Browsing by Subject "calcium"
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Item Calcium Intake and Risk of Colorectal Cancer According to Tumor-infiltrating T Cells(AACR, 2019-05) Yang, Wanshui; Liu, Li; Keum, NaNa; Qian, Zhi Rong; Nowak, Jonathan A.; Hamada, Tsuyoshi; Song, Mingyang; Cao, Yin; Nosho, Katsuhiko; Smith-Warner, Stephanie A.; Zhang, Sui; Masugi, Yohei; Ng, Kimmie; Kosumi, Keisuke; Ma, Yanan; Garrett, Wendy S.; Wang, Molin; Nan, Hongmei; Giannakis, Marios; Meyerhardt, Jeffrey A.; Chan, Andrew T.; Fuchs, Charles S.; Nishihara, Reiko; Wu, Kana; Giovannucci, Edward L.; Ogino, Shuji; Zhang, Xuehong; Epidemiology, School of Public HealthCalcium intake has been associated with a lower risk of colorectal cancer. Calcium signaling may enhance T-cell proliferation and differentiation, and contribute to T-cell–mediated antitumor immunity. In this prospective cohort study, we investigated the association between calcium intake and colorectal cancer risk according to tumor immunity status to provide additional insights into the role of calcium in colorectal carcinogenesis. The densities of tumor-infiltrating T-cell subsets [CD3+, CD8+, CD45RO (PTPRC)+, or FOXP3+ cell] were assessed using IHC and computer-assisted image analysis in 736 cancer cases that developed among 136,249 individuals in two cohorts. HRs and 95% confidence intervals (CI) were calculated using Cox proportional hazards regression. Total calcium intake was associated with a multivariable HR of 0.55 (comparing ≥1,200 vs. <600 mg/day; 95% CI, 0.36–0.84; Ptrend = 0.002) for CD8+ T-cell–low but not for CD8+ T-cell–high tumors (HR = 1.02; 95% CI, 0.67–1.55; Ptrend = 0.47). Similarly, the corresponding HRs (95% CIs) for calcium for low versus high T-cell–infiltrated tumors were 0.63 (0.42–0.94; Ptrend = 0.01) and 0.89 (0.58–1.35; Ptrend = 0.20) for CD3+; 0.58 (0.39–0.87; Ptrend = 0.006) and 1.04 (0.69–1.58; Ptrend = 0.54) for CD45RO+; and 0.56 (0.36–0.85; Ptrend = 0.006) and 1.10 (0.72–1.67; Ptrend = 0.47) for FOXP3+, although the differences by subtypes defined by T-cell density were not statistically significant. These potential differential associations generally appeared consistent regardless of sex, source of calcium intake, tumor location, and tumor microsatellite instability status. Our findings suggest a possible role of calcium in cancer immunoprevention via modulation of T-cell function.Item Coronary artery disease progression and calcification in metabolic syndrome(2014) McKenney, Mikaela Lee; Sturek, Michael Stephen; Evans-Molina, Carmella; Moe, Sharon M.; Tune, Johnathan D.For years, the leading killer of Americans has been coronary artery disease (CAD), which has a strong correlation to the U.S. obesity epidemic. Obesity, along with the presence of other risk factors including hyperglycemia, hypercholesterolemia, dyslipidemia, and high blood pressure, comprise of the diagnosis of metabolic syndrome (MetS). The presentation of multiple MetS risk factors increases a patients risk for adverse cardiovascular events. CAD is a complex progressive disease. We utilized the superb model of CAD and MetS, the Ossabaw miniature swine, to investigate underlying mechanisms of CAD progression. We studied the influence of coronary epicardial adipose tissue (cEAT) and coronary smooth muscle cell (CSM) intracellular Ca2+ regulation on CAD progression. By surgical excision of cEAT from MetS Ossabaw, we observed an attenuation of CAD progression. This finding provides evidence for a link between local cEAT and CAD progression. Intracellular Ca2+ is a tightly regulated messenger in CSM that initiates contraction, translation, proliferation and migration. When regulation is lost, CSM dedifferentiate from their mature, contractile phenotype found in the healthy vascular wall to a synthetic, proliferative phenotype. Synthetic CSM are found in intimal plaque of CAD patients. We investigated the changes in intracellular Ca2+ signaling in enzymatically isolated CSM from Ossabaw swine with varying stages of CAD using the fluorescent Ca2+ indicator, fura-2. This time course study revealed heightened Ca2+ signaling in early CAD followed by a significant drop off in late stage calcified plaque. Coronary artery calcification (CAC) is a result of dedifferentiation into an osteogenic CSM that secretes hydroxyapatite in the extracellular matrix. CAC is clinically detected by computed tomography (CT). Microcalcifications have been linked to plaque instability/rupture and cannot be detected by CT. We used 18F-NaF positron emission tomography (PET) to detect CAC in Ossabaw swine with early stage CAD shown by mild neointimal thickening. This study validated 18F-NaF PET as a diagnostic tool for early, molecular CAC at a stage prior to lesions detectable by CT. This is the first report showing non-invasive PET resolution of CAC and CSMC Ca2+ dysfunction at an early stage previously only characterized by invasive cellular Ca2+ imaging.Item Effects of PVP-Iodine pH and Calcium Concentration on Fluoride Varnish Anti-Caries Efficacy In Vitro(Quintessence, 2019) Aljamah, Ali F.; Hara, Anderson T.; Levon, John A.; Eckert, George J.; Lippert, Frank; Cariology, Operative Dentistry and Dental Public Health, School of DentistryPurpose: This laboratory study investigated the effects of PVP-iodine solutions with varying pH and calcium concentrations on enamel remineralization and fluoridation by subsequent treatment with fluoride varnish. Materials and Methods: Caries-like lesions were created in bovine enamel specimens (n = 15 per group) and characterized using Vickers surface microhardness (VHN). Specimens were treated with 10% PVP-iodine solutions varying in calcium concentration (0/10/100 mM) and pH (3.0/4.0/5.0), followed by 5% sodium fluoride varnish. A fluoride varnish-only control group was included. Specimens were then placed into artificial saliva for 16 h. The varnish was removed, hardness measured and enamel fluoride uptake (EFU) determined using the microbiopsy technique. Data were analyzed with one-way ANOVA. Results: Groups receiving PVP-iodine pre-treatments exhibited directionally greater rehardening (range: p = 0.0001 - 0.7008) and EFU (p = 0.0001-0.2670) than the control group. The presence of calcium in the pre-treatment enhanced rehardening. the groups '10mM Ca/pH 3.0' (∆VHN = 10.5 ± 6.3), '100mM Ca/pH 3.0' (∆VHN = 9.7 ± 4.1) and '10mM Ca/pH 5.0' (∆VHN = 8.7 ± 7.0) displayed the highest numerical gain vs the control (∆VHN=3.6±2.2). Different pH values had a minor effect on rehardening and EFU. The calcium effect was more pronounced for EFU than for rehardening with all three '100 mM Ca' groups exhibiting higher EFU (7.0 - 7.2 µg F/cm2) than all other groups (6.1 - 6.9 µg F/cm2). Conclusion: PVP-iodine pre-treatments can be modified to enhance the rehardening and fluoridating effect of fluoride varnishes, thereby potentially improving their ability to prevent caries in vivo. Although numerical differences between groups were small, the addition of high concentrations of calcium paired with a low pH appears most favorable under the present conditions.Item Evaluation of fluoride and calcium concentrations in drinking water from public water fountains on a university campus(AGD, 2022-11) Tamayo-Cabeza, Guillermo; Lippert, Frank; Cariology, Operative Dentistry and Dental Public Health, School of DentistryOptimal exposure to fluoride and calcium from tap water is beneficial for dental caries prevention. Water fountains may be an important source of drinking water in work and educational settings. The aims of this study were to quantify the fluoride and calcium concentrations of drinking water samples collected from public water fountains on the Indiana University-Purdue University Indianapolis campus; compare the fluoride and calcium concentrations in water collected at 2 different times; and determine whether the presence or absence of a visible external filter affects fluoride and calcium concentrations. Ninety samples were collected from 45 water fountains accessible to the public, and 90 duplicate samples were collected 1 month later. A fluoride ion-selective electrode was used in conjunction with an ion-specific meter to determine fluoride concentration, while atomic absorption spectrometry in an air-acetylene flame was implemented to quantify the calcium concentration. The fluoride and calcium concentration of drinking water samples displayed ranges of 0.62 mg/L to 0.97 mg/L and 56.61 mg/L to 89.11 