Cancer remains a significant barrier to human longevity and a leading cause of mortality worldwide. Despite advancements in cancer therapies, challenges such as cellular toxicity and drug resistance to chemotherapy persist. Regulated cell death (RCD), once regarded as a passive process, is now recognized as a programmed mechanism with distinct biochemical and morphological characteristics, thereby presenting new therapeutic opportunities. Ferroptosis, a novel form of RCD characterized by iron-dependent lipid peroxidation and unique mitochondrial damage, differs from apoptosis, autophagy, and necroptosis. It is driven by reactive oxygen species (ROS)-induced lipid peroxidation and is implicated in tumorigenesis, anti-tumor immunity, and resistance, particularly in tumors undergoing epithelial-mesenchymal transition. Moreover, ferroptosis is associated with ischemic organ damage, degenerative diseases, and aging, regulated by various cellular metabolic processes, including redox balance, iron metabolism, and amino acid, lipid, and glucose metabolism. This review focuses on the role of epigenetic factors in tumor ferroptosis, exploring their mechanisms and potential applications in cancer therapy. It synthesizes current knowledge to provide a comprehensive understanding of epigenetic regulation in tumor cell ferroptosis, offering insights for future research and clinical applications.

Bovine mammosphere-derived epithelial cell (MDEC) cultures are heterogeneous and enriched for stem and progenitor cells. We previously reported that the bovine MDEC secretome, comprised of all bioactive factors secreted by the cells, displays regenerative properties, exerts antimicrobial effects, and modulates neutrophil activity, positioning it as a promising non-antibiotic biologic therapy for infectious diseases important to the dairy industry, like mastitis. Mastitis is defined as inflammation of the udder, and it is typically caused by bacterial infection. The effect of the MDEC secretome on macrophages, a first line of defense against bacterial infections in the udder, is unknown and could impact the utility of the secretome as a therapy for mastitis. To address this, we isolated bovine monocytes from peripheral blood and maintained them as an unpolarized (M0) population or polarized them into M1 or M2 phenotypes. Macrophages cultured with the secretome of bovine MDECs were assessed for their ability to phagocytose labeled bacterial particles and accumulate reactive oxygen species (ROS). We used single-cell RNA sequencing (scRNA-seq) and fluorescence-activated cell sorting (FACS) to isolate a subpopulation of MDECs that exert enhanced effects on macrophages. We found that the secretome of MDECs that do not express cluster of differentiation (CD) 73, a cell surface enzyme used as a marker for mesenchymal stromal cells, most strongly increased macrophage phagocytosis and ROS accumulation. These findings will help optimize the generation of the bovine MDEC secretome as a suitable treatment option for mastitis.

In the current study, the mussels Mytilus galloprovincialis, exposed to four varying temperatures (17, 20, 23, and 26 °C), were contaminated with 50 μg/L of bisphenol A both with and without Nannochloropsis salina. The toxicity evaluation is determined by quantifying various biomarkers related to oxidative stress, neurotoxicity, and cellular damage. The key findings indicate that the toxicity of bisphenol A is heightened by rising temperature. The impact of bisphenol A is most evident at 26 °C, leading to excessive production of reactive oxygen species, depletion of non-enzymatic antioxidants, and activation of antioxidant enzymes (catalase and glutathione-S-transferase). The rise in malondialdehyde levels confirms lipid peroxidation caused by bisphenol A and intensified by thermal stress. These findings have been supported by strong molecular interactions between bisphenol A and lectin mytilec apo-form and proximal thread matrix protein 1 from M. galloprovincialis following the computational modeling assay. The incorporation of N. salina as a food additive helped, firstly, to mitigate the stress effects and, secondly, resulted in a noticeable enhancement of oxidative balance and filtration ability, along with decreased lipid peroxidation.

Renal fibrosis, particularly tubulointerstitial fibrosis, is a prevalent pathological process contributing to the progression of chronic kidney disease (CKD). A growing body of evidence indicates that fibroblast growth factors (FGFs) play critical roles in kidney pathophysiology. However, the role of FGF18 in the pathogenesis of kidney fibrosis and the underlying mechanisms remain unclear. In this study, we discovered a significant upregulation of FGF18 in a folic acid (FA)-induced renal fibrosis model, as well as in transforming growth factor β (TGF-β) stimulated human proximal tubular cells (HK-2 cells). Furthermore, overexpression of FGF18 in the kidney significantly alleviated FA-induced fibrosis and diminished oxidative stress. Mechanistically, FGF18 upregulated AMP-activated protein kinase (AMPK) phosphorylation via its receptor FGFR3, leading to decreased NOX4-ROS levels, reduced oxidative stress, and ultimately inhibited the expression of fibrosis-related proteins. In conclusion, our findings suggest that FGF18 attenuates FA-induced renal fibrosis, at least in partly via AMPK/NOX4 pathway.

Neuronal death has long been regarded as a pivotal pathological factor in the developmental neurotoxicity caused by the volatile anesthetic sevoflurane in the neonatal brain, but the detailed mechanism remains controversial. Ferroptosis is a novel type of regulated cell death driven by excess lipid peroxidation secondary to intracellular iron overload, and it is implicated in the pathogenesis of various neurological disorders. Acting as a death messenger, p53 is primarily activated by ATM during DNA damage and mediates various forms of cell death, including apoptosis, autophagy, and ferroptosis. JNK/p38 MAPK are important stress-responsive pathways that can exacerbate intracellular ROS production, thereby linking DNA damage to many pathological conditions such as neurodegeneration and ischemic injury. In our present study, we demonstrated that sevoflurane exposure-induced neuronal death was correlated with intracellular iron overload and lipid peroxidation in HT22 cells, primary hippocampal neurons, and the hippocampi of neonatal mice, consistent with the hallmarks of ferroptosis. Furthermore, we found that sevoflurane-induced neuronal ferroptosis was associated with ATM/p53 activation in response to DNA damage. Additionally, sevoflurane exposure caused JNK/p38 MAPK activation followed by intracellular ROS accumulation, ultimately leading to DNA damage. Mechanistically, ATM/p53 contributed to ferroptosis caused by sevoflurane via two pathways: (1) enhancing iron uptake (upregulating TFR and downregulating FPN) and (2) promoting lipid peroxidation through NOX4, ALOX12, ALOX15 activation and SLC7A11 suppression. Collectively, these findings demonstrated that sevoflurane exposure induced ferroptosis of neuronal cells in the neonatal brain, triggered by ATM/p53 activation via JNK/p38 MAPK-mediated ROS accumulation and subsequent DNA damage.

