The Integral Role of Magnesium in Muscle Integrity and Aging: A Comprehensive Review.

Aging is characterized by significant physiological changes, with the degree of decline varying significantly among individuals. The preservation of intrinsic capacity over the course of an individual's lifespan is fundamental for healthy aging. Locomotion, which entails the capacity for independent movement, is intricately connected with various dimensions of human life, including cognition, vitality, sensory perception, and psychological well-being. Notably, skeletal muscle functions as a pivotal nexus within this intricate framework. Any perturbation in its functionality can manifest as compromised physical performance and an elevated susceptibility to frailty. Magnesium is an essential mineral that plays a central role in approximately 800 biochemical reactions within the human body. Its distinctive physical and chemical attributes render it an indispensable stabilizing factor in the orchestration of diverse cellular reactions and organelle functions, thereby rendering it irreplaceable in processes directly impacting muscle health. This narrative review offers a comprehensive exploration of the pivotal role played by magnesium in maintaining skeletal muscle integrity, emphasizing the critical importance of maintaining optimal magnesium levels for promoting healthy aging.

Vitamin D, zinc and glutamine: Synergistic action with OncoTherad immunomodulator in interferon signaling and COVID­19 (Review).

Coronavirus disease 2019 (COVID­19), caused by severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2), was identified in December, 2019 in Wuhan, China. Since then, it has continued to spread rapidly in numerous countries, while the search for effective therapeutic options persists. Coronaviruses, including SARS­CoV­2, are known to suppress and evade the antiviral responses of the host organism mediated by interferon (IFN), a family of cytokines that plays an important role in antiviral defenses associated with innate immunity, and has been used therapeutically for chronic viral diseases and cancer. On the other hand, OncoTherad, a safe and effective immunotherapeutic agent in the treatment of non­muscle invasive bladder cancer (NMIBC), increases IFN signaling and has been shown to be a promising therapeutic approach for COVID­19 in a case report that described the rapid recovery of a 78­year­old patient with NMIBC with comorbidities. The present review discusses the possible synergistic action of OncoTherad with vitamin D, zinc and glutamine, nutrients that have been shown to facilitate immune responses mediated by IFN signaling, as well as the potential of this combination as a therapeutic option for COVID­19.

Antioxidant and anti­inflammatory mechanisms of action of astaxanthin in cardiovascular diseases (Review).

Cardiovascular diseases are the most common cause of mortality worldwide. Oxidative stress and inflammation are pathophysiological processes involved in the development of cardiovascular diseases; thus, anti­inflammatory and antioxidant agents that modulate redox balance have become research targets so as to evaluate their molecular mechanisms of action and therapeutic properties. Astaxanthin, a carotenoid of the xanthophyll group, has potent antioxidant properties due to its molecular structure and its arrangement in the plasma membrane, factors that favor the neutralization of reactive oxygen and nitrogen species. This carotenoid also has prominent anti­inflammatory activity, possibly interrelated with its antioxidant effect, and is also involved in the modulation of lipid and glucose metabolism. Considering the potential beneficial effects of astaxanthin on cardiovascular health evidenced by preclinical and clinical studies, the aim of the present review was to describe the molecular and cellular mechanisms associated with the antioxidant and anti­inflammatory properties of this carotenoid in cardiovascular diseases, particularly atherosclerosis. The beneficial properties and safety profile of astaxanthin indicate that this compound may be used for preventing progression or as an adjuvant in the treatment of cardiovascular diseases.

Zinc, Vitamin D and Vitamin C: Perspectives for COVID-19 With a Focus on Physical Tissue Barrier Integrity.

Some nutrients play key roles in maintaining the integrity and function of the immune system, presenting synergistic actions in steps determinant for the immune response. Among these elements, zinc and vitamins C and D stand out for having immunomodulatory functions and for playing roles in preserving physical tissue barriers. Considering the COVID-19 pandemic, nutrients that can optimize the immune system to prevent or lower the risk of severe progression and prognosis of this viral infection become relevant. Thus, the present review aims to provide a comprehensive overview of the roles of zinc and vitamins C and D in the immune response to viral infections, focusing on the synergistic action of these nutrients in the maintenance of physical tissue barriers, such as the skin and mucous membranes. The evidence found in the literature shows that deficiency of one or more of these three elements compromises the immune response, making an individual more vulnerable to viral infections and to a worse disease prognosis. Thus, during the COVID-19 pandemic, the adequate intake of zinc and vitamins C and D may represent a promising pharmacological tool due to the high demand for these nutrients in the case of contact with the virus and onset of the inflammatory process. Ongoing clinical trials will help to clarify the role of these nutrients for COVID-19 management.

