Search Results (4,039)

Glaucoma is the leading cause of irreversible blindness worldwide and is characterized by progressive retinal ganglion cell (RGC) loss and optic nerve degeneration. While elevated intraocular pressure (IOP) remains the primary modifiable risk factor, a certain proportion of patients continue to deteriorate despite adequate IOP control, pointing to IOP-independent mechanisms of neurodegeneration. Oxidative stress—defined as an imbalance between the production of reactive oxygen species and the capacity of endogenous antioxidant defenses—has emerged as a central, multi-tiered contributor to glaucoma pathogenesis. In the anterior segment, chronic oxidative damage to the trabecular meshwork impairs aqueous humor outflow and drives IOP elevation. In addition, oxidative stress may impair ocular biomechanical integrity, including corneal hysteresis and lamina cribrosa, resulting in heightened susceptibility to IOP fluctuations. In the posterior segment, oxidative stress directly contributes to mitochondrial damage and vascular endothelial injury, leading to RGC apoptosis. The nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) pathway coordinates the principal endogenous antioxidant response, while nicotinamide adenine dinucleotide (NAD⁺) depletion links redox imbalance to metabolic vulnerability of RGCs. This narrative review synthesizes evidence published up to March 2026 on the molecular mechanisms of oxidative stress in glaucoma, the role of biomarkers in aqueous humor and systemic circulation, and the translational landscape of antioxidant-based neuroprotection—including nicotinamide, coenzyme Q10, alpha-lipoic acid, and Nrf2-activating compounds. We highlight gaps between preclinical promise and clinical evidence, and outline priorities for future randomized controlled trials. Full article

Cold sensitivity restricts the natural distribution of subtropical evergreen trees. In a representative species such as Phoebe bournei, evaluating physiological divergence among provenances is therefore essential for identifying cold-hardy germplasm and understanding adaptive evolution. This study investigated the photosynthetic capacity, redox homeostasis, and carbon metabolism of saplings from three provenances (WY, AF, and SC) under chilling stress and subsequent recovery. The results showed that low temperature significantly inhibited the net photosynthetic rate and photochemical efficiency in all saplings through predominant non-stomatal limitations. The northern provenance WY prioritized structural integrity and redox homeostasis by enhancing cyclic electron flow and timely antioxidant activation. The mid-latitude provenance AF demonstrated higher physiological plasticity and achieved more rapid recovery of photosynthetic activity upon rewarming. In contrast, the southern provenance SC was highly sensitive to chilling stress, exhibiting disrupted energy dissipation, severe lipid peroxidation, and impaired coordination of carbon metabolism and hormonal regulation. Overall, the pronounced divergence in adaptive strategies among provenances is evident. These findings provide a physiological basis for understanding intraspecific variation in P. bournei and offer guidance for germplasm selection under climate change. Full article

Internet of things long range (IoT/LoRa) devices emit radiofrequency electromagnetic fields (RF-EMF), ensuring long-range, low-power communication, and their use in precision agriculture continuously expands. Thus, the interest in the impact of low-intensity but long-term EMF exposure on plants has increased. In this study, maize plants were exposed to 868 MHz, 10 mW EMF for the first 28 days of their development with soil-buried antennas. Plants were divided into three groups: Control, Sham-exposed, and EMF-exposed. Biological effects were followed on morphological, physiological, and biochemical levels every week. The plant height values were fitted to a Gompertz function modeling the growth. The results showed slightly faster early development of EMF-exposed plants in about 21 days. The relative dry-leaf biomass from EMF-affected plants was a bit higher than in the Control and Sham groups until day 21. Chlorophyll fluorescence analysis (JIP-test) indicated photosynthetic stability. Antioxidant enzyme activity, antioxidant capacity, content of malondialdehyde, hydrogen peroxide, and reducing sugars were measured, and principal component analysis was done for all parameters. Overall, the developmental stage accounts for most of the observed variations in the data rather than EMF exposure. The results suggest that under the tested conditions, IoT/LoRa-emitted EMF did not provoke adverse effects in maize and acted as a modest modulator of physiological functions. Full article

