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Oxidative stress and chronic inflammatory conditions contribute as key determinants in the development of vascular and renal diseases. Organosulfur compounds (OSCs) of oil macerated with garlic (OMG) are promising phytochemicals which could protect us from hyper-inflammation and oxidative stress-induced organ damage. The present work evaluated the effect of OMG intake in apolipoprotein E-knockout (ApoE-KO) mice. Adult female ApoE-KO mice were randomly divided into three groups and fed with control chow, oil-supplemented diet and OMG-supplemented diet. After 8 weeks, the animals were euthanized and blood, aorta, kidneys, liver and abdominal adipose tissues were obtained for further analysis. Biochemical parameters were measured in plasma, lipid peroxidation as malondialdehyde (MDA) levels was determined in the adipose tissue, oil red O was used to stain atherosclerotic lesions, and histological and ultrastructural analyses of the kidneys were performed. Renal expression levels of Tumor Necrosis Factor α (TNF-α), Interleukin-6 (IL-6) and Wilms' Tumor Protein (WT-1) were determined by western blotting and the co-immunoprecipitation assay (p53/WT-1). Also, transmission electron microscopy for studying the expression of mitofusin 2 (Mfn-2) was used to assess mitochondrial damage. The results showed that long-term moderate intake of OMG improved serum triglyceride levels, diminished the atheroma plaque area, and reduced lipid peroxidation. Furthermore, we found a decrease in oxidative and inflammatory markers, less apoptosis and reduced WT-1 expression in the kidneys. Also, OMG increased p53/WT-1 protein interactions and reduced mitochondrial damage. Our findings suggest that OMG intake would produce anti-atherosclerotic, antifibrotic, anti-inflammatory and antiapoptotic effects in adult ApoE-KO mice, conferring significant renovascular protective actions in a mechanism mediated, at least in part, by WT-1.

Conventional drug delivery systems often have several pharmacodynamic and pharmacokinetic limitations related to their low efficacy and bad safety. It is because these traditional systems cannot always be selectively addressed to their therapeutic target sites. Currently, target-specific and controlled drug delivery is one of the foremost challenges in the biomedical field. In this context, stimuli-responsive polymeric nanomaterials have been recognized as a topic of intense research. They have gained immense attention in therapeutics - particularly in the drug delivery area - due to the ease of tailorable behavior in response to the surroundings. Light irradiation is of particular interest among externally triggered stimuli because it may be specifically localized in a contact-free manner. Light-human body interactions may sometimes be harmful due to photothermal and photomechanical reactions that lead to cell death by photo-toxicity and/or photosensitization. However, these limitations may also be overcome by the use of photo-responsive polymeric nanostructures. This review summarizes recent developments in photo-responsive polymeric nanocarriers used in the field of drug delivery systems, including nanoparticles, nanogels, micelles, nanofibers, dendrimers, and polymersomes, as well as their classification and mechanisms of drug release.

Background: Most cannabinoids usually present several limitations when evaluating their clinical use, mainly related to the side effects they may cause at the central nervous system and other levels. In this regard, nanotechnology applied to the development of pharmacotherapeutic nanoformulations has become an attractive tool that allows taking advantage of the beneficial properties of multiple drugs while minimizing or avoiding their undesirable side effects. Nanotechnology is a relatively recent scientific field that involves the study, manipulation, development, and characterization of drug delivery systems at the nanoscale (1 to 1000 nm; 1 nm= 1x10-9 m). Usually, the physicochemical properties of matter at the nanoscale are significantly different compared to the matter at the macroscale, which provides several advantages over conventional therapeutic alternative types of organic and inorganic drug delivery nanosystems. Posology, size, composition, surface properties, and different physicochemical characteristics may directly or indirectly influence their pharmacodynamic and pharmacokinetic behavior and, consequently, their biomedical use. Purpose of Review: This mini-review summarizes the main recent findings on nanomedical strategies and applications for cannabinoid encapsulation, raising the possibility of transferring these advances to the therapy of addictions. Highlights Standpoints: The nano therapy significantly improves the pharmacokinetic and pharmacodynamic behavior of multiple active pharmaceutical ingredients with different limitations and disadvantages, thus enhancing the therapeutic compliance of patients. In general, cannabinoids loaded in nanoformulations offer greater efficacy, lower toxicity and more controlled/prolonged release than cannabinoids in free form.

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.

Vitamin D (vit D) is widely known for its role in calcium metabolism and its importance for the bone system. However, various studies have revealed a myriad of extra-skeletal functions, including cell differentiation and proliferation, antibacterial, antioxidant, immunomodulatory, and anti-inflammatory properties in various cells and tissues. Vit D mediates its function via regulation of gene expression by binding to its receptor (VDR) which is expressed in almost all cells within the body. This review summarizes the pleiotropic effects of vit D, emphasizing its anti-inflammatory effect on different organ systems. It also provides a comprehensive overview of the genetic and epigenetic effects of vit D and VDR on the expression of genes pertaining to immunity and anti-inflammation. We speculate that in the context of inflammation, vit D and its receptor VDR might fulfill their roles as gene regulators through not only direct gene regulation but also through epigenetic mechanisms.

