Search

Background: Quercetin (QCT) and citrulline (CIT) have been independently associated with improved antioxidant capacity and nitric oxide (NO) production, potentially enhancing cardiovascular function and exercise performance. This study aimed to evaluate the combined and independent effects of QCT and CIT supplementation on NO metabolites and antioxidant biomarkers in 50 trained cyclists undergoing a 20 km cycling time trial (TT). Methods: In a randomized, double-blind, placebo-controlled design, forty-two male and eight female trained cyclists were assigned to QCT + CIT, QCT, CIT, or placebo (PL) groups. Supplements were consumed twice daily for 28 days. Biochemical assessments included NO metabolites (nitrate/nitrite), ferric reducing antioxidant power (FRAP), superoxide dismutase (SOD) activity, and antioxidant capacity, measured pre- and post-TT. Results: NO metabolites were significantly elevated post-supplementation (p = 0.03); however, no significant interaction effects were observed for NO metabolites, FRAP, SOD, or antioxidant capacity across the groups (p > 0.05). Post-hoc analyses revealed that QCT significantly reduced FRAP concentrations compared to PL (p = 0.01), while no significant changes in SOD or antioxidant capacity were found across any groups. Conclusions: These findings suggest that combined and independent QCT and CIT supplementation did not significantly improve these biomarkers, suggesting that baseline training adaptations, supplementation timing, and individual variability may influence the efficacy of these compounds in enhancing exercise performance and oxidative stress markers. The ergogenic efficacy of QCT + CIT on antioxidant-related markers remains inconclusive. [ABSTRACT FROM AUTHOR]

Oxidative stress plays a pivotal role in the pathogenesis and progression of cardiovascular diseases (CVDs). This review focuses on the signaling pathways of oxidative stress during the development of CVDs, delving into the molecular regulatory networks underlying oxidative stress in various disease stages, particularly apoptosis, inflammation, fibrosis, and metabolic imbalance. By examining the dual roles of oxidative stress and the influences of sex differences on oxidative stress levels and cardiovascular disease susceptibility, this study offers a comprehensive understanding of the pathogenesis of cardiovascular diseases. The study integrates key findings from current research in three comprehensive ways. First, it outlines the major CVDs associated with oxidative stress and their respective signaling pathways, emphasizing oxidative stress's central role in cardiovascular pathology. Second, it summarizes the cardiovascular protective effects, mechanisms of action, and animal models of various antioxidants, offering insights into future drug development. Third, it discusses the applications, advantages, limitations, and potential molecular targets of gene therapy in CVDs, providing a foundation for novel therapeutic strategies. These tables underscore the systematic and integrative nature of this study while offering a theoretical basis for precision treatment for CVDs. A major contribution of this study is the systematic review of the differential effects of oxidative stress across different stages of CVDs, in addition to the proposal of innovative, multi-level intervention strategies, which open new avenues for precision treatment of the cardiovascular system. [ABSTRACT FROM AUTHOR]

Reduction–oxidation factor-1 or apurinic/apyrimidinic endonuclease 1 (Ref-1/APE1) is a crucial redox-sensitive activator of transcription factors such as NF-κB, HIF-1α, STAT-3 and others. It could contribute to key features of ocular neovascularization including inflammation and angiogenesis; these underlie diseases like neovascular age-related macular degeneration (nAMD). We previously revealed a role for Ref-1 in the growth of ocular endothelial cells and in choroidal neovascularization (CNV). Here, we set out to further explore Ref-1 in neovascular eye disease. Ref-1 was highly expressed in human nAMD, murine laser-induced CNV and Vldlr−/− mouse subretinal neovascularization (SRN). Ref-1’s interaction with a redox-specific small molecule inhibitor, APX2009, was shown by NMR and docking. This compound blocks crucial angiogenic features in multiple endothelial cell types. APX2009 also ameliorated murine laser-induced choroidal neovascularization (L-CNV) when delivered intravitreally. Moreover, systemic APX2009 reduced murine SRN and downregulated the expression of Ref-1 redox regulated HIF-1α target carbonic anhydrase 9 (CA9) in the Vldlr−/− mouse model. Our data validate the redox function of Ref-1 as a critical regulator of ocular angiogenesis, indicating that inhibition of Ref-1 holds therapeutic potential for treating nAMD. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammatory processes leading to significant disability. While the role of reactive oxygen species (ROS) in mitochondrial damage and macrophage dysfunction is well-established, the contribution of nitrosative stress remains largely unexplored. This study investigated the impact of nitrosative stress-induced membrane damage, loss of mitochondrial membrane potential (MMP), and the imbalance between M1/M2 macrophages in RA progression. Current strategies to repolarize M2 cells face challenges due to the persistence of ROS activity in the synovial joint. To address this, we developed a cutting-edge nano-therapy: Berberine-loaded folate-glycol chitosan nanoparticles (BFGCN), synthesized via nano-precipitation with a zero-order cross-linking technique. These spherical nanoparticles (~ 150 nm) were engineered to specifically target folate receptor-β (FR-β) on activated macrophages, confirmed through molecular docking studies. BFGCN demonstrated remarkable efficacy in reducing oxidative/nitrosative stress, restoring MMP, and promoting the repolarization of anti-inflammatory M2 macrophages. Our findings underscore the critical role of redox imbalances in RA pathogenesis, offering a promising therapeutic strategy for modulating macrophage reprogramming and mitigating disease progression. [ABSTRACT FROM AUTHOR]

The discovery that contracting skeletal muscle generates reactive oxygen species (ROS) was first reported over 40 years ago. The prevailing view in the 1980s was that exercise-induced ROS production promotes oxidation of proteins and lipids resulting in muscle damage. However, a paradigm shift occurred in the 1990s as growing research revealed that ROS are signaling molecules, capable of activating transcriptional activators/coactivators and promoting exercise-induced muscle adaptation. Growing evidence supports the notion that reduction-oxidation (redox) signaling pathways play an important role in the muscle remodeling that occurs in response to endurance exercise training. This review examines the specific role that redox signaling plays in this endurance exercise-induced skeletal muscle adaptation. We begin with a discussion of the primary sites of ROS production in contracting muscle fibers followed by a summary of the antioxidant enzymes involved in the regulation of ROS levels in the cell. We then discuss which redox-sensitive signaling pathways promote endurance exercise-induced muscle adaptation and debate the strength of the evidence supporting the notion that redox signaling plays an essential role in muscle adaptation to endurance exercise training. In hopes of stimulating future research, we highlight several important unanswered questions in this field.

