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Item Associations between Intake of Calcium, Magnesium, and Phosphorus and Risk of Pancreatic Cancer: A Population-Based, Case-Control Study in Minnesota(Cambridge UP, 2021) Fan, Hao; Yu, Yunpeng; Nan, Haocheng; Hoyt, Margaret; Reger, Michael K.; Prizment, Anna; Anderson, Kristin E.; Zhang, Jianjun; Epidemiology, School of Public HealthExperimental studies suggest that abnormal levels of calcium, magnesium, and phosphorus are implicated in pancreatic carcinogenesis. We investigated the associations between intakes of these minerals and the risk of pancreatic cancer in a case-control study conducted in 1994-1998. Cases of pancreatic cancer (n150) were recruited from all hospitals in the metropolitan area of the Twin Cities and Mayo Clinic, Minnesota. Controls (n459) were randomly selected from the general population and frequency matched to cases by age, sex, and race. All dietary variables were adjusted for energy intake using the residual method prior to data analysis. Logistic regression was performed to evaluate the associations between intake of three nutrients examined and the risk of pancreatic cancer. Total intake of calcium (936 vs. 1026 mg/day) and dietary intake of magnesium (315 vs. 331 mg/day) and phosphorus (1350 vs. 1402 mg/day) were significantly lower in cases than in controls. After adjustment for confounders, there were not significant associations of total and dietary intakes of calcium, magnesium, and phosphorus with the risk of pancreatic cancer. In addition, no significant interactions exist between intakes of these minerals and total fat on pancreatic cancer risk. In conclusion, the present study does not suggest that intakes of calcium, magnesium, and phosphorus were significantly associated with the risk of pancreatic cancer.Item Biomarker of Magnesium Status in Response to Mg Supplementation: A Dose- and Time-Response Meta-analysis of Randomized Controlled Trials(Office of the Vice Chancellor for Research, 2015-04-17) Zhang, Xi; Song, YiqingABSTRACT Background: Magnesium is a cofactor for hundreds of human enzymes and magnesium deficiency has been associated with cardiometabolic disorders. Although a panel of magnesium biomarkers are used to assess magnesium status, their relative predictive values or clinical usefulness in response to magnesium supplementation remain unclear. Objective: We quantitatively evaluated time- and dose-response relation of magnesium biomarkers from available randomized controlled trials (RCTs) of magnesium supplementation. Methods: We systematically identified RCTs assessing magnesium biomarkers’ responses after oral magnesium supplementation through search on MEDLINE and Cochrane Library up to November 2014. We calculated the pooled weight mean differences (WMDs) of biomarkers levels between treatment and placebo group after supplementation. A dose- and time-response meta-analysis was conducted to quantitatively compare the usefulness of biomarkers in assessing magnesium status. Results: This meta-analysis included 44 RCTs of magnesium supplementation that examined a total of 38 biomarkers of magnesium status. Total magnesium concentrations in blood (serum or plasma), RBC, and urine were significantly raised after magnesium supplementation by 0.05 mmol/l, 0.12 mmol/l, and 1.52 mmol/24h corresponding to 5.81%, 5.30%, and 28.3% increases relative to baseline magnesium levels, respectively. Our dose- and time-response meta-analyses showed that blood and urinary magnesium levels abruptly increased at the first 20-week supplementation and afterwards reached a plateau. Evidence was insufficient due to limited numbers of studies testing other potential biomarkers, including ionized Mg, muscle Mg, mononuclear Mg, intracellular Mg, IV Mg load, ultrafiltrable Mg, and fecal Mg.Item Comparative Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Serum Electrolyte Levels in Patients with Type 2 Diabetes: A Pairwise and Network Meta-Analysis of Randomized Controlled Trials(Wolters Kluwer, 2022-01-19) Zhang, Jingjing; Huan, Yonghong; Leibensperger, Mark; Seo, Bojung; Song, Yiqing; Epidemiology, School of Public HealthBackground: Previous studies have reported that sodium-glucose co-transporter 2 (SGLT2) inhibitors (SGLT2is) affect levels of serum electrolytes, especially magnesium. This study aimed to integrate direct and indirect trial evidence to maximize statistical power to clarify their overall and comparative effects in patients with type 2 diabetes (T2D). Methods: We systematically searched PubMed, EMBASE, CENTRAL, and ClinicalTrials.gov up to January 2021 to identify eligible randomized controlled trials (RCTs) of SGLT2is that reported mean changes in serum electrolytes, including magnesium, sodium, potassium, phosphate, and calcium. We performed both random-effects pairwise and network meta-analyses to calculate the weighted mean difference (WMD) and 95% confidence intervals (CI). Results: In total, we included 25 RCTs involving 28,269 patients with T2D and 6 SGLT2is. Compared with placebo, SGLT2is were significantly associated with elevations in serum magnesium by 0.07 mmol/L (95% CI, 0.06 to 0.08 mmol/L) and serum phosphate by 0.03 mmol/L (95% CI, 0.02 to 0.04 mmol/L). Our network meta-analysis showed no evidence of significantly superior efficacy of any specific SGLT2 inhibitor over the others, although dapagliflozin was associated