium dynamics. We assume that the cell is a linear, viscoelastic material and we model the calcium-induced contraction stress with a Hill function, i.e. saturating at high calcium levels. We also express, for the first time, the "stretch-activation" calcium flux in the early mechanochemical models as a bottom-up contribution from stretch-sensitive calcium channels on the cell membrane. We reduce the model to three ordinary differential equations and analyse its bifurcation structure semi-analytically as two bifurcation parameters vary-the [Formula: see text] concentration, and the "strength" of stretch activation, [Formula: see text]. The calcium system ([Formula: see text], no mechanics) exhibits relaxation oscillations for a certain range of [Formula: see text] values. As [Formula: see text] is increased the range of [Formula: see text] values decreases and oscillations eventually vanish at a sufficiently high value of [Formula: see text]. This result agrees with experimental evidence in embryonic cells which also links the loss of calcium oscillations to embryo abnormalities. Furthermore, as [Formula: see text] is increased the oscillation amplitude decreases but the frequency increases. Finally, we also identify the parameter range for oscillations as the mechanical responsiveness factor of the cytosol increases. This work addresses a very important and not well studied question regarding the coupling between chemical and mechanical signalling in embryogenesis.
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6.
In depth, thermodynamic analysis of Ca2+ binding to human cardiac troponin C: Extracting buffer-independent binding parameters.
Johnson, RA, Fulcher, LM, Vang, K, Palmer, CD, Grossoehme, NE, Spuches, AM
Biochimica et biophysica acta. Proteins and proteomics. 2019;(4):359-366
Abstract
BACKGROUND Characterizing the thermodynamic parameters behind metal-biomolecule interactions is fundamental to understanding the roles metal ions play in biology. Isothermal Titration Calorimetry (ITC) is a "gold-standard" for obtaining these data. However, in addition to metal-protein binding, additional equilibria such as metal-buffer interactions must be taken into consideration prior to making meaningful comparisons between metal-binding systems. METHODS In this study, the thermodynamics of Ca2+ binding to three buffers (Bis-Tris, MES, and MOPS) were obtained from Ca2+-EDTA titrations using ITC. These data were used to extract buffer-independent parameters for Ca2+ binding to human cardiac troponin C (hcTnC), an EF-hand containing protein required for heart muscle contraction. RESULTS The number of protons released upon Ca2+ binding to the C- and N-domain of hcTnC were found to be 1.1 and 1.2, respectively. These values permitted determination of buffer-independent thermodynamic parameters of Ca2+-hcTnC binding, and the extracted data agreed well among the buffers tested. Both buffer and pH-adjusted parameters were determined for Ca2+ binding to the N-domain of hcTnC and revealed that Ca2+ binding under aqueous conditions and physiological ionic strength is both thermodynamically favorable and driven by entropy. CONCLUSIONS Taken together, the consistency of these data between buffer systems and the similarity between theoretical and experimental proton release is indicative of the reliability of the method used and the importance of extracting metal-buffer interactions in these studies. GENERAL SIGNIFICANCE The experimental approach described herein is clearly applicable to other metal ions and other EF-hand protein systems.
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7.
A network of phosphatidylinositol 4,5-bisphosphate binding sites regulates gating of the Ca2+-activated Cl- channel ANO1 (TMEM16A).
Yu, K, Jiang, T, Cui, Y, Tajkhorshid, E, Hartzell, HC
Proceedings of the National Academy of Sciences of the United States of America. 2019;(40):19952-19962
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Abstract
ANO1 (TMEM16A) is a Ca2+-activated Cl- channel that regulates diverse cellular functions including fluid secretion, neuronal excitability, and smooth muscle contraction. ANO1 is activated by elevation of cytosolic Ca2+ and modulated by phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. Here, we describe a closely concerted experimental and computational study, including electrophysiology, mutagenesis, functional assays, and extended sampling of lipid-protein interactions with molecular dynamics (MD) to characterize PI(4,5)P2 binding modes and sites on ANO1. ANO1 currents in excised inside-out patches activated by 270 nM Ca2+ at +100 mV are increased by exogenous PI(4,5)P2 with an EC50 = 1.24 µM. The effect of PI(4,5)P2 is dependent on membrane voltage and Ca2+ and is explained by a stabilization of the ANO1 Ca2+-bound open state. Unbiased atomistic MD simulations with 1.4 mol% PI(4,5)P2 in a phosphatidylcholine bilayer identified 8 binding sites with significant probability of binding PI(4,5)P2 Three of these sites captured 85% of all ANO1-PI(4,5)P2 interactions. Mutagenesis of basic amino acids near the membrane-cytosol interface found 3 regions of ANO1 critical for PI(4,5)P2 regulation that correspond to the same 3 sites identified by MD. PI(4,5)P2 is stabilized by hydrogen bonding between amino acid side chains and phosphate/hydroxyl groups on PI(4,5)P2 Binding of PI(4,5)P2 alters the position of the cytoplasmic extension of TM6, which plays a crucial role in ANO1 channel gating, and increases the accessibility of the inner vestibule to Cl- ions. We propose a model consisting of a network of 3 PI(4,5)P2 binding sites at the cytoplasmic face of the membrane allosterically regulating ANO1 channel gating.
