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1.
Int J Mol Sci ; 25(15)2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-39125993

RESUMEN

Neurodegenerative diseases represent an increasing economic, social, and, above all, medical burden worldwide. The second most prevalent disease in this category is Parkinson's disease, surpassed only by Alzheimer's. It is a treatable but still incurable systemic disease with a pathogenesis that has not yet been elucidated. Several theories are currently being developed to explain the causes and progression of Parkinson's disease. Magnesium is one of the essential macronutrients and is absolutely necessary for life as we know it. The magnesium cation performs several important functions in the cell in the context of energetic metabolism, substrate metabolism, cell signalling, and the regulation of the homeostasis of other ions. Several of these cellular processes have been simultaneously described as being disrupted in the development and progression of Parkinson's disease. The relationship between magnesium homeostasis and the pathogenesis of Parkinson's disease has received little scientific attention to date. The aim of this review is to summarise and critically evaluate the current state of knowledge on the possible role of magnesium in the pathogenesis of Parkinson's disease and to outline possible future directions for research in this area.


Asunto(s)
Magnesio , Enfermedad de Parkinson , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Humanos , Magnesio/metabolismo , Homeostasis , Animales
2.
Gen Physiol Biophys ; 42(1): 77-85, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36705307

RESUMEN

Parkinson's disease (PD) is an oxidative stress-linked neurodegenerative disorder, with the highest prevalence among seniors. The objective of this study were: (1) to analyse levels of following oxidative stress parameters: total antioxidant capacity (TAC), uric acid (UA), total glutathione (tGSH), bilirubin (Bil) and albumin (Alb), in blood of PD patients and healthy controls; (2) to find possible associations of examined oxidative stress parameters with PD subtypes and levodopa treatment status; and (3) to evaluate power and relevance of the aforementioned oxidative stress parameter for the prediction of onset and progression of PD by utilizing Random Forest machine learning (RFML). Oxidative stress parameters were determined in 125 PD patients and 55 healthy controls. Evaluated with frequentist statistics, our data revealed that UA is the only oxidative stress parameter associated with PD. However, when the PD cohort was divided in gender-dependent manner, tGSH and Bil were also significantly associated with PD in subgroup of female patients. RFML rendered no predictive power of any of the tested oxidative stress parameters in respect to PD, its subtypes, and/or status of levodopa treatment. In conclusion, despite the positive association of UA with PD (in complete cohort of PD patients) and of tGSH and Bil with PD but only in female patients, these oxidative stress parameters are of no use in clinical practice due to the lack of the predictive/diagnostic power.


Asunto(s)
Enfermedad de Parkinson , Humanos , Femenino , Enfermedad de Parkinson/tratamiento farmacológico , Levodopa/uso terapéutico , Antioxidantes/metabolismo , Estrés Oxidativo , Ácido Úrico , Glutatión
3.
Int J Mol Sci ; 24(4)2023 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-36834741

RESUMEN

Alzheimer's disease (AD) is an incurable neurodegenerative disease and the most frequently diagnosed type of dementia, characterized by (1) perturbed cerebral perfusion, vasculature, and cortical metabolism; (2) induced proinflammatory processes; and (3) the aggregation of amyloid beta and hyperphosphorylated Tau proteins. Subclinical AD changes are commonly detectable by using radiological and nuclear neuroimaging methods such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and single-photon emission computed tomography (SPECT). Furthermore, other valuable modalities exist (in particular, structural volumetric, diffusion, perfusion, functional, and metabolic magnetic resonance methods) that can advance the diagnostic algorithm of AD and our understanding of its pathogenesis. Recently, new insights into AD pathoetiology revealed that deranged insulin homeostasis in the brain may play a role in the onset and progression of the disease. AD-related brain insulin resistance is closely linked to systemic insulin homeostasis disorders caused by pancreas and/or liver dysfunction. Indeed, in recent studies, linkages between the development and onset of AD and the liver and/or pancreas have been established. Aside from standard radiological and nuclear neuroimaging methods and clinically fewer common methods of magnetic resonance, this article also discusses the use of new suggestive non-neuronal imaging modalities to assess AD-associated structural changes in the liver and pancreas. Studying these changes might be of great clinical importance because of their possible involvement in AD pathogenesis during the prodromal phase of the disease.


