Polyphenolic antioxidants are incorporated into pharmaceutical, dermopharmaceutical, and cosmetic products because of their capacity to modulate oxidative stress, inflammation, microbial imbalance, skin aging, wound repair, and tumor-related processes. However, formulation is constrained by chemical instability, limited bioavailability, insufficient skin permeation, and degradation during processing or storage. This review integrates the chemical characteristics, natural sources, extraction approaches, antioxidant mechanisms, and evaluation of curcumin and chlorogenic acid, and critically examines their delivery through liposomes, niosomes, ethosomes, and transethosomes. Curcumin is lipophilic and poorly water-soluble, whereas chlorogenic acid is hydrophilic but permeability-limited. Their antioxidant activity is discussed through hydrogen atom transfer, single-electron transfer, interruption of lipid peroxidation, metal chelation, and localization within lipid interfaces, together with chemical, biomimetic, and cellular assessment methods. Vesicular carriers can improve encapsulation, stability, release control, skin interaction, biological performance, and incorporation into semisolid dosage forms. However, these benefits are accompanied by formulation-dependent trade-offs involving manufacturing complexity and cost, long-term stability and reproducibility, excipient-related skin tolerability, scale-up, and an application scope that depends on the intended dermal-delivery endpoint. Therefore, efficacy depends on the interplay among antioxidant properties, vesicle architecture, excipient selection, and processing conditions. Curcumin-loaded vesicles are better documented than chlorogenic-acid-loaded systems, particularly for deformable carriers. Future progress requires quality-by-design strategies, standardized characterization, predictive skin models, long-term stability and safety studies, and scalable manufacturing. Overall, antioxidant-loaded vesicles represent multifunctional platforms for developing stable and effective pharmaceutical and cosmetic products.
Porphyromonas gingivalis (Pg) is a keystone periodontal pathogen associated with biofilm formation and gingipain-mediated virulence. This study evaluated the antioxidant, antibacterial, antibiofilm, and antivirulence activities of a hexane extract of Lycopus lucidus (LLH) and its eight chromatographic fractions (H1–H8). Antioxidant activity was assessed using DPPH and ABTS radical-scavenging assays, whereas antibacterial activity, biofilm formation, and virulence-associated gene expression were evaluated using corresponding in vitro assays. LLH exhibited antioxidant and antibacterial activities, while H4 showed the strongest overall biological activity among the fractions. The DPPH IC50 values of LLH and H4 were 98.33 ± 2.05 and 60.67 ± 3.09 µg/mL, respectively, and the corresponding ABTS IC50 values were 89.24 ± 1.67 and 28.15 ± 1.21 µg/mL, respectively. H4 also showed greater inhibition of biofilm formation than LLH and more pronounced downregulation of several virulence-associated genes. LC–MS/MS analysis tentatively identified α-cyperone as a constituent of H4. Overall, chromatographic fractionation of LLH yielded H4 with enhanced biological activity across several measured endpoints, including radical-scavenging, antibacterial, and antibiofilm effects, together with more pronounced suppression of several virulence-associated genes. However, the contribution of α-cyperone or other individual constituents to these effects remains to be established.
Keloids are characterized by fibrosis and chronic inflammation, but links between mitochondrial dysfunction and keloid pathogenesis remain unclear. This study examined whether impaired PINK1/Parkin-dependent mitophagy is associated with mitochondrial DNA (mtDNA)-mediated innate immune activation and fibrosis in keloids, and evaluated mitochondrial transplantation as a potential therapeutic strategy. Primary keloid fibroblasts (KFs), normal skin fibroblasts (NFs), adipose-derived stem cells (ADSCs), human keloid tissues, and human keloid xenografts in immunodeficient BALB/c nude mice were analyzed using ultrastructural, molecular, and functional approaches. Freshly isolated NF-derived mitochondria (nMito) and ADSC-derived mitochondria (aMito) were compared at protein-equivalent doses. KFs exhibited mitochondrial abnormalities, impaired oxidative phosphorylation, increased reactive oxygen species, mtDNA leakage, and cGAS/STING pathway activation. Elevated PINK1 expression, reduced Parkin expression and p62 accumulation were consistent with impaired downstream mitophagic clearance. Both nMito and aMito were associated with improved mitochondrial function, changes in mitophagy-related markers, reduced cytosolic mtDNA and cGAS/STING signaling, and attenuated fibroblast activation, with greater aMito-associated changes in selected endpoints. In xenografts, intralesional administration of either mitochondria improved collagen organization and reduced fibrotic and inflammatory signaling. Together, these findings link altered PINK1/Parkin-dependent mitophagy to mtDNA-driven inflammation and fibrosis and support mitochondrial transplantation as a potential organelle-based therapeutic approach.
