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The relationship between nuclear factor erythroid 2-related factor 2 (Nrf2) and phytocannabinoids/endocannabinoids (pCBs/eCBs) has been investigated in a variety of models of peripheral illnesses, with little clarification on their interaction within the central nervous system (CNS). In this context, evidence suggests that the Nrf2-pCBs/eCBS interaction is relevant in modulating peroxidation processes and the antioxidant system. Nrf2, one of the regulators of cellular redox homeostasis, appears to have a protective role toward damaging insults to neurons and glia by enhancing those genes involved in the regulation of homeostatic processes. Specifically in microglia and macroglia cells, Nrf2 can be activated, and its signaling pathway modulated, by both pCBs and eCBs. However, the precise effects of pCBs and eCBs on the Nrf2 signaling pathway are not completely elucidated yet, making their potential clinical employment still not fully understood. [ABSTRACT FROM AUTHOR]

Hypertension stands as a pervasive global health challenge, contributing significantly to mortality rates worldwide. Various factors, including lifestyle choices and dietary habits, contribute to the development of hypertension. In recent years, oxidative stress has garnered significant attention as a factor influencing hypertension risk, prompting a shift in research focus towards exploring it as a potential target for prevention and treatment. Antioxidants found in our diet, such as vitamins C, E and carotenoids exhibit the ability to neutralize reactive oxygen species, thereby mitigating oxidative stress. In addition, Vitamin A has an antioxidant effect despite not being an antioxidant itself. Consequently, supplementation or increased intake of these antioxidants has been hypothesized to potentially lower blood pressure levels and aid in the management of hypertension, thereby potentially prolonging life expectancy. Research findings regarding this effect have been diverse. This paper examines the existing literature demonstrating favorable outcomes associated with antioxidant supplementation. [ABSTRACT FROM AUTHOR]

Hearing loss is a prevalent condition affecting millions of people worldwide. Hearing loss has been linked to oxidative stress as a major factor in its onset and progression. The goal of this thorough analysis is to investigate the connection between oxidative stress and hearing loss, with an emphasis on the underlying mechanisms and possible treatments. The review addressed the many forms of hearing loss, the role of reactive oxygen species (ROS) in causing damage to the cochlea, and the auditory system's antioxidant defensive mechanisms. The review also goes over the available data that support the use of antioxidants and other methods to lessen hearing loss brought on by oxidative stress. We found that oxidative stress is implicated in multiple types of hearing loss, including age-related, noise-induced, and ototoxic hearing impairment. The cochlea's unique anatomical and physiological characteristics, such as high metabolic activity and limited blood supply, make it particularly susceptible to oxidative damage. Antioxidant therapies have shown promising results in both animal models and clinical studies for preventing and mitigating hearing loss. Emerging therapeutic approaches, including targeted drug delivery systems and gene therapy, offer new possibilities for addressing oxidative stress in the auditory system. The significance of this review lies in its comprehensive analysis of the intricate relationship between oxidative stress and hearing loss. By synthesizing current knowledge and identifying gaps in understanding, this review provides valuable insights for both researchers and clinicians. It highlights the potential of antioxidant-based interventions and emphasizes the need for further research into personalized treatment strategies. Our findings on oxidative stress mechanisms may also affect clinical practice and future research directions. This review serves as a foundation for developing novel therapeutic approaches and may inform evidence-based strategies for the prevention and treatment of hearing loss, ultimately contributing to improved quality of life for millions affected by this condition worldwide. [ABSTRACT FROM AUTHOR]

Early life stress (ELS) is a risk factor for the development of chronic diseases resulting from functional alterations of organs in the cardiorespiratory and renal systems. This work studied the changes in oxidative stress enzyme activities (EAs) of SOD, CAT, GPX, GR, GST, NOS, MDA, and FRAP in different organs (heart, liver, kidney, adrenal glands (AGs), and pancreas) of male and female Sprague–Dawley rat pups on postnatal day (PN) 15, immediately after basal and acute or chronic stress conditions were accomplished, as follows: basal control (BC; undisturbed maternal pups care), stress control (SC; 3 h maternal separation on PN15), basal maternal separation (BMS; daily 3 h maternal separation on PN 1-14), and stress maternal separation (SMS; daily 3 h maternal separation on PN 1-14 and 3 h maternal separation on PN15). Acute or long-term stress resulted in overall oxidative stress, increase in EA, and reduced antioxidant capacity in these organs. Some different response patterns, due to precedent SMS, were observed in specific organs, especially in the AGs. Acute stress exposure increases the EA, but chronic stress generates a response in the antioxidant system in some of the organs studied and is damped in response to a further challenge. [ABSTRACT FROM AUTHOR]

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It was previously reported that crocin, a water-soluble carotenoid isolated from the Crocus sativus L. (saffron), has protective effects on cardiac cells and may neutralize and even prevent the formation of excess number of free radicals; however, functional mechanisms of crocin activity have been poorly understood. In the present research, we aimed to study the functional mechanism of crocin in the heart exposed to oxidative stress. Accordingly, oxidative stress was modeled in vitro on human umbilical vein endothelial cells (HUVECs) and in vivo in mice using cellular stressors. The beneficial effects of crocin were investigated at cellular and molecular levels in HUVECs and mice hearts. Results indicated that oral administration of crocin could have protective effects on HUVECs. In addition, it protects cardiac cells and significantly inhibits inflammation via modulating molecular signaling pathways TLR4/PTEN/AKT/mTOR/NF-κB and microRNA (miR-21). Here we show that crocin not only acts as a direct free radical scavenger but also modifies the gene expression profiles of HUVECs and protects mice hearts with anti-inflammatory action under oxidative stress. [ABSTRACT FROM AUTHOR]

Introduction: Gastrodia elata is the dried tuber of the orchid Gastrodia elata Bl. It is considered a food consisting of a source of precious medicinal herbs, whose chemical composition is relatively rich. Gastrodia elata and its extracted fractions have been shown to have neuroprotective effects. P-hydroxybenzaldehyde (p-HBA), as one of the main active components of Gastrodia elata, has antiinflammatory, antioxidative stress, and cerebral protective effects, which has potential for the treatment of Alzheimer's disease (AD). The aim of this study was to verify the role of p-HBA in AD treatment and to investigate its mechanism of action in depth based using the Caenorhabditis elegans (C. elegans) model. Methods: In this study, we used paralysis, lifespan, behavioral and antistress experiments to investigate the effects of p-HBA on AD and aging. Furthermore, we performed reactive oxygen species (ROS) assay, thioflavin S staining, RNA-seq analysis, qPCR validation, PCR Array, and GFP reporter gene worm experiment to determine the anti-AD effects of p-HBA, as well as in-depth studies on its mechanisms. Results: p-HBA was able to delay paralysis, improve mobility and resistance to stress, and delay aging in the AD nematode model. Further mechanistic studies showed that ROS and lipofuscin levels, Aβ aggregation, and toxicity were reduced after p-HBA treatment, suggesting that p-HBA ameliorated Aβ-induced toxicity by enhancing antioxidant and anti-aging activity and inhibiting Aβ aggregation. p-HBA had a therapeutic effect on AD by improving stress resistance, as indicated by the down-regulation of NLP-29 and UCR-11 expression and up-regulation of PQN-75 and LYS-3 expression. In addition, the gene microarray showed that p-HBA treatment played a positive role in genes related to AD, anti-aging, ribosomal protein pathway, and glucose metabolism, which were collectively involved in the anti-AD mechanism of p-HBA. Finally, we also found that p-HBA promoted nuclear localization of DAF-16 and increased the expression of SKN-1, SOD-3, and GST-4, which contributed significantly to inhibition of Aβ toxicity and enhancement of antioxidative stress. Conclusion: Our work suggests that p-HBA has some antioxidant and antiaging activities. It may be a viable candidate for the treatment and prevention of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a progressive neurodegenerative condition marked by the gradual deterioration of dopaminergic neurons in the substantia nigra. Oxidative stress has been identified as a key player in the development of PD in recent studies. In the first part, we discuss the sources of oxidative stress in PD, including mitochondrial dysfunction, dopamine metabolism, and neuroinflammation. This paper delves into the possibility of mitigating oxidative stress as a potential treatment approach for PD. In addition, we examine the hurdles and potential of antioxidant therapy, including the challenge of delivering antioxidants to the brain and the requirement for biomarkers to track oxidative stress in PD patients. However, even if antioxidant therapy holds promise, further investigation is needed to determine its efficacy and safety in PD treatment. [ABSTRACT FROM AUTHOR]

