Overproduction Of Reactive Oxygen Species Research Articles

Photoprotective Effects of Phytochemicals on Blue Light-Induced Retinal Damage: Current Evidence and Future Perspectives

The widespread use of light-emitting diodes (LEDs) has increased blue light (BL) exposure, raising concerns about its potential adverse effects on ocular health. Prolonged exposure to BL has been implicated in the pathogenesis of various retinal disorders, including age-related macular degeneration (AMD), primarily through mechanisms involving oxidative stress and inflammation mediated by the overproduction of reactive oxygen species (ROS). This review synthesizes current evidence on the photoprotective properties of dietary bioactive compounds, (e.g., anthocyanins, curcumin, quercetin, myricetin, and resveratrol), with a focus on their potential to mitigate BL-induced retinal damage. Accumulating research suggests that dietary antioxidants, particularly polyphenols, may offer photoprotective benefits. These phytochemicals act by neutralizing ROS and enhancing the retina’s endogenous antioxidant capacity. Based on these findings, this review advocates for a food-first approach in future investigations, emphasizing the development of evidence-based dietary recommendations to bolster retinal health and mitigate the risk of BL-related ocular diseases. Considering the current lack of empirical clinical studies examining the impact of BL on human ocular health, future research in the field of BL hazard should prioritize two key approaches: conducting large-scale epidemiological dietary surveys and implementing clinical trials on functional ingredients that have demonstrated beneficial effects against photodamage in preclinical animal studies.

Immune-Boosting and Antiviral Effects of Antioxidants in COVID-19 Pneumonia: A Therapeutic Perspective

The COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has profoundly impacted global health, with pneumonia emerging as a major complication in severe cases. The pathogenesis of COVID-19 is marked by the overproduction of reactive oxygen species (ROS) and an excessive inflammatory response, resulting in oxidative stress and significant tissue damage, particularly in the respiratory system. Antioxidants have garnered considerable attention for their potential role in managing COVID-19 pneumonia by mitigating oxidative stress and modulating immune responses. This review provides a comprehensive overview of the literature on the use of antioxidants in hospitalized patients with mild-to-moderate COVID-19. Studies exploring antioxidants, including vitamins, trace elements, nitric oxide (NO), ozone (O3), glutathione (GSH), L-carnitine, melatonin, bromelain, N-acetylcysteine (NAC), and numerous polyphenols, have yielded promising outcomes. Through their ROS-scavenging properties, these molecules support endothelial function, reduce the thrombosis risk, and may help mitigate the effects of the cytokine storm, a key contributor to COVID-19 morbidity and mortality. Clinical evidence suggests that antioxidant supplementation may improve patient outcomes by decreasing inflammation, supporting immune cell function, and potentially shortening recovery times. Furthermore, these molecules may mitigate the symptoms of COVID-19 by exerting direct antiviral effects that inhibit the infection process and genomic replication of SARS-CoV-2 in host cells. Moreover, antioxidants may work synergistically with standard antiviral treatments to reduce viral-induced oxidative damage. By integrating findings from the literature with real-world data from our clinical experience, we gain a more profound understanding of the role of antioxidants in managing COVID-19 pneumonia. Further research combining comprehensive literature reviews with real-world data analysis is crucial to validate the efficacy of antioxidants and establish evidence-based guidelines for their use in clinical practice.

Activation of endogenous tolerance to bleaching stress by high salinity in cloned endosymbiotic dinoflagellates from corals

BackgroundLarge-scale coral bleaching events have become increasingly frequent in recent years. This process occurs when corals are exposed to high temperatures and intense light stress, leading to an overproduction of reactive oxygen species (ROS) by their endosymbiotic dinoflagellates. The ROS buildup prompts corals to expel these symbiotic microalgae, resulting in the corals’ discoloration. Reducing ROS production and enhancing detoxification processes in these microalgae are crucial to prevent the collapse of coral reef ecosystems. However, research into the cell physiology and genetics of coral symbiotic dinoflagellates has been hindered by challenges associated with cloning these microalgae.ResultsA procedure for cloning coral symbiotic dinoflagellates was developed in this study. Several species of coral symbionts were successfully cloned, with two of them further characterized. Experiments with the two species isolated from Turbinaria sp. showed that damage from light intensity at 340 μmol photons/m2/s was more severe than from high temperature at 36 °C. Additionally, preincubation in high salinity conditions activated their endogenous tolerance to bleaching stress. Pretreatment at 50 ppt salinity reduced the percentage of cells stained for ROS by 59% and 64% in the two species under bleaching stress compared to those incubated at 30 ppt. Furthermore, their Fv’/Fm’ during the recovery period showed a significant improvement compared to the controls.ConclusionsThese findings suggest that intense light plays a more important role than high temperatures in coral bleaching by enhancing ROS generation in the symbiotic dinoflagellates. The findings also suggest the genomes of coral symbiotic dinoflagellates have undergone evolutionary processes to develop mechanisms, regulated by gene expression, to mitigate damages caused by high temperature and high light stress. Understanding this gene expression regulation could contribute to strengthening corals’ resilience against the impact of global climate change.

