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1.
Association of Vitamin D or Calcium Supplementation with Cardiovascular Outcomes and Mortality: A Meta-Analysis with Trial Sequential Analysis.
Zhang, Y, Li, Y, Liu, J, Wei, X, Tan, N, Zhang, J, Wang, W, Wang, Y
The journal of nutrition, health & aging. 2021;(2):263-270
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Abstract
BACKGROUND To exploring the role of vitamin D or calcium supplementation in reducing all-cause mortality and cardiovascular outcomes. METHODS The search was restricted to systematic reviews or meta-analyses published from January 1, 2010, to July 7, 2019. An additional search was performed to identify recently published randomized controlled trials (from January 1, 2015, to July 7, 2019). Homogeneous results from different studies were pooled using Revman 5.3 software. RESULTS Twenty-three studies involving 89,251 participants were ultimately included in this meta-analysis. No associations were observed between the supplementation and composite cardiovascular outcomes, consisting of all-cause mortality, cardiovascular mortality, myocardial infarction, and other MACEs. CONCLUSIONS Whether used alone or in combination, vitamin D and calcium supplementation do not exert meaningful effects on all-cause mortality, cardiovascular mortality, MACEs or MI among community-dwelling adults.
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Interaction of serum calcium and folic acid treatment on first stroke in hypertensive males.
Wu, H, Zhang, Y, Li, H, Li, J, Zhang, Y, Liang, M, Nie, J, Wang, B, Wang, X, Huo, Y, et al
Clinical nutrition (Edinburgh, Scotland). 2021;(4):2381-2388
Abstract
BACKGROUND & AIMS The role of serum calcium on the risk of stroke is still uncertain. We aimed to evaluate the effect of serum calcium on first stroke risk, and on the efficacy of folic acid treatment in prevention of first stroke among hypertensive patients. METHODS Our analyses included a total of 19,644 eligible hypertensive adults from the China Stroke Primary Prevention Trial (CSPPT). In the CSPPT, a total of 20,702 hypertensive patients were randomly assigned to a double-blind, daily treatment with either 10 mg enalapril and 0.8 mg folic acid or 10 mg enalapril alone. The primary outcome was a first stroke. RESULTS Over a median of 4.5 years, among those not receiving folic acid, a significantly higher risk of first stroke was found in hypertensive males with baseline albumin-corrected serum calcium ≥2.43 mmol/L (median) (vs. <2.43 mmol/L; 6.5% vs. 2.3%; adjusted HR, 2.47; 95% CI: 1.72, 3.55). For those with enalapril and folic acid treatment, compared with the enalapril only group, the risk of first stroke was reduced from 6.5% to 3.0% (adjusted HR, 0.49; 95% CI: 0.35, 0.68) in hypertensive males with baseline albumin-corrected serum calcium ≥2.43 mmol/L, whereas there was no significant effect among hypertensive males with baseline albumin-corrected serum calcium <2.43 mmol/L. However, among hypertensive females, serum calcium did not significantly affect the first stroke risk and the efficacy of folic acid in prevention of first stroke. CONCLUSIONS Among Chinese hypertensive males, those with elevated serum calcium levels had increased risk of first stroke, and this risk was reduced by 51% with folic acid treatment.
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The effect of soy isoflavone combined with calcium on bone mineral density in perimenopausal Chinese women: a 6-month randomised double-blind placebo-controlled study.
Zhang, X, Liu, Y, Xu, Q, Zhang, Y, Liu, L, Li, H, Li, F, Liu, Z, Yang, X, Yu, X, et al
International journal of food sciences and nutrition. 2020;(4):473-481
Abstract
This study was a prospective, randomised, double-blind, placebo-controlled clinical trial and aimed to compare the effect of placebo, soy isoflavone, calcium and soy isoflavone combined with calcium on bone mineral density (BMD). One hundred and sixty perimenopausal women with osteoporosis or osteopenia were enrolled and randomised into four groups: control, soy isoflavone, calcium and soy isoflavone combined with calcium groups. After intervention, compared with control, isoflavone and calcium groups, mean changes from their corresponding baseline values of BMD, calcium/phosphorus, vitamin D and glutathione peroxidase (GSH-pX) activity were significantly increased, however, those of phosphorus, osteocalcin, luteinizing hormone (LH) and follicle stimulating hormone (FSH) were significantly decreased in isoflavone combined with calcium group. The results showed that soy isoflavone, calcium and isoflavone combined with calcium therapy were effective and safe on attenuating BMD loss in perimenopausal women and isoflavone combined with calcium therapy was better than soy isoflavone and calcium alone.
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Impact of Serum Calcium Levels on Alzheimer's Disease: A Mendelian Randomization Study.