Oxidative stress and alterations in redox signalling have been implicated in the pathophysiology of myocardial infarction (MI). NADPH oxidase (Nox) is an important source of reactive oxygen species (ROS) in the infarcted myocardium. Alarmin S100A8/A9 amplifies acute myocardial inflammation in MI and has been shown to be a promising therapeutic target to improve cardiac function post-MI. We aimed to elucidate the underlying mechanisms linking S100A8/A9, oxidative stress and the inflammatory response in MI. MI was induced by permanent left coronary artery ligation in C57BL/6J mice, followed by treatment with the S100A8/A9 inhibitor ABR-238901 (30 mg/kg) or PBS for 3 days. The in-vivo experiments were complemented with mechanistic studies on cultured macrophages (Mac), important cellular effectors in MI. Compared to sham-operated animals, we detected significant increases in the Nox1, Nox2, Nox4 catalytic subunits at mRNA and protein levels, and NADPH-dependent ROS production in the left ventricle of MI mice. S100A8/A9 blockade prevented the up-regulation of Nox1/2/4 expression, reduced ROS formation, suppressed NF-kB activation and prevented NLRP3 inflammasome priming and activation, leading to reduced levels of active IL-1β. In-vitro, S100A8/A9 induced gene expression of Nox catalytic subtypes and NLRP3 in Mac in a TLR4-dependent and dose-dependent manner. These effects were counteracted by pharmacological inhibition of S100A8/9, TLR4, Nox1/4 and Nox2. In conclusion, we show that Nox upregulation and ROS formation triggered by S100A8/A9 contributes to NLRP3 inflammasome priming and increased IL-1β production in the infarcted myocardium. These mechanisms can be therapeutically targeted to prevent inflammatory and oxidant myocardial damage in acute MI.

Traumatic brain injury (TBI) is a leading cause of long-term disability worldwide, with secondary injury mechanisms, including neuroinflammation and oxidative stress, driving much of its chronic pathology. While NADPH oxidase 2 (NOX2)-mediated reactive oxygen species (ROS) production is a recognized factor in TBI, the specific role of microglial NOX2 in perpetuating oxidative and inflammatory damage remains underexplored. Addressing this gap is critical, as current therapeutic approaches primarily target acute symptoms and fail to interrupt the persistent neuroinflammation that contributes to progressive neurodegeneration. Besides NOX, other ROS-generating enzymes, such as CYP1B1, COX2, and XO, also play crucial roles in triggering oxidative stress and neuroinflammatory conditions in TBI. However, this review highlights the pathophysiological role of microglial NOX2 in TBI, focusing on its activation following injury and its impact on ROS generation, neuroinflammatory signaling, and neuronal loss. These insights reveal NOX2 as a critical driver of secondary injury, linked to worsened outcomes, particularly in aged individuals where NOX2 activation is more pronounced. In addition, this review evaluates emerging therapeutic approaches targeting NOX2, such as GSK2795039 and other selective NOX2 inhibitors, which show potential in reducing ROS levels, limiting neuroinflammation, and preserving neurological functions. By highlighting the specific role of NOX2 in microglial ROS production and secondary neurodegeneration, this study advocates for NOX2 inhibition as a promising strategy to improve TBI outcomes by addressing the unmet need for therapies targeting long-term inflammation and neuroprotection. Our review highlights the potential of NOX2-targeted interventions to disrupt the cycle of oxidative stress and inflammation, ultimately offering a pathway to mitigate the chronic impact of TBI.

Medical or surgical interventions are commonly used to alleviate the clinical symptoms of individuals suffering from ischemic heart disease (IHD), but global morbidity and mortality remain high. This is due to the complexity of disease progression and the pathological basis of IHD, which primarily includes myocardial infarction (MI), myocardial ischemia-reperfusion injury (IRI), and heart failure (HF), as well as underlying mechanisms, such as mitochondrial damage, inflammation, oxidative stress, and cardiomyocyte death. However, many drugs have limitations, such as poor stability and low bioavailability, and surgical strategies are often ineffective in preventing disease recurrence. To overcome these problems, it is necessary to develop effective drug delivery systems and technologies. Due to their advantages in enhancing drug utilization, nanomaterials are being used to control drug biodistribution and achieve targeted accumulation, addressing the therapeutic needs of IHD. In this work, we first described the clinical aspects of MI, IRI, and HF in the context of IHD as well as their shared pathological origins. Next, clinical interventional procedures for IHD are summarized. Finally, recent developments in the use of nanomaterials for the treatment of MI, IRI, and HF are highlighted, along with potential directions for future research.

The human endogenous retrovirus type W envelope glycoprotein (ERVWE1), located at chromosome 7q21-22, has been implicated in the pathophysiology of schizophrenia. Our previous studies have shown elevated ERVWE1 expression in schizophrenia patients. Growing evidence suggests that autophagy dysfunction contributes to schizophrenia, yet the relationship between ERVWE1 and autophagy remains unclear. In this study, bioinformatics analysis of the human prefrontal cortex RNA microarray dataset (GSE53987) revealed that differentially expressed genes were predominantly enriched in autophagy-related pathways. Clinical data further demonstrated that serum levels of microtubule-associated protein 1 light chain 3β (LC3B), a key marker of macroautophagy, were significantly elevated in schizophrenia patients compared to controls, and positively correlated with ERVWE1 expression. Cellular and molecular experiments suggested that ERVWE1 promoted macroautophagy by increasing the LC3B II/I ratio, enhancing autophagosome formation, and reducing sequestosome 1 (SQSTM1) expression via upregulation of NADPH oxidase activator 1 (NOXA1). Concurrently, NOXA1 downregulated the expression of key micromitophagy-related genes, including PTEN-induced kinase 1 (PINK1), Parkin RBR E3 ubiquitin-protein ligase (Parkin), and the pyruvate dehydrogenase E1 subunit α 1 (PDHA1). As a result, ERVWE1, via NOXA1, inhibited micromitophagy by suppressing the expression of PINK1, Parkin, and PDHA1, thereby leading to impaired production of mitochondrial-derived vesicles (MDVs). Mechanistically, ERVWE1 enhanced NOXA1 transcription by upregulating upstream transcription factor 2 (USF2). In conclusion, ERVWE1 promotes macroautophagy and inhibits micromitophagy through USF2-NOXA1 axis, providing novel mechanistic insight into the role autophagy dysregulation in schizophrenia. These findings suggest that targeting autophagy pathways may offer novel therapeutic strategies for schizophrenia treatment.

The prevention and treatment of acute ischemic stroke have been longstanding challenges. Therapies targeting angiogenesis hold promising potential for ischemic injury repair. Reactive oxygen species (ROS) production, induced by the overexpression of NADPH oxidase 4 (NOX4), is a key factor that inhibits angiogenesis during the acute phase of ischemia/reperfusion. Therefore, targeting NOX4 gene expression can reduce ROS production and promote angiogenesis. In this study, human neural progenitor cell (hNPC)-derived-exosomal miRNAs were identified using high-throughput sequencing and online database, with miR-100-5p showing potential to suppress NOX4 expression. We then incorporated exogenous miR-100-5p into hNPC-derived exosomes through electroporation. These miR-100-5p-loaded exosomes were then applied to in vitro models of mouse brain microvascular endothelial cells (bEND.3) subjected to oxygen glucose deprivation and reperfusion (OGD/R). The results showed that miR-100-5p could significantly reduce NOX4 expression and ROS levels induced by OGD/R in bEND.3 cells. Similarly, in vivo analysis showed that mice models of middle cerebral artery occlusion (MCAO) injected with hNPC-derived exosomes loaded with miR-100-5p exhibited smaller brain infarct size, reduced apoptosis, and improved neurological performance compared to MCAO mice receiving PBS. Our findings demonstrate the successful delivery of miR-100-5p via hNPC-derived exosomes and its protective effect on brain microvascular endothelial cells following ischemia injury.

