Neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's diseases, are characterized by progressive neuronal dysfunction and loss. Recent evidence highlights the importance of the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, a key regulator of cellular defense mechanisms, in maintaining neuronal health and function. A narrative literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar to identify relevant experimental, clinical, and review studies on NRF2 signaling, physical exercise, oxidative stress, muscle-brain crosstalk, and neurodegenerative diseases. Keywords included "NRF2", "Nrf2/Keap1/ARE", "physical exercise", "exercise-induced oxidative stress", "myokines", "exerkines", "Alzheimer's disease", "Parkinson's disease", "Huntington's disease", and "amyotrophic lateral sclerosis". NRF2 modulates the expression of a variety of antioxidant and cytoprotective genes, contributing to the protection of neurons against oxidative stress, inflammation, and protein aggregation, processes central to the pathogenesis of neurodegenerative diseases. Additionally, physical activity has been identified as a powerful modulator of NRF2 activation, with exercise offering neuroprotective effects through the induction of NRF2-mediated pathways. This review explores the interplay between NRF2 activation and physical exercise in the context of neurodegenerative diseases, detailing the molecular mechanisms by which exercise influences NRF2 activity to combat cellular damage and enhance neuroprotection. We discuss the therapeutic potential of combining exercise regimens with NRF2-targeted therapies, highlighting the promise of this dual approach in slowing disease progression, improving cognitive function, and enhancing quality of life in affected individuals. Furthermore, we examine the challenges and future directions for clinical implementation, including optimal exercise protocols and the development of NRF2-based pharmacological interventions. This review underscores the importance of NRF2 as a central mediator of neuroprotection and the therapeutic promise of physical activity in the management of neurodegenerative diseases.
Cancer continues to be a major health burden, with millions of new cases and deaths reported annually, and metastasis remains the leading cause of cancer-related mortality. Disruption of transmembrane proteins is a major regulator of tumor development and progression. This review highlights FXYD3, a single-transmembrane protein that regulates Na+ /K+ -ATPase activity and functions in maintaining ion balance, redox homeostasis, and proliferative signaling in both cancer stem cells and bulk tumor populations. Its expression varies across various cancers, such as breast, pancreatic, lung, colorectal, gastric, and endometrial cancer, where it is linked with tumor development, therapy resistance, and immune modulation. Its involvement in pathways such as PI3K-AKT and cGMP-PKG contributes to malignancy. It protects cells from oxidative stress, thereby promoting cell survival and inhibiting apoptosis. Accumulating evidence highlights the potential role of FXYD3 as an emerging biomarker with relevance to diagnosis, prognosis, and therapeutics. This review provides an overview of FXYD3's role in cancer biology from translational relevance to its potential as a diagnostic, prognostic, and therapeutic target.
