The Plasma Oxylipin Signature Provides a Deep Phenotyping of Metabolic Syndrome Complementary to the Clinical Criteria.

Metabolic syndrome (MetS) is a complex condition encompassing a constellation of cardiometabolic abnormalities. Oxylipins are a superfamily of lipid mediators regulating many cardiometabolic functions. Plasma oxylipin signature could provide a new clinical tool to enhance the phenotyping of MetS pathophysiology. A high-throughput validated mass spectrometry method, allowing for the quantitative profiling of over 130 oxylipins, was applied to identify and validate the oxylipin signature of MetS in two independent nested case/control studies involving 476 participants. We identified an oxylipin signature of MetS (coined OxyScore), including 23 oxylipins and having high performances in classification and replicability (cross-validated AUCROC of 89%, 95% CI: 85-93% and 78%, 95% CI: 72-85% in the Discovery and Replication studies, respectively). Correlation analysis and comparison with a classification model incorporating the MetS criteria showed that the oxylipin signature brings consistent and complementary information to the clinical criteria. Being linked with the regulation of various biological processes, the candidate oxylipins provide an integrative phenotyping of MetS regarding the activation and/or negative feedback regulation of crucial molecular pathways. This may help identify patients at higher risk of cardiometabolic diseases. The oxylipin signature of patients with metabolic syndrome enhances MetS phenotyping and may ultimately help to better stratify the risk of cardiometabolic diseases.

Magnesium Homeostasis in Myogenic Differentiation-A Focus on the Regulation of TRPM7, MagT1 and SLC41A1 Transporters.

Magnesium (Mg) is essential for skeletal muscle health, but little is known about the modulation of Mg and its transporters in myogenic differentiation. Here, we show in C2C12 murine myoblasts that Mg concentration fluctuates during their differentiation to myotubes, declining early in the process and reverting to basal levels once the cells are differentiated. The level of the Mg transporter MagT1 decreases at early time points and is restored at the end of the process, suggesting a possible role in the regulation of intracellular Mg concentration. In contrast, TRPM7 is rapidly downregulated and remains undetectable in myotubes. The reduced amounts of TRPM7 and MagT1 are due to autophagy, one of the proteolytic systems activated during myogenesis and essential for the membrane fusion process. Moreover, we investigated the levels of SLC41A1, which increase once cells are differentiated, mainly through transcriptional regulation. In conclusion, myogenesis is associated with alterations of Mg homeostasis finely tuned through the modulation of MagT1, TRPM7 and SLC41A1.

Magnesium and the Brain: A Focus on Neuroinflammation and Neurodegeneration.

Magnesium (Mg) is involved in the regulation of metabolism and in the maintenance of the homeostasis of all the tissues, including the brain, where it harmonizes nerve signal transmission and preserves the integrity of the blood-brain barrier. Mg deficiency contributes to systemic low-grade inflammation, the common denominator of most diseases. In particular, neuroinflammation is the hallmark of neurodegenerative disorders. Starting from a rapid overview on the role of magnesium in the brain, this narrative review provides evidences linking the derangement of magnesium balance with multiple sclerosis, Alzheimer's, and Parkinson's diseases.

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.

Magnesium Deficiency Alters Expression of Genes Critical for Muscle Magnesium Homeostasis and Physiology in Mice.

Chronic Mg2+ deficiency is the underlying cause of a broad range of health dysfunctions. As 25% of body Mg2+ is located in the skeletal muscle, Mg2+ transport and homeostasis systems (MgTHs) in the muscle are critical for whole-body Mg2+ homeostasis. In the present study, we assessed whether Mg2+ deficiency alters muscle fiber characteristics and major pathways regulating muscle physiology. C57BL/6J mice received either a control, mildly, or severely Mg2+-deficient diet (0.1%; 0.01%; and 0.003% Mg2+ wt/wt, respectively) for 14 days. Mg2+ deficiency slightly decreased body weight gain and muscle Mg2+ concentrations but was not associated with detectable variations in gastrocnemius muscle weight, fiber morphometry, and capillarization. Nonetheless, muscles exhibited decreased expression of several MgTHs (MagT1, CNNM2, CNNM4, and TRPM6). Moreover, TaqMan low-density array (TLDA) analyses further revealed that, before the emergence of major muscle dysfunctions, even a mild Mg2+ deficiency was sufficient to alter the expression of genes critical for muscle physiology, including energy metabolism, muscle regeneration, proteostasis, mitochondrial dynamics, and excitation-contraction coupling.