We live in a world increasingly dominated by plastic, leading to the generation of microplastic particles that pose significant global health concerns. Microplastics can enter the body via ingestion, inhalation, and direct contact, accumulating in various tissues and potentially causing harm. Despite this, the specific cellular mechanisms and signaling pathways involved remain poorly understood. Macrophages are essential in absorbing, distributing, and eliminating microplastics, playing a key role in the body's defense mechanisms. Recent evidence highlights oxidative stress signaling as a key pathway in microplastic-induced macrophage dysfunction. The accumulation of microplastics generates reactive oxygen species (ROS), disrupting normal macrophage functions and exacerbating inflammation and organ damage. This review serves as the first comprehensive examination of the interplay between microplastics, macrophages, and oxidative stress. It discusses how oxidative stress mediates macrophage responses to microplastics and explores the interactions with gut microbiota. Additionally, it reviews the organ damage resulting from alterations in macrophage function mediated by microplastics and offers a novel perspective on the defense, assessment, and treatment of microplastic-induced harm from the viewpoint of macrophages.

Reactive oxygen species (ROS), regulators of cellular behaviors ranging from signaling to cell death, have complex production and control mechanisms to maintain a dynamic redox balance under physiological conditions. Redox imbalance is frequently observed in tumor cells, where ROS within tolerable limits promote oncogenic transformation, while excessive ROS induce a range of regulated cell death (RCD). As such, targeting ROS-mediated regulated cell death as a vulnerability in cancer. However, the precise regulatory networks governing ROS-mediated cancer cell death and their therapeutic applications remain inadequately characterized. In this Review, we first provide a comprehensive overview of the mechanisms underlying ROS production and control within cells, highlighting their dynamic balance. Next, we discuss the paradoxical nature of the redox system in tumor cells, where ROS can promote tumor growth or suppress it, depending on the context. We also systematically explored the role of ROS in tumor signaling pathways and revealed the complex ROS-mediated cross-linking networks in cancer cells. Following this, we focus on the intricate regulation of ROS in RCD and its current applications in cancer therapy. We further summarize the potential of ROS-induced RCD-based therapies, particularly those mediated by drugs targeting specific redox balance mechanisms. Finally, we address the measurement of ROS and oxidative damage in research, discussing existing challenges and future prospects of targeting ROS-mediated RCD in cancer therapy. We hope this review will offer promise for the clinical application of targeting oxidative stress-mediated regulated cell death in cancer therapy.

The bone marrow microenvironment (BMM) plays a crucial role in the pathogenesis and progression of acute myeloid leukemia (AML). AML cells can modify the BMM to establish a more favorable environment for their survival. However, the mechanism about the complex regulatory interplay between the BMM and AML cells remains unclear. In this study, we used proteomic analysis to elucidate the potential mechanisms underlying the interaction between bone marrow stromal cells (BMSCs) and AML cells. We found that the co-culture of AML cells and BMSCs facilitated the proliferation of AML cells, suppressed the proliferation of BMSCs and triggered their senescence. Furthermore, we show the aberrant expression of S100A8 that plays a crucial role in the communication between AML cells and BMSCs. In the co-culture system, overexpression of S100A8 in AML cells activated NOX2 and induced the production of reactive oxygen species (ROS) in the supernatant, thereby suppressing the proliferation of BMSCs and facilitating the senescence of BMSCs. Subsequently, aging BMSCs secreted a variety of cytokines, including IL-6, CXCL5, MIP-1b, etc. as shown by Cytokine Array and qPCR analysis, which had stimulatory effects on the progression of AML. In conclusion, the present study reveals the crucial involvement of the S100A8-NOX2-ROS signaling pathway in mediating communication between AML cells and BMSCs, suggesting that targeting S100A8 may constitute an efficient strategy for AML therapy.

Receptor-mediated endocytosis (RME) is a commonly recognized receptor internalization process of receptor degradation or recycling. However, recent studies have supported that RME is closely related to signal propagation and amplification from the plasma membrane to the cytosol. Few studies have elucidated the role of H2O2, a mild oxidant among reactive oxygen species (ROS) in RME and second messenger of signal propagation. In the present study, we investigated the regulatory function of H2O2 in early endosomes during signaling throughout receptor-mediated endocytosis. In mammalian cells with a physiological amount of H2O2 generated during epidermal growth factor (EGF) activation, fluorescence imaging showed that the levels of two activating phosphorylations on Ser473 and Thr308 of Akt were transiently increased in the plasma membrane, but the predominant p-Akt on Ser473 appeared in early endosomes. To examine the role of endosomal H2O2 molecules as signaling mediators of Akt activation in endosomes, we modulated endosomal H2O2 through the ectopic expression of an endosomal-targeting catalase (Cat-Endo). The forced removal of endosomal H2O2 inhibited the Akt phosphorylation on Ser473 but not on Thr308. The levels of mSIN and rictor, two components of mTORC2 that work as a kinase in Akt phosphorylation on Ser473, were also selectively diminished in the early endosomes of Cat-Endo-expressing cells. We also observed a decrease in the endosomal level of the adaptor protein containing the PH domain, the PTB domain, and the Leucine zipper motif 1 (APPL1) protein, which is an effector of Rab5 and key player in the assembly of signaling complexes regulating the Akt pathway in Cat-Endo-expressing cells compared with those in normal cells. Therefore, the H2O2-dependent recruitment of the APPL1 adaptor protein into endosomes was required for full Akt activation. We proposed that endosomal H2O2 is a promoter of Akt signaling.

The genotoxic drug doxorubicin (Dox) remains one of the most powerful chemotherapeutic options available for a wide range of cancers including breast, ovarian, and other cancers. However, emerging evidence links Dox treatment with chemotherapy-induced cognitive impairment, a condition that is popularly referred to as Dox-induced neurotoxicity or "chemobrain", which limits the use of the drug. There are no specific treatments for Dox-induced neurotoxicity, only interventions to mitigate the neurotoxic effects of the drug. Accumulating evidence indicates that DNA damage, oxidative stress, dysregulation of autophagy and neurogenesis, inflammation, and apoptosis play central roles in Dox-induced neurotoxicity. Additionally, germline mutations in the tumour suppressor genes breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) increase the risk of breast, ovarian, and related cancers. BRCA1 and BRCA2 are distinct proteins that play crucial, unique roles in homologous recombination-mediated double-stranded break repair. Furthermore, BRCA1 and 2 mitigate oxidative stress in both neural cells and brain microvascular endothelial cells, which suggests that they have a critical role as regulators of pathways central to the development of Dox-induced neurotoxicity. Despite research on the effects of Dox on cognitive function, there is a gap in knowledge about the role of BRCA1 and BRCA2 in Dox-induced neurotoxicity. In this review, we discuss existing findings about the role of different mechanisms and the role of BRCA1 and BRCA2 in Dox-induced neurotoxicity, along with future perspectives.