Nrf2/ARE Pathway Modulation by Dietary Energy Regulation in Neurological Disorders.

Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of an array of enzymes with important detoxifying and antioxidant functions. Current findings support the role of high levels of oxidative stress in the pathogenesis of neurological disorders. Given the central role played by Nrf2 in counteracting oxidative damage, a number of studies have targeted the modulation of this transcription factor in order to confer neuroprotection. Nrf2 activity is tightly regulated by oxidative stress and energy-based stimuli. Thus, many dietary interventions based on energy intake regulation, such as dietary energy restriction (DER) or high-fat diet (HFD), modulate Nrf2 with consequences for a variety of cellular processes that affect brain health. DER, by either restricting calorie intake or meal frequency, activates Nrf2 thereby triggering its protective effects, whilst HFD inhibit this pathway, thereby exacerbating oxidative stress. Consequently, DER protocols can be valuable strategies in the management of central nervous system (CNS) disorders. Herein, we review current knowledge of the role of Nrf2 signaling in neurological diseases, namely Alzheimer's disease, Parkinson's disease, multiple sclerosis and cerebral ischemia, as well as the potential of energy intake regulation in the management of Nrf2 signaling.

Iron Bisglycinate Chelate and Polymaltose Iron for the Treatment of Iron Deficiency Anemia: A Pilot Randomized Trial.

BACKGROUND: Iron Deficiency Anemia (IDA) is a major public health problem worldwide. Iron Bisglycinate Chelate (FeBC) and polymaltose iron (FeP) are used for the treatment of IDA and exhibit good tolerability with a low incidence of adverse effects. However, these compounds have important differences in their structures and bioavailability. OBJECTIVE: To compare the efficacy of oral supplementation with FeBC and FeP in anemic children. METHODS: In this double-blind study, children aged 1 to 13 years who were diagnosed with IDA were randomly divided into two groups: i) FeBC, supplemented with iron bisglycinate chelate, and ii) FeP, supplemented with polymaltose iron (3.0 mg iron/kg body weight/day for 45 days for both groups). RESULTS: Both treatments resulted in significant increases in hemoglobin levels, Mean Corpuscular Volume (MCV) and Cell Distribution Width (RDW) and in a reduction of transferrin levels, relative to initial values. However, only FeBC treatment significantly increased ferritin and Mean Corpuscular Hemoglobin (MCH) levels. A significant negative correlation was observed between the increase in ferritin and initial hemoglobin levels in the FeBC group, indicating that the absorption of FeBC is regulated by the body iron demand. CONCLUSION: These results provide preliminary evidence to suggest a greater efficacy of FeBC than FeP in increasing iron stores.

Ouabain increases neuronal branching in hippocampus and improves spatial memory.

Previous research shows Ouabain (OUA) to bind Na, K-ATPase, thereby triggering a number of signaling pathways, including the transcription factors NFᴋB and CREB. These transcription factors play a key role in the regulation of BDNF and WNT-ß-catenin signaling cascades, which are involved in neuroprotection and memory regulation. This study investigated the effects of OUA (10 nM) in the modulation of the principal signaling pathways involved in morphological plasticity and memory formation in the hippocampus of adult rats. The results show intrahippocampal injection of OUA 10 nM to activate the Wnt/ß-Catenin signaling pathway and to increase CREB/BDNF and NFᴋB levels. These effects contribute to important changes in the cellular microenvironment, resulting in enhanced levels of dendritic branching in hippocampal neurons, in association with an improvement in spatial reference memory and the inhibition of long-term memory extinction.

NADPH oxidase contributes to streptozotocin-induced neurodegeneration.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the progressive loss of memory. The neurodegeneration induced by AD has been linked to oxidative damage. However, little is known about the involvement of NADPH oxidase 2 (Nox2), a multisubunit enzyme that catalyzes the reduction of oxygen to produce reactive oxygen species, in the pathogenesis of AD. The main purpose of this study was to investigate the involvement of Nox2 in memory, in AD-related brain abnormalities, oxidative damage, inflammation and neuronal death in the hippocampus in the streptozotocin (STZ)-induced AD-like state by comparing the effects of that drug on mice lacking gp91phox-/- and wild-type (Wt) mice. Nox2 gene expression was found increased in Wt mice after STZ injection. In object recognition test, Wt mice injected with STZ presented impairment in short- and long-term memory, which was not observed following Nox2 deletion. STZ treatment induced increased phosphorylation of Tau and increased amyloid-ß, apoptosis-inducing factor (AIF) and astrocyte and microglial markers expression in Wt mice but not in gp91phox-/-. STZ treatment increased oxidative damage and pro-inflammatory cytokines' release in Wt mice, which was not observed in gp91phox-/- mice. Nox2 deletion had a positive effect on the IL-10 baseline production, suggesting that this cytokine might contribute to the neuroprotection mechanism against STZ-induced neurodegeneration. In summary, our data suggest that the Nox2-dependent reactive oxygen species (ROS) generation contributes to the STZ-induced AD-like state.

