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Magnesium and the inflammatory response: Potential physiopathological implications
Abstract
The purpose of this review is to summarize experimental findings showing that magnesium modulates cellular events involved in inflammation. Experimental magnesium deficiency in the rat induces after a few days a clinical inflammatory syndrome characterized by leukocyte and macrophage activation, release of inflammatory cytokines and acute phase proteins, excessive production of free radicals. Increase in extracellular magnesium concentration, decreases inflammatory response while reduction in the extracellular magnesium results in cell activation. Because magnesium acts as a natural calcium antagonist, the molecular basis for inflammatory response is probably the result of modulation of intracellular calcium concentration. The priming of phagocytic cells, the opening calcium channel and activation of N-methyl-d-aspartate (NMDA) receptors, the activation of nuclear factor-kappa B (NFkappaB) have been considered as potential mechanisms. Moreover, magnesium deficiency induces a systemic stress response by activation of neuro endocrinological pathways. As nervous and immune systems interact bidirectionally, the roles of neuromediators have also been considered. Magnesium deficiency contributes to an exaggerated response to immune stress and oxidative stress is the consequence of the inflammatory response. Inflammation contributes to the pro-atherogenic changes in lipoprotein metabolism, endothelial dysfunction, thrombosis, hypertension and explains the aggravating effect of magnesium deficiency on the development of metabolic syndrome. Further studies are still needed to assess more accurately the role of magnesium in immune response in humans, but these experimental findings in animal models suggest that inflammation is the missing link to explain the role of magnesium in many pathological conditions.
... The dyslipidemia included serum and plasma increased phospholipid and triglyceride concentrations, variable cholesterol concentrations, and modifications in lipoproteins [19]. Magnesium deficiency also increased triglyceriderich lipoproteins that were associated with an increase in plasma apo B and a decrease in apo A1 and apo E [53]. In the heart, magnesium deficiency increases the oxidation of lipids and lipoproteins [19]. ...
... In one experiment, magnesium supplementation after magnesium deprivation increased serum Apo A1 and Apo B concentrations [15]. These findings contrast sharply with those obtained in rats [53]. Severe acute magnesium deficiency increased serum triglycerides and Apo B and decreased HDL-cholesterol and Apo A1 concentrations in rats. ...
In the past 20 years, a large number of epidemiological studies, randomized controlled trials, and meta-analyses have found an inverse relationship between magnesium intake or serum magnesium and cardiovascular disease, indicating that low magnesium status is associated with hypertension, coronary artery calcification, stroke, ischemic heart disease, atrial fibrillation, heart failure, and cardiac mortality. Controlled metabolic unit human depletion–repletion experiments found that a mild or moderate magnesium deficiency can cause physiological and metabolic changes that respond to magnesium supplementation, which indicates that these types of deficiencies or chronic latent magnesium deficiency are contributing factors to the occurrence and severity of cardiovascular disease. Mechanisms through which a mild or moderate magnesium deficiency can contribute to this risk include inflammatory stress, oxidative stress, dyslipidemia and deranged lipid metabolism, endothelial dysfunction, and dysregulation of cellular ion channels, transporters, and signaling. Based on USA official DRIs or on suggested modified DRIs based on body weight, a large number of individuals routinely consume less magnesium than the EAR. This especially occurs in populations that do not consume recommended amounts of whole grains, pulses, and green vegetables. Thus, inadequate magnesium status contributing to cardiovascular disease is widespread, making magnesium a nutrient of public health concern.
... The dyslipidemia included serum and plasma increased phospholipid and triglyceride concentrations, variable cholesterol concentrations, and modifications in lipoproteins [19]. Magnesium deficiency also increased triglyceride-rich lipoproteins that were associated with an increase plasma apo B and a decrease in apo A1 and apo E [53]. In the heart, magnesium deficiency increased the oxidation of lipids and lipoproteins [19]. ...
... In one experiment, magnesium supplementation after magnesium deprivation increased serum Apo A1 and Apo B concentrations [54]. These findings contrast sharply with those obtained in rats [53]. Severe acute magnesium deficiency increased serum triglycerides and Apo B, and decreased HDL-cholesterol and Apo A1 concentrations in rats. ...
In the past 20 years, a large number of epidemiological studies, randomized controlled trials, and meta-analyses have found an inverse relationship between magnesium intake or serum magnesium and cardiovascular disease indicating that a low magnesium status was associated with hypertension, coronary artery calcification, stroke, ischemic heart disease, atrial fibrillation, heart failure, and cardiac mortality. Controlled metabolic unit human depletion-repletion experiments found that a mild or moderate magnesium deficiency can cause physiological and metabolic changes that respond to magnesium supplementation, which indicates these types of deficiency or chronic latent magnesium deficiency are contributing factor to the occurrence and severity of cardiovascular disease. Mechanisms through which a mild or moderate magnesium deficiency can contribute to this risk include inflammatory stress, oxidative stress, dyslipidemia and deranged lipid metabolism, endothelial dysfunction, and dysregulation of cellular ion channels, transporters, and signaling. Based on USA official DRIs or on suggested modified DRIs based on body weight, a large number of individuals routinely consume less than the EAR for magnesium. This especially occurs in populations that do not consume recommended amounts of whole grains, pulses, green vegetables. Thus, inadequate magnesium status contributing to cardiovascular disease is widespread, making magnesium a nutrient of public health concern.
... As a result, the magnesium ion content within the mitochondria decreases, leading to reduced electron transport chain activity, increased mitochondrial ROS, inhibition of key antioxidant enzymes, and subsequent initiation of oxidative stress [19]. Simultaneously, magnesium ion deficiency, which antagonize calcium ions, increases intracellular calcium overload, activating numerous calcium-dependent kinases and proteins, such as nitric oxide synthase and calcium-dependent calcium-binding proteins, further augmenting ROS production [68]. Additionally, magnesium-deficiency-induced ROS overload activates transcription factors such as nuclear factor kappa-B (NF-κB), which induces lipid peroxidation and stimulates the secretion of proinflammatory cytokines, including interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α, triggering inflammatory responses and exacerbating ROS production [69]. ...
... Additionally, magnesium is an essential cofactor for the synthesis of immunoglobulins, C3 convertase, and the adhesion of immune cells [79]. Magnesium deficiency can increase chronic inflammation; enhance immune stress; and lead to the activation of TNF, IL-1, and IL-6, thereby stimulating tumor proliferation [68]. Therefore, maintaining adequate magnesium levels is crucial for cancer patients. ...
The magnesium ion is an essential cation in the human body and participates in numerous physiological activities. A deficiency in magnesium ions is closely associated with tumor development, and supplementation with magnesium ions has been shown to partially inhibit tumor growth. However, the specific mechanisms by which magnesium ions suppress tumor proliferation remain unclear. Currently, studies have revealed that mitochondria may serve as a crucial intermediate link in the regulation of tumors by magnesium ions. Mitochondria might intervene in the proliferation and invasion of tumor cells by modulating energy metabolism and oxidative stress levels. Regrettably, there has been no comprehensive review of the role of magnesium in cancer therapy to date. Therefore, this article provides a comprehensive scrutiny of the relationship between magnesium ions and tumors, aiming to offer insights for clinical tumor treatment strategies involving magnesium ion intervention.
... However, the height of alveolar ridge and tooth loss caused by magnesium deficiency may reduce bone loss if magnesium supplements are taken orally in time (16). In rodents, pro-inflammatory cytokines, associated proteins, and gingival congestion will all rise in response to a drop in serum magnesium ion concentration (17). Nevertheless, other research likewise revealed no distinction in serum magnesium concentrations between individuals consuming magnesium supplements and those who did not (16). ...
... It has been discovered that magnesium stimulates the M2 type differentiation of mononuclear macrophages, which in turn secrete cytokines that promote bone formation and reduce inflammation. Furthermore, magnesium has the ability to lower macrophage production of the pro-inflammatory factors TNF-α, IL-6, and IL-1β (17). Increasing the concentration of magnesium might also decrease immune cells' production of nitric oxide and reactive oxygen species, which means that biomaterials containing magnesium may have anti-inflammatory characteristics (42). ...
A common disturbing dental malaise which ultimately results in low quality of life is periodontitis, a chronic bacterial infections disease that is caused by the dental plaque biofilm. Both tissues and blood need enough magnesium, this is a natural and one of essential minerals that is highly abundant in the human body. Different diseases due to a magnesium deficiency can be formed. Results from clinical and nutritional data supported this hypothesis. However, The relationship between magnesium deficiency and periodontitis requires further research. This paper examines some possible ways in which these two are connected. This article focuses on presenting a valuable and resourceful material for those who are eager to acknowledge the role that magnesium level plays in periodontal disease as well as providing potential means to the creation of advanced and effective periodontitis prevention and treatment approaches.
... A potential alternative mechanism is the anti-inflammatory effect of Mg. Animal studies have shown that low Mg intake is associated with microglia activation and the production of pro-inflammatory cytokines, including interleukin 1 beta (IL-1), IL-6, and tumour necrosis factor alpha (TNF-α) [23]. Mg supplementation, in contrast, has an antiinflammatory impact by reducing the production of proinflammatory cytokines, including IL-1, IL-6, and TNF-α [24]. ...
... Our findings are in line with evidence from animal studies, which have demonstrated a relationship between lower Mg intake and higher neuroinflammation. Research has suggested that a reduction in Mg intake can trigger microglia activation, which may result in an increase in proinflammatory cytokines including IL-6, TNF-α, and nitric oxide [23]. Treatment with Mg has been shown to decrease microglia activation and inhibit TNF-α production in rats [24]. ...
Background
Consistent evidence shows that magnesium (Mg) intake is associated with lower blood pressure (BP), and that lower BP is associated with improved cerebral health. However, recent findings indicate that the positive effect of dietary Mg intake on cerebral health is not mediated by a decrease in BP. As Mg’s anti-inflammatory action is a plausible alternative mechanism, the objective of this study was to investigate the associations between Mg intake and inflammation to determine whether it mediates any neuroprotective effect.
Methods
Participants from the UK Biobank (n = 5775, aged 40–73 years, 54.7% female) were assessed for dietary magnesium using an online food questionnaire, brain and white matter lesion (WML) volumes were segmented with FreeSurfer software, and inflammation markers including high-sensitivity C-reactive protein (hs-CRP), leukocyte, erythrocyte count, and Glycoprotein acetylation (GlycA) were measured using specific laboratory techniques such as immunoturbidimetry, automated cell counting, and nuclear magnetic resonance. Hierarchical linear regression models were performed to investigate the association between dietary Mg, and inflammatory markers and between dietary Mg, brain and WMLs volumes. Mediation analysis was performed to test a possible mediation role of inflammation on the association between dietary Mg and brain and WMLs volumes.
Results
Higher dietary Mg intake was associated with lower inflammation: hs-CRP level (− 0.0497%; 95% confidence interval [CI] − 0.0497%, − 0.0199%) leukocytes count (− 0.0015%; 95%CI − 0.00151%, − 0.0011%), and GlycA (− 0.0519%; 95%CI − 0.1298%, − 0.0129%). Moreover, higher dietary Mg intake was associated with larger grey matter volume (0.010%; 95%CI 0.004%, 0.017%), white matter volume (0.012%; 95%CI 0.003, 0.022) and right hippocampal volume (0.002%; 95%CI 0.0007, –0.0025%). Lower hs-CRP levels mediated the positive association between higher dietary Mg intake and larger grey matter volume.
Conclusions
The anti-inflammatory effects of dietary Mg intake in the general population, appears to mediate its neuroprotective effect.
... Studies conducted on animals have conclusively shown that the relative depletion of magnesium may contribute to inappropriate triggering of the innate immune system while impairing the adaptive immune system, leading to systemic inflammation. Specifically, magnesium deficiency can activate polymorphonuclear leukocytes within the innate immune system, increasing phagocytosis and oxidative stress [54,55]. Magnesium is an essential cofactor in T helper cell adhesion, immunoglobulin synthesis, IgM lymphocyte binding, antibody-dependent cytolysis, and macrophage responses to lymphokines [56,57]. ...
... Inflammatory mediators can encourage the invasion of cancer cells into the environment during the early stages of the disease. An absence of magnesium in the body can trigger the activation of tumor necrosis factor (TNF), interleukin-1 (IL-1), and IL-6, which can further enhance the likelihood of cancer cell spread [54,76,77]. Some studies have shown that low magnesium levels can increase the risk of specific types of cancers, such as colorectal, pancreatic, and breast cancers. ...