Electronic nicotine delivery systems (ENDS) arrived on the U.S. market in 2007 and rapidly grew in popularity as a harm reduction tool for traditional cigarette users. While initially marketed as a healthier alternative to combustible cigarettes, the unique mixture of chemical constituents in ENDS products and their emissions have led to rising concern about their safety and the long-term health implications. Given the lack of long-term, epidemiological research on the health effects of these products, recent research has sought to understand the impacts on cellular components and gain understanding of acute effects to inform potential chronic health implications. Studies have demonstrated the deleterious effects the use of ENDS has on the oral cavity, respiratory, and cardiovascular systems. ENDS use has been linked to gingival inflammation and alterations in the oral microbiome contributing to periodontal disease. Further, the presence of heavy metals and other constituents in ENDS emissions contribute to aberrant oxidative stress and inflammation within the lung, contributing to alterations in functional lung capacity and respiratory symptoms in ENDS users. In addition, harmful components of ENDS emissions make their way to the circulatory system, leading to detrimental impacts in cardiovascular functioning such as a rise in blood pressure, impaired vascular functioning, and increased heart rate, all of which are known to underscore long-term cardiovascular ailments. This review will provide an in-depth discussion of the current literature available on the consequences of ENDS use on the oral cavity, respiratory, and cardiovascular systems as well as provide insight into long-term implications that may result.

Stroke is the leading cause of mortality and morbidity worldwide, significantly impacting human welfare and overall health. Myeloperoxidase (MPO), a heme peroxidase secreted by neutrophils, plays a crucial role in the body's defense mechanisms, exhibiting pro-inflammatory and pro-oxidative properties. Additionally, MPO compromises the structural integrity and functional capacity of blood vessels, potentially leading to the formation and dislodgement of atherosclerotic plaques, vascular stenosis, thrombosis, and ultimately contributing to stroke occurrence. Following a stroke, a significant influx of neutrophils infiltrates the cerebral tissue, leading to an excessive release of MPO-derived oxidants and the subsequent promotion of various inflammatory mediators, thereby exacerbating cerebral tissue damage. Numerous studies have consistently demonstrated the pivotal role of MPO in the pathogenesis and progression of stroke, establishing it as a reliable prognostic indicator. Exploring the association between MPO and stroke enhances our understanding of the pathological mechanisms underlying stroke and aids in the development of therapeutic interventions. This review provides a comprehensive analysis of the molecular structure and cellular localization of MPO, elucidating its critical role in mediating vascular injury, the formation of Neutrophil Extracellular Traps (NETs), oxidative stress, neuroinflammation, disruption of the blood-brain barrier (BBB), and neuronal apoptosis during stroke pathogenesis. Additionally, we discuss recent advancements in MPO-targeted drugs and Traditional Chinese Medicine compounds as potential therapeutic strategies for stroke treatment.

Reactive oxygen and nitrogen species are essential components of diverse intracellular signaling pathways. In addition to their involvement in apoptosis, reactive oxygen and nitrogen species are crucial in the regulation of multiple developmental and physiological processes. This review aims to summarize their role in the regulation of key ovarian stages: ovulation, maturation and postovulatory ageing of the oocyte, and the formation and regression of the corpus luteum. At the cellular level, a mild increase in reactive oxygen and nitrogen species is associated with the initiation of a number of regulatory mechanisms, which might be suppressed by increased activity of the antioxidant system. Moreover, a mild increase in reactive oxygen and nitrogen species has been linked to the control of mitochondrial biogenesis and abundance in response to increased cellular energy demands. Thus, reactive oxygen and nitrogen species should also be perceived in terms of their positive role in cellular signaling. On the other hand, an uncontrolled increase in reactive oxygen species production or strong down-regulation of the antioxidant system results in oxidative stress and damage of cellular components associated with ovarian pathologies and ageing. Similarly, the disturbance of signaling functions of reactive nitrogen species caused by dysregulation of nitric oxide production by nitric oxide synthases in ovarian tissues interferes with the proper regulation of physiological processes in the ovary.

Long-term reliability of microelectrodes implanted in the cortex is hindered due to the foreign body response that occurs at the electrode-tissue interface. Following implantation, there is disruption of the blood-brain-barrier and vasculature, resulting in activation of immune cells and release of erythrocytes. As a result of hemolysis, erythrocytes degrade to heme and then to free iron. Excess free iron can participate in the Fenton Reaction, producing reactive oxygen species (ROS). Iron-mediated ROS production can contribute to oxidation of lipids, proteins, and DNA, facilitating a hostile environment of oxidative stress leading to oxidative cellular damage, cytotoxicity, and cell death. The objective of this study was to show the iron accumulation and the downstream effects of oxidative stress at the injury site. A 16-channel microelectrode array (MEA) was implanted in the rat somatosensory cortex. Our results indicated significant elevation of NOX complex subunits across timepoints, suggesting sustained oxidative stress. In a separate group of animals, we administered an iron chelator, deferoxamine mesylate (DFX), to evaluate the effects of chelation on iron accumulation, oxidative stress and damage, and neuronal survival. Results indicate that animals with iron chelation showed reduced ferric iron and markers of oxidative stress and damage corresponding with increased expression of neuronal cell bodies and electrophysiological functional performance. In summary, the study reveals the role of iron in mediating oxidative stress and the effects of modulating iron levels using iron chelation at the electrode-tissue interface. STATEMENT OF SIGNIFICANCE: Iron accumulation has been observed in central nervous system injuries and in neurodegenerative diseases such as Alzheimer's and Parkinson's disease. While the role of iron is studied in various neurodegenerative diseases and traumatic brain injury, iron accumulation and its effect on oxidative stress is not known for intracortical implants where there is a persistent injury due to the presence of a foreign device in the brain tissue. The study seeks to understand the effects of iron accumulation on oxidative stress and damage at the electrode-tissue interface in intracortical implants by using iron chelation as a method of modulating iron levels at the interface.

Lysosomes are organelles that play pivotal roles in macromolecule digestion, signal transduction, autophagy, and cellular homeostasis. Lysosome instability, including the inhibition of lysosomal intracellular activity and the leakage of their contents, is associated with various pathologies, including cancer, neurodegenerative diseases, inflammatory diseases and infections. These lysosomal-related pathologies highlight the significance of factors contributing to lysosomal dysfunction. The vulnerability of the lysosomal membrane and its components to internal and external stimuli make lysosomes particularly susceptible to damage. Cells are equipped with mechanisms to repair or degrade damaged lysosomes to prevent cell death. Understanding the factors influencing lysosome stabilization and damage repair is essential for developing effective therapeutic interventions for diseases. This review explores the factors affecting lysosome acidification, membrane integrity, and functional homeostasis and examines the underlying mechanisms of lysosomal damage repair. In addition, we summarize how various risk factors impact lysosomal activity and cell fate.

