Elevation of Hyaluronan Synthase by Magnesium Supplementation Mediated through the Activation of GSK3 and CREB in Human Keratinocyte-Derived HaCaT Cells

Skin barrier damage is present in the patients with hereditary disorders of the magnesium channel, but the molecular mechanism has not been fully understood. We found that the expressions of hyaluronan synthase (HAS), HAS2 and HAS3 are influenced by MgCl2 concentration in human keratinocyte-derived HaCaT cells. The exposure of cells to a high concentration (5.8 mM) of MgCl2 induced the elevation of HAS2/3 expression, which was inhibited by mRNA knockdown of nonimprinted in Prader-Willi/Angelman syndrome-like domain containing 4 (NIPAL4). Similarly, the content of hyaluronic acid (HA) was changed according to MgCl2 concentration and the expression of NIPAL4. The MgCl2 supplementation increased the reporter activities of HAS2/3, which were inhibited by NIPAL4 knockdown, indicating that the expressions of HAS2/3 are up-regulated at the transcriptional level. The reporter activities and mRNA levels of HAS2/3, and the production of HA were inhibited by CHIR-99021, a glycogen synthase kinase-3 (GSK3) inhibitor, and naphthol AS-E, a cyclic AMP-response element binding protein (CREB) inhibitor. Furthermore, the mutation in putative CREB-binding sites of promoter region in HAS2/3 genes inhibited the MgCl2 supplementation-induced elevation of promoter activity. Our results indicate that the expressions of HAS2/3 are up-regulated by MgCl2 supplementation in HaCaT cells mediated through the activation of GSK3 and CREB. Magnesium may play a pivotal role in maintaining the skin barrier function and magnesium supplementation may be useful to enhance moisturization and wound repair in the skin.

Prophylactic Magnesium Supplementation and New-Onset Atrial Fibrillation in a General Critical Care Population: A Prescribing Preference Instrumental Variable Analysis

Aims Atrial fibrillation is frequently encountered in critical illness and causes adverse effects including haemodynamic decompensation, stroke and longer hospital stay. It is common to supplement serum magnesium for the purpose of preventing new-onset atrial fibrillation. However, no randomised studies support this practice in the non-cardiac surgery critical care population, and its effectiveness is unclear. We sought to investigate the effectiveness of magnesium supplementation in preventing new-onset atrial fibrillation in a mixed critical care population. Methods We conducted a single centre retrospective observational study of adult critical care patients. We employed a natural experiment design, using the supplementation preference of the bedside critical care nurse as an instrumental variable. Using the electronic patient record, magnesium supplementation opportunities were defined and linked to the bedside nurse. Nurse preference for administering magnesium was obtained using multilevel modelling. The results were used to define pro and anti supplementation groups, which were inputted into an instrumental variable regression to obtain an estimate of the effect of magnesium supplementation. Results 9,114 magnesium supplementation opportunities were analysed, representing 2,137 critical care admissions for 1,914 patients. There was significant variation in magnesium supplementation practices attributable to the individual nurse, after accounting for covariates. The instrumental variable analysis showed magnesium supplementation was associated with a 3% decreased chance of experiencing new-onset atrial fibrillation (95% CI -0.06 to -0.04, p = 0.03). Conclusions This study supports the strategy of routine magnesium supplementation, but further work is required to identify optimal serum magnesium targets for prophylaxis of atrial fibrillation.

Effect of Dapagliflozin and Magnesium Supplementation on Renal Magnesium Handling and Magnesium Homeostasis in Metabolic Syndrome

