Endothelial Aging Associated with Oxidative Stress Can Be Modulated by a Healthy Mediterranean Diet

Aging is a condition which favors the development of atherosclerosis, which has been associated with a breakdown in repair processes that occurs in response to cell damage. The dysregulation of the biological systems associated with aging are produced partly through damage which accumulates over time. One major source of this injury is oxidative stress, which can impair biological structures and the mechanisms by which they are repaired. These mechanisms are based on the pathogenesis of endothelial dysfunction, which in turn is associated with cardiovascular disease, carcinogenesis and aging. The dependent dysfunction of aging has been correlated with a reduction in the number and/or functional activity of endothelial progenitor cells, which could hinder the repair and regeneration of the endothelium. In addition, aging, inflammation and oxidative stress are endogenous factors that cause telomere shortening, which is dependent on oxidative cell damage. Moreover, telomere length correlates with lifestyle and the consumption of a healthy diet. Thus, diseases associated with aging and age may be caused by the long-term effects of oxidative damage, which are modified by genetic and environmental factors. Considering that diet is a very important source of antioxidants, in this review we will analyze the relationship between oxidative stress, aging, and the mechanisms which may be involved in a higher survival rate and a lower incidence of the diseases associated with aging in populations which follow a healthy diet.     

Oxidative Stress in Aging-Matters of the Heart and Mind

Oxidative damage is considered to be the primary cause of several aging associated disease pathologies. Cumulative oxidative damage tends to be pervasive among cellular macromolecules, impacting proteins, lipids, RNA and DNA of cells. At a systemic level, events subsequent to oxidative damage induce an inflammatory response to sites of oxidative damage, often contributing to additional oxidative stress. At a cellular level, oxidative damage to mitochondria results in acidification of the cytoplasm and release of cytochrome c, causing apoptosis. This review summarizes findings in the literature on oxidative stress and consequent damage on cells and tissues of the cardiovascular system and the central nervous system, with a focus on aging-related diseases that have well-documented evidence of oxidative damage in initiation and/or progression of the disease. The current understanding of the cellular mechanisms with a focus on macromolecular damage, impacted cellular pathways and gross morphological changes associated with oxidative damage is also reviewed. Additionally, the impact of calorific restriction with its profound impact on cardiovascular and neuronal aging is addressed.     

The Role of Oxidative Stress in Sarcoidosis

Sarcoidosis is a rare, systemic inflammatory disease whose diagnosis and management can pose a challenge for clinicians and specialists. Scientific knowledge on the molecular pathways that drive its development is still lacking, with no standardized therapies available and insufficient strategies to predict patient outcome. In recent years, oxidative stress has been highlighted as an important factor in the pathogenesis of sarcoidosis, involving several enzymes and molecules in the mechanism of the disease. This review presents current data on the role of oxidative stress in sarcoidosis and its interaction with inflammation, as well as the application of antioxidative therapy in the disease.     

Agmatine Mitigates Inflammation-Related Oxidative Stress in BV-2 Cells by Inducing a Pre-Adaptive Response

Neuroinflammation and microglial activation, common components of most neurodegenerative diseases, can be imitated in vitro by challenging microglia cells with Lps. We here aimed to evaluate the effects of agmatine pretreatment on Lps-induced oxidative stress in a mouse microglial BV-2 cell line. Our findings show that agmatine suppresses nitrosative and oxidative burst in Lps-stimulated microglia by reducing iNOS and XO activity and decreasing O₂⁻ levels, arresting lipid peroxidation, increasing total glutathione content, and preserving GR and CAT activity. In accordance with these results, agmatine suppresses inflammatory NF-kB, and stimulates antioxidant Nrf2 pathway, resulting in decreased TNF, IL-1 beta, and IL-6 release, and reduced iNOS and COX-2 levels. Together with increased ARG1, CD206 and HO-1 levels, our results imply that, in inflammatory conditions, agmatine pushes microglia towards an anti-inflammatory phenotype. Interestingly, we also discovered that agmatine alone increases lipid peroxidation end product levels, induces Nrf2 activation, increases total glutathione content, and GPx activity. Thus, we hypothesize that some of the effects of agmatine, observed in activated microglia, may be mediated by induced oxidative stress and adaptive response, prior to Lps stimulation.     