Controlled generation and regulation of reactive oxygen species (ROS) remains challenging when photochemical and redox processes are combined for cancer-related applications. Photothermal regulation of metal-centred redox kinetics provides a route to amplified ROS (1O2, ˙OH, O2˙-, etc.) generation in hybrid inorganic systems. In such systems, transition metal-mediated ROS generation is intrinsically governed by local coordination environments, redox kinetics, and energy-transfer pathways. Herein, we report a stepwise-assembled Ti3C2@UCNP@Cu-TCPP@LA system in which the redox chemistry of Cu(II)-tetrakis(4-carboxyphenyl)porphyrin (Cu-TCPP) is kinetically regulated by plasmon-assisted photothermal activation of Ti3C2 MXene under near-infrared (808 nm) irradiation. Ti3C2 nanosheets were integrated with aminated NaYF4:Yb3+/Er3+/Nd3+ upconversion nanoparticles (UCNPs) through interfacial hydrogen bonding. UCNPs serve as NIR-to-visible photonic intermediates for activating spatially segregated Cu-TCPP moieties covalently attached to the UCNP surface. This architecture suppresses π-π aggregation-induced ROS quenching, preserves the excited-state dynamics of Cu-TCPP, and facilitates efficient Förster resonance energy transfer (FRET) from the UCNPs. Under 808 nm irradiation, the integrated Ti3C2 component exhibits pronounced plasmon-derived photothermal behaviour (photothermal conversion efficiency ≈57%), which kinetically accelerates singlet oxygen (1O2) generation from photoexcited Cu-TCPP. Simultaneously, photothermal heating promotes intracellular Cu2+/Cu+ redox cycling and accelerates glutathione depletion and Fenton-like hydroxyl radical (˙OH) production, collectively amplifying chemodynamic reactivity. Ti3C2-mediated photothermal activation yields ∼4-fold higher 1O2 and ∼3-fold greater ˙OH generation than the UCNP@Cu-TCPP@LA system. Beyond photothermal activation, Ti3C2 serves as a conductive support that facilitates interfacial charge and energy transfer processes under NIR irradiation. Functionalisation with lactobionic acid (LA) improves aqueous dispersibility and enables receptor-mediated cellular uptake. In vitro studies confirm pH-responsive behaviour, efficient intracellular ROS generation, and significant cancer cell apoptosis (∼78%) under 808 nm excitation, highlighting the functional relevance of plasmon-assisted photothermal amplification of Cu-porphyrin redox chemistry on Ti3C2.
Intracellular oxidative stress is a common mechanism of cellular dysregulation as a result of supraphysiological levels of reactive oxygen species (ROS). Imbalances in redox homeostasis underly adverse responses arising from exposure to a wide variety of xenobiotics and environmental exposures. Observing oxidative cellular events in real time poses multiple analytical challenges, requiring sensitive and specific methodologies that are capable of detecting transient events with high spatiotemporal resolution. We review here the advantages that live-cell imaging offers as a non-destructive approach that is well suited for redox toxicology studies. The effectiveness of this approach is heavily reliant on the use of fluorescent redox sensitive probes, such as small molecule and genetically encoded sensors that report on specific ROS and redox couples. We discuss a variety of small molecule and genetically encoded sensors that are used in redox toxicology, as well as the caveats and limitations posed by their use.
Mitochondrial redox homeostasis is required for proper stem cell fate determination and tissue regeneration, and its dysregulation is a hallmark of aging-related stem cell dysfunction. This review systematically summarizes the multi-layered mechanisms by which aging-induced mitochondrial redox imbalance impairs stem cell identity, covering reactive oxygen species homeostasis, macromolecular metabolism, mitochondrial DNA integrity, mitochondrial dynamics, and the Sirtuin/forkhead box O (FoxO) signaling axis. We further highlight the context-specific metabolic features across different stem cell types and recent advances in targeted interventions to restore mitochondrial redox homeostasis, with a special focus on small molecule compounds with translational potential. This review further critically evaluates conflicting experimental evidence in current research, highlights major unresolved controversies and technical limitations in the field, providing a model that links mitochondrial redox status to epigenetic regulation for advancing both basic research and translational applications of mitochondrial redox-targeted interventions for stem cell aging.
Metabolism underpins cellular function by supplying energy, biosynthetic precursors, and redox balance and in yeast there are thousands of metabolic reactions that are tightly coordinated through multilayered regulation. The yeast Saccharomyces cerevisiae has become a central model for studying metabolism and its regulation and following publication of its genome in 1996, this yeast became pivotal in systems biology. Systems biology integrates experimental data with mathematical modeling to analyze complex cellular networks. A major advance for metabolic analysis was the development of flux balance analysis and genome sequencing enabled reconstruction of the first genome-scale metabolic model (GEM) for yeast. This initial GEM described how hundreds of genes, reactions, and metabolites interact across compartments. Subsequent models, including Yeast8 and Yeast9, expanded the coverage and predictive power, and these models enable metabolic comparison, physiological analysis, omics integration, and design of strains that can be used for production of chemicals and biopharmaceuticals. Overall, S. cerevisiae remains a cornerstone of systems biology and biotechnology, with continued advances expected in integrative modeling and engineering applications.