Salivary aldehyde dehydrogenases (ALDHs), particularly ALDH3A1, are increasingly recognized as potential contributors to oral defense against aldehyde-associated stress at the oral–environment interface. Unlike freely secreted salivary enzymes, measurable salivary ALDH activity primarily reflects intracellular and vesicle-associated enzymes derived from salivary gland epithelial cells, oral mucosal cells, immune cells, and exfoliated cellular components. Within the oral exposome, ALDHs expressed in oral epithelial and salivary gland tissues participate in the detoxification of reactive aldehydes, while salivary ALDH activity may serve as an indicator of local aldehyde-detoxification capacity and tissue redox status. Beyond aldehyde metabolism, emerging evidence suggests that ALDH-associated pathways are linked to redox regulation, epithelial stress adaptation, inflammatory signaling, and tissue repair through NAD(P)⁺-dependent processes and stress-responsive networks such as Nrf2 and SIRT1. This review provides a saliva-focused synthesis of ALDH biology, emphasizing isoform-specific functions and the potential importance of ALDH3A1 in oral epithelial defense. Altered salivary ALDH activity has been reported in association with oral conditions including periodontitis, oral lichen planus, radiation-induced salivary dysfunction, and oral squamous cell carcinoma (OSCC). Genetic factors, particularly ALDH2 polymorphisms, together with environmental exposures and microbial dysbiosis, may further influence aldehyde burden and oral disease susceptibility. Although current evidence supports the biological relevance of salivary ALDHs, their utility as clinical biomarkers or therapeutic targets remains investigational and requires further mechanistic and clinical validation. Full article

Diabetic neuropathy is typically diagnosed with distal sensory and nerve conduction abnormalities. These symptoms may reflect earlier disturbances of axonal maintenance. This review examines axonal transport and cytoskeletal failure as convergent cellular mechanisms of diabetic axonopathy. Long peripheral axons are particularly vulnerable to damage because their integrity depends on continuous communication between the neuronal soma and distal terminals. This process involves the continuous renewal of cytoskeletal and functional proteins and the involvement of organelles such as mitochondria. Diabetes in experimental models disrupts this system at several levels. It slows cargo transport. The supply of neurofilaments, tubulin and retrograde signaling is reduced, and regenerative growth after injury is weakened. Carbonyl stress and AGEs cause modifications of neural proteins, the extracellular matrix, vascular barriers, and the excitability of sensory neurons. RAGE ligands, including AGEs and the proteins HMGB1 and S100, link the diabetic tissue environment to redox and inflammatory signaling. This occurs in neural and glial compartments, as well as in vascular tissue and the immune system. RAGE interacts with DIAPH1 to activate GTPase signaling and remodel the cytoskeleton. The RAGE–DIAPH1 interaction provides a plausible route from diabetic ligand accumulation to cytoskeletal remodeling. These observations provide a mechanistic context for axonal transport, although not all represent direct measurements of cargo movement. Direct evidence for transport impairment comes mainly from experimental studies showing altered slow cytoskeletal transport, impaired retrograde signaling, and weakened regenerative responses. This work highlights the possibility of developing therapies that go beyond symptomatic relief. Verifying the effectiveness of interventions in protecting axonal transport and nerve fiber integrity in diabetic neuropathy may be therapeutically beneficial. Full article

The present investigation evaluated the therapeutic potential of ethanol-derived extracts from Kadsura coccinea root (KCR) against alcohol-induced liver injury (ALI) utilizing a murine experimental system. Male Balb/c mice were administered alcohol intragastrically in a stepwise manner over 8 weeks to establish the ALI model. Experimental outcomes demonstrated that KCR administration substantially improved hepatic functional status, evidenced by marked reductions in circulating hepatic enzymes, specifically aspartate aminotransferase (AST) and alanine aminotransferase (ALT). KCR also increased glutathione (GSH) activity, reduced malondialdehyde (MDA) levels in the liver, and exerted antioxidant effects by boosting the expression of enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase 4 (GPX4). Additionally, metabolomic and transcriptomic analyses identified metabolites and pathways closely linked to oxidative stress, including Glutathione metabolism and the MAPK signaling pathway. Further mechanistic studies revealed that KCR could decrease the phosphorylation of p38, JNK, and ERK, while increasing the expression of Nrf2, HO-1, and NQO1. In conclusion, KCR alleviates ALI by modulating the MAPK/Nrf2 pathway, restoring redox homeostasis, enhancing antioxidant defenses, and improving metabolic disorders. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) belongs to the group of killer human cancers. Its ferocity is sustained by an unusual mix of genetic changes—primarily in KRAS and TP53—a hypoxic as well as desmoplastic tumor microenvironment, plus metabolic and redox adaptations that allow tumor life amidst intense stress situations. Content: This paper will discuss the molecular networks of wild-type and mutant p53, wild-type and mutant KRAS, PUMA, TIGAR, PRMT5, NRF2, oxygen tension, reactive oxygen species (ROS), and oxidative stress pathways that contribute to pancreatic cancer. It will describe how these factors help set the tumor’s redox state and control apoptosis and therapeutic resistance. This shall therefore specifically discuss what role oxygen gradients play in pancreatic tissues, as well as retinoic acid, together with redox-targeted therapies that are specific to vulnerabilities within such types of networks. Summary and Outlook: An understanding of the crosstalk of these molecular pathways will be critical in designing rational therapeutic strategies. Genetics, metabolism, and microenvironmental integration may open a path toward combinatorial therapies that would resensitize PDAC to apoptosis and overcome resistance to current treatments. Full article