Asunto(s)
Enfermedad de Alzheimer , Resistencia a la Insulina , Insulinas , Enfermedades Neurodegenerativas , Humanos , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Tomografía de Emisión de Positrones/métodos , Neuroimagen/métodos , Imagen por Resonancia Magnética/métodos , Encéfalo/metabolismo , Insulinas/metabolismo
4.
Am J Physiol Renal Physiol ; 323(5): F553-F563, 2022 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-36049064

RESUMEN

Transcellular Mg2+ reabsorption in the distal convoluted tubule (DCT) of the kidneys plays an important role in maintaining systemic Mg2+ homeostasis. SLC41A1 is a Na+/Mg2+ exchanger that mediates Mg2+ efflux from cells and is hypothesized to facilitate basolateral extrusion of Mg2+ in the DCT. In this study, we generated a SLC41A1 knockout mouse model to examine the role of SLC41A1 in Mg2+ homeostasis. Slc41a1-/- mice exhibited similar serum and urine Mg2+ levels as their wild-type littermates. Dietary restriction of Mg2+ resulted in reduced serum Mg2+ concentration and urinary Mg2+ excretion, which was similar in the wild-type and knockout groups. Expression of genes encoding Mg2+ channels and transporters such as transient receptor potential melastatin 6 (Trpm6), transient receptor potential melastatin 7 (Trpm7), cyclin and CBS domain divalent metal cation transport mediator 2 (Cnnm2), and Slc41a3 were unchanged based on genotype. We investigated the potential redundancy of SLC41A1 and its homolog SLC41A3 by generating a double knockout mouse. Although Slc41a3-/- knockout mice showed significantly reduced serum Mg2+ compared with wild-type and Slc41a1-/- knockout groups, double knockout mice displayed similar serum Mg2+ levels as Slc41a3-/- knockout mice. In conclusion, our data show that SLC41A1 is not involved in the regulation of systemic Mg2+ homeostasis in mice. Our data also demonstrate that SLC41A1 does not compensate for the loss of SLC41A3, suggesting different functions of these SLC41 proteins in vivo.NEW & NOTEWORTHY SLC41A1 has been hypothesized to mediate Mg2+ extrusion in the distal convoluted tubule and thus regulate Mg2+ homeostasis. This study investigated the role of SLC41A1 in Mg2+ homeostasis in vivo using a transgenic mouse model. Our results demonstrate that SLC41A1 is not required to maintain normal Mg2+ balance in mice. We also show that SLC41A3 is more important than SLC41A1 in regulating systemic Mg2+ levels.


Asunto(s)
Proteínas de Transporte de Catión , Magnesio , Animales , Ratones , Cationes , Ciclinas/metabolismo , Homeostasis , Túbulos Renales Distales/metabolismo , Magnesio/metabolismo , Ratones Noqueados , Ratones Transgénicos , Canales Catiónicos TRPM/genética , Canales Catiónicos TRPM/metabolismo , Proteínas de Transporte de Catión/genética
5.
Eur J Nutr ; 61(7): 3697-3706, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35689124

RESUMEN

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


Asunto(s)
Magnesio , Humanos , Estándares de Referencia , Valores de Referencia
6.
Int J Mol Sci ; 23(3)2022 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-35163527