The importance of maintaining proper magnesium intake and total body magnesium content in preserving human health remains underappreciated among medical professionals and laymen. This review aimed to show the importance of hypomagnesemia as a modifiable risk factor for developing disease processes. We searched the PubMed database and Google Scholar using the keywords ‘magnesium’, ‘diabetes’, ‘cardiovascular disease’, ‘respiratory disease’, ‘immune system’, ‘inflammation’, ‘autoimmune disease’, ‘neurology’, ‘psychiatry’, ‘cognitive function’, ‘cancer’, and ‘vascular calcification’. In multiple contexts of the search terms, all reviews, animal experiments, and human observational data indicated that magnesium deficiency can lead to or contribute to developing many disease states. The conclusions of several in-depth reviews support our working hypothesis that magnesium and its supplementation are often undervalued and underutilized. Although much research has confirmed the importance of proper magnesium supply and tissue levels, simple and inexpensive magnesium supplementation has not yet been sufficiently recognized or promoted.
... Among patients with IBD, previous studies have noted associations between small bowel surgery, intestinal microbiota, and incidence of NASH (nonalcoholic steatohepatitis) and NAFLD (nonalcoholic fatty liver disease) [9,10,25]. Other studies have demonstrated that environmental risk factors in addition to genetic risk factors play a role in the development of IBD, noting nutritional marker differences and nutrition-related genetic variance between IBD patients and non-IBD patients [20][21][22][23][24][25][26][27][28];as well as alterations in the GM for obese compared to non-obese patients [36,[69][70][71][72][73]. However, the relationship between bariatric surgery, MD, and IBD-and gastrointestinal (GI) disease-related inpatient outcomes is not known. ...
... Factors such as comorbid PUD may be relevant secondary to treatment side effects, rather than or in addition to the primary disease pathology itself. For example, proton pump inhibitor use alters magnesium absorption within gastrointestinal endo/epithelium cells and increases the risk for hypomagnesemia-a critical micronutrient in thyroid function and essential for T4 to T3 conversion; and key factor in immune cell function, maturation, and development, activating phagocytic cells and initiating excessive production and release of (IL)-1β and tumor necrosis factor (TNF)-α; and also involved in platelet aggregation and adhesiveness and inhibition of endothelial growth and migration, potentially altering microvascular functions [69][70][71][72][73][89][90][91][92][93]. ...
Purpose
The association between bariatric surgery and IBD-related inpatient outcomes is not well characterized. We report, analyze, and compare inpatient trends and outcomes among encounters with a history of bariatric surgery (Hx-MBS) compared to those receiving bariatric surgery during index admission (PR-MBS) admitted from 2009 to 2020.
Methods
Retrospective cohort design: the 2009–2020 National Inpatient Sample (NIS) databases were used to identify hospital encounters with patients aged ≥ 18 years with a history of MBS (Hx-MBS) or with procedure coding indicating MBS procedure (PR-MBS) according to International Classification of Diseases, Ninth (ICD-9-CM/ ICD-9-PCS) or Tenth Revision (ICD-10-CM/ICD-10-PCS) Clinical Modification/Procedure Coding System during index admission (ICD-9-CM: V4586; ICD-10-CM: Z9884; ICD-9-PR: 4382, 4389; ICD-10-PR: 0DB64Z3, 0DB63ZZ). Pearson χ2 analysis, analysis of variance, multivariable regression analyses, and propensity matching on independent variables were conducted to analyze significant associations between variables and for primary outcome inflammatory bowel disease-related admission, and secondary outcomes: diagnosis of nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, or chronic mesenteric ischemia during admission.
Results
We identified 3,365,784 (76.20%) Hx-MBS hospitalizations and 1,050,900 hospitalizations with PR-MBS (23.80%). Propensity score matching analysis demonstrated significantly higher odds of inflammatory bowel disease, and chronic mesenteric ischemia for Hx-MBS compared to PR-MBS, and significantly lower odds of nonalcoholic steatohepatitis and nonalcoholic fatty liver disease for Hx-MBS compared to PR-MBS.
Conclusion
In our study, Hx-MBS was associated with significantly increased odds of inflammatory bowel disease and other GI pathologies compared to matched controls. The mechanism by which this occurs is unclear. Additional studies are needed to examine these findings.
Graphical abstract
... Contrastingly, MgD leads to the activation of the rennin-angiotensin system that also induces OS [51]. Inflammation is the other important cause of the OS that results from MgD [52]. MgD stimulates the production of acute phase proteins (e.g., C-reactive protein) [53]. ...
... Hypomagnesemia leads to inflammatory responses by several pathways which could contribute to the pathogenesis of various conditions such as diabetes, cardiovascular diseases, osteoporosis, and neurodegenerative diseases 99,100 . It could exacerbate inflammation by the activation of cellular oxidative stress, renin-angiotensin system, nuclear factor-κB signaling, phagocytic cells, and the transcription of cytokines and pro-inflammatory genes [101][102][103][104][105][106][107][108][109][110][111][112][113][114] . Accordingly, it seems that healthy eating habits and lifestyles might ameliorate the vulnerability of del/del homozygotes (rs11279109) for dyslipidemia. ...
ApoB insertion/deletion (ins/del) genetic variant (rs11279109) is thought to be related to cardio-metabolic markers and obesity. This association has the potential to be modified by dietary patterns. Since the majority of studies concerned the role of dietary acid load (DAL) or ApoB in type 2 diabetes mellitus (T2DM) and its complications independently, and due to the insufficient data regarding the possible interactions between ApoB genetic variants and DAL on anthropometric and metabolic markers, we aimed to study the interaction between this genetic variant and dietary acid load (DAL) on cardio-metabolic markers, along with leptin among Iranian individuals with T2DM. 700 T2DM patients were randomly recruited. A validated semi-quantitative food frequency questionnaire was used for DAL calculation including potential renal acid load (PRAL) and net-endogenous acid production (NEAP). The polymerase chain reaction was used for genotyping the ApoB ins/del (rs11279109). The general linear model was applied to find the interactions in the crude and adjusted models. Patients with del/del genotype (rs11279109) with high PRAL intake have lower low-density lipoprotein cholesterol (LDL-C) (Pinteraction = 0.004), LDL/HDL ratio (Pinteraction = 0.02), total cholesterol (TC) (Pinteraction = 0.04), triglyceride (TG) (Pinteraction = 0.04), leptin (Pinteraction = 0.04) and interleukin-18 (IL-18) (Pinteraction = 0.04). Moreover, the interaction of gene and DAL in the PRAL method on TG concentration (P = 0.04), waist circumference (WC) (P = 0.04), and LDL/HDL ratio (P = 0.04) were significant. Eventually, a positive relationship was observed between the presence of the del/del genotype (rs11279109) and higher levels of TG, TC, LDL-C, IL-18, and LDL/HDL, in individuals with lower adherence to DAL, after adjusting for various covariates. Further studies are needed to investigate and confirm these findings.
... Magnesium exhibits antioxidant properties by neutralizing free radicals of oxygen and reduces inflammation by regulating the expression of nuclear factor kappa B [27][28][29][30][31][32][33]. In hypomagnesemia, the inflammation that occurs also affects the balance of lipids by lipid peroxidation, which leads to dyslipidemia by raising lipids rich in triglycerides, boosting plasma levels of a protein called apolipoprotein B, and lowering the concentrations of high-density lipoprotein cholesterol (HDL-C) [33,34]. ...
Magnesium is a crucial mineral that supports various enzymatic processes in the body. It plays a vital role in maintaining vascular, metabolic, and electrical homeostasis, making it an important factor for cardiovascular health. Magnesium is also involved in oxidative and inflammatory responses. Low levels of magnesium are associated with several cardiovascular issues, including arrhythmias, coronary artery disease, stroke, high blood pressure, and abnormal lipid levels. This suggests that a deficiency in magnesium could be a risk factor for cardiovascular disease (CVD), which is a major public health concern. Monitoring serum magnesium levels might help in identifying cardiovascular problems and related risk factors. Additionally, magnesium supplementation could lead to new approaches for managing CVDs.
... TRPM7 regulates many cellular processes, including Mg 2+ homeostasis, cell growth/apoptosis, and differentiation [29,30]. Previous studies have shown that Mg 2+ is involved in many basic physiological and biochemical processes that can regulate cardiovascular function, including vasoconstriction and dilation, vascular inflammation and protein synthesis [31,32]. Magnesium is also a key cation in most enzymatic reactions and is essential for proper cardiovascular function. ...
Fibrosis is usually the final pathological state of many chronic inflammatory diseases and may lead to organ malfunction. Excessive deposition of extracellular matrix (ECM) molecules is a characteristic of most fibrotic tissues. The blood vessel wall contains three layers of membrane structure, including the intima, which is composed of endothelial cells; the media, which is composed of smooth muscle cells; and the adventitia, which is formed by the interaction of connective tissue and fibroblasts. The occurrence and progression of vascular remodeling are closely associated with cardiovascular diseases, and vascular remodeling can alter the original structure and function of the blood vessel. Dysregulation of the composition of the extracellular matrix in blood vessels leads to the continuous advancement of vascular stiffening and fibrosis. Vascular fibrosis reaction leads to excessive deposition of the extracellular matrix in the vascular adventitia, reduces vessel compliance, and ultimately alters key aspects of vascular biomechanics. The pathogenesis of fibrosis in the vasculature and strategies for its reversal have become interesting and important challenges. Ion channels are widely expressed in the cardiovascular system; they regulate blood pressure, maintain cardiovascular function homeostasis, and play important roles in ion transport, cell differentiation, proliferation. In blood vessels, different types of ion channels in fibroblasts, smooth muscle cells and endothelial cells may be relevant mediators of the development of fibrosis in organs or tissues. This review discusses the known roles of ion channels in vascular fibrosis remodeling and discusses potential therapeutic targets for regulating remodeling and repair after vascular injury.
... Magnesium deficiency may contribute to the development and progression of MASLD through several potential mechanisms, including inflammation, insulin resistance, and dysregulation of lipid metabolism 28 . Magnesium is recognized for its anti-inflammatory properties, and deficiency has been linked to increased production of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), both of which play crucial roles in the pathogenesis of MASLD 29,30 . Additionally, magnesium is essential for maintaining insulin sensitivity, and its deficiency may lead to insulin resistance, a key factor in the development of MASLD 31 . ...
The relationship between magnesium deficiency and metabolic dysfunction associated steatotic liver disease (MASLD) remains unclear. This study aimed to examine the association between the magnesium depletion score (MDS) and the risk of MASLD, as well as explore potential underlying mechanisms. Data from 12,024 participants from the National Health and Nutrition Examination Survey (NHANES) 2005–2018 were analyzed. MDS was calculated based on the use of diuretics and proton pump inhibitors, kidney function, and alcohol consumption. MASLD was defined using the fatty liver index. Logistic regression, restricted cubic spline analysis, and mediation analyses were conducted to evaluate the association between MDS and MASLD and to identify potential mediators. A higher MDS was significantly associated with an increased risk of MASLD (OR = 2.00, 95% CI [1.47, 2.74] for MDS 3 vs. 0). A dose-response relationship between MDS and MASLD risk was observed. Neutrophils, albumin, and white blood cells partially were identified as partial mediators of the association, with albumin exhibiting the highest mediating effect (14.05%). Elevated MDS is significantly associated with an increased risk of MASLD in U.S. adults. Inflammation and albumin may serve as potential mediators of this relationship. These findings underscore the importance of addressing magnesium deficiency in the prevention and management of MASLD.
... It is noteworthy that raising the level of extracellular Mg may confer anti-inflammatory benefits and influence phagocytic cell activity by decreasing intracellular calcium concentration, thereby reducing inflammation and oxidative stress [87]. A study validating Mg deficiency prediction in high-risk adults revealed increased mortality rates for total and cardiovascular diseases. ...
Chronic kidney disease (CKD) is a major cause of death and disability worldwide. It is usually diagnosed at early levels because of its slow progression. Treatment should consider CKD complications (such as electrolyte level imbalance, vascular calcification, and bone mineral disorders), as well as the development of CKD itself. Large-scale studies have shown that current treatment guidelines are nearly ineffective and fail to achieve treatment goals. Guidelines have not paid as much attention to magnesium (Mg) as the other electrolytes, while Mg has a significant role in the treatment goals of CKD. Hypomagnesemia is the only electrolyte imbalance that is equally prevalent in all stages of CKD. A lower plasma Mg level in each stage of CKD is associated with a higher risk of CKD progression and cardiac events. Magnesium exerts its effects both directly and via other ions. Mg supplementation increases insulin sensitivity while reducing proteinuria and inflammation. It lowers blood pressure and inhibits vascular calcification primarily because of its effects on calcium and phosphate, respectively. Vitamin D supplementation for low-active vitamin D in CKD patients increases vascular calcification and cardiac events, but magnesium supplementation enhances vitamin D levels and activity without increasing the risk of cardiac events. However, careful attention is required due to the potential threats of hypermagnesemia, particularly in advanced CKD stages. Starting magnesium supplementation early in patients’ treatment plans will result in fewer side effects and more advantages. More original research is needed to determine its optimal dose and serum levels.
