Sodium-glucose cotransporter-2 inhibitors protect tissues via cellular and mitochondrial pathways: Experimental and clinical evidence.

Mitochondrial dysfunction is a key driver of cardiovascular disease (CVD) in metabolic syndrome and diabetes. This dysfunction promotes the production of reactive oxygen species (ROS), which cause oxidative stress and inflammation. Angiotensin II, the main mediator of the renin-angiotensin-aldosterone system, also contributes to CVD by promoting ROS production. Reduced activity of sirtuins (SIRTs), a family of proteins that regulate cellular metabolism, also worsens oxidative stress. Reduction of energy production by mitochondria is a common feature of all metabolic disorders. High SIRT levels and 5' adenosine monophosphate-activated protein kinase signaling stimulate hypoxia-inducible factor 1 beta, which promotes ketosis. Ketosis, in turn, increases autophagy and mitophagy, processes that clear cells of debris and protect against damage. Sodium-glucose cotransporter-2 inhibitors (SGLT2i), a class of drugs used to treat type 2 diabetes, have a beneficial effect on these mechanisms. Randomized clinical trials have shown that SGLT2i improves cardiac function and reduces the rate of cardiovascular and renal events. SGLT2i also increase mitochondrial efficiency, reduce oxidative stress and inflammation, and strengthen tissues. These findings suggest that SGLT2i hold great potential for the treatment of CVD. Furthermore, they are proposed as anti-aging drugs; however, rigorous research is needed to validate these preliminary findings.

Magnetically modified-mitoxantrone mesoporous organosilica drugs: an emergent multimodal nanochemotherapy for breast cancer.

BACKGROUND: Chemotherapy, the mainstay treatment for metastatic cancer, presents serious side effects due to off-target exposure. In addition to the negative impact on patients' quality of life, side effects limit the dose that can be administered and thus the efficacy of the drug. Encapsulation of chemotherapeutic drugs in nanocarriers is a promising strategy to mitigate these issues. However, avoiding premature drug release from the nanocarriers and selectively targeting the tumour remains a challenge. RESULTS: In this study, we present a pioneering method for drug integration into nanoparticles known as mesoporous organosilica drugs (MODs), a distinctive variant of periodic mesoporous organosilica nanoparticles (PMOs) in which the drug is an inherent component of the silica nanoparticle structure. This groundbreaking approach involves the chemical modification of drugs to produce bis-organosilane prodrugs, which act as silica precursors for MOD synthesis. Mitoxantrone (MTO), a drug used to treat metastatic breast cancer, was selected for the development of MTO@MOD nanomedicines, which demonstrated a significant reduction in breast cancer cell viability. Several MODs with different amounts of MTO were synthesised and found to be efficient nanoplatforms for the sustained delivery of MTO after biodegradation. In addition, Fe3O4 NPs were incorporated into the MODs to generate magnetic MODs to actively target the tumour and further enhance drug efficacy. Importantly, magnetic MTO@MODs underwent a Fenton reaction, which increased cancer cell death twofold compared to non-magnetic MODs. CONCLUSIONS: A new PMO-based material, MOD nanomedicines, was synthesised using the chemotherapeutic drug MTO as a silica precursor. MTO@MOD nanomedicines demonstrated their efficacy in significantly reducing the viability of breast cancer cells. In addition, we incorporated Fe3O4 into MODs to generate magnetic MODs for active tumour targeting and enhanced drug efficacy by ROS generation. These findings pave the way for the designing of silica-based multitherapeutic nanomedicines for cancer treatment with improved drug delivery, reduced side effects and enhanced efficacy.

Promising Anticancer Prodrugs Based on Pt(IV) Complexes with Bis-organosilane Ligands in Axial Positions.

