The relevance of magnesium homeostasis in COVID-19.

PURPOSE: In less than one and a half year, the COVID-19 pandemic has nearly brought to a collapse our health care and economic systems. The scientific research community has concentrated all possible efforts to understand the pathogenesis of this complex disease, and several groups have recently emphasized recommendations for nutritional support in COVID-19 patients. In this scoping review, we aim at encouraging a deeper appreciation of magnesium in clinical nutrition, in view of the vital role of magnesium and the numerous links between the pathophysiology of SARS-CoV-2 infection and magnesium-dependent functions. METHODS: By searching PubMed and Google Scholar from 1990 to date, we review existing evidence from experimental and clinical studies on the role of magnesium in chronic non-communicable diseases and infectious diseases, and we focus on recent reports of alterations of magnesium homeostasis in COVID-19 patients and their association with disease outcomes. Importantly, we conduct a census on ongoing clinical trials specifically dedicated to disclosing the role of magnesium in COVID-19. RESULTS: Despite many methodological limitations, existing data seem to corroborate an association between deranged magnesium homeostasis and COVID-19, and call for further and better studies to explore the prophylactic or therapeutic potential of magnesium supplementation. CONCLUSION: We propose to reconsider the relevance of magnesium, frequently overlooked in clinical practice. Therefore, magnesemia should be monitored and, in case of imbalanced magnesium homeostasis, an appropriate nutritional regimen or supplementation might contribute to protect against SARS-CoV-2 infection, reduce severity of COVID-19 symptoms and facilitate the recovery after the acute phase.

Effect of magnesium and vitamin B6 supplementation on mental health and quality of life in stressed healthy adults: Post-hoc analysis of a randomised controlled trial.

Magnesium status and vitamin B6 intake have been linked to mental health and/or quality of life (QoL). In an 8-week Phase IV randomised controlled study in individuals with low magnesemia and severe/extremely severe stress but who were otherwise healthy, greater stress reduction was achieved with magnesium combined with vitamin B6 than with magnesium alone. We present a previously unreported secondary analysis of the effect of magnesium, with and without vitamin B6, on depression, anxiety, and QoL. Adults with Depression Anxiety Stress Scales (DASS-42) stress subscale score >18 were randomised 1:1 to magnesium + vitamin B6 combination (Magne B6® ; daily dose 300 and 30 mg, respectively) or magnesium alone (Magnespasmyl® ; daily dose 300 mg). Outcomes included changes from baseline in DASS-42 depression and anxiety scores, and QoL (Short Form-36 Health Survey). DASS-42 anxiety and depression scores significantly improved from baseline to week 8 with both treatments, particularly during the first 4 weeks. Improvement in QoL continued over 8 weeks. Participants' perceived capacity for physical activity in daily life showed greater improvement with magnesium + vitamin B6 than magnesium alone (Week 4). In conclusion, magnesium supplementation, with or without vitamin B6, could provide a meaningful clinical benefit in daily life for individuals with stress and low magnesemia.

Magnesium Status and Stress: The Vicious Circle Concept Revisited.

Magnesium deficiency and stress are both common conditions among the general population, which, over time, can increase the risk of health consequences. Numerous studies, both in pre-clinical and clinical settings, have investigated the interaction of magnesium with key mediators of the physiological stress response, and demonstrated that magnesium plays an inhibitory key role in the regulation and neurotransmission of the normal stress response. Furthermore, low magnesium status has been reported in several studies assessing nutritional aspects in subjects suffering from psychological stress or associated symptoms. This overlap in the results suggests that stress could increase magnesium loss, causing a deficiency; and in turn, magnesium deficiency could enhance the body's susceptibility to stress, resulting in a magnesium and stress vicious circle. This review revisits the magnesium and stress vicious circle concept, first introduced in the early 1990s, in light of recent available data.

Impact of magnesium supplementation, in combination with vitamin B6, on stress and magnesium status: secondary data from a randomized controlled trial.

Primary findings from a recent study reported that magnesium supplementation significantly reduced stress in severely stressed subjects with low magnesemia, and additional vitamin B6 enhanced this effect. The mechanism by which combining magnesium and vitamin B6 leads to reduced stress in these subjects remains to be elucidated. This secondary analysis investigated the impact of magnesium and vitamin B6 supplementation and perceived stress on erythrocyte magnesium levels, as a marker of body magnesium status. This was a secondary analysis from an 8-week randomized controlled trial comparing oral magnesium (300 mg) and magnesium-vitamin B6 (300 mg + 30 mg) supplementation. Stress level and erythrocyte magnesium level at baseline, and change in erythrocyte magnesium and serum vitamin B6 levels at weeks 4 and 8, were analyzed. Overall, 264 subjects were randomized to treatment and had evaluable Depression Anxiety Stress Scale scores (132 in each treatment arm). At baseline, stress scores, and mean serum magnesium, erythrocyte magnesium, and serum vitamin B6 concentrations were similar between arms. Although not significant between groups, a significant increase over time in erythrocyte magnesium levels was observed in the subgroup of subjects with low baseline erythrocyte magnesium levels (<1.6 mmol/L) following treatment with magnesium and magnesium-vitamin B6 (week 4:0.21 mmol/L [95% confidence interval (CI), 0.10 to 0.31], p = 0.0003; and 0.13 mmol/L [95% CI, 0.02 to 0.23], p = 0.0233, respectively). Change from baseline in circulating vitamin B6 levels at weeks 4 and 8 in the magnesium-vitamin B6 supplemented group (314.96 nmol/L [95%CI, 294.61 to 335.31]) was significantly different (p < 0.0001) compared with the magnesium supplemented group (-0.39 nmol/L [95% CI, -20.73 to 19.94]). Magnesium alone and magnesium-vitamin B6 provided statistically significant increases in erythrocyte magnesium in subjects with low magnesium status (<1.6mmol/L). Vitamin B6 supplementation did not further increase magnesium levels.