High-grade osteosarcoma presents a significant clinical challenge due to unpredictable therapeutic responses and aggressive progression. This study aimed to identify the critical molecular pathways driving chemotherapy resistance and aggressive phenotypes in osteosarcoma patients. Through transcriptomic and bioinformatic analyses, we identified cholesterol biosynthesis as a key upregulated metabolic pathway in poor chemotherapy responders, where squalene epoxidase (SQLE) emerged as an exploratory candidate hub gene whose elevated expression significantly correlates with shortened survival in the TCGA cohort. We validated these findings by administering terbinafine, a known SQLE inhibitor. In highly chemoresistant SaOS-2 cells exhibiting the highest baseline SQLE expression, terbinafine synergistically sensitized cells to doxorubicin by driving cell death partly through apoptosis, as confirmed by caspase inhibition. The combination also promoted ferroptosis, indicated by elevated ROS and MDA along with decreased FSP1 and GPX4 expression. Furthermore, the co-treatment effectively suppressed clonogenic potential, induced G2/M phase cell cycle arrest, and inhibited metastatic progression. These effects were mediated by the modulation of cell proliferation, metastasis, and survival genes through the coordinated regulation of the PI3K/AKT/mTOR, ERK, and JNK signaling cascades. Together, these results highlight the therapeutic potential of targeting the SQLE pathway to overcome doxorubicin resistance and suppress aggressive progression in high-grade osteosarcoma.
Amniotic oxidative stress in women with vaginal infection but no documented intra-amniotic infection has received little attention. In this prospective cohort study of 90 women undergoing elective cesarean delivery, 45 had symptomatic, culture- or Nugent-confirmed vaginal infection and 45 were asymptomatic controls. Amniotic fluid advanced oxidation protein products (AOPP) and malondialdehyde (MDA) were measured by commercial ELISA. Both were higher in the infection group (median 7.96 versus 5.77 ng/mL and 12.49 versus 7.73 nmol/mL, both p < 0.001), with lower cord blood pH (p = 0.003) and more frequent neonatal intensive care unit (NICU) admission (26.7% versus 4.4%, p = 0.007). AOPP was associated with NICU admission (area under the curve 0.917, 95% CI 0.777 to 0.999), although this rests on 14 events with thresholds derived and evaluated in the same sample. Elevations were largest in the bacterial vaginosis and aerobic bacterial subgroups, but the etiologies did not differ. Both kits were designed for serum and are not validated for amniotic fluid, and 16.7% of MDA measurements fell outside the calibration range, so the MDA results are semi-quantitative. Vaginal infection at cesarean delivery is associated with higher amniotic oxidative stress markers; these findings are exploratory and require external validation.
Skin aging is a complex process influenced by oxidative stress, protein glycation, chronic inflammation, and increased extracellular matrix remodeling. Intensive research is underway on new anti-aging substances with multi-target mechanisms of action while maintaining safety and efficacy. Ergothioneine, selenoneine, and ovothiol A are natural histidine derivatives of marine origin, in which the oxygen atom of the hydroxyl group has been replaced with sulphur or selenium. In recent years, a broad spectrum of their biological activity has been demonstrated. Despite the well-documented antioxidant potential of these compounds, their anti-aging effects, particularly in terms of antiglycation and anti-inflammatory activity, remain insufficiently understood. This study presents the current state of knowledge regarding the biological activity of ergothioneine, selenoneine, and ovothiol A, and discusses available cosmetic preparations and dietary supplements containing these compounds. Meanwhile, significant research gaps have been identified regarding their potential use in the prevention and treatment of skin aging.