The extracellular isoform of superoxide dismutase (SOD3) is decreased in patients and animals with pulmonary hypertension (PH). The human R213G single-nucleotide polymorphism (SNP) in SOD3 causes its release from tissue extracellular matrix (ECM) into extracellular fluids, without modulating enzyme activity, increasing cardiovascular disease risk in humans and exacerbating chronic hypoxic PH in mice. Given the importance of interstitial macrophages (IMs) to PH pathogenesis, this study aimed to determine whether R213G SOD3 increases IM accumulation and alters IM reprogramming in response to hypoxia. R213G mice and wild-type (WT) controls were exposed to hypobaric hypoxia for 4 or 14 days compared with normoxia. Flow cytometry demonstrated a transient increase in IMs at day 4 in both strains. Contrary to our hypothesis, the R213G SNP did not augment IM accumulation. To determine strain differences in the IM reprogramming response to hypoxia, we performed RNAsequencing on IMs isolated at each timepoint. We found that IMs from R213G mice exposed to hypoxia activated ECM-related pathways and a combination of alternative macrophage and proinflammatory signaling. Furthermore, when compared with WT responses, IMs from R213G mice lacked metabolic remodeling and demonstrated a blunted anti-inflammatory response between the early (day 4) and later (day 14) timepoints. We confirmed metabolic responses using Agilent Seahorse assays, whereby WT, but not R213G, IMs upregulated glycolysis at day 4 that returned to baseline at day 14. Finally, we identify differential regulation of several redox-sensitive upstream regulators that could be investigated in future studies. NEW & NOTEWORTHY: Redistributed expression of SOD3 out of tissue ECM due to the human R213G SNP exacerbates chronic hypoxic PH. Highlighting the importance of macrophage phenotype, our findings reveal that the R213G SNP does not exacerbate pulmonary macrophage accumulation in response to hypoxia but influences their metabolic and phenotypic reprogramming. We demonstrate a deficiency in the metabolic response to hypoxic stress in R213G macrophages, associated with weakened inflammatory resolution and activation of profibrotic pathways implicated in PH. [ABSTRACT FROM AUTHOR]

Redox reactions, involving electron transfer, are critical to human physiology. However, progress in understanding redox metabolism is hindered by flawed analytical methods. This review highlights emerging techniques that promise to revolutionize redox research, enhancing our comprehension of human health and disease. Oxygen, vital for aerobic metabolism, also produces reactive oxygen species (ROS), such as superoxide and hydrogen peroxide. While historically seen as harmful, ROS at low concentrations are now recognized as key regulators of cell signaling. A balance between ROS and antioxidants, known as redox balance, is crucial, and deviations can lead to oxidative stress. Recent studies have distinguished beneficial "oxidative eustress" from harmful "oxidative distress." New techniques, such as advanced mass spectrometry and high‐throughput immunoassays, offer improved accuracy in measuring redox states and oxidative damage. These advancements are pivotal for understanding redox signaling, cysteine oxidation, and their implications for disease. Looking ahead, the development of precision redox medicine could lead to better treatments for oxidative stress‐related diseases and foster interventions promoting health. [ABSTRACT FROM AUTHOR]

Skeletal tissue development and regeneration in mammals are intricate, multistep, and highly regulated processes. Various signaling pathways have been implicated in the regulation of these processes, including redox. Redox signaling is the signal transduction by electron transfer reactions involving free radicals or related species. Redox homeostasis is essential to cell metabolic states, as the ROS not only regulates cell biological processes but also mediates physiological processes. Following a bone fracture, redox signaling is also triggered to regulate bone healing and regeneration by targeting resident stromal cells, osteoblasts, osteoclasts and endothelial cells. This review will focus on how the redox signaling impact the bone development and bone regeneration. [ABSTRACT FROM AUTHOR]

• Contracting skeletal muscles generate reactive oxygen species (ROS) from several locations with the cell. • Although numerous ROS exist, hydrogen peroxide is recognized as a key ROS player in redox control of biological signaling. • Contraction-induced ROS production triggers signaling pathways regulating mitochondrial biogenesis and the expression of numerous genes expressing mitochondrial proteins and antioxidant enzymes. • Growing data indicate that exercise-induced ROS production is essential to achieve the full benefit of exercise-induced adaptation in skeletal muscles. The discovery that contracting skeletal muscle generates reactive oxygen species (ROS) was first reported over 40 years ago. The prevailing view in the 1980s was that exercise-induced ROS production promotes oxidation of proteins and lipids resulting in muscle damage. However, a paradigm shift occurred in the 1990s as growing research revealed that ROS are signaling molecules, capable of activating transcriptional activators/coactivators and promoting exercise-induced muscle adaptation. Growing evidence supports the notion that reduction-oxidation (redox) signaling pathways play an important role in the muscle remodeling that occurs in response to endurance exercise training. This review examines the specific role that redox signaling plays in this endurance exercise-induced skeletal muscle adaptation. We begin with a discussion of the primary sites of ROS production in contracting muscle fibers followed by a summary of the antioxidant enzymes involved in the regulation of ROS levels in the cell. We then discuss which redox-sensitive signaling pathways promote endurance exercise-induced muscle adaptation and debate the strength of the evidence supporting the notion that redox signaling plays an essential role in muscle adaptation to endurance exercise training. In hopes of stimulating future research, we highlight several important unanswered questions in this field. [Display omitted] [ABSTRACT FROM AUTHOR]

Flashes of superoxide anion (O2−) in mitochondria are generated spontaneously or during the opening of the permeability transition pore (mPTP) and a sudden change in the metabolic state of a cell. Under certain conditions, O2− can leave the mitochondrial matrix and perform signaling functions beyond mitochondria. In this work, we studied the kinetics of the release of O2− and H2O2 from isolated mitochondria upon mPTP opening and the modulation of the metabolic state of mitochondria by the substrates of respiration and oxidative phosphorylation. It was found that mPTP opening leads to suppression of H2O2 emission and activation of the O2− burst. When the induction of mPTP was blocked by its antagonists (cyclosporine A, ruthenium red, EGTA), the level of substrates of respiration and oxidative phosphorylation and the selective inhibitors of complexes I and V determined the type of reactive oxygen species (ROS) emitted by mitochondria. It was concluded that upon complete and partial reduction and complete oxidation of redox centers of the respiratory chain, mitochondria emit H2O2, O2−, and nothing, respectively. The results indicate that the mPTP- and substrate-dependent switching of the type of ROS leaving mitochondria may be the basis for O2−- and H2O2-selective redox signaling in a cell. [ABSTRACT FROM AUTHOR]

Diabetic bladder dysfunction (DBD) is the most prevalent complication of diabetes mellitus (DM), affecting >50% of all patients. Currently, no specific treatment is available for this condition. In the early stages of DBD, patients typically complain of frequent urination and often have difficulty sensing when their bladders are full. Over time, bladder function deteriorates to a decompensated state in which incontinence develops. Based on studies of diabetic changes in the eye, kidney, heart, and nerves, it is now recognized that DM causes tissue damage by altering redox signaling in target organs. NADPH oxidase (NOX), whose sole function is the production of reactive oxygen species (ROS), plays a pivotal role in other well-known and bothersome diabetic complications. However, there is a substantial gap in understanding how NOX controls bladder function in health and the impact of NOX on DBD. The current review provides a thorough overview of the various NOX isoforms and their roles in bladder function and discusses the importance of further investigating the role of NOXs as a key contributor to DBD pathogenesis, either as a trigger and/or an effector and potentially as a target. [ABSTRACT FROM AUTHOR]