We report two novel prodrug Pt(IV) complexes with bis-organosilane ligands in axial positions: cis-dichloro(diamine)-trans-[3-(triethoxysilyl)propylcarbamate]platinum(IV) (Pt(IV)-biSi-1) and cis-dichloro(diisopropylamine)-trans-[3-(triethoxysilyl) propyl carbamate]platinum(IV) (Pt(IV)-biSi-2). Pt(IV)-biSi-2 demonstrated enhanced in vitro cytotoxicity against colon cancer cells (HCT 116 and HT-29) compared with cisplatin and Pt(IV)-biSi-1. Notably, Pt(IV)-biSi-2 exhibited higher cytotoxicity toward cancer cells and lower toxicity on nontumorigenic intestinal cells (HIEC6). In preclinical mouse models of colorectal cancer, Pt(IV)-biSi-2 outperformed cisplatin in reducing tumor growth at lower concentrations, with reduced side effects. Mechanistically, Pt(IV)-biSi-2 induced permanent DNA damage independent of p53 levels. DNA damage such as double-strand breaks marked by histone gH2Ax was permanent after treatment with Pt(IV)-biSi-2, in contrast to cisplatin's transient effects. Pt(IV)-biSi-2's faster reduction to Pt(II) species upon exposure to biological reductants supports its superior biological response. These findings unveil a novel strategy for designing Pt(IV) anticancer prodrugs with enhanced activity and specificity, offering therapeutic opportunities beyond conventional Pt drugs.

Cellular and Mitochondrial Pathways Contribute to SGLT2 Inhibitors-mediated Tissue Protection: Experimental and Clinical Data.

In metabolic syndrome and diabetes, compromised mitochondrial function emerges as a critical driver of cardiovascular disease, fueling its development and persistence, culminating in cardiac remodeling and adverse events. In this context, angiotensin II - the main interlocutor of the renin-angiotensin-aldosterone system - promotes local and systemic oxidative inflammatory processes. To highlight, the low activity/expression of proteins called sirtuins negatively participates in these processes, allowing more significant oxidative imbalance, which impacts cellular and tissue responses, causing tissue damage, inflammation, and cardiac and vascular remodeling. The reduction in energy production of mitochondria has been widely described as a significant element in all types of metabolic disorders. Additionally, high sirtuin levels and AMPK signaling stimulate hypoxia- inducible factor 1 beta and promote ketonemia. Consequently, enhanced autophagy and mitophagy advance through cardiac cells, sweeping away debris and silencing the orchestra of oxidative stress and inflammation, ultimately protecting vulnerable tissue from damage. To highlight and of particular interest, SGLT2 inhibitors (SGLT2i) profoundly influence all these mechanisms. Randomized clinical trials have evidenced a compelling picture of SGLT2i emerging as game-changers, wielding their power to demonstrably improve cardiac function and slash the rates of cardiovascular and renal events. Furthermore, driven by recent evidence, SGLT2i emerge as cellular supermolecules, exerting their beneficial actions to increase mitochondrial efficiency, alleviate oxidative stress, and curb severe inflammation. Its actions strengthen tissues and create a resilient defense against disease. In conclusion, like a treasure chest brimming with untold riches, the influence of SGLT2i on mitochondrial function holds untold potential for cardiovascular health. Unlocking these secrets, like a map guiding adventurers to hidden riches, promises to pave the way for even more potent therapeutic strategies.

Low Plasma Levels of Hyaluronic Acid Might Rule Out Sinusoidal Obstruction Syndrome after Hematopoietic Stem Cell Transplantation.

Background: Sinusoidal obstructive syndrome (SOS) is a potentially fatal complication secondary to hematopoietic stem cell transplant (HSCT) conditioning. Endothelial damage plasma biomarkers such as plasminogen activator inhibitor-1 (PAI-1), hyaluronic acid (HA), and vascular adhesion molecule-1 (VCAM1) represent potential diagnostic tools for SOS. Methods: We prospectively collected serial citrated blood samples (baseline, day 0, day 7, and day 14) in all adult patients undergoing HSCT at La Paz Hospital, Madrid. Samples were later analyzed by ELISA (enzyme-linked immunosorbent assay) for HA, VCAM1, and PAI-1 concentrations. Results: During sixteen months, we prospectively recruited 47 patients. Seven patients (14%) were diagnosed with SOS according to the EBMT criteria for SOS/VOD diagnosis and received treatment with defibrotide. Our study showed a statistically significant elevation of HA on day 7 in SOS patients, preceding clinical SOS diagnosis, with a sensitivity of 100%. Furthermore, we observed a significant increase of HA and VCAM1 levels on day 14. Regarding risk factors, we observed a statistically significant association between SOS diagnosis and the fact that patients received 3 or more previous lines of treatment before HSCT. Conclusions: The early significant increase in HA levels observed opens the door to a noninvasive peripheral blood test which could have the potential to improve diagnosis and facilitate prophylactic and therapeutic management of SOS before clinical/histological damage is established.

Metabolic Syndrome and Cardiac Remodeling Due to Mitochondrial Oxidative Stress Involving Gliflozins and Sirtuins.