TiOx(OH)4-2x Nanosheets with Catalytic Antioxidative Activity Alleviate Oxidative Injury in Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM) is one of the most lethal complications of diabetes and is induced by the overproduction of reactive oxygen species (ROS) in cardiomyocytes due to sustained high glucose levels, leading to cardiac oxidative damage and final sudden death. Drugs and antioxidants currently applied to the clinical therapy of DCM fail to scavenge ROS efficiently, resulting in compromised therapeutic efficacy. Herein, a nanocatalytic antioxidative therapeutic strategy is proposed for DCM treatment. A two-dimensional TiOx(OH)4-2x nanosheet platform has been constructed with efficient ROS-scavenging activity, which can catalyze antioxidation reaction through redox cycling between TiIV/TiIII accompanied by inner-sphere two-electron transfer. Cellular experiments demonstrate that the TiOx(OH)4-2x nanosheet can not only protect cardiomyocytes from oxidative damage induced by a high glucose environment but also alleviate inflammation to further protect cardiomyocytes from inflammatory injury. The in vivo animal model confirms that the nanosheet alleviates myocardial oxidative injury and recovers cardiac function. Such a nanocatalytic antioxidation strategy is expected to provide a feasible approach for treating DCM and other cardiovascular diseases.

Characterizing Oxidative Stress induced by Aβ Oligomers and the Protective Role of Carnosine in Primary Mixed Glia Cultures.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. A critical aspect of AD pathology is represented by oxidative stress, which significantly contributes to neuronal damage and death. Microglia and astrocytes, the primary glial cells in the brain, are crucial for managing oxidative stress and supporting neuronal function. Carnosine is an endogenous dipeptide possessing a multimodal mechanism of action that includes antioxidant, anti-inflammatory, and anti-aggregant activities. The present study investigated the effects of Aβ1-42 oligomers (oAβ), small aggregates associated with the neurodegeneration observed in AD, on primary rat mixed glia cultures composed of both microglia and astrocytes, focusing on the ability of these detrimental species to induce oxidative stress. We assessed intracellular reactive oxygen species (ROS) and nitric oxide (NO) levels as markers of oxidative stress. Exposure to oAβ significantly elevated both ROS and NO intracellular levels compared to control cells. However, this effect was completely inhibited by the pre-treatment of mixed cultures with carnosine, resulting in ROS and NO levels similar to those observed in untreated (control) cells. Single-cell analysis of cellular responses to oAβ revealed heterogeneous ROS production, resulting in two distinct clusters of cells, one of which was very responsive to the treatment. The presence of carnosine counteracted the overproduction of ROS, also leading to a single, homogeneous cluster, similar to that observed in the case of control cells. Interestingly, unlike ROS response, single-cell analysis of NO production did not show any distinct clusters. Overall, our findings demonstrated the ability of carnosine to mitigate Aβ-induced oxidative stress in mixed glia cells, by rescuing ROS and NO intracellular levels, as well as to normalize the heterogeneous response to the treatment measured in terms of clusters' formation. The present study suggests a therapeutic potential of carnosine in pathologies characterized by oxidative stress including AD.

