Importance of Magnesium Status in COVID-19.

A large amount of published research points to the interesting concept (hypothesis) that magnesium (Mg) status may have relevance for the outcome of COVID-19 and that Mg could be protective during the COVID disease course. As an essential element, Mg plays basic biochemical, cellular, and physiological roles required for cardiovascular, immunological, respiratory, and neurological functions. Both low serum and dietary Mg have been associated with the severity of COVID-19 outcomes, including mortality; both are also associated with COVID-19 risk factors such as older age, obesity, type 2 diabetes, kidney disease, cardiovascular disease, hypertension, and asthma. In addition, populations with high rates of COVID-19 mortality and hospitalization tend to consume diets high in modern processed foods, which are generally low in Mg. In this review, we review the research to describe and consider the possible impact of Mg and Mg status on COVID-19 showing that (1) serum Mg between 2.19 and 2.26 mg/dL and dietary Mg intakes > 329 mg/day could be protective during the disease course and (2) inhaled Mg may improve oxygenation of hypoxic COVID-19 patients. In spite of such promise, oral Mg for COVID-19 has thus far been studied only in combination with other nutrients. Mg deficiency is involved in the occurrence and aggravation of neuropsychiatric complications of COVID-19, including memory loss, cognition, loss of taste and smell, ataxia, confusion, dizziness, and headache. Potential of zinc and/or Mg as useful for increasing drug therapy effectiveness or reducing adverse effect of anti-COVID-19 drugs is reviewed. Oral Mg trials of patients with COVID-19 are warranted.

Beneficial effects of an alkaline topical treatment in patients with mild atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is the most common cause of eczema. The skin condition affects millions of people worldwide. Severe cases of AD demand systemic treatment, but most AD cases rely on local therapy with topical corticosteroids, emollients, and moisturizing agents to alleviate eczema. Commonly, derma-cosmetics with a pH around 5.5 are used to treat eczematous lesions (EL). However, evidence is currently amassing that the use of mildly alkaline topical creams is beneficial for AD-related eczema treatment because of its effect on the inflammation in the skin. AIMS: To test an alkaline two-phase care concept for the treatment of eczema. PATIENTS/METHODS: An open-label study of 25 patients with eczema associated with mild AD. Patients were treated with Alkaline Build Up Caring Cream INTENSIVE and Alkaline Build Up Caring Cream PLUS+ (both Siriderma® ) for eight weeks. Dermatological, biochemical, and questionnaire-based examinations were conducted prior to the trial and after its completion. RESULTS: Topical administration of slightly alkaline creams led to small and statistically insignificant increases of skin pH. Clinical examination at the end of the observation period revealed a significant decrease of total eczematous-affected skin area, a significant decrease in average severity scores of EL, and significant improvements in patient-reported outcome parameters. Blood tests did not reveal any significant changes, except for small but significant increases in IL-8 and monocytes. CONCLUSION: Mildly alkaline topical creams seem to provide soothing effects on eczema-related skin inflammation and thus might contribute to treatment of local symptoms of eczema in patients with mild AD.

Effects of dietary protein-load and alkaline supplementation on acid-base balance and glucose metabolism in healthy elderly.

BACKGROUND/OBJECTIVES: Metabolism is controlled by macro- and micronutrients. Protein-rich diets should lead to latent acidosis at tissue level with further negative implications. Food supplements with alkaline salts are available and popular pretending to prevent these changes. SUBJECTS/METHODS: Within a randomised double-blind placebo-controlled trial we tested the hypotheses that (1) a 4-week protein-rich diet induces a latent tissue acidosis and (2) an alkaline supplement can compensate this. Acid-base balance and important metabolic parameters were determined before and after 4 weeks of supplementation by peripheral blood samples, indirect calorimetry and muscle microdialysis before and after a protein-rich test meal. RESULTS: Fourty volunteers were randomised 1:1 to either verum or placebo supplements. Protein-rich diet by itself did not significantly affect acid-base balance. Alkaline supplementation increased plasma bicarbonate concentration without changing pH. Postprandial increases in serum glucose and insulin tended to be lower for verum vs. placebo. Resting and postprandial energy metabolism, and carbohydrate and fat oxidation did not differ significantly before and after supplementation in both groups. In muscle, postprandial glucose uptake and aerobic glucose oxidation were significantly higher for verum. In addition, verum significantly increased serum magnesium concentrations. CONCLUSIONS: Four weeks of protein-rich diet did not significantly influence acid-base balance. However, alkaline supplementation improved systemic and tissue acid-base parameters and oxidative glucose metabolism.

PARK7/DJ-1 dysregulation by oxidative stress leads to magnesium deficiency: implications in degenerative and chronic diseases.