PURPOSE OF REVIEW: To address the mechanistic pathways focusing on mitochondria dysfunction, oxidative stress, sirtuins imbalance, and other contributors in patient with metabolic syndrome and cardiovascular disease. Sodium glucose co-transporter type 2 (SGLT-2) inhibitors deeply influence these mechanisms. Recent randomized clinical trials have shown impressive results in improving cardiac function and reducing cardiovascular and renal events. These unexpected results generate the need to deepen our understanding of the molecular mechanisms able to generate these effects to help explain such significant clinical outcomes. RECENT FINDINGS: Cardiovascular disease is highly prevalent among individuals with metabolic syndrome and diabetes. Furthermore, mitochondrial dysfunction is a principal player in its development and persistence, including the consequent cardiac remodeling and events. Another central protagonist is the renin-angiotensin system; the high angiotensin II (Ang II) activity fuel oxidative stress and local inflammatory responses. Additionally, sirtuins decline plays a pivotal role in the process; they enhance oxidative stress by regulating adaptive responses to the cellular environment and interacting with Ang II in many circumstances, including cardiac and vascular remodeling, inflammation, and fibrosis. Fasting and lower mitochondrial energy generation are conditions that substantially reduce most of the mentioned cardiometabolic syndrome disarrangements. In addition, it increases sirtuins levels, and adenosine monophosphate-activated protein kinase (AMPK) signaling stimulates hypoxia-inducible factor-1ß (HIF-1 beta) and favors ketosis. All these effects favor autophagy and mitophagy, clean the cardiac cells with damaged organelles, and reduce oxidative stress and inflammatory response, giving cardiac tissue protection. In this sense, SGLT-2 inhibitors enhance the level of at least four sirtuins, some located in the mitochondria. Moreover, late evidence shows that SLGT-2 inhibitors mimic this protective process, improving mitochondria function, oxidative stress, and inflammation. Considering the previously described protection at the cardiovascular level is necessary to go deeper in the knowledge of the effects of SGLT-2 inhibitors on the mitochondria function. Various of the protective effects these drugs clearly had shown in the trials, and we briefly describe it could depend on sirtuins enhance activity, oxidative stress reduction, inflammatory process attenuation, less interstitial fibrosis, and a consequent better cardiac function. This information could encourage investigating new therapeutic strategies for metabolic syndrome, diabetes, heart and renal failure, and other diseases.

L-arginine-containing mesoporous silica nanoparticles embedded in dental adhesive (Arg@MSN@DAdh) for targeting cariogenic bacteria.

Dental caries is the major biofilm-mediated oral disease in the world. The main treatment to restore caries lesions consists of the use of adhesive resin composites due to their good properties. However, the progressive degradation of the adhesive in the medium term makes possible the proliferation of cariogenic bacteria allowing secondary caries to emerge. In this study, a dental adhesive incorporating a drug delivery system based on L-arginine-containing mesoporous silica nanoparticles (MSNs) was used to release this essential amino acid as a source of basicity to neutralize the harmful acidic conditions that mediate the development of dental secondary caries. The in vitro and bacterial culture experiments proved that L-arginine was released in a sustained way from MSNs and diffused out from the dental adhesive, effectively contributing to the reduction of the bacterial strains Streptococcus mutans and Lactobacillus casei. Furthermore, the mechanical and bonding properties of the dental adhesive did not change significantly after the incorporation of L-arginine-containing MSNs. These results are yielding glimmers of promise for the cost-effective prevention of secondary caries.

Cannabinoids as Potential Molecules for Addiction Disorders.

BACKGROUND: Addictions are a group of chronic and recurrent diseases of the brain characterized by a pathological search for reward or relief through the use of a substance or other action. This situation implies an inability to control behavior, difficulty in permanent abstinence, a compelling desire to consume, decreased recognition of significant problems caused by behavior and interpersonal relationships, and a dysfunctional emotional response. The result is a decrease in the quality of life of the affected person, generating problems in their work, academic activities, social relationships, or family or partner relationships. Unfortunately, there are not enough pharmacotherapeutic solutions to treat addictions due to the complexity of their physiopathology and signaling pathways. Therefore, it is an imperative search for new pharmacological alternatives which may be used for this purpose. PURPOSE OF REVIEW: This review summarizes the main recent findings of the potential therapeutic effects of different cannabinoids on treating several addictions, including alcohol, opioids, methamphetamine, cocaine, and nicotine use disorders. Highlights Standpoints: It has been demonstrated that many phyto, synthetic, and endogenous cannabinoids may act as therapeutic molecules in this psychiatric pathology through their action on multiple cannabinoid receptors. To highlight, cannabinoid receptors, types 1 and 2 (CB1 and CB2) have a crucial role in modulating the anti-addictive properties of these compounds.