The excessive production of various reactive oxidant species over endogenous antioxidant defense mechanisms leads to the development of a state of oxidative stress, with serious biological consequences. The consequences of oxidative stress depend on the balance between the generation of reactive oxidant species and the antioxidant defense and include oxidative damage of biomolecules, disruption of signal transduction, mutation, and cell apoptosis. Accumulating evidence suggests that oxidative stress is involved in the physiopathology of various debilitating illnesses associated with chronic inflammation, including cardiovascular diseases, diabetes, cancer, or neurodegenerative processes, that need continuous pharmacological treatment. Oxidative stress and chronic inflammation are tightly linked pathophysiological processes, one of which can be simply promoted by another. Although, many antioxidant trials have been unsuccessful (some of the trials showed either no effect or even harmful effects) in human patients as a preventive or curative measure, targeting oxidative stress remains an interesting therapeutic approach for the development of new agents to design novel anti-inflammatory drugs with a reliable safety profile. In this regard, several natural antioxidant compounds were explored as potential therapeutic options for the treatment of chronic inflammatory diseases. Several metalloenzymes, such as superoxide dismutase, catalase, and glutathione peroxidase, are among the essential enzymes that maintain the low nanomolar physiological concentrations of superoxide (O2⋅-) and hydrogen peroxide (H2O2), the major redox signaling molecules, and thus play important roles in the alteration of the redox homeostasis. These enzymes have become a striking source of motivation to design catalytic drugs to enhance the action of these enzymes under pathological conditions related to chronic inflammation. This review is focused on several major representatives of natural and synthetic antioxidants as potential drug candidates for the treatment of chronic inflammatory diseases. [ABSTRACT FROM AUTHOR]

The etiology of hearing impairment is multifactorial, with contributions from both genetic and environmental factors. Although genetic studies have yielded valuable insights into the development and function of the auditory system, the contribution of gene products and their interaction with alternate environmental factors for the maintenance and development of auditory function requires further elaboration. In this review, we provide an overview of the current knowledge on the role of redox dysregulation as the converging factor between genetic and environmental factor-dependent development of hearing loss, with a focus on understanding the interaction of oxidative stress with the physical components of the peripheral auditory system in auditory disfunction. The potential involvement of molecular factors linked to auditory function in driving redox imbalance is an important promoter of the development of hearing loss over time. [ABSTRACT FROM AUTHOR]

Emerging data indicate that lung macrophages (LM) may provide a novel biomarker to classify disease endotypes in bronchopulmonary dysplasia (BPD), a form of infant chronic lung disease, and that augmentation of the LM phenotype may be a potential therapeutic target. To contribute to this area of research, we first used Optical Redox Imaging (ORI) to characterize the responses to H2O2-induced oxidative stress and caffeine treatment in an in vitro model of mouse alveolar macrophages (AM). H2O2 caused a dose-dependent decrease in NADH and an increase in FAD-containing flavoproteins (Fp) and the redox ratio Fp/(NADH + Fp). Caffeine treatment did not affect Fp but significantly decreased NADH with doses of ≥50 µM, and 1000 µM caffeine treatment significantly increased the redox ratio and decreased the baseline level of mitochondrial ROS (reactive oxygen species). However, regardless of whether AM were pretreated with caffeine or not, the mitochondrial ROS levels increased to similar levels after H2O2 challenge. We then investigated the feasibility of utilizing ORI to examine macrophage redox status in tracheal aspirate (TA) samples obtained from premature infants receiving invasive ventilation. We observed significant heterogeneity in NADH, Fp, Fp/(NADH + Fp), and mitochondrial ROS of the TA macrophages. We found a possible positive correlation between gestational age and NADH and a negative correlation between mean airway pressure and NADH that provides hypotheses for future testing. Our study demonstrates that ORI is a feasible technique to characterize macrophage redox state in infant TA samples and supports further use of this method to investigate lung macrophage-mediated disease endotypes in BPD. [ABSTRACT FROM AUTHOR]

Bacterial infections trigger a multifaceted interplay between inflammatory mediators and redox regulation. Recently, accumulating evidence has shown that redox signaling plays a significant role in immune initiation and subsequent immune cell functions. This review addresses the crucial role of the thioredoxin (Trx) system in the initiation of immune reactions and regulation of inflammatory responses during bacterial infections. Downstream signaling pathways in various immune cells involve thiol-dependent redox regulation, highlighting the pivotal roles of thiol redox systems in defense mechanisms. Conversely, the survival and virulence of pathogenic bacteria are enhanced by their ability to counteract oxidative stress and immune attacks. This is achieved through the reduction of oxidized proteins and the modulation of redox-sensitive signaling pathways, which are functions of the Trx system, thereby fortifying bacterial resistance. Moreover, some selenium/sulfur-containing compounds could potentially be developed into targeted therapeutic interventions for pathogenic bacteria. Taken together, the Trx system is a key player in redox regulation during bacterial infection, and contributes to host–pathogen interactions, offering valuable insights for future research and therapeutic development. [ABSTRACT FROM AUTHOR]

Introduction: The present review aimed to systematically summarize the impacts of environmental enrichment (EE) on cerebral oxidative balance in rodents exposed to normal and unfavorable environmental conditions. Methods: In this systematic review, four databases were used: PubMed (830 articles), Scopus (126 articles), Embase (127 articles), and Science Direct (794 articles). Eligibility criteria were applied based on the Population, Intervention, Comparison, Outcomes, and Study (PICOS) strategy to reduce the risk of bias. The searches were carried out by two independent researchers; in case of disagreement, a third participant was requested. After the selection and inclusion of articles, data related to sample characteristics and the EE protocol (time of exposure to EE, number of animals, and size of the environment) were extracted, as well as data related to brain tissues and biomarkers of oxidative balance, including carbonyls, malondialdehyde, nitrotyrosine, oxygen-reactive species, and glutathione (reduced/oxidized). Results: A total of 1,877 articles were found in the four databases, of which 16 studies were included in this systematic review. The results showed that different EE protocols were able to produce a global increase in antioxidant capacity, both enzymatic and non-enzymatic, which are the main factors for the neuroprotective effects in the central nervous system (CNS) subjected to unfavorable conditions. Furthermore, it was possible to notice a slowdown in neural dysfunction associated with oxidative damage, especially in the prefrontal structure in mice. Discussion: In conclusion, EE protocols were determined to be valid tools for improving oxidative balance in the CNS. The global decrease in oxidative stress biomarkers indicates refinement in reactive oxygen species detoxification, triggering an improvement in the antioxidant network. [ABSTRACT FROM AUTHOR]

Oxidative stress is caused by an imbalance between the production of reactive oxygen species (ROS) and the body's ability to counteract their harmful effects, playing a key role in the pathogenesis of brain and lung-related diseases. This review comprehensively examines the intricate mechanisms by which oxidative stress influences cellular and molecular pathways, contributing to neurodegenerative, cardiovascular, and respiratory disorders. Emphasizing the detrimental effects on both brain and lung health, we discuss innovative diagnostic biomarkers, such as 8-hydroxy-20-deoxyguanosine (8-OHdG), and the potential of antioxidant therapies. For these topics, we provide insights into future research directions in the field of oxidative stress treatment, including the development of personalized treatment approaches, the discovery and validation of novel biomarkers, and the development of new drug delivery systems. This review not only provides a new perspective on understanding the role of oxidative stress in brain and lung-related diseases but also offers new insights for future clinical treatments. [ABSTRACT FROM AUTHOR]

