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Mechanism of doxorubicin cardiotoxicity evaluated by integrating multiple molecular effects into a biophysical model.
Fernandez-Chas, M, Curtis, MJ, Niederer, SA
British journal of pharmacology. 2018;(5):763-781
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Abstract
BACKGROUND AND PURPOSE Doxorubicin (DOX) is an effective cancer therapeutic agent but causes therapy-limiting cardiotoxicity. The effects of DOX and its metabolite doxorubicinol (DOXL) on individual channels have been well characterized in isolation. However, it is unknown how the action and interaction of affected channels combine to generate the phenotypic cardiotoxic outcome. We sought to develop an in silico model that links drug effects on channels to action potential duration (APD) and intracellular Ca2+ concentration in order to address this gap in knowledge. EXPERIMENTAL APPROACH We first propose two methods to obtain, from published values, consensus drug effects on the currents of individual channels, transporters and pumps. Separately, we obtained equivalent values for APD and Ca2+ concentration (the readouts used as surrogates for cardiotoxicity). Once derived, the consensus effects on the currents were incorporated into established biophysical models of the cardiac myocyte and were refined adjusting the sarcoplasmic reticulum Ca2+ leak current (ILeak ) until the consensus effects on APD and Ca2+ dynamics were replicated. Using factorial analysis, we then quantified the relative contribution of each channel to DOX and DOXL cardiotoxicity. KEY RESULTS The factorial analysis identified the rapid delayed rectifying K+ current, the L-type Ca2+ current and the sarcoplasmic reticulum ILeak as the targets primarily responsible for the cardiotoxic effects on APD and Ca2+ dynamics. CONCLUSIONS AND IMPLICATIONS This study provides insight into the mechanisms of DOX-induced cardiotoxicity and a framework for the development of future diagnostic and therapeutic strategies.
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Electrophysiological properties of human beta-cell lines EndoC-βH1 and -βH2 conform with human beta-cells.
Hastoy, B, Godazgar, M, Clark, A, Nylander, V, Spiliotis, I, van de Bunt, M, Chibalina, MV, Barrett, A, Burrows, C, Tarasov, AI, et al
Scientific reports. 2018;(1):16994
Abstract
Limited access to human islets has prompted the development of human beta cell models. The human beta cell lines EndoC-βH1 and EndoC-βH2 are increasingly used by the research community. However, little is known of their electrophysiological and secretory properties. Here, we monitored parameters that constitute the glucose-triggering pathway of insulin release. Both cell lines respond to glucose (6 and 20 mM) with 2- to 3-fold stimulation of insulin secretion which correlated with an elevation of [Ca2+]i, membrane depolarisation and increased action potential firing. Similar to human primary beta cells, KATP channel activity is low at 1 mM glucose and is further reduced upon increasing glucose concentration; an effect that was mimicked by the KATP channel blocker tolbutamide. The upstroke of the action potentials reflects the activation of Ca2+ channels with some small contribution of TTX-sensitive Na+ channels. The repolarisation involves activation of voltage-gated Kv2.2 channels and large-conductance Ca2+-activated K+ channels. Exocytosis presented a similar kinetics to human primary beta cells. The ultrastructure of these cells shows insulin vesicles composed of an electron-dense core surrounded by a thin clear halo. We conclude that the EndoC-βH1 and -βH2 cells share many features of primary human β-cells and thus represent a useful experimental model.
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[Altered urinary calcium excretion in prostate cancer patients subjected to androgen deprivation. Preliminary pilot study results.].
Díaz-Convalía, EJ, Arrabal-Martín, M, Arrabal-Polo, MÁ, Miján-Ortiz, JL, Cózar-Olmo, JM
Archivos espanoles de urologia. 2018;(7):569-574
Abstract
OBJECTIVES Androgen deprivation therapy (ADT) in prostate cancer is associated with the appearance of different adverse effects. Among these effects, notable ones that may affect metabolism are osteoporosis and metabolic syndrome. The aim of this study is to analyse lithogenic risk markers three months after initiating treatment with LHRH analogue. METHODS Pilot study encompassing 15 prostate cancer patients who were candidates for ADT, which they received in the form of quarterly doses of goserelin 10.8 mg. A blood and urine analyses for lithogenic risk, bone and metabolic markers were carried out, as was a study of metabolic syndrome criteria. Statistical analysis was performed with SPSS 17.0, taking P≤.05 to be statistically significant. RESULTS Patients included in the study had a mean age of 72.46 ± 6.61 years. We observed a significant increase in the percentage of metabolic syndrome (20% versus 46.7%; P<.05) and insulin resistance index (1.87 versus 2.96; P=.01) at 3 months treatment. There was a notable increase in bone remodelling markers and significant increases in 24 h urinary calcium values (9.46 versus 14.57 mg/dl; P=.008), 24 h urinary calcium excretion index (0.10 versus 0.13 mg/dl GF [glomerular filtration]; P=.01) and the fasting calcium/ creatinine ratio (0.107 versus 0.195; P=.007), without any changes to other lithogenous risk markers. CONCLUSIONS Androgen deprivation therapy can lead to the short-term appearance, primarily when fasting, of hypercalciuria in prostate cancer patients, possibly in association with bone metabolism.