The Role of Steroid Hormones in the Modulation of Neuroinflammation by Dietary Interventions.

Steroid hormones, such as sex hormones and glucocorticoids, have been demonstrated to play a role in different cellular processes in the central nervous system, ranging from neurodevelopment to neurodegeneration. Environmental factors, such as calorie intake or fasting frequency, may also impact on such processes, indicating the importance of external factors in the development and preservation of a healthy brain. The hypothalamic-pituitary-adrenal axis and glucocorticoid activity play a role in neurodegenerative processes, including in disorders such as in Alzheimer's and Parkinson's diseases. Sex hormones have also been shown to modulate cognitive functioning. Inflammation is a common feature in neurodegenerative disorders, and sex hormones/glucocorticoids can act to regulate inflammatory processes. Intermittent fasting can protect the brain against cognitive decline that is induced by an inflammatory stimulus. On the other hand, obesity increases susceptibility to inflammation, while metabolic syndromes, such as diabetes, are associated with neurodegeneration. Consequently, given that gonadal and/or adrenal steroids may significantly impact the pathophysiology of neurodegeneration, via their effect on inflammatory processes, this review focuses on how environmental factors, such as calorie intake and intermittent fasting, acting through their modulation of steroid hormones, impact on inflammation that contributes to cognitive and neurodegenerative processes.

Age-related neuroinflammation and changes in AKT-GSK-3ß and WNT/ ß-CATENIN signaling in rat hippocampus.

Aging is a multifactorial process associated with an increased susceptibility to neurodegenerative disorders which can be related to chronic inflammation. Chronic inflammation, however, can be characterized by the persistent elevated glucocorticoid (GCs) levels, activation of the proinflammatory transcription factor NF-кB, as well as an increase in cytokines. Interestingly, both NF-кB and cytokines can be even modulated by Glycogen Synthase Kinase 3 beta (GSK-3ß) activity, which is a key protein that can intermediate inflammation and metabolism, once it has a critical role in AKT signaling pathway, and can also intermediate WNT/ß-CATENIN signaling pathway. The aim of this study was to verify age-related changes in inflammatory status, as well as in the AKT and WNT signaling pathways. Results showed an age-related increase in neuroinflammation as indicated by NF-кB activation, TNF-α and GCs increased levels, a decrease in AKT activation and an increase in GSK-3ß activity in both 12- and 24- month old animals. Aging also seems to induce a progressive decrease in canonical WNT/ß-CATENIN signaling pathway once there is a decrease in DVL-2 levels and in the transcription of Axin2 gene. Little is known about the DVL-2 regulation as well as its roles in WNT signaling pathway, but for the first time it was suggested that DVL-2 expression can be changed along aging.

Longevity Pathways (mTOR, SIRT, Insulin/IGF-1) as Key Modulatory Targets on Aging and Neurodegeneration.

Recent data from epidemiologic studies have shown that the majority of the public health costs are related to age-related disorders, and most of these diseases can lead to neuronal death. The specific signaling mechanisms underpinning neurodegeneration and aging are incompletely understood. Much work has been directed to the search for the etiology of neurodegeneration and aging and to new therapeutic strategies, including not only drugs but also non-pharmacological approaches, such as physical exercise and low-calorie dietary intake. The most important processes in aging-associated conditions, including neurodegeneration, include the mammalian (or mechanistic target of rapamycin (mTOR, sirtuin (SIRT and insulin/insulin growth factor 1 signaling (IIS pathways. These longevity pathways are involved in an array of different processes, including metabolism, cognition, stress response and brain plasticity. In this review we focus on the current advances involving the mTOR, SIRT and IIS longevity pathways during the course of healthy aging processes and neurodegenerative diseases, bringing new insights in the form of a better understanding of the signaling mechanisms underpinning neurodegeneration and how these differ from physiological normal aging processes. This also provides new targets for the therapeutic management and/or prevention of these devastating age-related disorders.

Effects of intermittent fasting on age-related changes on Na,K-ATPase activity and oxidative status induced by lipopolysaccharide in rat hippocampus.