Vascular inflammation is one of the main activating stimuli of cardiovascular disease and its uncontrolled development may worsen the progression and prognosis of these pathologies. Therefore, the search for new therapeutic options to treat this condition is undoubtedly needed. In this regard, it may be better to repurpose endogenous anti-inflammatory compounds already known, in addition to synthesizing new compounds for therapeutic purposes. It is well known that vitamin D, anandamide, and melatonin are promising endogenous substances with powerful and wide-spread anti-inflammatory properties. Currently, the epigenetic mechanisms underlying these effects are often unknown. This review summarizes the potential epigenetic mechanisms by which vitamin D, anandamide, and melatonin attenuate vascular inflammation. This information could contribute to the improvement in the therapeutic management of multiple pathologies associated with blood vessel inflammation, through the pharmacological manipulation of new target sites that until now have not been addressed.

The leading cause of complications or death from COVID-19 is due to the development of acute respiratory distress syndrome (ARDS). This syndrome is characterized by exacerbated inflammation, mainly at the pulmonary level, and an over-activation of the renin-angiotensin-aldosterone system (RAAS), usually culminating in death or permanent respiratory sequelae in the SARS-CoV-2 infected patients. In this sense, it has been proposed that vitamin D exerts numerous immunomodulatory effects by acting on various types of immune and epithelial cells, as well as being able to stimulate the protective arm (ACE2/Ang-(1-7)) and inhibit the harmful arm (ACE/Ang-II) of the RAAS. Therefore, some of the main mechanisms underlying these effects mediated by vitamin D and its receptors are discussed in the present review. The analysis of these mechanisms would positively influence the prevention and treatment of ARDS, thus preventing the progression of the disease and improving the prognosis of the patients. Fil: Carmona, Maximiliano. Gobierno de la Provincia de Mendoza. Hospital Luis Lagomaggiore.; Argentina. Ministerio de Salud de la Nación; Argentina. Ministerio de Desarrollo Social; Argentina. Ministerio de Desarrollo Social. Secretaria de Deportes de la Nacion; Argentina Fil: Martín Giménez, Virna Margarita. Universidad Catolica de Cuyo - Sede San Juan. Facultad de Ciencias de la Alimentación, Bioquímicas y Farmacéuticas. Instituto de Investigación en Ciencias Químicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza; Argentina Fil: Manucha, Walter Ariel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Departamento de Patología; Argentina

COVID-19 is said to be a pandemic that does not distinguish skin color or ethnic origin, but data in many parts of the world, especially in the United States, begins to show that there is a sector of society that is suffering a more significant impact from this pandemic. The black population is being more vulnerable than the white population to infection and death by COVID-19, and hypertension and diabetes mellitus seems to predispose to this vulnerability. Over time, multiple disparities have been observed between the health of blacks and whites, mainly associated with inequalities in the socio-economic scope. However, little by little, some mechanisms and pathophysiological susceptibilities that are directly related to the higher prevalence of multiple diseases in the black population, including infection and death by COVID-19, begin to be elucidated.Plasma vitamin D levels and evolutionary adaptations of the renin-angiotensin-aldosterone system in black people are considerably different between this and other races, and it is well established their role in the development and progression of hypertension and multiple lung diseases, among them, COVID-19 infection.This letter to discuss and proposes whether or not vitamin D and renin-angiotensin-aldosterone system ethnical disparities influence susceptibility to infection and death by COVID-19 in black people and suggests possible mechanisms for this susceptibility. Fil: Martín Giménez, Virna Margarita. Universidad Catolica de Cuyo - Sede San Juan. Facultad de Ciencias de la Alimentación, Bioquímicas y Farmacéuticas. Instituto de Investigación en Ciencias Químicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Inserra, Felipe. Universidad Maimónides; Argentina Fil: Ferder, Leon Fernando. Universidad Maimónides; Argentina Fil: García, Joxel. Ambitious Solutions for Health Cures; Estados Unidos Fil: Manucha, Walter Ariel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina

Background: The kidney and cardiovascular system are closely related to each other during the modulation of the cardiovascular homeostasis. However, the search for new alternatives for the treatment and diagnosis of cardiovascular diseases does not take into account this relationship, so their evaluation results and the advantages offered by their global and integrative analysis are wasted. For example, a variety of receptors that are overexpressed in both pathologies is large enough to allow expansion in the search for new molecular targets and ligands. Nanotechnology offers pharmacological targeting strategies to kidney, heart, and blood vessels for overcoming one of the essential restrictions of traditional cardiovascular therapies the ones related to their unspecific pharmacodynamics distribution in these critical organs. Recent Findings: Drug or contrast agent nano-targeting for treatment or diagnosis of atherosclerosis, thrombosis, renal cancer or fibrosis, glomerulonephritis, among other renal, cardiac and blood vessels pathologies would allow an increase in their efficacy and a reduction of their side effects. Such effects are possible because, through pharmacological targeting, the drug is mainly found at the desired site. Review Purpose: In this mini-review, active, passive, and physical targeting strategies of several nanocarriers that have been assessed and proposed for the treatment and diagnosis of different cardiovascular diseases, are being addressed.

