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1.
Nutrients ; 16(10)2024 May 07.
Article in English | MEDLINE | ID: mdl-38794644

ABSTRACT

Endothelial dysfunction is a crucial event in the early pathogenesis of cardiovascular diseases and is linked to magnesium (Mg) deficiency. Indeed, in endothelial cells, low Mg levels promote the acquisition of a pro-inflammatory and pro-atherogenic phenotype. This paper investigates the mechanisms by which Mg deficiency promotes oxidative stress and affects endothelial behavior in human umbilical vascular endothelial cells (HUVECs). Our data show that low Mg levels trigger oxidative stress initially by increasing NAPDH oxidase activity and then by upregulating the pro-oxidant thioredoxin-interacting protein TXNIP. The overproduction of reactive oxygen species (ROS) activates NF-κB, leading to its increased binding to the inducible nitric oxide synthase (iNOS) promoter, with the consequent increase in iNOS expression. The increased levels of nitric oxide (NO) generated by upregulated iNOS contribute to disrupting endothelial cell function by inhibiting growth and increasing permeability. In conclusion, we provide evidence that multiple mechanisms contribute to generate a pro-oxidant state under low-Mg conditions, ultimately affecting endothelial physiology. These data add support to the notion that adequate Mg levels play a significant role in preserving cardiovascular health and may suggest new approaches to prevent or manage cardiovascular diseases.


Subject(s)
Human Umbilical Vein Endothelial Cells , Magnesium Deficiency , Magnesium , Nitric Oxide Synthase Type II , Nitric Oxide , Oxidative Stress , Reactive Oxygen Species , Humans , Nitric Oxide Synthase Type II/metabolism , Nitric Oxide Synthase Type II/genetics , Magnesium Deficiency/metabolism , Reactive Oxygen Species/metabolism , Nitric Oxide/metabolism , Magnesium/metabolism , NF-kappa B/metabolism , Carrier Proteins/metabolism , Carrier Proteins/genetics , Endothelium, Vascular/metabolism
2.
Magnes Res ; 0(0)2024 Apr 23.
Article in English | MEDLINE | ID: mdl-38652733

ABSTRACT

Since the start of the COVID-19 pandemic, it has become increasingly clear that the disease can have relevant multisystemic and long-term effects, and several studies have attempted to identify key determinants of the disease course. Here we discuss recent evidence suggesting that, in long COVID patients, combined magnesium and vitamin D deficiencies associate with a higher number of clinical manifestations, as compared to patients with normal levels of both nutrients. We highlight the potential synergistic effects of these deficiencies and propose that future studies should explore a causal link with the risk of developing long COVID. Most importantly, randomized clinical trials are needed to determine if magnesium and vitamin D supplementation can improve long COVID symptoms, providing a safe and affordable support therapy to the benefit of patients and society.

4.
Magnes Res ; 35(2): 71-79, 2022 10 10.
Article in English | MEDLINE | ID: mdl-36214488

Subject(s)
Magnesium , Humans
5.
Eur J Nutr ; 61(7): 3697-3706, 2022 Oct.
Article in English | MEDLINE | ID: mdl-35689124

ABSTRACT

PURPOSE: Serum magnesium is the most frequently used laboratory test for evaluating clinical magnesium status. Hypomagnesemia (low magnesium status), which is associated with many chronic diseases, is diagnosed using the serum magnesium reference range. Currently, no international consensus for a magnesemia normal range exists. Two independent groups designated 0.85 mmol/L (2.07 mg/dL; 1.7 mEq/L) as the low cut-off point defining hypomagnesemia. MaGNet discussions revealed differences in serum magnesium reference ranges used by members' hospitals and laboratories, presenting an urgent need for standardization. METHODS: We gathered and compared serum magnesium reference range values from our institutions, hospitals, and colleagues worldwide. RESULTS: Serum magnesium levels designating "hypomagnesemia" differ widely. Of 43 collected values, only 2 met 0.85 mmol/L as the low cut-off point to define hypomagnesemia. The remainder had lower cut-off values, which may underestimate hypomagnesemia diagnosis in hospital, clinical, and research assessments. Current serum magnesium reference ranges stem from "normal" populations, which unknowingly include persons with chronic latent magnesium deficit (CLMD). Serum magnesium levels of patients with CLMD fall within widely used "normal" ranges, but their magnesium status is too low for long-term health. The lower serum magnesium reference (0.85 mmol/L) proposed specifically prevents the inclusion of patients with CLMD. CONCLUSIONS: Widely varying serum magnesium reference ranges render our use of this important medical tool imprecise, minimizing impacts of low magnesium status or hypomagnesemia as a marker of disease risk. To appropriately diagnose, increase awareness of, and manage magnesium status, it is critical to standardize lower reference values for serum magnesium at 0.85 mmol/L (2.07 mg/dL; 1.7 mEq/L).