with a larger increment in serum magnesium (WMD=0.16 mmol/L) compared with other SGLT2is. Similarly, no statistically detectable differences among the effects of SGLT2is on serum levels of other electrolytes were detected. Conclusions: SGLT2is significantly increased serum magnesium and phosphate levels, consistent with a class effect of SGLT2 inhibition. However, further investigations of long-term efficacy and safety in patients with T2D with different clinical phenotypes are needed.Item The correlation of serum magnesium with clinical nutritional status(1986) Amerman, BarbaraItem High-Resolution Crystal Structures Reveal Plasticity in the Metal Binding Site of Apurinic/Apyrimidinic Endonuclease I(American Chemical Society, 2014-10-21) He, Hongzhen; Chen, Qiujia; Georgiadis, Millie M.; Department of Biochemistry & Molecular Biology, IU School of MedicineApurinic/apyrimidinic endonuclease I (APE1) is an essential base excision repair enzyme that catalyzes a Mg2+-dependent reaction in which the phosphodiester backbone is cleaved 5′ of an abasic site in duplex DNA. This reaction has been proposed to involve either one or two metal ions bound to the active site. In the present study, we report crystal structures of Mg2+, Mn2+, and apo-APE1 determined at 1.4, 2.2, and 1.65 Å, respectively, representing two of the highest resolution structures yet reported for APE1. In our structures, a single well-ordered Mn2+ ion was observed coordinated by D70 and E96; the Mg2+ site exhibited disorder modeled as two closely positioned sites coordinated by D70 and E96 or E96 alone. Direct metal binding analysis of wild-type, D70A, and E96A APE1, as assessed by differential scanning fluorimetry, indicated a role for D70 and E96 in binding of Mg2+ or Mn2+ to APE1. Consistent with the disorder exhibited by Mg2+ bound to the active site, two different conformations of E96 were observed coordinated to Mg2+. A third conformation for E96 in the apo structure is similar to that observed in the APE1–DNA–Mg2+ complex structure. Thus, binding of Mg2+ in three different positions within the active site of APE1 in these crystal structures corresponds directly with three different conformations of E96. Taken together, our results are consistent with the initial capture of metal by D70 and E96 and repositioning of Mg2+ facilitated by the structural plasticity of E96 in the active site.Item Mineral Content of Water From Public Fountains Along the Monon Trail in Central Indiana(2024) Bakhaider, Renad Fahad; Lippert, Frank; E. Soto Rojas, Armando; Capin, OrianaBackground: The Monon trail is one of the most popular trails located in central Indiana that the public uses for various physical activities, such as cycling, jogging, and walking. Physical activity, especially in the summer, causes the body to dehydrate and lose some of its electrolytes via sweating (e.g., calcium, magnesium, potassium, and sodium). These minerals are considered important in regulating some of the body’s chemical and biological reactions. Therefore, water fountains are located along the trail. However, no study has thus far investigated the mineral composition of water provided along the Monon trail and how it compares with commonly used bottled water. Fluoride is added to tap water in many communities in the US for the prevention of dental caries (community water fluoridation). However, whether water provided by these fountains meets the recommended fluoride level by the CDC for caries prevention has not been established. Therefore, this study aimed to determine the fluoride, calcium, magnesium, potassium, and sodium contents from water samples collected from all water fountains along the Monon trail and to compare their mineral concentrations to commercially available bottled waters. As an exploratory objective, we also assessed the utilization of theses fountains by the users of the Monon trail. Objectives: The primary aim of this study was to evaluate the fluoride, calcium, magnesium, potassium, and sodium contents of water from public drinking water fountains along the Monon trail in central Indiana. The secondary aim was to compare the nutritional value of the collected water samples to that of commercially available bottled waters. An exploratory objective will be to study the utilization of these fountains by users of the Monon trail. Methodology: Two 50-ml samples of water from each fountain along the Monon Trail were collected. The fluoride concentration was determined using a fluoride ion-specific electrode (Orion #96-909-00). The calcium, magnesium, sodium, and potassium contents were determined by atomic absorption spectrometer, equipped with deuterium and cathode lamps at wave lengths of 422.7 nm, 285.2 nm, 589.0 nm, and 766.5 nm, respectively. Data collected from water samples were compared to those of bottled water available in Indianapolis, Indiana, using data from a recently conducted study. Mineral data of water samples were compared to recommended dietary allowances (calcium and magnesium) or adequate intakes (potassium and sodium) as established by the Institutes of Medicine. The utilization of those fountains by cyclists, runners/joggers, and walkers was also investigated by conducting an observational study at each water fountain during a one-hour period in mid- to late afternoon during a weekday and weekend. Data collection was taken twice, one month apart. The statistical analyses