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.

Vitamin D as a Modulator of Neuroinflammation: Implications for Brain Health.

Neuroinflammation represents a critical immune response within the brain, playing a pivotal role in defense against injury and infection. However, when this response becomes chronic, it can contribute to the development of various neurodegenerative and psychiatric disorders. This bibliographic review delves into the role of vitamin D in modulating neuroinflammation and its implications for brain health, particularly in the context of neurological and psychiatric disorders. While vitamin D is traditionally associated with calcium homeostasis and bone health, it also exerts immunomodulatory and neuroprotective effects within the central nervous system. Through comprehensive analysis of preclinical and clinical studies, we uncover how vitamin D, acting through its receptors in glial cells, may influence the production of proinflammatory cytokines and antioxidants, potentially mitigating the cascade of events leading to neuronal damage. Clinical research has identified vitamin D deficiency as a common thread in the increased risks of multiple sclerosis, Parkinson's disease, Alzheimer's, and depression, among others. Furthermore, preclinical models suggest vitamin D's regulatory capacity over inflammatory mediators, its protective role against neuronal apoptosis, and its contribution to neurogenesis and synaptic plasticity. These insights underscore the potential of vitamin D supplementation not only in slowing the progression of neurodegenerative diseases but also in improving the quality of life for patients suffering from psychiatric conditions. Future clinical studies are essential to validate these findings and further our understanding of vitamin D's capacity to prevent or alleviate symptoms, opening new avenues for therapeutic strategies against neuroinflammation-related pathologies. Neuroinflammation is a crucial immune response in the brain against injuries or infections, but its persistence can lead to diseases such as Alzheimer's, Parkinson's, multiple sclerosis, and depression. Cholecalciferol (Vitamin D3) emerges as a regulator of neuroinflammation, present in brain cells such as astrocytes and microglia, modulating immune function. Vitamin D's mechanisms of action include cytokine modulation and regulation of nuclear and mitochondrial genes. It adjusts inflammatory mediators and antioxidants, resulting in neuroprotective effects. Additionally, vitamin D impacts neurotransmitter synthesis and brain plasticity. This positions vitamin D as a potential adjunct in treating diseases like Alzheimer's and Parkinson's. Lastly, its role in intestinal microbiota and serotonin synthesis contributes to psychiatric disorders like schizophrenia and depression. Thus, vitamin D presents a novel therapeutic approach for neuroinflammatory, neurodegenerative, and neuropsychiatric diseases.

Nanopharmacology as a new approach to treat neuroinflammatory disorders.

Neuroinflammation, a complex process involving the activation of microglia, astrocytes, and other immune cells in the brain, plays a role in neurodegeneration and psychiatric disorders. Current therapeutic strategies for neuroinflammation are limited, necessitating the development of improved approaches. Nanopharmacology offers unprecedented opportunities to access and treat neuroinflammatory disorders at the brain level. Nanoscaffolds can target specific cells or tissues and protect drugs from degradation or elimination, making them ideal candidates for treating neurodegenerative and psychiatric diseases. Recent advancements in nanoparticle development have enabled the targeting of microglia, astrocytes, and other immune cells in the brain, reducing neuroinflammation and protecting neurons from injury. Nanoparticles targeting specific neurons have also been developed. Clinical trials are in progress to evaluate the safety and efficacy of nano drugs for treating neuroinflammatory, neurodegenerative, and psychiatric diseases. The successful development of these nanodrugs holds immense promise for treating these devastating and increasingly prevalent conditions. On the other hand, several limitations and unanswered questions remain. First, the long-term effects of nanoparticles on the brain need to be thoroughly investigated to ensure their safety. Second, optimizing the targeting and delivery of nanoparticles to specific brain regions remains a challenge. Understanding the complex interplay between nanoparticles and the brain's immune system is crucial for developing effective nanotherapies. Despite these limitations, nanopharmacology presents a transformative approach to treating neuroinflammatory disorders. Future research should address the aforementioned limitations and further elucidate the mechanisms of nanoparticle-mediated therapy. The successful development of safe and effective nanodrugs can revolutionize the treatment of neuroinflammatory disorders, alleviating the suffering of millions.

Gut Microbiota Dysbiosis in COVID-19: Modulation and Approaches for Prevention and Therapy.