Artemisinin-based combination therapies are the cornerstone of Plasmodium falciparum malaria treatment; however, delayed parasite clearance and treatment failure occur even in the absence of established parasite genetic resistance. While parasite-intrinsic resistance mechanisms have been extensively studied, the contribution of host erythroid heterogeneity to antimalarial drug response remains poorly defined. Highly purified human CD71+ve reticulocytes and mature erythrocytes were used to assess parasite invasion, intraerythrocytic development, and drug susceptibility. Integrated metabolomic and proteomic analyses characterized host cell environments. Parasite responses to artemisinin derivatives and antimalarials with distinct mechanisms of action were systematically evaluated. P. falciparum preferentially invaded reticulocytes and exhibited accelerated asexual development within these cells. Multi-omics analyses demonstrated that reticulocytes provide a metabolically enriched, antioxidant-modulated intracellular environment, marked by increased nucleotide precursors, enhanced glutathione metabolism, and elevated levels of reactive oxygen species (ROS)-detoxifying enzymes. Parasites developing within reticulocytes showed significantly reduced susceptibility to artemisinin and dihydroartemisinin, as well as to other redox-active antimalarials, while maintaining comparable sensitivity to drugs with non-oxidative mechanisms. Reticulocyte-resident parasites also demonstrated enhanced survival and recrudescence following artemisinin exposure. Erythroid maturation state is a key host determinant of antimalarial drug efficacy. Reticulocytes form a redox-protected intracellular niche that attenuates drug-induced oxidative stress and promotes parasite persistence, consistent with a host cell-mediated tolerance phenotype. These findings provide a mechanistic framework for variability in treatment outcomes associated with reticulocytosis and anemia.
Mercury contamination poses a significant risk to worldwide crop yields, negatively impacting their development and metabolic processes. Effective mitigation strategies can enhance plant resilience under such stress conditions. This study investigates the combined mitigation potential of Kibdelosporangium sp. and chitosan nanoparticles (CSNPs) in mitigating Hg toxicity in two Phaseolus vulgaris L. cultivars: the sensitive 'Nebraska' and the tolerant 'Giza 6'. Hg exposure reduced biomass and impaired photosynthesis, with fresh weight and photosynthetic rates declining by up to 57% and 65%, respectively, in Nebraska cultivar. However, the combined application of Kibdelosporangium sp. and CSNPs alleviated these stress effects, increasing fresh weight up to 84.7% and reducing Hg accumulation from 86.58 to 48.23 μg g-1 DW in Nebraska. The combined application restored photosynthesis and increasing the bioavailability of primary sugars. These served as essential carbon skeletons and energy precursors for the biosynthesis of organic, amino, and fatty acids. Consequently, the combined treatment reduced H2O2 accumulation and lipid peroxidation by approximately 38-45% in Nebraska compared with the Hg-only treatment. Antioxidant defences (e.g., CAT, DHAR, SOD, TAC) were increased by 34-111% in Nebraska and 52-160% in Giza 6. under Hg stress, and combined treatments further increase this defence response. Hg significantly increased total soluble sugars in Nebraska (85%) and Giza 6 (100%), while proline rose by 33% in Nebraska. However, combined treatment mitigated these effects, normalizing sugar levels and balancing carbon allocation, especially in Giza 6. By stabilizing antioxidant systems and metabolic balance, the intervention effectively maintained high tocopherol levels. Particularly, the sensitive Nebraska cultivar showed greater recovery, pointing out higher responsiveness. This study demonstrates an innovative approach to enhancing legume resilience through microbial and nano-mitigants that optimize photosynthesis, metabolic accumulation, and redox homeostasis in heavy-metal-polluted environments.