mg/L, respectively. The concentrations of fluoride and calcium in drinking water were slightly lower at the second collection period (P < 0.001; Wilcoxon signed rank test). No statistically significant differences were observed in the fluoride or calcium concentration of drinking water collected from water fountains with an external filter cartridge in comparison with fountains that did not have a filter. Fluoride concentrations were within the optimal range recommended by the US Public Health Service for fluoridated drinking water, and calcium concentrations were consistent with those reported in previous surveillance studies.Item Executive summary of the 2017 KDIGO Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD) Guideline Update: what’s changed and why it matters(Elsevier, 2017-07) Ketteler, Markus; Block, Geoffrey A.; Evenepoel, Pieter; Fukagawa, Masafumi; Herzog, Charles A.; McCann, Linda; Moe, Sharon M.; Shroff, Rukshana; Tonelli, Marcello A.; Toussaint, Nigel D.; Vervloet, Marc G.; Leonard, Mary B.; Medicine, School of MedicineThe KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of CKD-MBD represents a selective update of the prior CKD-MBD Guideline published in 2009. This update, along with the 2009 publication, is intended to assist the practitioner caring for adults and children with chronic kidney disease (CKD), those on chronic dialysis therapy, or individuals with a kidney transplant. This review highlights key aspects of the 2017 CKD-MBD Guideline Update, with an emphasis on the rationale for the changes made to the original guideline document. Topic areas encompassing updated recommendations include diagnosis of bone abnormalities in CKD–mineral and bone disorder (MBD), treatment of CKD-MBD by targeting phosphate lowering and calcium maintenance, treatment of abnormalities in parathyroid hormone in CKD-MBD, treatment of bone abnormalities by antiresorptives and other osteoporosis therapies, and evaluation and treatment of kidney transplant bone disease.Item Intakes of magnesium, calcium and risk of fatty liver disease and prediabetes(Cambridge, 2018-08) Li, Wenshuai; Zhu, Xiangzhu; Song, Yiqing; Fan, Lei; Wu, Lijun; Kabagambe, Edmond; Hou, Lifang; Shrubsole, Martha; Liu, Jie; Dai, Qi; Epidemiology, School of Public HealthObjective Obesity and insulin resistance play important roles in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Mg intake is linked to a reduced risk of metabolic syndrome and insulin resistance; people with NAFLD or alcoholic liver disease are at high risk of Mg deficiency. The present study aimed to investigate whether Mg and Ca intakes were associated with risk of fatty liver disease and prediabetes by alcohol drinking status. Design We analysed the association between Ca or Mg intake and fatty liver disease, prediabetes or both prediabetes and fatty liver disease in cross-sectional analyses. Setting Third National Health and Nutrition Examination Survey (NHANES III) follow-up cohort of US adults. Subjects Nationally representative sample of US adults in NHANES (n 13 489). Results After adjusting for potential confounders, Mg intake was associated with approximately 30 % reduced odds of fatty liver disease and prediabetes, comparing the highest intake quartile v. the lowest. Mg intake may only be related to reduced odds of fatty liver disease and prediabetes in those whose Ca intake is less than 1200 mg/d. Mg intake may also only be associated with reduced odds of fatty liver disease among alcohol drinkers. Conclusions The study suggests that high intake of Mg may be associated with reduced risks of fatty liver disease and prediabetes. Further large studies, particularly prospective cohort studies, are warranted to confirm the findings.Item Investigating the molecular mechanism of phospholamban regulation of the Ca²-pump of cardiac sarcoplasmic reticulum(2010-12) Akin, Brandy Lee; Jones, Larry R.; Field, Loren J.; Hudmon, Andrew; Hurley, Thomas D., 1961-; Roach, Peter J.The Ca2+ pump or Ca2+-ATPase of cardiac sarcoplasmic reticulum, SERCA2a, is regulated by phospholamban (PLB), a small inhibitory phosphoprotein that decreases the apparent Ca2+ affinity of the enzyme. We propose that PLB decreases Ca2+ affinity by stabilizing the