Inflammation and oxidative stress are critical underlying mechanisms associated with COVID-19 that contribute to the complications and clinical deterioration of patients. Additionally, COVID-19 has the potential to alter the composition of patients' gut microbiota, characterized by a decreased abundance of bacteria with probiotic effects. Interestingly, certain strains of these bacteria produce metabolites that can target the S protein of other coronaviruses, thereby preventing their transmission and harmful effects. At the same time, the presence of gut dysbiosis can exacerbate inflammation and oxidative stress, creating a vicious cycle that perpetuates the disease. Furthermore, it is widely recognized that the gut microbiota can metabolize various foods and drugs, producing by-products that may have either beneficial or detrimental effects. In this regard, a decrease in short-chain fatty acid (SCFA), such as acetate, propionate, and butyrate, can influence the overall inflammatory and oxidative state, affecting the prevention, treatment, or worsening of COVID-19. This review aims to explore the current evidence regarding gut dysbiosis in patients with COVID-19, its association with inflammation and oxidative stress, the molecular mechanisms involved, and the potential of gut microbiota modulation in preventing and treating SARS-CoV-2 infection. Given that gut microbiota has demonstrated high adaptability, exploring ways and strategies to maintain good intestinal health, as well as an appropriate diversity and composition of the gut microbiome, becomes crucial in the battle against COVID-19.

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.

Aging-Related Ovarian Failure and Infertility: Melatonin to the Rescue.

Aging has a major detrimental effect on the optimal function of the ovary with changes in this organ preceding the age-related deterioration in other tissues, with the middle-aged shutdown leading to infertility. Reduced fertility and consequent inability to conceive by women in present-day societies who choose to have children later in life leads to increased frustration. Melatonin is known to have anti-aging properties related to its antioxidant and anti-inflammatory actions. Its higher follicular fluid levels relative to blood concentrations and its likely synthesis in the oocyte, granulosa, and luteal cells suggest that it is optimally positioned to interfere with age-associated deterioration of the ovary. Additionally, the end of the female reproductive span coincides with a significant reduction in endogenous melatonin levels. Thus, the aims are to review the literature indicating melatonin production in mitochondria of oocytes, granulosa cells, and luteal cells, identify the multiple processes underlying changes in the ovary, especially late in the cessation of the reproductive life span, summarize the physiological and molecular actions of melatonin in the maintenance of normal ovaries and in the aging ovaries, and integrate the acquired information into an explanation for considering melatonin in the treatment of age-related infertility. Use of supplemental melatonin may help preserve fertility later in life and alleviate frustration in women delaying childbearing age, reduce the necessity of in vitro fertilization-embryo transfer (IVF-ET) procedures, and help solve the progressively increasing problem of non-aging-related infertility in women throughout their reproductive life span. While additional research is needed to fully understand the effects of melatonin supplementation on potentially enhancing fertility, studies published to date suggest it may be a promising option for those struggling with infertility.

Genomic or Non-Genomic? A Question about the Pleiotropic Roles of Vitamin D in Inflammatory-Based Diseases.

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.

Polymeric Nanomicelles Loaded with Anandamide and Their Renal Effects as a Therapeutic Alternative for Hypertension Treatment by Passive Targeting.

We have previously demonstrated significant in vitro natriuretic effects of anandamide (AEA) nanoformulation in polymeric nanoparticles, whose size prevents their accumulation in organs, such as the kidneys. Therefore, it is of particular interest to design and test nanostructures that can pharmacologically accumulate in these organs. In this regard, we prepared and characterized polymeric nanomicelles (~14 and 40 nm). Likewise, their biodistribution was determined. Spontaneously hypertensive rats (SHR) and normotensive rats (WKY), n = 3 per group, were divided into five treatment conditions: control, sham, free AEA freshly dispersed in aqueous solution or 24 h after its dispersion, and AEA encapsulated in nanomicelles. The kidneys were the main site of accumulation of the nanoformulation after 24 h. Freshly dispersed free AEA showed its classical triphasic response in SHR, which was absent from all other treatments. Nanoformulated AEA produced a sustained antihypertensive effect over 2 h, accompanied by a significant increase in fractional sodium excretion (FSE %). These effects were not observed in WKY, sham, or free AEA-treated rats after 24 h of its aqueous dispersion. Without precedent, we demonstrate in vivo natriuretic, diuretic, and hypotensive effects of AEA nanoformulation in polymeric nanomicelles, suggesting its possible use as a new antihypertensive agent with intravenous administration and passive renal accumulation.