Oxygen molecules accept electrons from the respiratory chain in the mitochondria and are responsible for energy production in aerobic organisms. The reactive oxygen species formed via these oxygen reduction processes undergo complicated electron transfer reactions with other biological substances, which leads to alterations in their physiological functions and cause diverse biological and pathophysiological consequences (e.g., oxidative stress). Oxygen accounts for only a small proportion of the redox reactions in organisms, especially under aerobic or hypoxic conditions but not under anaerobic and hypoxic conditions. This article discusses a completely new concept of redox biology, which is governed by redox-active supersulfides, i.e., sulfur-catenated molecular species. These species are present in abundance in all organisms but remain largely unexplored in terms of redox biology and life science research. In fact, accumulating evidence shows that supersulfides have extensive redox chemical properties and that they can be readily ionized or radicalized to participate in energy metabolism, redox signaling, and oxidative stress responses in cells and in vivo. Thus, pharmacological intervention and medicinal modulation of supersulfide activities have been shown to benefit the regulation of disease pathogenesis as well as disease control. [Display omitted] • Supersulfides are key players in cell signaling. • Reactive hydropersulfides scavenge cellular electrophiles, such as 8-nitro-cGMP. • Inflammatory responses are regulated by supersulfides. • Radical scavenging properties of hydropersulfides enable their prevention of lipid peroxidation and ferroptosis. • Supersulfides regulate and contribute to mitochondrial respiration. [ABSTRACT FROM AUTHOR]

Nuclear factor erythroid‐2‐related factor 2 (Nrf2) is essential for the control of cellular redox homeostasis. When activated, Nrf2 elicits cytoprotective effects through the expression of several genes encoding antioxidant and detoxifying enzymes. Nrf2 can also improve antioxidant defense via the pentose phosphate pathway by increasing NADPH availability to regenerate glutathione. Microarray and genome‐wide localization analyses have identified many Nrf2 target genes beyond those linked to its redox‐regulatory capacity. Nrf2 regulates several intermediary metabolic pathways and is involved in cancer cell metabolic reprogramming, contributing to malignant phenotypes. Nrf2 also modulates substrate utilization for mitochondrial respiration. Here we review the experimental evidence supporting the essential role of Nrf2 in the regulation of energy metabolism and mitochondrial function. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) are well‐established signaling molecules implicated in a wide range of cellular processes, including both oxidative stress and intracellular redox signaling. In the context of insulin action within its target tissues, ROS have been reported to exert both positive and negative regulatory effects. However, the precise molecular mechanisms underlying this duality remain unclear. This Review examines the complex role of ROS in insulin action, with a particular focus on skeletal muscle. We aim to address three critical aspects: (a) the proposed intracellular pro‐oxidative redox shift elicited by insulin, (b) the evidence supporting that redox‐sensitive cysteine modifications impact insulin signaling and action, and (c) cellular mechanisms underlying how ROS can paradoxically act as both enhancers and inhibitors of insulin action. This Review underscores the urgent need for more systematic research to identify specific reactive species, redox targets, and the physiological significance of redox signaling in maintaining insulin action and metabolic health, with a particular emphasis on human skeletal muscle. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is widely recognized for its role in regulating renal function and blood pressure. However, the precise mechanisms by which NO affects renal epithelial cells remain understudied. Our previous research has shown that NO signaling in glomerular podocytes can be initiated by Angiotensin II (ANG II) but not by ATP. This study aims to elucidate the crucial interplay between the renin-angiotensin system (RAS) and NO production in podocytes. To conduct our research, we used cultured human podocytes and freshly isolated rat glomeruli. A variety of RAS peptides were used, alongside confocal microscopy, to detect NO production and NO/Ca2+ cross talk. Dynamic changes in the podocyte cytoskeleton, mediated by RAS-NO intracellular signaling, were observed using fluorescent labeling for F-actin and scanning probe microscopy. The experiments demonstrated that ANG II and ANG III generated high levels of NO by activating the angiotensin II type 2 receptor (AT2R). We did not detect functional MAS receptor presence in podocytes, and the moderate NO response to ANG 1–7 was also mediated through AT2R. Furthermore, NO production impacted intracellular Ca2+ signaling and correlated with an increase in podocyte volume and growth. Scanning probe experiments revealed that AT2R activation and the corresponding NO generation are responsible for the protrusion of podocyte lamellipodia. Taken together, our data indicate that AT2R activation enhances NO production in podocytes and subsequently mediates changes in Ca2+ signaling and podocyte volume dynamics. These mechanisms may play a significant role in both physiological and pathophysiological interactions between the RAS and podocytes. NEW & NOTEWORTHY: The renin-angiotensin system plays a crucial role in the production of intracellular nitric oxide within podocytes. This mechanism operates through the activation of the angiotensin II type 2 receptor, leading to dynamic modifications in intracellular calcium levels and the actin filament network. This intricate process is vital for linking the activity of angiotensin receptors to podocyte function. [ABSTRACT FROM AUTHOR]

ABSTRACT Rhizobia associate with legumes and induce the formation of nitrogen-fixing nodules. The regulation of bacterial redox state plays a major role in symbiosis, and reactive oxygen species produced by the plant are known to activate signaling pathways. However, only a few redox-sensing transcriptional regulators (TRs) have been characterized in the microsymbiont. Here, we describe SydR, a novel redox-sensing TR of Sinorhizobium meliloti that is essential for the establishment of symbiosis with Medicago truncatula. SydR, a MarR-type TR, represses the expression of the adjacent gene SMa2023 in growing cultures, and this repression is alleviated by NaOCl, tert-butyl hydroperoxide, or H2O2 treatment. Transcriptional psydR-gfp and pSMa2023-gfp fusions, as well as gel shift assays, showed that SydR binds two independent sites of the sydR-SMa2023 intergenic region. This binding is redox-dependent, and site-directed mutagenesis demonstrated that the conserved C16 is essential for SydR redox sensing. The inactivation of sydR did not alter the sensitivity of S. meliloti to NaOCl, tert-butyl hydroperoxide, or H2O2, nor did it affect the response to oxidants of the roGFP2-Orp1 redox biosensor expressed within bacteria. However, in planta, ΔsydR mutation impaired the formation of root nodules. Microscopic observations and analyses of plant marker gene expression showed that the ΔsydR mutant is defective at an early stage of the bacterial infection process. Altogether, these results demonstrated that SydR is a redox-sensing MarR-type TR that plays a key role in the regulation of nitrogen-fixing symbiosis with M. truncatula.IMPORTANCEThe nitrogen-fixing symbiosis between rhizobia and legumes has an important ecological role in the nitrogen cycle, contributes to nitrogen enrichment of soils, and can improve plant growth in agriculture. This interaction is initiated in the rhizosphere by a molecular dialog between the two partners, resulting in plant root infection and the formation of root nodules, where bacteria reduce the atmospheric nitrogen into ammonium. This symbiosis involves modifications of the bacterial redox state in response to reactive oxygen species produced by the plant partner. Here, we show that SydR, a transcriptional regulator of the Medicago symbiont Sinorhizobium meliloti, acts as a redox-responsive repressor that is crucial for the development of root nodules and contributes to the regulation of bacterial infection in S. meliloti/Medicago truncatula symbiotic interaction.

