Search Results (4,163)

Polycystic ovary syndrome (PCOS) is a multifactorial endocrine disorder characterized by chronic inflammation, insulin resistance, and reproductive dysfunction. Although empagliflozin, a sodium-glucose cotransporter-2 inhibitor, has demonstrated anti-inflammatory and metabolic benefits, its molecular mechanisms in PCOS remain poorly understood. This study investigated the anti-inflammatory mechanisms of empagliflozin in PCOS using network pharmacology, molecular docking, and molecular dynamics simulations. Potential drug targets were identified using SwissTargetPrediction and SuperPred, while PCOS- and inflammation-related genes were obtained from GeneCards. Overlapping targets were subjected to Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, protein–protein interaction network, and hub gene analyses. Molecular docking and 50 ns molecular dynamics simulations were performed to evaluate binding affinity and complex stability. Key inflammatory targets identified included TNF, IL6, IL1B, TLR4, STAT3, and PTGS2, with significant enrichment in cytokine-mediated signaling, TNF signaling, and NF-κB pathways. Empagliflozin showed strong binding affinities for PTGS2 (−9.0 kcal/mol) and TLR4 (−8.8 kcal/mol), while molecular dynamics simulations demonstrated stable protein–ligand complexes throughout the simulation. These findings suggest that empagliflozin may alleviate PCOS-associated inflammation by modulating the TLR4/NF-κB/PTGS2 signaling axis, supporting its potential as a repurposed therapeutic agent for PCOS and providing a foundation for future experimental validation. Full article

Preservation of mitochondrial integrity has emerged as a central hub in the anti-inflammatory effect of exercise. This narrative review advances a framework in which mitochondrial damage-associated molecular patterns (mtDAMPs) serve as the mechanistic bridge between exercise and inflammation. Mitochondrial dysfunction releases mtDAMPs, including mitochondrial DNA (mtDNA), reactive oxygen species, cardiolipin, N-formyl peptides, and ATP, which activate cGAS–STING, the NLRP3 inflammasome, TLR9, AIM2, ZBP1, and NF-κB signaling. Crosstalk among these pathways allows mild mitochondrial damage to escalate into chronic inflammation. Exercise opposes this cascade through the AMPK–PGC-1α axis, which coordinately activates four mitochondrial quality control (MQC) modules: biogenesis, antioxidant defense, dynamics, and mitophagy. The cardiovascular system illustrates this framework, as myocardial inflammation runs mainly through mtDNA–cGAS–STING signaling and vascular inflammation through oxidized mtDNA–NLRP3 signaling, while cardiovascular aging engages both axes at once. Throughout, exercise refers to repeated training rather than to a single bout, and the framework targets middle-aged and older adults with, or at risk of, cardiovascular disease. The upstream half of the sequence, in which training raises mitochondrial content and antioxidant capacity, rests on human muscle biopsy data; the downstream half remains largely preclinical. MQC is therefore proposed as a testable target rather than an established one. Full article

Background/Objectives: Osteoarthritis (OA) is biologically heterogeneous, and the relationship between MRI-detected inflammation and circulating innate immune activity remains uncertain. This study aimed to determine whether serum soluble Toll-like receptor 4 (sTLR4) and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) distinguish between the study-specific MRI-defined INF-OA and non-INF-OA categories, and whether these biomarkers are associated with OA disease burden. Methods: This prospective, single-center, cross-sectional study included 30 patients with knee OA and 30 asymptomatic healthy controls. Patients with active OA flare-up, defined by a Knee Osteoarthritis Flare-Ups Score (KOFUS) ≥ 7, were excluded before MRI assessment and category assignment. Patients with OA were assigned to study-specific MRI-defined categories using MRI Osteoarthritis Knee Score (MOAKS) features: INF-OA (n = 16) required effusion-synovitis and/or Hoffa-synovitis-related signal alteration graded ≥ 1, whereas non-INF-OA (n = 14) required grade 0 for both features. Biomarkers were measured by enzyme-linked immunosorbent assay. Primary within-OA biomarker comparisons were Holm-corrected, and adjusted models included age, sex, and body mass index (BMI). Results: Serum sTLR4 and sTREM-1 did not differ between INF-OA and non-INF-OA after Holm correction (adjusted p = 0.710 for both). In age-, sex-, and BMI-adjusted models, the INF-OA versus non-INF-OA geometric mean ratios were 1.15 (95% CI 0.92–1.44; p = 0.219) for sTLR4 and 1.09 (95% CI 0.89–1.35; p = 0.398) for sTREM-1. Given the modest within-OA subgroup sizes, smaller or moderate between-category differences cannot be excluded. After covariate adjustment, the overall OA cohort had higher geometric mean concentrations than controls for sTLR4 (ratio 1.85, 95% confidence interval 1.56–2.20; p < 0.001) and sTREM-1 (ratio 1.67, 95% confidence interval 1.43–1.97; p < 0.001). None of the systemic inflammatory measurements significantly distinguished INF-OA from non-INF-OA after correction for multiple comparisons. Within the OA cohort, each 1 ng/mL increase in sTLR4 was associated with a 4.99-point higher Western Ontario and McMaster Universities Osteoarthritis Index total score after adjustment for age and body mass index (95% confidence interval 2.28–7.70; p < 0.001). Conclusions: Circulating sTLR4 and sTREM-1 concentrations were higher in patients with OA than in asymptomatic healthy controls but did not distinguish the study-specific INF-OA and non-INF-OA categories in this sample. These findings should not be interpreted as evidence of biological equivalence between the MRI-defined categories. sTLR4 warrants further evaluation as a circulating correlate of current OA burden in larger longitudinal and multimodal studies. Full article

