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.

Magnesium Metabolism in Chronic Alcohol-Use Disorder: Meta-Analysis and Systematic Review

Chronic alcohol-use disorder has been imputed as a possible cause of dietary magnesium depletion. The purpose of this study was to assess the prevalence of hypomagnesemia in chronic alcohol-use disorder, and to provide information on intracellular magnesium and on its renal handling. We carried out a structured literature search up to November 2020, which returned 2719 potentially relevant records. After excluding non-significant records, 25 were retained for the final analysis. The meta-analysis disclosed that both total and ionized circulating magnesium are markedly reduced in chronic alcohol-use disorder. The funnel plot and the Egger’s test did not disclose significant publication bias. The I2-test demonstrated significant statistical heterogeneity between studies. We also found that the skeletal muscle magnesium content is reduced and the kidney’s normal response to hypomagnesemia is blunted. In conclusion, magnesium depletion is common in chronic alcohol-use disorder. Furthermore, the kidney plays a crucial role in the development of magnesium depletion.

A Comparison of Doxorubicin-Resistant Colon Cancer LoVo and Leukemia HL60 Cells: Common Features, Different Underlying Mechanisms

Chemoresistance causes cancer relapse and metastasis, thus remaining the major obstacle to cancer therapy. While some light has been shed on the underlying mechanisms, it is clear that chemoresistance is a multifaceted problem strictly interconnected with the high heterogeneity of neoplastic cells. We utilized two different human cell lines, i.e., LoVo colon cancer and promyelocytic leukemia HL60 cells sensitive and resistant to doxorubicin (DXR), largely used as a chemotherapeutic and frequently leading to chemoresistance. LoVo and HL60 resistant cells accumulate less reactive oxygen species by differently modulating the levels of some pro- and antioxidant proteins. Moreover, the content of intracellular magnesium, known to contribute to protect cells from oxidative stress, is increased in DXR-resistant LoVo through the upregulation of MagT1 and in DXR-resistant HL60 because of the overexpression of TRPM7. In addition, while no major differences in mitochondrial mass are observed in resistant HL60 and LoVo cells, fragmented mitochondria due to increased fission and decreased fusion are detected only in resistant LoVo cells. We conclude that DXR-resistant cells evolve adaptive mechanisms to survive DXR cytotoxicity by activating different molecular pathways.

Differences in Erythrocyte Magnesium Levels between Men with Schizophrenia Treated with Risperidone and Haloperidol in Prof. Dr. M Ildrem Psychiatric Hospital Medan

BACKGROUND: Schizophrenia according to the world health organization is one of the top ten causes of disability in developed countries around the world. Because of the severity, chronicity, and prevalence of schizophrenia, it has a very large economic burden. Magnesium is a micronutrient needed by the body which can affect mental health. Erythrocyte magnesium levels are considered more sensitive than serum magnesium levels to reflect intracellular magnesium status. AIM: The objective of the study was to determine the differences in erythrocyte magnesium levels between men with schizophrenia who received risperidone and haloperidol treatment at Prof. Dr. M Ildrem Psychiatric Hospital, Medan. METHODS: This study is an intention to treat and is an experimental pre-test and post-test that compares two groups, namely the intervention group and the control group. The sampling method is non-probability sampling with a consecutive sampling type. The research was conducted at Prof. Dr. M. Ildrem Psychiatric Hospital Medan between July and October 2019. The subjects of the study were 60 men with schizophrenia, namely, 30 who received risperidone and 30 who received haloperidol. RESULTS: There was a difference in the levels of male erythrocyte magnesium with schizophrenia who received risperidone and haloperidol between the initial week and the third week with a value of p = 0.007. Where there was a higher increase in the haloperidol group which showed a significant difference, namely, p < 0.05. CONCLUSION: The increase in magnesium levels will improve the symptoms of schizophrenia where magnesium activity decreases glutamate release associated with N-Methyl D-Aspartate receptors and results in the activity of the gamma-aminobutyric acid-ergic system.