Background: Diabetes Mellitus is associated with disturbances in male reproductive function and fertility. Studies have shown that oxidative stress with the subsequent inflammation and apoptosis cause these complications in diabetes. Garlic (G) (Allium sativum L) and Citrullus colocynthis (L.) Schrad (C) both have antidiabetic and antioxidant properties. Recently, we demonstrated their synergistic effects in alleviating reproductive complications when administered concomitantly. However, as even medicinal plants in long term usage may lead to some unwanted side effects of their own, we examined whether with half the original doses of these two medicinal plants we could achieve the desired results. Methods: Thirty-five male Wistar rats were divided into five groups (n = 7/group): Control, Diabetic, Diabetic + G (0.5 ml/100 g BW), Diabetic + C (5 mg/kg BW) and Diabetic + GC (0.5 ml/100 g BW of garlic and 5 mg/kg BW of C. colocynthis) groups. The experimental period was 30 days. Results: Oxidative stress, advanced glycation end products (AGEs), immunoexpression of caspase-3, and expression of mRNAs for receptor for advanced glycation end products (RAGE), NADPH oxidase-4 (NOX-4) and nuclear factor kappa B increased in testis of diabetic rats. Treatment with garlic and C. colocynthis alone showed some beneficial effects, but in the combination form the effectiveness was more profound. Conclusions: We conclude that the combination therapy of diabetic rats with lower doses is still as efficient as higher doses; therefore, the way forward for reducing complications in long term consumption. [ABSTRACT FROM AUTHOR]

The current study was conducted to evaluate the cardioprotective potential of eugenol against hypertension induced by doxorubicin in rats. Rats were exposed to Doxorubicin HCl (2mg/kg body weight) intraperitoneally to induce cardiotoxicity and treated with eugenol (5 mg/kg) orally for 5 weeks. At the end of the study, the blood pressure was assessed in the tested animals and the levels of serum lipid profile and oxidative stress markers were assessed. Also, the heart was dissected and the oxidative stress and apoptotic markers in heart homogenate were assessed. There was a high statistically significant difference between all the tested groups regarding the systolic blood pressure and mean arterial pressure. The Serum oxidative stress markers and lipid profile markers showed a statistically significant increase in the positive control group compared to other groups. The heart homogenate level of all the tested parameters showed a statistically significant increase in the positive group compared to other groups except for the MDA levels that were comparable between the positive group and protection group. Eugenol's antioxidant and lipid-lowering properties protect against hypertension. Eugenol's antioxidant and antiapoptotic effects protect the heart from hypertension's long-term effects at the tissue level. [ABSTRACT FROM AUTHOR]

Arachidonic acid (AA) is a main component of cell membrane lipids. AA is mainly metabolized by three enzymes: cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP450). Esterified AA is hydrolysed by phospholipase A2 into a free form that is further metabolized by COX, LOX and CYP450 to a wide range of bioactive mediators, including prostaglandins, lipoxins, thromboxanes, leukotrienes, hydroxyeicosatetraenoic acids and epoxyeicosatrienoic acids. Increased mitochondrial oxidative stress is considered to be a central mechanism in the pathophysiology of the kidney. Along with increased oxidative stress, apoptosis, inflammation and tissue fibrosis drive the progressive loss of kidney function, affecting the glomerular filtration barrier and the tubulointerstitium. Recent studies have shown that AA and its active derivative eicosanoids play important roles in the regulation of physiological kidney function and the pathogenesis of kidney disease. These factors are potentially novel biomarkers, especially in the context of their involvement in inflammatory processes and oxidative stress. In this review, we introduce the three main metabolic pathways of AA and discuss the molecular mechanisms by which these pathways affect the progression of acute kidney injury (AKI), diabetic nephropathy (DN) and renal cell carcinoma (RCC). This review may provide new therapeutic targets for the identification of AKI to CKD continuum. [ABSTRACT FROM AUTHOR]

Background: The halophilic bacterium Halomonas elongata is an industrially important strain for ectoine production, with high value and intense research focus. While existing studies primarily delve into the adaptive mechanisms of this bacterium under fixed salt concentrations, there is a notable dearth of attention regarding its response to fluctuating saline environments. Consequently, the stress response of H. elongata to salt shock remains inadequately understood. Results: This study investigated the stress response mechanism of H. elongata when exposed to NaCl shock at short- and long-time scales. Results showed that NaCl shock induced two major stresses, namely osmotic stress and oxidative stress. In response to the former, within the cell's tolerable range (1–8% NaCl shock), H. elongata urgently balanced the surging osmotic pressure by uptaking sodium and potassium ions and augmenting intracellular amino acid pools, particularly glutamate and glutamine. However, ectoine content started to increase until 20 min post-shock, rapidly becoming the dominant osmoprotectant, and reaching the maximum productivity (1450 ± 99 mg/L/h). Transcriptomic data also confirmed the delayed response in ectoine biosynthesis, and we speculate that this might be attributed to an intracellular energy crisis caused by NaCl shock. In response to oxidative stress, transcription factor cysB was significantly upregulated, positively regulating the sulfur metabolism and cysteine biosynthesis. Furthermore, the upregulation of the crucial peroxidase gene (HELO_RS18165) and the simultaneous enhancement of peroxidase (POD) and catalase (CAT) activities collectively constitute the antioxidant defense in H. elongata following shock. When exceeding the tolerance threshold of H. elongata (1–13% NaCl shock), the sustained compromised energy status, resulting from the pronounced inhibition of the respiratory chain and ATP synthase, may be a crucial factor leading to the stagnation of both cell growth and ectoine biosynthesis. Conclusions: This study conducted a comprehensive analysis of H. elongata's stress response to NaCl shock at multiple scales. It extends the understanding of stress response of halophilic bacteria to NaCl shock and provides promising theoretical insights to guide future improvements in optimizing industrial ectoine production. [ABSTRACT FROM AUTHOR]

Currently, coronary artery bypass and reperfusion therapies are considered the gold standard in long-term treatments to restore heart function after acute myocardial infarction. As a drawback of these restoring strategies, reperfusion after an ischemic insult and sudden oxygen exposure lead to the exacerbated synthesis of additional reactive oxidative species and the persistence of increased oxidation levels. Attempts based on antioxidant treatment have failed to achieve an effective therapy for cardiovascular disease patients. The controversial use of vitamin C as an antioxidant in clinical practice is comprehensively systematized and discussed in this review. The dose-dependent adsorption and release kinetics mechanism of vitamin C is complex; however, this review may provide a holistic perspective on its potential as a preventive supplement and/or for combined precise and targeted therapeutics in cardiovascular management therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Gentle touch has been repeatedly shown to have a positive effect on livestock. The purpose of this study was to determine potential changes in physiological indicators in lambs subjected to gentle stroking. A total of 40 lambs of two breeds were assigned to two control groups (n = 20) and two experimental groups (n = 20). Lambs from the experimental groups received treatment (the gentle stroking procedure). Analyses consisted of determining the following parameters: heart rate (HR), saturation (S) and biochemical analysis. An increase in cortisol levels and a decrease in total protein levels indicate a disruption of homeostasis. At the same time, a significant increase in glycogen and a significant decrease in glucose and heart rate values suggest reduced stress levels. The results obtained in the experimental groups suggest that interactions with humans, even of a positive nature, can be a source of stress, but this is a transient and adaptive reaction. Interactions with humans can be a source of stress, but long-term and positive ones will lead to positive changes and easier handling of animals. The aim of the study was to determine changes in physiological indicators in lambs subjected to gentle stroking. The study included 40 three-week-old lambs (20 females of the synthetic prolific-meat (BCP) line and 20 females of the Świniarka (SW) breed). The animals were assigned to two control groups (n = 20) and two experimental groups (n = 20). Lambs from the experimental groups received treatment. Analyses consisted of determining the following parameters: heart rate (HR), saturation (S) and biochemical analysis. In the groups of sheep subjected to gentle massage, the analyses revealed a significant increase in the levels of cortisol, CAT, GST, GPx, among others, and a significant decrease in the levels of total protein, SOD, TAC, uric acid and Na+. At the same time, indicators of reduced stress levels were revealed, i.e., a significant increase in glycogen levels and a significant decrease in glucose and HR values. These results suggest that the introduction of gentle touch can induce positive states in lambs, and that the stress response may be transient and adaptive. Nevertheless, it is important to note that these interactions can be a source of stress, even if the behavioral response does not necessarily indicate stress. [ABSTRACT FROM AUTHOR]