RESUMEN

SLC41A1 (A1) SNPs rs11240569 and rs823156 are associated with altered risk for Parkinson's disease (PD), predominantly in Asian populations, and rs708727 has been linked to Alzheimer's disease (AD). In this study, we have examined a potential association of the three aforementioned SNPs and of rs9438393, rs56152218, and rs61822602 (all three lying in the A1 promoter region) with PD in the Slovak population. Out of the six tested SNPs, we have identified only rs708727 as being associated with an increased risk for PD onset in Slovaks. The minor allele (A) in rs708727 is associated with PD in dominant and completely over-dominant genetic models (ORD = 1.36 (1.05-1.77), p = 0.02, and ORCOD = 1.34 (1.04-1.72), p = 0.02). Furthermore, the genotypic triplet GG(rs708727) + AG(rs823156) + CC(rs61822602) might be clinically relevant despite showing a medium (h ≥ 0.5) size difference (h = 0.522) between the PD and the control populations. RandomForest modeling has identified the power of the tested SNPs for discriminating between PD-patients and the controls to be essentially zero. The identified association of rs708727 with PD in the Slovak population leads us to hypothesize that this A1 polymorphism, which is involved in the epigenetic regulation of the expression of the AD-linked gene PM20D1, is also involved in the pathoetiology of PD (or universally in neurodegeneration) through the same or similar mechanism as in AD.


Asunto(s)
Enfermedad de Alzheimer/genética , Proteínas de Transporte de Catión/genética , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN/métodos , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Epigénesis Genética , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Eslovaquia
7.
Rev Physiol Biochem Pharmacol ; 176: 65-105, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30406297

RESUMEN

Magnesium research has boomed within the last 20 years. The real breakthrough came at the start of the new millennium with the discovery of a plethora of possible Mg homeostatic factors that, in particular, included putative Mg2+ transporters. Until that point, Mg research was limited to biochemical and physiological work, as no target molecular entities were known that could be used to explore the molecular biology of Mg homeostasis at the level of the cell, tissue, organ, or organism and to translate such knowledge into the field of clinical medicine and pharmacology. Because of the aforementioned, Mg2+ and Mg homeostasis, both of which had been heavily marginalized within the biomedical field in the twentieth century, have become overnight a focal point of many studies ranging from primary biomedical research to translational medicine.The amount of literature concerning cellular Mg2+ transport and cellular Mg homeostasis is increasing, together with a certain amount of confusion, especially about the function(s) of the newly discovered and, in the majority of instances, still only putative Mg2+ transporters/Mg2+ homeostatic factors. Newcomers to the field of Mg research will thus find it particularly difficult to orient themselves.Here, we briefly but critically summarize the status quo of the current understanding of the molecular entities behind cellular Mg2+ homeostasis in mammalian/human cells other than TRPM6/7 chanzymes, which have been universally accepted as being unspecific cation channel kinases allowing the flux of Mg2+ while constituting the major gateway for Mg2+ to enter the cell.


Asunto(s)
Magnesio/metabolismo , Canales Catiónicos TRPM/metabolismo , Animales , Homeostasis , Humanos , Proteínas Serina-Treonina Quinasas
8.
BMC Neurol ; 21(1): 293, 2021 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-34311727

RESUMEN

BACKGROUND: Charcot-Marie-Tooth 1C (CMT1C) is a rare form of dominantly inherited CMT1 neuropathy caused by a mutated gene encoding lipopolysaccharide-induced tumour necrosis alpha factor (LITAF). CASE PRESENTATION: We report a 56-year-old patient with an atypical clinical phenotype of CMT1C, which started as progressive weakness of a single upper limb resembling acquired inflammatory neuropathy. Nerve conduction studies (NCS) and temporarily limited and partial effects of immunotherapy supported the diagnosis of inflammatory neuropathy. Significant progression of polyneuropathy, despite intensive long-lasting immunotherapy, together with repeatedly negative auxiliary investigations (CSF, MRI and antibodies) and genetic testing results finally led to the diagnosis of CMT1C neuropathy. CONCLUSIONS: CMT1C should be added to the list of inherited neuropathies that need to be considered in suspected cases of inflammatory demyelinating neuropathy.


Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , Enfermedad de Charcot-Marie-Tooth/clasificación , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Conducción Nerviosa , Examen Neurológico , Linaje , Fenotipo
9.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-34202712

RESUMEN

Adequate amounts of a wide range of micronutrients are needed by body tissues to maintain health. Dietary intake must be sufficient to meet these micronutrient requirements. Mineral deficiency does not seem to be the result of a physically active life or of athletic training but is more likely to arise from disturbances in the quality and quantity of ingested food. The lack of some minerals in the body appears to be symbolic of the modern era reflecting either the excessive intake of empty calories or a negative energy balance from drastic weight-loss diets. Several animal studies provide convincing evidence for an association between dietary micronutrient availability and microbial composition in the gut. However, the influence of human gut microbiota on the bioaccessibility and bioavailability of trace elements in human food has rarely been studied. Bacteria play a role by effecting mineral bioavailability and bioaccessibility, which are further increased through the fermentation of cereals and the soaking and germination of crops. Moreover, probiotics have a positive effect on iron, calcium, selenium, and zinc in relation to gut microbiome composition and metabolism. The current literature reveals the beneficial effects of bacteria on mineral bioaccessibility and bioavailability in supporting both the human gut microbiome and overall health. This review focuses on interactions between the gut microbiota and several minerals in sport nutrition, as related to a physically active lifestyle.


Asunto(s)
Dieta , Microbioma Gastrointestinal , Micronutrientes/metabolismo , Minerales/metabolismo , Animales , Disponibilidad Biológica , Calcio de la Dieta , Absorción Gastrointestinal , Humanos , Probióticos , Oligoelementos/metabolismo
10.
Int J Mol Sci ; 22(11)2021 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-34072724

RESUMEN

At the onset of lactation, dairy cows suffer from insulin resistance, insulin deficiency or both, similar to human diabetes, resulting in lipolysis, ketosis and fatty liver. This work explored the combined effects of different levels of magnesium (0.1, 0.3, 1 and 3 mM) and insulin (25, 250 and 25,000 pM) on metabolic pathways and the expression of magnesium-responsive genes in a bovine adipocyte model. Magnesium starvation (0.1 mM) and low insulin (25 pM) independently decreased or tended to decrease the accumulation of non-polar lipids and uptake of the glucose analog 6-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-6-deoxyglucose (6-NBDG). Activity of glycerol 3-phosphate dehydrogenase (GPDH) was highest at 25 pM insulin and 3 mM magnesium. Expression of SLC41A1 and SLC41A3 was reduced at 0.1 mM magnesium either across insulin concentrations (SLC41A1) or at 250 pM insulin (SLC41A3). MAGT1 expression was reduced at 3 mM magnesium. NIPA1 expression was reduced at 3 mM and 0.1 mM magnesium at 25 and 250 pM insulin, respectively. Expression of SLC41A2, CNNM2, TRPM6 and TRPM7 was not affected. We conclude that magnesium promotes lipogenesis in adipocytes and inversely regulates the transcription of genes that increase vs. decrease cytosolic magnesium concentration. The induction of GAPDH activity by surplus magnesium at low insulin concentration can counteract excessive lipomobilization.


Asunto(s)
Adipocitos/metabolismo , Metabolismo Energético , Regulación de la Expresión Génica , Homeostasis , Insulina/metabolismo , Magnesio/metabolismo , Adipocitos/efectos de los fármacos , Animales , Bovinos , Células Cultivadas , Metabolismo Energético/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/metabolismo , Insulina/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Magnesio/farmacología , Oxidorreductasas de Alcohol Dependientes de NAD (+) y NADP (+)/metabolismo
11.
Int J Mol Sci ; 21(17)2020 Aug 25.
Artículo en Inglés | MEDLINE | ID: mdl-32854318