The gut microbiota dysbiosis represents a triggering factor for cardiovascular diseases, including hypertension. In addition to the harmful impact caused by hypertension on different target organs, gut dysbiosis is capable of causing direct damage to critical organs such as the brain, heart, blood vessels, and kidneys. In this sense, it should be noted that pharmacological and nutritional interventions may influence gut microbiota composition, either inducing or preventing the development of hypertension. Some of the most important nutritional interventions at this level are represented by pro-, pre-, post- and/or syn-biotics, as well as polysaccharides, polyunsaturated fatty acids ω-3, polyphenols and fiber contained in different foods. Meanwhile, certain natural and synthetic active pharmaceutical ingredients, including antibiotics, antihypertensive and immunosuppressive drugs, vegetable extracts and vitamins, may also have a key role in the modulation of both gut microbiota and cardiovascular health. Additionally, gut microbiota may influence drugs and food-derived bioactive compounds metabolism, positively or negatively affecting their biological behavior facing established hypertension. The understanding of the complex interactions between gut microbiome and drug/food response results of great importance to developing improved pharmacological therapies for hypertension prevention and treatment. The purpose of this review is to critically outline the most relevant and recent findings on cardiovascular, renal and brain physiopathological mechanisms involved in the development of hypertension associated with changes in gut microbiota, besides the nutritional and pharmacological interventions potentially valuable for the prevention and treatment of this prevalent pathology. Finally, harmful food/drug interventions on gut microbiota are also described.

The use of nanosized particles has emerged to facilitate selective applications in medicine. Drug-delivery systems represent novel opportunities to provide stricter, focused, and fine-tuned therapy, enhancing the therapeutic efficacy of chemical agents at the molecular level while reducing their toxic effects. Melatonin (N-acetyl-5-methoxytriptamine) is a small indoleamine secreted essentially by the pineal gland during darkness, but also produced by most cells in a non-circadian manner from which it is not released into the blood. Although the therapeutic promise of melatonin is indisputable, aspects regarding optimal dosage, biotransformation and metabolism, route and time of administration, and targeted therapy remain to be examined for proper treatment results. Recently, prolonged release of melatonin has shown greater efficacy and safety when combined with a nanostructured formulation. This review summarizes the role of melatonin incorporated into different nanocarriers (e.g., lipid-based vesicles, polymeric vesicles, non-ionic surfactant-based vesicles, charge carriers in graphene, electro spun nanofibers, silica-based carriers, metallic and nonmetallic nanocomposites) as drug delivery system platforms or multilevel determinations in various in vivo and in vitro experimental conditions. Melatonin incorporated into nanosized materials exhibits superior effectiveness in multiple diseases and pathological processes than does free melatonin; thus, such information has functional significance for clinical intervention. Fil: Chuffa, Luiz Gustavo de Almeida. Universidade de Sao Paulo; Brasil Fil: Seiva, Fábio Rodrigues Ferreira. Universidade Estadual do Norte do Paraná; Brasil Fil: Novais, Adriana Alonso. Universidade Federal do Mato Grosso do Sul; Brasil Fil: Simão, Vinícius Augusto. Universidade de Sao Paulo; Brasil Fil: Martín Giménez, Virna Margarita. Universidad Católica de Cuyo. Facultad de Ciencias Químicas y Tecnológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina Fil: Manucha, Walter Ariel Fernando. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Zuccari, Debora Aparecida Pires de Campos. Faculdade de Medicina de São José do Rio Preto; Brasil Fil: Reiter, Russel. University of Texas at San Antonio; Estados Unidos

Exaggerated oxidative stress and hyper-inflammation are essential features of oxidative/inflammatory diseases. Simultaneously, both processes may be the cause or consequence of mitochondrial dysfunction, thus establishing a vicious cycle among these three factors. However, several natural substances, including melatonin and micronutrients, may prevent or attenuate mitochondrial damage and may preserve an optimal state of health by managing the general oxidative and inflammatory status. This review aims to describe the crucial role of mitochondria in the development and progression of multiple diseases as well as the close relationship among mitochondrial dysfunction, oxidative stress, and cytokine storm. Likewise, it attempts to summarize the main findings related to the powerful effects of melatonin and some micronutrients (vitamins and minerals), which may be useful (alone or in combination) as therapeutic agents in the treatment of several examples of oxidative/inflammatory pathologies, including sepsis, as well as cardiovascular, renal, neurodegenerative, and metabolic disorders.

Hypertension and diabetes are two of the leading causes of morbidity and mortality in the current world population, especially in Western societies. These two pathological conditions are key risk factors for the onset and progression of many cardiovascular diseases such as stroke, atherosclerosis, pulmonary hypertension, thrombosis, and heart failure. In general, hypertension and diabetes mellitus coexist in most patients with metabolic disorders. Both pathologies usually develop concomitantly or consecutively in the same individual due to different underlying pathophysiologic mechanisms that are shared between them. Some of these mechanisms include inadequate renin-angiotensin-aldosterone system activation, insulin resistance, dysfunctional immune response, inflammation, oxidative stress, abnormal sodium renal management, exacerbated sympathetic nervous system activation, and endothelial dysfunction, among others.