Combined Effects of Spirulina Liquid Extract and Endurance Training on Aerobic Performance and Muscle Metabolism Adaptation in Wistar Rats

Background: Physical activity, such as running, protects against cardiovascular disease and obesity but can induce oxidative stress. Athletes often consume antioxidants to counteract the overproduction of reactive oxygen and nitrogen species during exercise. Spirulina, particularly its phycocyanin content, activates the Nrf2 pathway, stimulating antioxidant responses. Studies show that phycocyanin enhances antioxidant defenses and reduces inflammation, potentially improving muscle adaptation and recovery. This study evaluates a Spirulina liquid extract (SLE) supplementation during endurance training, hypothesizing that phycocyanin improves oxidant status and performance in soleus and extensor digitorum longus muscles. Methods: Three-week-old male Wistar rats were divided into four groups: a sedentary control group (C), a sedentary group supplemented with SLE (SP), an endurance training group (T), and an endurance training group supplemented with SLE (SPT). After 8 weeks of treadmill training, blood and muscle were collected. Biochemical parameters and gene expression analyses were performed to assess the effects of training and supplementation. Results: The maximal aerobic speed improved significantly in the SPT group. Plasma lipid profiles showed a reduction in triglyceridemia, cholesterolemia, and atherogenic index in the trained groups, especially with SLE supplementation. Muscle malondialdehyde levels decreased in the SPT group compared to T. Gene expression analysis revealed upregulation of Nrf2 and mitochondrial biogenesis genes in both muscles, with differences between groups for genes related to glycogen storage and β-oxidation. Conclusions: This study demonstrated that SLE supplementation enhanced exercise performance and promoted muscle molecular adaptations. These findings suggest SLE as a promising functional food supplement for athletes, optimizing recovery and performance.

Senkyunolide I prevent chondrocytes from oxidative stress through Nrf2/HO-1 signaling pathway.

Osteoarthritis (OA) is a degenerative musculoskeletal disease, featured by the destruction of articular cartilage. Oxidative stress, one of the drivers of the extracellular matrix degradation in cartilage, plays a vital role in OA pathogenesis. Senkyunolide I (SEI) is a natural compound with a prominent anti-oxidative stress property against multiple diseases. However, the protective effect of SEI on OA has not been explored. Here, we aimed to elucidate the effect of SEI on OA in vitro. Our results showed that SEI suppressed the expression of senescence-related markers such as P16 and P21 in IL-1β-induced chondrocytes. Besides, SEI alleviated IL-1β-induced the degradation of extracellular matrix (ECM) by suppressing the matrix proteinase like MMP13 and ATAMDS5 while promoting matrix synthesis regulated biomarkers like COL2A1 and ACAN in chondrocytes. Mechanically, the mitochondrial dysfunction and overproduction of intracellular reactive oxygen species (ROS) in chondrocytes induced by IL-1β were reversed by SEI. Additionally, the ROS inhibitor N-acetylcysteine (NAC) synergistically enhanced the biological effect of SEI in IL-1β-induced chondrocytes. Moreover, it was also found that the expression of Nrf2 and HO-1 was increased by the treatment of SEI in IL-1β-stimulated chondrocytes, while the Nrf2 inhibitor ML385 reversed the protective effect of SEI on OA chondrocytes. In conclusion, SEI could inhibit senescence, the degradation of ECM, and the production of ROS through activating Nrf2/ HO-1 signaling pathway, which provide a novel candidate for OA treatment.

Ameliorating macrophage pyroptosis via ANXA1/NLRP3/Caspase-1/GSDMD pathway：Ac2-26/OGP-loaded intelligent hydrogel enhances bone healing in diabetic periodontitis.

Craniofacial bone defect healing in periodontitis patients with diabetes background has long been difficult due to increased blood glucose levels which cause overproduction of reactive oxygen species (ROS) and a low pH environment. These conditions negatively affect the function of macrophages, worsen inflammation and oxidative stress, and ultimately, hinder osteoblasts' bone repair potential. In this study, we for the first time found that ANXA1 expression in macrophages was reduced in a diabetic periodontitis environment, with the activation of the NLRP3/Caspase-1/GSDMD signaling pathway, and, eventually, increased macrophage pyroptosis. Next, we have developed a new GPPG intelligent hydrogel system which was ROS and pH responsive, and loaded with Ac2-26, an ANXA1 bioactive peptide, and osteogenic peptide OGP as well. We found that Ac2-26/OGP/GPPG can effectively reduce ROS, mitigates macrophage pyroptosis via the ANXA1/NLRP3/Caspase-1/GSDMD pathway and enhanced osteogenic differentiation. The effect of Ac2-26/OGP/GPPG in regulation of pyroptosis and bone defect repair was also further validated by animal experiments on periodontitis-induced tooth loss model in diabetic rats. To conclude, our study unveils the effect of ANXA1 on macrophage pyroptosis in periodontitis patients with diabetes, based on which we introduced a promising innovative hydrogel system for improvement of bone defects repair in diabetic periodontitis patients via targeting macrophage pyroptosis and enhancing osteogenic potential.