RESUMEN

Multiple sclerosis (MS) is an autoimmune disease with expanding axonal and neuronal degeneration in the central nervous system leading to motoric dysfunctions, psychical disability, and cognitive impairment during MS progression. The exact cascade of pathological processes (inflammation, demyelination, excitotoxicity, diffuse neuro-axonal degeneration, oxidative and metabolic stress, etc.) causing MS onset is still not fully understood, although several accompanying biomarkers are particularly suitable for the detection of early subclinical changes. Magnetic resonance (MR) methods are generally considered to be the most sensitive diagnostic tools. Their advantages include their noninvasive nature and their ability to image tissue in vivo. In particular, MR spectroscopy (proton 1H and phosphorus 31P MRS) is a powerful analytical tool for the detection and analysis of biomedically relevant metabolites, amino acids, and bioelements, and thus for providing information about neuro-axonal degradation, demyelination, reactive gliosis, mitochondrial and neurotransmitter failure, cellular energetic and membrane alternation, and the imbalance of magnesium homeostasis in specific tissues. Furthermore, the MR relaxometry-based detection of accumulated biogenic iron in the brain tissue is useful in disease evaluation. The early description and understanding of the developing pathological process might be critical for establishing clinically effective MS-modifying therapies.


Asunto(s)
Biomarcadores/metabolismo , Imagen por Resonancia Magnética/métodos , Esclerosis Múltiple/diagnóstico por imagen , Progresión de la Enfermedad , Diagnóstico Precoz , Metabolismo Energético , Homeostasis , Humanos , Magnesio/metabolismo , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología
12.
Int J Mol Sci ; 21(21)2020 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-33153064

RESUMEN

Cardiomyocytes are among the most energy-intensive cell types. Interplay between the components of cellular magnesium (Mg) homeostasis and energy metabolism in cardiomyocytes is poorly understood. We have investigated the effects of dietary Mg content and presence/functionality of the Na+/Mg2+ exchanger SLC41A1 on enzymatic functions of selected constituents of the Krebs cycle and complexes of the electron transport chain (ETC). The activities of aconitate hydratase (ACON), isocitrate dehydrogenase (ICDH), α-ketoglutarate dehydrogenase (KGDH), and ETC complexes CI-CV have been determined in vitro in mitochondria isolated from hearts of wild-type (WT) and Slc41a1-/- mice fed a diet with either normal or low Mg content. Our data demonstrate that both, the type of Mg diet and the Slc41a1 genotype largely impact on the activities of enzymes of the Krebs cycle and ETC. Moreover, a compensatory effect of Slc41a1-/- genotype on the effect of low Mg diet on activities of the tested Krebs cycle enzymes has been identified. A machine-learning analysis identified activities of ICDH, CI, CIV, and CV as common predictors of the type of Mg diet and of CII as suitable predictor of Slc41a1 genotype. Thus, our data delineate the effect of dietary Mg content and of SLC41A1 functionality on the energy-production in cardiac mitochondria.


Asunto(s)
Proteínas de Transporte de Catión/metabolismo , Magnesio/farmacología , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Animales , Antiportadores/fisiología , Proteínas de Transporte de Catión/genética , Células Cultivadas , Ciclo del Ácido Cítrico/efectos de los fármacos , Ciclo del Ácido Cítrico/genética , Dieta , Ingestión de Alimentos/fisiología , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/genética , Magnesio/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Oxidación-Reducción/efectos de los fármacos
13.
Int J Mol Sci ; 20(19)2019 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-31546642

RESUMEN

Gene SLC41A1 (A1) is localized within Parkinson's disease-(PD)-susceptibility locus PARK16 and encodes for the Na+/Mg2+-exchanger. The association of several A1 SNPs with PD has been studied. Two, rs11240569 and rs823156, have been associated with reduced PD-susceptibility primarily in Asian populations. Here, we examined the association of rs11240569, rs708727, and rs823156 with PD in the Slovak population and their power to discriminate between PD patients and healthy controls. The study included 150 PD patients and 120 controls. Genotyping was performed with the TaqMan® approach. Data were analyzed by conventional statistics and Random Forest machine-learning (ML) algorithm. Individually, none of the three SNPs is associated with an altered risk for PD-onset in Slovaks. However, a combination of genotypes of SNP-triplet GG(rs11240569)/AG(rs708727)/AA(rs823156) is significantly (p < 0.05) more frequent in the PD (13.3%) than in the control (5%) cohort. ML identified the power of the tested SNPs in isolation or of their singlets (joined), duplets and triplets to discriminate between PD-patients and healthy controls as zero. Our data further substantiate differences between diverse populations regarding the association of A1 polymorphisms with PD-susceptibility. Lack of power of the tested SNPs to discriminate between PD and healthy cases render their clinical/diagnostic relevance in the Slovak population negligible.