of the study were carried out using two-sided two sample t-tests at 5-% significance level. Results: The author identified seven water fountains along the Monon trail during the study period. Fluoride concentration was generally high (mean 1.01 parts per million [ppm]). Calcium concentration ranged from 45 ppm to 81 ppm (mean, 60.9 ppm) which was greater than those of magnesium (range, 4.8 ppm to 13.7 ppm; mean 8.4 ppm), sodium (range, 14.7 ppm to 78.1 ppm; mean 40.5 ppm), and potassium (range, 1.2 ppm to 2.2 ppm; mean 1.6 ppm). Overall, water fountains provided meaningful contributions to adequate intake of fluoride. However, the contributions to adequate intake of sodium and potassium, or to the recommended dietary allowances for calcium and magnesium were lower. Moreover, water from fountains was found to contain higher mineral concentrations than most bottled waters. Conclusion: Within the limitations of this study, it was found that water fountains are a valuable source of rehydration and essential mineral replenishment during and after physical activity, as they provide greater nutritious values than most bottled waters. Furthermore, it was found that F concentration in water fountains satisfies the standards needed to prevent dental caries.Item Pseudomonas aeruginosa Magnesium Transporter MgtE Inhibits Type III Secretion System Gene Expression by Stimulating rsmYZ Transcription(American Society for Microbiology, 2017-10-31) Chakravarty, Shubham; Melton, Cameron N.; Bailin, Adam; Yahr, Timothy L.; Anderson, Gregory G.; Biology, School of SciencePseudomonas aeruginosa causes numerous acute and chronic opportunistic infections in humans. One of its most formidable weapons is a type III secretion system (T3SS), which injects powerful toxins directly into host cells. The toxins lead to cell dysfunction and, ultimately, cell death. Identification of regulatory pathways that control T3SS gene expression may lead to the discovery of novel therapeutics to treat P. aeruginosa infections. In a previous study, we found that expression of the magnesium transporter gene mgtE inhibits T3SS gene transcription. MgtE-dependent inhibition appeared to interfere with the synthesis or function of the master T3SS transcriptional activator ExsA, although the exact mechanism was unclear. We now demonstrate that mgtE expression acts through the GacAS two-component system to activate rsmY and rsmZ transcription. This event ultimately leads to inhibition of exsA translation. This inhibitory effect is specific to exsA as translation of other genes in the exsCEBA operon is not inhibited by mgtE Moreover, our data reveal that MgtE acts solely through this pathway to regulate T3SS gene transcription. Our study reveals an important mechanism that may allow P. aeruginosa to fine-tune T3SS activity in response to certain environmental stimuli.IMPORTANCE The type III secretion system (T3SS) is a critical virulence factor utilized by numerous Gram-negative bacteria, including Pseudomonas aeruginosa, to intoxicate and kill host cells. Elucidating T3SS regulatory mechanisms may uncover targets for novel anti-P. aeruginosa therapeutics and provide deeper understanding of bacterial pathogenesis. We previously found that the magnesium transporter MgtE inhibits T3SS gene transcription in P. aeruginosa In this study, we describe the mechanism of MgtE-dependent inhibition of the T3SS. Our report also illustrates how MgtE might respond to environmental cues, such as magnesium levels, to fine-tune T3SS gene expression.Item The role of Mg2+ and the Mg2+-stimulated ATPase in oxidative phosphorylation(1970) Chao, David Li-ShanItem Serum magnesium concentration and incident cognitive impairment: the reasons for geographic and racial differences in stroke study(Springer, 2021) Chen, Cheng; Xun, Pengcheng; Unverzagt, Frederick; McClure, Leslie A.; Ryan Irvin, Marguerite; Judd, Suzanne; Cushman, Mary; He, Ka; Psychiatry, School of MedicinePurpose: To examine the prospective association between serum Mg level and the incidence of cognitive impairment. Methods: A random sub-cohort (n = 2063) from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort was included in this study. Baseline serum Mg concentration was measured using inductively coupled plasma mass spectrometry. According to the current reference interval of serum magnesium (0.75-0.95 mmol/L), we classified participants below the interval as Level 1 and used it as the referent. The rest of the study population were equally divided into three groups, named Level 2 to 4. Incident cognitive impairment was identified using the Six-Item Screener. Multivariable-adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using logistic regression models. Results: After adjustment for potential confounders, an inverse threshold association between serum Mg level and incident cognitive impairment was observed. Compared to those with hypomagnesemia (Level 1: < 0.75 mmol/L), the relative odds of incident cognitive impairment was reduced by 41% in the second level [OR (95% CI) = 0.59 (0.37, 0.94)]; higher serum Mg level did not provide further benefits [Level 3 and 4 versus Level 1: OR (95% CI) = 0.54 (0.34, 0.88) and 0.59 (0.36, 0.96), P for linear trend = 0.08]. Conclusions: Findings from this prospective study suggest that sufficient Mg status within the normal range may be beneficial to cognitive health in the US general population.