Dimethyl phthalate (DMP) can enter the human body and be absorbed into the bloodstream to produce monomethyl phthalate (MMP). MMP in the environment can also enter the bloodstream. However, little is known about the toxicity of the phthalate metabolite MMP in most organisms. In this study, the erythrocyte toxicity of MMP and a preventive approach were investigated using Sprague-Dawley (SD) rats as the model animal under MMP concentrations of 5-250 mg/kg (sub-chronic exposure in vivo) and 1.25-100 μg/mL (acute exposure in vitro). The experimental results indicate that the interaction of MMP with erythrocytes caused oxidative damage, which decreased the number of red blood cells and the hemoglobin content and increased the content of methemoglobin and the iron release of hemoglobin in rat blood. However, the above results were not observed when MMP directly interacted with hemoglobin. The antioxidants vitamin C and vitamin E improved the above blood indicators in rats. The results of this study provide certain theoretical guidance for the evaluation of the potential risks of phthalate metabolites.

Cardiomyopathies comprise a heterogeneous group of cardiac disorders characterized by structural and functional abnormalities in the absence of significant coronary artery disease, hypertension, valvular disease, or congenital defects. Major subtypes include hypertrophic, dilated, arrhythmogenic, and stress-induced cardiomyopathies. Oxidative stress (OS), resulting from an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, has emerged as a key contributor to the pathogenesis of these conditions. ROS-mediated injury drives inflammation, protease activation, mitochondrial dysfunction, and cardiomyocyte damage, thereby promoting cardiac remodeling and functional decline. Although numerous studies implicate OS in cardiomyopathy progression, the precise molecular mechanisms remain incompletely defined. This review provides an updated synthesis of current findings on OS-related signaling pathways across cardiomyopathy subtypes, emphasizing emerging therapeutic targets within redox-regulatory networks. A deeper understanding of these mechanisms may guide the development of targeted antioxidant strategies to improve clinical outcomes in affected patients.

Aging-associated mitochondrial oxidative stress has been implicated in ventricular tachyarrhythmias (VT), but the specific proarrhythmic mechanisms of mitochondrial pro-oxidative systems remain unclear. NADPH oxidase 4 (NOX4) expression in the heart increases with age, leading to mitochondrial oxidative stress, dysfunction, and adverse myocardial remodeling. This study investigated the susceptibility to aging-associated ventricular arrhythmia and the associated triggers and substrates using transgenic mice with mitochondria-targeted Nox4 overexpression (Nox4TG mice). Nox4TG mice showed a significantly higher incidence of pacing-induced VT, associated with shorter action potential duration (APD) due to increased transient outward potassium currents. Fractional sarcoplasmic reticulum (SR) Ca2+ release and Ca2+ leak remained intact despite these changes. However, the frequency of Ca2+ sparks was reduced, and ryanodine receptor 2 (RyR2) oxidation was observed. Compensatory upregulation of SERCA expression in response to RyR2 inhibition accelerated SR Ca2+ reuptake and improved cardiomyocyte mechanical relaxation. Nox4TG mice exhibited extensive ventricular fibrosis and marked pro-inflammatory macrophage infiltration, with elevated TNF, TGF-β, and MKI67 expression. Treatment with Setanaxib, a NOX1/NOX4 inhibitor, or co-expression of mitochondrial catalase in Nox4TG (Nox4TG + mCAT) mice, mitigated fibrosis, reduced inflammation, and protected against VT. These findings suggest that mitochondrial NOX4 overexpression promotes VT through electrical remodeling and pro-arrhythmogenic structural changes despite RyR2 oxidation and dysfunction. In conclusion, aging-related NOX4-driven mitochondrial oxidative stress increases the risk of VT by promoting changes in the electrical and structural properties of the myocardium, highlighting potential therapeutic strategies that target NOX4 in cardiac pathologies associated with aging.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder with uncleared mechanisms. Short-chain enoyl-CoA hydratase 1 (ECHS1) is a mitochondrial enzyme critical for the β-oxidation of fatty acids and ATP production. This study aims to explore the roles of ECHS1 in PD by using rotenone-induced experimental PD models.

To evaluate the role of ECHS1 in rotenone-induced dopaminergic neurodegeneration, adeno-associated virus (AAV)-ECHS1 was stereotactically injected into the substantia nigra region of mice to overexpress ECHS1. Motor function of mice among groups was detected by rotarod test and gait analysis. Neurodegeneration, mitochondrial dysfunction and apoptosis were determined by immunohistochemistry, immunofluorescence staining, Western blot or kits, respectively.

The expression and activity of ECHS1 were decreased in PD mice and positive correlations between ECHS1 reduction and dopaminergic neurodegeneration were observed. Overexpression of ECHS1 by AAV delivery attenuated loss of dopaminergic neuron and motor deficits in PD mice. Mechanistically, ECHS1 attenuated rotenone-induced mitochondrial swelling and loss of cristae as well as decrease of ATP production, mitochondrial membrane potential, complex I/IV activities and oxygen consumption rate (OCR). Mitochondrial ROS (mtROS)-targeted antioxidant mito-TEMPO prevented ECHS1 silence-mediated mitochondrial dysfunction. Furthermore, we found that ECHS1 interacted with NADPH oxidase 4 (NOX4), resulting in decrease of NOX4 activation and subsequent reduction of mtROS production and mitochondrial dysfunction. Finally, inhibition of NOX4 by GLX351322 or mtROS production by mito-TEMPO greatly reduced ECHS1 silence-mediated apoptosis in rotenone-treated SH-SY5Y cells.

ECHS1 counteracted dopaminergic neurodegeneration through inhibition of mtROS and restoration of mitochondrial function via interaction with NOX4. Given the central role of mitochondrial dysfunction in PD pathogenesis, elucidating the role of ECHS1 holds great promise for uncovering novel therapeutic targets.

Myocardial ischemia-reperfusion injury (MIRI) is fatal to patients, leading to cardiomyocyte death and myocardial remodeling. Reactive oxygen species (ROS) and oxidative stress play important roles in MIRI. There is a complex crosstalk between ROS and regulatory cell deaths (RCD) in cardiomyocytes, such as apoptosis, pyroptosis, autophagy, and ferroptosis. ROS is a double-edged sword. A reasonable level of ROS maintains the normal physiological activity of myocardial cells. However, during myocardial ischemia-reperfusion, excessive ROS generation accelerates myocardial damage through a variety of biological pathways. ROS regulates cardiomyocyte RCD through various molecular mechanisms. Targeting the removal of excess ROS has been considered an effective way to reverse myocardial damage. Many studies have applied antioxidant drugs or new advanced materials to reduce ROS levels to alleviate MIRI. Although the road from laboratory to clinic has been difficult, many scholars still persevere. This article reviews the molecular mechanisms of ROS inhibition to regulate cardiomyocyte RCD, with a view to providing new insights into prevention and treatment strategies for MIRI.