Melatonin may be a powerful auxiliary therapy in the prevention and treatment of viral infections, such as coronavirus disease 2019 (COVID-19). Casually, the so-called ‘super immunity’ of bats and the usually high levels of melatonin in children could contribute to their high resistance to the SARS-CoV-2 virus. Melatonin seems to play a key role in suppressing COVID-19 infections. This endogenous antioxidant inhibits cell apoptosis, blocks the inflammasomes that mediate lung inflammation, reduces blood vessel permeability which limits alveolar edema, improves anxiety and sleeps habits that stimulate general immunity and prevents lung fibrosis. These complications, which are usually the main consequences of COVID-19, may be significantly attenuated by melatonin... Fil: Martín Giménez, Virna Margarita. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina. Universidad Católica de Cuyo. Facultad de Ciencias Químicas y Tecnológicas; Argentina Fil: Prado, Natalia Jorgelina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Departamento de Patología; Argentina Fil: Diez, Emiliano Raúl. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Fisiología; Argentina Fil: Manucha, Walter Ariel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Fisiología; Argentina Fil: Reiter, Russel. University of Texas at San Antonio; Estados Unidos

The COVID-19 pandemic has reached most of the countries worldwide causing death, which often results from an inflammatory storm associated with severe acute respiratory syndrome (SARS). This has prompted researchers to seek specific novel and definitive treatments urgently. In this context, it is interesting to evaluate the preventive and therapeutic effects of existing pharmacological agents that could be useful. In this regard, vitamin D supplementation, particularly in individuals likely to be deficient, may be a promising option. Vitamin D is a hormone that modulates many of the same inflammatory and oxidative signaling pathways triggered during COVID-19. For example, vitamin D suppresses the actions of the renin-angiotensin system, which has a determining role in the pathophysiology of the inflammatory response related to COVID-19. This paper analyzes the evidence that vitamin D supplementation might be a valuable preventive/therapeutic measure in groups at risk of or infected with COVID-19. It also discusses how clinical studies could be best designed to evaluate the possible advantages of vitamin D supplementation for the benefit of public health during the pandemic. Fil: Ferder, Leon Fernando. Universidad Maimónides; Argentina Fil: Martín Giménez, Virna Margarita. Universidad Catolica de Cuyo - Sede San Juan. Facultad de Cs. de la Alimentación, Bioquímicas y Farmacéuticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina Fil: Inserra, Felipe. Universidad Maimónides; Argentina Fil: Tajer, Carlos Daniel. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic; Argentina Fil: Antonietti, Laura. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic; Argentina. Universidad Nacional Arturo Jauretche; Argentina Fil: Mariani, Javier. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic; Argentina Fil: Manucha, Walter Ariel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina

Due to its high degree of contagiousness and like almost no other virus, SARS-CoV-2 has put the health of the world population on alert. COVID-19 can provoke an acute inflammatory process and uncontrolled oxidative stress, which predisposes one to respiratory syndrome, and in the worst case, death. Recent evidence suggests the mechanistic role of mitochondria and vitamin D in the development of COVID-19. Indeed, mitochondrial dynamics contribute to the maintenance of cellular homeostasis, and its uncoupling involves pathological situations. SARS-CoV-2 infection is associated with altered mitochondrial dynamics with consequent oxidative stress, pro-inflammatory state, cytokine production, and cell death. Furthermore, vitamin D deficiency seems to be associated with increased COVID-19 risk. In contrast, vitamin D can normalize mitochondrial dynamics, which would improve oxidative stress, pro-inflammatory state, and cytokine production. Furthermore, vitamin D reduces renin–angiotensin–aldosterone system activation and, consequently, decreases ROS generation and improves the prognosis of SARS-CoV-2 infection. Thus, the purpose of this review is to deepen the knowledge about the role of mitochondria and vitamin D directly involved in the regulation of oxidative stress and the inflammatory state in SARS-CoV-2 infection. As future prospects, evidence suggests enhancing the vitamin D levels of the world population, especially of those individuals with additional risk factors that predispose to the lethal consequences of SARS-CoV-2 infection. Fil: de Las Heras, Natalia. Universidad Complutense de Madrid. Facultad de Medicina. Departamento de Fisiología; España Fil: Martín Giménez, Virna Margarita. Universidad Catolica de Cuyo. Facultad de Ciencias Quimicas y Tecnologicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina Fil: Ferder, León. Universidad Maimónides; Argentina Fil: Manucha, Walter Ariel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Lahera Juliá, Vicente. Universidad Complutense de Madrid. Facultad de Medicina. Departamento de Fisiología; España