The immunomodulatory potential of chickpea protein hydrolysate via ROS and NO pathways.

The uncontrolled overproduction of Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) is linked to chronic inflammation, although they are also essential signaling molecules for the immune system against infectious agents. Bioactive compounds hold promise as functional bioactive nutrients, contributing to the immunomodulatory response. This study investigates the potential of chickpea protein hydrolysate to modulate ROS/RNS stress and inflammatory responses in a cellular low-grade chronic inflammatory model. This study was focused on their effects on endogenous antioxidant enzyme activities and key pro-inflammatory markers. ROS and nitric oxide (NO) production and molecular biology techniques were used to evaluate cell metabolism. Hydrolysate exposure notably increased ROS and NO release in a dose-dependent manner, while also exhibiting significant anti-inflammatory effects by inhibiting NF-κB and NLRP3 inflammasome components in treated cells. Therefore, chickpea protein hydrolysates hold promise as functional bioactive compounds for use in therapeutic applications, promoting human health and well-being.

Radioprotective Effects of Vitamin C, Cimetidine, and Famotidine on Lipid Peroxidase and Hepatic Glutathione Levels in Mouse Liver.

Radiation therapy is one of the most effective treatments for approximately 60% of patients with cancer. During radiation exposure, the overproduction of reactive oxygen species (ROS) disrupts the lipid layer of the membrane, leading to subsequent peroxide radical formation. Cimetidine (Cim) and famotidine (Fam) are histamine H2 receptor antagonists (H2 blocker), also known as peptic ulcer drugs, that exert radioprotective effects. Vitamin C (Vit.C) is an effective free radical and ROS scavenger with significant radioprotective effects. In this experimental study, male mice (6-8 weeks and 28 ± 3 g) were used in five groups. To evaluate ionizing radiation, gamma rays were used at two doses of 2 and 4 Gy and different doses of Cim, Fam, and Vit.C administered as the protectives. Finally, the livers of the mice were isolated and homogenized. The levels of lipid peroxidase and reduced and oxidized glutathione were measured using standard methods. With increasing radiation dose, lipid peroxidase activity, GSSG level, and glutathione content increased. The findings showed that in the drug-only group, Vit.C had better protection than the other two drugs, and the combination of the three drugs had excellent radiation protection. Radiation protection of normal cells in radiotherapy is a valuable necessity. A number of drugs can protect cells against ionizing radiation through different mechanisms. The results suggest that Fam, Cim, and Vit.C can be radioprotective individually or in combination.

Light enhanced cytotoxicity and antitumoral effect of a ruthenium-based photosensitizer inspired from natural alkaloids.

In this work, we report on the synthesis and properties of a new sensitizer for photodynamic therapy applications, constituted by a ruthenium(ii) complex (1) featuring a ligand inspired from natural isoquinoline alkaloids. The spectroscopic analysis revealed that 1 is characterized by an intense red emission (λ em = 620 nm, Φ = 0.17) when excited at 550 nm, a low energy radiation warranting for a safe therapeutic approach. The phototoxicity of 1 on human breast cancer (Hs578T) and melanoma (A375) cell lines was assessed after irradiation using a LED lamp (525 nm, total fluence 10 J cm-2). In vitro biological assays indicated that the cytotoxicity of 1 was significantly enhanced by light reaching IC50 values below the micromolar threshold. The cell damage induced by 1 proved to be strictly connected with the overproduction of reactive oxygen species (ROS) responsible for mitochondrial dysfunction leading to the activation of caspases and then to apoptosis, and for DNA photocleavage leading to cell cycle arrest.

Nanotherapeutics-mediated restoration of pancreatic homeostasis and intestinal barrier for the treatment of severe acute pancreatitis.