Background: Aluminum-adjuvanted hepatitis B vaccines effectively prevent primary HBV infection but predominantly favor humoral immunity and have limited capacity to induce strong cellular responses. To improve immune-response quality, we developed a Ganoderma lucidum polysaccharide-modified hybrid nanoparticle adjuvant (GHNP) for hepatitis B surface antigen (HBsAg) vaccination. Methods: Cationic PEG-PCL/DOTAP hybrid nanoparticles (HNPs) were surface-modified with Ganoderma lucidum polysaccharide (GLP) at different mass ratios and characterized by particle size, polydispersity index, zeta potential, and transmission electron microscopy. Antigen uptake, RAW264.7 cell viability, MHC II expression, and TLR2/4-associated TNF-α secretion were evaluated in vitro. C57BL/6 mice were immunized intramuscularly with PBS, HBsAg, HBsAg + Aluminum, HBsAg@HNP, or HBsAg@GHNP6 on Days 0, 14, and 28. HBsAg-specific antibodies, splenocyte activation, proliferation, and cytokine secretion were assessed. Results: GHNP6 showed suitable physicochemical properties, acceptable cytocompatibility at concentrations up to 10 μg·mL⁻¹, and efficient model-antigen uptake. GHNP increased MHC II expression in RAW264.7 cells, and TLR2/4 inhibition reduced nanoparticle-associated TNF-α secretion, supporting involvement of these pathways in immune activation. In vivo, HBsAg@GHNP6 induced robust HBsAg-specific IgG responses and a higher IgG2a/IgG1 ratio than HBsAg@HNP and HBsAg + Aluminum. It also produced the highest splenocyte proliferation after HBsAg restimulation, with lower IL-6 secretion than HBsAg + Aluminum and moderately increased IFN-γ compared with PBS and free HBsAg. Conclusions: GHNP integrates nanoparticle-assisted antigen delivery with GLP-mediated immunomodulation and represents a promising strategy for enhancing cellular immune responses while maintaining humoral immunity in HBsAg vaccination. Full article

Metabolic syndrome (MetS) is associated with ectopic fat deposition, chronic systemic inflammation, oxidative stress, and increased susceptibility to organ dysfunction. While its cardiovascular consequences have been extensively studied, pulmonary al-terations remain less well characterized, particularly with respect to ferropto-sis-regulatory pathways. In this study, we evaluated ectopic fat deposition, TLR4/NF-κB signaling pathway, and ferroptosis-regulatory markers in a MetS rat model and analyzed the therapeutic potential of combined resveratrol plus quercetin (combined R + Q) supplementation. Rats were maintained for five months with 30% sucrose in drinking water to induce MetS and subsequently treated for 4 weeks with the R + Q combination (50 and 0.95 mg/kg/day, respectively). Lung tissue was analyzed by fluorescence microscopy to assess fat deposition, by colorimetric histology to evaluate hemosiderin-containing cells, including the quantification of hemosiderin-laden macrophages (HLMs), and by immunoblotting to determine TLR4, p-p65, and glutathione peroxidase 4 (GPX4), as well as cystine/glutamate antiporter SLC7A11 (xCT) protein expression. Lungs from MetS rats exhibited significantly higher fat deposits, pathological HLMs accumulation, upregulated TLR4/p-p65 signaling, elevated compensatory GPX4 expression, and depressed xCT levels compared with controls. Notably, the combined R + Q treatment markedly attenuated alterations in TLR4/NF-κB signaling and successfully restored xCT expression (p = 0.0116), stabilizing pulmonary redox homeostasis and limiting overall tissue susceptibility to lipotoxic injury. Full article

