Dietary Mg Supplementation Decreases Oxidative Stress, Inflammation, and Vascular Dysfunction in an Experimental Model of Metabolic Syndrome with Renal Failure

Background: Metabolic syndrome (MetS) and chronic kidney disease (CKD) are commonly associated with cardiovascular disease (CVD) and in these patients Mg concentration is usually decreased. This study evaluated whether a dietary Mg supplementation might attenuate vascular dysfunction through the modulation of oxidative stress and inflammation in concurrent MetS and CKD. Methods: A rat model of MetS (Zucker strain) with CKD (5/6 nephrectomy, Nx) was used. Nephrectomized animals were fed a normal 0.1%Mg (MetS+Nx+Mg 0.1%) or a supplemented 0.6%Mg (MetS+Nx+Mg0.6%) diet; Sham-operated rats with MetS receiving 0.1%Mg were used as controls. Results: As compared to controls, the MetS+Nx-Mg0.1% group showed a significant increase in oxidative stress and inflammation biomarkers (lipid peroxidation and aortic interleukin-1b and -6 expression) and Endothelin-1 levels, a decrease in nitric oxide and a worsening in uremia and MetS associated pathology as hypertension, and abnormal glucose and lipid profile. Moreover, proteomic evaluation revealed changes mainly related to lipid metabolism and CVD markers. By contrast, in the MetS+Nx+Mg0.6% group, these parameters remained largely similar to controls. Conclusion: In concurrent MetS and CKD, dietary Mg supplementation reduced inflammation and oxidative stress and improved vascular function.This research was funded by a Spanish government grant from the Programa Nacional I+D+I 2008–2011 from the MINECO-Instituto de Salud Carlos III (PI20/0660 and PI21/00654) with co-financing from European Funds (FEDER) and EUTOX and REDinREN from the ISCIII, Consejería de Salud (grants PI-0071-2021) from the Junta de Andalucía and Grant PY20_00773 from Consejería de Innovación, Ciencia y Empleo from the Junta de Andalucía. J.M.D.-T. hold a Sara Borrell contract by the Spanish Ministry of Science, Innovation and Universities, Carlos III Health Institute (ISCIII), co-funded by European Social Fund (European Social Fund-Investment in your future). Y.A. and J.R.M.-C. are senior researchers supported by the Nicolás Monardes Programme, Consejería de Salud-SAS (Junta de Andalucía)

TGF-b Prevents Phosphate-Induced Osteogenesis through Inhibition of BMP and Wnt/b-Catenin Pathways

Background: Transforming growth factor-b (TGF-b) is a key cytokine during differentiation of mesenchymal stem cells (MSC) into vascular smooth muscle cells (VSMC). High phosphate induces a phenotypic transformation of vascular smooth muscle cells (VSMC) into osteogenic-like cells. This study was aimed to evaluate signaling pathways involved during VSMC differentiation of MSC in presence or not of high phosphate. Results: Our results showed that TGF-b induced nuclear translocation of Smad3 as well as the expression of vascular smooth muscle markers, such as smooth muscle alpha actin, SM22a, myocardin, and smooth muscle-myosin heavy chain. The addition of high phosphate to MSC promoted nuclear translocation of Smad1/5/8 and the activation of canonical Wnt/bcatenin in addition to an increase in BMP-2 expression, calcium deposition and alkaline phosphatase activity. The administration of TGF-b to MSC treated with high phosphate abolished all these effects by inhibiting canonical Wnt, BMP and TGF-b pathways. A similar outcome was observed in high phosphate-treated cells after the inhibition of canonical Wnt signaling with Dkk-1. Conversely, addition of both Wnt/b-catenin activators CHIR98014 and lithium chloride enhanced the effect of high phosphate on BMP-2, calcium deposition and alkaline phosphatase activity. Conclusions: Full VSMC differentiation induced by TGF-b may not be achieved when extracellular phosphate levels are high. Moreover, TGF-b prevents high phosphate-induced osteogenesis by decreasing the nuclear translocation of Smad 1/5/8 and avoiding the activation of Wnt/b-catenin pathway.Sources of Funding: This study has been carried out with the funding of ‘‘Proyecto de Excelencia P09-CTS-5205’’ from Consejerı ́a de Economı ́a, Cienciay Empresa from Junta de Andalucı ́a, FIS PI11/02055 from Instituto de Salud Carlos III and PI-0127 from Consejerı ́a de Salud, Junta de Andalucia. The funders hadno role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Magnesium supplementation reduces inflammation in rats with induced chronic kidney disease

Background Inflammation is a common feature in chronic kidney disease (CKD) that appears specifically associated with cardiovascular derangements in CKD patients. Observational studies have revealed a link between low Mg levels and inflammation. In this study, we hypothesize that Mg might have a modulatory effect on the inflammation induced under the uraemic milieu. Methods In vivo studies were performed in a 5/6 nephrectomized rat model of CKD. Furthermore, a possible direct effect of Mg was addressed through in vitro studies with vascular smooth muscle cells (VSMCs). Results Uraemic rats fed a normal (0.1%) Mg diet showed a systemic inflammatory response evidenced by the elevation in plasma of the pro‐inflammatory cytokines TNF‐α, IL‐1β and IL‐6, and GPx activity, a marker of oxidative stress. Importantly, an increased expression of these cytokines in the aortic tissue was also observed. In contrast, a dietary Mg supplementation (0.6%) greatly prevented the oxidative stress and the pro‐inflammatory response. In vitro, in VSMCs cultured in a pro‐inflammatory high phosphate medium, incubation with Mg 1.6 mM inhibited the increase in the production of ROS, the rise in the expression of TNF‐α, IL‐1β, IL‐6 and IL‐8 and the activation of NF‐κB signalling that was observed in cells incubated with a normal (0.8 mM) Mg. Conclusion Mg supplementation reduced inflammation associated with CKD, exerting a direct effect on vascular cells. These findings support a possible beneficial effect of Mg supplementation along the clinical management of CKD patients