The combined toxicity of polyvinyl chloride microplastics (MP) and cadmium (Cd) is widespread in the environment, but their effects on plants are poorly understood. Allantoin (ALA) is a growth regulator that acts as a nitrogen reservoir, osmolyte, and radical scavenger under stress. This study aimed to investigate the role of allantoin in mitigating the phytotoxic effects of MP and Cd in pea plants. Foliar application of ALA (300 mg L1) was given to plants challenged with 100 mg kg1 Cd and 200 mg kg1 MP, as single or combined treatments. Growth, chlorophyll concentration, photosynthesis efficiency, leaf relative water content, nutrient acquisition, radical detoxification, oxidative stress markers, antioxidant enzyme activities, and anatomical features were measured. Histochemical staining was used to detect reactive oxygen species (ROS) and membrane damage, while concentrations of hydrogen sulfide and nitric oxide were assessed. Exposure to Cd and MP, as single or combined treatments, severely impaired plant performance by diminishing growth, photosynthetic efficiency, and nutrient acquisition. Parllel to this, MP and Cd induced severe oxidative stress, marked by elevated ROS levels (O2•, H2O2, and •OH) and lipid peroxidation, which caused significant membrane damage as confirmed by histochemical analyses. Exogenous ALA countered these impairments by upregulating hydrogen sulfide and nitric oxide production and enhancing antioxidant enzyme activities. These ALA-mediated shifts restored nutrient acquisition, enhanced cellular protection, and mitigated the vascular and structural damage induced by MP and Cd toxicity. Allantoin effectively mitigates the synergistic phytotoxicity of MP and Cd in pea plants by enhancing antioxidant defense, maintaining ion homeostasis, protecting microstructure, and facilitating nutrient uptake.
Mitochondrial iron handling and immune surveillance are intertwined in tumor biology. Mitochondrial ferritin (FTMT) buffers redox-active iron in mitochondria, while MICB is an NKG2D ligand that can promote anti-tumor cytotoxicity when expressed on tumor cells. However, whether FTMT has a causal relationship with non-small cell lung cancer (NSCLC) risk-and how this might connect to MICB biology-remains uncertain. We applied a genetics-omics-validation workflow. We conducted two-sample Mendelian randomization (MR) and mediation MR using plasma proteomic pQTL summary statistics (UK Biobank Pharma Proteomics Project) and NSCLC GWAS summary statistics from FinnGen (R12). To contextualize results in the tumor microenvironment, we interrogated single-cell RNA-seq datasets via TISCH2 and explored pharmacogenomic associations using GDSC. Mechanistic plausibility was tested in A549 lung adenocarcinoma cells using FTMT overexpression followed by qPCR and Western blotting. Genetically predicted higher FTMT levels were associated with reduced NSCLC risk (IVW OR per 1-SD increase ≈ 0.91). Mediation MR suggested that MICB-related signals accounted for a modest proportion of the FTMT effect. Single-cell analyses showed FTMT enrichment in malignant epithelial cells, whereas MICB was expressed across multiple compartments. In vitro, FTMT overexpression increased MICB mRNA and protein abundance. Integrating genetic evidence, tumor-context transcriptomics, and cell-based validation supports FTMT as a protective factor for NSCLC and points to a mitochondrial-immune axis involving MICB. Observed differences between blood-based genetic proxies and tumor-cell experiments are consistent with context-dependent regulation (e.g., circulating MICB can reflect shedding, whereas tumor-cell MICB reflects surface stress-ligand programs).