Oxidative balance plays a pivotal role in physiological homeostasis, and many diseases, particularly age-related conditions, are closely associated with oxidative imbalance. While the strategic role of oxidative regulation in various diseases is well-established, the specific involvement of oxidative stress in atherosclerosis remains elusive. Atherosclerosis is a chronic inflammatory disorder characterized by plaque formation within the arteries. Alterations in the oxidative status of vascular tissues are linked to the onset, progression, and outcome of atherosclerosis. This review examines the role of redox signaling in atherosclerosis, including its impact on risk factors such as dyslipidemia, hyperglycemia, inflammation, and unhealthy lifestyle, along with dysregulation, vascular homeostasis, immune system interaction, and therapeutic considerations. Understanding redox signal transduction and the regulation of redox signaling will offer valuable insights into the pathogenesis of atherosclerosis and guide the development of novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Plants fully depend on their immune systems to defend against pathogens. Upon pathogen attack, plants not only activate immune responses at the infection site but also trigger a defense mechanism known as systemic acquired resistance (SAR) in distal systemic tissues to prevent subsequent infections by a broad-spectrum of pathogens. SAR is induced by mobile signals produced at the infection site. Accumulating evidence suggests that reactive oxygen species (ROS) play a central role in SAR signaling. ROS burst at the infection site is one of the earliest cellular responses following pathogen infection and can spread to systemic tissues through membrane-associated NADPH oxidase-dependent relay production of ROS. It is well known that ROS ignite redox signaling and, when in excess, cause oxidative stress, damaging cellular components. In this review, we summarize current knowledge on redox regulation of several SAR signaling components. We discuss the ROS amplification loop in systemic tissues involving multiple SAR mobile signals. Moreover, we highlight the essential role of oxidative stress in generating SAR signals including azelaic acid and extracellular NAD(P) [eNAD(P)]. Finally, we propose that eNAD(P) is a damage-associated molecular pattern serving as a converging point of SAR mobile signals in systemic tissues. [ABSTRACT FROM AUTHOR]

Significance: Peroxisome proliferator-activated receptors (PPARs) have a moderately preserved amino-terminal domain, an extremely preserved DNA-binding domain, an integral hinge region, and a distinct ligand-binding domain that are frequently encountered with the other nuclear receptors. PPAR-β/δ is among the three nuclear receptor superfamily members in the PPAR group. Recent Advances: Emerging studies provide an insight on natural compounds that have gained increasing attention as potential anticancer agents due to their ability to target multiple pathways involved in cancer development and progression. Critical Issues: Modulation of PPAR-β/δ activity has been suggested as a potential therapeutic strategy for cancer management. This review focuses on the ability of bioactive phytocompounds to impact reactive oxygen species (ROS) and redox signaling by targeting PPAR-β/δ for cancer therapy. The rise of ROS in cancer cells may play an important part in the initiation and progression of cancer. However, excessive levels of ROS stress can also be toxic to the cells and cancer cells with increased oxidative stress are likely to be more vulnerable to damage by further ROS insults induced by exogenous agents, such as phytocompounds and therapeutic agents. Therefore, redox modulation is a way to selectively kill cancer cells without causing significant toxicity to normal cells. However, use of antioxidants together with cancer drugs may risk the effect of treatment as both act through opposite mechanisms. Future Directions: It is advisable to employ more thorough and detailed methodologies to undertake mechanistic explorations of numerous phytocompounds. Moreover, conducting additional clinical studies is recommended to establish optimal dosages, efficacy, and the impact of different phytochemicals on PPAR-β/δ. [ABSTRACT FROM AUTHOR]

Peroxiporins are a specialized subset of aquaporins, which are integral membrane proteins primarily known for facilitating water transport across cell membranes. In addition to the classical water transport function, peroxiporins have the unique capability to transport hydrogen peroxide (H2O2), a reactive oxygen species involved in various cellular signaling pathways and regulation of oxidative stress responses. The regulation of H2O2 levels is crucial for maintaining cellular homeostasis, and peroxiporins play a significant role in this process by modulating its intracellular and extracellular concentrations. This ability to facilitate the passage of H2O2 positions peroxiporins as key players in redox biology and cellular signaling, with implications for understanding and treating various diseases linked to oxidative stress and inflammation. This review provides updated information on the physiological roles of peroxiporins and their implications in disease, emphasizing their potential as novel biomarkers and drug targets in conditions where they are dysregulated, such as inflammation and cancer. [ABSTRACT FROM AUTHOR]

Mitochondria (mt) represent the vital hub of the molecular physiology of the cell, being decision-makers in cell life/death and information signaling, including major redox regulations and redox signaling. Now we review recent advances in understanding mitochondrial redox homeostasis, including superoxide sources and H2O2 consumers, i.e., antioxidant mechanisms, as well as exemplar situations of physiological redox signaling, including the intramitochondrial one and mt-to-cytosol redox signals, which may be classified as acute and long-term signals. This review exemplifies the acute redox signals in hypoxic cell adaptation and upon insulin secretion in pancreatic β-cells. We also show how metabolic changes under these circumstances are linked to mitochondrial cristae narrowing at higher intensity of ATP synthesis. Also, we will discuss major redox buffers, namely the peroxiredoxin system, which may also promote redox signaling. We will point out that pathological thresholds exist, specific for each cell type, above which the superoxide sources exceed regular antioxidant capacity and the concomitant harmful processes of oxidative stress subsequently initiate etiology of numerous diseases. The redox signaling may be impaired when sunk in such excessive pro-oxidative state. [ABSTRACT FROM AUTHOR]

Antioxidants play a pivotal role in neutralizing reactive oxygen species (ROS), which are known to induce oxidative stress. In the context of cancer development, cancer cells adeptly maintain elevated levels of both ROS and antioxidants through a process termed "redox reprogramming". This balance optimizes the proliferative influence of ROS while simultaneously reducing the potential for ROS to cause damage to the cell. In some cases, the adapted antioxidant machinery can hamper the efficacy of treatments for neoplastic diseases, representing a significant facet of the resistance mechanisms observed in cancer therapy. In this review, we outline the contribution of antioxidant systems to therapeutic resistance. We detail the fundamental constituents of these systems, encompassing the central regulatory mechanisms involving transcription factors (of particular importance is the KEAP1/NRF2 signaling axis), the molecular effectors of antioxidants, and the auxiliary systems responsible for NADPH generation. Furthermore, we present recent clinical trials based on targeted antioxidant systems for the treatment of cancer, assessing the potential as well as challenges of this strategy in cancer therapy. Additionally, we summarize the pressing issues in the field, with the aim of illuminating a path toward the emergence of novel anticancer therapeutic approaches by orchestrating redox signaling. [ABSTRACT FROM AUTHOR]