Monitorización del estrés ambiental en el medio acuático mediante la evaluación de biomarcadores inducidos por cadmio en Carassius auratus (Linneo, 1758)

La contaminación en el medio acuático es un problema cada vez más serio y que va en aumento. Los organismos acuáticos, pueden acumular los xenobióticos del agua contaminada o de la cadena trófica. El cadmio es un metal que puede alcanzar el medio acuático y producir efectos adversos en los organismos debido a su alta toxicidad, incluso en baja concentración. Es por este motivo que es de gran importancia la monitorización ambiental de este metal por medio de bioensayos. El objetivo de este estudio fue evaluar los efectos tóxicos tempranos del cadmio sobre peces de la especie Carassius auratus (L), mediante el desarrollo de bioensayos de laboratorio con diferentes concentraciones (0,01; 0,1 y 1 mg/L) y analizando biomarcadores de exposición y efecto como, la detección histológica de la bioacumulación de Cd en los órganos branquias e hígado mediante la tinción de Ditizona, el daño genotóxico mediante el test de micronúcleos y la inducción de estrés oxidativo mediante la cuantificación de daño oxidativo (peroxidación lipídica) y de la respuesta antioxidante [enzimas superóxido dismutasa (SOD) y catalasa (CAT)]. Los resultados obtenidos mostraron que las tres concentraciones de cadmio provocaron la acumulación del metal en los dos órganos estudiados. Así mismo, se observó un aumento en la cantidad de micronúcleos en los eritrocitos de los peces expuestos a la mayor concentración de cadmio (700%, respecto al control). Además, se pudo identificar daño oxidativo con la medida de la peroxidación lipídica, un aumento del 72% (branquias) y del 90% (hígado) en los niveles de hidroperóxidos frente al control en los peces expuestos a 1 mg/L de cadmio. En relación con la respuesta antioxidante, la actividad SOD presentó un aumento del 67% (branquias) y 98% (hígado) frente al control en los peces expuestos a 1 mg/L. En el caso de la CAT, el aumento fue significativo desde la menor concentración en branquias, aumentando un 32% frente al control, y en la mayor concentración en hígado (en un 68%). En conclusión, este estudio muestra que en peces expuestos a bajas concentraciones de cadmio se produce una bioacumulación del mismo en los tejidos que se asocia con la inducción de estrés oxidativo y el desarrollo de daño genotóxico. Además, estos efectos ocurren de manera muy rápida, detectándose a las 96 horas de exposición. Por ello, los biomarcadores tempranos de exposición y efecto utilizados en este estudio aparecen como herramientas útiles para la biomonitorización de la contaminación ambiental por este metal en el medio acuático

Serum Magnesium is associated with Carotid Atherosclerosis in patients with high cardiovascular risk (CORDIOP REV Study)

This study aimed to ascertain whether there is an independent association between serum magnesium (Mg) and the Carotid Intima-Media Thickness (IMT-CC), a well-accepted atherosclerotic-biomarker surrogate of cardiovascular disease (CVD), in a population with high cardiovascular risk. Serum Mg and traditional atherosclerotic risk factors were recorded in 939 patients (mean age, 59.6 ± 0.3 years, 83.2% men) with coronary heart disease (CHD) enrolled in the CORDIOPREV trial. Serum Mg strongly associated with IMT-CC. Before adjusting for potential confounding factors, IMT-CC decreased by 0.111 ± 0.011 mm per mg/dl increase in serum Mg (p < 0.001). After adjustment, the effect of Mg did not appear mediated through factors related to glucose metabolism, the lipid profile or the mineral metabolism and renal function. Multivariate models showed the lower Mg levels (quartile 1) as a strong independent factor contributing to IMT-CC along with age, sex, SBP, HDL-C, and diuretic use. Logistic regression analysis confirmed the predictive ability of serum Mg to differentiate patients at higher atherosclerotic risk as defined by an IMT-CC ≥ 1.0 mm, yielding a OR for the lower quartile of 10.623 (95%CI 2.311–48.845; P = 0.002) and a ROC-derived cutoff of 1.61 mg/dl. Therefore, our findings outline low serum magnesium as a possible independent risk factor for carotid atherosclerosis.We would like to thank the EASP (Escuela Andaluza de Salud Publica), Granada, Spain, who performed the randomization process for this study. The CORDIOPREV study is supported by Fundacion Patrimonio Comunal Olivarero. CITOLIVA and CEAS, Consejeria de Economia, Innovacion y Ciencia (CVI-7450); Ministerio de Economia (AGL2015-67896-P, PIE14/00005, PIE14/00031); Instituto de Salud Carlos III (FIS 14/00872; FIS 17/01024), co-funded with FEDER (European Regional Development Fund). Y. A. is supported by Nicolas Monardes Programme, Consejeria de Salud-SAS. CIBEROBN is an initiative of Instituto de Salud Carlos III