Circulating 25-hydroxyvitamin D is the standard marker of vitamin D status, but tissue responses to vitamin D vary across organs, inflammatory states, and clinical settings. This review frames vitamin D biology as a cellular endocrine system in which substrate transport, local CYP27B1-mediated activation, CYP24A1-mediated inactivation, and VDR responsiveness form tissue-specific microcircuits. Evidence from barrier epithelia, immune cells, and brain-resident cells indicates that megalin/cubilin-dependent uptake, local enzyme balance, redox state, and downstream transcriptional competence can decouple serum 25-hydroxyvitamin D from intracellular vitamin D activity. We use metabolic vitamin D resistance to describe acquired low-responsiveness states driven by inflammation, aging, redox stress, or chronic disease. This framework clarifies biomarker interpretation and supports more context-aware approaches to supplementation, trial design, and tissue-targeted intervention.
The tumor microenvironment (TME) is a major driver of therapeutic resistance, shaped by abnormal vasculature, metabolic rewiring, redox imbalance, dense extracellular matrix deposition, and immunosuppressive signaling. These biochemical and biophysical barriers restrict drug delivery, promote tumor progression, and limit the efficacy of cancer therapy. Enzyme-based nanomedicine offers a catalytic strategy to modulate TME features through localized enzymatic reactions. This Review discusses two major platforms: enzyme-loaded nanoparticles, which protect and deliver natural enzymes, and enzyme-mimicking nanomaterials, or nanozymes, in which the nanomaterial itself provides catalytic activity. We focus on how material design regulates enzyme stability, catalytic accessibility, tumor delivery, and biological activity, with particular emphasis on redox regulation and metabolic modulation, where mechanistic and preclinical evidence is most developed. We also discuss extracellular matrix remodeling and immune modulation as important but more context-dependent applications that may improve drug penetration or support immunotherapy in tumors. Finally, we examine key translational challenges, including catalytic specificity, substrate heterogeneity, delivery barriers, immune recognition, manufacturing complexity, and long-term safety. Aligning catalytic function with tumor biology may enable enzyme-based nanomedicine to improve the performance of current cancer therapies.
<p indent="0mm">Necrosis by sodium overload (NECSO) is a distinct cell death modality induced by the chemical regulator necrocide 1 (NC1), which targets the transient receptor potential melastatin 4 (TRPM4) channel to drive excessive sodium influx and potassium efflux. This unique necrosis is characterized by the exchange of monovalent ions, a restrained ATP supply, redox disorder and a final membrane rupture as main features. Real-time monitoring of metabolic and redox causality during the whole process in living cells has been technically challenging. To bridge this gap, we integrate an advanced toolset of genetically encoded fluorescent sensors to monitor monovalent ions, energy metabolites, and redox equivalents with high spatiotemporal resolution. By directing these sensors to specific subcellular compartments, we successfully capture the real-time choreography of potassium loss specifically induced by NC1 via TRPM4. Furthermore, we establish a precise detection paradigm for evaluating energy currency by integrating sensors for NADH and ATP that are capable of subcellular imaging. We observe general and rapid NADH accumulation along with an ATP shortage in the mitochondria and cytosol. A concomitant reduction in mitochondrial oxidative stress is observed. This study not only elucidates the metabolic progression of a peculiar type of necrosis but also establishes a robust methodological framework for applying genetically encoded sensors to broader physiological and toxicological research.</p>.