He, Y, Zhang, H, Wang, T, Han, Z, Ni, QB, Wang, K, Wang, L, Zhang, Y, Hu, Y, Jin, S, et al
Journal of Alzheimer's disease : JAD. 2020;(2):713-724
Abstract
BACKGROUND Altered calcium homeostasis is hypothesized to underlie Alzheimer's disease (AD). However, it remains unclear whether serum calcium levels are genetically associated with AD risk. OBJECTIVE To develop effective therapies, we should establish the causal link between serum calcium levels and AD. METHODS Here, we performed a Mendelian randomization study to investigate the causal association of increased serum calcium levels with AD risk using the genetic variants from a large-scale serum calcium genome-wide association study (GWAS) dataset (61,079 individuals of European descent) and a large-scale AD GWAS dataset (54,162 individuals including 17,008 AD cases and 37,154 controls of European descent). Here, we selected the inverse-variance weighted (IVW) as the main analysis method. Meanwhile, we selected other three sensitivity analysis methods to examine the robustness of the IVW estimate. RESULTS IVW analysis showed that the increased serum calcium level (per 1 standard deviation (SD) increase 0.5 mg/dL) was significantly associated with a reduced AD risk (OR = 0.57, 95% CI 0.35-0.95, p = 0.031). Meanwhile, all the estimates from other sensitivity analysis methods were consistent with the IVW estimate in terms of direction and magnitude. CONCLUSION In summary, we provided evidence that increased serum calcium levels could reduce the risk of AD. Meanwhile, randomized controlled study should be conducted to clarify whether diet calcium intake or calcium supplement, or both could reduce the risk of AD.
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Dual Ca2+-dependent gates in human Bestrophin1 underlie disease-causing mechanisms of gain-of-function mutations.
Ji, C, Kittredge, A, Hopiavuori, A, Ward, N, Chen, S, Fukuda, Y, Zhang, Y, Yang, T
Communications biology. 2019;:240
Abstract
Mutations of human BEST1, encoding a Ca2+-activated Cl- channel (hBest1), cause macular degenerative disorders. Best1 homolog structures reveal an evolutionarily conserved channel architecture highlighted by two landmark restrictions (named the "neck" and "aperture", respectively) in the ion conducting pathway, suggesting a unique dual-switch gating mechanism, which, however, has not been characterized well. Using patch clamp and crystallography, we demonstrate that both the neck and aperture in hBest1 are Ca2+-dependent gates essential for preventing channel leakage resulting from Ca2+-independent, spontaneous gate opening. Importantly, three patient-derived mutations (D203A, I205T and Y236C) lead to Ca2+-independent leakage and elevated Ca2+-dependent anion currents due to enhanced opening of the gates. Moreover, we identify a network of residues critically involved in gate operation. Together, our results suggest an indispensable role of the neck and aperture of hBest1 for channel gating, and uncover disease-causing mechanisms of hBest1 gain-of-function mutations.
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Collective cell migration has distinct directionality and speed dynamics.
Zhang, Y, Xu, G, Lee, RM, Zhu, Z, Wu, J, Liao, S, Zhang, G, Sun, Y, Mogilner, A, Losert, W, et al
Cellular and molecular life sciences : CMLS. 2017;(20):3841-3850
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Abstract
When a constraint is removed, confluent cells migrate directionally into the available space. How the migration directionality and speed increase are initiated at the leading edge and propagate into neighboring cells are not well understood. Using a quantitative visualization technique-Particle Image Velocimetry (PIV)-we revealed that migration directionality and speed had strikingly different dynamics. Migration directionality increases as a wave propagating from the leading edge into the cell sheet, while the increase in cell migration speed is maintained only at the leading edge. The overall directionality steadily increases with time as cells migrate into the cell-free space, but migration speed remains largely the same. A particle-based compass (PBC) model suggests cellular interplay (which depends on cell-cell distance) and migration speed are sufficient to capture the dynamics of migration directionality revealed experimentally. Extracellular Ca2+ regulated both migration speed and directionality, but in a significantly different way, suggested by the correlation between directionality and speed only in some dynamic ranges. Our experimental and modeling results reveal distinct directionality and speed dynamics in collective migration, and these factors can be regulated by extracellular Ca2+ through cellular interplay. Quantitative visualization using PIV and our PBC model thus provide a powerful approach to dissect the mechanisms of collective cell migration.
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Patient-specific mutations impair BESTROPHIN1's essential role in mediating Ca2+-dependent Cl- currents in human RPE.
Li, Y, Zhang, Y, Xu, Y, Kittredge, A, Ward, N, Chen, S, Tsang, SH, Yang, T
eLife. 2017
Abstract
Mutations in the human BEST1 gene lead to retinal degenerative diseases displaying progressive vision loss and even blindness. BESTROPHIN1, encoded by BEST1, is predominantly expressed in retinal pigment epithelium (RPE), but its physiological role has been a mystery for the last two decades. Using a patient-specific iPSC-based disease model and interdisciplinary approaches, we comprehensively analyzed two distinct BEST1 patient mutations, and discovered mechanistic correlations between patient clinical phenotypes, electrophysiology in their RPEs, and the structure and function of BESTROPHIN1 mutant channels. Our results revealed that the disease-causing mechanism of BEST1 mutations is centered on the indispensable role of BESTROPHIN1 in mediating the long speculated Ca2+-dependent Cl- current in RPE, and demonstrate that the pathological potential of BEST1 mutations can be evaluated and predicted with our iPSC-based 'disease-in-a-dish' approach. Moreover, we demonstrated that patient RPE is rescuable with viral gene supplementation, providing a proof-of-concept for curing BEST1-associated diseases.