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 Influences Membrane Fusion during Myogenesis by Modulating Oxidative Stress in C2C12 Myoblasts.

Magnesium (Mg) is essential to skeletal muscle where it plays a key role in myofiber relaxation. Although the importance of Mg in the mature skeletal muscle is well established, little is known about the role of Mg in myogenesis. We studied the effects of low and high extracellular Mg in C2C12 myogenic differentiation. Non-physiological Mg concentrations induce oxidative stress in myoblasts. The increase of reactive oxygen species, which occurs during the early phase of the differentiation process, inhibits myoblast membrane fusion, thus impairing myogenesis. Therefore, correct Mg homeostasis, also maintained through a correct dietary intake, is essential to assure the regenerative capacity of skeletal muscle fibers.

Magnesium and inflammation: Advances and perspectives.

Magnesium is an essential element of life, involved in the regulation of metabolism and homeostasis of all the tissues. It also regulates immunological functions, acting on the cells of innate and adaptive immune systems. Magnesium deficiency primes phagocytes, enhances granulocyte oxidative burst, activates endothelial cells and increases the levels of cytokines, thus promoting inflammation. Consequently, a low magnesium status, which is often underdiagnosed, potentiates the reactivity to various immune challenges and is implicated in the pathophysiology of many common chronic diseases. Here we summarize recent advances supporting the link between magnesium deficiency, inflammatory responses and diseases, and offer new hints towards a better understanding of the underlying mechanisms.

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.

The COVID-19 pandemic: is there a role for magnesium? Hypotheses and perspectives.

More and more studies are accumulating about COVID-19. Some aspects of the pathogenesis of the disease recall events occurring in Mg deficiency, such as a drop of T cells, increased plasma concentration of inflammatory cytokines, and endothelial dysfunction. We hypothesize that a low Mg status, which is rather common, might foment the transition from mild to critical clinical manifestations of the disease. Epidemiological, clinical, and fundamental research is needed to clarify the potential role of Mg deficiency in COVID-19.

Dysmagnesemia in Covid-19 cohort patients: prevalence and associated factors.

Hypomagnesemia and hypermagnesemia could have serious implications and possibly lead to progress from a mild form to a severe outcome of Covid-19. Susceptibility of subjects with low magnesium status to develop and enhance this infection is possible. There is little data on the magnesium status of patients with Covid-19 with different degrees of severity. This study was conducted to evaluate prevalence of dysmagnesemia in a prospective Covid-19 cohort study according to the severity of the clinical manifestations and to identify factors associated. Serum magnesium was measured in 300 of 549 patients admitted to the hospital due to severe Covid-19. According to the WHO guidelines, patients were classified as moderate, severe, or critical. 48% patients had a magnesemia below 0.75 mmol/L (defined as magnesium deficiency) including 13% with a marked hypomagnesemia (<0.65 mmol/L). 9.6% had values equal to or higher than 0.95 mmol/L. Serum magnesium concentrations were significantly lower in female than in male (0.73 ± 0.12 vs 0.80 ± 0.13 mmol/L), whereas the sex ratio M/F was higher in severe and critical form (p<0.001). In a bivariate analysis, the risk of magnesium deficiency was significantly and negatively associated with infection severity (p<0.001), sex ratio (M/F, p<0.001), oxygenotherapy (p<0.001), stay in critical care unit (p=0.028), and positively with nephropathy (p=0.026). Logistic regression analysis revealed that the strongest predictors of magnesium deficiency were female sex (OR=2.67, p<0.001) and nephropathy (OR=2.12, p=0.032) and after exclusion of sex ratio, the severity of infection (OR=0.46, p=0.04 and OR=0.39 p=0.01), for critical and moderate forms, respectively. This transversal study reveals a high prevalence of hypomagnesemia in hospitalized patients for Covid-19, while high-level serum magnesium concentration was more prevalent in critical form.