Chronic neuroinflammation is a common characteristic of neurodegenerative diseases, and lipopolysaccharide (LPS) signaling is linked to glutamate-nitric oxide-Na,K-ATPase isoforms pathway in central nervous system (CNS) and also causes neuroinflammation. Intermittent fasting (IF) induces adaptive responses in the brain that can suppress inflammation, but the age-related effect of IF on LPS modulatory influence on nitric oxide-Na,K-ATPase isoforms is unknown. This work compared the effects of LPS on the activity of α1,α2,3 Na,K-ATPase, nitric oxide synthase gene expression and/or activity, cyclic guanosine monophosphate, 3-nitrotyrosine-containing proteins, and levels of thiobarbituric acid-reactive substances in CNS of young and older rats submitted to the IF protocol for 30 days. LPS induced an age-related effect in neuronal nitric oxide synthase activity, cyclic guanosine monophosphate, and levels of thiobarbituric acid-reactive substances in rat hippocampus that was linked to changes in α2,3-Na,K-ATPase activity, 3-nitrotyrosine proteins, and inducible nitric oxide synthase gene expression. IF induced adaptative cellular stress-response signaling pathways reverting LPS effects in rat hippocampus of young and older rats. The results suggest that IF in both ages would reduce the risk for deficits on brain function and neurodegenerative disorders linked to inflammatory response in the CNS.

Signaling function of Na,K-ATPase induced by ouabain against LPS as an inflammation model in hippocampus.

BACKGROUND: Ouabain (OUA) is a newly recognized hormone that is synthesized in the adrenal cortex and hypothalamus. Low doses of OUA can activate a signaling pathway by interaction with Na,K-ATPase, which is protective against a number of insults. OUA has central and peripheral anti-inflammatory effects. Lipopolysaccharide (LPS), via toll-like receptor 4 activation, is a widely used model to induce systemic inflammation. This study used a low OUA dose to evaluate its effects on inflammation induced by LPS injection in rats. METHODS: Adult male Wistar rats received acute intraperitoneal (ip) OUA (1.8 µg/kg) or saline 20 minutes before LPS (200 µg/kg, ip) or saline injection. Some of the animals had their femoral artery catheterized in order to assess arterial blood pressure values before and after OUA administration. Na,K-ATPase activity, cytokine mRNA levels, apoptosis-related proteins, NF-κB activation brain-derived neurotrophic factor BDNF, corticosterone and TNF-α levels were measured. RESULTS: OUA pretreatment decreased mRNA levels of the pro-inflammatory cytokines, inducible nitric oxide synthase (iNOS) and IL-1ß, which are activated by LPS in the hippocampus, but with no effect on serum measures of these factors. None of these OUA effects were linked to Na,K-ATPase activity. The involvement of the inflammatory transcription factor NF-κB in the OUA effect was indicated by its prevention of LPS-induced nuclear translocation of the NF-κB subunit, RELA (p65), as well as the decreased cytosol levels of the NF-κB inhibitor, IKB, in the hippocampus. OUA pretreatment reversed the LPS-induced glial fibrillary acidic protein (GFAP) activation and associated inflammation in the dentate gyrus. OUA also prevented LPS-induced increases in the hippocampal Bax/Bcl2 ratio suggesting an anti-apoptotic action in the brain. CONCLUSION: Our results suggest that a low dose of OUA has an important anti-inflammatory effect in the rat hippocampus. This effect was associated with decreased GFAP induction by LPS in the dentate gyrus, a brain area linked to adult neurogenesis.

Age-related changes in nitric oxide activity, cyclic GMP, and TBARS levels in platelets and erythrocytes reflect the oxidative status in central nervous system.

Aging is associated with an increased susceptibility to neurodegenerative disorders which has been linked to chronic inflammation. This process generates oxygen-reactive species, ultimately responsible for a process known as oxidative stress, leading to changes in nitric oxide (NO), and cyclic guanosine monophosphate (cyclic GMP) signaling pathway. In previous studies, we showed that human aging was associated with an increase in NO Synthase (NOS) activity, a decrease in basal cyclic GMP levels in human platelets, and an increase in thiobarbituric acid-reactant substances (TBARS) in erythrocytes. The aim of the present work was to evaluate NOS activity, TBARS and cyclic GMP levels in hippocampus and frontal cortex and its correlation to platelets and erythrocytes of 4-, 12-, and 24-month-old rats. The result showed an age-related decrease in cyclic GMP levels which was linked to an increase in NOS activity and TBARS in both central areas as well as in platelets and erythrocytes of rats. The present data confirmed our previous studies performed in human platelets and erythrocytes and validate NOS activity and cyclic GMP in human platelet as well as TBARS in erythrocytes as biomarkers to study age-related disorders and new anti-aging therapies.