Subject(s)
Magnesium , Humans , Reference Standards , Reference Values
6.
Eur J Nutr ; 61(2): 625-636, 2022 Mar.
Article in English | MEDLINE | ID: mdl-34687321

ABSTRACT

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.


Subject(s)
COVID-19 , Homeostasis , Humans , Magnesium , Pandemics , SARS-CoV-2
7.
Nutrients ; 13(12)2021 Nov 23.
Article in English | MEDLINE | ID: mdl-34959740

ABSTRACT

Nutritional deficiencies are common in inflammatory bowel diseases (IBD). In patients, magnesium (Mg) deficiency is associated with disease severity, while in murine models, dietary Mg supplementation contributes to restoring mucosal function. Since Mg availability modulates key bacterial functions, including growth and virulence, we investigated whether the beneficial effects of Mg supplementation during colitis might be mediated by gut microbiota. The effects of dietary Mg modulation were assessed in a murine model of dextran sodium sulfate (DSS)-induced colitis by monitoring magnesemia, weight, and fecal consistency. Gut microbiota were analyzed by 16S-rRNA based profiling on fecal samples. Mg supplementation improved microbiota richness in colitic mice, increased abundance of Bifidobacterium and reduced Enterobacteriaceae. KEEG pathway analysis predicted an increase in biosynthetic metabolism, DNA repair and translation pathways during Mg supplementation and in the presence of colitis, while low Mg conditions favored catabolic processes. Thus, dietary Mg supplementation increases bacteria involved in intestinal health and metabolic homeostasis, and reduces bacteria involved in inflammation and associated with human diseases, such as IBD. These findings suggest that Mg supplementation may be a safe and cost-effective strategy to ameliorate disease symptoms and restore a beneficial intestinal flora in IBD patients.


Subject(s)
Colitis/microbiology , Colitis/therapy , Gastrointestinal Microbiome/drug effects , Magnesium/pharmacology , Animals , Colitis/chemically induced , Dextran Sulfate , Disease Models, Animal , Dysbiosis/microbiology , Dysbiosis/therapy , Feces/microbiology , Female , Magnesium Deficiency/microbiology , Magnesium Deficiency/therapy , Mice , Mice, Inbred C57BL , RNA, Ribosomal, 16S
9.
Nutrients ; 12(11)2020 Oct 26.
Article in English | MEDLINE | ID: mdl-33114586

ABSTRACT

Hypomagnesemia is very commonly observed in cancer patients, most frequently in association with therapy with cetuximab (CTX), a monoclonal antibody targeting the epithelial growth factor receptor (EGFR). CTX-induced hypomagnesemia has been ascribed to renal magnesium (Mg) wasting. Here, we sought to clarify whether CTX may also influence intestinal Mg absorption and if Mg supplementation may interfere with CTX activity. We used human colon carcinoma CaCo-2 cells as an in vitro model to study the mechanisms underlying Mg transport and CTX activity. Our findings demonstrate that TRPM6 is the key channel that mediates Mg influx in intestinal cells and that EGF stimulates such influx; consequently, CTX downregulates TRPM6-mediated Mg influx by interfering with EGF signaling. Moreover, we show that Mg supplementation does not modify either the CTX IC50 or CTX-dependent inhibition of ERK1/2 phosphorylation. Our results suggest that reduced Mg absorption in the intestine may contribute to the severe hypomagnesemia that occurs in CTX-treated patients, and Mg supplementation may represent a safe and effective nutritional intervention to restore Mg status without impairing the CTX efficacy.