Versatile and Resistant Electroless Pore-Plated Pd-Membranes for H2-Separation: Morphology and Performance of Internal Layers in PSS Tubes.

Pd-membranes are interesting in multiple ultra-pure hydrogen production processes, although they can suffer inhibition by certain species or abrasion under fluidization conditions in membrane reactors, thus requiring additional protective layers to ensure long and stable operation. The ability to incorporate intermediate and palladium films with enough adherence on both external and internal surfaces of tubular porous supports becomes crucial to minimize their complexity and cost. This study addresses the incorporation of CeO2 and Pd films onto the internal side of PSS tubes for applications in which further protection could be required. The membranes so prepared, with a Pd-thickness around 12-15 µm, show an excellent mechanical resistance and similar performance to those prepared on the external surface. A good fit to Sieverts' law with an H2-permeance of 4.571 × 10-3 mol m-2 s-1 Pa-0.5 at 400 °C, activation energy around 15.031 kJ mol-1, and complete ideal perm-selectivity was observed. The permeate fluxes reached in H2 mixtures with N2, He, or CO2 decreased with dilution and temperature due to the inherent concentration-polarization. The presence of CO in mixtures provoked a higher decrease because of a further inhibition effect. However, the original flux was completely recovered after feeding again with pure hydrogen, maintaining stable operation for at least 1000 h.

Procoagulant State of Sleep Apnea Depends on Systemic Inflammation and Endothelial Damage.

INTRODUCTION: Growing evidence shows a hypercoagulable state in obstructive sleep apnea (OSA) that could be a risk factor for thromboembolic disease. OBJECTIVES: We aimed to elucidate mechanisms involved in the procoagulant profile observed in patients with OSA and to investigate the potential utility of global tests in its characterization. METHODS: Thirty-eight patients with severe OSA without previous history of thrombosis and nineteen healthy age- and sex-matched controls were included. Kinetic of clot formation was determined using rotational thromboelastometry. Haemostatic capacity of plasma and microparticles was determined by Calibrated Automated Thrombinography. Platelet surface receptors, activation markers and formation of platelet/leukocytes aggregates were analyzed by flow cytometry. RESULTS: Thromboelastometry showed a procoagulant state in patients with OSA that did not seem to be related to a basal activation of platelets but by the increased existence of platelet/leukocyte aggregates. Patients with OSA presented many signs of endothelial damage such as increased plasma levels of E-selectin and cfDNA and enhanced thrombin generation due to the presence of microparticles rich in tissue-factor, which is related to OSA severity. CONCLUSIONS: OSA induces an enhancement in the dynamics of clot formation which appears to be caused by at least two pathological mechanisms. First, a greater formation of platelet-leukocyte aggregates; secondly, endothelial damage which provokes a greater procoagulant potential due to the increase in tissue factor-rich microparticles. Moreover, this study has identified thromboelastometry and thrombin generation assay as useful tools to evaluate the prothrombotic state in these patients.

Cytostatic and Cytotoxic Effects of Hollow-Shell Mesoporous Silica Nanoparticles Containing Magnetic Iron Oxide.

Among the different types of nanoparticles used in biomedical applications, Fe nanoparticles and mesoporous siliceous materials have been extensively investigated because of their possible theranostic applications. Here, we present hollow-shell mesoporous silica nanoparticles that encapsulate iron oxide and that are prepared using a drug-structure-directing agent concept (DSDA), composed of the model drug tryptophan modified by carbon aliphatic hydrocarbon chains. The modified tryptophan can behave as an organic template that allows directing the hollow-shell mesoporous silica framework, as a result of its micellisation and subsequent assembly of the silica around it. The one-pot synthesis procedure facilitates the incorporation of hydrophobically stabilised iron oxide nanoparticles into the hollow internal silica cavities, with the model drug tryptophan in the shell pores, thus enabling the incorporation of different functionalities into the all-in-one nanoparticles named mesoporous silica nanoparticles containing magnetic iron oxide (Fe3O4@MSNs). Additionally, the drug loading capability and the release of tryptophan from the silica nanoparticles were examined, as well as the cytostaticity and cytotoxicity of the Fe3O4@MSNs in different colon cancer cell lines. The results indicate that Fe3O4@MSNs have great potential for drug loading and drug delivery into specific target cells, thereby overcoming the limitations associated with conventional drug formulations, which are unable to selectively reach the sites of interest.