Assessment and Imaging of Intracellular Magnesium in SaOS-2 Osteosarcoma Cells and Its Role in Proliferation

Magnesium is an essential nutrient involved in many important processes in living organisms, including protein synthesis, cellular energy production and storage, cell growth and nucleic acid synthesis. In this study, we analysed the effect of magnesium deficiency on the proliferation of SaOS-2 osteosarcoma cells. When quiescent magnesium-starved cells were induced to proliferate by serum addition, the magnesium content was 2–3 times lower in cells maintained in a medium without magnesium compared with cells growing in the presence of the ion. Magnesium depletion inhibited cell cycle progression and caused the inhibition of cell proliferation, which was associated with mTOR hypophosphorylation at Serine 2448. In order to map the intracellular magnesium distribution, an analytical approach using synchrotron-based X-ray techniques was applied. When cell growth was stimulated, magnesium was mainly localized near the plasma membrane in cells maintained in a medium without magnesium. In non-proliferating cells growing in the presence of the ion, high concentration areas inside the cell were observed. These results support the role of magnesium in the control of cell proliferation, suggesting that mTOR may represent an important target for the antiproliferative effect of magnesium. Selective control of magnesium availability could be a useful strategy for inhibiting osteosarcoma cell growth.

Stress in children and adolescent is a burning issue of today

Introduction.Stress and stress-induced disorders are not uncommon in pediatric practice. The range of causal stressors (information environment, gadgets, pandemic, armed conflicts, etc.) has expanded significantly these days. The article depicts the main clinical manifestations of stress reactions, pathogenetic mechanisms of their development, provides rational approaches to the therapy of elimination of stress manifestations and consequences in children and adolescents from a pediatric perspective.Objective:To study the influence of stress on the psychoemotional sphere and cognitive functions in children aged 7 to 9 years from the armed conflict zone in the Donbass.Materials and methods. 234 children of primary school age were included in the study, of whom 123 children had lived at the armed conflict zone in Donbass for a year. The psychoemotional state and cognitive functions status were determined by children’s tests using a scoring method to assess test results.Results and discussion.The tests with a scoring method to assess test results showed that 100% of children from the armed conflict zone had a chronic stress, 63% had a moderate to severe stress, a high frequency of various types of phobias, as well as impaired concentration and memory.Therapeutic approaches to the management of stress reactions directly depend on the cause and clinical manifestations of such reactions. The therapy strategy includes among other things general strengthening actions, psychotherapy, symptomatic and pathogenetic methods of treatment. In addition, both acute and chronic stress leads to intracellular magnesium deficiency and increased urinary magnesium wasting, as a large amount of catecholamines is released under stress conditions, which contributes to shifting magnesium out of cells. The magnesium deficiency results in increased permeability of cell membranes for calcium ions, which creates conditions for electrical instability and excessive excitability of cells, most significantly of neurons. This is reflected in the fact that the process of excitation prevails over inhibitory reactions, and stress reactions develop as the clinical manifestations. It has been established that an adequate balance of magnesium increases the adaptive capabilities in people. Its neurotropic effects made it possible to consider magnesium as an effective pathogenetic agent that can increase stress resistance, stress management, and activate the body’s adaptive reserves.Conclusion. The causal stressors are manifold, the paediatrician has to deal with stress reactions in children much more often than doctors of other specialties. Magnesium supplements currently form the basis of treatment and rehabilitation actions in children with stress.

Extracellular and Intracellular Magnesium Deficiency Found in Pregnant Women with Preeclampsia and Gestational Diabetes Is Associated with Overexpression of Notch Proteins, Cytokines, p53, NF-kB and Proto-Oncogenes: Potential Importance in Growth Retardation, Stillbirths, Fetal Mutations and Increased Cardiovascular Risks and Stroke with Advancing Age in Pregnant Women

In 1983, three of us reported in “Science” that umbilical-placental arteries and veins, obtained from normal pregnant women at term delivery, when exposed in vitro to low concentrations of Mg2+ went into vasospasm; the lower the Mg2+, the greater the contractile force developed. These blood vessels also demonstrated amplified contractile force development when challenged with circulating amines and peptides (e.g., norepinephrine, 5-HT, angiotensin II, etc.). We suggested that severe Mg deficiency during pregnancy could in part be responsible for spontaneous abortions, loss of fetuses, stillbirths, and developmental alterations in infants. Using short-term dietary Mg deficient animals, we have noted a great many molecular and biochemical alterations in ventricular, atrial and somatic vascular smooth muscle alterations including DNA methylation and histone changes leading us to speculate that Mg deficiency may represent a genotoxin promoting mutations and causing epigenetic changes. Over the last 35 years, we have new data on severely preeclamptic and gestational diabetic pregnant women that gives credence to our original hypothesis and demonstrates that recently- discovered developmental proteins, originally found 100 years ago in Drosophila fruit flies termed the “Notch pathway”, due to effects on its wings, appears to be important in development of the umbilical-placental blood vessels in pregnant women. Along with the developmental molecule, p53, these Notch proteins clearly alter the behavior of the umbilical-placental vessels. We believe these new findings probably help to explain many of the genetic-toxicity effects seen in women later in life who develop strokes and cardiovascular diseases. Notch alterations could also play an important role in babies born with cardiac defects.