Reactive oxygen species (ROS) play an important role in the pathogenesis of pulmonary arterial hypertension (PAH) and NADPH oxidases (NOXs) as sources of ROS are implicated in the development of the disease. We previously showed that NOX isozyme 1 (NOX1)-derived ROS contributes to pulmonary vascular endothelial cell (EC) proliferation in response to PAH triggers in vitro. However, whether and how NOX1 is involved in PAH in vivo have not been explored nor has NOX1 been examined as a viable and effective therapeutic disease target.

Herein, infusion of mice exposed to Sugen/hypoxia (10 % O2) with a specific NOX1 inhibitor, NOXA1ds, delivered via osmotic minipumps (i.p.), significantly suppressed pathological changes in hemodynamic parameters characteristic of PAH. Furthermore, lungs of human patients with idiopathic PAH (iPAH) and exploratory RNA-seq analysis of hypoxic human pulmonary ECs, in which NOX1 was suppressed, were probed. The findings showed a clear indication of NOX1 in the promotion of both protein disulfide isomerase (PDI) and the unfolded protein response (UPR; in particular, the PERK arm of the pathway including eIF2α and ATF4) leading to proliferation. In aggregate, these results are consistent with a causal role for NOX1 in the development of mouse and human PAH and reveal a novel and mechanistic pathway by which NOX1 activates the UPR response during EC proliferation.

NOX1 promotes phenotypic changes in ECs that are pivotal to proliferation and PAH through activation of the UPR. Taken together, our results are consistent with selective inhibition of NOX1 as a novel modality for attenuating PAH.

Preeclampsia (PE) is a frequent and dangerous multisystemic pregnancy complication, associated with blood pressure control. Some antioxidants, including chocolate-derived epicatechin, can effectively attenuate hypertensive disorders.

This study aimed to assess whether epicatechin or dark chocolate (DC) could revert vascular increased reactivity and oxidative stress, both features of an experimental PE model.

Rats from healthy pregnant or PE groups received vehicle, epicatechin (10 mg/kg/day) po, or DC (1 g) po, administered on days 1-14 (early) or days 7-21(late) of pregnancy. Blood pressure was measured by the tail-cuff plethysmography method. Aorta contractility was evaluated using a conventional isolated organ bath, and oxidative stress was determined by nicotine adenine dinucleotide phosphate reduced (NADPH) serum activity.

Epicatechin and DC significantly reduced hypertension, decreased abdominal aorta contractility, and decreased NADPH activity of the PE animals. The effects were more evident when administered during the last 2 weeks of pregnancy.

Results suggest that epicatechin has a significant antihypertensive effect in PE mediated by an antioxidant activity that improves vascular contractility.

Cancer cells are capable of surviving, proliferating, and invading or migrating within hypoxic environments by regulating various adaptive mechanisms. Due to the activation of oncogenes and the inactivation of tumor suppressor genes, and relative deficiencies in oxygen and nutrients, cancer cells demonstrate elevated production of reactive oxygen species (ROS), primarily sourced from NADPH oxidases (NOX family). A key aspect of the reorientation of tumor cell metabolism is the combating of cellular oxidative stress through the promotion of antioxidant molecule synthesis to counteract ROS production. Given that most cancers experience hypoxia and that NOX is closely linked to numerous redox-dependent signaling pathways, the expression and function of NOX are altered in various malignancies. Therefore, this review summarizes the characteristics of NOX family members, their influence on tumor proliferation, invasion, and migration, the role of NOX in promoting tumor angiogenesis, the impact of NOX on the function of immune cells within the tumor microenvironment, and the potential of targeting NOX in tumor therapy. This aims to offer a fresh viewpoint on a comprehensive understanding of the functions of NOX family members.

(1) Background: Silicosis, a chronic lung fibrosis disorder triggered by the accumulation of silica dust in the deep lung regions, is characterized by intricate molecular mechanisms. Among these, the NOX2 (NADPH oxidase 2) and JNK (C-Jun N-terminal kinase) signaling pathways play pivotal roles in the progression of pulmonary fibrosis. Despite their significance, the precise mechanisms underlying the crosstalk between these pathways remain largely unexplored. (2) Methods: To unravel these interactions, we examined the interplay between JNK and NOX2 in human epithelial cells subjected to silica dust exposure through in vivo assays, followed by validation using single-cell sequencing. Our findings consistently revealed elevated expression levels of key components from both the JNK signaling pathway and NOX2 in the lungs of silicosis-induced mice and silica-treated human epithelial cells. (3) Results: Notably, the activation of these pathways was linked to increased ROS (reactive oxygen species) production, elevated levels of profibrogenic factors, and diminished cell proliferation in silica-exposed human lung epithelial cells. Further mechanistic analyses demonstrated that JNK signaling amplifies NOX2 expression and ROS production induced by silica exposure, while treatment with the JNK inhibitor SP600125 mitigates these effects. Conversely, overexpression of NOX2 enhanced silica-induced JNK activation and the expression of epithelial-mesenchymal transition (EMT)-related factors, whereas NOX2 knockdown exerted the opposite effect. These results suggest a positive feedback loop between JNK and NOX2 signaling, which may drive EMT in lung epithelial cells following silica exposure. (4) Conclusions: This reciprocal interaction appears to play a critical role in lung epithelial cell damage and the pathogenesis of silicosis, shedding light on the molecular mechanisms underlying profibrogenic disease and offering potential avenues for therapeutic intervention.

The overproduction of peroxynitrite (ONOO-) in mitochondria has been associated with various pathophysiological conditions and disorders. However, the use of fluorescent probes to visualize mitochondrial ONOO- in biological systems is limited due to their low emission wavelengths and small Stokes shifts, which present significant challenges. In this study, we designed and synthesized julolidine-based near-infrared (NIR) fluorescent probes, named JQMe and JCN, specifically to monitor mitochondrial ONOO-. Comparative photophysical studies revealed that JQMe exhibits superior properties for sensing ONOO- compared to JCN. Initially, JQMe emitted fluorescence emission at 706 nm via an intramolecular charge transfer (ICT) mechanism. Upon the addition of ONOO-, the NIR fluorescence emission of JQMe at 706 nm was suppressed, resulting in a rapid on-off fluorescence response within 5 minutes. JQMe exhibited high specific selectivity towards ONOO- over other competing interferents, accompanied by a colorimetric change from deep blue to colorless. Additionally, JQMe exhibited a significant Stokes shift of 106 nm and a low detection limit of 6.5 nM. The proposed sensing mechanism was validated through ESI mass spectrometry and DFT studies. Furthermore, JQMe was successfully employed to monitor both endogenous and exogenous ONOO- in living cells using inducer and inhibitor tests. Remarkably, time-dependent colocalization experiments revealed that JQMe effectively targets and reacts with mitochondrial ONOO-.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and synaptic dysfunction. The accumulation of amyloid beta (Aβ) plaques and hyperphosphorylated tau protein leads to neuronal dysfunction, neuroinflammation, and glial cell activation. Emerging evidence suggests that peripheral insulin resistance and chronic inflammation, often associated with type 2 diabetes (T2D) and obesity, promote increased proinflammatory cytokines, oxidative stress, and immune cell infiltration. These conditions further damage the blood-brain barrier (BBB) integrity and promote neurotoxicity and chronic glial cell activation. This induces neuroinflammation and impaired neuronal insulin signaling, reducing glucose metabolism and exacerbating Aβ accumulation and tau hyperphosphorylation. Indeed, epidemiological studies have linked T2D and obesity with an increased risk of developing AD, reinforcing the connection between metabolic disorders and neurodegeneration. This review explores the relationships between peripheral insulin resistance, inflammation, and BBB dysfunction, highlighting their role in glial activation and the exacerbation of AD pathology.