Kidney-Protector Lipidic Cilastatin Derivatives as Structure-Directing Agents for the Synthesis of Mesoporous Silica Nanoparticles for Drug Delivery.

Mesoporous silica nanomaterials have emerged as promising vehicles in controlled drug delivery systems due to their ability to selectively transport, protect, and release pharmaceuticals in a controlled and sustained manner. One drawback of these drug delivery systems is their preparation procedure that usually requires several steps including the removal of the structure-directing agent (surfactant) and the later loading of the drug into the porous structure. Herein, we describe the preparation of mesoporous silica nanoparticles, as drug delivery systems from structure-directing agents based on the kidney-protector drug cilastatin in a simple, fast, and one-step process. The concept of drug-structure-directing agent (DSDA) allows the use of lipidic derivatives of cilastatin to direct the successful formation of mesoporous silica nanoparticles (MSNs). The inherent pharmacological activity of the surfactant DSDA cilastatin-based template permits that the MSNs can be directly employed as drug delivery nanocarriers, without the need of extra steps. MSNs thus synthesized have shown good sphericity and remarkable textural properties. The size of the nanoparticles can be adjusted by simply selecting the stirring speed, time, and aging temperature during the synthesis procedure. Moreover, the release experiments performed on these materials afforded a slow and sustained drug release over several days, which illustrates the MSNs potential utility as drug delivery system for the cilastatin cargo kidney protector. While most nanotechnology strategies focused on combating the different illnesses this methodology emphasizes on reducing the kidney toxicity associated to cancer chemotherapy.

The Importance of Platelet Glycoside Residues in the Haemostasis of Patients with Immune Thrombocytopaenia.

Loss of sialic acid from the carbohydrate side chains of platelet glycoproteins can affect platelet clearance, a proposed mechanism involved in the etiopathogenesis of immune thrombocytopaenia (ITP). We aimed to assess whether changes in platelet glycosylation in patients with ITP affected platelet counts, function, and apoptosis. This observational, prospective, and transversal study included 82 patients with chronic primary ITP and 115 healthy controls. We measured platelet activation markers and assayed platelet glycosylation and caspase activity, analysing samples using flow cytometry. Platelets from patients with ITP with a platelet count <30 × 103/µL presented less sialic acid. Levels of α1,6-fucose (a glycan residue that can directly regulate antibody-dependent cellular cytotoxicity) and α-mannose (which can be recognised by mannose-binding-lectin and activate the complement pathway) were increased in the platelets from these patients. Platelet surface exposure of other glycoside residues due to sialic acid loss inversely correlated with platelet count and the ability to be activated. Moreover, loss of sialic acid induced the ingestion of platelets by human hepatome HepG2 cells. Changes in glycoside composition of glycoproteins on the platelets' surface impaired their functional capacity and increased their apoptosis. These changes in platelet glycoside residues appeared to be related to ITP severity.

Whole-Exome Sequencing and C9orf72 Analysis in Primary Progressive Aphasia.

Primary progressive aphasia (PPA) is mainly considered a sporadic disease and few studies have systematically analyzed its genetic basis. We here report the analyses of C9orf72 genotyping and whole-exome sequencing data in a consecutive and well-characterized cohort of 50 patients with PPA. We identified three pathogenic GRN variants, one of them unreported, and two cases with C9orf72 expansions. In addition, one likely pathogenic variant was found in the SQSTM1 gene. Overall, we found 12%of patients carrying pathogenic or likely pathogenic variants. These results support the genetic role in the pathophysiology of a proportion of patients with PPA.

Effective H2 Separation through Electroless Pore-Plated Pd Membranes Containing Graphite Lead Barriers.