Ca2+-free, E2·ATP state of the enzyme, thus blocking the transition to E1, the high Ca2+ affinity state required for Ca2+ binding and ATP hydrolysis. The purpose of this dissertation research is to critically evaluate this idea using series of cross-linkable PLB mutants of increasing inhibitory strength (N30C-PLB < PLB3 < PLB4). Three hypotheses were tested; each specifically designed to address a fundamental point in the mechanism of PLB action. Hypothesis 1: SERCA2a with PLB bound is catalytically inactive. The catalytic activity of SERCA2a irreversibly cross-linked to PLB (PLB/SER) was assessed. Ca2+-ATPase activity, and formation of the phosphorylated intermediates were all completely inhibited. Thus, PLB/SER is entirely catalytically inactive. Hypothesis 2: PLB decreases the Ca2+ affinity of SERCA2a by competing with Ca2+ for binding to SERCA2a. The functional effects of N30C-PLB, PLB3, and PLB4 on Ca2+-ATPase activity and phosphoenzyme formation were measured, and correlated with their binding interactions with SERCA2a measured by chemical cross-linking. Successively higher Ca2+ concentrations were required to both activate the enzyme co-expressed with N30C-PLB, PLB3, and PLB4 and to dissociate N30C-PLB, PLB3, and PLB4 from SERCA2a, suggesting competition between PLB and Ca2+ for binding to SERCA2a. This was confirmed with the Ca2+ pump mutant, D351A, which is catalytically inactive but retains strong Ca2+ binding. Increasingly higher Ca2+ concentrations were also required to dissociate N30C-PLB, PLB3, and PLB4 from D351A, demonstrating directly that PLB competes with Ca2+ for binding to the Ca2+ pump. Hypothesis 3: PLB binds exclusively to the Ca2+-free E2 state with bound nucleotide (E2·ATP). Thapsigargin, vanadate, and nucleotide effects on PLB cross-linking to SERCA2a were determined. All three PLB mutants bound preferentially to E2 state with bound nucleotide (E2·ATP), and not at all to the thapsigargin or vanadate bound states. We conclude that PLB inhibits SERCA2a activity by stabilizing a unique E2·ATP conformation that cannot bind Ca2+.Item An investigation into the potential anticaries benefits and contributions to mineral intake of bottled water(Elsevier, 2020-12) Almejrad, Lamya; Levon, John A.; Soto-Rojas, Armando E.; Tang, Qing; Lippert, Frank; Prosthodontics, School of DentistryBACKGROUND: Bottled water has become the most consumed beverage in the United States. The authors aimed to inform the dental profession about the potential anticaries benefits of some bottled waters and to provide information about their possible contributions to fluoride, calcium, magnesium, sodium, and potassium intakes. METHODS: The authors chose a convenience sample by purchasing all different bottled waters from the main supermarkets operating in Indianapolis, Indiana. The authors analyzed the fluoride content using a fluoride ion-specific electrode and metal concentrations using atomic absorption spectroscopy. They used dietary reference intakes to calculate hypothetical intakes of all minerals. RESULTS: The authors identified 92 different bottled waters. Fluoride concentrations were generally low (mean, 0.11 parts per million [ppm]; median, 0.04 ppm). Only 2 waters contained more than 0.7 ppm fluoride (0.95 ppm and 1.22 ppm). Metal concentrations varied considerably among waters. Calcium concentrations ranged from less than 0.1 through 360 ppm (mean, 26.9 ppm; median, 5.2 ppm), which were greater than those of magnesium (range, < 0.01-106 ppm; mean, 7.5 ppm; median, 1.9 ppm), sodium (range, < 0.01-109 ppm; mean, 11.1 ppm; median, 2.9 ppm), and potassium (range, < 0.01-43 ppm; mean, 3.6 ppm; median, 1.2 ppm). Overall, most bottled waters do not contribute to adequate intakes of fluoride, potassium, or sodium or to recommended dietary allowances for calcium and magnesium. Nonetheless, some waters can provide meaningful contributions to fluoride, calcium, and magnesium intake. CONCLUSIONS: The fluoride concentration in 90 of the 92 studied bottled waters is insufficient to contribute to caries prevention. Only a few bottled waters can be considered health-promoting. PRACTICAL IMPLICATIONS: Dental professionals should consider the mineral content of water consumed by their patients during