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Molecular basis of vitamin D action in neurodegeneration: the story of a team perspective.
Gezen-Ak, D, Dursun, E
Hormones (Athens, Greece). 2019;(1):17-21
Abstract
Vitamin D, a secosteroid hormone, has, over the years, mainly been known for its classic role in the maintenance of calcium homeostasis of the human body. However, there is increasing understanding that vitamin D contributes to the regulation of Ca2+ homeostasis, especially via voltage-gated calcium channels, in another major organ that uses calcium, the brain. Almost 30 years ago, the role of dysregulation in the aging brain and in Alzheimer's disease (AD) gave rise to the Ca2+ hypothesis of brain aging and dementia. We thus made calcium homeostasis the starting point of our studies, proposing the notion that the consequences of long-term deficiency and/or inefficient utilization of vitamin D may cause the disruption of calcium homeostasis in neurons, this creating a vulnerability of neurons to aging and neurodegeneration. In this mini-review, we aim to describe the potential of vitamin D (cholecalciferol) as a neurosteroid based on our findings and conclusions.
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Negligible Effects of β-Hydroxy-β-Methylbutyrate Free Acid and Calcium Salt on Strength and Hypertrophic Responses to Resistance Training: A Randomized, Placebo-Controlled Study.
Tritto, AC, Bueno, S, Rodrigues, RMP, Gualano, B, Roschel, H, Artioli, GG
International journal of sport nutrition and exercise metabolism. 2019;(5):505-511
Abstract
This study evaluated the effects of β-hydroxy-β-methylbutyrate free acid (HMB-FA) and calcium salt (HMB-Ca) on strength, hypertrophy, and markers of muscle damage. In this randomized, double-blind, placebo-controlled study, 44 resistance-trained men (age: 26 ± 4 years; body mass: 84.9 ± 12.0 kg) consuming ≥1.7 g·kg-1·day-1 of protein received HMB-FA (3 g/day; n = 14), HMB-Ca (3 g/day; n = 15), or placebo (PL; cornstarch, 3 g/day; n = 15) for 12 weeks, while performing a periodized resistance training program. Before and after intervention, lean body mass (measured with dual X-ray absorptiometry), maximal dynamic strength (one-repetition maximum), knee extension maximal isometric strength (maximal voluntary isometric contraction [MVIC]), cross-sectional area (measured with ultrasound), and muscle soreness were assessed. MVIC was also measured 48 hr after the first and the last training sessions. All groups increased lean body mass (main time effect: p < .0001; HMB-FA: 1.8 ± 1.8 kg; HMB-Ca: 0.8 ± 1.4 kg; PL: 0.9 ± 1.4 kg), cross-sectional area (main time effect: p < .0001; HMB-FA: 6.6 ± 3.8%; HMB-Ca: 4.7 ± 4.4%; PL: 6.9 ± 3.8%), one-repetition maximum bench press (main time effect: p < .0001; HMB-FA: 14.8 ± 8.4 kg; HMB-Ca: 11.8 ± 7.4 kg; PL: 11.2 ± 6.6 kg), MVIC (main time effect: p < .0001; HMB-FA: 34.4 ± 39.3%; HMB-Ca: 32.3 ± 27.4%; PL: 17.7 ± 20.9%) after the intervention, but no differences between groups were shown. HMB-FA group showed greater leg press strength after the intervention than HMB-Ca and PL groups (Group × Time interaction: p < .05; HMB-FA: 47.7 ± 31.2 kg; HMB-Ca: 43.8 ± 31.7 kg; PL: 30.2 ± 20.9 kg). MVIC measured 48 hr after the first and the last sessions showed no attenuation of force decline with supplementation. Muscle soreness following the first and last sessions was not different between groups. The authors concluded that neither HMB-Ca nor HMB-FA improved hypertrophy or reduced muscle damage in resistance-trained men undergoing resistance training ingesting optimal amounts of protein. HMB-FA but not HMB-Ca resulted in a statistically significant yet minor improvement on leg press one-repetition maximum.
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10.
Vitamin D in burn-injured patients.
Rech, MA, Colon Hidalgo, D, Larson, J, Zavala, S, Mosier, M
Burns : journal of the International Society for Burn Injuries. 2019;(1):32-41
Abstract
Recently, many studies have demonstrated pleotropic effects of vitamin D, including immune modulation and cardiovascular system activity. Sufficient vitamin D concentrations and supplementation of vitamin D may be of benefit in burn-injured patients. Low 25(OH)D has been observed in nearly all pediatric and most adult burn patients. Vitamin D has primarily been studied in pediatric burn patients, focusing on bone marker measurements and the incidence of fractures. The preferred vitamin D dose, formulation, and route of administration remain unknown, and there is limited data on the impact of vitamin D status on clinical outcomes. Further research should focus on determining optimal monitoring strategies, supplementation regimens and clinical outcomes like mortality, length of stay and incidence of sepsis.