The Aging Stress Response and Its Implication for AMD Pathogenesis

Aging induces several stress response pathways to counterbalance detrimental changes associated with this process. These pathways include nutrient signaling, proteostasis, mitochondrial quality control and DNA damage response. At the cellular level, these pathways are controlled by evolutionarily conserved signaling molecules, such as 5’AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), insulin/insulin-like growth factor 1 (IGF-1) and sirtuins, including SIRT1. Peroxisome proliferation-activated receptor coactivator 1 alpha (PGC-1α), encoded by the PPARGC1A gene, playing an important role in antioxidant defense and mitochondrial biogenesis, may interact with these molecules influencing lifespan and general fitness. Perturbation in the aging stress response may lead to aging-related disorders, including age-related macular degeneration (AMD), the main reason for vision loss in the elderly. This is supported by studies showing an important role of disturbances in mitochondrial metabolism, DDR and autophagy in AMD pathogenesis. In addition, disturbed expression of PGC-1α was shown to associate with AMD. Therefore, the aging stress response may be critical for AMD pathogenesis, and further studies are needed to precisely determine mechanisms underlying its role in AMD. These studies can include research on retinal cells produced from pluripotent stem cells obtained from AMD donors with the mutations, either native or engineered, in the critical genes for the aging stress response, including AMPK, IGF1, MTOR, SIRT1 and PPARGC1A.     

Role of microRNA and Oxidative Stress in Influenza A Virus Pathogenesis

MicroRNAs (miRNAs) are non-coding RNAs that regulate diverse cellular pathways by controlling gene expression. Increasing evidence has revealed their critical involvement in influenza A virus (IAV) pathogenesis. Host–IAV interactions induce different levels of oxidative stress (OS) by disrupting the balance between reactive oxygen species (ROS) and antioxidant factors. It is thought that miRNA may regulate the expression of ROS; conversely, ROS can induce or suppress miRNA expression during IAV infection. Thus, miRNA and OS are the two key factors of IAV infection and pathogenesis. Accordingly, interactions between OS and miRNA during IAV infection might be a critical area for further research. In this review, we discuss the crosstalk between miRNAs and OS during IAV infection. Additionally, we highlight the potential of miRNAs as diagnostic markers and therapeutic targets for IAV infections. This knowledge will help us to study host–virus interactions with novel intervention strategies.     

Oxidative Stress and Neurodegenerative Disorders

Living cells continually generate reactive oxygen species (ROS) through the respiratory chain during energetic metabolism. ROS at low or moderate concentration can play important physiological roles. However, an excessive amount of ROS under oxidative stress would be extremely deleterious. The central nervous system (CNS) is particularly vulnerable to oxidative stress due to its high oxygen consumption, weakly antioxidative systems and the terminal-differentiation characteristic of neurons. Thus, oxidative stress elicits various neurodegenerative diseases. In addition, chemotherapy could result in severe side effects on the CNS and peripheral nervous system (PNS) of cancer patients, and a growing body of evidence demonstrates the involvement of ROS in drug-induced neurotoxicities as well. Therefore, development of antioxidants as neuroprotective drugs is a potentially beneficial strategy for clinical therapy. In this review, we summarize the source, balance maintenance and physiologic functions of ROS, oxidative stress and its toxic mechanisms underlying a number of neurodegenerative diseases, and the possible involvement of ROS in chemotherapy-induced toxicity to the CNS and PNS. We ultimately assess the value for antioxidants as neuroprotective drugs and provide our comments on the unmet needs.     

Treadmill Exercise Attenuates Retinal Oxidative Stress in Naturally-Aged Mice: An Immunohistochemical Study

In the retina, a number of degenerative diseases, including glaucoma, diabetic retinopathy, and age-related macular degeneration, may occur as a result of aging. Oxidative damage is believed to contribute to the pathogenesis of aging as well as to age-related retinal disease. Although physiological exercise has been shown to reduce oxidative stress in rats and mice, it is not known whether it has a similar effect in retinal tissues. The aim of this study was to evaluate retinal oxidative stress in naturally-aged mice. In addition, we evaluated the effects of aerobic training on retinal oxidative stress by immunohistochemically evaluating oxidative stress markers. A group of twelve-week-old male mice were not exercised (young control). Two groups of twenty-two-month-old male mice were created: an old control group and a treadmill exercise group. The old control group mice were not exercised. The treadmill exercise group mice ran on a treadmill (5 to 12 m/min, 30 to 60 min/day, 3 days/week for 12 weeks). The retinal thickness and number of cells in the ganglion cell layer of the naturally-aged mice were reduced compared to those in the young control mice. However, treadmill exercise reversed these morphological changes in the retinas. We evaluated retinal expression of carboxymethyllysine (CML), 8-hydroxy-2′-deoxyguanosine (8-OHdG) and nitrotyrosine. The retinas from the aged mice showed increased CML, 8-OHdG, and nitrotyrosine immunostaining intensities compared to young control mice. The exercise group exhibited significantly lower CML levels and nitro-oxidative stress than the old control group. These results suggest that regular exercise can reduce retinal oxidative stress and that physiological exercise may be distinctly advantageous in reducing retinal oxidative stress.     

