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IntroductionAnandamide (AEA) is an endocannabinoid that has recently been recognized as a regulator of various inflammatory diseases as well as cancer. While AEA was thought to predominantly engage cannabinoid (CB) receptors, recent findings suggest that, given its protective anti-inflammatory role in pathological conditions, anandamide may engage not only CB receptors.MethodsIn this study, we studied the role of exogenous AEA in a mouse AirPouch model of acute inflammation by examining immune cell infiltrates by flow cytometry. Human primary immune cells were used to validate findings towards immune cell activation and migration by flow cytometry and bead-based ELISA.ResultsWe found that AEA decreases the acute infiltration of myeloid cells including granulocytes and monocytes into the inflamed area, but unexpectedly increases the number of T cells at the site of inflammation. This was related to AEA signaling through nuclear receptor subfamily 4A (NR4A) transcription factors rather than CB receptors. Exploring regulatory mechanisms in the human system, we found that AEA broadly inhibits the migratory capacity of immune cells, arguing for blocked emigration of T cells from the inflamed tissue. Taking a closer look at the impact of AEA on T cells revealed that AEA profoundly alters the activation and exhaustion status of CD4+ T and CD8+ T cells, thereby strongly inhibiting TH17 responses, while not altering TH1 differentiation.DiscussionThese data suggest that AEA has the potential to block chronic inflammation without influencing crucial anti-viral and anti-microbial immune defense mechanisms, and may therefore be an attractive molecule to interfere with the establishment of chronic inflammation.

Background: Cardiovascular disease (CVD), especially heart failure (HF) as its common final pathway, is the leading cause of morbidity and mortality worldwide. Furthermore, oxidative and inflammatory processes represent fundamental underlying mechanisms for the development and progression of HF. Of interest, in recent years the development of markers with diagnostic and prognostic value for this pathology and other related CVD has been revalued. Objectives: This study was done to quantify and evaluate inflammatory markers, such as ultra-sensitive C-reactive protein (uCRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and heat shock protein 70 (Hsp70) in the serum of patients with HF and to compare them with healthy individuals, also correlate the values obtained from oxidative stress markers and nitric oxide (NO) bioavailability previously investigated in these patients with the coexistence or not of secondary pulmonary hypertension (SPH) associated with HF. Methods: The determination of all parameters was achieved with standardized, reproducible, accurate, and affordable biochemical methods. Results: The values obtained for uCRP, IL-6, and TNF-α were following the pattern of oxidative markers previously found in these patients. These findings indicate the coexistence of oxidative stress and inflammation during HF. Of particular interest, such markers are more exacerbated when were associated with SPH, increasing its value as possible biomarkers in this pathology. However, the found levels of Hsp70 were controversial. Conclusion: The pattern of oxidative-inflammatory markers suggests their value as possible biomarkers in this cardiovascular disease. Nevertheless, additional studies are needed to assess in greater detail the importance of the relationship between serum Hsp70 expression and SPH-associated or non-SPH morbidity in HF.

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.

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.

COVID-19 is said to be a pandemic that does not distinguish between skin color or ethnic origin. However, data in many parts of the world, especially in the United States, begin to show that there is a sector of society suffering a more significant impact from this pandemic. The Black population is more vulnerable than the White population to infection and death by COVID-19, with hypertension and diabetes mellitus as probable predisposing factors. Over time, multiple disparities have been observed between the health of Black and White populations, associated mainly with socioeconomic inequalities. However, some mechanisms and pathophysiological susceptibilities begin to be elucidated that are related directly to the higher prevalence of multiple diseases in the Black population, including infection and death by COVID-19. Plasma vitamin D levels and evolutionary adaptations of the renin-angiotensin-aldosterone system (RAAS) in Black people differ considerably from those of other races. The role of these factors in the development and progression of hypertension and multiple lung diseases, among them SARS-CoV-2 infection, is well established. In this sense, the present review attempts to elucidate the link between vitamin D and RAAS ethnic disparities and susceptibility to infection and death by COVID-19 in Black people, and suggests possible mechanisms for this susceptibility.

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 non-metallic 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.

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.

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.