Hydrogen promotion as a clean energy vector could provide an efficient strategy for realizing real decarbonization of the current energy system. Purification steps are usually required in most H2-production processes, providing the use of Pd-based membranes, particularly those supported on porous stainless steel (PSS), important advantages against other alternatives. In this work, new composite membranes were prepared by modifying PSS supports with graphite, as an intermediate layer, before incorporating a palladium film by electroless pore-plating. Fully dense Pd layers were reached, with an estimated thickness of around 17 µm. Permeation measurements were carried out in two different modes: H2 permeation from the inner to the outer side of the membrane (in-out) and in the opposite way (out-in). H2 permeances between 3.24 × 10-4 and 4.33 × 10-4 mol m-2 s-1 Pa-0.5 with αH2/N2 ≥ 10,000 were reached at 350-450 °C when permeating from the outer to the inner surface. Despite a general linear trend between permeating H2 fluxes and pressures, the predicted intercept in (0,0) by the Sieverts' law was missed due to the partial Pd infiltration inside the pores. H2-permeances progressively decreased up to around 33% for binary H2-N2 mixtures containing 40 vol% N2 due to concentration-polarization phenomena. Finally, the good performance of these membranes was maintained after reversing the direction of the permeate flux. This fact practically demonstrates an adequate mechanical resistance despite generating tensile stress on the Pd layer during operation, which is not accomplished in other Pd membranes.

Insights into the Procoagulant Profile of Patients with Systemic Lupus Erythematosus without Antiphospholipid Antibodies.

We aimed to identify the key players in the prothrombotic profile of patients with systemic lupus erythematosus (SLE) not mediated by antiphospholipid antibodies, as well as the potential utility of global coagulation tests to characterize hemostasis in these patients. Patients with SLE without antiphospholipid antibodies and without signs of thrombosis were included. The kinetics of clot formation were determined by ROTEM®. Platelet activation markers were determined by flow cytometry. Thrombin generation associated with Neutrophil Extracellular Traps (NETs) and microparticles (MPs) was measured by calibrated automated thrombogram (CAT). The plasma levels of PAI-1 were also determined. ROTEM® showed a procoagulant profile in SLE patients. SLE patients had activated platelets and more leukocyte/platelet aggregates at basal conditions. The plasma PAI-1 and platelet aggregates correlated with several ROTEM® parameters. The thrombin generation associated withthe tissue factor (TF) content of MPs and with NETs was increased. Our results suggest the utility of global tests for studying hemostasis in SLE patients because they detect their procoagulant profile, despite having had neither antiphospholipid antibodies nor any previous thrombotic event. A global appraisal of hemostasis should, if possible, be incorporated into clinical practice to detect the risk of a thrombotic event in patients with SLE and to consequently act to prevent its occurrence.

La interacción vitamina D-mitocondria podría modular el camino de señalización involucrado en el desarrollo de la hipertensión: una visión integrativa translacional / Vitamin D-mitochondria cross-talk could modulate the signaling pathway involved in hypertension development: a translational integrative overview

El déficit de vitamina D es una pandemia a nivel mundial y trae como consecuencia osteoporosis, hipertensión arterial (HTA) y otras enfermedades cardiovasculares. A nivel celular produce mayor carga oxidativa, marcadores inflamatorios y daño mitocondrial. Existe cada vez más evidencia sobre el protagonismo de la vitamina D en la regulación del sistema renina-angiotensina-aldosterona (RAAS), con posibles implicancias cardiovasculares así como para el sistema inmunológico. Valores de vitamina D inferiores a 25 ng/mL se relacionan con un aumento de tono vascular mediado por la contracción del músculo liso, ya sea a través de efectos directos sobre las células vasculares del músculo liso, sobrerregulación del RAAS, y/o a través de la modulación del metabolismo del calcio con hiperparatiroidismo secundario; lo cual predispone en los pacientes a desarrollar hipertrofia del ventrículo izquierdo y de la pared vascular originando HTA. En este trabajo se realizó una revisión de los principales mecanismos involucrados en el desarrollo de la HTA asociados al déficit de vitamina D. Entre ellos se destaca el vínculo que se establece entre los niveles de fosfato inorgánico extramitocondrial, sus principales hormonas reguladoras -como la vitamina D-, el aparato cardiovascular, las especies reactivas del oxígeno y el metabolismo mitocondrial. El papel del receptor de vitamina D a nivel mitocondrial y la regulación de la cadena respiratoria influirían en el remodelamiento arterial, ya que su activación reduciría el daño oxidativo y preservaría la vida celular. No obstante, existen aspectos aún no comprendidos sobre la intrincada red de señalización que resultan simples en ensayos experimentales, pero complejos en los estudios clínicos. En este sentido, la concreción de nuevos estudios como el VITAL podría clarificar, y así apoyar o refutar, los posibles beneficios de la vitamina D en la enfermedad cardiovascular hipertensiva