Significance: Neutrophils are crucial components of the innate immune system that combat invading pathogens and maintain homeostasis. Nitric oxide (NO•) exerts regulatory influence on neutrophil rolling, adhesion, oxidative burst, chemotaxis, phagocytosis, cytoneme, apoptosis, and NETosis by diverse mechanisms in an autocrine and paracrine manner. Recent Advances: Recent research has identified the critical role of NO• in the proliferation of neutrophil progenitors, differentiation, survival, and other functions. Further, NO• responses depend on the concentration, proximity, and redox environment, highlighting the intricate and context-dependent mechanisms by which NO• influences neutrophil responses. Critical Issues: Neutrophils express two constitutive isoforms of nitric oxide synthase (NOS), namely iNOS and nNOS. The production of NO• or superoxide (O2•−) radical by these isoforms depends on levels of substrates L-arginine and oxygen, and cofactors such as NADPH, FAD, FMN, and redox-sensitive BH4. Importantly, the interaction between NO• and superoxide generates potent oxidants within the phagolysosomes. The coordinated collaboration and regulation of NO• and O2•− are crucial for redox signaling and neutrophil properties. Future Directions: The activity of neutrophil NOS is regulated at multiple levels, including transcriptional regulation, cofactor availability, protein-protein interactions, and post-translational modifications. However, our understanding of regulatory mechanisms during various neutrophil functions remains limited. While we now recognize the neutrophil heterogeneity, metabolic adaptability, and anti-tumoral ability; however, reports identifying NOS/NO• role remain largely unexplored on these aspects in infections, inflammation, and immunosuppression. Future studies addressing these intriguing areas will be crucial in unraveling the role of NO•/NOS signaling in neutrophils across diverse pathologies and may present therapeutic opportunities. [ABSTRACT FROM AUTHOR]

ABSTRACT For bacteria, an intricate coordination between sensing and regulating iron levels and managing oxidative stress is required as their levels are tightly interlinked. While various oxidative stress and heme-based redox sensors have been reported for both pathogenic and non-pathogenic bacteria, the mechanisms governing the modulation of intracellular iron levels in response to changes in redox status remain unclear. In this study, a gene-inactivated strain of mycobacterial sensor kinase PdtaS showed dysregulated expression of genes associated with iron metabolism, including Fe-S clusters, NADH dehydrogenases, and iron uptake. The strain showed poor growth in nutrient-limiting conditions, a defect rescuable by heme but not by Fe3+ supplementation. This observation was associated with the PAS domain of the PdtaS sensor kinase. Biochemical and biophysical experiments established heme-binding to the PAS domain and its inhibitory effect on PdtaS auto-kinase activity, suggesting that the absence of heme induces activation of this sensor kinase. Interestingly, despite having an endogenous heme biosynthetic pathway or even external heme supplementation, the ∆pdtaS mutant exhibited persistent low intracellular iron levels concomitant with elevated oxidative stress. Antioxidant supplementation mitigated growth defects, emphasizing the link between oxidative stress, intracellular iron levels, and PdtaS activity. RNA-IP identified key targets associated with redox homeostasis and iron metabolism as targets of the PdtaR response regulator. The study proposes a novel role for the PdtaS-PdtaR TCS in sensing heme, regulation of intracellular iron levels, and redox balance.IMPORTANCEThe research article investigates the intricate interplay between bacteria’s ability to take and utilize iron without inducing excess iron’s toxic effects, including oxidative stress. The study shows that bacteria achieve this by sensing intracellular iron available as heme through a sensory protein PdtaS, which turns off when heme is in excess and prevents iron uptake and iron efflux. The process shields bacteria from generating Fe-dependent free radicals and allows it to maintain viability. The absence of sensor kinase abrogates all these processes, increasing bacteria susceptibility to ROS and thereby slowing growth. This feature of the sensor kinase PdtaS makes it an attractive co-therapeutic target for tuberculosis therapy, where its inhibition will prevent iron uptake, even in the presence of low iron, thereby halting bacterial proliferation.

Reactive Oxygen Species (ROS) refer to a variety of derivatives of molecular oxygen that play crucial roles in regulating a wide range of physiological and pathological processes. Excessive ROS levels can cause oxidative stress, leading to cellular damage and even cell demise. However, moderately elevated levels of ROS can mediate the oxidative post-translational modifications (oxPTMs) of redox-sensitive proteins, thereby affecting protein functions and regulating various cellular signaling pathways. Among the oxPTMs, ROS-induced reversible protein sulfenylation represents the initial form of cysteine oxidation for sensing redox signaling. In this review, we will summarize the discovery, chemical formation, and detection approaches of protein sulfenylation. In addition, we will highlight recent findings for the roles of protein sulfenylation in various diseases, including thrombotic disorders, diabetes, cardiovascular diseases, neurodegenerative diseases, and cancer.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are global health burdens with rising prevalence. Their bidirectional relationship with cardiovascular dysfunction, manifesting as cardio-renal syndromes (CRS) types 3 and 4, underscores the interconnectedness and interdependence of these vital organ systems. Both the kidney and the heart are critically reliant on mitochondrial function. This organelle is currently recognized as a hub in signaling pathways, with emphasis on the redox regulation mediated by glutathione (GSH). Mitochondrial dysfunction, including impaired bioenergetics, redox, and biogenesis pathways, are central to the progression of AKI to CKD and the development of CRS type 3 and 4. This review delves into the metabolic reprogramming and mitochondrial redox signaling and biogenesis alterations in AKI, CKD, and CRS. We examine the pathophysiological mechanisms involving GSH redox signaling and the AMP-activated protein kinase (AMPK)-sirtuin (SIRT)1/3-peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) axis in these conditions. Additionally, we explore the therapeutic potential of GSH synthesis inducers in mitigating these mitochondrial dysfunctions, as well as their effects on inflammation and the progression of CKD and CRS types 3 and 4.

We asked whether acute redox signaling from mitochondria exists concomitantly to fatty acid- (FA-) stimulated insulin secretion (FASIS) at low glucose by pancreatic β-cells. We show that FA β-oxidation produces superoxide/H2O2, providing: i) mitochondria-to-plasma-membrane redox signaling, closing KATP-channels synergically with elevated ATP (substituting NADPH-oxidase-4-mediated H2O2-signaling upon glucose-stimulated insulin secretion); ii) activation of redox-sensitive phospholipase iPLA2γ/PNPLA8, cleaving mitochondrial FAs, enabling metabotropic GPR40 receptors to amplify insulin secretion (IS). At fasting glucose, palmitic acid stimulated IS in wt mice; palmitic, stearic, lauric, oleic, linoleic, and hexanoic acids also in perifused pancreatic islets (PIs), with suppressed 1st phases in iPLA2γ/PNPLA8-knockout mice/PIs. Extracellular/cytosolic H2O2-monitoring indicated knockout-independent redox signals, blocked by mitochondrial antioxidant SkQ1, etomoxir, CPT1 silencing, and catalase overexpression, all inhibiting FASIS, keeping ATP-sensitive K+-channels open, and diminishing cytosolic [Ca2+]-oscillations. FASIS in mice was a postprandially delayed physiological event. Redox signals of FA β-oxidation are thus documented, reaching the plasma membrane, essentially co-stimulating IS.