Since the evolution of the aerobic metabolism, reactive oxygen species (ROS) have represented significant challenges to diverse life forms. In recent decades, increasing knowledge has revealed a dual role for ROS in cell physiology, showing they serve as a major source of cellular damage while also functioning as important signaling molecules in various biological processes. Our understanding of ROS homeostasis and ROS-mediated cellular signaling pathways has presumed that they are ancient and highly conserved mechanisms shared by most organisms. However, emerging evidence highlights the complexity and plasticity of ROS signaling, particularly in animals that have evolved in extreme environments. In this review, we focus on ROS generation, antioxidative systems and the main signaling pathways that are influenced by ROS. In addition, we discuss ROS's responsive transcription regulation and how it may have been shaped over the course of evolution. [ABSTRACT FROM AUTHOR]

Adipose tissue undergoes changes with aging, leading to increased adiposity, inflammatory cell infiltration, reduced angiogenesis, heightened oxidative stress, and alterations in its metabolic function. Regular exercise has been recognized as a powerful intervention that can positively influence adipose tissue health and mitigate the effects of aging. However, the molecular mechanisms underlying the benefits of regular exercise on aging adipose tissue function remain poorly understood. Adipokines released through regular exercise play a potential role in mitigating adipose tissue aging, enhancing the metabolism of glucose and lipids, reducing inflammation and fibrosis, and promoting fat browning and thermogenesis. This review comprehensively summarizes the benefits of regular exercise in addressing the age-related decline in adipose tissue function. Utilizing relevant examples of this approach, we address the possibility of designing therapeutic interventions based on these molecular mechanisms. [ABSTRACT FROM AUTHOR]

Background: Angiopoietin-like 2 (ANGPTL2) is a pro-inflammatory and pro- oxidant circulating protein that predicts and promotes chronic inflammatory diseases such as atherosclerosis in humans. Transgenic murine models demonstrated the deleterious role of ANGPTL2 in vascular diseases, while deletion of ANGPTL2 was protective. The nature of its role in cardiac tissues is, however, less clear. Indeed, in adultmice knocked down (KD) for ANGPTL2, we recently reported a mild left ventricular (LV) dysfunction originating from a congenital aortic valve stenosis, demonstrating that ANGPTL2 is essential to cardiac development and function. Hypothesis: Because we originally demonstrated that the KD of ANGPTL2 protected vascular endothelial function via an upregulation of arterial NOX4, promoting the beneficial production of dilatory H2O2,wetestedthe hypothesis that increased cardiac NOX4 could negatively affect cardiac redox and remodeling and contribute to LV dysfunction observed in adult -KD mice. Methods and results: Cardiac expression and activity of NOX4 were higher in KD mice, promoting higher levels of cardiac H2O2 when compared to wild-type (WT) mice. Immunofluorescence showed that ANGPTL2 and NOX4 were co-expressed in cardiac cells from WT mice and both proteins co-immunoprecipitated in HEK293 cells, suggesting that ANGPTL2 and NOX4 physically interact. Pressure overload induced by transverse aortic constriction surgery (TAC) promoted LV systolic dysfunction in WT mice but did not further exacerbate the dysfunction in KD mice. Importantly, the severity of LV systolic dysfunction in KD mice (TAC and control SHAM) correlated with cardiac expression. Injection of an adeno-associated virus (AAV9) delivering shRNA targeting cardiac expression fully reversed LV systolic dysfunction in KD-SHAM mice, demonstrating the causal role of NOX4 in cardiac dysfunction in KDmice. Targeting cardiac expression in KDmice also induced an antioxidant response characterized by increased expression of NRF2/KEAP1 and catalase. Conclusion: Together, these data reveal that the absence of ANGPTL2 induces an upregulation of cardiac NOX4 that contributes to oxidative stress and LV dysfunction. By interacting and repressing cardiac NOX4, ANGPTL2 could play a new beneficial role in the maintenance of cardiac redox homeostasis and function. [ABSTRACT FROM AUTHOR]

Background. Oxidative stress is involved in pathogenesis of some psychiatric disorders. To examine the role of oxidative stress in the etiopathogenesis of obsessive-compulsive disorder (OCD), we aimed to determine oxidative stress indices, including malondialdehyde (MDA) levels in serum and red blood cells (RBC) membrane, total antioxidant capacity (TAC), serum glutathione (GSH) levels, serum antioxidant vitamins (A and E), and Na+/K+-ATPase activity, in patients with the mentioned disorder vs. healthy controls. Method. 39 OCD patients diagnosed based on Diagnostic and Statistical Manual of Mental Disorders (DSM-V) and 39 volunteer healthy subjects were included in this study. MDA levels in serum and RBC membrane were measured using fluorometric method. Serum TAC level, serum GSH level, and Na+/K+-ATPase activity were also measured using spectrophotometric methods. Serum levels of vitamins were calculated by reversed-phase high-performance liquid chromatography (RP-HPLC). Result. There was a significantly higher MDA level in serum (p < 0.0001) and RBC membrane (p = 0.002) of OCD patients compared with those in controls. A significant reduction in vitamin A (p = 0.001) and vitamin E (p = 0.024) levels was found in OCD patients vs. controls. There was significantly lower activity of erythrocyte membrane Na+/K+-ATPase in RBC membrane of OCD patients vs. controls (p < 0.0001). Conclusion. Our findings indicate significantly higher levels MDA in both serum and RBC membrane, lower levels of serum vitamins A and E, and lower activity of membrane Na+/K+-ATPase in OCD patients compared to controls. These suggest an imbalance between oxidant and antioxidant factors in OCD patients that might play a fundamental role in the etiopathogenesis of OCD. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) were formerly known as mere byproducts of metabolism with damaging effects on cellular structures. The discovery and description of NADPH oxidases (Nox) as a whole enzyme family that only produce this harmful group of molecules was surprising. After intensive research, seven Nox isoforms were discovered, described and extensively studied. Among them, the NADPH oxidase 3 is the perhaps most underrated Nox isoform, since it was firstly discovered in the inner ear. This stigma of Nox3 as "being only expressed in the inner ear" was also used by me several times. Therefore, the question arose whether this sentence is still valid or even usable. To this end, this review solely focuses on Nox3 and summarizes its discovery, the structural components, the activating and regulating factors, the expression in cells, tissues and organs, as well as the beneficial and detrimental effects of Nox3-mediated ROS production on body functions. Furthermore, the involvement of Nox3-derived ROS in diseases progression and, accordingly, as a potential target for disease treatment, will be discussed. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) are produced under normal physiological conditions and may have beneficial and harmful effects on biological systems. ROS are involved in many physiological processes such as differentiation, proliferation, necrosis, autophagy, and apoptosis by acting as signaling molecules or regulators of transcription factors. In this case, maintaining proper cellular ROS levels is known as redox homeostasis. Oxidative stress occurs because of the imbalance between the production of ROS and antioxidant defenses. Sources of ROS include the mitochondria, auto‐oxidation of glucose, and enzymatic pathways such as nicotinamide adenine dinucleotide phosphate reduced (NAD[P]H) oxidase. The possible ROS pathways are NF‐κB, MAPKs, PI3K‐Akt, and the Keap1‐Nrf2‐ARE signaling pathway. This review covers the literature pertaining to the possible ROS pathways and strategies to inhibit them. Additionally, this review summarizes the literature related to finding ROS inhibitors. [ABSTRACT FROM AUTHOR]

NADPH oxidase 4 (NOX4) plays an important role in the regulation of oxidative stress, which is associated with endometriosis. This study aims to investigate the effects of NOX4 in endometriosis and its molecular mechanisms. Clinical specimens were collected, and human endometrial stromal cells (HESCs) were isolated. The knockdown of NOX4 cell lines was established on the HESCs and induced by peritoneal fluid. The levels of NOX4 were determined by using immunohistochemistry (IHC) staining, western blotting, and qPCR, respectively. The levels of oxidative stress markers were determined by using western blotting and ELISAs, respectively. The correlation of NOX4 and oxidative stress markers was analyzed by the Pearson correlation coefficient. The levels of NOX4 were dramatically elevated in the ectopic endometrium. Besides, oxidative stress biomarkers were also dysregulated in the ectopic endometrium as compared to the normal endometrium. Pearson's correlation coefficient analysis revealed a relationship between NOX4 and oxidative stress biomarkers in the ectopic endometrium. NOX4 modulated the expressions of oxidative stress markers in endometrial stromal cells stimulated by the peritoneal fluid from endometriosis. The effects of NOX4 on endometriosis are in part by its regulatory effects against oxidative stress. [ABSTRACT FROM AUTHOR]