Astrocytes are essential for maintaining neuronal homeostasis, yet their stage-specific contribution to mild cognitive impairment (MCI) and Alzheimer's disease (AD) remains insufficiently understood. This study aimed to investigate astrocyte-associated transcriptional and metabolic alterations across the control-MCI-AD continuum using integrated transcriptomic and genome-scale metabolic modeling approaches. Transcriptomic profiles from hippocampal CA1 tissue (GSE28146) were analyzed across four clinical conditions (control, early MCI, advanced MCI, and AD). Astrocyte-associated expression programs were inferred using the unsupervised deconvolution algorithm CDSeq and validated through canonical marker enrichment, correlation with external reference signatures, and comparison with an independent single-nucleus RNA-seq astrocyte pseudobulk dataset. The inferred profiles were integrated into a curated human astrocyte genome-scale metabolic model to generate condition-specific models, which were analyzed using flux balance analysis (FBA) and flux variability analysis (FVA). The analyses supported stage-dependent remodeling of astrocyte-associated transcriptional and metabolic programs during disease progression. Early MCI was associated with signaling and stress-adaptation changes, whereas advanced MCI and AD showed broader disruption of synaptic support, redox homeostasis, and inflammatory-related programs. Model predictions indicated a progressive reduction in a biomass-derived maintenance proxy from control to advanced MCI, followed by a partial rebound in AD, suggesting a compensatory shift toward reactive-like astrocyte states rather than full functional recovery. Flux variability analysis revealed reduced metabolic flexibility across disease stages, particularly in glutamate-glutamine cycling, glutathione/redox metabolism, glycolysis-pyruvate metabolism, cholesterol handling, and one-carbon/folate metabolism. These findings support the view that astrocytes undergo progressive, stage-specific metabolic reprogramming during the transition from healthy aging to AD. Early alterations in redox regulation, neurotransmitter cycling, and mitochondrial function may contribute to early neuronal vulnerability. This work highlights astrocyte-centered pathways as potential targets for future experimental validation and therapeutic exploration.
Ultraviolet radiation (UVR), particularly UVA and UVB, is a major environmental source of photo-oxidative stress in skin. Absorption of UV photons by endogenous chromophores triggers excessive generation of reactive oxygen species (ROS), resulting in oxidative stress (OS), lipid peroxidation, mitochondrial dysfunction, DNA damage, and inflammation. These events contribute to photoaging, pigmentary alterations, impaired wound repair, and photocarcinogenesis. Adaptive responses are orchestrated by stress-responsive transcriptional networks, notably BTB and CNC homology 1 (Bach1) and BTB and CNC homology 2 (Bach2), members of the Broad-Complex, Tramtrack, and Bric-à-brac (BTB) and Cap 'n' Collar (CNC) family. Bach proteins function as redox-sensitive repressors that compete with Nuclear factor erythroid 2-related factor 2 (Nrf2) for antioxidant response elements (AREs) binding in association with small Maf proteins. Under basal conditions, Bach1 suppresses transcription of cytoprotective genes, including heme oxygenase-1 (HO-1), thereby maintaining a restrained antioxidant activity. UV-induced oxidative or heme stress promotes Bach1 nuclear export anddegradation, enabling Nrf2-driven antioxidant gene expression. Persistent or dysregulated Bach1 activity following chronic UV exposure has been linked to enhanced ferroptotic susceptibility, iron-dependent lipid peroxidation, mitochondrial metabolic imbalance, and increased genomic instability, promoting photodamage and tumor-associated redox adaptation. In contrast, Bach2 appears to exert context-dependent effects on immune regulation, autophagy, and cellular senescence, indicating functional divergence. Emerging evidence further indicates that Bach-mediated transcription intersects with iron metabolism, mitochondrial biogenesis, inflammatory signaling, and metabolic reprogramming, positioning these factors as central modulators of UV-induced redox thresholds. The dynamic balance between Bach proteins and Nrf2 defines the magnitude and duration of antioxidant responses following acute or chronic irradiation. Targeting this regulatory axis with natural antioxidants (e.g., eriodictyol, cannabidiol, and 3-acetyl-11-keto-β-boswellic acid), small-molecule modulators, or photodynamic strategies offers potential to enhance photoprotection and mitigate UV-driven pathology. A deeper mechanistic understanding of Bach-dependent signaling in photo-oxidative stress will advance the development of precision interventions for light-induced skin disorders and photocarcinogenesis.