... Considering the importance of magnesium for the improvement of nerve conduction, a low magnesium level in serum is a risk factor for the development of DPN (Razzaghi et al. 2018;Rodrıǵuez-Morán and Guerrero-Romero 2001;Tosiello 1996;Bresäter et al. 1996;Bhardwaj et al. 2018;Amighi et al. 2004;Garland 1992;Stroud et al. 1994;Engelen et al. 2000). Based on evidence, taking magnesium supplements prevents NF-κB (Mazur et al. 2007). Also, due to the catalysis of malonyl-CoA formation, the element plays a role in the secretion of insulin (Kowluru et al. 2001). ...
Diabetes-induced hyperglycemia leads to excessive production of oxygen free radicals, inflammatory cytokines, and oxidative stress, which initiates diabetic peripheral neuropathy (DPN). Currently, this condition affects 20% of adults with diabetes. Despite significant advances in the treatment of diabetes, the incidence of its complications, including DPN, is still high. Thus, there is a growing research interest in developing more effective and treatment approaches with less side effects for diabetes and its complications. Nigellasativa L. (NS) has received much research attention as an antioxidant, anti-yperglycemic factor, and anti-inflammatory agent. This natural compound demonstrates its antidiabetic neuropathy effect through various pathways, including the reduction of lipid peroxidation, the enhancement of catalase and superoxide dismutase enzyme activity, and the decrease in inflammatory cytokine levels. The present review focuses on the bioactive and nutraceutical components of black cumin (Nigella sativa L.) and their effects on DPN. In addition, we have also summarized the findings obtained from several experimental and clinical studies regarding the antidiabetic neuropathy effect of NS in animal models and human subjects.
... In addition to being essential for the production of DNA, RNA and the antioxidant glutathione, it also aids in the structural development of the bone. Additionally, magnesium participates in the active transport of calcium and potassium ions across cell membranes, which is crucial for the transmission of nerve impulses, the contraction of muscles, and a regular heartbeat (Mazur et al. 2007, Fiorentini et al. 2021. Studies have found that people with autoimmune thyroid disorder, particularly Hashimoto's thyroiditis, tend to have lower levels of serum magnesium than healthy individuals. ...
Magnesium is a trace element that is closely linked to thyroid function and autoimmune thyroiditis. Numerous chronic disorders are also linked to low serum magnesium levels; however, it is unclear how its level relates to the development of autoimmune thyroiditis. In the present study, we evaluated the relationship between Hashimoto's thyroiditis (HT) and serum magnesium levels in 104 patients: 52 with low and 52 with normal serum magnesium levels. Patient records were retrospectively evaluated and the demographic data, serum levels of thyroid-stimulating hormone, anti-thyroid peroxidase antibody (TPOAb), anti-thyroglobulin antibody (TGAb) and serum magnesium levels were recorded. Patients with low magnesium levels were found to have higher levels of TPOAb, TGAb and radiological evidence of HT when compared to those with normal magnesium levels (P = 0.001, P = 0.007, and P = 0.001, respectively). In logistic regression analysis, ultrasonographic HT findings were found to be significantly more common in the magnesium deficient group (P = 0.001). The serum magnesium level of 0.72 mmol L-1 was determined to be the appropriate cutoff point for the presence of HT ultra-sonographic findings with 68.9% sensitivity and 64.4% specificity. As a result, in the present study, low serum magnesium levels were found to be associated with significantly higher incidence of ultrasonographic findings of HT, which may suggest that adequate magnesium supple-mentation may be an independent protective factor against Hashimoto's Thyroiditis.
... Magnesium acts as a natural calcium channel blocker, thereby it inhibits the activation of N-methyl-D-aspartate receptors and decreases central sensitization and preexisting pain hypersensitivity. [14,15] Topical moisturizers are used to combat xerosis and transepidermal water loss, thereby increasing hydration and reducing pruritus, erythema, fissuring, and lichenification. [16] Conventionally, coconut oil is used to moisturize and treat skin infections. ...
A 75-day-old male infant presented to the Naturopathy and Yoga Hospital by his mother with complaints of a dry, scaly, and itchy scalp, dry skin, and crying while passing stools for a month. He was diagnosed with atopic dermatitis (AD) using the Hanifin–Rajka criteria. The infant has been administered two topical applications on the entire body for ten days using Epsom salt (5 g) (magnesium sulfate) mixed with Aloe vera (15 g), turmeric powder (about 0.6 g) in warm coconut oil. Modifications in the mother’s diet were also advised. The case report shows remarkable changes in the symptoms with a reduction in the scaly patches on the scalp and rashes over the body. Following ten days of intervention, the baby stopped crying while passing stools. On follow-up, 30 days after the discharge, no relapses were reported, and the child was healthy. This case report shows the simple topical application of Epsom salt, coconut oil, Aloe vera , and turmeric combinations in the management of pediatric AD, inferring that, naturopathy interventions can be safe, and cost-effective in managing the AD in infants. However, further large-scale studies are warranted in this area for establishing safety, and efficacy and for large-scale applications in pediatric cases.
... All of these specific minerals have a crucial function in constructing the body. Magnesium is a vital component in a broad range of primary cellular reactions, and its absence has been linked to pathological conditions in humans (Mazur et al., 2007). The nutritional significance of magnesium's presence in fruit contributes to a well-balanced diet. ...
Non-timber forest products such as lianas provide essential nutrients for human health and should be exploited in
Burkina Faso. In order to better valorization, this study aimed to investigate the nutritional potential of Saba
senegalensis fruit. The samples of fruit were obtained from three climatic regions then biochemical composition
and nutritional content of it pulp were analyzed according to standard methods.
The results showed that pulps were acidic with pH varying from 2.85±0.12 to 3.16±0.70 and titratable acidity
4.52±0.20% to 4.89±0.40%. Brix degree, moisture content, and ash were ranged respectively from 20.11±1.50%
to 23.50±1.10%, 84.50±3.15% to 86.50±4.25%, 4.44±0.30 g/kg to 5.85±0.40 g/kg. Macronutrients contents were
3.89±0.10 to 3.89±0.10 g/kg, 4.65±0.70 to 7.78±0.50 g/kg, 19.44±1.80 to 23.80±1.40 g/kg, 146.40±11.25 to
155.70±14.50 g/kg respectively for lipids, proteins, total fibers and total carbohydrates. Vitamines rates of pulps
were respectively 15.50 ± 1.91 to 17.14 ± 1.90 mg/kg, 0.25 ± 0.05 to 0.55 ± 0.08 mg/kg, and 22.6 ± 2.30 to 27.8
± 2.90 mg/kg for vitamins B6, A and C. Pulp contain of phytonutrient and anti-nutritional factors were 105.18 ±
10.14 to 132.80 ± 15.00 mg/100g and 19.17 ± 1.16 to 39.60 ± 1.10 mg/100g for total polyphenols and flavonoids
and yet ranged 105.25 ±5.15 to 121.80 ±2.20 mg/100g, 78.51 ±0.13 to 80.30 ±1.50 mg/100g, and 20.57 ±3.50 to
26.49 ±1.30 mg/100g respectively for phytates, tannins and oxalates.
The mineral composition exhibited higher Mg, Ca, and P content as presented in the results. Principal component
analysis (PCA) revealed specific variation on nutritional composition of pulp according to climatic zone. The
study demonstrates that S. senegalensis is good nutritional source and could contribute to food security
... In relation to membrane barrier/transport/gate control functions, which modulate the cell compartment distribution of, mainly, calcium [460,461], magnesium [462,463], zinc [464][465][466], and iron [393,467] as part of their signaling/cofactor functions. Evidently, the Na + /K + equilibrium is another critical factor, often altered over the development of inflammation [468,469] because of its signaling and transport functions. ...
This review focuses on the question of metabolic syndrome (MS) being a complex, but essentially monophyletic, galaxy of associated diseases/disorders, or just a syndrome of related but rather independent pathologies. The human nature of MS (its exceptionality in Nature and its close interdependence with human action and evolution) is presented and discussed. The text also describes the close interdependence of its components, with special emphasis on the description of their interrelations (including their syndromic development and recruitment), as well as their consequences upon energy handling and partition. The main theories on MS’s origin and development are presented in relation to hepatic steatosis, type 2 diabetes, and obesity, but encompass most of the MS components described so far. The differential effects of sex and its biological consequences are considered under the light of human social needs and evolution, which are also directly related to MS epidemiology, severity, and relations with senescence. The triggering and maintenance factors of MS are discussed, with especial emphasis on inflammation, a complex process affecting different levels of organization and which is a critical element for MS development. Inflammation is also related to the operation of connective tissue (including the adipose organ) and the widely studied and acknowledged influence of diet. The role of diet composition, including the transcendence of the anaplerotic maintenance of the Krebs cycle from dietary amino acid supply (and its timing), is developed in the context of testosterone and β-estradiol control of the insulin-glycaemia hepatic core system of carbohydrate-triacylglycerol energy handling. The high probability of MS acting as a unique complex biological control system (essentially monophyletic) is presented, together with additional perspectives/considerations on the treatment of this ‘very’ human disease.
... 38 The type and duration of immune response, as well as the types and duration of cellular reactions involved, can greatly influence the healing outcome of damaged tissues, from fibrosis formation to regeneration. 39,40 Our results indicated that treatment with MgNPs/GA significantly increased the number of M2 macrophages and up-regulated the expression of M2-associated genes, while also significantly reducing pro-inflammatory factors. The density of M2 macrophages at the site of injury is crucial for achieving optimal therapeutic effects. ...
Introduction
Excessive generation of reactive oxygen species (ROS) following myocardial ischemia-reperfusion (I/R) can result in additional death of myocardial cells. The rapid clearance of ROS after reperfusion injury and intervention during subsequent cardiac repair stages are crucial for the ultimate recovery of cardiac function.
Methods
Magnesium-doped mesoporous bioactive glasses were prepared and loaded with the antioxidant drug gallic acid into MgNPs by sol-gel method. The antioxidant effects of MgNPs/GA were tested for their pro-angiogenic and anti-inflammatory effects based on the release characteristics of GA and Mg²⁺ from MgNPs/GA. Later, we confirmed in our in vivo tests through immunofluorescence staining of tissue sections at various time points that MgNPs/GA exhibited initial antioxidant effects and had both pro-angiogenic and anti-inflammatory effects during the cardiac repair phase. Finally, we evaluated the cardiac function in mice treated with MgNPs/GA.
Results
We provide evidence that GA released by MgNPs/GA can effectively eliminate ROS in the early stage, decreasing myocardial cell apoptosis. During the subsequent cardiac repair phase, the gradual release of Mg²⁺ from MgNPs/GA stimulated angiogenesis and promoted M2 macrophage polarization, thereby reducing the release of inflammatory factors.
Conclusion
MgNPs/GA acting on multiple cell types is an integrated solution for comprehensive attenuation of myocardial ischaemia-reperfusion injury and cardiac function protection.
... All of these specific minerals have a crucial function in constructing the body. Magnesium is a vital component in a broad range of primary cellular reactions, and its absence has been linked to pathological conditions in humans (Mazur et al., 2007). The nutritional significance of magnesium's presence in fruit contributes to a well-balanced diet. ...
Non-timber forest products such as lianas provide essential nutrients for human health and should be exploited in Burkina Faso. In order to better valorization, this study aimed to investigate the nutritional potential of Saba senegalensis fruit. The samples of fruit were obtained from three climatic regions then biochemical composition and nutritional content of it pulp were analyzed according to standard methods. The results showed that pulps were acidic with pH varying from 2.85±0.12 to 3.16±0.70 and titratable acidity 4.52±0.20% to 4.89±0.40%. Brix degree, moisture content, and ash were ranged respectively from 20.11±1.50% to 23.50±1.10%, 84.50±3.15% to 86.50±4.25%, 4.44±0.30 g/kg to 5.85±0.40 g/kg. Macronutrients contents were 3.89±0.10 to 3.89±0.10 g/kg, 4.65±0.70 to 7.78±0.50 g/kg, 19.44±1.80 to 23.80±1.40 g/kg, 146.40±11.25 to 155.70±14.50 g/kg respectively for lipids, proteins, total fibers and total carbohydrates. Vitamines rates of pulps were respectively 15.50 ± 1.91 to 17.14 ± 1.90 mg/kg, 0.25 ± 0.05 to 0.55 ± 0.08 mg/kg, and 22.6 ± 2.30 to 27.8 ± 2.90 mg/kg for vitamins B6, A and C. Pulp contain of phytonutrient and anti-nutritional factors were 105.18 ± 10.14 to 132.80 ± 15.00 mg/100g and 19.17 ± 1.16 to 39.60 ± 1.10 mg/100g for total polyphenols and flavonoids and yet ranged 105.25 ±5.15 to 121.80 ±2.20 mg/100g, 78.51 ±0.13 to 80.30 ±1.50 mg/100g, and 20.57 ±3.50 to 26.49 ±1.30 mg/100g respectively for phytates, tannins and oxalates. The mineral composition exhibited higher Mg, Ca, and P content as presented in the results. Principal component analysis (PCA) revealed specific variation on nutritional composition of pulp according to climatic zone. The study demonstrates that S. senegalensis is good nutritional source and could contribute to food security.