Purpose Hypertensive lesions induce alterations at hemodynamic, peripheral, and central levels. Anandamide (N-arachidonoylethanolamine; AEA) protects neurons from inflammatory damage, but its free administration may cause central adverse effects. AEA controlled release by nanoformulations could reduce/eliminate its side effects. The present study aimed to evaluate the effects of nanoformulated AEA (nf-AEA) on systolic blood pressure (SBP), behavior, and central/peripheral inflammatory, oxidative, and apoptotic state in spontaneously hypertensive rats (SHR). Materials/methods Male rats were used, both Wistar Kyoto (WKY) and SHR (n ​= ​10 per group), with/without treatment with nf-AEA (obtained by electrospraying) at a weekly dose of 5 ​mg/kg IP for 4 weeks. SBP was measured and behavioral tests were performed. Inflammatory/oxidative markers were quantified at the central (brain cortex) and peripheral (serum) level. Results SHR showed hyperactivity, low anxiety, and high concentrations of central/peripheral inflammatory/oxidative markers, also higher apoptosis of brain cortical cells compared to WKY. As opposed to this group, treatment with nf-AEA in SHR significantly reduced SBP, peripheral/central inflammatory/oxidative makers, and central apoptosis. Nf-AEA also increased neuroprotective mechanisms mediated by intracellular heat shock protein 70 (Hsp70), which were attenuated in untreated SHR. Additionally, nf-AEA reversed the abnormal behaviors observed in SHR without producing central adverse effects. Conclusions Our results suggest protective properties of nf-AEA, both peripherally and centrally, through a signaling pathway that would involve the type I angiotensin II receptor, Wilms tumor transcription factor 1, Hsp70, and iNOS. Considering non-nf-AEA limitations, this nanoformulation could contribute to the development of new antihypertensive and behavioral disorder treatments associated with neuroinflammation.

COVID-19 pandemic has a high mortality rate and is affecting practically the entire world population. The leading cause of death is severe acute respiratory syndrome as a consequence of exacerbated inflammatory response accompanied by uncontrolled oxidative stress as well as the inflammatory reaction at the lung level. Until now, there is not a specific and definitive treatment for this pathology that worries the world population, especially the older adults who constitute the main risk group. In this context, it results in a particular interest in the evaluation of the efficacy of existing pharmacological agents that may be used for overcoming or attenuating the severity of this pulmonary complication that has ended the lives of many people worldwide. Vitamin D and melatonin could be good options for achieving this aim, taking into account that they have many shared underlying mechanisms that are able to modulate and control the immune adequately and oxidative response against COVID-19 infection, possibly even through a synergistic interaction. The renin-angiotensin system exaltation with consequent inflammatory response has a leading role in the physiopathology of COVID-19 infection; and it may be down-regulated by vitamin D and melatonin in many organs. Therefore, it is also essential to analyze this potential therapeutic association and their relation with RAS as part of this new approach., Graphical abstract Graphical overview of key common signaling pathways between melatonin and vitamin D as a new potential synergistic treatment in COVID-19 lung infection: The cross-talk between melatonin-RAS-vitamin D, a rational protagonist triad in COVID-19? Solid lines indicate stimulation/induction, while dashed lines indicate inhibition/blocking. The thicker dashed lines suggest a more significant inhibitory or blocking effect due to a possible synergistic action between melatonin and associated vitamin D. This figure was created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com.Unlabelled Image

Generally, the development and progression of neurodegenerative diseases are associated with advancing age, so they are usually diagnosed in late adulthood. A primary mechanism underlying the onset of neurodegenerative diseases is neuroinflammation. Based on this background, the concept of "neuroinflammaging" has emerged. In this deregulated neuroinflammatory process, a variety of immune cells participate, especially glial cells, proinflammatory cytokines, receptors, and subcellular organelles including mitochondria, which are mainly responsible for maintaining redox balance at the cellular level. Senescence and autophagic processes also play a crucial role in the neuroinflammatory disease associated with aging. Of particular interest, melatonin, cannabinoids, and the receptors of both molecules which are closely related, exert beneficial effects on the neuroinflammatory processes that precede the onset of neurodegenerative pathologies such as Parkinson's and Alzheimer's diseases. Some of these neuroprotective effects are fundamentally related to its anti-inflammatory and antioxidative actions at the mitochondrial level due to the strategic functions of this organelle. The aim of this review is to summarize the most recent advances in the study of neuroinflammation and neurodegeneration associated with age and to consider the use of new mitochondrial therapeutic targets related to the endocannabinoid system and the pineal gland.