Potassium conductances provide a biologically well-established lever for regulating neuronal excitability across heterogeneous disorders, controlling threshold, repolarization, adaptation and bursting at low energetic cost. However, translating this biology into patient-level therapeutic stratification remains an incompletely validated task. This review therefore distinguishes established potassium-channel mechanisms from conceptual integration and future-facing translational proposals. Drawing on literature identified through searches of PubMed/MEDLINE, Embase, Web of Science Core Collection and Scopus (inception - May 2026)advances a patient-level 'excitability fingerprint' as a conceptual translational framework linking microdomain-resolved gating to network stability and future biomarker-enriched therapeutic development. Voltage-gated potassium channels (Kv), big-conductance Ca2 + -activated K+ channels (BK)/small-conductance Ca2 + -activated K+ channels (SK), inwardly rectifying potassium channels (Kir)/ATP-sensitive potassium channels (KATP), and two-pore domain potassium (K2P) channels, including TWIK-related acid-sensitive K+ channels (TASK)/TWIK-related K+ channels (TREK), are gated by phosphatidylinositol 4,5-bisphosphate (PIP₂), Ca2 +, redox, and pH across subcellular domains, including glia - neuron K+ coupling. A tri-axial fingerprint is defined: electroencephalography (EEG)/high-frequency oscillation (HFO) and transcranial magnetic stimulation (TMS) metrics; microdomain tone (PIP₂/redox); and astroglial K+ buffering, modulated by age, sex, genetics, and metabolic - inflammatory comorbidities. Biomarker-anchored titration uses electrophysiology (HFO; resting motor threshold [RMT]/motor-evoked potential [MEP]/short-interval intracortical inhibition [SICI]/cortical silent period [CSP]), molecular panels (reduced glutathione [GSH]/glutathione disulfide [GSSG]; cysteine/cystine; acid - base), and patient-derived induced pluripotent stem cell (iPSC) assays of PIP₂-dependent M-current rescue. Fingerprint-guided K+ modulation can compress time-to-response and manage network-level risk, supporting standardized pipelines, practical microdomain assays, and response-adaptive, fingerprint-enriched trials to implement individualized therapeutic windows.
Seminal plasma, traditionally regarded as a passive vehicle for sperm transport, is now recognized as a biologically active fluid that is important for normal sperm function and optimal male fertility. This review summarizes how androgen-regulated secretions from the seminal vesicles, prostate, and epididymis influence sperm competence at ejaculation. Key components include seminal vesicle-derived lipids (e.g., oleic acid), prostatic citrate, carbohydrates, ions, and antioxidants that rapidly remodel membranes, activate motility, and preserve genome integrity. Androgen signaling via testosterone and dihydrotestosterone coordinates metabolic programs such as oleic-acid synthesis in the seminal vesicles and citrate secretion in the prostate. Seminal-vesicle fatty acids fuel mitochondrial respiration and support linear motility, whereas prostatic citrate primarily buffers pH and chelates divalent cations that stabilize membranes and acrosomal status. In addition, seminal plasma supplies precursors for cysteine and glutathione biosynthesis, supporting redox homeostasis in sperm. Beyond physiology, timed supplementation with whole seminal plasma or defined components improves motility and fertilization outcomes in livestock and humans. By focusing on how androgen-regulated seminal plasma synthesis influences sperm function, this review outlines mechanisms that are relevant to both male fertility biology and reproductive technologies.
In inflammatory tissue niches, macrophages encounter intense oxidative stress due to their own production of reactive oxygen and nitrogen species as part of antimicrobial defense. Our findings reveal that inflammatory macrophages deploy distinct, context-dependent redox-protective mechanisms to survive this self-inflicted stress, thereby avoiding ferroptotic cell death. Specifically, LPS-activated macrophages, M(LPS), rely on the GTP cyclohydrolase 1 (GCH1)-tetrahydrobiopterin (BH4) pathway for ferroptosis resistance, whereas LPS + IFN-γ-activated macrophages, M(LPS-IFN-γ), depend primarily on nitric oxide produced by inducible nitric oxide synthase (iNOS)-with the BH4 pathway suppressing cell death in the absence of nitric oxide. These distinct adaptations highlight a novel GCH1-BH4-iNOS axis that governs macrophage ferroptosis susceptibility. In both the LPS or the LPS + IFN-γ-activated settings, the redox-protective phenotype is reversible: Removal of inflammatory stimuli abolishes the protection, indicating that this metabolic programming requires continuous stimulation and is not a permanently fixed state. These findings uncover redox metabolism-guided metabolic distinctions between inflammatory macrophages and reveal how they preserve viability over prolonged inflammatory activation. Ultimately, our findings establish the GCH1-BH4-iNOS axis as a central, targetable mechanism to manipulate macrophage ferroptosis resistance for therapeutic purposes.