Successful embryo implantation requires intimate crosstalk between the blastocyst and the uterine epithelium within a defined window of receptivity. However, the metabolic signals that mediate this process in mammals remain poorly understood. In this study, pregnant mice, primary uterine cell culture and uterine epithelial organoids were used to examine the regulation and function of heme oxygenase-1 (HO-1) during mouse embryo implantation and decidualization. We demonstrate that embryo-derived lactic acid drives heme catabolism and regulates epithelial receptivity in mice through a hypoxia-inducible factor 1α (HIF1α) -heme oxygenase-1 (HO-1) signaling axis. Specifically, lactic acid stabilizes HIF1α to induce HO-1 expression in uterine epithelial cells by promoting von Hippel-Lindau (VHL) nucleolar sequestration and downregulating PHD2/3. Additionally, lactic acid suppresses the transcriptional repressor BACH1, further facilitating HO-1 induction. At physiological heme levels, HO-1-derived bilirubin promotes epithelial receptivity by increasing phosphorylated STAT3 (p-STAT3) and downregulating MUC1. A low dose of hemin promotes epithelial receptivity and decidualization, whereas a high dose of hemin suppresses these processes. Pharmacological inhibition of HO-1 in mice markedly reduces implantation sites, establishing the functional necessity of this pathway. However, when heme levels exceed the regulatory capacity of HO-1, epithelial dysfunction ensues, characterized by reduced p-STAT3 and elevated MUC1, which ultimately disrupts implantation. Consistent with this, chronic heme exposure by oral gavage in mice increases uterine heme levels and upregulates BACH1, thereby suppressing HO-1 and trapping the uterus in a non-receptive state, causing implantation failure. Our findings define a lactic acid-HIF1α-HO-1-heme metabolic checkpoint that couples glycolytic signaling to heme regulation and endometrial receptivity. Dysregulation of this checkpoint may contribute to implantation disorders associated with heme stress, providing mechanistic insights into heme stress-related uterine receptivity failure.
Mung bean seed coat (MBSC) is a byproduct of commercial vermicelli production that possesses essential activities capable of delaying diabetic wound progression. This study aimed to evaluate the potential of MBSC extracts to promote diabetic wound healing, an effect that has not yet been reported. The hypoglycemic effect was assessed by glucose uptake stimulation in L6 myotubes and by an α-glucosidase inhibition assay. Antiglycation was determined by BSA-glucose and BSA-methylglyoxal assays. Intracellular reactive oxygen species (ROS) reduction and wound healing were assessed in human keratinocytes (HaCaT) exposed to high glucose (HG), and gene expression in HG-wounded cells was analyzed by qPCR. The results demonstrated that the ethanolic extract (EE) from MBSC exhibited glucose-lowering effects and suppressed glycation reactions at the early and intermediate stages, with IC50 values of 75 and 140 µg/mL, respectively. EE reduced ROS by 70%, stimulated cell proliferation by 57% in the high-glucose (HG)-exposed HaCaT cells, and accelerated cell migration to close the HG-exposed wound. EE increased the gene expression of Nrf2, NQO-1, SOD2, and CAT. It also downregulated TNF-α, upregulated TGF-β1, and downregulated MMP-9. In conclusion, EE has the potential to delay the progression of diabetic wounds by lowering blood glucose levels, inhibiting AGE and ROS formation, and enhancing cell proliferation and migration in HG-exposed HaCaT cells. The gene regulatory effects of EE were demonstrated as an Nrf2 activator that reduced oxidative stress, exerted anti-inflammatory effects, and regulated ECM balance. The preparation of oral and topical products could be further developed.