Oxidative stress (OS) plays a pivotal role in the development of many diseases. Therefore, many efforts have been undertaken to minimize the consequences of OS or improve antioxidant defense systems. One solution expected to improve redox homeostasis is the ketogenic diet (KD). KD is a low-carbohydrate, high-fat diet leading to a ketosis state. The shift in metabolism occurring in ketosis can affect the reactive oxygen species (ROS)-producing pathways and influence the expression of enzymes involved in redox homeostasis. Therefore, this review summarizes and discusses existing knowledge about KD and ROS homeostasis. The available tools for evaluating OS status are presented, listing their potential and drawbacks. An important aspect is the summary of the current knowledge about the effect of KD on OS conducted in vitro, in vivo, and in clinical trials. Finally, the review addresses future studies needed to understand the connection between KD and OS. [ABSTRACT FROM AUTHOR]

Most previous studies on fungal NADPH oxidases (Nox) focused on multicellular fungi and highlighted the important roles of Nox-derived reactive oxygen species (ROS) in cellular differentiation and signaling communication. However, there are few reports about Nox in unicellular fungi. A novel NOX ortholog, CAGL0K05863g (named CgNOX1), in Candida glabrata was investigated in this study. Deletion of CgNOX1 led to a decrease in both intracellular and extracellular ROS production. In addition, the Cgnox1∆ mutant exhibited hypersensitivity to hydrogen peroxide and menadione. Also, the wild-type strain showed higher levels of both CgNOX1 mRNA expression and ROS production under oxidative stress. Moreover, the absence of CgNOX1 resulted in impaired ferric reductase activity. Although there was no effect on in vitro biofilm formation, the CgNOX1 mutant did not produce hepatic apoptosis, which might be mediated by fungal Nox-derived ROS during co-incubation. Together, these results indicated that the novel NOX gene plays important roles in unicellular pathogenic C. glabrata and its interaction with host cells. [ABSTRACT FROM AUTHOR]

NADPH oxidase (NOX) is a primary mediator of superoxides, which promote oxidative stress, neurodegeneration, and neuroinflammation after diisopropylfluorophosphate (DFP) intoxication. Although orally administered mitoapocynin (MPO, 10 mg/kg), a mitochondrial-targeted NOX inhibitor, reduced oxidative stress and proinflammatory cytokines in the periphery, its efficacy in the brain regions of DFP-exposed rats was limited. In this study, we encapsulated MPO in polyanhydride nanoparticles (NPs) based on 1,6-bis(p-carboxyphenoxy) hexane (CPH) and sebacic anhydride (SA) for enhanced drug delivery to the brain and compared with a high oral dose of MPO (30 mg/kg). NOX2 (GP91phox) regulation and microglial (IBA1) morphology were analyzed to determine the efficacy of MPO-NP vs. MPO-oral in an 8-day study in the rat DFP model. Compared to the control, DFP-exposed animals exhibited significant upregulation of NOX2 and a reduced length and number of microglial processes, indicative of reactive microglia. Neither MPO treatment attenuated the DFP effect. Neurodegeneration (FJB+NeuN) was significantly greater in DFP-exposed groups regardless of treatment. Interestingly, neuronal loss in DFP+MPO-treated animals was not significantly different from the control. MPO-oral rescued inhibitory neuronal loss in the CA1 region of the hippocampus. Notably, MPO-NP and MPO-oral significantly reduced astrogliosis (absolute GFAP counts) and reactive gliosis (C3+GFAP). An analysis of inwardly rectifying potassium channels (Kir4.1) in astroglia revealed a significant reduction in the brain regions of the DFP+VEH group, but MPO had no effect. Overall, both NP-encapsulated and orally administered MPO had similar effects. Our findings demonstrate that MPO effectively mitigates DFP-induced reactive astrogliosis in several key brain regions and protects neurons in CA1, which may have long-term beneficial effects on spontaneous seizures and behavioral comorbidities. Long-term telemetry and behavioral studies and a different dosing regimen of MPO are required to understand its therapeutic potential. [ABSTRACT FROM AUTHOR]

Obesity is a characteristic disease of the twenty-first century that is affecting an increasing percentage of society. Obesity expresses itself in different phenotypes: normal-weight obesity (NWO), metabolically obese normal-weight (MONW), metabolically healthy obesity (MHO), and metabolically unhealthy obesity (MUO). A range of pathophysiological mechanisms underlie the occurrence of obesity, including inflammation, oxidative stress, adipokine secretion, and other processes related to the pathophysiology of adipose tissue (AT). Body mass index (BMI) is the key indicator in the diagnosis of obesity; however, in the case of the NWO and MONW phenotypes, the metabolic disturbances are present despite BMI being within the normal range. On the other hand, MHO subjects with elevated BMI values do not present metabolic abnormalities. The MUO phenotype involves both a high BMI value and an abnormal metabolic profile. In this regard, attention has been focused on the variety of molecules produced by AT and their role in the development of obesity. Nesfatin-1, neuregulin 4, myonectin, irisin, and brain-derived neurotrophic factor (BDNF) all seem to have protective effects against obesity. The primary mechanism underlying the action of nesfatin-1 involves an increase in insulin sensitivity and reduced food intake. Neuregulin 4 sup-presses lipogenesis, decreases lipid accumulation, and reduces chronic low-grade inflammation. Myonectin lowers the amount of fatty acids in the bloodstream by increasing their absorption in the liver and AT. Irisin stimulates the browning of white adipose tissue (WAT) and consequently in-creases energy expenditure, additionally regulating glucose metabolism. Another molecule, BDNF, has anorexigenic effects. Decorin protects against the development of hyperglycemia, but may also contribute to proinflammatory processes. Similar effects are shown in the case of visfatin and chemerin, which may predispose to obesity. Visfatin increases adipogenesis, causes cholesterol accumulation in macrophages, and contributes to the development of glucose intolerance. Chemerin induces angiogenesis, which promotes the expansion of AT. This review aims to discuss the role of adipokines and myokines in the pathogenesis of the different obesity phenotypes. [ABSTRACT FROM AUTHOR]

Spontaneous subarachnoid hemorrhage (SAH) is one of the most devastating forms of stroke, with limited treatment modalities and poor patient outcomes. Previous studies have proposed multiple prognostic factors; however, relative research on treatment has not yet yielded favorable clinical outcomes. Moreover, recent studies have suggested that early brain injury (EBI) occurring within 72 h after SAH may contribute to its poor clinical outcomes. Oxidative stress is recognized as one of the main mechanisms of EBI, which causes damage to various subcellular organelles, including the mitochondria, nucleus, endoplasmic reticulum (ER), and lysosomes. This could lead to significant impairment of numerous cellular functions, such as energy supply, protein synthesis, and autophagy, which may directly contribute to the development of EBI and poor long‐term prognostic outcomes. In this review, the mechanisms underlying the connection between oxidative stress and subcellular organelles after SAH are discussed, and promising therapeutic options based on these mechanisms are summarized. [ABSTRACT FROM AUTHOR]

The present study focused on examining the impact of vitamin C (Vit C) administration on the function of memory and the status of oxidative stress (OS) in the hippocampal area of the brain using an unpredictable chronic mild stress (UCMS) model in rats. To this end, 50 male Wistar rats (11-12 weeks of age at the start of the study) were assigned to five groups of six animals, including control, UCMS, UCMS + Vit C 50 mg/Kg, UCMS + Vit C 100 mg/Kg, and UCMS + Vit C 400 mg/Kg. The animals received daily intraperitoneal injections of Vit C at a certain time (9 am) before the initiation of a stressor. UCMS, including a progression of typical stressors, was applied for four weeks. Subsequently, using the passive avoidance (PA) and Morris water maze (MWM) tests were performed to investigate learning and memory. Eventually, hippocampal tissues were evaluated in terms of OS criteria. The results revealed that the latency to enter the dark chamber (P < 0. 01 and P < 0.05, PA test) and the time spent in the target quadrant (P < 0.0001, MWM test) were shorter in the UCMS group, while latency to discover the platform was longer (P < 0.05 and P < 0.001, MWM test) compared to the control group. However, UCMS decreased the content of thiol (P < 0.0001), as well as the activities of catalase (P < 0.0001) and superoxide dismutase (P < 0.0001), whereas the concentration of malondialdehyde (P < 0.01) increased in the hippocampal region of the brain in comparison to the control group. Interestingly, Vit C treatment reversed the mentioned effects of UCMS. Therefore, the latency to enter the dark chamber (P < 0. 05 and P < 0.01,1 and 24 h after the shock, PA test, UCMS + Vit C 400) and the time spent in the target quadrant (P < 0. 01 and P < 0.05, MWM test, UCMS + Vit C 400 and UCMS + Vit C 100, respectively) were longer in the UCMS + Vit C groups. Moreover, Vit C increased the content of thiol (P < 0.05, UCMS + Vit C 400), as well as the activity of catalase (P < 0.001, UCMS + Vit C 400) and superoxide dismutase (P < 0.0001, UCMS + Vit C 400, UCMS + Vit C 100), whereas the concentration of malondialdehyde (P < 0. 05 and P < 0.01, UCMS + Vit C 100, UCMS + Vit C 400) decreased in the hippocampal region of the brain in comparison to the UCMS group. Overall, these results suggest that Vit C could reverse UCMS-induced learning and memory impairment possibly through the modulation of brain OS. Key points Memory and learning impairments were induced by unpredictable chronic mild stress (UCMS) Vitamin C could prevent cognitive impairments caused by UCMS in rats by attenuation of oxidative stress in the brain. [ABSTRACT FROM AUTHOR]