Metal ion homeostasis is an essential physiological mechanism necessary for achieving an adequate balance of these ions' concentrations in the different cellular compartments. This fact is of great importance because both an excess and a deficiency of cellular metal ion levels are usually equally harmful due to the exacerbated increase in oxidative stress that may occur in both cases. Metal ion homeostasis ensures an equilibrium among multiple functions associated with the body's antioxidative defense network controlled by metallic micronutrients such as zinc and copper, some of the central regulators of redox processes. These micronutrients significantly modulate the activity of some isoforms of superoxide dismutase (SOD) and other enzymes such as metallothioneins (MTs) and ceruloplasmin (CP), which are directly or indirectly involved in the regulation of redox homeostasis. Although it is well known that both melatonin (MEL) and vitamin D have important roles as natural antioxidants, often some of these effects are related to their actions on antioxidative processes dependent on metal ions. Thus, in addition to their classical antioxidative properties usually associated with mitochondrial effects, it is known that MEL and vitamin D modulate the expression and activity of Cu/Zn-dependent SOD isoforms, MTs and CP; function as copper chelators and regulate genomic and non-genomic mechanisms related to the zinc transport. This review summarizes the main findings related to the crucial participation of zinc and copper in physiological antioxidative status and their relationship with the non-classical antioxidant effects of MEL and vitamin D, suggesting a potential synergism among these four micronutrients.

Atherosclerosis, a known and prevalent disease, causes progressive deterioration of affected vessels, inducing a blood flow reduction with different complications, and its symptoms usually manifest in advanced stages of the disease. Therefore, the classic therapeutic alternatives are insufficient because the damages are many times irreversible. For this reason, there is a need to implement intelligent forms of drug administration and develop new therapeutic targets that reduce the progression of atherosclerotic lesion. The implementation of new tools for prevention, diagnosis and treatment of this cardiovascular disease is of special interest, focusing our attention on achieving a more effective control of the immune system. Finally, this review highlights the latest knowledge about nanotechnology as a powerful, modern, and promising therapeutic alternative applied to atherosclerotic disease, as well as warning of the potential complications with their use.

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.

Drug encapsulation in nanocarriers such as polymeric nanoparticles (Nps) may help to overcome the limitations associated with cannabinoids. In this sense, our work aimed to highlight the use of electrospraying technique for the development of carrier Nps of anandamide (AEA), an endocannabinoid with attractive pharmacological effects but underestimated due to its unfavorable physicochemical and pharmacokinetic properties added to its undesirable effects at the level of the central nervous system. We characterized physicochemically and evaluated in vitro biological activity of anandamide/ε-polycaprolactone nanoparticles (Nps-AEA/PCL) obtained by electrospraying in epithelial cells of human proximal tubule (HK2), to prove the utility of this method and to validate the biological effect of Nps-AEA/PCL. We obtained particles from 100 to 900 nm of diameter with a predominance of 200 a 400 nm. Their zeta potential was -20±1.86 mV. We demonstrated the stable encapsulation of AEA in Nps-AEA/PCL, as well as its dose-dependent capacity to induce the expression of iNOS and NO levels and to decrease the Na+/K+ ATPase activity in HK2 cells. Obtaining Nps-AEA/PCL by electrospraying would represent a promising methodology for a novel AEA pharmaceutical formulation development with optimal physicochemical properties, physical stability and biological activity on HK2 cells. Fil: Martín Giménez, Virna Margarita. Universidad Católica de Cuyo - Sede San Juan; Argentina Fil: Russo, Marcos Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; Argentina Fil: Narda, Griselda Edith. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; Argentina Fil: Fuentes, Lucía B.. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentina Fil: Mazzei, Luciana Jorgelina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Gamarra Luques, Carlos Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Kassuha, Diego Enrique. Universidad Católica de Cuyo - Sede San Juan; Argentina Fil: Manucha, Walter Ariel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; Argentina

Anandamide (AEA), an endogenous cannabinoid, has a relevant antihypertensive effect. However, its cardioprotective role has been barely explored due to unfavorable physico-chemical properties and, sometimes, undesirable psychoactive effects. In this context, drug encapsulation in nanocarriers could overcome the limitations associated with the administration of AEA in free form. The aim of the present study was to encapsulate AEA in poly-ε-caprolactone/Pluronic® F127 nanoparticles (AEA/PCL/PF127 NPs)by means of electrospraying, to characterize their physico-chemical properties and cytocompatibility and to evaluate their effect in an in vivo model of cardiovascular remodeling caused by hypertension. AEA/PCL/PF127 NPs were characterized in terms of morphology, size, polydispersity, Z-potential, hydrophilicity, thermal and spectroscopic properties. Also, the encapsulation and loading efficiencies and in vitro release of AEA were analyzed. AEA/PCL/PF127 NPs (700?1000 nm)showed adequate cytocompatibility. For the cardiovascular remodeling studies, normotensive (WKY)and hypertensive (SHR)male rats were treated or not with AEA/PCL/PF127 NPs (5 mg/Kg, intraperitoneal injection)weekly for 1 month. Inflammatory markers and hemodynamic, structural and cardiac functional parameters were monitored. In SHR, the treatment with AEA/PCL/PF127 NPs reversed all altered cardiovascular markers and parameters (p < 0.05). Overall, nanoformulated AEA obtained by electrospraying proved to be effective for the treatment of hypertension and its comorbidities, especially cardiovascular remodeling. Fil: Martín Giménez, Virna Margarita. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Católica de Cuyo - Sede San Juan; Argentina Fil: Díaz Rodríguez, Patricia. Universidad de Santiago de Compostela; España Fil: Sanz, Raúl Lelio. Universidad Nacional de Cuyo; Argentina Fil: Vivero Lopez, María. Universidad de Santiago de Compostela; España Fil: Concheiro, Angel. Universidad de Santiago de Compostela; España Fil: Diez, Emiliano Raúl. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Cuyo; Argentina Fil: Prado, Natalia Jorgelina. Universidad Nacional de Cuyo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Kassuha, Diego Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Católica de Cuyo - Sede San Juan; Argentina Fil: Alvarez Lorenzo, Carmen. Universidad de Santiago de Compostela; España Fil: Manucha, Walter Ariel Fernando. Universidad Nacional de Cuyo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina

The electrospraying technique provides nano and microparticles that can be used as drug delivery systems. The aims of this study were, firstly, to optimize the influent parameters of electrospraying for the manufacture of a Bosentan (BOS) nanoparticulate platform, and secondly, to evaluate its physicochemical properties and in vitro biopharmaceutical behavior. Particles were characterized by scanning electron microscopy (SEM), powder X‐ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetry (TG) and Fourier transformed Infrared spectroscopy (FTIR). Drug loading, encapsulation efficiency and kinetic dissolution were determined. Additionally, Bosentan release assays at 24 and 72 h were performed in vitro to evaluate biopharmaceutical properties of nano‐scaffolds by diffusion technique through dialysis bag. The nanostructures had heterogeneous sizes predominantly smaller than 550 nm and they were semicrystalline according to PXRD, indicating a partial amorphization of BOS during the encapsulation in the polymer matrix. FT‐IR and DSC showed an absence of chemical interactions between BOS and ε‐Polycaprolactone (PCL), suggesting that both components behaved as a physical mixture in these particles. The drug loading was 25.98%, and the encapsulation efficiency was 58.51%. Additionally, the release assays showed an extended and controlled release of BOS, in comparison to non‐encapsulated BOS. These data also showed to fit with the Cubic Root kinetic dissolution. As a conclusion, we demonstrate that the use of electrospraying for the manufacture of BOS (or similar drugs) controlled release nanoplatforms would represent an interesting contribution in the development of new therapeutic alternatives for the treatment of pathologies such as pulmonary hypertension and other related diseases. Fil: Martín Giménez, Virna Margarita. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Catolica de Cuyo - Sede San Juan. Facultad de Ciencias de la Alimentación, Bioquímicas y Farmacéuticas. Instituto de Investigación en Ciencias Químicas; Argentina Fil: Sperandeo, Norma Rebeca. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina Fil: Faudone, Sonia Nerina. Provincia de Córdoba. Ministerio de Ciencia y Técnica. Centro de Excelencia en Productos y Procesos de Córdoba; Argentina Fil: Noriega, Sandra. Universidad Catolica de Cuyo - Sede San Juan. Facultad de Ciencias de la Alimentación, Bioquímicas y Farmacéuticas. Instituto de Investigación en Ciencias Químicas; Argentina Fil: Manucha, Walter Ariel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; Argentina Fil: Kassuha, Diego Enrique. Universidad Catolica de Cuyo - Sede San Juan. Facultad de Ciencias de la Alimentación, Bioquímicas y Farmacéuticas. Instituto de Investigación en Ciencias Químicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina

Atherosclerosis provokes a continuous worsening of affected vessels causing a blood flow diminution with several complications and with clinical manifestations that generally appear in advanced phases of the illness. Hence, the conventional therapies are not enough because the atherosclerotic injuries are often irrevocable. For this reason, emerges the necessity to implement smart ways of drug supply and develop new therapeutic targets that decrease the advance atherosclerotic lesion. It results due to particular interest to use new tools for prevention, diagnosis, and treatment of this cardiovascular disease, thus concentrating our attention to accomplish better management on the immune system. Finally, this mini-review highlights the most recent knowledge about nanotechnology as a robust, novel and promissory therapeutic option applied to atherosclerotic pathology, nevertheless, we also alert for possible issues associated with their use. Fil: Martín Giménez, Virna Margarita. Universidad Catolica de Cuyo - Sede San Juan. Facultad de Ciencias de la Alimentación, Bioquímicas y Farmacéuticas. Instituto de Investigación en Ciencias Químicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Camargo, Alejandra Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Biología Agrícola de Mendoza. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias. Instituto de Biología Agrícola de Mendoza; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales; Argentina Fil: Kassuha, Diego Enrique. Universidad Catolica de Cuyo - Sede San Juan. Facultad de Ciencias de la Alimentación, Bioquímicas y Farmacéuticas. Instituto de Investigación en Ciencias Químicas; Argentina Fil: Manucha, Walter Ariel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; Argentina