Oxidative Stress and Immune Response in Melanoma: Ion Channels as Targets of Therapy

Oxidative stress and immune response play an important role in the development of several cancers, including melanoma. Ion channels are aberrantly expressed in tumour cells and regulate neoplastic transformation, malignant progression, and resistance to therapy. Ion channels are localized in the plasma membrane or other cellular membranes and are targets of oxidative stress, which is particularly elevated in melanoma. At the same time, ion channels are crucial for normal and cancer cell physiology and are subject to multiple layers of regulation, and therefore represent promising targets for therapeutic intervention. In this review, we analyzed the effects of oxidative stress on ion channels on a molecular and cellular level and in the context of melanoma progression and immune evasion. The possible role of ion channels as targets of alternative therapeutic strategies in melanoma was discussed.     

Role of Oxidative Stress in Refractory Epilepsy: Evidence in Patients and Experimental Models

Oxidative stress, a state of imbalance in the production of reactive oxygen species and nitrogen, is induced by a wide variety of factors. This biochemical state is associated with systemic diseases, and diseases affecting the central nervous system. Epilepsy is a chronic neurological disorder with refractoriness to drug therapy at about 30%. Currently, experimental evidence supports the involvement of oxidative stress in seizures, in the process of their generation, and in the mechanisms associated with refractoriness to drug therapy. Hence, the aim of this review is to present information in order to facilitate the handling of this evidence and determine the therapeutic impact of the biochemical status for this pathology.     

Protective Role of Melatonin and Its Metabolites in Skin Aging

The skin, being the largest organ in the human body, is exposed to the environment and suffers from both intrinsic and extrinsic aging factors. The skin aging process is characterized by several clinical features such as wrinkling, loss of elasticity, and rough-textured appearance. This complex process is accompanied with phenotypic and functional changes in cutaneous and immune cells, as well as structural and functional disturbances in extracellular matrix components such as collagens and elastin. Because skin health is considered one of the principal factors representing overall “well-being” and the perception of “health” in humans, several anti-aging strategies have recently been developed. Thus, while the fundamental mechanisms regarding skin aging are known, new substances should be considered for introduction into dermatological treatments. Herein, we describe melatonin and its metabolites as potential “aging neutralizers”. Melatonin, an evolutionarily ancient derivative of serotonin with hormonal properties, is the main neuroendocrine secretory product of the pineal gland. It regulates circadian rhythmicity and also exerts anti-oxidative, anti-inflammatory, immunomodulatory, and anti-tumor capacities. The intention of this review is to summarize changes within skin aging, research advances on the molecular mechanisms leading to these changes, and the impact of the melatoninergic anti-oxidative system controlled by melatonin and its metabolites, targeting the prevention or reversal of skin aging.     

Pathogenesis of Target Organ Damage in Hypertension: Role of Mitochondrial Oxidative Stress

Hypertension causes target organ damage (TOD) that involves vasculature, heart, brain and kidneys. Complex biochemical, hormonal and hemodynamic mechanisms are involved in the pathogenesis of TOD. Common to all these processes is an increased bioavailability of reactive oxygen species (ROS). Both in vitro and in vivo studies explored the role of mitochondrial oxidative stress as a mechanism involved in the pathogenesis of TOD in hypertension, especially focusing on atherosclerosis, heart disease, renal failure, cerebrovascular disease. Both dysfunction of mitochondrial proteins, such as uncoupling protein-2 (UCP2), superoxide dismutase (SOD) 2, peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), calcium channels, and the interaction between mitochondria and other sources of ROS, such as NADPH oxidase, play an important role in the development of endothelial dysfunction, cardiac hypertrophy, renal and cerebral damage in hypertension. Commonly used anti-hypertensive drugs have shown protective effects against mitochondrial-dependent oxidative stress. Notably, few mitochondrial proteins can be considered therapeutic targets on their own. In fact, antioxidant therapies specifically targeted at mitochondria represent promising strategies to reduce mitochondrial dysfunction and related hypertensive TOD. In the present article, we discuss the role of mitochondrial oxidative stress as a contributing factor to hypertensive TOD development. We also provide an overview of mitochondria-based treatment strategies that may reveal useful to prevent TOD and reduce its progression.     