... The participation of Mg 2+ in various cellular processes and its immune regulatory role has been reported. Mg 2+ regulates cytokine production and ROS production in macrophages (19,36,37). It was proposed that Mg 2+ acted intracellularly because Mg 2+ exposure rapidly increased the intracellular Mg 2+ content, and decreased pro-inflammatory cytokine production (20). ...
Neurotransmitter receptors are increasingly recognized to play important roles in anti-tumor immunity. The expression of the ion channel N-methyl-D-aspartate receptor (NMDAR) on macrophages was reported, but the role of NMDAR on macrophages in the tumor microenvironment (TME) remains unknown. Here, we show that the activation of NMDAR triggered calcium influx and reactive oxygen species production, which fueled immunosuppressive activities in tumor-associated macrophages (TAMs) in the hepatocellular sarcoma and fibrosarcoma tumor settings. NMDAR antagonists, MK-801, memantine, and magnesium, effectively suppressed these processes in TAMs. Single-cell RNA sequencing analysis revealed that blocking NMDAR functionally and metabolically altered TAM phenotypes, such that they could better promote T cell- and Natural killer (NK) cell-mediated anti-tumor immunity. Treatment with NMDAR antagonists in combination with anti-PD-1 antibody led to the elimination of the majority of established preclinical liver tumors. Thus, our study uncovered an unknown role for NMDAR in regulating macrophages in the TME of hepatocellular sarcoma and provided a rationale for targeting NMDAR for tumor immunotherapy.
... Feeding mice with a diet lacking Mg ions accelerates the spread and metastasis of cancer cells [131,132]. Mg deficiency leads to an increase in systemic inflammation, which is characterized by increased serum levels of TNFα and other inflammatory cytokines while reduced production of antiinflammatory cytokines [133]. It has been observed that pharmacological dosages of MgSO 4 , which are conventionally administered as a tocolytic agent to impede preterm labor, effectively inhibit cytokine production [134]. ...
Metals are essential components of both micronutrients and macronutrients in living organisms and are involved in a variety of immune processes in the forms of free ions or protein-coupled complexes (metalloproteins). Multiple aspects of the immune system, from the structural and functional control of immune-related proteins to the cellular responses to immunotherapy, could be affected by metals. Therefore, the employment of metal for the regulation of immunity, termed as metalloimmunology, is gaining interest as a prevalent and efficacious approach to combating cancer. However, the manipulation of metalloimmunology using traditional drugs presents several challenges, including limited bioavailability, adverse effects, and a lack of targeting specificity. This review provides an overview of the latest findings in metal and metal-regulatory therapeutic agents for the treatment of cancer. Essential trace metal elements, such as iron, zinc, copper, manganese, magnesium, and calcium, as well as heavy metal drugs and their mechanisms of action, will be discussed with a particular focus on their roles in regulating the tumor-immune interplay. The latest nanotechnology employed in the administration of metal-regulatory drugs and the design concepts for tailored therapeutic interventions will be discussed. These concepts and information offer promising clinical possibilities of modulating cancer immunology by targeting metal metabolism.
... It has even been suggested that the hydrophobicity of SO causes retinal dehydration [5]. SO transmits more blue light, leading to phototoxicity, [37,38] and SO stimulates the production of a large number of phagocytes and pigment cells, leading to an increase in inflammatory mediators that cause retinal cell denaturation and necrosis [39]. However, there is no clear and uniform answer to this question. ...
Introduction
The tamponade of silicone oil (SO) can affect both the structure and blood flow of the retina. However, there are few studies on the effect of SO tamponade on choroidal blood flow. Our study aimed to compare the effects of SO tamponade on the choroidal vascular index (CVI) and choroidal thickness (CT) in patients with unilateral rhegmatogenous retinal detachment (RRD) with operated eyes and fellow healthy eyes.
Methods
We retrospectively collected demographic and clinical data from 36 patients who underwent 23G pars plana vitrectomy and SO tamponade for unilateral complicated RRD. Enhanced depth imaging-optical coherence tomography (EDI-OCT) scans were performed both within 1 week before SO removal and at the last follow-up visit after SO removal. Using ImageJ software, images were binarized to segment the total choroidal area, luminal area, and stromal area, respectively. The CVI was calculated as CVI=(luminal area)/(total choroidal area), and CT was also evaluated.
Results
During SO tamponade, the CVI and luminal area in operated eyes were significantly lower compared to fellow eyes (57.616 ± 0.030 vs. 60.042 ± 0.019, P < 0.0001; 0.909 [0.694; 1.185] vs. 1.091 [0.785; 1.296], P = 0.007). Even after SO removal, the CVI remained lower in operated eyes than in fellow eyes (59.530 ± 0.018 vs. 60.319 ± 0.020, P = 0.031). Both CVI and luminal area were lower in operated eyes before SO removal than after SO removal (57.616 ± 0.030 vs. 59.530 ± 0.018, P = 0.0003; 0.909 [0.694; 1.185] vs. 0.994 [0.712; 1.348], P = 0.028). The duration of SO tamponade was positively correlated with the difference in CVI between fellow eyes and operated eyes during SO tamponade (P = 0.035). Total choroidal area, stromal area, and CT did not differ significantly between fellow eyes and operated eyes or between pre- and post-SO removal.
Conclusions
SO tamponade reduces CVI and decreases choroidal blood circulation in patients with retinal detachments required vitrectomy combined with SO tamponade. The longer the SO tamponade time, the more CVI reduction. In future work, we will aim to reduce these side effects by shortening the duration of silicone oil filling.
... After signi cant magnesium de ciency occurs, patients often present with increased neuromuscular excitability, cardiac arrhythmias, pregnancy complications, osteoporosis, and impaired motor function [6]. In recent years, more and more studies have found that magnesium de ciency is associated with oxidative stress, cardiovascular disease, cognitive impairment and metabolic syndrome [7][8][9][10][11][12]. Some researches proposed that low extracellular Mg 2+ slows down endothelial cell proliferation, stimulates monocyte adhesion, signi cantly damages endothelial function, affects vascular structure and function, and stimulates atherosclerosis formation [13,14]. ...
Object: The association between magnesium depletion score (MDS) and kidney stone disease (KSD) remains unknown. This study was designed to investigate the association of MDS with KSD in adults.
Methods: A total of 19,654 participants were enrolled from the National Health and Nutrition Examination Surveys (NHANES). The MDS was calculated by assessing four aspects, including alcohol assumption, renal function, and use of diuretics and proton pump inhibitor (PPI). Multivariable logistic regressions were performed to explore the associations between MDS and the prevalence of KSD. Linear correlations were conducted explore the relationship of testosterone with MDS.
Results: In the multivariable logistic regressions with full adjustment for confounding variables, the odds ratio of MDS associating with KSD was 1.28 (95% CI: 1.04–1.58, P = 0.022) in total population, and 1.70 (95% CI: 1.16–2.50, P = 0.007) in female participants. Besides, compared to the lowest MDS, the highest MDS was associated with a lower testosterone (β = -11.548, P = 0.001) after full adjustment in non-menopause women.
Conclusion: This study highlighted a positive correlation of high MDS with KSD in female population, which may be associated low level of serum testosterone.
... Our findings contradict these results. According to previous knowledge, deficiency of Mg in blood cause inward flow of calcium ions which further results in increased stimulation of the N-methyl-d-aspartate (NMDA) receptor [25,26]. This leads to the release of inflammatory medium such as Substance P and inflammatory cytokines including interleukin-6 and tumor necrosis factor [27][28][29]. ...
Background
The relationship between Mg (magnesium), Cu (copper), and K (potassium) intakes and the risk of rheumatoid arthritis (RA) remains limited. The aim of present study was to examine the associations between Mg, Cu and K intakes with RA.
Methods
Using data from the National Health and Nutrition Examination Survey (NHANES) 2003–2018, we examined the association between Mg, Cu and K intakes and the risk of RA among US adults. After adjustment for age, sex, race, BMI, educational level, smoking history, alcohol consumption, family Poverty Income Ratio (PIR), diabetes and total daily energy intake, logistic regression models and smooth curve fitting were applied to examine the associations of Mg, Cu and K intakes with RA.
Results
A total of 18,338 participants were included (1,008 participants with RA). The multivariate adjusted ORs (95% CI) of RA were [0.66 (0.51, 0.84)], [0.76 (0.60, 0.97)], and [0.75 (0.58, 0.97)] in the highest versus lowest quartile of magnesium intakes, respectively. A nonlinear association between Cu intakes and RA was found. When Cu intake (ln) was between 0.6–2.2 mg, the risk of RA reduced by 26% for every 1 mg increase of intake in Cu [0.74 (0.58, 0.96)].
Conclusions
Higher Mg, Cu and K intakes may be inversely associated with the risk of RA among US adults, and an inverse L-shaped association between dietary Cu and RA was found.
... 71,72 Mg 2+ deficiency is a common cause of oxidative stress and inflammation-induced oxidative stress that underlies the development of many cancers. 70,73 Congruent with this, IPA of DEGs in Trpm7-Em KO 4C and 8C embryos showed an overrepresentation of canonical oxidative stress pathways. These changes translated into metabolic consequences indicative of oxidative stress and compromised mitochondrial function, confirmed by decreasing JC-1 fluorescence ratios in Trpm7-Em KO embryos. ...
TRPM7 (transient receptor potential cation channel subfamily M member 7) is a chanzyme with channel and kinase domains essential for embryo development. Using gamete-specific Trpm7-null lines, we report that TRPM7-mediated Mg²⁺ influx is indispensable for reaching the blastocyst stage. TRPM7 is expressed dynamically from gametes to blastocysts; displays stage-specific localization on the plasma membrane, cytoplasm, and nucleus; and undergoes cleavage that produces C-terminal kinase fragments. TRPM7 underpins Mg²⁺ homeostasis, and excess Mg²⁺ but not Zn²⁺ or Ca²⁺ overcomes the arrest of Trpm7-null embryos; expressing Trpm7 mRNA restores development, but mutant versions fail or are partially rescued. Transcriptomic analyses of Trpm7-null embryos reveal an abundance of oxidative stress-pathway genes, confirmed by mitochondrial dysfunction, and a reduction in transcription factor networks essential for proliferation; Mg²⁺ supplementation corrects these defects. Hence, TRPM7 underpins Mg²⁺ homeostasis in preimplantation embryos, prevents oxidative stress, and promotes gene expression patterns necessary for developmental progression and cell-lineage specification.
... Inflammatory and oxidative stress biomarkers participate in the pathophysiology of CKD and are associated with CVD progression. Evidence suggests that inflammation and oxidative stress may be influenced by Mg 2+ levels [12,13]. Few studies have evaluated the correlation between Mg 2+ serum levels and inflammatory and oxidative stress biomarkers in kidney replacement therapy treatments, such as hemodialysis (HD) and peritoneal dialysis (PD). ...
Background:
Magnesium (Mg2+) is a fundamental mineral that maintains cellular function, and low levels may be linked to inflammation in patients with chronic kidney disease (CKD). This cross-sectional study evaluated the correlation between serum Mg2+ levels and the inflammatory status in patients undergoing dialysis.
Methods:
Two hundred patients with CKD [150 undergoing hemodialysis (HD), 50 (18) years; BMI 24 (4.8) kg/m²; and 50 patients on peritoneal dialysis (PD), 54 (17.7) years; BMI, 27.5 (7.3) kg/m²] were included. Serum Mg2+ levels were evaluated using a colourimetric test and commercial kit. Inflammatory markers were assessed by ELISA and multiplex bead-based assay. Lipid peroxidation was evaluated using thiobarbituric acid-reactive substances.