Nanomedicine and Addictive Disorders: A New Approach With Cannabinoids.

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.

Physiopathological mechanisms involved in the development of hypertension associated with gut dysbiosis and the effect of nutritional/pharmacological interventions.

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.

Epigenetic Mechanisms Involved in Inflammaging-Associated Hypertension.

PURPOSE OF REVIEW: This review summarizes the involvement of inflammaging in vascular damage with focus on the epigenetic mechanisms by which inflammaging-induced hypertension is triggered. RECENT FINDINGS: Inflammaging in hypertension is a complex condition associated with the production of inflammatory mediators by the immune cells, enhancement of oxidative stress, and tissue remodeling in vascular smooth muscle cells and endothelial cells. Cellular processes are numerous, including inflammasome assembly and cell senescence which may involve mitochondrial dysfunction, autophagy, DNA damage response, dysbiosis, and many others. More recently, a series of noncoding RNAs, mainly microRNAs, have been described as possessing epigenetic actions on the regulation of inflammasome-related hypertension, emerging as a promising therapeutic strategy. Although there are a variety of pharmacological agents that effectively regulate inflammaging-related hypertension, a deeper understanding of the epigenetic events behind the control of vessel deterioration is needed for the treatment or even to prevent the disease onset.

Consumption of oil macerated with garlic produces renovascular protective effects in adult apolipoprotein E-deficient mice.

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.

Melatonin as an Anti-Aging Therapy for Age-Related Cardiovascular and Neurodegenerative Diseases.

The concept of "aging" is defined as the set of gradual and progressive changes in an organism that leads to an increased risk of weakness, disease, and death. This process may occur at the cellular and organ level, as well as in the entire organism of any living being. During aging, there is a decrease in biological functions and in the ability to adapt to metabolic stress. General effects of aging include mitochondrial, cellular, and organic dysfunction, immune impairment or inflammaging, oxidative stress, cognitive and cardiovascular alterations, among others. Therefore, one of the main harmful consequences of aging is the development and progression of multiple diseases related to these processes, especially at the cardiovascular and central nervous system levels. Both cardiovascular and neurodegenerative pathologies are highly disabling and, in many cases, lethal. In this context, melatonin, an endogenous compound naturally synthesized not only by the pineal gland but also by many cell types, may have a key role in the modulation of multiple mechanisms associated with aging. Additionally, this indoleamine is also a therapeutic agent, which may be administered exogenously with a high degree of safety. For this reason, melatonin could become an attractive and low-cost alternative for slowing the processes of aging and its associated diseases, including cardiovascular and neurodegenerative disorders.

High-dose vitamin D versus placebo to prevent complications in COVID-19 patients: Multicentre randomized controlled clinical trial.

BACKGROUND: The role of oral vitamin D3 supplementation for hospitalized patients with COVID-19 remains to be determined. The study was aimed to evaluate whether vitamin D3 supplementation could prevent respiratory worsening among hospitalized patients with COVID-19. METHODS AND FINDINGS: We designed a multicentre, randomized, double-blind, sequential, placebo-controlled clinical trial. The study was conducted in 17 second and third level hospitals, located in four provinces of Argentina, from 14 August 2020 to 22 June 2021. We enrolled 218 adult patients, hospitalized in general wards with SARS-CoV-2 confirmed infection, mild-to-moderate COVID-19 and risk factors for disease progression. Participants were randomized to a single oral dose of 500 000 IU of vitamin D3 or matching placebo. Randomization ratio was 1:1, with permuted blocks and stratified for study site, diabetes and age (≤60 vs >60 years). The primary outcome was the change in the respiratory Sepsis related Organ Failure Assessment score between baseline and the highest value recorded up to day 7. Secondary outcomes included the length of hospital stay; intensive care unit admission; and in-hospital mortality. Overall, 115 participants were assigned to vitamin D3 and 105 to placebo (mean [SD] age, 59.1 [10.7] years; 103 [47.2%] women). There were no significant differences in the primary outcome between groups (median [IQR] 0.0 [0.0-1.0] vs 0.0 [0.0-1.0], for vitamin D3 and placebo, respectively; p = 0.925). Median [IQR] length of hospital stay was not significantly different between vitamin D3 group (6.0 [4.0-9.0] days) and placebo group (6.0 [4.0-10.0] days; p = 0.632). There were no significant differences for intensive care unit admissions (7.8% vs 10.7%; RR 0.73; 95% CI 0.32 to 1.70; p = 0.622), or in-hospital mortality (4.3% vs 1.9%; RR 2.24; 95% CI 0.44 to 11.29; p = 0.451). There were no significant differences in serious adverse events (vitamin D3 = 14.8%, placebo = 11.7%). CONCLUSIONS: Among hospitalized patients with mild-to-moderate COVID-19 and risk factors, a single high oral dose of vitamin D3 as compared with placebo, did not prevent the respiratory worsening. TRIAL REGISTRATION: ClincicalTrials.gov Identifier: NCT04411446.