Subcellular organelle targeting is changing the way nanomedicine is designed, moving the field beyond simple cellular entry toward more precise intracellular localization, controlled cargo release, and functional activity within disease-relevant compartments. This review critically discusses nanomaterial-based strategies for targeting the nucleus, mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus, and cytoskeleton-associated trafficking pathways. Its main novelty is the use of a cross-organelle, mechanism-based framework that links nanocarrier physicochemical properties with intracellular transport biology, rather than examining each organelle or delivery platform separately. Lipid nanoparticles, polymeric carriers, dendrimers, inorganic nanomaterials, biomimetic systems, and engineered extracellular vesicles are compared according to their targeting mechanisms, cargo compatibility, therapeutic potential, and translational limitations. Particular attention is given to nuclear import mediated by NLS-, CPP/TAT-, and aptamer-based strategies; mitochondrial delivery shaped by membrane potential, membrane fusion, and redox-responsive release; lysosomal targeting for pH- and enzyme-activated therapies; and ER/Golgi-directed delivery through retrograde trafficking, retention motifs, and modulation of stress-related pathways. The review also brings together several emerging directions, including stimuli-responsive release, biomimetic surface engineering, extracellular vesicle scalability, CRISPR/Cas delivery, base and prime editing, and targeted protein degradation, all of which may support more programmable forms of intracellular therapy. Importantly, it separates true organelle localization from transient trafficking or nonspecific perinuclear accumulation, emphasizing the need for stronger and more reliable validation methods. Key barriers remain, including inefficient endosomal escape, off-target intracellular accumulation, organelle-specific toxicity, long-term safety concerns, reproducibility, scalable manufacturing, and regulatory classification. Overall, this review frames organelle-directed nanomedicine as a rational design strategy for improving therapeutic precision, while also stressing that clinical translation will depend on clear evidence of durable, safe, and measurable therapeutic benefit at the organelle level.
Lactic acid bacteria (LAB) are widely recognized as beneficial microorganisms within the human microbiome; however, the mechanisms underlying their health-promoting effects remain largely elusive. Here, we show that Latilactobacillus sakei ZFM232 (LS232) exhibits tolerance to acidic conditions and moderate salt stress, along with relatively stable antioxidant capacity in vitro. Using Caenorhabditis elegans as an in vivo model, we found that long-term intake of LS232 significantly improved nematode survival under oxidative, osmotic, and heavy-metal stress conditions, with increases of 40%, 36.5%, and 11.9%, respectively, compared to the control group. LS232 feeding also reduced age-related lipid droplet accumulation and triglyceride levels, indicating improved lipid metabolic status during aging. Concurrently, LS232 enhanced glutathione S-transferase 4 (GST-4) activity, promoted superoxide clearance, and improved redox balance in vivo. Moreover, LS232 feeding was associated with increased nhr-49 expression, enhanced nuclear enrichment of NHR-49, and upregulation of lipid metabolism-related genes, including fat-5, fat-6, fat-7, and acs-2. In the nhr-49 mutant background, the beneficial effects of LS232 on lipid accumulation and redox balance were significantly attenuated, further supporting the involvement of an NHR-49-associated regulatory program in mediating these responses. Overall, these results suggest that LS232 has potential applications in alleviating aging-related lipid metabolism disorders and oxidative damage.