Ischemia/reperfusion injury (IRI) of the heart involves the activation of oxidative and proapoptotic pathways. Simultaneously Klotho protein presents anti-aging, antiapoptotic and antioxidative properties. Therefore, this study aimed to evaluate the effect of Klotho protein on oxidative stress in hearts subjected to IRI. Isolated rat hearts perfused with the Langendorff method were subjected to ischemia, followed by reperfusion, in the presence or absence of recombinant rat Klotho protein. The factors involved in the activation of insulin-like growth factor receptor (IGF1R)/phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) signalling pathway were evaluated. IRI caused activation of the IGF1R (p = 0.0122)/PI3K (p = 0.0022) signalling, as compared to the aerobic control group. Infusion supply of Klotho protein during IRI significantly reduced the level of phospho-IGF1R (p = 0.0436), PI3K (p = 0.0218) and phospho-AKT (p = 0.0020). Transcriptional activity of forkhead box protein O3 (FOXO3) was reduced (p = 0.0207) in hearts subjected to IRI, compared to aerobic control. Administration of Klotho decreased phosphorylation of FOXO3 (p = 0.0355), and enhanced activity of glutathione peroxidase (p = 0.0452) and superoxide dismutase (p = 0.0060) in IRI + Klotho group. The levels of reactive oxygen/nitrogen species (ROS/RNS) (p = 0.0480) and hydrogen peroxide (H2O2) (p = 0.0460), and heart injury (p = 0.0005) were significantly increased in hearts from the IRI group in comparison to the aerobic group. Klotho reduced NADPH oxidase 2 (NOX2) (p = 0.0390), ROS/RNS (p = 0.0435) and H2O2 (p = 0.0392) levels, and heart damage (p = 0.0286) in the hearts subjected to IRI. In conclusion, Klotho contributed to the protection of the heart against IRI and oxidative stress via inhibition of the IGF1R/PI3K/AKT pathway, thus can be recognized as a novel cardiopreventive/cardioprotective agent. [ABSTRACT FROM AUTHOR]

In plants, sucrose is the main transported disaccharide that is the primary product of photosynthesis and controls a multitude of aspects of the plant life cycle including structure, growth, development, and stress response. Sucrose is a signaling molecule facilitating various stress adaptations by crosstalk with other hormones, but the molecular mechanisms are not well understood. Accumulation of high sucrose concentrations is a hallmark of many abiotic and biotic stresses, resulting in the accumulation of reactive oxygen species and secondary metabolite anthocyanins that have antioxidant properties. Previous studies have shown that several MYeloBlastosis family/MYB transcription factors are positive and negative regulators of sucrose-induced anthocyanin accumulation and subject to microRNA (miRNA)--mediated post-transcriptional silencing, consistent with the notion that miRNAs may be "nodes" in crosstalk signaling by virtue of their sequence-guided targeting of different homologous family members. In this study, we endeavored to uncover by deep sequencing small RNA and mRNA transcriptomes the effects of exogenous high sucrose stress on miRNA abundances and their validated target transcripts in Arabidopsis. We focused on genotype-by-treatment effects of high sucrose stress in Production of Anthocyanin Pigment 1-Dominant/pap1-D, an activation-tagged dominant allele of MYB75 transcription factor, a positive effector of secondary metabolite anthocyanin pathway. In the process, we discovered links to reactive oxygen species signaling through miR158/161/173-targeted Pentatrico Peptide Repeat genes and two novel non-canonical targets of high sucrose-induced miR408 and miR398b*(star), relevant to carbon metabolic fluxes: Flavonoid 3'-Hydroxlase (F3'H), an important enzyme in determining the B-ring hydroxylation pattern of flavonoids, and ORANGE a post-translational regulator of Phytoene Synthase expression, respectively. Taken together, our results contribute to understanding the molecular mechanisms of carbon flux shifts from primary to secondary metabolites in response to high sugar stress. [ABSTRACT FROM AUTHOR]

Cisplatin is a commonly used chemotherapeutic agent with proven efficacy in treating various malignancies, including testicular, ovarian, cervical, breast, bladder, head and neck, and lung cancer. Cisplatin is also used to treat tumors in children, such as neuroblastoma, osteosarcoma, and hepatoblastoma. However, its clinical use is limited by severe side effects, including ototoxicity, nephrotoxicity, neurotoxicity, hepatotoxicity, gastrointestinal toxicity, and retinal toxicity. Cisplatin-induced ototoxicity manifests as irreversible, bilateral, high-frequency sensorineural hearing loss in 40–60% of adults and in up to 60% of children. Hearing loss can lead to social isolation, depression, and cognitive decline in adults, and speech and language developmental delays in children. Cisplatin causes hair cell death by forming DNA adducts, mitochondrial dysfunction, oxidative stress, and inflammation, culminating in programmed cell death by apoptosis, necroptosis, pyroptosis, or ferroptosis. Contemporary medical interventions for cisplatin ototoxicity are limited to prosthetic devices, such as hearing aids, but these have significant limitations because the cochlea remains damaged. Recently, the U.S. Food and Drug Administration (FDA) approved the first therapy, sodium thiosulfate, to prevent cisplatin-induced hearing loss in pediatric patients with localized, non-metastatic solid tumors. Other pharmacological treatments for cisplatin ototoxicity are in various stages of preclinical and clinical development. This narrative review aims to highlight the molecular mechanisms involved in cisplatin-induced ototoxicity, focusing on cochlear inflammation, and shed light on potential antioxidant and anti-inflammatory therapeutic interventions to prevent or mitigate the ototoxic effects of cisplatin. We conducted a comprehensive literature search (Google Scholar, PubMed) focusing on publications in the last five years. [ABSTRACT FROM AUTHOR]

This Special Issue highlights the most recent advances in all the aspects of ROS signaling with examples of H SB 2 sb O SB 2 sb signaling in I E. coli i , plants and animals. Amongst ROS, hydrogen peroxide (H SB 2 sb O SB 2 sb ) best fits the properties of a signaling molecule and is recognizable as the major ROS in the oxidative regulation of physiological activity [[6]]. Reactive oxygen species (ROS) were originally described as toxic by-products of aerobic cellular energy metabolism associated with the development of several diseases, such as cancer, neurodegenerative diseases, and diabetes [[1], [3]]. [Extracted from the article]

Thyroid cancer (TC), the most frequent malignancy of the endocrine system, has recorded an increasing incidence in the last decades. The etiology of TC remains at least partly unknown and, among modifiable risk factors, the gut microbiota and dietary nutrients (vitamins, essential microelements, polyphenols, probiotics) have been recognized to not only influence thyroid function, but exert critical effects on TC development and progression. Recent discoveries on the existence of tumor microbiota also in the TC microenvironment provide further evidence for the essential role of tumor microorganisms in TC etiology and severity, as well as acting as prognostic markers and as a potential target of adjuvant care in the treatment of TC patients. Therefore, in this review, we summarize current knowledge on the relationship of the tumor microbiome with the clinical tumor characteristics and TC progression, also illustrating the molecular mechanisms underlying this association, and how antioxidant nutrients may be used as a novel strategy to both control gut health and reduce the risk for TC. Furthermore, we discuss how new technologies might be exploited for the development of new foods with high nutritional values, antioxidant capability, and even attractiveness to the individual in terms of sensory and emotional features. [ABSTRACT FROM AUTHOR]