caries risk assessment.Item Matrix vesicles induce calcification of recipient vascular smooth muscle cells through multiple signaling pathways(Elsevier, 2018-02) Chen, Neal X.; O'Neill, Kalisha D.; Moe, Sharon M.; Medicine, School of MedicineIn patients with chronic kidney and end-stage renal diseases, the major risk factor for progression of arterial calcification is the presence of existing (baseline) calcification. Here, we tested whether calcification of arteries is extended from calcified vascular smooth muscle cells (VSMCs) to adjacent normal cells by matrix vesicle–induced alteration of cell signaling. Matrix vesicles isolated from VSMC of rats with chronic kidney disease were co-cultured with VSMCs from normal littermates. Endocytosis of vesicles by recipient cells was confirmed by confocal microscopy. The addition of cellular matrix vesicles with characteristics of exosomes and low fetuin-A content enhanced the calcification of recipient VSMC. Further, only cellular-derived matrix vesicles induced an increase in intracellular calcium ion concentration, NOX1 (NADPH oxidase) and the anti-oxidant superoxide dismutase-2 in recipient normal VSMC. The increase in intracellular calcium ion concentration was due to release from endoplasmic reticulum and partially attributed to the activation of both NOX1 and mitogen-activated protein kinase (MEK1 and Erk1/2) signaling, since inhibiting both pathways blocked the increase in intracellular calcium ion in recipient VSMC. In contrast, matrix vesicles isolated from the media had no effect on the intracellular calcium ion concentration or MEK1 signaling, and did not induce calcification. However, media matrix vesicles did increase Erk1/2, although not to the level of cellular matrix vesicles, and NOX1 expression. Blockade of NOX activity further inhibited the cellular matrix vesicle–induced accelerated calcification of recipient VSMC, suggesting a potential therapeutic role of such inhibition. Thus, addition of cellular-derived matrix vesicles from calcifying VSMC can accelerate calcification by inducing cell signaling changes and phenotypic alteration of recipient VSMC.Item Mutant huntingtin fails to directly impair brain mitochondria(Wiley, 2019) Hamilton, James; Brustovetsky, Tatiana; Brustovetsky, Nickolay; Pharmacology and Toxicology, School of MedicineAlthough the mechanisms by which mutant huntingtin (mHtt) results in Huntington's disease (HD) remain unclear, mHtt‐induced mitochondrial defects were implicated in HD pathogenesis. The effect of mHtt could be mediated by transcriptional alterations, by direct interaction with mitochondria, or by both. In the present study, we tested a hypothesis that mHtt directly damages mitochondria. To test this hypothesis, we applied brain cytosolic fraction from YAC128 mice, containing mHtt, to brain non‐synaptic and synaptic mitochondria from wild‐type mice and assessed mitochondrial respiration with a Clark‐type oxygen electrode, membrane potential and Ca2+ uptake capacity with tetraphenylphosphonium (TPP+)‐ and Ca2+‐sensitive electrodes, respectively, and, reactive oxygen species production with Amplex Red assay. The amount of mHtt bound to mitochondria following incubation with mHtt‐containing cytosolic fraction was greater than the amount of mHtt bound to brain mitochondria isolated from YAC128 mice. Despite mHtt binding to wild‐type mitochondria, no abnormalities in mitochondrial functions were detected. This is consistent with our previous results demonstrating the lack of defects in brain mitochondria isolated from R6/2 and YAC128 mice. This, however, could be because of partial loss of mitochondrially bound mHtt during the isolation procedure. Consequently, we increased the amount of mitochondrially bound mHtt by incubating brain non‐synaptic and synaptic mitochondria isolated from YAC128 mice with mHtt‐containing cytosolic fraction. Despite the enrichment of YAC128 brain mitochondria with mHtt, mitochondrial functions (respiration, membrane potential, reactive oxygen species production, Ca2+ uptake capacity) remained unchanged. Overall, our results suggest that mHtt does not directly impair mitochondrial functions, arguing against the involvement of this mechanism in HD pathogenesis.