Preeclampsia is a hypertension condition of human pregnancy that poses a significant risk to pregnant women and their fetus. It complicates about 2-8% of human pregnancies worldwide and displays multifactorial pathogenesis, including increased placental oxidative stress because of disturbed utero-placental blood flow. Recent evidence suggests that increased oxidative stress promotes acceleration of the placental senescence which is implicated in the pathogenesis of preeclampsia. This review focuses on the mechanisms that lead to oxidative stress in preeclamptic patients and examines the role of oxidative stress-induced placental senescence in the pathogenesis of the disease.

In this study, the impact of light-emitting diodes (LEDs) in different spectrums was investigated on the seed germination and post-germinative performance of Capsicum frutescens seedlings. The seeds were exposed to different LED lights (full spectrum, white, red, blue, and red-blue) for 0, 1, 2, and 4 h (h). The seeds were placed for a week in darkness to investigate germination, and then the growth mechanisms were studied in four-week-old seedlings. Results indicated that germination percentage was promoted markedly under 2 h red and full lights and also in 1 h blue, which was accompanied by the regulation of H2O2 level and NADPH oxidase (NOX) activity. Sprout growth and height were more heightened under 2 h red light, but their contents decreased considerably under blue light with a rising incubation time. Red light induced more biomass yield, chlorophyll (Chl) pigments, Chl a/b ratio and florescence in four-week-old seedlings. Blue light also increased Chl pigments, but decreased biomass yield by enhancing malondialdehyde (MDA) level. Increased growth in seedlings treated to red light was associated with upregulating Rubisco gene expressions (rbcL and rbcS) and its activity. Red and red-blue lights promoted the activity of superoxide dismutase, glutathione reductase, and ascorbate peroxidase enzymes to increase ascorbic acid (ASA) production in the ascorbate-glutathione cycle. Total phenolic (0.22 mg DAG g- 1 DW), ASA (89.58 mg 100 g- 1 FW) and capsaicinoids (2.73 mg g- 1 DW) contents were heightened under red light, while carotenoid (11.78 µg g- 1 FW) content was more accumulated under blue light. The findings of this study suggest red light modulates NOX activity and H2O2 level for inducing seed germination and seedling quality in C. frutescens, which can create important implications for the production of antioxidant metabolites and increase the cultivation area of this plant.

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by a pathology that includes the aggregation of alpha-synuclein (α-syn), oxidative stress, and neuroinflammation. While existing treatments can alleviate motor symptoms, they have limited efficacy in slowing disease progression and improving non-motor symptoms. In recent years, molecular hydrogen has been recognized for its potential neuroprotective effects, attributed to its selective antioxidant and anti-inflammatory properties. While preclinical studies demonstrate promising results, clinical trials conducted thus far have yielded mixed outcomes, with some trials reporting limited or no therapeutic benefit. This review systematically analyzes the mechanisms of action of molecular hydrogen in PD and related neurodegenerative disorders, emphasizing its antioxidant, anti-inflammatory, and anti-apoptotic properties. By evaluating evidence from both preclinical and clinical studies, this paper explores the potential of molecular hydrogen to attenuate oxidative stress, modulate inflammatory responses, and inhibit apoptosis in neuronal cells, while also identifying key gaps in current research. As a novel neuroprotective agent, molecular hydrogen holds potential in PD and other neurodegenerative diseases, but further well-designed clinical trials are needed to validate its efficacy. Future studies should focus on elucidating the mechanisms through which hydrogen exerts its neuroprotective effects, particularly concerning α-syn aggregation and its clearance pathways, as well as Nrf2-mediated immunomodulation. Furthermore, large-scale, multicenter clinical trials are necessary to establish efficacy benchmarks and personalized delivery protocols.

Small cell lung cancer (SCLC) is one of the malignancies with the worst prognosis, and there have been no major breakthroughs in its treatment for a long time. The majority of patients are diagnosed at the extensive stage, where the only option is chemotherapy, and even the addition of immune checkpoint inhibitors results in only modest benefits. The characterization of the molecular mechanisms behind therapy resistance has relevance in finding novel therapeutic approaches. Previous studies showed the possibility of annexin A1's (ANXA1) involvement in the immunosuppressive tumor microenvironment in SCLC, and there are studies showing the direct effects of ANXA1 modulation on cancer cell aggressiveness.

We aimed to characterize the roles of ANXA1 expression using publicly available transcriptomic data, the RNA-seq-based predictive algorithms EPIC and ESTIMATE, and immunohistochemistry on patient samples. For the in vitro studies, we silenced ANXA1 expression with short hairpin RNA in three SCLC cell lines, measured the growth rate with the trypan blue exclusion assay, assessed the chemosensitivity to cisplatin and etoposide with the Presto BlueTM viability assay, and performed Western blots to assess changes in the levels of metabolic and mesenchymal markers and transcriptional drivers.

ANXA1-high tumors are associated with significantly increased immune infiltrates, stromality, and tumor-associated macrophages (TAMs). The ANXA1 protein is expressed on tumor cells and TAMs at the tissue level. ANXA1 silencing in H841 cells did not affect the growth rate; in SW1271 cells, shANXA1 cells grew significantly slower than shCTRL cells. Meanwhile, in H1048 cells, proliferation was significantly faster. Despite the different growth rates of the tested cell lines, ANXA1 silencing decreased the chemosensitivity to both cisplatin and etoposide in all three cell lines. Gene expression changes in mesenchymal markers, metabolic markers, dominant transcriptional drivers, and immune-relevant molecules were also characterized.

This is the first comprehensive characterization of ANXA1 in SCLC to reveal its role in the tumor's cell biology and the TME, aiming to boost further research in the field.