Asunto(s)
Proteínas de Transporte de Catión/genética , Enfermedad de Parkinson/genética , Adulto , Anciano , Anciano de 80 o más Años , Proteínas de Transporte de Catión/sangre , Estudios de Cohortes , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Eslovaquia , Adulto Joven
14.
Cells Tissues Organs ; 204(1): 13-24, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28494459

RESUMEN

To establish the influence of fetal bovine serum (FBS) and bovine serum lipids (BSL) on cell differentiation marker expression, bovine adipose-derived stem cells from subcutaneous tissue were incubated for 14 days in 4 types of differentiation media containing 10% FBS and 10 µL/mL BSL (TRT-1), no FBS and 10 µL/mL of BSL (TRT-2), 10% FBS and no BSL (TRT-3), or no supplements (TRT-4). Cells were subjected to Nile red staining, immunocytochemistry (CD73, CD90, CD105, DLK1, FabP4), and quantitative real-time PCR (CD73, CD90, CD105, FabP4). The number of cells presenting FabP4 and the percentage of mature adipocytes with large lipid droplets were increased in TRT-2, accompanied by a robust increase in FabP4 mRNA abundance and a decrease in DLK1-positive cells. In preadipocytes, CD73 was present around the nucleus and translocated towards cell membranes during differentiation. Although the percentage of CD73-positive cells was not different among treatments, its mRNA abundance, immunocytochemical staining intensity, and translocation towards cell membranes were decreased when the medium contained no FBS (TRT-2 and TRT-4). All cells showed a diffuse distribution of CD90 and CD105 and remained positive for these markers irrespective of the treatment. However, the CD90 and CD105 mRNA abundance was decreased in TRT-2 and TRT-4; i.e., in media containing no FBS. The presence of FBS increased the absolute number of cell nuclei as assessed by DAPI fluorescence. Our results suggest that bovine subcutaneous preadipocytes display typical stem cell markers. The differentiation into mature adipocytes is promoted by BSL, whereas FBS endorses cell proliferation.


Asunto(s)
Adipocitos/metabolismo , Técnicas de Cultivo de Célula/métodos , Células Cultivadas/metabolismo , Inmunohistoquímica/métodos , Lípidos/sangre , Adipocitos/citología , Animales , Bovinos , Diferenciación Celular
16.
Pflugers Arch ; 468(7): 1223-1240, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27068403

RESUMEN

CNNM2 is associated with the regulation of serum Mg concentration, and when mutated, with severe familial hypomagnesemia. The function and cellular localization of CNNM2 and its isomorphs (Iso) remain controversial. The objective of this work was to examine the following: (1) the transcription-responsiveness of CNNM2 to Mg starvation, (2) the cellular localization of Iso1 and Iso2, (3) the ability of Iso1 and Iso2 to transport Mg(2+), and (4) the complex-forming ability and spectra of potential interactors of Iso1 and Iso2. The five main findings are as follows. (1) Mg-starvation induces CNNM2 overexpression that is markedly higher in JVM-13 cells (lymphoblasts) compared with Jurkat cells (T-lymphocytes). (2) Iso1 and Iso2 localize throughout various subcellular compartments in transgenic HEK293 cells overexpressing Iso1 or Iso2. (3) Iso1 and Iso2 do not transport Mg(2+) in an electrogenic or electroneutral mode in transgenic HEK293 cells overexpressing Iso1 or Iso2. (4) Both Iso1 and Iso2 form complexes of a higher molecular order. (5) The spectrum of potential interactors of Iso1 is ten times smaller than that of Iso2. We conclude that sensitivity of CNNM2 expression to extracellular Mg(2+) depletion depends on cell type. Iso1 and Iso2 exhibit a dispersed pattern of cellular distribution; thus, they are not exclusively integral to the cytoplasmic membrane. Iso1 and Iso2 are not Mg(2+) transporters per se. Both isomorphs form protein complexes, and divergent spectra of potential interactors of Iso1 and Iso2 indicate that each isomorph has a distinctive function. CNNM2 is therefore the first ever identified Mg(2+) homeostatic factor without being a Mg(2+) transporter per se.