Metformin (MET) plays crucial regulatory roles in mammalian oocyte meiosis, yet the concentration-dependent biphasic impacts of MET on porcine oocyte in vitro maturation (IVM) and the related molecular mechanisms remain poorly clarified. This study aimed to explore the distinct effects and underlying pathways of low- and high-dose MET in porcine oocytes. Different concentrations of MET (0, 7.5, 15, 30, 150, and 300 μM) were supplemented during oocyte IVM, with phenotypic detection, untargeted metabolomic analysis, and Nrf2 inhibitor (ML385) intervention performed for mechanism exploration. Results showed that 15 μM low-dose MET facilitated oocyte maturation, mitochondrial function and redox balance, while 300 μM high-dose MET caused obvious developmental damage. Mechanistically, low-dose MET triggered noncanonical AMPK activation independent of the AMP/ATP ratio and enhanced AMPK–Nrf2 antioxidant signaling, whereas high-dose MET induced energy stress and oxidative injury via inhibiting mitochondrial complex I. Blockade of Nrf2 further abolished the protective effects of low-dose MET. Collectively, this finding illustrates the biphasic actions of MET on porcine oocytes and provides a theoretical reference for optimizing porcine in vitro embryo production. Full article

Background/Objectives: Age-related functional decline is increasingly linked to chronic low-grade inflammation (inflammaging) and sarcopenia, two interconnected processes contributing to frailty, metabolic dysregulation, and impaired physical function. These conditions share several underlying mechanisms, including immune dysregulation, mitochondrial dysfunction, oxidative stress, and impaired anabolic signaling. This narrative review critically evaluated the mechanistic and translational interactions between natural bioactive compounds and lifestyle interventions in modulating inflammaging and sarcopenia. Methods: Evidence from molecular, experimental, epidemiological, and clinical studies was synthesized to examine the effects of bioactive compounds—including polyphenols, flavonoids, carotenoids, and omega-3 fatty acids—as well as physical activity and dietary patterns. Particular emphasis was placed on inflammatory regulation, redox homeostasis, mitochondrial adaptation, and muscle metabolism, including NF-κB, AMPK–mTOR, and Nrf2 signaling pathways. Results: Observational studies and randomized controlled trials generally indicate that anti-inflammatory dietary patterns and regular physical activity are associated with improved muscle strength, physical performance, and inflammatory status in older adults. Mechanistically, nutritional bioactives and exercise appear to converge on several pathways involved in mitochondrial function, oxidative stress, anabolic signaling, and immune activation. Emerging evidence suggests potential convergence and interaction of biological pathways affected by nutritional and lifestyle interventions; however, formal evidence demonstrating true synergistic effects in humans remains limited. Nevertheless, substantial heterogeneity persists regarding intervention protocols, dosage strategies, bioavailability, and long-term clinical outcomes. Conclusions: Natural bioactive compounds and lifestyle-based interventions represent promising approaches for targeting biological processes implicated in inflammaging and sarcopenia. By integrating current evidence within a hormesis-oriented geroscience framework, this review highlights the importance of adaptive redox regulation, metabolic resilience, and evidence-based lifestyle strategies in healthy aging. Future well-designed longitudinal and intervention studies are needed to clarify the clinical relevance of these interactions and optimize translational implementation. Full article