Severe acute pancreatitis (SAP) is an inflammatory disease of the pancreas accompanied with intestinal injury, and effective therapeutic modalities are still highly lacking. Herein, a facile and effective nanotherapeutics (pHA@IBNCs) is developed to alleviate pancreatic inflammation and restore intestinal barrier for SAP treatment. Epigallocatechin gallate (EGCG, an anti-oxidant), interleukin-22 (IL-22, an anti-inflammatory and epithelial barrier-protecting cytokine), and bovine serum albumin (a framework protein), are assembled via non-covalent interactions to form nanocomplexes (IBNCs). Then, phenylboronic acid-modified hyaluronic acid (pHA) is synthesized and coated onto IBNCs via formation of the reversible boronate ester bonds to obtain pHA@IBNCs. Upon intravenous injection, pHA@IBNCs could efficiently accumulate at the lesion sites of sodium taurocholate (STC)-induced SAP mice, based on their prolonged blood circulation time and pHA-mediated targeting of activated intestinal epithelial cells and macrophages. Inside the inflammatory microenvironment, over-produced reactive oxygen species (ROS) trigger the shedding of the pHA layer and release of the drug payloads. Thereby, EGCG cooperates with IL-22 to attenuate pancreatitis and restore the intestinal barrier by scavenging ROS, suppressing pro-inflammatory cytokines secretion, and promoting the repair of intestinal epithelia. Such a nano-therapeutic approach targeting multiple pathological events may serve as a promising paradigm for the effective management of SAP.

[Gly14]-Humanin ameliorates high glucose-induced endothelial senescence via SIRT6

High glucose (HG) induced endothelial senescence is related to endothelial dysfunction and cardiovascular complications in diabetic patients. Humanin, a member of mitochondrial derived peptides (MDPs), is thought to contribute to aging-related cardiovascular protection. The goal of the study is to explore the pathogenesis of HG-induced endothelial senescence and potential anti-senescent effects of Humanin. Human umbilical vein endothelial cells (HUVECs) were exposed to glucose to induce senescence, determined by β-galactosidase staining and the expressions of p21, p53, and p16. A clinically relevant dose of HG (15 mM, HG) induced endothelial senescence after 72 h incubation without elevated apoptosis. HG-induced senescence was attributed to the induction of reactive oxygen species (ROS) caused by SIRT6 downregulation, as ROS inhibitor N-acetyl cysteine blocked HG-induced senescence, while inactivation of SIRT6 increased ROS levels and promoted senescence. Strikingly. pretreatment with [Gly14]-Humanin (HNG) antagonized the downregulation of SIRT6 in response to HG and alleviated ROS production and cell senescence. HG-induced reduction of SIRT6 results in ROS overproduction and endothelial senescence. Humanin protects against HG-induced endothelial senescence via SIRT6. This study provides new directions for biological products related to Humanin to be a potential candidate for the prevention of vascular aging in diabetes.

A Three-In-One Heptamethine Cyanine Dye Induces Endoplasmic Reticulum Stress and Apoptosis in Colorectal Cancer.

One of the most significant challenges for image-guided cancer-targeted therapy is to develop multifunctional optical contrast agents enabling simultaneous targeting and therapy. Herein, a feasible strategy is based on the incorporation of therapeutic moieties into the non-delocalized structure of polymethine indocyanines, known as the "structure-inherent targeting" concept. By possessing a rigid chloro-cyclohexenyl ring in the heptamethine cyanine backbone, a new type of multifunctional near-infrared fluorescent dye, Ph790H, that targets tumor without the need for additional targeting ligands is synthesized. Armed with a phthalimide pharmacophore holding a prominent position in medicinal chemistry, Ph790H simultaneously induces endoplasmic reticulum (ER) stress to exert targeted therapeutic effects on HT-29 colorectal cancer xenografts. In terms of molecular mechanism, the lipophilic cationic Ph790H can be actively internalized into HT-29 cells through clathrin-mediated endocytosis. Consequently, mitochondrial reactive oxygen species (ROS) overproduction further induces activation of ER stress, demonstrated by increased ROS concentration and decreased mitochondrial membrane potential, which contributes to cell apoptosis and inhibition of tumor growth. Overall, Ph790H represents an effective "three-in-one" agent for the integration of cancer targeting, imaging, and therapy, which may provide a practical strategy to develop multifunctional small molecule theranostic agents for simultaneous cancer diagnosis and therapy.