Association between consumption of fruit or processed fruit and chronic diseases and their risk factors: a systematic review of meta-analyses.

CONTEXT: The degree of fruit processing is rarely considered in epidemiological studies of fruit consumption. OBJECTIVE: Pooled analyses and meta-analyses of cohort studies and randomized controlled trials that linked fruit consumption with the risk of chronic disease and metabolic deregulation were reviewed systematically to examine the effects of fruit processing. DATA SOURCES: The Web of Science and Cochrane Library databases were searched until June 2018. Search terms, querying the article title only, were based on multiple combinations and included the following: type of publication, fruit products, and chronic diseases and their risk factors. STUDY SELECTION: The selection of studies and the systematic review were carried out in accordance with the PRISMA statement. DATA EXTRACTION: The literature search identified 189 pooled analyses and meta-analyses, 10 of which met the inclusion criteria. RESULTS: The results showed that the degree of processing influences the health effects of fruit-based products. Fresh and dried fruits appeared to have a neutral or protective effect on health, 100% fruit juices had intermediary effects, and high consumption of canned fruit and sweetened fruit juice was positively associated with the risk of all-cause mortality and type 2 diabetes, respectively. CONCLUSIONS: The results support the need to consider the degree of food processing in future epidemiological studies and randomized controlled trials in order to adjust official recommendations for fruit consumption.

Muscle Loss Associated Changes of Oxylipin Signatures During Biological Aging: An Exploratory Study From the PROOF Cohort.

Characterizations of the multiple mechanisms determining biological aging are required to better understand the etiology and identify early biomarkers of sarcopenia. Oxylipins refer to a large family of signaling lipids involved in the regulation of various biological processes that become dysregulated during aging. To investigate whether comprehensive oxylipin profiling could provide an integrated and fine characterization of the early phases of sarcopenia, we performed a quantitative targeted metabolomics of oxylipins in plasma of 81-year-old subjects from the PROOF cohort with decreased (n = 12), stable (n = 16), or increased appendicular muscle mass (n = 14). Multivariate and univariate analyses identified significant and concordant changes of oxylipin profiles according to the muscle status. Of note, 90% of the most discriminant oxylipins were derived from EPA and DHA and were increased in the sarcopenic subjects. The oxylipins signatures of sarcopenic subjects revealed subtle activation of inflammatory resolution pathways, coagulation processes, and oxidative stress as well as the inhibition of angiogenesis. Heat maps highlighted relationships between oxylipins and the cardiometabolic health parameters which were mainly lost in sarcopenic subjects. This exploratory study supports that targeted metabolomics of oxylipins could provide relevant and subtle characterization of early disturbances associated with muscle loss during aging.

Magnesium transport and homeostasis-related gene expression in skeletal muscle of young and old adults: analysis of the transcriptomic data from the PROOF cohort Study.

Magnesium (Mg2+) is critical for a number of biological processes and 25% body Mg2+ is located in the skeletal muscle. Mg2+ transport and homeostasis systems (MgTHs) regulate intracellular Mg2+ concentration and muscle MgTHs are thus related to whole body Mg2+ homeostasis. Nonetheless, few studies have investigated the regulation of muscle MgTHs under (patho)physiological conditions. Herein, we assessed the relationship between the expression of MgTHs genes (Trpm6, Trpm7, Magt1, Mrs2, Cnnm1-4, Slc41a1-3) and relevant pathways in human sarcopenia, which is one of the most dramatic physiologic changes affecting the human body. Transcriptomic data were compared between young adult (YO, 22 y, n = 11) and old (EL, 73 y, n = 13) men from the PROOF cohort. MgTH mRNA levels did not change with aging, with the exception of a slight decrease for Slc41a3. Nevertheless, interindividual variations of mRNA levels revealed strong correlations between MgTHs in the YO group, while few were maintained in the EL muscle. Moreover, in the YO muscle, different clusters of MgTH mRNAs strongly correlated with divers physiological (BMI, blood pressure) and muscle characteristics (intramyocellular droplets, capillarization); however, most correlations changed or disappeared in the EL muscle. Further investigations of the whole transcriptome identified several sets of mRNAs correlated with defined MgTHs. There again was a sharp difference between YO and EL muscles, as the number of mRNAs correlated with MgTHs strongly decreased with aging. Gene ontology analyses of these sets of correlated mRNAs revealed 6 biological processes common to YO and EL, 3 specific to the YO (RNA processing, translation, respiration), and 2 (regulation of catabolic process, Wnt signaling) to the EL muscle. Overall, these observations lead to questions about potential resilience to muscle Mg2+ homeostasis in the elderly.