Early-life antibiotic exposure is a critical environmental trigger for developmental metabolic disorders and long-term obesity risk. Lactational enrofloxacin exposure exerts potential metabolic programming toxicity, but its long-term effects and underlying mechanisms remain poorly defined. This study aimed to investigate the persistent influences of lactational enrofloxacin exposure on postnatal growth, lipid metabolism and adipogenesis in mouse offspring and explore the potential gut microbiota-associated regulatory mechanism. A combined in vivo and in vitro approach was utilized. In vivo mouse models with lactational enrofloxacin exposure were established to assess growth phenotypes, serum lipid profiles, adipose morphology, and gut microbial composition via high-throughput sequencing. Antibiotic cocktail treatment was performed to deplete gut microbiota. In vitro 3T3-L1 cell models and pharmacological inhibition assays were used to investigate the downstream signaling pathway. Lactational enrofloxacin exposure was associated with disrupted postnatal growth, persistent weight gain, fat accumulation and progressive dyslipidemia in offspring. Adipose expansion was mainly attributed to adipocyte hyperplasia. It triggered sustained gut dysbiosis, increased Gram-negative Proteobacteria, and elevated circulating lipopolysaccharide (LPS) levels (systemic endotoxemia). Microbiota depletion largely reversed these metabolic abnormalities. In vitro, LPS facilitated preadipocyte differentiation and lipid deposition, consistent with activation of a PPARγ-dependent mechanism (putatively via TLR4). Our findings suggest that lactational enrofloxacin exposure is associated with persistent fat accumulation and lipid metabolism disorders in offspring and support a key role for the gut microbiota–LPS–PPARγ signaling pathway, with TLR4 as the putative upstream receptor, in this process. These findings provide insights into the developmental metabolic toxicity of early-life fluoroquinolone exposure and offer a theoretical basis for preventing early-onset metabolic diseases. Full article

Background/Objectives: Oxidative stress, chronic inflammation, disrupted apoptosis, and altered autophagy are biological processes implicated in colorectal tumor development. Morin is a plant-derived flavonoid with antioxidant and anti-inflammatory properties, but its limited solubility and bioavailability may limit its biological activity. This study evaluated the effects of free morin and morin-loaded liposomes (MOR-Lips) on 1,2-dimethylhydrazine (DMH)-associated colonic biochemical, molecular, and histopathological alterations in rats. Methods: Rats were randomly assigned to six groups—vehicle control, MOR, MOR-Lips, DMH, DMH + MOR, and DMH + MOR-Lips—and treated for 10 weeks. Serum and colonic tissues were evaluated for cancer-associated biomarkers (CEA, CA19-9, CA125, HMG-CoA reductase), oxidative stress and antioxidant indices, nitrosative and oxidative DNA-damage markers (MDA, NO, 8-OHdG), inflammatory mediators (TLR4/NF-κB/COX-2, cytokines, MPO), proliferative indices (Ki-67, PCNA), apoptotic and autophagy-related regulators (Bax, caspase-3, p53, cytochrome c, BCL-2, p-AKT, LC3-II, Beclin-1, p62), and histopathological and immunohistochemical changes. Results: DMH exposure was associated with increased CEA, CA19-9, CA125, HMG-CoA reductase, MDA, NO, 8-OHdG, TLR4/NF-κB/COX-2, cytokines, MPO, Ki-67, and PCNA. DMH also reduced NRF2/HO-1 signaling and antioxidant defenses, shifted apoptosis-related markers toward a pro-survival profile, altered autophagy-related markers, and produced marked colonic histopathological abnormalities. Both free MOR and MOR-Lips attenuated several of these DMH-associated alterations, with MOR-Lips generally producing greater effects than free MOR. MOR-LIP treatment was associated with restoration of antioxidant marker profiles, reduced levels of inflammatory and proliferative markers, a shift toward a pro-apoptotic marker profile, partial normalization of autophagy-related markers, and improved colonic histopathological appearance. Conclusions: In DMH-exposed rats, MOR-Lips were associated with more favorable redox, inflammatory, proliferative, apoptosis-related, autophagy-related, and histopathological profiles than free MOR. These findings support further investigation of MOR-Lips as a formulation strategy for improving the biological activity of morin. Because quantitative preneoplastic and neoplastic endpoints were not measured, the results do not establish inhibition of colorectal carcinogenesis or chemopreventive efficacy. Full article