Resistant starch grafted cerium-sulfasalazine infinite coordination polymers synergistically remold intestinal metabolic microenvironment for inflammatory bowel disease therapy

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disease which is closely related with the overproduced reactive oxygen species (ROS), increased pro-inflammatory cytokines and disordered intestinal microbes. However, current therapeutic methods usually ignored the interrelation among the pathogenesis, and mainly focused on a single factor, inducing clinical outcomes unsatisfied. Herein, biocompatible infinite coordination polymers of drugs (Ce-SASP-RS ICPs) composed of Ce ions, FDA-approved drug sulfasalazine (SASP) and natural ingredient resistant starch (RS) were developed for synergistic treatment of IBD. The proper Ce3+/Ce4+ ratio in Ce-SASP-RS ICPs can endow them with SOD-like activities, POD-like activities and •OH scavenging ability, which guarantee Ce-SASP-RS ICPs to simultaneously kill bacteria and maintain ROS balance through cascade reactions. Owing to the recovered redox balance microenvironment, SASP in Ce-SASP-RS ICPs can better play their anti-inflammatory function. Moreover, benefitting from the recovered metabolic balance of ROS and inflammatory cytokines in colon, resistant starch can also function better in modifying gut microbiota through generating short-chain fatty acids. Collectively, Ce-SASP-RS ICPs can synergistically restore intestinal metabolic microenvironment through modulating redox balance, attenuating inflammation and modifying intestinal flora. Hence, in view of the mutual influences among IBD pathogenesis, this work presents a synergistic intervention approach for effectively treating IBD.Graphical

Engineering Dual Active Sites and Defect Structure in Nanozymes to Reprogram Jawbone Microenvironment for Osteoradionecrosis Therapy.

Four to eight percent of patients with head and neck cancer will develop osteoradionecrosis of the jaw (ORNJ) after radiotherapy. Various radiation-induced tissue injuries are associated with reactive oxygen and nitrogen species (RONS) overproduction. Herein, Fe doping is used in VOx (Fe-VOx) nanozymes with multienzyme activities for ORNJ treatment via RONS scavenging. Fe doping can induce structure reconstruction of nanozymes with abundant defect production, including Fe substitution and oxygen vacancies (OVs), which markedly increased multiple enzyme-mimicking activity. Catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) enzyme-like performance of Fe-VOx can effectively reprogram jawbone microenvironment to restore mitochondrial dysfunction and enhance mitophagy. Moreover, the surface plasmon resonance (SPR) effect of Fe-VOx made it a good photothermal nanoagents for inhibiting jaw infection. Thus, this work demonstrated that Fe-VOx nanozymes can efficiently scavenge RONS, activate mitophagy, and inhibit bacteria, which is potential for ORNJ treatment.

Targeting Reactive Oxygen Species for Diagnosis of Various Diseases.

Reactive oxygen species (ROS) are generated predominantly during cellular respiration and play a significant role in signaling within the cell and between cells. However, excessive accumulation of ROS can lead to cellular dysfunction, disease progression, and apoptosis that can lead to organ dysfunction. To overcome the short half-life of ROS and the relatively small amount produced, various imaging methods have been developed, using both endogenous and exogenous means to monitor ROS in disease settings. In this review, we discuss the molecular mechanisms underlying ROS production and explore the methods and materials that could be used to detect ROS overproduction, including iron-based materials, ROS-responsive chemical bond containing polymers, and ROS-responsive molecule containing biomaterials. We also discuss various imaging and imaging techniques that could be used to target and detect ROS overproduction. We discuss the ROS imaging potentials of established clinical imaging methods, such as magnetic resonance imaging (MRI), sonographic imaging, and fluorescence imaging. ROS imaging potentials of other imaging methods, such as photoacoustic imaging (PAI) and Raman imaging (RI) that are currently in preclinical stage are also discussed. Finally, this paper focuses on various diseases that are associated with ROS overproduction, and the current and the future clinical applications of ROS-targeted imaging. While the most widely used clinical condition is cardiovascular diseases, its potential extends into non-cardiovascular clinical conditions, such as neurovascular, neurodegenerative, and other ROS-associated conditions, such as cancers, skin aging, acute kidney injury, and inflammatory arthritis.

Mitochondrial pathways of copper neurotoxicity: focus on mitochondrial dynamics and mitophagy.