Subject(s)
Cetuximab/adverse effects , Epidermal Growth Factor/metabolism , Intestinal Absorption/drug effects , Magnesium/metabolism , TRPM Cation Channels/metabolism , Caco-2 Cells , Colon/metabolism , Humans , Renal Tubular Transport, Inborn Errors/chemically induced , Renal Tubular Transport, Inborn Errors/metabolism
10.
Dig Liver Dis ; 52(10): 1188-1194, 2020 10.
Article in English | MEDLINE | ID: mdl-32505565

ABSTRACT

BACKGROUND: Inflammatory bowel disease (IBD) predisposes to colorectal cancer (CRC) with some specific features that distinguish it from sporadic CRC. Magnesium (Mg) homeostasis is severely compromised in IBD patients, which may affect both inflammation and tumor development. Efficient transcellular Mg transport in intestinal cells depends on the transient receptor potential melastatin (TRPM) channels type 6 and 7, but their expression has never been investigated in the context of IBD-related CRC. AIMS: We sought to study the expression pattern of TRPM6 and TRPM7 in CRC, and to compare IBD-related cases to sporadic cases. METHODS: TRPM6 and TRPM7 protein expression was evaluated by immunohistochemistry in surgical specimens from 16 IBD and 13 NON-IBD CRC patients. RESULTS: TRPM7 expression was higher in tumor tissue than in the adjacent non-neoplastic tissue in both IBD and NON-IBD patients. Overall, adenocarcinomas showed a higher TRPM7 expression than adenomas. TRPM7 expression also positively correlated with tumor grade. Conversely, TRPM6 expression was higher in tumor tissues in both IBD and NON-IBD CRC, but it did not correlate with tumor stage or grade. CONCLUSIONS: We report a possible participation of TRPM6 and 7 in both IBD-related and sporadic CRC and suggest that TRPM7 might serve as a marker of malignant transformation and lack of differentiation.


Subject(s)
Adenocarcinoma/genetics , Colorectal Neoplasms/genetics , Inflammatory Bowel Diseases/genetics , Protein Serine-Threonine Kinases/genetics , TRPM Cation Channels/genetics , Adenocarcinoma/etiology , Biomarkers/blood , Case-Control Studies , Colorectal Neoplasms/etiology , Colorectal Neoplasms/pathology , Female , Gene Expression , Humans , Inflammatory Bowel Diseases/complications , Magnesium/metabolism , Male
11.
Magnes Res ; 33(2): 21-27, 2020 May 01.
Article in English | MEDLINE | ID: mdl-32554340

ABSTRACT

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.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/blood , Magnesium Deficiency/blood , Magnesium/blood , Pneumonia, Viral/blood , Animals , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Disease Progression , Host-Pathogen Interactions , Humans , Inflammation Mediators/blood , Magnesium Deficiency/epidemiology , Magnesium Deficiency/immunology , Magnesium Deficiency/virology , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Prognosis , SARS-CoV-2 , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/virology , Time Factors
13.
Cell Calcium ; 83: 102078, 2019 11.
Article in English | MEDLINE | ID: mdl-31493712

ABSTRACT

Derangement of magnesium homeostasis underlies the pathophysiology of many diseases, including cancer. Recent advances support the view that aberrant expression of Mg2+ channels and other Mg2+ homeostatic factors may affect many hallmarks of cancer. The seminal idea of magnesium as a key regulator of cell proliferation has been enriched by novel intriguing findings that link magnesium and Mg2+ transporters to distinctive and complementary capabilities that enable tumour growth and metastatic dissemination. In this review, we examine the evidence on the involvement of members from the TRPM, CNNM and SCL41 protein families in cancer progression, and discuss their potential as therapeutic targets.


Subject(s)
Biomarkers, Tumor/metabolism , Cell Membrane/metabolism , Neoplasms/metabolism , Transient Receptor Potential Channels/metabolism , Animals , Cell Proliferation , Homeostasis , Humans , Protein Conformation , Protein Domains/genetics , Structure-Activity Relationship
15.
Nutrients ; 10(6)2018 Jun 18.
Article in English | MEDLINE | ID: mdl-29912157