Results:
The median serum Mg2+ levels were 2.3 (0.5) mg/dL, and 21% of patients presented Mg2+ deficiency (< 2.07 mg/dL or 0.85 mmol/L). We found no difference in Mg2+ serum levels between the two groups. A significant negative correlation was observed between serum Mg2+ levels and plasma hs-CRP (r =-0.17, p = 0.01), IL-8 (r =-0.35, p = 0.01), and MCP-1 (r =-0.31, p = 0.03) levels.
Conclusion:
Mg2+ serum levels were negatively correlated with inflammatory status in patients with CKD on dialysis.
... In addition to its direct antioxidant actions, magnesium influences the expression and activity of several proteins involved in the regulation of oxidative stress. Magnesium has been demonstrated to increase the expression of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which is important for activating the antioxidant response element (ARE) pathway [39]. When the Nrf2-ARE pathway is activated, the synthesis of endogenous antioxidants such as glutathione and heme oxygenase-1 (HO-1) increases, which protects against oxidative stress-induced cellular damage [40]. ...
Diabetic nephropathy (DN) is a major cause of end-stage renal disease worldwide, resulting from uncontrolled diabetes. Oxidative stress plays a critical role in the pathophysiology of DN, leading to cellular damage and disease progression. Magnesium, an essential mineral, has emerged as a potential therapeutic agent due to its antioxidative, anti-inflammatory, and antifibrotic properties. An extensive literature search was conducted on Medline using the keywords "Diabetic nephropathy," "Magnesium," and "Chronic Kidney Disease," and the results published after 2000 were exclusively studied to build this review. This review aims to summarize the role of magnesium in DN and explore its therapeutic potential. Magnesium acts as a cofactor for antioxidant enzymes, directly scavenges reactive oxygen species, and enhances the expression of antioxidant proteins. Furthermore, magnesium exhibits anti-inflammatory effects by suppressing pro-inflammatory cytokine production and inhibiting inflammatory signaling pathways. Magnesium supplementation has been shown to reduce oxidative stress markers and improve antioxidant enzyme activities in clinical studies. Additionally, magnesium has been found to mitigate renal fibrosis, maintain tubular integrity and function, improve endothelial function, and modulate renal hemodynamics. Although limited clinical trials suggest the renoprotective effects of magnesium in DN, further research is needed to determine the optimal dosage, duration, and long-term effects of magnesium supplementation. Despite existing drawbacks and gaps in the literature, magnesium holds promise as adjunctive therapy for DN by targeting oxidative stress and preserving renal function.
High blood pressure (BP) is a significant contributor to the disease burden globally and is emerging as an important cause of morbidity and mortality in the young as well as the old. The well-established impact of high BP on neurodegeneration, cognitive impairment, and dementia is widely acknowledged. However, the influence of BP across its full range remains unclear. This review aims to explore in more detail the effects of BP levels on neurodegeneration, cognitive function, and dementia. Moreover, given the pressing need to identify strategies to reduce BP levels, particular attention is placed on reviewing the role of magnesium (Mg) in ageing and its capacity to lower BP levels, and therefore potentially promote brain health. Overall, the review aims to provide a comprehensive synthesis of the evidence linking BP, Mg and brain health. It is hoped that these insights will inform the development of cost-effective and scalable interventions to protect brain health in the ageing population.
Magnesium (Mg²⁺) is crucial for several cellular and physiological processes and is tightly regulated due to health risks associated with imbalances. Mg²⁺, calcium (Ca²⁺), parathyroid hormone, and vitamin D3 are tightly coupled, ensuring proper bone metabolism and intestinal and renal absorption of Mg²⁺ and Ca²⁺. While several Ca²⁺ homeostasis models exist, no computational model has been developed to study Mg²⁺ homeostasis. We developed a computational model of Mg²⁺ homeostasis in male rats, integrating it with an existing Ca²⁺ homeostasis model, to understand the interconnected physiological processes regulating their homeostasis. We then analyzed adaptations in these interconnected processes under (1) dietary Mg²⁺ deficiency, (2) low/high dietary Ca²⁺ with Mg²⁺ deficiency, and (3) vitamin D3 deficiency. Model simulations predicted severe hypomagnesemia and mild hypocalcemia with significant dietary Mg²⁺ deficiency. Low dietary Ca²⁺ improved, while high dietary Ca²⁺ worsened Mg²⁺ deficiency. Finally, vitamin D3 deficiency caused severe hypocalcemia, with minimal impact on Mg²⁺ homeostasis.
The inflammatory status of the kidneys, vasculature, and perivascular adipose tissue (PVAT) has a significant influence on blood pressure and hypertension. Numerous micronutrients play an influential role in hypertension-driving inflammatory processes, and recent reports have provided bases for potential targeted modulation of these micronutrients to reduce hypertension. Iron overload in adipose tissue macrophages and adipocytes engenders an inflammatory environment and may contribute to impaired anticontractile signalling, and thus a treatment such as chelation therapy may hold a key to reducing blood pressure. Similarly, magnesium intake has proven to greatly influence inflammatory signalling and concurrent hypertension in both healthy animals and in a model for chronic kidney disease, demonstrating its potential clinical utility. These findings highlight the importance of further research to determine the efficacy of micronutrient-targeted treatments for the amelioration of hypertension and their potential translation into clinical application.
Magnesium (Mg) deficiency is associated with increased risk and malignancy in colorectal cancer (CRC), yet the underlying mechanisms remain elusive. Here, we used genomic, proteomic, and phosphoproteomic data to elucidate the impact of Mg deficiency on CRC. Genomic analysis identified 160 genes with higher mutation frequencies in Low-Mg tumors, including key driver genes such as KMT2C and ERBB3. Unexpectedly, initiation driver genes of CRC, such as TP53 and APC, displayed higher mutation frequencies in High-Mg tumors. Additionally, proteomic and phosphoproteomic data indicated that low Mg content in tumors may activate epithelial–mesenchymal transition (EMT) by modulating inflammation or remodeling the phosphoproteome of cancer cells. Notably, we observed a negative correlation between the phosphorylation of DBN1 at S142 (DBN1S142p) and Mg content. A mutation in S142 to D (DBN1S142D) mimicking DBN1S142p upregulated MMP2 and enhanced cell migration, while treatment with MgCl2 reduced DBN1S142p, thereby reversing this phenotype. Mechanistically, Mg2+ attenuated the DBN1–ACTN4 interaction by decreasing DBN1S142p, which in turn enhanced the binding of ACTN4 to F-actin and promoted F-actin polymerization, ultimately reducing MMP2 expression. These findings shed new light on the crucial role of Mg deficiency in CRC progression and suggest that Mg supplementation may be a promising preventive and therapeutic strategy for CRC.
Background:
Higher magnesium intake was linked to lower risk of hepatocellular carcinoma (HCC). However, the relationship between blood magnesium level and HCC has not been fully characterized, especially among liver cirrhosis patients who are at higher risk for HCC.
Methods:
In the Mass General Brigham Biobank, we developed a new prospective cohort of 1,460 liver cirrhosis patients without liver cancer history using the validated International Classification of Diseases codes. We used Cox proportional hazard models to generate hazard ratios (HRs) with 95% confidence intervals (CIs) for incident HCC, and used generalized estimating equations to compare changes in liver biomarkers according to baseline blood magnesium, adjusting for age, sex, race, lifestyles, body mass index, type 2 diabetes, model for end-stage liver disease score, and hepatitis infection.
Results:
During a median follow-up period of 4.26 years, 109 developed HCC. Magnesium deficiency (<1.70mg/dL; N = 158) was associated with a higher risk of HCC (HR =1.88; 95%CI:1.10-3.22) compared to magnesium sufficiency. This association remained robust in the 1-year lag analysis (HR=2.19; 95%CI:1.12-4.29) and in sensitivity analysis excluding patients with alcoholic liver disease (HR=2.26; 95%CI:1.16-4.42). Magnesium in the lowest quartile was associated with a faster increase in alanine transaminase (β=3.74; 95%CI:0.51-6.97), direct bilirubin (β=0.18; 95%CI:0.01-0.35), and total bilirubin (β=0.20; 95%CI:0.02-0.37), compared to the highest quartile.
Conclusions:
Lower blood magnesium level is associated with higher HCC risk and unfavorable liver biomarkers changes.
Impact:
If confirmed, our findings may potentially enable better identification of high-risk patients for HCC and inform better management strategies for liver cirrhosis.
Introduction: Rotator cuff tear (RCT) is a common shoulder injury impacting mobility and quality of life, while traditional surgeries often result in poor healing. Tissue engineering offers a promising solution, with poly (ε-caprolactone) (PCL) being favored due to its slow degradation, biocompatibility, and non-toxicity. However, PCL lacks sufficient compression resistance. Incorporating Mg, which promotes bone growth and has antibacterial effects, could enhance RCT repair.
Methods: The Mg-incorporated PCL-based scaffolds were fabricated using a 3D printing technique. The scaffolds were incorporated with different percentages of Mg (0%, 5%, 10%, 15%, and 20%). The osteogenic activities and anti-inflammatory properties of the scaffolds were evaluated in vitro using human osteoblasts and macrophages. The tissue ingrowth and biocompatibility of the scaffolds were assessed in vivo using a rat model of RCT repair. The ability of the scaffolds to enhance macrophage polarization towards the M2 subtype and inhibit inflammation signaling activation was also investigated.
Results: It was found that when incorporated with 10% Mg, PCL-based scaffolds exhibited the optimal bone repairing ability in vitro and in vivo. The in vitro experiments indicated that the successfully constructed 10 Mg/PCL scaffolds enhance osteogenic activities and anti-inflammatory properties. Besides, the in vivo studies demonstrated that 10 Mg/PCL scaffolds promoted tissue ingrowth and enhanced biocompatibility compared to the control PCL scaffolds. Furthermore, the 10 Mg/PCL scaffolds enhanced the macrophages’ ability to polarize towards the M2 subtype and inhibited inflammation signaling activation.
Discussion: These findings suggest that 3D-printed Mg-incorporated PCL scaffolds have the potential to improve RCT by enhancing osteogenesis, reducing inflammation, and promoting macrophage polarization. The incorporation of 10% Mg into PCL-based scaffolds provided the optimal combination of properties for RCT repair augmentation. This study highlights the potential of tissue engineering approaches in improving the outcomes of RCT repair and provides a foundation for future clinical applications.
Cardiovascular diseases (CVDs) pose a significant global health challenge, with diet playing a crucial role beyond conventional risk factors. Nutrient deficiencies and dietary elements significantly impact CVD susceptibility and severity, notably influencing thrombosis, a key contributor to CVDs like venous thromboembolism (VTE), coronary artery disease (CAD), and stroke. Understanding the dietary impact on thrombosis and CVD pathophysiology is essential for mitigating genetic predispositions through dietary adjustments. This chapter explores the protective effects of daily dietary nutrients, including vitamins, minerals, omega fatty acids, polyphenols, carbohydrates, fiber, and caloric balance, on common CVDs. It also investigates various dietary constituents' effects on thrombus formation mechanisms. These insights will assist healthcare professionals in guiding patients to modify dietary habits for CVD prevention and management, underscoring the importance of informed dietary choices in reducing the burden of CVDs.
The relationship between chronic kidney disease-mineral and bone disorder (CKD-MBD) and cognitive function remains largely unknown. This cross-sectional study aimed to explore the association between CKD-MBD and cognitive function in patients on hemodialysis.
Hemodialysis patients aged ≥ 65 years without diagnosed dementia were included. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). CKD-MBD markers, serum magnesium, intact parathyroid hormone (PTH), 25-hydroxyvitamin D (25-OHD), fibroblast growth factor (FGF)-23, and soluble α-klotho were measured.
Overall, 390 patients with a median age of 74 (interquartile range, 70–80) years, mean serum magnesium level of 2.4 ± 0.3 mg/dL, and median MoCA and MMSE scores of 25 (22–26) and 28 (26–29), respectively, were analyzed. MoCA and MMSE scores were significantly higher (preserved cognitive function) in the high-magnesium group than in the low-magnesium group according to the unadjusted linear regression analysis (β coefficient [95% confidence interval (CI)] 1.05 [0.19, 1.92], P = 0.017 for MoCA; 1.2 [0.46, 1.94], P = 0.002 for MMSE) and adjusted multivariate analysis with risk factors for dementia (β coefficient [95% CI] 1.12 [0.22, 2.02], P = 0.015 for MoCA; 0.92 [0.19, 1.65], P = 0.014 for MMSE).
Higher serum magnesium levels might be associated with preserved cognitive function in hemodialysis patients. Conversely, significant associations were not observed between cognitive function and intact PTH, 25-OHD, FGF-23, or soluble α-klotho levels.