Copper (Cu) is essential for brain development and function, yet its overload induces neuronal damage and contributes to neurodegeneration and other neurological disorders. Multiple studies demonstrated that Cu neurotoxicity is associated with mitochondrial dysfunction, routinely assessed by reduction of mitochondrial membrane potential. Nonetheless, the role of alterations of mitochondrial dynamics in brain mitochondrial dysfunction induced by Cu exposure is still debatable. Therefore, the objective of the present narrative review was to discuss the role of mitochondrial dysfunction in Cu-induced neurotoxicity with special emphasis on its influence on brain mitochondrial fusion and fission, as well as mitochondrial clearance by mitophagy. Existing data demonstrate that, in addition to mitochondrial electron transport chain inhibition, membrane damage, and mitochondrial reactive oxygen species (ROS) overproduction, Cu overexposure inhibits mitochondrial fusion by down-regulation of Opa1, Mfn1, and Mfn2 expression, while promoting mitochondrial fission through up-regulation of Drp1. It has been also demonstrated that Cu exposure induces PINK1/Parkin-dependent mitophagy in brain cells, that is considered a compensatory response to Cu-induced mitochondrial dysfunction. However, long-term high-dose Cu exposure impairs mitophagy, resulting in accumulation of dysfunctional mitochondria. Cu-induced inhibition of mitochondrial biogenesis due to down-regulation of PGC-1α further aggravates mitochondrial dysfunction in brain. Studies from non-brain cells corroborate these findings, also offering additional evidence that dysregulation of mitochondrial dynamics and mitophagy may be involved in Cu-induced damage in brain. Finally, Cu exposure induces cuproptosis in brain cells due mitochondrial proteotoxic stress, that may also contribute to neuronal damage and pathogenesis of certain brain diseases. Based on these findings, it is assumed that development of mitoprotective agents, specifically targeting mechanisms of mitochondrial quality control, would be useful for prevention of neurotoxic effects of Cu overload.

Targeting Ferroptosis in Parkinson's Disease: Mechanisms and Emerging Therapeutic Strategies.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein in the brain. Ferroptosis, a recently identified form of regulated cell death, is critical in PD pathogenesis due to its association with iron deposition, overproduction of reactive oxygen species, iron-dependent lipid peroxidation and impaired lipid peroxidation clearance. This cell death mechanism is closely linked to several pathogenic processes in PD, including α-synuclein aggregation, oxidative stress, mitochondrial dysfunction, microglia-induced neuroinflammation, and neuromelanin accumulation. Given the significant role of ferroptosis in these mechanisms, there is increasing interest in targeting ferroptosis for PD treatment. Several drugs have shown potential in alleviating PD symptoms by inhibiting ferroptosis. This review aims to consolidate current knowledge on ferroptosis in PD and assess the therapeutic potential of anti-ferroptosis drugs, highlighting promising directions for future research and clinical applications.

EP300-mediated H3 acetylation elevates MTHFD2 expression to reduce mitochondrial dysfunction in lipopolysaccharide-induced tubular epithelial cells.

Sepsis represents an organ dysfunction resulting from the host's maladjusted response to infection, and can give rise to acute kidney injury (AKI), which significantly increase the morbidity and mortality of septic patients. This study strived for identifying a novel therapeutic strategy for patients with sepsis-induced AKI (SI-AKI). Rat tubular epithelial NRK-52E cells were subjected to lipopolysaccharide (LPS) exposure for induction of in-vitro SI-AKI. The expressions of E1A binding protein p300 (EP300) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in NRK-52E cells were assessed by western blot and qRT-PCR, and their interaction was explored by chromatin immunoprecipitation performed with antibody for H3K27 acetylation (H3K27ac). The effect of them on SI-AKI-associated mitochondrial dysfunction of tubular epithelial cells was investigated using transfection, MTT assay, TUNEL staining, 2',7'-Dichlorodihydrofluorescein diacetate probe assay, Mitosox assay, and JC-1 staining. MTHFD2 and EP300 were upregulated by LPS exposure in NRK-52E cells. LPS increased the acetylation of H3 histone in the MTHFD2 promoter region, and EP300 suppressed the effect of LPS. EP300 ablation inhibited the expression of MTHFD2. MTHFD2 overexpression antagonized LPS-induced viability reduction, apoptosis promotion, reactive oxygen species overproduction, and mitochondrial membrane potential collapse of NRK-52E cells. By contrast, MTHFD2 knockdown and EP300 ablation brought about opposite consequences. Furthermore, MTHFD2 overexpress and EP300 ablation counteracted each other's effect in LPS-exposed NRK-52E cells. EP300-mediated H3 acetylation elevates MTHFD2 expression to reduce mitochondrial dysfunction of tubular epithelial cells in SI-AKI.