Background: Postpartum hypogalactia is a prevalent obstetric complication worldwide, closely associated with excessive oxidative stress and impaired antioxidant defense in mammary tissue. Current hormone-based therapies carry endocrine disruption risks, while natural antioxidant bioactive agents such as extracellular vesicles (EVs) are largely limited by rapid in vivo clearance and poor tissue retention. Methods: We constructed an injectable gelatin methacryloyl (GelMA) hydrogel system to encapsulate chemically induced mammary epithelial cell-derived EVs (CiMECs-EVs) and systematically evaluated their antioxidant and lactogenic activities via multi-omics analysis, cellular functional assays and a bromocriptine-induced murine hypogalactia model. Results: CiMECs-EVs induced a functional mammary epithelial-like phenotype in fibroblasts in a dose-dependent manner with functional cargo enriched in glutathione metabolism and redox-regulatory miRNAs. The GelMA matrix protected EV integrity and enabled sustained release, and the composite system significantly ameliorated mammary duct structure and lactation function in vivo with specific mammary tropism and no systemic toxicity, outperforming free EV treatment. Conclusions: This study presents a safe protein biomacromolecule-based antioxidant delivery platform that effectively restores mammary redox balance and antioxidant defenses, providing a promising non-hormonal therapeutic strategy for postpartum hypogalactia.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration and chronic neuroinflammation in the brain and spinal cord, involving complex interactions between neurons and immune cells. Carnosine (β-alanyl-L-histidine) has pathophysiological relevance due to its ability to detoxify reactive carbonyl species, including α,β-unsaturated aldehydes, scavenge free radicals, and chelate zinc, and has also been proposed to function in the central nervous system as a histidine reservoir for histamine synthesis. Here, we investigated the effects of carnosine supplementation on the cerebellar proteome of SOD1G93A ALS rats using quantitative proteomics. Carnosine treatment extensively remodeled mitochondrial, antioxidant, and synaptic vesicle-trafficking protein networks and increased the abundance of glutamatergic and GABAergic receptor subunits relative to untreated ALS animals, with several of these changes exceeding wild-type levels. Pathway enrichment analyses identified significant up-regulation of Rab-mediated vesicle trafficking, synaptic vesicle cycling, and neurotransmitter transport/secretion pathways, alongside a partial reduction in RNA splicing and proteasomal subunits that were elevated in untreated ALS animals. Cross-comparison with the ALS-associated proteomic signature revealed that most carnosine-responsive proteins followed, rather than reversed, the direction of disease-associated change, indicating that carnosine predominantly potentiates an endogenous compensatory program rather than restoring a wild-type-like proteome. Collectively, these findings show that carnosine drives systems-level remodeling of mitochondrial and synaptic networks in the ALS cerebellum, identifying candidate compensatory pathways and supporting further functional validation of carnosine as a component of multimodal therapeutic strategies in ALS.
Herbs and spices are traditionally added to food in cuisines around the world. Antioxidant activity and content of bioactive compounds were compared in oregano, sage, basil, rosemary, and herbal mixtures. After optimization of ultrasound-assisted extraction of the ethanol–water extracts, the content of reducing compounds of the herb extracts was tested using the Folin–Ciocalteu method, and antioxidant capacity was evaluated with ABTS (2,2’-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)diammonium salt) and DPPH (2,2-diphenyl-1-picrylhydrazyl radical) assays. Oregano showed the highest antioxidant activity in all tests used (2.6 mg of gallic acid equivalent (GAE) per mL in the Folin–Ciocalteu test, 4.6 mg Trolox/mL in the ABTS assay, and 3.3 mg Trolox/mL in the DPPH assay) while rosemary had the lowest antioxidant activity (1.2 mg GAE/mL (Folin–Ciocalteu), 1.5 mg Trolox/mL (ABTS), and 1.3 mg Trolox/mL (DPPH)). Apart from antioxidant properties, the content of bioactive compounds was determined with the use of high-performance liquid chromatography–tandem mass spectrometry (LC-MS/MS). It was found that in all tested Lamiaceae herbs and the herbal mixes, rosmarinic acid widely predominates as a major non-volatile phenolic constituent, and its content varies from 1121 µg/g in rosemary to 10,255 µg/g in herbes de Provence. High concentrations were also observed for quinic acid in both oregano and rosemary. Interestingly, the concentrations of rosmarinic acid in the group of herbs studied are positively correlated with the results obtained in the Folin–Ciocalteu, ABTS, and DPPH tests (Spearman’s correlation coefficient 0.7030, 0.6657, and 0.7188, respectively), whereas no such correlation is observed for quinic acid. Overall, the findings indicate that these herbs share a common hydroxycinnamate-based phytochemical framework but display clear species-specific differences reflecting their intrinsic metabolism. Furthermore, the concentration of 3-caffeoylquinic acid in the Sicilian herbs (1021 µg/g) was approximately 10 times higher compared to the samples of Dalmatian herbs, herbes de Provence, and pure herbs, which demonstrates the unique chemical composition of that mixture, including the presence of dried tomatoes and tarragon, which were not included in other tested herbal mixtures.