Asunto(s)
Ciclinas/metabolismo , Magnesio/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Transporte Biológico/fisiología , Proteínas de Transporte de Catión , Línea Celular Tumoral , Membrana Celular/metabolismo , Células HEK293 , Homeostasis/fisiología , Humanos , Células Jurkat , Transcripción Genética/fisiología
17.
J Nutr ; 145(11): 2440-7, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26355001

RESUMEN

BACKGROUND: Magnesium deficiency is a common complication of diabetes with an unclear molecular background. OBJECTIVE: We investigated the effect of the insulin (INS)-signaling pathway (ISP) on the regulation of Mg(2+) efflux (Mg(2+)E) conducted by solute carrier family 41, member A1 (SLC41A1; activated by protein kinase A) in transgenic human embryonic kidney (HEK) 293 cells. METHODS: HEK293 cells overexpressing SLC41A1 were loaded with the Mg(2+) fluorescent indicator mag-fura-2 and Mg(2+). Measurements of Mg(2+)E were conducted in Mg(2+)-free buffer by using fast-filter fluorescence spectrometry. We examined the effects of INS, inhibitors of ISP or p38 mitogen-activated protein kinase (p38 MAPK), an activator of adenylate cyclase (ADC), and their combinations on SLC41A1-attributed Mg(2+)E. RESULTS: The application of 400 µU/mL INS inhibited SLC41A1-mediated Mg(2+)E by up to 50.6% compared with INS-untreated cells (P < 0.001). Moreover, INS evoked the early onset of Mg(2+) release from intracellular stores. The application of 0.1 µM wortmannin or 10 µM zardaverine (both ISP inhibitors) restored SLC41A1 Mg(2+)E capacity in the presence of INS to the same levels in INS-untreated cells. The simultaneous application of 10 µM forskolin, an ADC activator, and INS resulted in a reduction of Mg(2+)E of up to 59% compared with untreated cells (P < 0.001), which was comparable to that in cells treated with INS alone. Inhibition of p38 MAPK with 10 µM SB 202190 (SB) in the absence of INS resulted in a decrease (P < 0.001) of SLC41A1-dependent Mg(2+)E (by up to 49%) compared with Mg(2+)E measured in untreated cells. Simultaneous exposure of cells to SB and INS had a stronger inhibitory effect on SLC41A1 activity than INS alone (P < 0.05). CONCLUSIONS: INS affects intracellular Mg(2+) concentration in transgenic HEK293 cells by regulating SLC41A1 activity (via ISP) and by influencing the compartmentalization and cellular distribution of Mg(2+). In addition, p38 MAPK activates SLC41A1 independently of INS action.


Asunto(s)
Proteínas de Transporte de Catión/metabolismo , Insulina/metabolismo , Magnesio/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Adenilil Ciclasas/metabolismo , Androstadienos/farmacología , Proteínas de Transporte de Catión/genética , Colforsina/farmacología , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Piridazinas/farmacología , Transducción de Señal , Espectrometría de Fluorescencia , Wortmanina , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/genética
18.
Clin Sci (Lond) ; 129(12): 1143-50, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26453619