Superiority of magnesium and vitamin B6 over magnesium alone on severe stress in healthy adults with low magnesemia: A randomized, single-blind clinical trial.

INTRODUCTION: Animal and clinical studies suggest complementary effects of magnesium and high-dose pyridoxine (vitamin B6) on stress reduction. This is the first randomized trial evaluating the effects of combined magnesium and vitamin B6 supplementation on stress in a stressed population with low magnesemia using a validated measure of perceived stress. METHODS: In this Phase IV, investigator-blinded trial (EudraCT: 2015-003749-24), healthy adults with Depression Anxiety Stress Scales (DASS-42) stress subscale score >18 and serum magnesium concentration 0.45 mmol/L-0.85 mmol/L, were randomized 1:1 to magnesium-vitamin B6 combination (Magne B6 [Mg-vitamin B6]; daily dose 300 mg and 30 mg, respectively) or magnesium alone (Magnespasmyl [Mg]; daily dose 300 mg). Outcomes included change in DASS-42 stress subscale score from baseline to Week 8 (primary endpoint) and Week 4, and incidence of adverse events (AEs). RESULTS: In the modified intention-to-treat analysis (N = 264 subjects), both treatment arms substantially reduced DASS-42 stress subscale score from baseline to Week 8 (Mg-vitamin B6, 44.9%; Mg 42.4%); no statistical difference between arms was observed (p>0.05). An interaction (p = 0.0097) between baseline stress level and treatment warranted subgroup analysis (as per statistical plan); adults with severe/extremely severe stress (DASS-42 stress subscale score ≥25; N = 162) had a 24% greater improvement with Mg-vitamin B6 versus Mg at Week 8 (3.16 points, 95% CI 0.50 to 5.82, p = 0.0203). Consistent results were observed in the per protocol analysis and at Week 4. Overall, 12.1% of Mg-vitamin B6 treated and 17.4% of Mg-treated subjects experienced AEs potentially treatment related. CONCLUSIONS: These findings suggest oral Mg supplementation alleviated stress in healthy adults with low magnesemia and the addition of vitamin B6 to Mg was not superior to Mg supplementation alone. With regard to subjects with severe/extremely severe stress, this study provides clinical support for greater benefit of Mg combined with vitamin B6.

Major phenolic compounds in olive oil modulate bone loss in an ovariectomy/inflammation experimental model.

This study was conducted to determine whether the daily consumption for 84 days of tyrosol and hydroxytyrosol, the main olive oil phenolic compounds, and olive oil mill wastewater (OMWW), a byproduct of olive oil production, rich in micronutrients, may improve bone loss in ovariectomized rats (an experimental model of postmenopausal osteoporosis) and in ovariectomized rats with granulomatosis inflammation (a model set up for senile osteoporosis). As expected, an induced chronic inflammation provoked further bone loss at total, metaphyseal, and diaphyseal sites in ovariectomized rats. Tyrosol and hydroxytyrosol prevented this osteopenia by increasing bone formation ( p < 0.05), probably because of their antioxidant properties. The two doses of OMWW extracts had the same protective effect on bone ( p < 0.05), whereas OMWW did not reverse established osteopenia. In conclusion, polyphenol consumption seems to be an interesting way to prevent bone loss.

Renal anemia induced by chronic ingestion of depleted uranium in rats.