LATS1 Is a Mediator of Melanogenesis in Response to Oxidative Stress and Regulator of Melanoma Growth

The LATS1 kinase has been described as a tumor suppressor in various cancers. However, its role in melanoma has not been fully elucidated. There are several processes involved in tumorigenesis, including melanin production. Melanin content positively correlates with the level of reactive oxygen species (ROS) inside the cell. Accordingly, the purpose of the study was to assess the role of LATS1 in melanogenesis and oxidative stress and its influence on tumor growth. We have knocked down LATS1 in primary melanocytes and melanoma cells and found that its expression is crucial for melanin synthesis, ROS production, and oxidative stress response. We showed that LATS1 ablation significantly decreased the melanogenesis markers’ expression and melanin synthesis in melanocyte and melanoma cell lines. Moreover, silencing LATS1 resulted in enhanced oxidative stress. Reduced melanin content in LATS1 knocked down tumors was associated with increased tumor growth, pointing to melanin’s protective role in this process. The study demonstrated that LATS1 is highly engaged in melanogenesis and oxidative stress control and affects melanoma growth. Our results may find the implications in the diagnosis and treatment of pigmentation disorders, including melanoma.     

Isocitrate Dehydrogenase Alpha-1 Modulates Lifespan and Oxidative Stress Tolerance in Caenorhabditis elegans

Altered metabolism is a hallmark of aging. The tricarboxylic acid cycle (TCA cycle) is an essential metabolic pathway and plays an important role in lifespan regulation. Supplementation of α-ketoglutarate, a metabolite converted by isocitrate dehydrogenase alpha-1 (idha-1) in the TCA cycle, increases lifespan in C. elegans. However, whether idha-1 can regulate lifespan in C. elegans remains unknown. Here, we reported that the expression of idha-1 modulates lifespan and oxidative stress tolerance in C. elegans. Transgenic overexpression of idha-1 extends lifespan, increases the levels of NADPH/NADP⁺ ratio, and elevates the tolerance to oxidative stress. Conversely, RNAi knockdown of idha-1 exhibits the opposite effects. In addition, the longevity of eat-2 (ad1116) mutant via dietary restriction (DR) was reduced by idha-1 knockdown, indicating that idha-1 may play a role in DR-mediated longevity. Furthermore, idha-1 mediated lifespan may depend on the target of rapamycin (TOR) signaling. Moreover, the phosphorylation levels of S6 kinase (p-S6K) inversely correlate with idha-1 expression, supporting that the idha-1-mediated lifespan regulation may involve the TOR signaling pathway. Together, our data provide new insights into the understanding of idha-1 new function in lifespan regulation probably via DR and TOR signaling and in oxidative stress tolerance in C. elegans.     

Low Psychological Resilience in Older Individuals: An Association with Increased Inflammation,Oxidative Stress and the Presence of Chronic Medical Conditions

The term resilience, which has been present in science for almost half a century, stands for the capacity of some system needed to overcome an amount of disturbance from the environment in order to avoid a change to another stable state. In medicine, the concept of resilience means the ability to deal with daily stress and disturbance to our homeostasis with the intention of protecting it from disturbance. With aging, the organism becomes more sensitive to environmental impacts and more susceptible to changes. Mental disturbances and a decline in psychological resilience in older people are potentiated with many social and environmental factors along with a subjective perception of decreasing health. Distinct from findings in younger age groups, mental and physical medical conditions in older people are closely associated with each other, sharing common mechanisms and potentiating each other’s development. Increased inflammation and oxidative stress have been recognized as the main driving mechanisms in the development of aging diseases. This paper aims to reveal, through a translational approach, physiological and molecular mechanisms of emotional distress and low psychological resilience in older individuals as driving mechanisms for the accelerated development of chronic aging diseases, and to systematize the available information sources on strategies for mitigation of low resilience in order to prevent chronic diseases.     

Oxidative Stress Response in Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells

Reactive oxygen species (ROS) can irreversibly damage biological molecules, a process known as oxidative stress. Elevated ROS levels are associated with immune cell activation. Sustained immune system activation can affect many different cells in the environment. One cell type that has been detected in almost all tissues of the body is mesenchymal stem/stromal cells (MSC). MSC possess proliferation and differentiation potential, thus facilitating regeneration processes. However, the regenerative capacity of MSC might be impaired by oxidative stress, and the effects of long-term oxidative stress on MSC functions are sparsely described. The examination of oxidative stress is often performed by exposure to H₂O₂. Since H₂O₂ is rapidly degraded, we additionally exposed the cell cultures to glucose oxidase (GOx), resulting in sustained exposure to H₂O₂. Using these model systems, we have focused on the effects of short- and long-term oxidative stress on viability, migration, differentiation, and signaling. All cellular functions examined were affected by the applied oxidative stress. The differences that occur between pulsed and sustained oxidative stress indicated higher oxidative stress in MSC upon direct H₂O₂ exposure, whereas the GOx-induced prolonged exposure to H₂O₂ seems to allow for better cellular adaptation. The mechanisms underlying these different responses are currently unknown.