Vitamin D deficiency is a worldwide pandemic and results in osteoporosis, hypertension, and other cardiovascular diseases. At the cellular level, it produces significant oxidative stress, inflammatory markers, and mitochondrial damage. There is increasing evidence about the role of vitamin D in the regulation of the renin-angiotensin-aldosterone system (RAAS). Moreover, there is evidence of involvement in cardiovascular complications, as well as in the immune system disorders. Vitamin D values below 25 ng/mL are related to an increase in vascular tone mediated by smooth muscle contraction. Furthermore, it can produce direct effects on vascular smooth muscle cells, RAAS over-regulation, modulation of calcium metabolism, and secondary hyperparathyroidism. All this predisposes patients to develop hypertrophy of the left ventricle and vascular wall, causing hypertension. In this work, a review is presented of the main mechanisms involved in the development of hypertension due to vitamin D deficiency. Among them are the link established between the levels of extra-mitochondrial inorganic phosphate, its main regulatory hormones -such as vitamin D-, the cardiovascular system, reactive oxygen species, and mitochondrial metabolism. The role of the mitochondrial vitamin D receptor and the regulation of the respiratory chain could influence arterial remodelling since its activation would reduce oxidative damage and preserve cell life. However, there are aspects not yet understood about the intricate signalling network that appeared simple in experimental trials, but complex in clinical studies. In this way, the completion of new studies as VITAL, could clarify, and thus support or refute the possible benefits of vitamin D in hypertensive cardiovascular disease

Vitamin D-RAAS Connection: An Integrative Standpoint into Cardiovascular and Neuroinflammatory Disorders.

BACKGROUND: The neuroinflammatory process is associated with the pathogenesis of many cardiovascular disorders, particularly with hypertension. In this regard, the deficiency of vitamin D seems to increase the risk of cardiovascular pathologies related to neuroinflammation. Long-term lack of vitamin D leads to over-activation of the renin-angiotensin-aldosterone system (RAAS), one of the essential mechanisms of blood pressure regulation. PURPOSE OF REVIEW: This review summarizes the latest studies carried out to evaluate the primary mechanisms underlying the neuroprotective effect of vitamin D and its receptors (VDR) in the central nervous system. Besides, the present article condenses the evidence supporting the link between vitamin D and the RAAS in hypertension and neuroinflammation. Highlights Standpoints: Vitamin D deficiency is highly prevalent in the world, and the rising prevalence of neuroinflammatory diseases and associated pathologies such as hypertension around the world justifies the urgent need of searching new and more effective therapeutic methods that could be related to RAAS modulation and vitamin D levels management.

Vitamin D-mitochondria cross-talk could modulate the signaling pathway involved in hypertension development: a translational integrative overview. / La interacción vitamina D-mitocondria podría modular el camino de señalización involucrado en el desarrollo de la hipertensión: una visión integrativa translacional.

Vitamin D deficiency is a worldwide pandemic and results in osteoporosis, hypertension, and other cardiovascular diseases. At the cellular level, it produces significant oxidative stress, inflammatory markers, and mitochondrial damage. There is increasing evidence about the role of vitamin D in the regulation of the renin-angiotensin-aldosterone system (RAAS). Moreover, there is evidence of involvement in cardiovascular complications, as well as in the immune system disorders. Vitamin D values below 25ng/mL are related to an increase in vascular tone mediated by smooth muscle contraction. Furthermore, it can produce direct effects on vascular smooth muscle cells, RAAS over-regulation, modulation of calcium metabolism, and secondary hyperparathyroidism. All this predisposes patients to develop hypertrophy of the left ventricle and vascular wall, causing hypertension. In this work, a review is presented of the main mechanisms involved in the development of hypertension due to vitamin D deficiency. Among them are the link established between the levels of extra-mitochondrial inorganic phosphate, its main regulatory hormones -such as vitamin D-, the cardiovascular system, reactive oxygen species, and mitochondrial metabolism. The role of the mitochondrial vitamin D receptor and the regulation of the respiratory chain could influence arterial remodelling since its activation would reduce oxidative damage and preserve cell life. However, there are aspects not yet understood about the intricate signalling network that appeared simple in experimental trials, but complex in clinical studies. In this way, the completion of new studies as VITAL, could clarify, and thus support or refute the possible benefits of vitamin D in hypertensive cardiovascular disease.