Scorpion venom peptides, with their stable disulfide backbone, compact structural framework, and highly selective regulation of ion channels, have long been regarded as important molecular probes in neuropharmacology. However, recent studies have revealed their potential for regulating oxidative stress, inflammation, and neuroprotection, making them a new research frontier. In this article, we focus on scorpion venom peptides as drugs, constructing an integrated knowledge framework from structural classification to clinical translation. First, scorpion venom peptides are systematically classified based on cysteine arrangement patterns and three-dimensional folding topology, and their structure–activity relationships are summarized. Based on this, the molecular mechanisms by which scorpion venom peptides regulate ion channels are systematically analyzed. We review the emerging pharmacological activities of scorpion venom peptides. Of particular note, the representative molecule SVHRSP has shown multi-target synergistic antioxidant and neuroprotective activity in models of Parkinson’s disease. We also systematically evaluate the application of engineering strategies, including cyclisation modification, nanodelivery, recombinant expression, and AI-assisted optimization, to overcome the translational bottlenecks in the development of scorpion venom peptides. However, it should be noted that most SVHRSP-related findings have been reported by a single research group; independent replication, pharmacokinetic characterization, and human efficacy data are still lacking. Its IND approval permits clinical investigation but does not yet constitute proven therapeutic benefit in patients. By integrating molecular structure, redox regulation mechanisms, and translational medicine perspectives, this review aims at providing a theoretical basis and practical pathways for scorpion venom peptides as precision therapeutic molecules for oxidative stress-related diseases. Full article

Mitochondrial reactive oxygen species (mtROS) are central regulators of cellular function, yet their biological roles are often reduced to an oxidative-stress/antioxidant dichotomy. This review reframes mtROS through the concept of mitohormesis, in which outcomes are neither inherently harmful nor beneficial but are determined by a defined set of contextual variables. We present a mechanistic framework in which mtROS effects depend on chemical species identity, sub-mitochondrial site of production, temporal dynamics, redox-buffering capacity, and metabolic state; together, these variables determine whether mtROS promote adaptive eustress or pathological distress. We then show that, across polyphenols, isothiocyanates, terpenoids, alkaloids, and quinones, the biologically relevant effects of natural redox-modulating compounds are mediated less by direct radical scavenging than by pro-hormetic mechanisms, including mild electron transport chain perturbation, nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (NRF2/KEAP1) activation, modulation of mitochondrial membrane potential, mitochondrial quality control, and NAD⁺/NADPH regulation. Applying this framework to disease reveals strong tissue and state dependence: neurodegeneration favors buffering expansion and mitophagy; metabolic disease may benefit from exercise-mimetic and NRF2-activating strategies; cardiovascular disease illustrates mitohormesis through ischemic preconditioning and CoQ10 supplementation; and cancer requires distinction between prevention and therapy because redox buffering can either protect normal tissue or support tumor survival. Finally, we argue that the failure of non-specific antioxidant supplementation is mechanistically predictable and propose context-aware, biomarker-guided, temporally optimized, and compartment-targeted redox interventions as a more rational translational path. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder traditionally defined by dopaminergic neuronal loss and Lewy body pathology; however, increasing evidence indicates that metabolic dysfunction contributes to both motor and non-motor manifestations of disease. While metabolomics studies in PD have largely focused on peripheral biofluids or subcortical brain regions, metabolic remodeling within cortical regions critical for cognition remains poorly characterized. Here, we applied LC-MS/MS-based untargeted metabolomics to post-mortem frontal cortex tissue from PD and neurologically normal control donors, with statistical models adjusted for age, sex, and post-mortem interval. A total of 893 metabolites were quantified, of which 234 exhibited significant differential abundance following false discovery rate correction. Pathway enrichment and network-based integration revealed coordinated metabolic remodeling characterized by predicted inhibition of β-alanine metabolism and pantothenate-dependent coenzyme A biosynthesis alongside activation of amino acid, vitamin B-dependent, cofactor-related, redox-associated, oxidative stress, and inflammatory pathways. Recurrent alterations in pantothenic acid, β-alanine-related intermediates, arginine- and histidine-derived metabolites, lumichrome, and vitamin B₆-associated species may reflect cortical metabolic perturbations associated with mitochondrial bioenergetic vulnerability and oxidative stress. Together, these findings indicate selective metabolic vulnerability in the PD frontal cortex rather than diffuse metabolic collapse. Full article