Kidney disease is a frequent consequence of heavy metal exposure and renal anemia occurs secondarily to the progression of kidney deterioration into chronic disease. In contrast, little is known about effects on kidney of chronic exposure to low levels of depleted uranium (DU). Study was performed with rats exposed to DU at 40 mg/l by chronic ingestion during 9 months. In the present work, a approximately 20% reduction in red blood cell (RBC) count was observed after DU exposure. Hence, three hypotheses were tested to determinate origin of RBC loss: (1) reduced erythropoiesis, (2) increased RBC degradation, and/or (3) kidney dysfunction. Erythropoiesis was not reduced after exposure to DU as revealed by erythroid progenitors, blood Flt3 ligand and erythropoietin (EPO) blood and kidney levels. Concerning messenger RNA (mRNA) and protein levels of spleen iron recycling markers from RBC degradation (DMT1 [divalent metal transporter 1], iron regulated protein 1, HO1, HO2 [heme oxygenase 1 and 2], cluster of differentiation 36), increase in HO2 and DMT1 mRNA level was induced after chronic exposure to DU. Kidneys of DU-contaminated rats had more frequently high grade tubulo-interstitial and glomerular lesions, accumulated iron more frequently and presented more apoptotic cells. In addition, chronic exposure to DU induced increased gene expression of ceruloplasmin (x12), of DMT1 (x2.5), and decreased mRNA levels of erythropoietin receptor (x0.2). Increased mRNA level of DMT1 was associated to decreased protein level (x0.25). To conclude, a chronic ingestion of DU leads mainly to kidney deterioration that is probably responsible for RBC count decrease in rats. Spleen erythropoiesis and molecules involved in erythrocyte degradation were also modified by chronic DU exposure.

Caffeic acid inhibits oxidative Stress and reduces hypercholesterolemia induced by iron overload in rats.

The effects of caffeic acid, a major phenolic compound of the diet, on oxidative stress and cholesterolemia are studied in rats submitted to oxidative stress by iron overload. Male Wistar rats were fed semi-synthetic diets containing regular (50 mg/kg diet) or high (2000 mg/kg) doses of iron with and without caffeic acid (6460 mg/kg) for 4 weeks. The high doses of iron induced an increase of lipid oxidation in the liver, as measured by thiobarbituric acid-reactive substances (TBARS), and an increase of cholesterolemia. Caffeic acid fully prevented the pro-oxidant effects of high iron doses (p < 0.001). It also reduced lipid peroxidation in rats fed the low iron dose (p < 0.05). Caffeic acid also increased vitamin E levels in plasma (2.74 micromol/L to 4.09 micromol/L for normal diet; p < 0.001; 2.78 micromol/L to 4.94 micromol/L for iron supplemented diet p < 0.001). Iron-induced hypercholesterolemia was inhibited by caffeic acid (1.07 g/L to 0.82 g/L; p < 0.001). These results demonstrate the antioxidative capacity of caffeic acid, a highly bioavailable polyphenol, in an in vivo model of oxidative stress.

Effects of sulphate- and bicarbonate-rich mineral waters on net and fractional intestinal absorption and urinary excretion of magnesium in rats.

Magnesium (Mg) intake is below the recommended daily allowances in many developed countries. Mg-rich mineral waters can provide significant amounts of energy-free Mg and thus help to meet Mg requirements. We assessed the effects of different Mg-rich mineral waters on overall intestinal Mg absorption and urinary Mg excretion in 40 rats split into four groups: one received distilled water, another a solution of MgCl(2) and the others two different mineral waters, sulphated water (Hépar) and carbonated water (Badoit) mixed with the diet and as drinking water, for four weeks. The rats were given 3 mg of (26)Mg orally and 0.5 mg of (25)Mg intravenously. They were placed in metabolic cages, and diet consumption, and faeces and urine excretion were monitored during the last four days of the experiment. The rats were then sacrificed and blood was sampled. Mg levels in the diet, faeces, urine and biological samples were measured by atomic absorption spectrometry. Mg stable isotope measurements were performed by ICP/MS. Mg-rich mineral waters significantly increased net intestinal absorption of Mg by more than 30%, but the proportions of both apparent and true intestinal absorption of Mg were similar in all four groups. Thus, net and fractional retention of Mg were similar in the three Mg-supplemented groups. In conclusion, both types of Mg-rich mineral waters studied similarly increased both absorption and urinary excretion of Mg with no positive effect on the overall retention of Mg, probably because the Mg status of the rats was already satisfactory.

Lyophilized apple counteracts the development of hypercholesterolemia, oxidative stress, and renal dysfunction in obese Zucker rats.

Apples may have selective effects on abnormalities associated with the plurimetabolic syndrome. Therefore, the effects of 20% lyophilized apple supplementation on plasma and tissue lipids and on protection against susceptibility to oxidative stress and renal dysfunction were investigated in Zucker lean (Fa/-) or obese (fa/fa) rats. The experimental diets were equilibrated for sugar supply, contained 0.25 g/100 g cholesterol and provided only one third of the vitamin E requirement. Obese Zucker rats were hypercholesterolemic with cholesterol accumulation in LDL and HDL fractions. The apple diet lowered plasma and LDL cholesterol (-22 and -70%, respectively, P < 0.01) in obese Zucker rats and, in parallel, reduced triglyceride accumulation in heart and liver. Zucker rats fed the apple diet also had a larger intestinal pool and greater fecal excretion of bile acids. The heart concentration and urinary excretion of malondialdehyde were reduced by apple consumption in obese Zucker rats, suggesting better protection against peroxidation. Glucosuria and proteinuria in obese Zucker rats were also suppressed by the apple diet. In conclusion, despite their moderate fiber content, apples improve substantially the lipid status and peroxidative parameters in obese Zucker rats, suggesting that other plant constituents such as polyphenols are involved in these effects.