The prevalence of metabolic syndrome (MetS) is increasing, and patients with MetS are at an increased risk of cardiovascular disease and diabetes. There is a close link between hypomagnesemia and MetS. Administration of sodium-glucose transporter 2 (SGLT2) inhibitors has been reported to increase serum magnesium levels in patients with diabetes. We investigated the alterations in renal magnesium handling in an animal model of MetS and analyzed the effects of SGLT2 inhibitors. Adult rats were fed a fructose-rich diet to induce MetS in the first 3 months and were then treated with either dapagliflozin or magnesium sulfate-containing drinking water for another 3 months. Fructose-fed animals had increased insulin resistance, hypomagnesemia, and decreased urinary magnesium excretion. Dapagliflozin treatment improved insulin resistance by decreasing glucose and insulin levels, increased serum magnesium levels, and reduced urinary magnesium excretion. Serum vitamin D and parathyroid hormone levels were decreased in fructose-fed animals, and the levels remained low despite dapagliflozin and magnesium supplementation. In the kidney, claudin-16, TRPM6/7, and FXDY expression was increased in fructose-fed animals. Dapagliflozin increased intracellular magnesium concentration, and this effect was inhibited by TRPM6 blockade and the EGFR antagonist. We concluded that high fructose intake combined with a low-magnesium diet induced MetS and hypomagnesemia. Both dapagliflozin and magnesium sulfate supplementation improved the features of MetS and increased serum magnesium levels. Expression levels of magnesium transporters such as claudin-16, TRPM6/7, and FXYD2 were increased in fructose-fed animals and in those administered dapagliflozin and magnesium sulfate. Dapagliflozin enhances TRPM6-mediated trans-epithelial magnesium transport in renal tubule cells.

Association between Hypomagnesemia, COVID-19, Respiratory Tract and Lung Disease

The complexity of COVID-19 is also related to the multiple molecular pathways triggered by SARS-CoV-2, which is able to cause type I pneumocyte death, trigger intravascular coagulation, interfere with the renin-angiotensin system, dysregulate iron metabolism, ending with the insurgence of a cytokine storm which may lead to death. Old adults with obesity, hypertension, and diabetes are among the high-risk category groups more prone to SARS-CoV-2 infection. Magnesium has been reported to play a major role both in physiology and in pathology, particularly in elderly people, regulating cytotoxic functions of natural killer (NK) cells and CD8+ T lymphocytes. In spite of the absence of controlled trials, the possibility of magnesium supplementation for supportive treatment in patients with COVID-19 should be encouraged. This could be useful in all phases of the COVID-19 disease.

Effect of Hypomagnesemia On The Prognosis of Patients With Sepsis in ICU: A Retrospective Cohort Study

Objective Existing studies have shown that the incidence of hypomagnesemia may be as high as 60%. However, the correlation between hypomagnesia and sepsis mortality remains elusive. The current study evaluated the effect of hypomagnesemia on the prognosis of patients with sepsis in ICU. Methods It was a retrospective cohort study based on an online database named MIMIC III. A total of 1448 sepsis patients with serum magnesium were admitted to the database, among which 645 patients were screened out. Results At 28 days, 99 patients (30.84%) in the hypomagnesemia group and 123 patients (38.0%) (P = 0.06) in the non-hypomagnesemia group died. There was no correlation between hypomagnesemia and 28-day mortality in patients with sepsis (HR = 1.07; P = 0.87, 95% CI). However, the duration of mechanical ventilation (P < 0.01), the duration of vasoactive drug use (P < 0.01), the length of ICU stay (P < 0.01), and the length of hospital stay (P < 0.01) of patients in the hypomagnesemia group were higher than those in the non-hypomagnesemia group. In the subgroup analysis, the time of no vasopressor (P < 0.01) and the time of no mechanical ventilation (P < 0.01) in the magnesium supplementation group were significantly longer than those in the non-magnesium supplementation group. More importantly, the 14-day mortality (30.8% vs 48.9%, P < 0.01) and 28-day mortality (33.8% vs 48.9%, P = 0.03) in patients with magnesium supplementation were lower than patients without magnesium supplementation. Conclusions For sepsis patients in ICU, although hypomagnesemia had no significant correlation with 28-day mortality, it still prolonged the duration of mechanical ventilation and vasoactive drug use, and increased the length of ICU stay and hospital stay. Even for patients with normal serum magnesium levels, optimizing serum magnesium levels may improve the prognosis of patients with sepsis.