ABSTRACT

Intestinal magnesium (Mg) uptake is essential for systemic Mg homeostasis. Colon cells express the two highly homologous transient receptor potential melastatin type (TRPM) 6 and 7 Mg2+ channels, but their precise function and the consequences of their mutual interaction are not clear. To explore the functional role of TRPM6 and TRPM7 in the colon, we used human colon cell lines that innately express both channels and analyzed the functional consequences of genetic knocking-down, by RNA interference, or pharmacological inhibition, by NS8593, of either channel. TRPM7 silencing caused an increase in Mg2+ influx, and correspondingly enhanced cell proliferation and migration, while downregulation of TRPM6 did not affect significantly either Mg2+ influx or cell proliferation. Exposure to the specific TRPM6/7 inhibitor NS8593 reduced Mg2+ influx, and consequently cell proliferation and migration, but Mg supplementation rescued the inhibition. We propose a model whereby in colon cells the functional Mg2+ channel at the plasma membrane may consist of both TRPM7 homomers and TRPM6/7 heteromers. A different expression ratio between the two proteins may result in different functional properties. Altogether, our findings confirm that TRPM6 cannot be replaced by TRPM7, and that TRPM6/7 complexes and TRPM6/7-mediated Mg2+ influx are indispensable in human epithelial colon cells.


Subject(s)
Colon/cytology , Colon/metabolism , Epithelial Cells/physiology , Magnesium/metabolism , Protein Serine-Threonine Kinases/metabolism , TRPM Cation Channels/metabolism , Cell Line, Tumor , Humans , Intestinal Mucosa/cytology , Protein Serine-Threonine Kinases/genetics , Reverse Transcriptase Polymerase Chain Reaction , TRPM Cation Channels/genetics
16.
Inflamm Bowel Dis ; 24(10): 2198-2210, 2018 09 15.
Article in English | MEDLINE | ID: mdl-29788266

ABSTRACT

Background: Magnesium (Mg) is essential for human health and is absorbed mainly in the intestine. In view of the likely occurrence of an Mg deficit in inflammatory bowel disease (IBD) and the documented role of Mg in modulating inflammation, the present study addresses whether Mg availability can affect the onset and progression of intestinal inflammation. Methods: To study the correlation between Mg status and disease activity, we measured magnesemia by atomic absorption spectroscopy in a cohort of IBD patients. The effects of dietary Mg modulation were assessed in a murine model of dextran sodium sulfate (DSS)-induced colitis by monitoring magnesemia, weight, fecal occult blood, diarrhea, colon length, and histology. Expression of the transient receptor potential melastatin (TRPM) 6 channel was assessed by real-time reverse transcription polymerase chain reaction and immunohistochemistry in murine colon tissues. The effect of Mg on epithelial barrier formation/repair was evaluated in human colon cell lines. Results: Inflammatory bowel disease patients presented with a substantial Mg deficit, and serum Mg levels were inversely correlated with disease activity. In mice, an Mg-deficient diet caused hypomagnesemia and aggravated DSS-induced colitis. Colitis severely compromised intestinal Mg2+ absorption due to mucosal damage and reduction in TRPM6 expression, but Mg supplementation resulted in better restoration of mucosal integrity and channel expression. Conclusions: Our results highlight the importance of evaluating and correcting magnesemia in IBD patients. The murine model suggests that Mg supplementation may represent a safe and cost-effective strategy to reduce inflammation and restore normal mucosal function.


Subject(s)
Colitis, Ulcerative/complications , Colitis/prevention & control , Crohn Disease/complications , Diet , Hypocalcemia/metabolism , Magnesium Deficiency/congenital , Magnesium/administration & dosage , TRPM Cation Channels/metabolism , Adult , Aged , Aged, 80 and over , Animals , Case-Control Studies , Colitis/chemically induced , Colitis/metabolism , Colitis/pathology , Colitis, Ulcerative/metabolism , Colitis, Ulcerative/physiopathology , Crohn Disease/metabolism , Crohn Disease/physiopathology , Dextran Sulfate/toxicity , Female , Follow-Up Studies , Humans , Hypocalcemia/etiology , Hypocalcemia/pathology , Magnesium/metabolism , Magnesium Deficiency/etiology , Magnesium Deficiency/metabolism , Magnesium Deficiency/pathology , Male , Mice, Inbred C57BL , Middle Aged , Prognosis , TRPM Cation Channels/genetics , Young Adult
17.
Med Teach ; 39(9): 981-986, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28552022