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The role of STIM1 in the Cr(vi)-induced [Ca2+]i increase and cell injury in L-02 hepatocytes.
Yi, X, Zhang, Y, Zhong, C, Zhong, X, Xiao, F
Metallomics : integrated biometal science. 2016;(12):1273-1282
Abstract
Hexavalent chromium [Cr(vi)] is a potent cytotoxin and carcinogen. In recent years, drinking water contamination with Cr(vi) has become a worldwide problem of significant public health importance, thus much attention has been paid to the investigation of Cr(vi)-induced hepatotoxicity. The concentration of intracellular calcium ions ([Ca2+]i) was found to be increased after Cr(vi) exposure, but the exact underlying mechanisms involved in the Ca2+ homeostasis imbalance remain poorly characterized. In the present study, by utilizing the antagonist of store-operated calcium channels (SOCCs) 2-aminoethoxydiphenyl borate (2-APB), small interfering RNA against stromal interaction molecule 1 (si-STIM1) and antioxidant N-acetylcysteine (NAC), we found that Cr(vi) induces [Ca2+]i increase, cell viability loss and transaminase (AST/ALT) leakage, and that these could be suppressed by both 2-APB and si-STIM1. NAC significantly alleviated Cr(vi)-induced up-regulation of STIM1, phosphorylated-extracellular-signal-regulated kinases 1 and 2 (p-ERK1/2), ERK1/2 and nuclear factor κB (NF-κB). By utilizing the ERK inhibitor U0126 and the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC), we confirmed that STIM1 can be regulated by ERK and NF-κB. Thus we concluded that STIM1 plays a role in the Cr(vi)-induced [Ca2+]i increase and cell injury. Our current data provide new insights into the mechanisms of STIM1 function in Cr(vi)-induced hepatotoxicity, and may provide experimental clues for the prevention and treatment of liver diseases in the occupational population exposed to Cr(vi).
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Pitavastatin calcium improves endothelial function and delays the progress of atherosclerosis in patients with hypercholesterolemia.
Zhao, J, Yan, HM, Li, Y, Wang, J, Han, L, Wang, ZH, Tang, MX, Zhang, W, Zhang, Y, Zhong, M
Journal of Zhejiang University. Science. B. 2015;(5):380-7
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Abstract
BACKGROUND Statins have proven efficacy in inhibiting the onset and progress of atherosclerosis. The effectiveness of pitavastatin in reversing carotid atherosclerosis associated with hypercholesterolemia (HC) is unknown. OBJECTIVES To explore the simultaneous effects of pitavastatin calcium on brachial arterial flow-mediated vasodilatation (FMD), carotid intima-media thickness (IMT), and arterial stiffness (β), three surrogate markers of atherosclerosis were studied in HC patients. METHODS A randomized, double-blind trial was performed with 40 HC subjects who fulfilled the inclusion/exclusion criteria. Patients were given pitavastatin calcium 1 mg/d (Group 1) or 2 mg/d (Group 2) for 8 weeks. There were 20 patients in each group, and 30 gender- and age-matched healthy subjects as controls were recruited. FMD of the brachial artery, carotid IMT, and arterial stiffness indicated by β were measured at baseline and at 8 weeks after starting pitavastatin calcium therapy using ultrasound techniques. Biochemical tests were also made on all subjects. RESULTS At baseline, higher total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), reduced FMD, and increased β and IMT were observed in HC patients (P<0.001 for all) compared with controls. After 8 weeks, TC was decreased by 20.59%/27.56% and LDL-C 30.92%/35.64%, respectively, in comparison to baseline groups; the HC groups had reduced β and improved endothelial function over the 8-week follow-up (P<0.05-0.001); nonetheless, no significant alterations of IMT were found (P>0.05). Significant negative interactions between TC/LDL and FMD (P<0.05-0.001), positive interactions between TC and IMT (P=0.003) and between TC/LDL and β (P<0.001-0.000) were found. CONCLUSIONS Treatment with pitavastatin calcium exerted favorable effects on endothelial function and arterial stiffness. It also improved carotid atherosclerosis in patients with HC.
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Cross-talk between nitric oxide and Ca (2+) in elevated CO 2-induced lateral root formation.
Wang, H, Niu, Y, Chai, R, Liu, M, Zhang, Y
Plant signaling & behavior. 2013;(2):e23106
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Abstract
This study demonstrates a potential signaling pathway of CO 2-dependent stimulation in lateral root (LR) formation. Elevated CO 2 increases production of nitric oxide (NO), which subsequently stimulates the generation of cytosolic Ca (2+) concentration by activating plasma membrane and/or intracellular Ca (2+)-permeable channels. Meanwhile, nitric oxide synthase (NOS), as one of the main NO source, requires Ca (2+) and CaM as cofactors. This complex interaction involves transduction cascades of multiple signals that lead to the LR formation and development. Finally, this review highlights the the role of Ca (2+) in the process that elevated CO 2 enhances the development of LRs through increased NO level.