Oxidative stress plays a pivotal role in the pathogenesis and progression of cardiovascular diseases (CVDs). This review focuses on the signaling pathways of oxidative stress during the development of CVDs, delving into the molecular regulatory networks underlying oxidative stress in various disease stages, particularly apoptosis, inflammation, fibrosis, and metabolic imbalance. By examining the dual roles of oxidative stress and the influences of sex differences on oxidative stress levels and cardiovascular disease susceptibility, this study offers a comprehensive understanding of the pathogenesis of cardiovascular diseases. The study integrates key findings from current research in three comprehensive ways. First, it outlines the major CVDs associated with oxidative stress and their respective signaling pathways, emphasizing oxidative stress’s central role in cardiovascular pathology. Second, it summarizes the cardiovascular protective effects, mechanisms of action, and animal models of various antioxidants, offering insights into future drug development. Third, it discusses the applications, advantages, limitations, and potential molecular targets of gene therapy in CVDs, providing a foundation for novel therapeutic strategies. These tables underscore the systematic and integrative nature of this study while offering a theoretical basis for precision treatment for CVDs. A major contribution of this study is the systematic review of the differential effects of oxidative stress across different stages of CVDs, in addition to the proposal of innovative, multi-level intervention strategies, which open new avenues for precision treatment of the cardiovascular system.

Oxidative stress and lipid peroxidation play important roles in numerous physiological and pathological processes, while the bioactive products of lipid peroxidation, lipid hydroperoxides and reactive aldehydes, act as important mediators of redox signaling in normal and malignant cells. Many types of cancer, including osteosarcoma, express altered redox signaling pathways. Such redox signaling pathways protect cancer cells from the cytotoxic effects of oxidative stress, thus supporting malignant transformation, and eventually from cytotoxic anticancer therapies associated with oxidative stress. In this review, we aim to explore the status of lipid peroxidation in osteosarcoma and highlight the involvement of lipid peroxidation products in redox signaling pathways, including the involvement of lipid peroxidation in osteosarcoma therapies. [ABSTRACT FROM AUTHOR]

Loss of E‐cadherin (ECAD) is required in tumor metastasis. Protein degradation of ECAD in response to oxidative stress is found in metastasis of hepatocellular carcinoma (HCC) and is independent of transcriptional repression as usually known. Mechanistically, protein kinase A (PKA) senses oxidative stress by redox modification in its β catalytic subunit (PRKACB) at Cys200 and Cys344. The activation of PKA kinase activity subsequently induces RNF25 phosphorylation at Ser450 to initiate RNF25‐catalyzed degradation of ECAD. Functionally, RNF25 repression induces ECAD protein expression and inhibits HCC metastasis in vitro and in vivo. Altogether, these results indicate that RNF25 is a critical regulator of ECAD protein turnover, and PKA is a necessary redox sensor to enable this process. This study provides some mechanistic insight into how oxidative stress‐induced ECAD degradation promotes tumor metastasis of HCC. [ABSTRACT FROM AUTHOR]

Cysteine is one of the least abundant but most conserved amino acid residues in proteins, playing a role in their structure, metal binding, catalysis, and redox chemistry. Thiols present in cysteines can be modified by post-translational modifications like sulfenylation, acylation, or glutathionylation, regulating protein activity and function and serving as signals. Their modification depends on their position in the structure, surrounding amino acids, solvent accessibility, pH, etc. The most studied modifications are the redox modifications by reactive oxygen, nitrogen, and sulfur species, leading to reversible changes that serve as cell signals or irreversible changes indicating oxidative stress and cell damage. Selected antioxidants undergoing reversible oxidative modifications like peroxiredoxin-thioredoxin system are involved in a redox-relay signaling that can propagate to target proteins. Cysteine thiols can also be modified by acyl moieties' addition (derived from lipid metabolism), resulting in protein functional modification or changes in protein anchoring in the membrane. In this review, we update the current knowledge on cysteine modifications and their consequences in pancreatic β-cells. Because β-cells exhibit well-balanced redox homeostasis, the redox modifications of cysteines here serve primarily for signaling purposes. Similarly, lipid metabolism provides regulatory intermediates that have been shown to be necessary in addition to redox modifications for proper β-cell function and, in particular, for efficient insulin secretion. On the contrary, the excess of reactive oxygen, nitrogen, and sulfur species and the imbalance of lipids under pathological conditions cause irreversible changes and contribute to oxidative stress leading to cell failure and the development of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Significance: Reactive oxygen species (ROS), the reactive oxygen-carrying chemicals moieties, act as pleiotropic signal transducers to maintain various biological processes/functions, including immune response. Increased ROS production leads to oxidative stress, which is implicated in xenobiotic-induced adverse effects. Understanding the immunoregulatory mechanisms and immunotoxicity is of interest to developing therapeutics against xenobiotic insults. Recent Advances: While developmental studies have established the essential roles of ROS in the establishment and proper functioning of the immune system, toxicological studies have demonstrated high ROS generation as one of the potential mechanisms of immunotoxicity induced by environmental chemicals, including heavy metals, pesticides, aromatic hydrocarbons (benzene and derivatives), plastics, and nanoparticles. Mitochondrial electron transport and various signaling components, including NADH oxidase, toll-like receptors (TLRs), NF-κB, JNK, NRF2, p53, and STAT3, are involved in xenobiotic-induced ROS generation and immunotoxicity. Critical Issues: With many studies demonstrating the role of ROS and oxidative stress in xenobiotic-induced immunotoxicity, rigorous and orthogonal approaches are needed to achieve in-depth and precise understanding. The association of xenobiotic-induced immunotoxicity with disease susceptibility and progression needs more data acquisition. Furthermore, the general methodology needs to be possibly replaced with high-throughput precise techniques. Future Directions: The progression of xenobiotic-induced immunotoxicity into disease manifestation is not well documented. Immunotoxicological studies about the combination of xenobiotics, age-related sensitivity, and their involvement in human disease incidence and pathogenesis are warranted. Antioxid. Redox Signal. 40, 691–714. [ABSTRACT FROM AUTHOR]

The evidence for physical activity (PA) as a major public health preventive approach and a potent medical therapy has increased exponentially in the last decades. The biomolecular mechanisms supporting the associations between PA and/or structured exercise training with health maintenance and disease prevention are not completely characterized. However, increasing evidence pointed out the role of epigenetic modifications in exercise adaptation and health-enhancing PA throughout life, DNA methylation being the most intensely studied epigenetic modification induced by acute and chronic exercise. The current data on the modulation of DNA methylation determined by physically active behavior or exercise interventions points out genes related to energy regulation, mitochondrial function, and biosynthesis, as well as muscle regeneration, calcium signaling pathways, and brain plasticity, all consistent with the known exercise-induced redox signaling and/or reactive oxygen species (ROS) unbalance. Thus, the main focus of this review is to discuss the role of ROS and redox-signaling on DNA methylation profile and its impact on exercise-induced health benefits in humans. [Display omitted] • Exercise modifies DNA methylation, influencing various biological processes in different tissues. • Exercise-induced DNA methylation prevents numerous non-communicable diseases and promotes health across age group. • Exercise-triggered ROS unbalance and redox signaling regulate DNA methylation during physical activity. [ABSTRACT FROM AUTHOR]