N-acetylcysteine (NAC), an acetylated derivative of the amino acid L-cysteine, has been widely used as a mucolytic agent and antidote for acetaminophen overdose since the 1960s and the 1980s, respectively. NAC possesses antioxidant, cytoprotective, anti-inflammatory, antimicrobial, and mucolytic properties, making it a promising therapeutic agent for a wide range of diseases in both humans and domesticated animals. Oxidative stress and inflammation play a major role in the onset and progression of all these diseases. NAC's primary role is to replenish glutathione (GSH) stores, the master antioxidant in all tissues; however, it can also reduce levels of pro-inflammatory tumor necrosis factor-alpha (TNF-∝) and interleukins (IL-6 and IL-1β), inhibit the formation of microbial biofilms and destroy biofilms, and break down disulfide bonds between mucin molecules. Many experimental studies have been conducted on the use of NAC to address a wide range of pathological conditions; however, its effectiveness in clinical trials remains limited and studies often have conflicting results. The purpose of this review is to provide a concise overview of promising NAC usages for the treatment of different human and domestic animal disorders. [ABSTRACT FROM AUTHOR]

Consumption of high amounts of ethanol is a risk factor for development of cardiovascular diseases such as arterial hypertension. The hypertensive state induced by ethanol is a complex multi-factorial event, and oxidative stress is a pathophysiological hallmark of vascular dysfunction associated with ethanol consumption. Increasing levels of reactive oxygen species (ROS) in the vasculature trigger important processes underlying vascular injury, including accumulation of intracellular Ca2+ ions, reduced bioavailability of nitric oxide (NO), activation of mitogen-activated protein kinases (MAPKs), endothelial dysfunction, and loss of the anticontractile effect of perivascular adipose tissue (PVAT). The enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase plays a central role in vascular ROS generation in response to ethanol. Activation of the renin–angiotensin–aldosterone system (RAAS) is an upstream mechanism which contributes to NADPH oxidase stimulation, overproduction of ROS, and vascular dysfunction. This review discusses the mechanisms of vascular dysfunction induced by ethanol, detailing the contribution of ROS to these processes. Data examining the association between neuroendocrine changes and vascular oxidative stress induced by ethanol are also reviewed and discussed. These issues are of paramount interest to public health as ethanol contributes to blood pressure elevation in the general population, and it is linked to cardiovascular conditions and diseases. [ABSTRACT FROM AUTHOR]

The gastrointestinal (GI) barrier acts as the primary interface between humans and the external environment. It constantly faces the risk of inflammation and oxidative stress due to exposure to foreign substances and microorganisms. Thus, maintaining the structural and functional integrity of the GI barrier is crucial for overall well-being, as it helps prevent systemic inflammation and oxidative stress, which are major contributors to age-related diseases. A healthy gut relies on maintaining gut redox homeostasis, which involves several essential elements. Firstly, it requires establishing a baseline electrophilic tone and an electrophilic mucosal gradient. Secondly, the electrophilic system needs to have sufficient capacity to generate reactive oxygen species, enabling effective elimination of invading microorganisms and rapid restoration of the barrier integrity following breaches. These elements depend on physiological redox signaling mediated by electrophilic pathways such as NOX2 and the H2O2 pathway. Additionally, the nucleophilic arm of redox homeostasis should exhibit sufficient reactivity to restore the redox balance after an electrophilic surge. Factors contributing to the nucleophilic arm include the availability of reductive substrates and redox signaling mediated by the cytoprotective Keap1-Nrf2 pathway. Future research should focus on identifying preventive and therapeutic strategies that enhance the strength and responsiveness of GI redox homeostasis. These strategies aim to reduce the vulnerability of the gut to harmful stimuli and address the decline in reactivity often observed during the aging process. By strengthening GI redox homeostasis, we can potentially mitigate the risks associated with age-related gut dyshomeostasis and optimize overall health and longevity. [ABSTRACT FROM AUTHOR]

Introduction: Spinal muscular atrophy (SMA) is a fatal neurodegenerative disorder, characterized by motor neuron (MN) degeneration and severe muscular atrophy and caused by Survival of Motor Neuron (SMN) depletion. Therapies aimed at increasing SMN in patients have proven their efficiency in alleviating SMA symptoms but not for all patients. Thus, combinational therapies are warranted. Here, we investigated the involvement of NADPH oxidase 4 (NOX4) in SMA-induced spinal MN death and if the modulation of Nox4 activity could be beneficial for SMA patients. Methods: We analysed in the spinal cord of severe type SMA-like mice before and at the disease onset, the level of oxidative stress and Nox4 expression. Then, we tested the effect of Nox4 inhibition by GKT137831/Setanaxib, a drug presently in clinical development, by intrathecal injection on MN survival and motor behaviour. Finally, we tested if GKT137831/Setanaxib could act synergistically with FDA-validated SMN-upregulating treatment (nusinersen). Results: We show that NOX4 is overexpressed in SMA and its inhibition by GKT137831/Setanaxib protected spinal MN from SMA-induced degeneration. These improvements were associated with a significant increase in lifespan and motor behaviour of the mice. At the molecular level, GKT137831 activated the prosurvival AKT/CREB signaling pathway, leading to an increase in SMN expression in SMA MNs. Most importantly, we found that the per os administration of GKT137831 acted synergistically with a FDA-validated SMN-upregulating treatment. Conclusion: The pharmacological inhibition of NOX4 by GKT137831/Setanaxib is neuroprotector and could represent a complementary therapeutic strategy to fight against SMA. [ABSTRACT FROM AUTHOR]

Antioxidants have been proposed as a treatment for diseases of the central nervous system. However, few studies actually studied their effects in the brain. To test central actions of antioxidants, we used the lithium-pilocarpine (Li-Pilo) model of status epilepticus (SE) in the rat in which seizures are accompanied by significant oxidative stress. We used in vivo microdialysis to determine isoprostane levels during SE in real time and brain homogenates for other measures of oxidative stress. Six different antioxidants were tested in acute and preventive experiments (vitamin C, vitamin E, ebselen, resveratrol, n-tert-butyl-α-phenylnitrone and coenzyme Q10). None of the antioxidants had an effect when given acutely during SE. In contrast, when antioxidants were given for 3 days prior to seizure induction, vitamins C and E reduced isoprostane formation by 58% and 65%, respectively. Pretreatment with the other antioxidants was ineffective. In brain homogenates prepared after 90 min of seizures, SE decreased the ratio of reduced vs. oxidized glutathione (GSH/ GSSG ratio) from 60.8 to 7.50 and caused a twofold increase of 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels and protein carbonyls. Pretreatment with vitamin C or vitamin E mitigated these effects and increased the GSH/GSSG ratio to 23.9 and 28.3, respectively. Again, the other antioxidants were not effective. We conclude that preventive treatment with vitamin C or vitamin E ameliorates seizure-induced oxidative damage in the brain. Several well-studied antioxidants were inactive, possibly due to limited brain permeability or a lack of chain-breaking antioxidant activity in hydrophilic compounds. [ABSTRACT FROM AUTHOR]

Oxidative stress-mediated damage is often a downstream result of Parkinson's disease (PD), which is marked by sharp decline in dopaminergic neurons within the nigrostriatal regions of the brain, accounting for the symptomatic motor deficits in patients. Regulating the level of oxidative stress may present a beneficial approach in preventing PD pathology. Here, we assessed the efficacy of a nicotinamide adenine phosphate (NADPH) oxidase (NOX) inhibitor, an exogenous reactive oxygen species (ROS) regulator synthesized by Aptabio therapeutics with the specificity to NOX-1, 2 and 4. Utilizing N27 rat dopaminergic cells and C57Bl/6 mice, we confirmed that the exposures of alpha-synuclein preformed fibrils (PFF) induced protein aggregation, a hallmark in PD pathology. In vitro assessment of the novel compound revealed an increase in cell viability and decreases in cytotoxicity, ROS, and protein aggregation (Thioflavin-T stain) against PFF exposure at the optimal concentration of 10 nM. Concomitantly, the oral treatment alleviated motor-deficits in behavioral tests, such as hindlimb clasping, rotarod, pole, nesting and grooming test, via reducing protein aggregation, based on rescued dopaminergic neuronal loss. The suppression of NOX-1, 2 and 4 within the striatum and ventral midbrain regions including Substantia Nigra compacta (SNc) contributed to neuroprotective/recovery effects, making it a potential therapeutic option for PD. [ABSTRACT FROM AUTHOR]