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Fine-tuning of store-operated calcium entry by fast and slow Ca2+-dependent inactivation: Involvement of SARAF.
Jardín, I, Albarran, L, Salido, GM, López, JJ, Sage, SO, Rosado, JA
Biochimica et biophysica acta. Molecular cell research. 2018;(3):463-469
Abstract
Store-operated Ca2+ entry (SOCE) is a functionally relevant mechanism for Ca2+ influx present in electrically excitable and non-excitable cells. Regulation of Ca2+ entry through store-operated channels is essential to maintain an appropriate intracellular Ca2+ homeostasis and prevent cell damage. Calcium-release activated channels exhibit Ca2+-dependent inactivation mediated by two temporally separated mechanisms: fast Ca2+-dependent inactivation takes effect in the order of milliseconds and involves the interaction of Ca2+ with residues in the channel pore while slow Ca2+-dependent inactivation (SCDI) develops over tens of seconds, requires a global rise in [Ca2+]cyt and is a mechanism regulated by mitochondria. Recent studies have provided evidence that the protein SARAF (SOCE-associated regulatory factor) is involved in the mechanism underlying SCDI of Orai1. SARAF is an endoplasmic reticulum (ER) membrane protein that associates with STIM1 and translocate to plasma membrane-ER junctions in a STIM1-dependent manner upon store depletion to modulate SOCE. SCDI mediated by SARAF depends on the location of the STIM1-Orai1 complex within a PI(4,5)P2-rich microdomain. SARAF also interacts with Orai1 and TRPC1 in cells endogenously expressing STIM1 and cells with a low STIM1 expression and modulates channel function. This review focuses on the modulation by SARAF of SOCE and other forms of Ca2+ influx mediated by Orai1 and TRPC1 in order to provide spatio-temporally regulated Ca2+ signals.
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Mechanism of freeze-thaw injury and recovery: A cool retrospective and warming up to new ideas.
Arora, R
Plant science : an international journal of experimental plant biology. 2018;:301-313
Abstract
Understanding cellular mechanism(s) of freeze-thaw injury (FTI) is key to the efforts for improving plant freeze-tolerance by cultural methods or molecular/genetic approaches. However, not much work has been done in the last 25+ years to advance our understanding of the nature and cellular loci of FTI. Currently, two FTI lesions are predominantly implicated: 1) structural and functional perturbations in plasma membrane; 2) ROS-induced oxidative damage. While both have stood the test of time, many questions remain unresolved and other potentially significant lesions need to be investigated. Additionally, molecular mechanism of post-thaw recovery (PTR), a critical component of frost-survival, has not been well investigated. Mechanistic understanding of repair after reversible injury could expand the options for strategies to improve frost-hardiness. In this review, without claiming to be exhaustive, I have attempted to synthesize major discoveries from last several decades on the mechanisms of FTI and the relatively little research conducted thus far on PTR mechanisms. It is followed by proposing of hypotheses for mechanism(s) for irreversible FTI or PTR involving cytosolic calcium and ROS signaling. Perspective is presented on some unresolved questions and research on new ideas to fill the knowledge gaps and advance the field.
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Is severe hypercalcemia immediately life-threatening?