RESUMEN

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


Asunto(s)
Enfermedades Cardiovasculares/etiología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Deficiencia de Magnesio/etiología , Enfermedades Metabólicas/etiología , Enfermedades Neurodegenerativas/etiología , Proteínas Oncogénicas/metabolismo , Estrés Oxidativo , Transducción de Señal , Animales , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/prevención & control , Proteínas de Transporte de Catión/antagonistas & inhibidores , Proteínas de Transporte de Catión/metabolismo , Enfermedad Crónica , Humanos , Imipramina/uso terapéutico , Deficiencia de Magnesio/tratamiento farmacológico , Deficiencia de Magnesio/metabolismo , Enfermedades Metabólicas/metabolismo , Enfermedades Metabólicas/prevención & control , Terapia Molecular Dirigida , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/prevención & control , Estrés Oxidativo/efectos de los fármacos , Proteína Desglicasa DJ-1 , Receptores Androgénicos/metabolismo , Factores de Riesgo , Regulación hacia Arriba
19.
Curr Top Membr ; 73: 383-410, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24745990

RESUMEN

The solute carrier family 41 (SLC41) encompasses three members A1, A2, and A3. Based on their distant homology to the bacterial Mg²âº channel MgtE, all have been linked to Mg²âº transport. There is only very limited knowledge on the molecular biology and exact functions of SLC41A2 and SLC41A3. SLC41A1 is ubiquitously expressed and data on its functional and molecular properties, regulation, complex-forming ability, and spectrum of binding partners are available. SLC41A1 was recently identified as being the Na⁺/Mg²âº exchanger (NME)-a predominant Mg²âº efflux system. Mg²âº-dependent and hormonal regulation of NME activity is now known to depend on the intracellular N terminus of SLC41A1 that is involved in Mg²âº sensing and contains phosphorylation sites for protein kinase (PK) A and PKC. Data showing a link between SLC41A1 and human disorders such as Parkinson's disease, nephronophthisis (induced by the null mutation c.698G>T in renal SLC41A1), and preeclampsia make the protein a candidate therapeutic target.


Asunto(s)
Proteínas de Transporte de Catión/química , Proteínas de Transporte de Catión/metabolismo , Animales , Enfermedad , Humanos , Magnesio/metabolismo , Transporte de Proteínas , Sodio/metabolismo
20.
Metabolites ; 14(7)2024 Jun 23.
Artículo en Inglés | MEDLINE | ID: mdl-39057679

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease type of motor neuron disorder characterized by degeneration of the upper and lower motor neurons resulting in dysfunction of the somatic muscles of the body. The ALS condition is manifested in progressive skeletal muscle atrophy and spasticity. It leads to death, mostly due to respiratory failure. Within the pathophysiology of the disease, muscle energy metabolism seems to be an important part. In our study, we used blood plasma from 25 patients with ALS diagnosed by definitive El Escorial criteria according to ALSFR-R (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) criteria and 25 age and sex-matched subjects. Aside from standard clinical biochemical parameters, we used the NMR (nuclear magnetic resonance) metabolomics approach to determine relative plasma levels of metabolites. We observed a decrease in total protein level in blood; however, despite accelerated skeletal muscle catabolism characteristic for ALS patients, we did not detect changes in plasma levels of essential amino acids. When focused on alterations in energy metabolism within muscle, compromised creatine uptake was accompanied by decreased plasma creatinine. We did not observe changes in plasma levels of BCAAs (branched chain amino acids; leucine, isoleucine, valine); however, the observed decrease in plasma levels of all three BCKAs (branched chain alpha-keto acids derived from BCAAs) suggests enhanced utilization of BCKAs as energy substrate. Glutamine, found to be increased in blood plasma in ALS patients, besides serving for ammonia detoxification, could also be considered a potential TCA (tricarboxylic acid) cycle contributor in times of decreased pyruvate utilization. When analyzing the data by using a cross-validated Random Forest algorithm, it finished with an AUC of 0.92, oob error of 8%, and an MCC (Matthew's correlation coefficient) of 0.84 when relative plasma levels of metabolites were used as input variables. Although the discriminatory power of the system used was promising, additional features are needed to create a robust discriminatory model.

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