This book chapter delves into the intricate relationship between psychopharmacology, psychiatric disorders, and food intake. Psychiatric disorders such as depression, anxiety, bipolar disorder, and schizophrenia are often associated with alterations in appetite, eating behaviors, and food preferences, which can profoundly impact nutritional status and overall health outcomes. The chapter explores the multifaceted effects of psychotropic medications on food intake, metabolism, and weight regulation, elucidating both therapeutic and adverse effects. Furthermore, it examines the bidirectional influence between nutritional factors and psychotropic medications, emphasizing the importance of a comprehensive approach to treatment that considers both pharmacological and dietary interventions. Insights from preclinical and clinical studies shed light on the complex mechanisms underlying the interplay between psychopharmacology and food intake, offering valuable implications for personalized treatment strategies and the management of psychiatric disorders.
Magnesium (Mg), a nutritional element which is essential for bone development and mineralization, has a role in the progression of osteoporosis. Osteoporosis is a multifactorial disease characterized by significant deterioration of bone microstructure and bone loss. Mg deficiency can affect bone structure in an indirect way through the two main regulators of calcium homeostasis (parathyroid hormone and vitamin D). In human osteoblasts (OBs), parathyroid hormone regulates the expression of receptor activator of nuclear factor-κ B ligand (RANKL) and osteoprotegerin (OPG) to affect osteoclast (OC) formation. In addition, Mg may also affect the vitamin D3 -mediated bone remodeling activity. vitamin D3 usually coordinates the activation of the OB and OC. The unbalanced activation OC leads to bone resorption. The RANK/RANKL/OPG axis is considered to be a key factor in the molecular mechanism of osteoporosis. Mg participates in the pathogenesis of osteoporosis by affecting the regulation of parathyroid hormone and vitamin D levels to affect the RANK/RANKL/OPG axis. Different factors affecting the axis and enhancing OC function led to bone loss and bone tissue microstructure damage, which leads to the occurrence of osteoporosis. Clinical research has shown that Mg supplementation can alleviate the symptoms of osteoporosis to some extent.
The magnesium ion is an essential cation in the human body and participates in numerous physiological activities. A deficiency in magnesium ions is closely associated with tumor development, and supplementation with magnesium ions has been shown to partially inhibit tumor growth. However, the specific mechanisms by which magnesium ions suppress tumor proliferation remain unclear. Currently, studies have revealed that mitochondria may serve as a crucial intermediate link in the regulation of tumors by magnesium ions. Mitochondria might intervene in the proliferation and invasion of tumor cells by modulating energy metabolism and oxidative stress levels. Therefore, this article provides a comprehensive review of the relationship between magnesium ions and tumors, the mechanisms by which magnesium ions regulate mitochondrial function, and the theoretical basis and prospects of magnesium ion regulation of mitochondrial function for tumor treatment. This review aims to offer insights for clinical tumor treatment strategies involving magnesium ion intervention.
The problem of treating inflammatory bowel disease continues to be a topic of great interest for researchers. Despite the complexity surrounding their treatment and strategies to prolong periods of remission, there is a promising exploration of various compounds that have potential in combating inflammation and alleviating symptoms. Selenium, calcium, magnesium, zinc, and iron are among these compounds, offering a glimpse of hope in the treatment of IBD. These essential minerals not only hold the promise of reducing inflammation in these diseases, but also show the potential to enhance immune function and possibly influence the balance of intestinal microflora. By potentially modulating the gut microbiota, they may help support overall immune health. Furthermore, these compounds could play a crucial role in mitigating inflammation and minimising complications in patients with IBD. Furthermore, the protective effect of these compounds against mucosal damage in IBD and the protective effect of calcium itself against osteoporosis in this group of patients are notable.
Background
Regular physical exercise is an essential part of a healthy lifestyle, maintaining and strengthening public health. Recently, a steady increase in the number of recurrent musculoskeletal injuries occurring during physical exercise is being diagnosed. A serious risk factor for such damage is initial connective tissue pathology. Pathognomonic dysplastic phenotypes, indicating a particular susceptibility to injuries, were established. The decisive role in increasing connective tissue disorders severity is attributed in part to magnesium deficiency that is one of the most common deficient human conditions.
Objective
To present the magnesium role in connective tissue homeostasis for pathogenetic substantiation of magnesium correction in persons with predisposition to musculoskeletal injuries.
Methods
An analytical review of recent data published between January 2004 and December 2023 in the electronic resources such as Global Health, ScienceDirect, Elsevier, Medline, Embase, PubMed-NCBI, RSCI Scopus, Cochrane Library, e-Library, Google Academy, and CyberLeninka was conducted. Data analysis was performed from January 2023 to December 2023.
Results
The analysis of the obtained data allowed to identify the main pathogenetic mechanisms of magnesium deficiency effect on connective tissues, including RNA cell destabilization, inactivation of hyaluronan synthetases, modulation of hyaluronidase activity, stimulation of matrix metalloproteinases, deactivation of elastase, realization of autoimmune reaction, lysyl oxidase, and transglutaminase activation. These processes result in increased degradation of collagen, elastin, and hyaluronan polysaccharide chains; reduction of cross-linking of fibrous structure; and intensification of inflammatory processes. This leads to defective connective tissue formation and increases sensitivity to physical stress and the risk of injury. Active magnesium participates in almost all biochemical reactions of connective tissue metabolism, and the impossibility of its synthesis in the body requires sufficient intake of this element with food and water. In the case of moderate-to-severe magnesium deficiency, it is pathogenetically reasonable to prescribe magnesium supplementation, which should take into account comorbidities, severity of deficiency, and age.
Conclusion
Regular therapy with magnesium preparations helps to improve the mechanical properties of connective tissues, prevent the progression of dysplastic disorders, reduce the risk of injury, and maintain health during physical exercise.
Magnesium is an essential ion in the human body that regulates numerous physiological and pathological processes. Magnesium deficiency is very common in old age. Age-related chronic diseases and the aging process itself are frequently associated with low-grade chronic inflammation, called ‘inflammaging’. Because chronic magnesium insufficiency has been linked to excessive generation of inflammatory markers and free radicals, inducing a chronic inflammatory state, we formerly hypothesized that magnesium inadequacy may be considered among the intermediaries helping us explain the link between inflammaging and aging-associated diseases. We show in this review evidence of the relationship of magnesium with all the hallmarks of aging (genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, disabled autophagy, dysbiosis, and chronic inflammation), which may positively affect the human healthspan. It is feasible to hypothesize that maintaining an optimal balance of magnesium during one’s life course may turn out to be a safe and economical strategy contributing to the promotion of healthy aging. Future well-designed studies are necessary to further explore this hypothesis.
Treatment of bone defects resulting after tumor surgeries, accidents, or non-unions is an actual problem linked to morbidity and the necessity of a second surgery and often requires a critical healthcare cost. Although the surgical technique has changed in a modern way, the treatment outcome is still influenced by patient age, localization of the bone defect, associated comorbidities, the surgeon approach, and systemic disorders. Three-dimensional magnesium-based scaffolds are considered an important step because they can have precise bone defect geometry, high porosity grade, anatomical pore shape, and mechanical properties close to the human bone. In addition, magnesium has been proven in in vitro and in vivo studies to influence bone regeneration and new blood vessel formation positively. In this review paper, we describe the magnesium alloy’s effect on bone regenerative processes, starting with a short description of magnesium’s role in the bone healing process, host immune response modulation, and finishing with the primary biological mechanism of magnesium ions in angiogenesis and osteogenesis by presenting a detailed analysis based on a literature review. A strategy that must be followed when a patient-adapted scaffold dedicated to bone tissue engineering is proposed and the main fabrication technologies are combined, in some cases with artificial intelligence for Mg alloy scaffolds, are presented with examples. We emphasized the microstructure, mechanical properties, corrosion behavior, and biocompatibility of each study and made a basis for the researchers who want to start to apply the regenerative potential of magnesium-based scaffolds in clinical practice. Challenges, future directions, and special potential clinical applications such as osteosarcoma and persistent infection treatment are present at the end of our review paper.
Rheumatoid arthritis (RA) is a type of the autoimmune disease that adversely effects on the quality of life of the patient, primarily by affecting the joints. Different underlying immune system diseases through a common pathway may proceed to onset of rheumatoid arthritis. Magnesium (Mg) is one of the other essential minerals having significant role in the management of normal immune responses in inflammatory conditions. The exact role of magnesium deficiency (MgD) in pathophysiology of rheumatoid arthritis is still under debate, but several mechanisms are proposed through which, MgD leads to generation of inappropriate immune system functions. Most of the dietary Mg is absorbed in small intestine through paracellular passive mechanism while small amount is transported in blood through Transient Receptor Potential Channel Melastatin member 6 and 7 (TRPM6 and TRPM7). Genetic alterations in TRPM gene results in hypomagnesaemia, which may in turn, increase the risk of onset of pro-inflammatory mediators.
Experimental Mg deficiency leads to alterations in the immune response. Reduction of thymus weight and histological changes were previously observed in Mg-deficient rats after several weeks on a deficient diet, suggesting that functions of this immune organ may be affected by Mg deficiency. More recently, changes in the immune system during early Mg deficiency were shown. Thus, in the present study we examined modifications in the thymus during the early stages of Mg deficiency in weanling rats. From our results, it appears that Mg deficiency accelerates thymus involution. The assessment of apoptosis (enumeration of apoptotic cells on the basis of morphological criteria and intranucleosomal degradation of genomic DNA) showed greater values in thymuses from Mg-deficient rats as compared with controls. This was observed very early, since a significant difference was shown on the second day of deficiency, before reduced weight of thymus, which was recorded in the later period. These results indicate the relationship of accelerated thymus involution with an active process of cell death. Mg deficiency led to histological changes in the thymus. In the early stage of deficiency (second day) the presence of inflammatory cells was shown, suggesting that the inflammatory process was already occurring in the tissue studied. Later (eighth day) an increased proportion of epithelial reticular cells in the cortex was shown, indicating a remodelling process occurring in this period. Enhanced susceptibility to peroxidation also occurred very early during Mg deficiency. It may be hypothesized that disturbances in Mg status of short duration could have cellular effects with various deleterious consequences.
1. Weanling Wistar rats were pair fed for 10 weeks on a purified diet containing either normal or suboptimal quantities of magnesium (960 or 80 mg/kg respectively).
2. At week 2, hypomagnesaemia was accompanied by hypertriglyceridaemia, an increase in plasma cholesterol and a decrease in high-density-lipoprotein-cholesterol in animals fed on the Mg-deficient diet. At week 10, the increase in triglycerides observed in Mg-deficient animals was less marked while the increase in total cholesterol was more important.
3. During the whole experimental period, Mg-deficient animals never showed hypertension. At week 2, mean arterial blood pressure was significantly lower in Mg-deficient rats than in their respective controls, while heart rate was significantly increased. However, hypotension accompanied by tachycardia was a transitory phenomenon which appeared only in the early phase of deficiency.
4. Vascular reactivity was studied in vagotomized anaesthetized rats after ganglionic blockade with pentolinium and atropine sulphate. The reactivity to noradrenaline was significantly higher in Mg-deficient rats compared with pair-fed controls after 2 weeks on the experimental diet.
Preexisting magnesium deficiency may alter the susceptibility of rat hearts to postischemic oxidative injury (free radicals). This was examined in rats maintained for 3 weeks on a magnesium-deficient (Mg-D) diet with or without concurrent vitamin E treatment (1.2 mg/day, SC). Magnesium-sufficient (Mg-S) rats received the same diet supplemented with 100 mmol Mg/kg feed. Following sacrifice, isolated working hearts were subjected to 30-, 40-, or 60-min global ischemia and 30-min reperfusion. Postischemic production of free radicals was monitored using electron spin resonance (ESR) spectroscopy and spin trapping with alpha-phenyl-N-tert butylnitrone (PBN, 3 mM final); preischemic and postischemic effluent samples were collected and then extracted with toluene. PBN/alkoxyl adduct(s) (PBN/RO.; alpha H = 1.93 G, alpha N = 13.63 G) were the dominant signals detected in untreated Mg-S and Mg-D postischemic hearts, with comparably higher signal intensities observed for the Mg-D group following any ischemic duration. Time courses of postischemic PBN/RO. detection were biphasic for both groups (maxima: 2-4 and 8.5-12.5 min), and linear relationships between the extent of PBN/RO. production and the severity of both mechanical dysfunction and tissue injury were determined. Following each duration of ischemia, Mg-D hearts displayed greater levels of total PBN adduct production (1.7-2.0 times higher) and lower recovery of cardiac function (42-48% less) than Mg-S hearts. Pretreating Mg-D rats with vitamin E prior to imposing 40-min ischemia/reperfusion, led to a 49% reduction in total PBN/RO. production, a 55% lower LDH release and a 2.2-fold improvement in functional recovery, compared to untreated Mg-D hearts. These data suggest that magnesium deficiency predisposes postischemic hearts to enhanced oxidative injury and functional loss, and that antioxidants may offer significant protection against the pro-oxidant influence(s) of magnesium deficiency.