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.

French infant total diet study: Exposure to selected trace elements and associated health risks.

A total diet study (TDS) was conducted between 2010 and 2016 to assess the risk associated with chemicals in food of non-breast-fed children under three living in France. 291 composite food samples were prepared "as consumed" and analyzed for 16 trace elements: aluminium (Al), antimony (Sb), arsenic (As), barium (Ba), cobalt (Co), chromium (Cr), gallium (Ga), germanium (Ge), lead (Pb), mercury (Hg), nickel (Ni), silver (Ag), strontium (Sr), tellurium (Te), tin (Sn), vanadium (V). Dietary exposure was assessed for 705 representative children using food consumptions recorded through a 3-consecutive-days record. For inorganic mercury, chromium III, and antimony, the exposure levels were lower than the health-based guidance values and the risk was considered tolerable. Conversely, the exposure levels to inorganic arsenic, lead and nickel were higher than the health-based guidance values for a part of children and were considered as a concern, requiring management measures to reduce the exposure. For aluminium, methylmercury, strontium, chromium VI, cobalt, and barium, a risk could not be ruled out because of uncertainty sources. As a precautionary measure, reducing the exposure is recommended. For chemicals without robust health-based guidance value (organic arsenic, gallium, germanium, silver, tin, tellurium and vanadium), additional data are needed for risk assessment.

Insight into the contribution of isoprostanoids to the health effects of omega 3 PUFAs.

Omega 3 polyunsaturated fatty acids have been reported to confer beneficial health effects notably in the field of cardiovascular and inflammatory diseases. The current knowledge suggests a significant portion of the effects of omega 3 polyunsaturated fatty acids are mediated by their oxygenated metabolites. This review attempts to cover the current literature about the contribution of specific omega 3 oxygenated metabolites, namely omega 3 isoprostanoids, which are produced through free-radical mediated oxidation. A special emphasis has been given to the most biologically relevant omega 3 polyunsaturated fatty acids namely the α-linolenic, eicosapentaenoic and docosahexaenoic acids. The review includes a comprehensive description of the biosynthetic pathways, a summary of studies related to the biological significance of omega 3 isoprostanoids as well as a critical description of analytical development in the field of omega 3 isoprostanoids profiling in biological samples.

Iron absorption in dysmetabolic iron overload syndrome is decreased and correlates with increased plasma hepcidin.

BACKGROUND/AIMS: The dysmetabolic iron overload syndrome (DIOS) is a common disorder but its origin remains unclear. METHODS: A case-control study was conducted to compare intestinal absorption of iron in 16 men with DIOS (age 53 +/- 11 years, serum ferritin 750 +/- 372 microg/l, hepatic iron 78 +/- 25 micromol/g) and in 32 age-matched controls with normal body iron stores (16 overweight subjects and 16 lean subjects). Intestinal absorption was calculated as the area under the curve (AUC) of 58Fe administered orally and correlated with plasma hepcidin and with insulin resistance parameters including HOMA. RESULTS: Intestinal iron absorption was lower in DIOS (AUC = 22.4 +/- 15.9 microg/l/h) compared to both overweight controls (AUC = 40.5 +/- 29.4 microg/l/h, p=0.04) and to lean controls (AUC = 102.5 +/- 113.5 microg/l/h, p < 0.01). There was an inverse correlation between intestinal iron absorption and plasma hepcidin (r = -0.61, p < 0.001), HOMA (r = -0.35, p = 0.01) and C reactive protein (r = -0.52, p < 0.001). CONCLUSIONS: In overweight subjects with normal iron stores, iron absorption is decreased through hepcidin upregulation. In patients with DIOS, this decrease is more pronounced due to an additional effect of iron excess on circulating hepcidin levels.