The production performance, muscle quality, and gut microbiota of aquatic animals are closely associated with host growth stage and disease status. This study therefore compared the gut health, antioxidant capacity, and muscle nutritional composition of greenhouse-cultured Pelodiscus sinensis covering two growth stages (juvenile and adult) and two physiological states (healthy and diseased). The results showed that healthy turtles possessed significantly longer and denser intestinal villi compared with diseased turtles (p < 0.01), and adult turtles maintained higher activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and lysozyme (LZM) than juveniles regardless of health condition. Digestive enzyme profiles varied with age and health. Compared with adult turtles, juveniles exhibited significantly higher trypsin activity in both healthy and diseased groups (p < 0.001). Conversely, juveniles displayed significantly lower lipase activity than adults in the diseased group (p = 0.008). For muscle nutritional composition, adults contained higher crude protein (CP), essential amino acids (EAAs), and umami amino acids (UAAs) than juveniles, while healthy turtles had significantly better muscle quality indices than diseased individuals (p < 0.05). Meanwhile, gut microbial composition differed significantly between growth stages and health states (p = 0.001). The relative abundance of unclassified_f_Lachnospiraceae and Clostridium_sensu_stricto_2 was positively correlated with GSH-Px and muscle nutritional composition indicators (CP, EAAs, and UAAs), whereas it was negatively correlated with liver alkaline phosphatase (ALP), acid phosphatase (ACP), and intestinal enzyme activities. Data also showed that unclassified_o_Bacteroidales and unclassified_f_Lachnospiraceae may affect muscle nutritional composition and non-specific immunity by regulating the microbial functional pathways of amino acid metabolism, the digestive system, and non-specific immunity system. Collectively, these observations offer insights into variations in physiological traits of greenhouse-cultured P. sinensis. These correlational findings suggest that gut microbiota are closely associated with muscle nutrition and antioxidant status, providing valuable insights for sustainable soft-shelled turtle aquaculture.
Amphibians of the family Phyllomedusidae produce complex cutaneous secretions with ecological and pharmacological relevance. Here, we investigated the skin morphology of Pithecopus oreades and P. azureus and the antioxidant function of the tryptophyllin PaT-2 in microglial cells. Histological and histochemical analyses revealed a conserved glandular organization, with mucous glands rich in neutral mucopolysaccharides and serous glands containing acidic and sulfated polysaccharides, concentrated predominantly in the dorsal and cephalic regions. MALDI mass spectrometry imaging showed that PaT-2 (m/z 696.4) is heterogeneously distributed. A second ion (m/z 1626.8), assigned to a truncated form of a phylloseptin-like antimicrobial peptide, was predominantly localized in limb tissues and partially overlapped with PaT-2, suggesting co-deployment of antioxidant and antimicrobial molecules on the skin. In BV2 microglial cells, menadione (10 µM) induced oxidative stress reflected by increased oxidized glutathione (GSSG) and higher total glutathione levels, consistent with a compensatory increase in glutathione synthesis. Synthetic PaT-2 (50 µM) was associated with numerically lower GSSG accumulation and a smaller increase in total glutathione when co-administered with menadione, showing no cytotoxicity while demonstrating modulation of endogenous glutathione status. These findings advance the integumentary biology of Pithecopus, suggest differences in peptide distribution between the specimens examined, and extend the antioxidant characterization of PaT-2 to the level of glutathione status, supporting its further investigation as a candidate molecule for oxidative stress-related research.
Cardiovascular diseases remain the leading cause of global mortality, and environmental toxic metals and metalloids (TMMs) exposure has emerged as an important and potentially modifiable cardiovascular (CV) risk factor. Due to their persistence, bioaccumulation, and widespread distribution, represent a significant public health concern and have been associated with adverse CV outcomes. Mechanistically, TMM-induced cardiotoxicity is primarily mediated through oxidative stress (OS) and inflammatory pathways. Accordingly, related biomarkers, may be considered markers of biological effect and potential pathophysiological mediators associated with TMM exposure. This narrative review summarizes epidemiological evidence linking environmental TMMs exposure with OS and inflammatory biomarkers to CV outcomes. A structured literature search identified 1915 records in PubMed, of which 42 epidemiological studies met the inclusion criteria. The reviewed evidence consistently indicates that environmental and occupational TMMs exposure is associated with significant alterations in biomarkers of lipid peroxidation, antioxidant defense, systemic inflammation, and endothelial dysfunction, all of which reflect early biological CV effects associated with exposure. However, substantial heterogeneity across studies and the predominance of cross-sectional designs limit causal inference and the evaluation of their predictive capacity for future CV events. Future prospective studies integrating mixture-based exposure assessment, standardized biomarker measurements, and multi-omics approaches are needed to clarify whether these biomarkers can serve as markers of biological effect or subclinical CV toxicity and as potential mediators of CV risk, while also assessing their potential contribution to cardiovascular risk stratification in exposed populations.