Guimard, C, Batard, E, Lavainne, F, Trewick, D
European journal of emergency medicine : official journal of the European Society for Emergency Medicine. 2018;(2):110-113
Abstract
OBJECTIVE Severe hypercalcemia is often considered an emergency because of a potential risk of cardiac arrest or coma. However, there is little evidence to support this. The aim of our study was to assess whether severe hypercalcemia (Ca>4 mmol/l or 16 mg/dl) was associated with immediately life-threatening cardiac arrhythmias or neurological complications in patients admitted to the Emergency Department (ED). METHODS A retrospective observational study was carried out over a 5-year period (2008-2012). Eligible patients were admitted to the Adult Emergency Department of Nantes University Hospital and had a calcium concentration in excess of 4 mmol/l. There were no exclusion criteria. The primary outcome was the number of life-threatening cardiac arrhythmias and/or neurological complications during the stay in the ED. The secondary outcomes were correlation between calcium concentrations/ECG QTc intervals and mortality. RESULTS A total of 126 204 adult patients had calcium concentrations measured. Thirty one (0.025%) patients had severe hypercalcemia as defined in our study. The median calcium concentration was 4.3 mmol/l (Q1, 4.2; Q3, 4.7) and the median albumin-adjusted calcium concentration was 4.3 mmol/l (Q1, 4.1; Q3, 4.7). No patient presented with a life-threatening cardiac event during stay in the ED. The median ED stay was 7 h 32 min. One patient presented with a coma of multifactorial origin. There was no correlation between calcemia and QTc intervals (P=0.60). Mortality at 1 year was 55% (17 patients). CONCLUSION We found no cases of immediately life-threatening cardiac arrhythmias or neurological complications associated with hypercalcemia above 4 mmol/l over a 5-year period in a large tertiary ED.
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Vitamin D and calcium supplementation, skeletal muscle strength and serum testosterone in young healthy adult males: Randomized control trial.
Saha, S, Goswami, R, Ramakrishnan, L, Vishnubhatla, S, Mahtab, S, Kar, P, Srinivasan, S, Singh, N, Singh, U
Clinical endocrinology. 2018;(2):217-226
Abstract
BACKGROUND Cholecalciferol and/or calcium supplementation might increase skeletal muscle strength and serum testosterone in young adult males. OBJECTIVE We performed a randomized control trial assessing the effect of cholecalciferol/calcium on skeletal muscle strength and serum testosterone in vitamin D deficient young males. DESIGN Two-by-two factorial RCT. SUBJECT AND INTERVENTION Two-hundred and twenty-eight young males were block-randomized to (i) double-placebo, (ii) calcium/placebo, (iii) cholecalciferol/placebo and (iv) cholecalciferol/calcium. Doses for cholecalciferol were 60 000 IU/wk for 8 weeks followed by 60 000 IU/fortnightly, and doses for elemental calcium were 500 mg/twice daily for 6 months. A total of 180 subjects completed the study protocol. Their ean age, body mass index and baseline 25(OH)D were 20.2 ± 2.2 years, 23.0 ± 3.6 kg/m2 and 21.5 ± 9.5 nmol/L, respectively. MEASUREMENTS Handgrip (primary outcome), pinch-grip strength, distance walked in 6 minutes, dyspnoea-score, quality of life by Short Form 36, serum 25(OH)D, 1,25(OH)2 D, iPTH, total testosterone and free androgen index (FAI). RESULTS After intervention, mean serum 25(OH)D was >75.0 nmol/L in cholecalciferol groups. However, the handgrip strength (29.7 ± 4.4, 29.3 ± 4.6, 30.6 ± 5.0 and 28.8 ± 4.3 kg, P = .28) was comparable in the 4 groups. Subgroups analysis among subjects with baseline serum 25OH)D < 25.0 and <12.0 nmol/L showed similar results. The mean serum testosterone decreased significantly at 6 months; however, delta change was similar in 4 groups. Change in handgrip strength and other outcomes was similar in 4 groups with and without adjustment for delta testosterone and FAI. CONCLUSIONS Six months of cholecalciferol/calcium supplementation had no significant effect on skeletal muscle strength and serum testosterone in young adult males.
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Risk of cardiovascular mortality predicted by the serum calcium level and calcification score at the initiation of dialysis.