Disturbed magnesium (Mg(2+)) homoeostasis and increased levels of OS (oxidative stress) are associated with poor clinical outcomes in patients suffering from neurodegenerative, cardiovascular and metabolic diseases. Data from clinical and animal studies suggest that MD (Mg(2+) deficiency) is correlated with increased production of ROS (reactive oxygen species) in cells, but a straightforward causal relationship (including molecular mechanisms) between the two conditions is lacking. The multifactorial protein PARK7/DJ-1 is a major antioxidant protein, playing a key role in cellular redox homoeostasis, and is a positive regulator of AR (androgen receptor)-dependent transcription. SLC41A1 (solute carrier family 41 member 1), the gene encoding a ubiquitous cellular Mg(2+)E (Mg(2+)efflux) system, has been shown to be regulated by activated AR. We hypothesize that overexpression/up-regulation of PARK7/DJ-1, attributable to OS and related activation of AR, is an important event regulating the expression of SLC41A1 and consequently, modulating the Mg(2+)E capacity. This would involve changes in the transcriptional activity of PARK7/DJ-1, AR and SLC41A1, which may serve as biomarkers of intracellular MD and may have clinical relevance. Imipramine, in use as an antidepressant, has been shown to reduce the Mg(2+)E activity of SLC41A1 and OS. We therefore hypothesize further that administration of imipramine or related drugs will be beneficial in MD- and OS-associated diseases, especially when combined with Mg(2+) supplementation. If proved true, the OS-responsive functional axis, PARK7/DJ-1-AR-SLC41A1, may be a putative mechanism underlying intracellular MD secondary to OS caused by pro-oxidative stimuli, including extracellular MD. Furthermore, it will advance our understanding of the link between OS and MD.

Substitution p.A350V in Na⁺/Mg²âº exchanger SLC41A1, potentially associated with Parkinson's disease, is a gain-of-function mutation.

Parkinson's disease (PD) is a complex multifactorial ailment predetermined by the interplay of various environmental and genetic factors. Systemic and intracellular magnesium (Mg) deficiency has long been suspected to contribute to the development and progress of PD and other neurodegenerative diseases. However, the molecular background is unknown. Interestingly, gene SLC41A1 located in the novel PD locus PARK16 has recently been identified as being a Na⁺/Mg²âº exchanger (NME, Mg²âº efflux system), a key component of cellular magnesium homeostasis. Here, we demonstrate that the substitution p.A350V potentially associated with PD is a gain-of-function mutation that enhances a core function of SLC41A1, namely Na⁺-dependent Mg²âº efflux by 69±10% under our experimental conditions (10-minute incubation in high-Na⁺ (145 mM) and completely Mg²âº-free medium). The increased efflux capacity is accompanied by an insensitivity of mutant NME to cAMP stimulation suggesting disturbed hormonal regulation and leads to a reduced proliferation rate in p.A350V compared with wt cells. We hypothesize that enhanced Mg²âº-efflux conducted by SLC41A1 variant p.A350V might result, in the long-term, in chronic intracellular Mg²âº-deficiency, a condition that is found in various brain regions of PD patients and that exacerbates processes triggering neuronal damage.

Nature of SLC41A1 complexes: report on the split-ubiquitin yeast two hybrid assay.

The Na(+)/Mg(2+) exchanger SLC41A1 is involved in the pathophysiology of various disease conditions. It forms high-molecular-mass, possibly hetero-oligomeric protein complexes in transgenic HEK293 cells. Therefore, we attempted to identify binding partners of SLC41A1 by utilizing the split-ubiquitin modification of the yeast two-hybrid assay. As the most prominent binding partners in our experimental system, we identified 3-beta-hydroxysteroid-Δ(8),Δ(7)-isomerase and B-cell receptor associated-protein 31. Other polytons (interactors appearing in the screen more than once) included: IER3IP1, PPIB, UPF0480 protein C15orf24, SPINT2, C14orf1/PEBP28, NIFIE14, YIPF6, and KCP2. In total, 20 polytons and 38 singletons (interactors appearing in the screen only once) were identified. The polytons identified were mostly endoplasmic reticulum-located, integral proteins involved in protein maturation, N-glycosylation, protein folding, anterograde transport of proteins, protein secretion, and the regulation of apoptosis. Among the singletons, we identified SLC31A2, SLC35B1, SLC39A13, CRACM1, and MTCH2 as putative binding partners of SLC41A1. Interestingly, we did not identify interactions among SLC41A1 molecules. Most of the identified interactors are integral proteins localized in cellular compartments other than the cytoplasmic membrane, whereas SLC41A1 is targeted to the cytoplasmic membrane where it performs its core function. None of the interactors was confirmed by mass spectrometry. Instead, we identified among the proteins co-purified with strep-tagged SLC41A1: ACCA1, UBB, ATX2L, HSP7C and TBB. We therefore conclude that: (1) identified interactors form transient rather than stable complexes with SLC41A1, (2) the molecular interactors identified primarily among the polytons might contribute to the production, proper folding, and maturation of SLC41A1 in the endoplasmic reticulum and Golgi apparatus, (3) most of the interactors identified among singletons might undergo similar maturation steps (post-translational modification), anterograde transport, and protein sorting as SLC41A1.

Dietary, metabolic, physiologic, and disease-related aspects of acid-base balance: foreword to the contributions of the second International Acid-Base Symposium.

The role of nutrition in human acid-base homeostasis has gained increasing attention in recent years. Although in healthy humans, homeostatic mechanisms and the kidneys' capacity to excrete acid equivalents can prevent strong diet-induced alterations in blood pH, even moderate increases in blood hydrogen ion levels as a result of unfavorable diet composition can have long-term consequences for the occurrence and progression of a number of diseases. The Second International Acid-Base Symposium, Nutrition-Health-Disease, provided deeper insight and updates in the scientific basis of the relation among diet, acid-base homeostasis, physiology, and pathophysiological consequences.