Magnesium deficiency produces a pro-oxidant systemic inflammation in rats. The purpose of these experiments was to determine if and when there is any oxidation of cellular proteins. We have found there is a significant increase in protein oxidation products, protein carbonyls, in both the brain and the kidney within 2 to 3 weeks on a magnesium deficient diet. These changes occur prior to any detectable changes in cellular glutathione, tissue damage or dysfunction. We conclude that oxidation of cellular proteins occur early in magnesium deficiency and may contribute to the tissue damage and loss of function observed in the later stages of the deficiency. This is the first demonstration of the time course of protein oxidation product development in magnesium deficient animals.
Recent data have revealed that the plasma concentration of inflammatory mediators, such as tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), is increased in the insulin resistant states of obesity and type 2 diabetes, raising questions about the mechanisms underlying inflammation in these two conditions. It is also intriguing that an increase in inflammatory mediators or indices predicts the future development of obesity and diabetes. Two mechanisms might be involved in the pathogenesis of inflammation. Firstly, glucose and macronutrient intake causes oxidative stress and inflammatory changes. Chronic overnutrition (obesity) might thus be a proinflammatory state with oxidative stress. Secondly, the increased concentrations of TNF-α and IL-6, associated with obesity and type 2 diabetes, might interfere with insulin action by suppressing insulin signal transduction. This might interfere with the anti-inflammatory effect of insulin, which in turn might promote inflammation.
Context Type 2 diabetes and attendant cardiovascular morbidity are becoming major health concerns globally. Obesity-related type 2 diabetes is rapidly rising in prevalence, probably largely because of increased longevity and sedentary lifestyles. Insulin resistance and type 2 diabetes are associated with increased coronary heart disease, but the severity of glycaemia during the diabetic phase can only to a minor extent explain the increased risk. Increased levels of the acute-phase inflammatory marker, C-reactive protein (CRP), are related to insulin resistance and the metabolic syndrome, suggesting a role for chronic low-grade inflammation. CRP levels might predict the development of type 2 diabetes. Starting point Subodh Verma and associates (Circulation 2004; 109: 2058-67) recently showed that CRP attenuates the survival, differentiation, and function of endothelial progenitor cells, partly by CRP reducing expression of endothelial nitric-oxide synthase. Rosiglitazone, a peroxisome-proliferator-activator receptor gamma agonist, inhibits the negative effects of CRP on endothelial progenitor cells. The results are consistent with the suggestion that CRP directly promotes atherosclerotic processes and endothelial cell inflammation. CRP might thus directly trigger the development of a proinflammatory and proatherosclerotic state, leading to atherothrombosis. Where next Cell-surface CRP receptors and signalling pathways need to be characterised. From such study might come novel drugs that will defer proinflammatory reactions leading to insulin resistance and atherothrombosis.
The NF-κB family consists of a group of inducible transcription factors which regulate immune and inflammatory responses and protect cells from undergoing apoptosis in response to cellular stress. A number of signal transduction cascades can activate the NF-κB pathway to result in the translocation of the NF-κB proteins from the cytoplasm to the nucleus where they activate the expression of specific cellular genes. In this review, we discuss cellular genes which are regulated by NF-κB and disease states which are associated with constitutive activation of the NF-κB pathway. Strategies to prevent prolonged activation of the NF-κB pathway are also discussed.
The Silences of the Archives, the Reknown of the Story.
The Martin Guerre affair has been told many times since Jean de Coras and Guillaume Lesueur published their stories in 1561. It is in many ways a perfect intrigue with uncanny resemblance, persuasive deception and a surprizing end when the two Martin stood face to face, memory to memory, before captivated judges and a guilty feeling Bertrande de Rols. The historian wanted to go beyond the known story in order to discover the world of the heroes. This research led to disappointments and surprizes as documents were discovered concerning the environment of Artigat’s inhabitants and bearing directly on the main characters thanks to notarial contracts. Along the way, study of the works of Coras and Lesueur took a new direction. Coming back to the affair a quarter century later did not result in finding new documents (some are perhaps still buried in Spanish archives), but by going back over her tracks, the historian could only be struck by the silences of the archives that refuse to reveal their secrets and, at the same time, by the possible openings they suggest, by the intuition that almost invisible threads link here and there characters and events.
The objective of this study was to examine the relationships of serum and dietary magnesium (Mg) with prevalent cardiovascular disease (CVD), hypertension, diabetes mellitus, fasting insulin, and average carotid intimal-medial wall thickness measured by B-mode ultrasound. A cross-sectional design was used. The setting was the Atherosclerosis Risk in Communities (ARIC) Study in four US communities. A total of 15,248 participants took part, male and female, black and white, aged 45–64 years. Fasting serum Mg, lipids, fasting glucose and insulin were measured; as was usual dietary intake by food frequency questionnaire and carotid intima-media thickness by standardized B-mode ultrasound methods. The results showed that serum Mg levels and dietary Mg intake were both lower in blacks than whites. Mean serum Mg levels were significantly lower in participants with prevalent CVD, hypertension, and diabetes than in those free of these diseases. In participants without CVD, serum Mg levels were also inversely associated with fasting serum insulin, glucose, systolic blood pressure and smoking. Dietary Mg intake was inversely associated with fasting serum insulin, plasma high density lipoprotein-cholesterol, systolic and diastolic blood pressure. Adjusted for age, race, body mass index, smoking, hypertension, Low density lipoprotein-cholesterol, and field center, mean carotid wall thickness increased in women by 0.0118mm (p = 0.006) in diuretic users and 0.0048 mm (p = 0.017) in nonusers for each 0.1 mmol/1 decrease in serum Mg level; the multivariate association in men was not significant. In conclusion, low serum and dietary Mg may be related to the etiologies of CVD, hypertension, diabetes, and atherosclerosis.
The importance of inflammatory processes in the pathology of Mg deficiency has been recently reconsidered but the sequence of events leading to the inflammatory response remains unclear. Thus, the purpose of the present study was to characterize more precisely the acute phase response following Mg deficiency in the rat. Weaning male Wistar rats were pair-fed either a Mg-deficient or a control diet for either 4 or 8 days. The characteristic allergy-like crisis of Mg-deficient rats was accompanied by a blood leukocyte response and changes in leukocytes subpopulations. A significant increase in interleukin-6 (IL-6) plasma level was observed in Mg-deficient rats compared to rats fed a control diet. The inflammatory process was accompanied by an increase in plasma levels of acute phase proteins. The concentrations of α2-macroglobulin and α1-acid glycoprotein in the plasma of Mg-deficient rats were higher than in control rats. This was accompanied in the liver by an increase in the level of mRNA coding for these proteins. Moreover, Mg-deficient rats showed a significant increase in plasma fibrinogen and a significant decrease in albumin concentrations. Macrophages found in greater number in the peritoneal cavity of Mg-deficient rats were activated endogenously and appeared to be primed for superoxide production following phorbol myristate acetate stimulation. A high plasma level of IL-6 could be detected as early as day 4 for the Mg-deficient diet. Substance P does not appear to be the initiator of inflammation since IL-6 increase was observed without plasma elevation of this neuropeptide. The fact that the inflammatory response was an early consequence of Mg deficiency suggests that reduced extracellular Mg might be responsible for the activated state of immune cells.
Magnesium (Mg)-deficient rats develop a mechanical hyperalgesia which is reversed by a N-Methyl-D-Aspartate (NMDA) receptor antagonist. Given that functioning of this receptor-channel is modulated by Mg, we wondered whether facilitated activation of NMDA receptors in Mg deficiency state may in turn trigger a cascade of specific intracellular events present in persistent pain. Hence, we tested several antagonists of NMDA and non-NMDA receptors as well as compounds interfering with the functioning of intracellular second messengers for effects on hyperalgesia in Mg-deficient rats.
Hyperalgesic Mg-deficient rats were administered intrathecally (10 μl) or intraperitoneally with different antagonists. After drug injection, pain sensitivity was evaluated by assessing the vocalization threshold in response to a mechanical stimulus (paw pressure test) over 2 h.
Intrathecal administration of MgSO4 (1.6, 3.2, 4.8, 6.6 μmol) as well as NMDA receptor antagonists such as MK-801 (0.6, 6.0, 60 nmol), AP-5 (10.2, 40.6, 162.3 nmol) and DCKA (0.97, 9.7, 97 nmol) dose-dependently reversed the hyperalgesia. Chelerythrine chloride, a protein kinase C (PKC) inhibitor (1, 10.4, 104.2 nmol) and 7-NI, a specific nitric oxide (NO) synthase inhibitor (37.5, 75, 150 μmol kg−1, i.p.) induced an anti-hyperalgesic effect in a dose-dependent manner. SR-140333 (0.15, 1.5, 15 nmol) and SR-48968 (0.17, 1.7, 17 nmol), antagonists of neurokinin receptors, produced a significant, but moderate, increase in vocalization threshold.
These results demonstrate that Mg-deficiency induces a sensitization of nociceptive pathways in the spinal cord which involves NMDA and non-NMDA receptors. Furthermore, the data is consistent with an active role of PKC, NO and, to a lesser extent substance P in the intracellular mechanisms leading to hyperalgesia.
British Journal of Pharmacology (2001) 134, 1227–1236; doi:10.1038/sj.bjp.0704354
For several decades the animal models of Mg-deficiency have been studied with particular attention to the cardiomyopathy that develops due to dietary deficiency. In recent years we have studied the effects of nutrients and drugs with antioxidant properties on the development of the cardiomyopathy. We have found that treatment of the Mg-deficient animals with alpha-tocopherol, a naturally-occurring antioxidant, significantly diminishes the number and size of lesions. In addition, treatment with lipophilic drugs with antioxidant properties (probucol, propranolol) or water-soluble drugs that scavenge hydroxyl radicals (captopril, epicaptopril), also provided significant protection. In view of these findings, we suggest that chronic hypomagnesemia results in a pro-inflammatory condition leading to excessive production of oxygen-derived free radicals. Subsequently, the tissue antioxidant capacity is overwhelmed and oxidative tissue destruction results.
Previous studies in our laboratory have indicated a role for free radical participation in magnesium deficiency cardiomyopathy. We have demonstrated the ability of various antioxidant drugs and nutrients to protect against magnesium deficiency-induced myocardial injury. In this study, we have examined erythrocytes from normal and magnesium-deficient animals and compared their susceptibility to an in vitro oxidative stress. Syrian male hamsters were placed on either magnesium-deficient or magnesium-supplemented diets. Animals from each group also received vitamin E in doses of 10 and 25 mg as subcutaneous implants. Erythrocytes obtained after 14 days on the diet were exposed to an exogenous hydroxyl (.OH) radical generating system (dihydroxyfumarate not equal to Fe3+ ADP) at 37 degrees C for 20 min. Erythrocyte crenation was observed and quantified by scanning electron microscopy. Lipid peroxidation, hemolysis (%), and intracellular glutathione levels were determined. In addition, serum lipid changes and membrane phospholipids were characterized. Our data demonstrate that erythrocytes from magnesium-deficient animals are more susceptible to free radical injury, supporting our hypothesis that magnesium deficiency reduces the threshold antioxidant capacity.
During the progression of Mg deficiency in a rodent model, we have observed dramatic increases in serum levels of inflammatory cytokines [interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha)] after 3 wk on a Mg-deficient diet. Sequential analyses of these cytokine changes in the serum of rats revealed an initial rise at day 12, followed by a major elevation in all three cytokine levels by day 21. Of greater interest was an early peak in the serum level of the neuropeptide substance P after only 5 days on the diet. This "neuronal" tachykinin is thought to be released from neural tissues, and it is known to stimulate production of certain cytokines, including IL-1, IL-6, and TNF-alpha. In addition, there was a concomitant increase in histamine levels, which may have resulted from stimulation and degranulation of mast cells by substance P. Thus we hypothesize that the release of substance P may be the earliest pathophysiological event leading to stimulation of the inflammatory cytokines, which may then stimulate the free radical mechanisms of injury previously confirmed by our work.