Oxidative stress has been implicated in the pathogenesis of diverse disease states. The present study was designed to examine the effects of magnesium sulphate (MgSO4) against hydrogen peroxide (H2O2) induced behaviour impairment and oxidative damage in rats. Eighteen rats were equally divided into three groups. The first group was kept as a control. In the second group, H2O2 was given in drinking water at 3% during 5 days. In the third group, rats were subjected to daily administration of H2O2 and MgSO4 (100 mg/kg; b.w) for 5 days. Animals were subjected to behavioural tests (elevated plus maze and open field). At the end of experiment, brains were extracted for oxidative stress biomarkers assessment including levels of malondialdéhyde and hydrogen peroxide and activities of superoxide dismutase and catalase. Our findings showed that H2O2 treated rat exhibited anxiogenic behaviour and the genesis of free radicals in the brain. Magnesium showed amelioration against oxidative stress and significant decrease in anxiety levels. Stress is a powerful process that disrupts brain homeostasis by inducing oxidative stress and its appear that magnesium may have potential therapeutic benefits by reducing oxidative stress and inducing anxiolytic effect. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an immune-mediated, chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS). Immune cell infiltration can lead to permanent activation of macrophages and microglia in the parenchyma, resulting in demyelination and neurodegeneration. Thus, neurodegeneration that begins with acute lymphocytic inflammation may progress to chronic inflammation. This chronic inflammation is thought to underlie the development of so-called smouldering lesions. These lesions evolve from acute inflammatory lesions and are associated with continuous low-grade demyelination and neurodegeneration over many years. Their presence is associated with poor disease prognosis and promotes the transition to progressive MS, which may later manifest clinically as progressive MS when neurodegeneration exceeds the upper limit of functional compensation. In smouldering lesions, in the presence of only moderate inflammatory activity, a toxic environment is clearly identifiable and contributes to the progressive degeneration of neurons, axons, and oligodendrocytes and, thus, to clinical disease progression. In addition to the cells of the immune system, the development of oxidative stress in MS lesions, mitochondrial damage, and hypoxia caused by the resulting energy deficit and iron accumulation are thought to play a role in this process. In addition to classical immune mediators, this chronic toxic environment contains high concentrations of oxidants and iron ions, as well as the excitatory neurotransmitter glutamate. In this review, we will discuss how these pathobiochemical markers and mechanisms, alone or in combination, lead to neuronal, axonal, and glial cell death and ultimately to the process of neuroinflammation and neurodegeneration, and then discuss the concepts and conclusions that emerge from these findings. Understanding the role of these pathobiochemical markers would be important to gain a better insight into the relationship between the clinical classification and the pathomechanism of MS. [ABSTRACT FROM AUTHOR]

NADPH:thioredoxin reductase (TrxR) is considered a potential target for anticancer agents. Several nitroheterocyclic sulfones, such as Stattic and Tri-1, irreversibly inhibit TrxR, which presumably accounts for their antitumor activity. However, it is necessary to distinguish the roles of enzymatic redox cycling, an inherent property of nitroaromatics (ArNO2), and the inhibition of TrxR in their cytotoxicity. In this study, we calculated the previously unavailable values of single-electron reduction potentials of known inhibitors of TrxR (Stattic, Tri-1, and 1-chloro-2,4-dinitrobenzene (CDNB)) and inhibitors identified (nitrofuran NSC697923 and nitrobenzene BTB06584). These calculations were according to the rates of their enzymatic single-electron reduction (PMID: 34098820). This enabled us to compare their cytotoxicity with that of model redox cycling ArNO2. In MH22a and HCT-116 cells, Tri-1, Stattic, CDNB, and NSC697023 possessed at least 10-fold greater cytotoxicity than can be expected from their redox cycling activity. This may be related to TrxR inhibition. The absence of enhanced cytotoxicity in BTB06548 may be attributed to its instability. Another known inhibitor of TrxR, tetryl, also did not possess enhanced cytotoxicity, probably because of its detoxification by DT-diaphorase (NQO1). Apart from the reactions with NQO1, the additional mechanisms influencing the cytotoxicity of the examined inhibitors of TrxR are their reactions with cytochromes P-450. Furthermore, some inhibitors, such as Stattic and NSC697923, may also inhibit glutathione reductase. We suggest that these data may be instrumental in the search for TrxR inhibitors with enhanced cytotoxic/anticancer activity. [ABSTRACT FROM AUTHOR]

Although the trigger for the neurodegenerative disease process is unknown, the relevance of aging stands out as a major risk for the development of neurodegeneration. In this review, we highlighted the relationship between the different cellular mechanisms that occur as a consequence of aging and transcription factor nuclear factor erythroid-2-related factor 2 (NRF2) and the connection with the TAU protein. We focused on the relevance of NRF2 in the main processes involved in neurodegeneration and associated with aging, such as genomic instability, protein degradation systems (proteasomes/autophagy), cellular senescence, and stem cell exhaustion, as well as inflammation. We also analyzed the effect of aging on TAU protein levels and its aggregation and spread process. Finally, we investigated the interconnection between NRF2 and TAU and the relevance of alterations in the NRF2 signaling pathway in both primary and secondary tauopathies. All these points highlight NRF2 as a possible therapeutic target for tauopathies. [ABSTRACT FROM AUTHOR]

Leydig cells are essential for steroidogenesis and spermatogenesis. An imbalance in the production of reactive oxygen species (ROS) and the cellular antioxidant level brings about oxidative stress. Oxidative stress (OS) results in the dysfunction of Leydig cells, thereby impairing steroidogenesis, spermatogenesis, and ultimately, male infertility. To prevent Leydig cells from oxidative insults, there needs to be a balance between the ROS production and the cellular protective capacity of antioxidants. Evidence indicates that medicinal plants could improve Leydig cell function at specific concentrations under basal or OS conditions. The increased usage of medicinal plants has been considered a possible alternative treatment for male infertility. This review aims to provide an overview of the impact of oxidative stress on Leydig cells as well as the effects of various medicinal plant extracts on TM3 Leydig cells. The medicinal plants of interest include Aspalathus linearis, Camellia sinensis, Moringa oleifera, Morinda officinale, Taraxacum officinale, Trichilia emetica, Terminalia sambesiaca, Peltophorum africanum, Ximenia caffra, Serenoa repens, Zingiber officinale, Eugenia jambolana, and a combination of dandelion and fermented rooibos (CRS-10). According to the findings obtained from studies conducted on the evaluated medicinal plants, it can, therefore, be concluded that the medicinal plants maintain the antioxidant profile of Leydig cells under basal conditions and have protective or restorative effects following exposure to oxidative stress. The available data suggest that the protective role exhibited by the evaluated plants may be attributed to their antioxidant content. Additionally, the use of the optimal dosage or concentration of the extracts in the management of oxidative stress is of the utmost importance, and the measurement of their oxidation reduction potential is recommended. [ABSTRACT FROM AUTHOR]

Oxidative stress and inflammation play an important role in the pathophysiological changes of liver diseases. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that positively regulates the basal and inducible expression of a large battery of cytoprotective genes, thus playing a key role in protecting against oxidative damage. Cyclooxygenase-2 (COX-2) is a key enzyme in prostaglandin biosynthesis. Its expression has always been associated with the induction of inflammation, but we have shown that, in addition to possessing other benefits, the constitutive expression of COX-2 in hepatocytes is beneficial in reducing inflammation and oxidative stress in multiple liver diseases. In this review, we summarized the role of NRF2 as a main agent in the resolution of oxidative stress, the crucial role of NRF2 signaling pathways during the development of chronic liver diseases, and, finally we related its action to that of COX-2, where it appears to operate as its partner in providing a hepatoprotective effect. [ABSTRACT FROM AUTHOR]