Sato, H, Nagasawa, T, Saito, A, Miyazaki, M
Clinical and experimental nephrology. 2018;(4):957-966
Abstract
BACKGROUND The relationship between serum corrected calcium (CCa) level and vessel calcification at dialysis initiation and survival has seldom been evaluated. Therefore, we evaluated the efficacy of CCa levels and the calcification score at the initiation of dialysis for predicting all-cause and cardiovascular (CV) mortality in patients with end-stage renal disease (ESRD). METHODS The study group included 407 patients with ESRD, who started hemodialysis between January 2009 and December 2016 at the Red Cross Ishinomaki Hospital. The primary outcomes were the 1- and 3-year all-cause and CV mortality rate, with the association between CCa level and CVD-specific mortality evaluated using the Kaplan-Meier method and Cox proportional hazard regression analysis. RESULTS Patients with a high initial CCa level were at higher risk for CVD-related, but not all-cause, mortality than patients with a low initial CCa level [hazard ratio (HR) 2.81; 95% confidence interval 1.05-7.55]. The HR for CVD-related mortality was also higher for patients with an Agatston vessel calcification score > 2000 (HR 13.9; 95% CI 1.63-118.2). Overall, the 3-year CVD-free rate was 88.2% (range 76.4-94.3%). Higher CCa level was associated with a higher Agatston score and cardiac valve calcification. CONCLUSION High serum CCa levels and an Agatston score > 2000 are independent risk factors of CVD mortality due to advanced vessel calcification.
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Comparison of serum concentration of Ca, P, Mg, and Fe between hemifacial spasm patients and healthy controls; prospective randomized controlled study.
Ulusoy, EK, Ulusoy, DM, Kilic, S
Nigerian journal of clinical practice. 2018;(11):1537-1541
Abstract
PURPOSE In this study, we aimed to measure the serum vitamin D level in hemifacial spasmic (HFS) patients and show the role of HFS in the pathogenesis and place in etiology. MATERIALS AND METHODS This study included 43 prospective newly diagnosed HFS patients and 43 healthy volunteers in the neurology clinic. The serum (Ca, P, Mg, Fe) concentration of 4 essential elements was measured with a biochemical device. The groups were correlated in terms of four essential element concentrations. The severity of the disease was measured using Lee's Quality of Life Scale and correlated with the concentration of four trace elements. The results were compared using the independent t-test and Mann-Whitney U-test. RESULTS Concentration of serum Ca, P, and Mg in the HFS patients was found to be lower in the control group which was statistically significant (P < 0.05). There was no statistically difference between the groups in terms of Fe concentration (P > 0.05). There was no significant correlation between trace element concentration and severity of illness and daily life quality in the patient group. CONCLUSION These results show us the role of HFS in the pathogenesis of these four trace elements and the importance of its location in etiology. We think that changes in the concentration of trace elements in HFS can lead to demyelinization, which may lead to spasm.
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Effects of Supplemental Calcium and Vitamin D on Expression of Toll-Like Receptors and Phospho-IKKα/β in the Normal Rectal Mucosa of Colorectal Adenoma Patients.
Hodge, R, Mandle, HB, Ray, S, Tandon, S, Peterson, M, Henry, A, Jahan, FA, Bostick, RM, Baron, JA, Barry, EL, et al
Cancer prevention research (Philadelphia, Pa.). 2018;(11):707-716
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Abstract
Chronic inflammation in the colorectum, a significant contributor to colorectal carcinogenesis, can be triggered by the activation of proinflammatory signaling pathways such as those initiated by Toll-like receptors (TLR) and nuclear factor κB (NF-κB). Although experimental evidence supports calcium and vitamin D potentially modifying these proinflammatory pathways in the colorectum, human data in these regards are scarce. We investigated supplemental calcium (1,200 mg daily) and/or vitamin D3 (1,000 IU daily) effects on inflammatory signaling pathway-related biomarkers in a subset of 105 participants from a colorectal adenoma recurrence chemoprevention clinical trial. We assessed expression of TLR4 and TLR5, which recognize the bacterial components lipopolysaccharides and flagellin, respectively, and phospho-IKKα/β (pIKKα/β), a biomarker of inflammation, in the normal-appearing rectal crypt epithelium and stroma using standardized, automated immunohistochemistry and quantitative image analysis. Following 1 year of treatment, TLR4, TLR5, and pIKKα/β expression in the rectal mucosa did not statistically significantly change with vitamin D or calcium supplementation, taken alone or in combination. Several baseline participant characteristics, including body mass index, history of sessile serrated adenomas, high red/processed meat intake, and high levels of rectal epithelial cell proliferation (as measured by MIB-1/Ki-67), were associated with higher baseline expression of TLRs or pIKKα/β. Our findings suggest that vitamin D and calcium may have no substantial effect on the investigated biomarkers. However, several modifiable lifestyle factors may be associated with TLRs and pIKKα/β expression in the normal rectal mucosa, supporting their future investigation as potentially treatable, preneoplastic risk factors for colorectal neoplasms. Cancer Prev Res; 11(11); 707-16. ©2018 AACR.