Nucleus pulposus cells (NPCs) age mainly because reactive oxygen species (ROS) build up too much. Excess ROS is associated with intervertebral disc degeneration (IVDD). In this study, we prepared ergothioneine-derived carbon dots (EGT-Fe-CDs) as an antioxidant nanozyme. EGT-Fe-CDs showed good biocompatibility, superoxide dismutase-like and catalase-like activities, and high total antioxidant capacity. In H2O2-treated NPCs, EGT-Fe-CDs reduced cell damage. Local EGT-Fe-CDs treatment also reduced degeneration in the animal model, based on imaging, disc height index (DHI), and Pfirrmann grade. EGT-Fe-CDs also reduced mitochondrial damage associated with excess ROS. They slow down NPC ageing and help control IVDD. Based on these characteristics, the nanozyme could be a useful option for clinical therapy in the future.
Escherichia coli-induced enteritis imposes a substantial economic burden on the global livestock industry. In the current context of reducing and restricting antibiotic use, there is an urgent need for novel therapeutic strategies. Based on traditional Chinese medicine compatibility, anemoside B4 (AB4) and oleanolic acid (OA) form nanoscale assemblies (AB4-OA NPs) through hydrogen bonds and van der Waals forces. Physicochemical characterization quantified the NPs as spherical particles with an average hydrodynamic diameter of 164.16 nm, a PDI of 0.280, zeta potential of −22.16 mV, and stable particle size for 28 days; the hemolysis ratio remained below 3.38% at concentrations up to 2 mg/mL, confirming favorable biosafety. In vitro assays confirmed that AB4-OA NPs outperformed AB4/OA physical mixtures in anti-inflammatory and antioxidant activity by restraining pro-inflammatory factors and activating antioxidant enzymes, verifying nanotechnology’s potency in boosting their bioactivity. In mice challenged intraperitoneally with E. coli, AB4-OA NPs elevated SOD, CAT, GSH-Px and lowered MDA; they inhibited the NF-κB pathway, activated the Nrf2 pathway, balanced inflammatory cytokines, alleviated intestinal leakage, upregulated tight junction proteins and reshaped gut microbiota by reducing Proteobacteria and enriching Firmicutes. Spearman’s correlation study indicated a strong positive relationship between Lactobacillus and Faecalibacterium with intestinal barrier function (Occludin and ZO-1) as well as antioxidant capacity, while Enterococcus was significantly and positively correlated with pro-inflammatory cytokines. These findings demonstrate that AB4-OA NPs exert pronounced protective therapeutic effects on E. coli-induced enteritis via inhibition of inflammation, attenuation of oxidative stress, protection of the intestinal barrier, and regulation of gut microbiota, and that these effects were greater than those of the corresponding physical mixture. This study proposes a novel therapeutic strategy for managing E. coli-induced enteritis and highlights the therapeutic potential of phytochemical-based self-assembled nanomedicines.
Oxidative stress drives skin aging, barrier impairment, and inflammatory amplification, making dietary antioxidants potential systemic contributors to cutaneous redox homeostasis. Edible fungi are distinctive sources of redox-active metabolites, particularly ergothioneine, a stable sulfur-containing antioxidant whose cellular uptake is mediated by the ergothioneine transporter OCTN1 (SLC22A4). This review evaluates ergothioneine, polysaccharides and β-glucans, cordycepin, phenolics, and Ganoderma triterpenoids as processing-sensitive dietary bioactives with redox relevance rather than topical cosmetic ingredients. We examine how cultivation, drying, cooking, extraction, fermentation, and microbial biomanufacturing determine antioxidant formation, retention, oral bioaccessibility, and dose realism, and how antioxidant response, inflammatory, mitochondrial, and gut microbiota-mediated pathways connect intake to skin endpoints. The strongest oral evidence concerns biomarker-linked ergothioneine-rich Pleurotus. Smaller Flammulina velutipes and Sparassis crispa trials report hydration or transepidermal water loss signals without comparable exposure biomarkers, whereas purified ergothioneine provides provisional non-mushroom food evidence. Compared with better-established oral ingredients, edible fungi offer distinctive food technology advantages but a narrower human evidence base. Priorities include processing-aware quality and safety markers, contaminant control, standardized digestion models, dose-realistic exposure estimates, and biomarker-anchored randomized human trials.
Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy (prevalence ~1:4000) and a leading Mendelian cause of working-age blindness. Despite marked genetic heterogeneity, its progression converges on a common secondary cascade of outer-retinal hyperoxia, increased reactive oxygen species (ROS), and mitochondrial dysfunction that drives cone degeneration and central vision loss. Because this oxidative cascade is largely genotype-independent and pharmacologically tractable, oxidative stress is a cross-cutting therapeutic target. Within it, mitochondrial DNA (mtDNA) is a key element: once released from damaged photoreceptors—free or within exosomes—it may act as a damage-associated molecular pattern (DAMP), engaging TLR9, cGAS–STING, and the NLRP3 inflammasome and sustaining chronic neuroinflammation. Extracellular mtDNA is therefore a potential integrative marker, simultaneously reflecting oxidative stress, mitochondrial dysfunction, cell death, and innate-immune activation. A central knowledge gap, however, remains: the mechanistic steps linking mtDNA to inflammation and to photoreceptor death have not been demonstrated in RP itself, and extracellular mtDNA has never been quantified in the ocular fluids of RP patients. In this review we appraise oxidative biomarkers in RP, propose extracellular mtDNA as a candidate biomarker of disease activity, and examine antioxidant and redox-modulating therapies—from N-acetylcysteine and elamipretide trials to DAMP-sensor inhibition—across experimental and clinical models. Finally, we propose extracellular mtDNA as a candidate pharmacodynamic endpoint and outline a path toward its validation.
Background: Trimethylamine N-oxide (TMAO) arises from the interaction of diet, gut microbial metabolism, hepatic oxidation, and renal clearance. Experimental work links TMAO exposure to mitochondrial oxidative stress, NLRP3 inflammasome activation, impaired nitric oxide signaling, vascular smooth muscle cell dysfunction, and thrombosis. How far these findings explain human vascular disease remains uncertain. Purpose: We examine TMAO and related metabolites in carotid atherosclerosis, aortic disease (abdominal aortic aneurysm, AAA, and dissection), and peripheral artery disease (PAD), focusing on redox biology and the obstacles that still limit clinical translation. Position: Current evidence makes the pathway biologically credible, but it does not support routine TMAO measurement, a universal cutoff, or treatment decisions based on a single metabolite. The recent association between γ-butyrobetaine and limb outcomes also suggests that TMAO may not always be the most informative component of the pathway. Most causal evidence remains preclinical, and no TMAO-lowering or redox-directed intervention has improved a vascular clinical endpoint. Conclusions: For now, the TMAO pathway remains investigational. Progress will depend on multicenter studies that measure several pathway metabolites with harmonized assays and carefully account for renal function, diet, and sex. Interventional studies are premature until safety and biological target engagement have been established.
As the only mammalian appendage capable of complete regeneration, deer antlers serve as an invaluable model to investigate cartilage regrowth, but the underlying mechanism remains unclear. This study revealed that addition of palmitic acid (PA), an abundant long-chain saturated free fatty acid, inhibited the proliferation and hypertrophy of antler chondrocytes while promoting chondrocyte apoptosis. PA treatment activated NOTCH1 signaling and restrained the transport of Ca2+ from the cytosol to the endoplasmic reticulum (ER) via RBPJ (recombination signal-binding protein for immunoglobulin kappa J region)-targeted TMTC4 (transmembrane O-mannosyltransferase targeting cadherins 4), resulting in a reduction in ER Ca2+. Meanwhile, PA disrupted the structure and function of mitochondria-associated ER membranes (MAMs) via TGM2 (transglutaminase 2) through the cytosolic Ca2+-mediated PPP3CB (protein phosphatase 3 catalytic subunit beta)-NFATC2 (nuclear factor of activated T cells cytoplasmic 2) pathway. Further analysis demonstrated that PA induced mitochondrial dysfunction via MAM-mediated mitochondrial Ca2+ insufficiency, thereby restricting mitophagy and attenuating lysosomal acidification. This caused the leakage of mitochondrial reactive oxygen species (mtROS) from depolarized mitochondria into the cytosol via the mitochondrial permeability transition pore, thereby inducing lipid peroxidation, while the addition of ROS scavengers prevented the negative effects of chondrocyte proliferation and hypertrophy and protected chondrocytes from apoptosis in the context of PA. Collectively, PA treatment regulated the proliferation, apoptosis and hypertrophy of antler chondrocytes by disrupting MAM function.