Lipid peroxidation (LPO) is a process where polyunsaturated fatty acids (PUFA) in cellular membranes are oxidized. This process is mediated by reactive oxygen species (ROS) and leads to the formation of reactive products, including 4-hydroxynonenal (4-HNE), malondialdehyde (MDA), and oxidized phospholipids. At low concentrations these products act as second messengers in adaptive redox signalling and metabolic homeostasis, whereas at higher concentrations they compromise membrane integrity and promote cell death. Lipid peroxidation plays a crucial role in anticancer therapies. Here we focus on three mechanistically complementary drugs—sorafenib, cisplatin, and olaparib—because each converges, directly or indirectly, on the redox/LPO axis (system xc−/GPX4 modulation, mitochondrial ROS, and SLC7A11 regulation, respectively), modulating tumor cell responses by inducing PUFA oxidation, mitochondrial dysfunction, and membrane damage. However, tumor cells have several protective pathways against oxidative stress, such as increased expression of glutathione peroxidase 4 (GPX4), the SLC7A11 system Xc, and detoxification of reactive aldehydes. Enrichment of membranes with PUFA increases susceptibility to lipid peroxidation and ferroptosis, thereby sensitizing tumor cells to therapy, whereas enrichment with monounsaturated fatty acids (MUFA), driven by the SREBP1–SCD1 axis, limits peroxidation and confers resistance. Among regulated cell death modalities, ferroptosis is strictly dependent on lipid peroxidation, whereas apoptosis, necrosis, necroptosis, pyroptosis, and immunogenic cell death can be modulated by lipid peroxidation but do not universally require it. Collectively, these mechanisms indicate that lipid peroxidation is an important—though not exclusive—determinant of anticancer drug sensitivity and resistance, and that its dual, context-dependent role (tumor-suppressive at high flux, tumor-promoting under chronic, sub-lethal exposure) must be considered when designing LPO-based therapeutic strategies. Full article

Chronic kidney disease (CKD) affects approximately 700 million people worldwide and is a major contributor to end-stage renal disease (ESRD), cardiovascular morbidity, and premature mortality. Although oxidative stress has long been considered central to CKD progression, conventional antioxidant strategies have not consistently improved clinical outcomes, suggesting that excess reactive oxygen species (ROS) alone cannot fully account for the underlying disease pathophysiology. Emerging evidence supports a broader paradigm of redox network failure, characterized by the disruption of coordinated signaling among ROS, nitric oxide (NO), and reactive sulfur species (RSS). Within this framework, hydrogen sulfide (H₂S), a major endogenous RSS, functions as a key regulator of renal redox homeostasis. CKD is consistently associated with systemic and renal H₂S deficiency, accompanied by downregulation of cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST), as well as impaired transsulfuration and disrupted mitochondrial sulfide oxidation. Importantly, this deficiency cannot be explained solely by reduced renal function but instead reflects active suppression of H₂S biosynthesis. Uremic toxins, particularly indoxyl sulfate (IS), contribute to this process through activation of the aryl hydrocarbon receptor (AhR), which inhibits specificity protein 1 (Sp1)-dependent transcription of H₂S-producing enzymes. This IS–AhR–Sp1 axis provides a mechanistic link between toxin accumulation and disruption of the sulfur arm of the redox network, amplifying oxidative stress, endothelial dysfunction, mitochondrial impairment, ferroptotic vulnerability, and fibrotic remodeling. Beyond H₂S itself, downstream RSS, including persulfides, polysulfides, and thiosulfate, may represent the principal bioactive mediators of sulfur-dependent redox signaling, and their coordinated depletion in CKD may impair redox buffering capacity beyond what H₂S measurement alone reflects. This review integrates current evidence to propose a conceptual model in which CKD progression involves failure of coordinated redox signaling—characterized by feed-forward network collapse and threshold-dependent transition to a self-sustaining high-ROS state—with H₂S deficiency representing one mechanistically supported component of this broader network disruption. This framework highlights the therapeutic potential of targeting redox network restoration rather than isolated oxidative pathways in CKD. Full article

Intervertebral disk degeneration (IVDD) is widely recognized as a major contributor to discogenic low back pain (LBP), imposing a substantial burden on global public health and socioeconomic systems. Growing evidence confirms that disrupted redox homeostasis, excessive reactive oxygen species (ROS) accumulation, and oxidative stress act as major convergent mechanisms that propagate inflammatory cascades, nucleus pulposus cell dysfunction, and extracellular matrix degradation. Although conventional conservative therapies and surgical interventions are clinically effective in relieving macrostructural compression, they remain limited in resolving localized molecular dysregulation. In recent years, nanotechnology has emerged as a promising strategy for overcoming the limitations of traditional therapy for IVDD. This review provides an analysis of four categories of antioxidant nanotherapies for IVDD, including inorganic functional nanozymes, bioactive nanomaterials, stimuli-responsive nanosystems, and nanocomposite scaffolds. We elaborate on their mechanisms in scavenging excessive ROS, restoring redox equilibrium, protecting mitochondrial function, and ameliorating oxidative stress-induced degeneration. Integrating structural biomimicry with microenvironmental responsiveness enables the engineering of composite nanosystems with multi-pathway ROS-scavenging capabilities. Therefore, these platforms emerge as promising therapeutic strategies for arresting IVDD progression. Finally, we discuss the key obstacles to clinical translation. Overall, this review provides insights into the development of redox-targeted therapies. Full article