ABSTRACT

CONTEXT: The emerging global-health paradigm requires medical teaching to be continuously redefined and updated; to this end, transnational approaches should be encouraged and medical training harmonized. Infectious diseases (ID) teaching in the current context of emerging infections, fast-increasing bacterial resistance and large-scale human migration, was chosen to develop a common international course. OBJECTIVE: We report the successful implementation of a joint European undergraduate course aiming to (i) develop a common ID core curriculum among European medical schools; (ii) promote mobility among teachers and students (iii) promote international cooperation among European teachers. METHODS: The course was built around teachers' mobility. It was delivered in English by a team of European medical educators from Paris Descartes University, Università Cattolica del Sacro Cuore in Rome and the University of Edinburgh to groups of 25-30 undergraduate medical students at each university. Partner Institutions officially recognized the course as substitutive of or additive to the regular curriculum. RESULTS: The course has been running for 3 years and received excellent satisfaction scores by students and staff as regards to scientific content, pedagogy and international exchanges. CONCLUSION: This cooperative approach demonstrates the feasibility of a harmonized European undergraduate medical education, having ID as a test experiment for future developments.


Subject(s)
Communicable Diseases , Curriculum , Education, Medical, Undergraduate/methods , Global Health/education , Students, Medical , Teaching , Communicable Diseases, Emerging , Drug Resistance, Bacterial , Education, Medical , Europe , Humans , Public Health , Schools, Medical , Transients and Migrants
18.
Sci Rep ; 7: 40538, 2017 01 17.
Article in English | MEDLINE | ID: mdl-28094304

ABSTRACT

The processes leading to anticancer drug resistance are not completely unraveled. To get insights into the underlying mechanisms, we compared colon carcinoma cells sensitive to doxorubicin with their resistant counterpart. We found that resistant cells are growth retarded, and show staminal and ultrastructural features profoundly different from sensitive cells. The resistant phenotype is accompanied by the upregulation of the magnesium transporter MagT1 and the downregulation of the ion channel kinase TRPM7. We demonstrate that the different amounts of TRPM7 and MagT1 account for the different proliferation rate of sensitive and resistant colon carcinoma cells. It remains to be verified whether they are also involved in the control of other "staminal" traits.


Subject(s)
Antibiotics, Antineoplastic/pharmacology , Cation Transport Proteins/genetics , Colonic Neoplasms/genetics , Doxorubicin/pharmacology , Drug Resistance, Neoplasm/genetics , Protein Serine-Threonine Kinases/genetics , TRPM Cation Channels/genetics , Cell Proliferation , Gene Expression Regulation, Neoplastic , Gene Silencing , Humans
20.
Chem Res Toxicol ; 29(3): 317-22, 2016 Mar 21.
Article in English | MEDLINE | ID: mdl-26918850

ABSTRACT

Magnesium is directly involved in the control of cell growth and survival, but its role in cancer biology and therapy is multifaceted; in particular, it is highly controversial whether magnesium levels can affect therapy outcomes. Here we investigated whether magnesium availability can modulate cellular responses to the widely used chemotherapeutic doxorubicin. We used an in vitro model consisting of mammary epithelial HC11 cells and found that high magnesium availability was correlated with diminished sensitivity both in cells chronically adapted to high magnesium concentrations and in acutely magnesium-supplemented cells. This decrease in sensitivity resulted from reduced intracellular doxorubicin accumulation in the face of a similar drug uptake rate. We observed that high-magnesium conditions caused a decrease in intracellular drug retention by altering drug lysosomal sequestration and trafficking. In our model, magnesium supplementation correspondingly modulated expression of the TRPM7 channel, which is known to control cytoskeletal organization and dynamics and may be involved in the proposed mechanism. Our findings suggest that magnesium supplementation in hypomagnesemic cancer patients may hinder response to therapy.


Subject(s)
Antibiotics, Antineoplastic/metabolism , Antibiotics, Antineoplastic/pharmacology , Doxorubicin/metabolism , Doxorubicin/pharmacology , Lysosomes/drug effects , Lysosomes/metabolism , Magnesium/pharmacology , Cell Proliferation/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Humans , MCF-7 Cells , Protein Serine-Threonine Kinases/metabolism , Structure-Activity Relationship , TRPM Cation Channels/metabolism
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