A circadian clock regulates efflux by the blood-brain barrier in mice and human cells

The blood-brain barrier (BBB) is critical for neural function. We report here circadian regulation of the BBB in mammals. Efflux of xenobiotics by the BBB oscillates in mice, with highest levels during the active phase and lowest during the resting phase. This oscillation is abrogated in circadian clock mutants. To elucidate mechanisms of circadian regulation, we profiled the transcriptome of brain endothelial cells; interestingly, we detected limited circadian regulation of transcription, with no evident oscillations in efflux transporters. We recapitulated the cycling of xenobiotic efflux using a human microvascular endothelial cell line to find that the molecular clock drives cycling of intracellular magnesium through transcriptional regulation of TRPM7, which appears to contribute to the rhythm in efflux. Our findings suggest that considering circadian regulation may be important when therapeutically targeting efflux transporter substrates to the CNS.

Deranged Fractional Excretion of Magnesium and Serum Magnesium Levels in Relation to Retrograde Glycaemic Regulation in Patients with Type 2 Diabetes Mellitus

Background: Type 2 diabetes (T2DM) has been associated with deficiencies in serum magnesium level, decreasing insulin sensitivity and glucose metabolism. Glycosylated hemoglobin (Hb1Ac) is a biomarker of glucose values within the half-life of the erythrocyte, that is, 3 months. Low circulating and intracellular magnesium levels can modify glucose metabolism and insulin sensitivity. Renal solute management is a parameter little used to estimate circulating and excreted concentrations of elements such as magnesium. Objective: The purpose of this study was to assess and associated fractional excretion of magnesium (FEMg) and serum magnesium with metabolic parameters, especially Hb1Ac percent, in a group of well characterized subjects with T2DM and non-diabetics subjects (ND). Methods: According to Hb1Ac, two groups were compared and associated with existing biochemical parameters, included Hb1Ac, fasting glucose, lipid profile, serum creatinine, serum magnesium and urinary creatinine for FEMg. Results: HbA1c levels were explained by serum magnesium in 25%. Serum magnesium levels in the ND group were higher than in the T2DM group and this was a statistically significant difference. Serum magnesium ≤1.8 is a risk factor (OD 16.1; P=0.021) for an HbA1c ≥ 6.5%. Conclusion: In this study, hypomagnesemia was a parameter strongly associated with the diagnosis and progression of T2DM, while FEMg showed no significant association.

Intra-erythrocytes magnesium deficiency could reflect cognitive impairment status due to vascular disease: a pilot study

Background and aims Magnesium is a fundamental cation that regulates neuronal transmission, protein synthesis, energy metabolism. Magnesium deficiency mostly affects nervous and cardiovascular systems determining weakness, tremors, seizure and arrhythmias. This condition retains also a role in memory function and neuronal plasticity. Importantly magnesium deficiency could remain latent and asymptomatic resulting a risk factor for cardiovascular disease. In this sense we aim to determine magnesium status in patient presenting cognitive impairment of vascular origin. Methods 21 healthy subjects and 27 patients presenting vascular cognitive impairment were included in this study. Both plasma and intraerythrocitary magnesium level were measured to detect magnesium deficiency and cognitive performance was evaluated trough Mini Mental State Evaluation (MMSE). Results Here we showed that patients presenting vascular cognitive impairment present intraerythrocitary magnesium level lower than age-matched healthy subjects. To note their plasma magnesium resulted within reference limit. Conclusion We suggest that intracellular magnesium laboratory measurement is needed to detect occult magnesium deficiency in population at risk. Magnesium supplementation could represent an adjuvant for healthy aging in high risk population.