Cisplatin (cis -Dichlorodiamineplatinum[II], CDDP) is generally accepted as a platinum-based alkylating agent type of the DNA-damaging anticancer drug, which is widely administrated in clinical treatment of many solid tumors. The pharmacological effect of CDDP is mainly achieved by replacing the chloride ion (Cl − ) in its structure with H 2 O to form active substances with the strong electrophilic properties and then react with any nucleophilic molecules, primarily leading to genomic DNA damage and subsequent cell death. In this process, those target genes driven by the consensus electrophilic and/or antioxidant response elements (EpREs/AREs) in their promoter regions are also activated or repressed by CDDP. Thereby, we here examined the expression profiling of such genes regulated by two principal antioxidant transcription factors Nrf1 and Nrf2 (both encoded by Nfe2l1 and Nfe2l2, respectively) in diverse cellular signaling responses to this intervention. The results demonstrated distinct cellular metabolisms, molecular pathways and signaling response mechanisms by which Nrf1 and Nrf2 as the drug targets differentially contribute to the anticancer efficacy of CDDP on hepatoma cells and xenograft tumor mice. Interestingly, the role of Nrf1, rather than Nrf2, is required for the anticancer effect of CDDP, to suppress malignant behavior of HepG2 cells by differentially monitoring multi-hierarchical signaling to gene regulatory networks. To our surprise, it was found there exists a closer relationship of Nrf1α than Nrf2 with DNA repair, but the hyperactive Nrf2 in Nrf1α –∕– cells manifests a strong correlation with its resistance to CDDP, albeit their mechanistic details remain elusive. [Display omitted] • Differential activation of Nrf1 and Nrf2 in distinct cellular responses to cisplatin. • Distinct mechanisms whereby Nrf1 and Nrf2 contribute to the efficacy of cisplatin. • Substantial repression of WT rather than Nrf1α –∕– tumor by cisplatin in model mice. • Significant chemoresistance of Nrf1α –∕– rather than Nrf2 –∕– cell lines to cisplatin. • A rather requirement of Nrf1 than Nrf2 for transcription of H2AX in the DNA repair. [ABSTRACT FROM AUTHOR]

Significance: Physiological levels of reactive oxygen and nitrogen species (ROS/RNS) function as fundamental messengers for many cellular and developmental processes in the cardiovascular system. ROS/RNS involved in cardiac redox-signaling originate from diverse sources, and their levels are tightly controlled by key endogenous antioxidant systems that counteract their accumulation. However, dysregulated redox-stress resulting from inefficient removal of ROS/RNS leads to inflammation, mitochondrial dysfunction, and cell death, contributing to the development and progression of cardiovascular disease (CVD). Recent Advances: Basic and clinical studies demonstrate the critical role of selenium (Se) and selenoproteins (unique proteins that incorporate Se into their active site in the form of the 21st proteinogenic amino acid selenocysteine [Sec]), including glutathione peroxidase and thioredoxin reductase, in cardiovascular redox homeostasis, representing a first-line enzymatic antioxidant defense of the heart. Increasing attention has been paid to emerging selenoproteins in the endoplasmic reticulum (ER) (i.e., a multifunctional intracellular organelle whose disruption triggers cardiac inflammation and oxidative stress, leading to multiple CVD), which are crucially involved in redox balance, antioxidant activity, and calcium and ER homeostasis. Critical Issues: This review focuses on endogenous antioxidant strategies with therapeutic potential, particularly selenoproteins, which are very promising but deserve more detailed and clinical studies. Future Directions: The importance of selective selenoproteins in embryonic development and the consequences of their mutations and inborn errors highlight the need to improve knowledge of their biological function in myocardial redox signaling. This could facilitate the development of personalized approaches for the diagnosis, prevention, and treatment of CVD. Antioxid. Redox Signal. 40, 369–432. [ABSTRACT FROM AUTHOR]

Morphinone (MO) is an electrophilic metabolite of morphine. Electrophiles can modify thiol groups of proteins, resulting in the activation of redox signaling pathways and toxicity. We have previously reported that the atmospheric electrophile, 1,4-naphthoquinone, and electrophilic organometallic compound, methylmercury, activate protein kinase B (Akt) signaling through modification of phosphatase and tensin homolog deleted from chromosome 10 (PTEN), which is a negative regulator of Akt. In the present study, we examined whether MO activates Akt signaling. Exposure of HepG2 cells to MO enhanced translocation of Akt to the nucleus in a concentration-dependent manner. MO phosphorylated Akt and its downstream protein, cAMP response element-binding protein (CREB), and upregulated B-cell lymphoma 2 (Bcl-2), an anti-apoptotic protein. An analogue of MO dihydromorphinone that was not electrophilic did not enhance the phosphorylation of Akt and CREB or expression of Bcl-2, suggesting the importance of electrophilicity of MO in activation of the cascade. Pretreatment of the cells with wortmannin suppressed MO-mediated phosphorylation of Akt and CREB and expression of Bcl-2, and enhanced MO-induced cytotoxicity, indicating that MO activates Akt-CREB-Bcl-2 signaling in HepG2 cells. This signaling pathway might be capable of modulating MO-mediated toxicity in cells. [ABSTRACT FROM AUTHOR]

The chaperone protein EROS (“Essential for Reactive Oxygen Species”) was recently discovered in phagocytes. EROS was shown to regulate the abundance of the ROS-producing enzyme NADPH oxidase isoform 2 (NOX2) and to control ROS-mediated cell killing. Reactive oxygen species are important not only in immune surveillance, but also modulate physiological signaling responses in multiple tissues. The roles of EROS have not been previously explored in the context of oxidant-modulated cell signaling. Here we show that EROS plays a key role in ROS-dependent signal transduction in vascular endothelial cells. We used siRNA-mediated knockdown and developed CRISPR/Cas9 knockout of EROS in human umbilical vein endothelial cells (HUVEC), both of which cause a significant decrease in the abundance of NOX2 protein, associated with a marked decrease in RAC1, a small G protein that activates NOX2. Loss of EROS also attenuates receptor-mediated hydrogen peroxide (H2O2) and Ca2+ signaling, disrupts cytoskeleton organization, decreases cell migration, and promotes cellular senescence. EROS knockdown blocks agonist-modulated eNOS phosphorylation and nitric oxide (NO●) generation. These effects of EROS knockdown are strikingly similar to the alterations in endothelial cell responses that we previously observed following RAC1 knockdown. Proteomic analyses following EROS or RAC1 knockdown in endothelial cells showed that reduced abundance of these two distinct proteins led to largely overlapping effects on endothelial biological processes, including oxidoreductase, protein phosphorylation, and endothelial nitric oxide synthase (eNOS) pathways. These studies demonstrate that EROS plays a central role in oxidant-modulated endothelial cell signaling by modulating NOX2 and RAC1.

Cancer mortality is primarily a consequence of its metastatic spread. Here, we report that methionine sulfoxide reductase A (MSRA), which can reduce oxidized methionine residues, acts as a suppressor of pancreatic ductal adenocarcinoma (PDA) metastasis. MSRA expression is decreased in the metastatic tumors of PDA patients, whereas MSRA loss in primary PDA cells promotes migration and invasion. Chemoproteomic profiling of pancreatic organoids revealed that MSRA loss results in the selective oxidation of a methionine residue (M239) in pyruvate kinase M2 (PKM2). Moreover, M239 oxidation sustains PKM2 in an active tetrameric state to promote respiration, migration, and metastasis, whereas pharmacological activation of PKM2 increases cell migration and metastasis in vivo. These results demonstrate that methionine residues can act as reversible redox switches governing distinct signaling outcomes and that the MSRA-PKM2 axis serves as a regulatory nexus between redox biology and cancer metabolism to control tumor metastasis.