Magnesium deficit may be considered as a cardiovascular risk because of its aetiopathogenic role in the genesis of atherogenous dyslipidaemias and the so-called "idiopathic" mitral valve prolapse. It does not, however, constitute a major antihypertensive factor, though it may sometimes be an accessory co-factor. Plasma magnesium is generally normal in untreated hypertensive patients and normotension is the rule during magnesium deficit. An inverse relationship between magnesium and renin in the plasma of hypertensives has not been confirmed. In practice, plasma magnesium seems to be related to the evolution of the disease. An inverse correlation between blood pressure and erythrocyte total and free magnesium levels has been observed in diverse selected populations but no adjustment has been made in these studies for important covariables. A weak positive association between blood pressure and erythrocyte free magnesium was lost in a multivariate regression analysis. As a rule there is no difference between erythrocyte, leucocyte, and lymphocyte magnesium in hypertensives and controls. More often no relation between urinary magnesium and blood pressure is observed. Daily urine magnesium may be increased with increased excretion of urine adrenaline. Epidemiological data on dietary magnesium, particularly in drinking water, should be carefully scrutinized: these studies do not establish a major role for magnesium as an antihypertensive factor but confirm the importance of magnesium deficit as a nephrocardiovascular risk factor and sometimes gives support for a role of magnesium as an antihypertensive cofactor. The use of magnesium-depleting drugs in hypertensive patients may induce magnesium depletion which must be palliated.(ABSTRACT TRUNCATED AT 250 WORDS)
The relationship between experimental magnesium deficiency and blood pressure is complex and still the subject of much debate. The effect of Mg deficiency and blood pressure in Wistar rats receiving a Mg deficient diet (0.080 g/kg) for 40 weeks was examined. Deficient rats, when compared to controls, showed an initial transitory phase of hypotension, followed by normalization of blood pressure and then hypertension beginning after 15 weeks on the deficient diet. During the whole experimental period, heart rate was significantly increased in deficient rats as compared to controls. The fact that hypotension resulting from Mg deficiency of short duration can be inhibited by antihistamines and by indomethacin suggests that various mediators seen during the inflammatory period of Mg deficiency could be involved. Mg deficiency of long duration was accompanied by hypertension. When Mg-deficient rats received the control diet for a period of 3 weeks, Mg supplementation only partially corrected the hypertension. The hypertension was not a consequence of stimulation of the renin-angiotensin system since the plasma renin activity was not modified and ACE activity was reduced. These deficient rats showed a significantly lower vasopressor response to noradrenaline than control rats. Several factors such as increase in collagen, changes in elastin and arterial elasticity, total lipid content, and calcifications may account for the hyporesponsiveness to contractile agonists.(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of nifedipine on the survival rate and the cardiovascular calcinosis were investigated in dietary magnesium (Mg)-deficient mice. Male mice aged 8 to 10 weeks were fed with a diet which was either normal (0.07%) or deficient (0.007%) in Mg for 30 d. Nifedipine was added to the Mg-deficient diet for 30 d in a concentration of 1000 ppm. About 65% of Mg-deficient mice died within 30 d. In contrast, all the nifedipine-treated mice survived for 30 d. Mg-deficient mice showed hypomagnesaemia and hypocalcaemia which were not influenced by nifedipine treatment. Aortic and cardiac calcium contents increased in Mg-deficient mice, and these increments were normalized by nifedipine treatment. These results suggest that the life-saving effect of nifedipine in Mg-deficient mice might relate, at least in part, to the prevention of a deleterious increase in Ca in cardiovascular tissues.
The effect of magnesium (Mg)-deficient culture on endothelial cell susceptibility to oxidative stress was examined. Bovine endothelial cells were cultured in either control sufficient (0.8 mM) or deficient (0.4 mM) levels of MgCl2. Oxygen radicals were produced extracellularly by the addition of dihydroxyfumarate and Fe(3+)-ADP. Isolated Mg-deficient endothelial cells produced 2- to 3-fold higher levels of thiobarbituric acid (TBA)-reactive materials when incubated with this free radical system. Additional studies were performed using digitized video microscopy and 2',7'-dichlorofluorescein diacetate (DCFDA) as an intracellular indicator for oxidative events at the single cell level. In response to the exogenous oxidative stress, endothelial cells exhibited a time-dependent increase in fluorescence, suggestive of intracellular lipid peroxidation. The increase in cellular fluorescence began within 1 min of free radical addition; the Mg-deficient cells exhibited a more rapid increase in fluorescence than that of Mg-sufficient cells. In separate experiments, cellular viability was assessed using the Trypan blue exclusion assay. Mg deficiency increased cytotoxicity of the added oxyradicals, but the loss of cellular viability began to occur only after 15 min of free radical exposure, lagging behind the detection of intracellular oxidation products. These results suggest that increased oxidative endothelial cell injury may contribute to vascular injury during Mg deficiency.
We have developed two rodent models of diet-induced magnesium-deficiency in which histologically defined cardiac lesions can be induced within two to three weeks. During the development of these lesions, the magnesium-deficient animals exhibit circulating cytokine levels which are indicative of a generalized inflammatory state. Dramatic elevations of the macrophage-derived cytokines, IL-1, IL-6, and TNF-alpha together with significantly elevated levels of the endothelial cell-derived cytokine, endothelin, were detected in the plasma of these animals. We believe that the pathophysiological effects caused by the action of these cytokines may play a role in the promotion of cardiovascular pathology associated with magnesium deficiency.
Previous studies in our laboratory have indicated free radical participation in magnesium deficiency cardiomyopathy. In this study, we examined the capacity of the magnesium-deficient animals to withstand an in vivo oxidative stress. Syrian hamsters were placed on either magnesium-deficient diet or a magnesium-supplemented control diet. Animals from each group also received vitamin E. After 14 days some of animals were given the catecholamine isoprenaline; 2 days later the animals were killed. The severity of the isoprenaline-induced injury was assessed by a morphometric analysis. The isoprenaline-induced injury was dramatically increased in the magnesium-deficient animals. The addition of vitamin E reduced the severity of the injury by 81% in these animals, indicating that the injury process was primarily due to an oxidative mechanism. These data show that magnesium deficiency increases the susceptibility of the cardiovascular system to oxidative stress.
Weanling rats were pair-fed for 8 d with control and Mg-deficient diets containing 960 and 30 mg of Mg/kg, respectively. The marked reduction in plasma Mg levels indicated that the rats fed the Mg-deficient diet were indeed deficient. In the Mg-deficient rats the percent composition of triglycerides in VLDL, LDL and HDL was elevated and that of protein was reduced. Although the proportion of cholesterol was reduced in LDL and HDL, that of phospholipid was decreased only in HDL. Magnesium deficiency induced a decrease in the percent composition of apolipoprotein (apo) E and a relative increase in the apo C for VLDL. In HDL from Mg-deficient rats, the proportion of apo AI was higher than normal, apo AIV was lower than normal and apo E was virtually absent. The percent composition of oleic and linoleic acids was increased but that of stearic and arachidonic acids was depressed in both VLDL and HDL derived from Mg-deficient rats compared with pair-fed controls. Whether these alterations in lipoprotein profile contribute to hyperlipoproteinemia or are the results of the metabolic changes that produce hyperlipoproteinemia remain to be determined.
Previous studies have provided evidence that Mg deficiency affects lipid metabolism. The present experiments were designed to assess whether the hypertriglyceridemia associated with Mg deficiency was related to alterations in post-heparin lipase activity (PHLA). Mg-deficient and control diets were pair-fed to weanling Wistar rats for eight days and plasma lipoproteins were separated into various density classes by sequential preparative ultracentrifugation. Triglycerides were significantly increased in chylomicrons and in the very low density lipoprotein, low density lipoprotein and high density lipoprotein (HDL) fractions. Cholesterol and phospholipid levels were significantly lower in the HDL fraction. PHLA in deficient rat was substantially lower than in control rats. The inverse correlation between plasma triglyceride concentration and PHLA strongly suggests that hypertriglyceridemia is the result of defective lipolysis of plasma triglycerides in Mg-deficient rats. Further examination of the PHLA was carried out by salt-mediated inhibition of lipoprotein lipase (LPL) and by heparin sepharose affinity chromatography and purified rat LPL antiserum. The results indicate that hepatic lipase is significantly decreased in Mg-deficient rats but the low PHLA is due mainly to a decline in LPL. However, total LPL activity, that is, both the intracellular and the extracellular pools of LPL in adipose tissue, heart and diaphragm, were unaffected by Mg deficiency. The results suggest that the decrease of LPL activity in the plasma of Mg-deficient rats may be due to a selective decrease in the heparin-releasable pool of enzyme.
In this study, we have examined the effects of variation in dietary Mg on the atherogenic process. Oral supplementation of rabbits fed a high cholesterol diet (1% or 2%) with the Mg salt magnesium aspartate hydrochloride (Magnesiocard) (i) lowers the level of serum cholesterol and triglycerides in normal (25-35%) as well as atherosclerotic (20-40%) animals and (ii) attenuates the atherosclerotic process markedly. In addition, we found that dietary deficiency of Mg augments atherogenesis markedly and stimulates (or activates) macrophages of the reticuloendothelial system. Evidence is presented to indicate that the hypercholesterolemic state may cause the loss of Mg from soft tissues to the serum, thereby masking an underlying Mg deficiency.
Syrian male hamsters weighing 80-100g were placed on either a magnesium deficient diet (MgD) or an identical diet supplemented with 100 mmols/Kg MgCl. Animals from each group received vitamin E 10, 15, and 25mg three-week slow release pellets, as subcutaneous implants. The animals were sacrificed after 14 days and their hearts isolated for morphological analysis. H&E stained sections were examined by a computer image analysis system for a morphometric determination of the severity of myocardial injury. Vitamin E significantly (p less than 0.01) reduced both the numerical density and the area fraction of MgD lesions. These data indicate possible free radical participation in the mechanism of injury.
The erythrocyte membrane was investigated in weanling male rats pair fed with magnesium-deficient and control diets for 8 days. Fluorescence polarization studies revealed a 15% increase in the fluidity of membranes from deficient rats. A similar increase in the fluidity of liposomes indicated that protein was not involved. The change was associated with decreased osmotic fragility of intact erythrocytes; the cells lost their biconcavity and had a flattened appearance with surface irregularities. Analysis of the membranes showed decreased amounts of magnesium, cholesterol, and sphingomyelin in the deficient group. The reduced ratios of cholesterol to phospholipid and sphingomyelin to phosphatidylcholine were consistent with the increased fluidity. Addition of physiological amounts of magnesium to the medium rigidified membranes incubated in tris(hydroxymethyl)-aminomethane buffer, and this was prevented by the presence of EDTA. Cross-incubation experiments with erythrocyte ghosts and plasma from the two groups of rats showed that magnesium-deficient plasma increased the fluidity of control ghosts and control plasma rigidified ghosts from magnesium-deficient rats. Addition of sufficient magnesium chloride to raise the magnesium content of deficient plasma to normal had no significant effect. These results show that the increased fluidity of the erythrocyte membrane in magnesium deficiency is due to physicochemical exchange with the plasma. Although magnesium can directly influence membrane fluidity, the change during its deficiency in vivo is mainly mediated indirectly via disturbances in lipid metabolism.
The relation between histamine metabolism and an appearance of pinnal hyperaemia during magnesium (Mg) deficiency, and the effects of some factors on these were studied in 3-week-old Wistar rats. On a Mg-deficient diet (Mg 0.001%), the histamine concentrations in plasma and urine increased after 4-5 d, and reached a maximum after 6-12 d. Pinnal hyperaemia appeared during the same time course. The hyperaemia was reduced by the administration of antihistamines (cimetidine and diphenhydramine). These results indicate that pinnal hyperaemia during Mg deficiency is mediated by histamine. The administration of oestradiol benzoate (0.08 mg/100g body weight subcutaneously once a day for 8 d) and/or gamma-ray irradiation (600 rad/d before experiments) reduced the appearance of pinnal hyperaemia and the increment in the urinary histamine during Mg deficiency. The histamine content increased in the spleen and some tissues after 8 d, but not in the skin, with increasing the activity of histamine synthesis. The treatments mentioned above depressed the increment of histamine content. These results suggest that the pinnal hyperaemia and the increment of the urinary histamine in the Mg-deficient rat are related to the increment of both the histamine synthesis and release.
The effects of a magnesium deficient diet fed to rats for approximately 65 days were assessed with special reference to changes in the thymus. The thymus was enlarged in 18 to 52% of deficient animals surviving more than 6 to 7 wk in various experiments. The remainder demonstrated glands that were smaller than controls. The enlarged thymuses showed marked cellular changes with the normal structure being replaced by cells that morphologically resembled transformed lymphocytes. Of the small glands, 19% had focal or lobular cellular changes similar to those seen in enlarged thymuses. No distant metastases were found and the changes were interpreted as hyperplastic rather than neoplastic. Prolonged magnesium depletion was accompanied by hypomagnesemia and hypercalcemia or normocalcemia. Marked leukocytosis was present during the early stages of the deficiency. Splenomegaly was consistently found in the magnesium depleted animals.