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.

COVID-19 and neurological sequelae: Vitamin D as a possible neuroprotective and/or neuroreparative agent.

SARS-CoV-2, the etiological agent of the current COVID-19 pandemic, belongs to a broad family of coronaviruses that also affect humans. SARS-CoV-2 infection usually leads to bilateral atypical pneumonia with significant impairment of respiratory function. However, the infectious capacity of SARS-CoV-2 is not limited to the respiratory system, but may also affect other vital organs such as the brain. The central nervous system is vulnerable to cell damage via direct invasion or indirect virus-related effects leading to a neuroinflammatory response, processes possibly associated with a decrease in the activity of angiotensin II converting enzyme (ACE2), the canonical cell-surface receptor for SARS-CoV-2. This enzyme regulates neuroprotective and neuroimmunomodulatory functions and can neutralize both inflammation and oxidative stress generated at the cellular level. Furthermore, there is evidence of an association between vitamin D deficiency and predisposition to the development of severe forms of COVID-19, with its possible neurological and neuropsychiatric sequelae: vitamin D has the ability to down-modulate the effects of neuroinflammatory cytokines, among other anti-inflammatory/immunomodulatory effects, thus attenuating harmful consequences of COVID-19. This review critically analyzes current evidence supporting the notion that vitamin D may act as a neuroprotective and neuroreparative agent against the neurological sequelae of COVID-19.

Anti-inflammatory, antioxidant, antihypertensive, and antiarrhythmic effect of indole-3-carbinol, a phytochemical derived from cruciferous vegetables.

BACKGROUND: Cardiovascular inflammation and oxidative stress are determining factors in high blood pressure and arrhythmias. Indole-3-carbinol is a cruciferous-derived phytochemical with potential anti-inflammatory and antioxidant effects. However, its implications on the modulation of cardiovascular inflammatory-oxidative markers are unknown. OBJECTIVES: To establish the effects of indole-3-carbinol on the oxidative-inflammatory-proarrhythmic conditions associated with hypertension. MATERIALS: Histological, biochemical, molecular, and functional aspects were evaluated in 1) Culture of mouse BV-2 glial cells subjected to oxidative-inflammatory damage by lipopolysaccharides (100 ng/mL) in the presence or absence of 40 µM indole-3-carbinol (n = 5); 2) Male spontaneously hypertensive rats (SHR) and Wistar Kyoto rats receiving indole-3-carbinol (2000 ppm/day, orally) during the first 8 weeks of life (n = 15); 3) Isolated rat hearts were submitted to 10 min regional ischemia and 10 min reperfusion. RESULTS: 1) lipopolysaccharides induced oxidative stress and increased inflammatory markers; indole-3-carbinol reversed both conditions (interleukin 6, tumor necrosis factor α, the activity of nicotinamide adenine dinucleotide phosphate oxidase, nitric oxide, inducible nitric oxide synthase, heat shock protein 70, all p < 0.01 vs lipopolysaccharides). 2) SHR rats showed histological, structural, and functional changes with increasing systolic blood pressure (154 ± 8 mmHg vs. 122 ± 7 mmHg in Wistar Kyoto rats, p < 0.01); Inflammatory-oxidative markers also increased, and nitric oxide and heat shock protein 70 decreased. Conversely, indole-3-carbinol reduced oxidative-inflammatory markers and systolic blood pressure (133 ± 8 mmHg, p < 0.01 vs. SHR). 3) indole-3-carbinol reduced reperfusion arrhythmias from 8/10 in SHR to 0/10 (p = 0.0007 by Fisher's exact test). CONCLUSIONS: Indole-3-carbinol reduces the inflammatory-oxidative-proarrhythmic process of hypertension. The nitric oxide and heat shock protein 70 are relevant mechanisms of indole-3-carbinol protective actions. Further studies with this pleiotropic phytochemical as a promising cardioprotective are guaranteed.