Rac and Rap1A are small GTPases with the redox-sensitive GX4GK(S/T)C/ECS and NKCD motif. Of the known NADPH oxidase (NOX) isoforms, NOX1 and NOX2 function with the redox-sensitive Rac. Both exhibit an oxidative burst in which superoxide production is initially lagged but then accelerated. This burst is a reflection of NOX1 and NOX2 autoactivations occurring alongside the redox-dependent Rac autoactivation. NOX2 also contains the redox-sensitive Rap1A. However, its role in NOX2 function was unknown. In this study, we show that Rap1A is also autoactivated by its redox response, which is coupled to Rac and NOX2 autoactivations. This coupling is found to be mediated through the Rap1A-dependent recruitment of the Rac GEF P-REX1 to the NOX2 system. We further show that the initiation threshold and propagation rate of Rap1A autoactivation are lower and slower, respectively, than those of Rac and NOX2. The low-threshold Rap1A autoactivation recruits P-REX1 to the NOX2 system, resulting in the production of active Rac, thereby aiding the high-threshold initiation and propagation of Rac and NOX2 autoactivations. This results in the rapid completion of the NOX2 oxidative burst, which is specific to NOX2 because NOX1 lacks Rap1A. The redox response differences between the Rap1A NKCD motif and the Rac GX4GK(S/T)C/ECS motif appear to be the basis for the feature differences between Rap1A autoactivation and those of Rac and NOX2 autoactivations. The GX4GK(S/T)C/ECS and NKCD motifs are found in many redox-sensitive Rho/Rab and Ras family GTPases, respectively. Findings here shed light on previously unknown redox-dependent functional distinctions between these small GTPases.

Cancer drug resistance occurs when cancer cells evade cell death following treatment with chemotherapy, radiation therapy, and targeted therapies. This resistance is often linked to the reprogramming of programmed cell death (PCD) pathways, allowing cancer cells to survive drug-induced stress. However, certain anticancer therapies, when combined with specific agents or inhibitors, can induce ferroptosis-a form of cell death driven by iron-dependent lipid peroxidation. Currently, extensive preclinical and clinical research is underway to investigate the molecular, cellular, and tissue-specific mechanisms underlying ferroptosis, with the goal of identifying strategies to overcome drug resistance in cancers unresponsive to conventional PCD pathways. By harnessing ferroptosis, cancer cells can be compelled to undergo lipid peroxidation-induced death, potentially improving therapeutic outcomes in patients with cancer. This short review aims to enhance the understanding of ferroptosis inducers in cancer therapy and stimulate further research into ferroptosis-based approaches for more effective clinical cancer treatment.

Mesenchymal stem cell derived extracellular vesicles (MSC-EVs) are key paracrine mediators involved in various autoimmune diseases. While current research on EVs predominantly focuses on their protein and nucleic acid components, small peptides received less attention. In this study, we found IFN-γ-treated MSC-EVs, as engineered EVs, exhibit better anti-inflammatory effects both in vitro and in vivo. Through LC-MS/MS and bioinformatics analysis, we identified four peptides-C3-1, C3-2, B2M-1, and IFIT3-1-that are highly expressed in IFN-γ-treated MSCs-EVs. These peptides significantly mitigate the proliferation inhibition of HUVEC cells induced by H₂O₂ and enhance their migratory capacity. Furthermore, they downregulate the expression of inflammatory cytokines TNF-α and IL-6 in H₂O₂-induced oxidative stress models of HUVEC and LPS-induced inflammatory models of RAW264.7 macrophages. The peptides also upregulate p-AKT and HIF-1α, with C3-1 demonstrating superior anti-inflammatory efficacy in both cell models. Consistent with the in vitro findings, in vivo experiments revealed that C3-1 reduces LPS-induced inflammatory cell infiltration in liver tissue and restores hepatocyte structural integrity, as evidenced by HE-stained liver sections. Western blot analysis further confirmed that C3-1 upregulates p-AKT expression and suppresses inflammatory cytokines. Collectively, these findings suggest that C3-1 exerts its anti-inflammatory effects via activation of the AKT signaling pathway and regulation of TNF-α and IL-6. This study not only highlights the anti-inflammatory potential of IFN-γ-treated MSC-derived EVs but also identifies C3-1 as a promising candidate for anti-inflammatory drug development. Notably, this is the first study to identify degraded peptides within EVs, providing a foundation for future research in this area.

Heat stress (HS) is one of the most important stressors in chickens, and its adverse effects are primarily caused by disturbing the redox homeostasis. An increase in electron leakage from the mitochondrial electron transport chain is the major source of free radical production under HS, which triggers other enzymatic systems to generate more radicals. As a defense mechanism, cells have enzymatic and non-enzymatic antioxidant systems that work cooperatively against free radicals. The generation of free radicals, particularly the reactive oxygen species (ROS) and reactive nitrogen species (RNS), under HS condition outweighs the cellular antioxidant capacity, resulting in oxidative damage to macromolecules, including lipids, carbohydrates, proteins, and DNA. Understanding these detrimental oxidative processes and protective defense mechanisms is important in developing mitigation strategies against HS. This review summarizes the current understanding of major oxidative and antioxidant systems and their molecular mechanisms in generating or neutralizing the ROS/RNS. Importantly, this review explores the potential mechanisms that lead to the development of oxidative stress in heat-stressed chickens, highlighting their unique behavioral and physiological responses against thermal stress. Further, we summarize the major findings associated with these oxidative and antioxidant mechanisms in chickens.

Hyperphosphataemia is a key contributor to oxidative stress (OS) and cellular dysfunction across various pathological conditions. While numerous studies have associated phosphate overload with redox imbalances, the role of NADPH oxidase (NOX) in this process has received limited attention. NOX enzymes are major enzymatic sources of reactive oxygen species (ROS), and their activation has been implicated in the progression of chronic kidney disease, vascular calcification, metabolic disorders, and cancer development. Under hyperphosphataemic conditions, excessive ROS production exacerbates endothelial dysfunction, promotes vascular smooth muscle cell transdifferentiation, induces chronic inflammation, and facilitates tumour progression. Despite increasing evidence linking phosphate metabolism to NOX activation, the underlying molecular mechanisms remain poorly characterised. This review critically examines the relationship between hyperphosphataemia and NADPH oxidase-mediated OS and explores its impact on disease pathophysiology. By providing an integrated analysis of the current findings, this work aims to highlight the pathological consequences of phosphate-induced OS and identify potential therapeutic strategies to mitigate its effects.

Oxidative stress, a pivotal driver of neurodegenerative diseases, results from an imbalance between the generation of reactive oxygen species (ROS) and cellular antioxidant defenses. This review provides a comprehensive analysis of key oxidative stress sources, focusing on NADPH oxidase (NOX) hyperactivity and mitochondrial Uncoupling Protein (UCP) downregulation. Critically, we examine the therapeutic potential of phytochemicals in mitigating NOX-mediated ROS generation through direct enzyme inhibition, including impacts on NOX subunit assembly and gene expression. Furthermore, we explore the ability of phytochemicals to bolster cellular antioxidant defenses by activating the Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway, elucidating the upregulation of antioxidant genes, such as GPx, SOD, CAT, and HO-1. This review expands beyond confined overviews; emphasizes specific molecular interactions between phytochemicals and target proteins, including NOX isoforms; and provides an in-depth analysis of the specific antioxidant genes upregulated via Nrf2. This approach aims to pave the way for targeted and translatable therapeutic strategies in neurodegenerative diseases. Ultimately, this review illuminates the intricate molecular dynamics of oxidative stress in neurodegenerative diseases; underscores the potential of phytochemicals to restore redox homeostasis and reverse pathological conditions through precise modulation of key signaling pathways.