Flashes of superoxide anion (O2−) in mitochondria are generated spontaneously or during the opening of the permeability transition pore (mPTP) and a sudden change in the metabolic state of a cell. Under certain conditions, O2− can leave the mitochondrial matrix and perform signaling functions beyond mitochondria. In this work, we studied the kinetics of the release of O2− and H2O2 from isolated mitochondria upon mPTP opening and the modulation of the metabolic state of mitochondria by the substrates of respiration and oxidative phosphorylation. It was found that mPTP opening leads to suppression of H2O2 emission and activation of the O2− burst. When the induction of mPTP was blocked by its antagonists (cyclosporine A, ruthenium red, EGTA), the level of substrates of respiration and oxidative phosphorylation and the selective inhibitors of complexes I and V determined the type of reactive oxygen species (ROS) emitted by mitochondria. It was concluded that upon complete and partial reduction and complete oxidation of redox centers of the respiratory chain, mitochondria emit H2O2, O2−, and nothing, respectively. The results indicate that the mPTP- and substrate-dependent switching of the type of ROS leaving mitochondria may be the basis for O2−- and H2O2-selective redox signaling in a cell.

NADPH-dependent thioredoxin reductase C (NTRC) redox interaction with protein CP12 plays a role in cold acclimation. A recent study by Teh et al. describes the underlying molecular mechanisms that leads to dissociation of the autoinhibitory PRK/CP12/GAPDH (phosphoribulokinase/CP12/glyceraldehyde-3-phosphate dehydrogenase) supracomplex. We propose that chloroplast-to-nucleus retrograde signaling precedes the described mechanism. [ABSTRACT FROM AUTHOR]

Diabetic bladder dysfunction (DBD) is the most prevalent complication of diabetes mellitus (DM), affecting >50% of all patients. Currently, no specific treatment is available for this condition. In the early stages of DBD, patients typically complain of frequent urination and often have difficulty sensing when their bladders are full. Over time, bladder function deteriorates to a decompensated state in which incontinence develops. Based on studies of diabetic changes in the eye, kidney, heart, and nerves, it is now recognized that DM causes tissue damage by altering redox signaling in target organs. NADPH oxidase (NOX), whose sole function is the production of reactive oxygen species (ROS), plays a pivotal role in other well-known and bothersome diabetic complications. However, there is a substantial gap in understanding how NOX controls bladder function in health and the impact of NOX on DBD. The current review provides a thorough overview of the various NOX isoforms and their roles in bladder function and discusses the importance of further investigating the role of NOXs as a key contributor to DBD pathogenesis, either as a trigger and/or an effector and potentially as a target.

Diabetes mellitus is a non-communicable metabolic disease hallmarked by chronic hyperglycemia caused by beta-cell failure. Diabetic complications affect the vasculature and result in macro- and microangiopathies, which account for a significantly increased morbidity and mortality. The rising incidence and prevalence of diabetes is a major global health burden. There are no feasible strategies for beta-cell preservation available in daily clinical practice. Therefore, patients rely on antidiabetic drugs or the application of exogenous insulin. Glutaredoxins (Grxs) are ubiquitously expressed and highly conserved members of the thioredoxin family of proteins. They have specific functions in redox-mediated signal transduction, iron homeostasis and biosynthesis of iron-sulfur (FeS) proteins, and the regulation of cell proliferation, survival, and function. The involvement of Grxs in chronic diseases has been a topic of research for several decades, suggesting them as therapeutic targets. Little is known about their role in diabetes and its complications. Therefore, this review summarizes the available literature on the significance of Grxs in diabetes and its complications. In conclusion, Grxs are differentially expressed in the endocrine pancreas and in tissues affected by diabetic complications, such as the heart, the kidneys, the eye, and the vasculature. They are involved in several pathways essential for insulin signaling, metabolic inflammation, glucose and fatty acid uptake and processing, cell survival, and iron and mitochondrial metabolism. Most studies describe significant changes in glutaredoxin expression and/or activity in response to the diabetic metabolism.In general, mitigated levels of Grxs are associated with oxidative distress, cell damage, and even cell death. The induced overexpression is considered a potential part of the cellular stress-response, counteracting oxidative distress and exerting beneficial impact on cell function such as insulin secretion, cytokine expression, and enzyme activity.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key cellular enzyme, with major roles in both glycolysis, and 'moonlighting' activities in the nucleus (uracil DNA glycosylase activity, nuclear protein nitrosylation), as a regulator of mRNA stability, a transferrin receptor, and as an antimicrobial agent. These activities are dependent, at least in part, on the integrity of an active site Cys residue, and a second neighboring Cys. These residues are differentially sensitive to oxidation, and determine both its catalytic activity and the redox signaling capacity of the protein. Such Cys modification is critical to cellular adaptation to oxidative environments by re-routing metabolic pathways to favor NADPH generation and antioxidant defenses. Despite the susceptibility of GAPDH to oxidation, it remains a puzzle as to how this enzyme acts as a redox signaling hub for oxidants such as hydrogen peroxide (H 2 O 2) in the presence of high concentrations of specialized high-efficiency peroxide-removing enzymes. One possibility is that crowded environments, such as the cell cytosol, alter the oxidation pathways of GAPDH. In this study, we investigated the role of crowding (induced by dextran) on H 2 O 2 - and SIN-1-induced GAPDH oxidation, with data for crowded and dilute conditions compared. LC-MS/MS data revealed a lower extent of modification of the catalytic Cys under crowded conditions (i.e. less monomer units modified), but enhanced formation of the sulfonic acid resulting from hyper-oxidation. This effect was not observed with SIN-1. These data indicate that molecular crowding can modulate the oxidation pathways of GAPDH and its extent of oxidation and inactivation. [Display omitted] • Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has an oxidant-sensitive cysteine (Cys) in its active site. • Effects of macromolecular crowding on GAPDH oxidation by H 2 O 2 and SIN-1 was investigated. • Dextran differentially affects H 2 O 2 - and SIN-1-mediated GAPDH cross-linking. • Higher yields of active site Cys-derived sulfonic acids were detected with crowding. [ABSTRACT FROM AUTHOR]

We have studied the reduction reactions of two cytosolic human peroxiredoxins (Prx) in their disulfide form by three thioredoxins (Trx; two human and one bacterial), with the aim of better understanding the rate and mechanism of those reactions, and their relevance in the context of the catalytic cycle of Prx. We have developed a new methodology based on stopped‐flow and intrinsic fluorescence to study the bimolecular reactions, and found rate constants in the range of 105–106 m−1 s−1 in all cases, showing that there is no marked kinetic preference for the expected Trx partner. By combining experimental findings and molecular dynamics studies, we found that the reactivity of the nucleophilic cysteine (CN) in the Trx is greatly affected by the formation of the Prx–Trx complex. The protein–protein interaction forces the CN thiolate into an unfavorable hydrophobic microenvironment that reduces its hydration and results in a remarkable acceleration of the thiol‐disulfide exchange reactions by more than three orders of magnitude and also produces a measurable shift in the pKa of the CN. This mechanism of activation of the thiol disulfide exchange may help understand the reduction of Prx by alternative reductants involved in redox signaling. [ABSTRACT FROM AUTHOR]