Cardiovascular disease is currently not adequately managed and has become one of the main causes of morbidity and mortality worldwide. Current therapies are inadequate in terms of preventing its progression. There are several limitations, such as poor oral bioavailability, side effects, low adherence to treatment, and high dosage frequency of formulations due to the short half-life of the active ingredients used, among others. This review aims to highlight the most relevant aspects of the relationship between the cardiovascular system and the endocannabinoid system, with special attention to the possible translational effect of the use of anandamide in cardiovascular health. The deep and detailed knowledge of this interaction, not always beneficial, and that for years has gone unnoticed, is essential for the development of new therapies. We discuss the most recent and representative results obtained in the field of basic research, referring to the aforementioned subject, emphasizing fundamentally the main role of nitric oxide, renal physiology and its deregulation in pathological processes. Fil: Martín Giménez, Virna Margarita. Universidad Catolica de Cuyo - Sede San Juan. Facultad de Cs. de la Alimentación, Bioquímicas y Farmacéuticas. Instituto de Investigación En Ciencias Químicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Noriega, Sandra. Universidad Catolica de Cuyo - Sede San Juan. Facultad de Cs. de la Alimentación, Bioquímicas y Farmacéuticas. Instituto de Investigación En Ciencias Químicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Kassuha, Diego Enrique. Universidad Catolica de Cuyo - Sede San Juan. Facultad de Cs. de la Alimentación, Bioquímicas y Farmacéuticas. Instituto de Investigación En Ciencias Químicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Fuentes, Lucia Beatriz. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentina Fil: Manucha, Walter Ariel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina

La aterosclerosis, una conocida enfermedad arterial prevalente, ocasiona el deterioro progresivo de los vasos afectados provocando reducción del flujo sanguíneo con diversas complicaciones, y los síntomas suelen manifestarse en estadios avanzados de la enfermedad. En este sentido, las clásicas alternativas terapéuticas resultan insuficientes debido al carácter muchas veces irreversible del daño provocado. Por lo tanto, emerge la necesidad de implementar novedosas formas más eficaces para administrar fármacos y también el desarrollo de nuevas dianas terapéuticas que reduzcan la progresión de la lesión aterosclerótica. Además, resulta de especial interés la implementación de nuevas herramientas para la prevención, diagnóstico y tratamiento de esta patología cardiovascular, focalizando la atención en lograr un mejor control sobre el sistema inmunológico. En esta revisión se pone en relieve el conocimiento actual sobre la nanotecnología como una alternativa terapéutica potencial, moderna y prometedora, aplicada a la patología aterosclerótica, pero se advierte también sobre posibles complicaciones de su uso. Atherosclerosis, a known and prevalent disease, causes progressive deterioration of affected vessels, inducing a blood flow reduction with different complications, and its symptoms usually manifest in advanced stages of the disease. Therefore, the classic therapeutic alternatives are insufficient because the damages are many times irreversible. For this reason, there is a need to implement intelligent forms of drug administration and develop new therapeutic targets that reduce the progression of atherosclerotic lesion. The implementation of new tools for prevention, diagnosis and treatment of this cardiovascular disease is of special interest, focusing our attention on achieving a more effective control of the immune system. Finally, this review highlights the latest knowledge about nanotechnology as a powerful, modern, and promising therapeutic alternative applied to atherosclerotic disease, as well as warning of the potential complications with their use. Fil: Martín Giménez, Virna Margarita. Universidad Catolica de Cuyo - Sede San Juan. Facultad de Cs. de la Alimentación, Bioquímicas y Farmacéuticas. Instituto de Investigación En Ciencias Químicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Ruiz Roso, María Belén. Universidad Complutense de Madrid. Facultad de Medicina. Departamento de Fisiología; España Fil: Camargo, Alejandra Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Biología Agrícola de Mendoza. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias. Instituto de Biología Agrícola de Mendoza; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales; Argentina Fil: Kassuha, Diego Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Catolica de Cuyo - Sede San Juan. Facultad de Cs. de la Alimentación, Bioquímicas y Farmacéuticas. Instituto de Investigación En Ciencias Químicas; Argentina Fil: Manucha, Walter Ariel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina

Cardiovascular diseases are a major cause of disability and they are currently responsible for a significant number of deaths in a large percentage of the world population. A large number of therapeutic options have been developed for the management of cardiovascular diseases. However, they are insufficient to stop or significantly reduce the progression of these diseases, and may produce unpleasant side effects. In this situation, the need arises to continue exploring new technologies and strategies in order to overcome the disadvantages and limitations of conventional therapeutic options. Thus, treatment of cardiovascular diseases has become one of the major focuses of scientific and technological development in recent times. More specifically, there have been important advances in the area of nanotechnology and the controlled release of drugs, destined to circumvent many limitations of conventional therapies for the treatment of diseases such as hyperlipidemia, hypertension, myocardial infarction, stroke and thrombosis. Fil: Martín Giménez, Virna Margarita. Universidad Catolica de Cuyo - Sede San Juan. Facultad de Cs. de la Alimentación, Bioquímicas y Farmacéuticas. Instituto de Investigación En Ciencias Químicas; Argentina Fil: Kassuha, Diego Enrique. Universidad Catolica de Cuyo - Sede San Juan. Facultad de Cs. de la Alimentación, Bioquímicas y Farmacéuticas. Instituto de Investigación En Ciencias Químicas; Argentina Fil: Manucha, Walter Ariel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; Argentina