The global transition to antibiotic-free livestock production, accelerated by antimicrobial-resistance concerns, has intensified the search for alternatives to antibiotic growth promoters, and phytobiotics have emerged as key candidates. Cangzhu, the dried rhizome of Atractylodes lancea (Thunb.) DC, is a crude drug of traditional Chinese medicine that has attracted substantial attention as a multipurpose phytobiotic. This review synthesizes current knowledge on the phytochemistry, gut-protective mechanisms, and practical application of Cangzhu in sustainable livestock production. Its principal bioactive constituents are sesquiterpenoids (atractylone, β-eudesmol, hinesol, atractylenolides I–III), polyacetylenes (including atractylodin), polysaccharides, and flavonoids. Reported gut-protective mechanisms comprise upregulation of tight junction proteins (ZO-1, occludin, claudin-1); dual suppression of the NF-κB and MAPK-signaling pathways; activation of the Nrf2–Keap1 antioxidant axis; modulation of the gut microbiota; and TLR4-mediated stimulation of mucosal immunity. In swine, poultry, and ruminant studies, Atractylodes-based supplementation has been associated with improved growth performance, a lower incidence of diarrhea, favorable intestinal morphology, downregulated pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), beneficial microbiota shifts, and inhibited pathogens. However, much of the mechanistic evidence derives from rodent and in vitro models, and much of the in vivo livestock evidence from the related species A. macrocephala (Baizhu) or multi-herb formulations; direct livestock trials with pure A. lancea remain limited for several endpoints, and the responses observed in these heterogeneous studies depend on the formulation, dose, and animal species used, as indicated by the explicit evidence-tier and source-species tags applied throughout the text, tables, and figures. The reported effective inclusion levels should be read as experimental study ranges and not as standardized dose recommendations. Framed within the One Health paradigm, Cangzhu is therefore best characterized as a mechanistically substantiated candidate alternative to antibiotic growth promoters whose adoption requires species-specific dose validation, quality standardization, and commercial-scale economic confirmation. Full article

Vietnam harbors exceptional genetic diversity among at least 26 indigenous pig breeds. We analyzed genome-wide single-nucleotide polymorphism (SNP) data from 90 animals representing 15 local Vietnamese breeds and six Landrace pigs using principal component analysis, the windowed fixation index (FST), cross-population extended haplotype homozygosity (XP-EHH), within-population integrated haplotype score (iHS), and runs of homozygosity (ROHs). The population structure was consistent with a north–south differentiation axis, and Ba Xuyen showed elevated heterozygosity, providing suggestive evidence of a European genetic contribution; the f3 statistic was positive (f3 = +0.015), and formal evidence of admixture requires a significantly negative f3, so this criterion was not met. Integration of FST and XP-EHH identified GPC5, E2F6, NOS1, and TLR4 as top Northern candidate loci and CRYM/ZP2 as the leading Central candidate locus, and these windows were recovered at both the 90th and 95th percentile thresholds, indicating analytical robustness rather than independent biological validation. iHS was elevated at E2F6 in Northern breeds (|iHS| = 3.04) and at NOS1 across all regional groups (|iHS| = 2.66–3.36). Breed-level phenotypic XP-EHH, based on published breed descriptions and coat color rather than individual body-composition measurements, identified GALNT2 as a candidate shared across breed groups; HCAR1 and ATG10 as candidates specific to the extreme-fat/prolific breed group; and EFNA5 and HIPK2 as candidates specific to the medium-bodied breed group. ROHs identified Soc, Co, and Hung as breeds warranting particular attention in conservation planning due to elevated autozygosity. Because each breed was represented by only six individuals, and because no individual-level phenotypic measurements were available, all findings are reported as exploratory population-genomic signals requiring replication in larger cohorts. Overall, we describe genomic differentiation and candidate selection signatures among local Vietnamese pig breeds and provide a foundation for further genomic studies of these breeds. Full article

Recurrent vulvovaginal candidiasis (RVVC), commonly defined as ≥3 symptomatic episodes per year, affects an estimated 138 million women worldwide. This structured narrative review (PubMed/MEDLINE and open-indexed sources, January 2020–July 2026, as well as selected pre-2020 landmark studies) synthesizes epidemiological and metabolic risk factors (including SGLT2-inhibitor-associated susceptibility), host immunogenetic and vaginal microbiome mechanisms, emerging preventive pharmacotherapies, and patient-reported outcomes within a unified clinical framework. RVVC arises from interacting host, microbial, metabolic, behavioral, and iatrogenic domains—diabetes-related hyperglycemia, innate immune polymorphisms (MBL2, TLR2), altered bacterial–fungal vaginal communities, and non-albicans Candida in difficult-to-treat cases. Fluconazole maintenance remains a guideline-supported suppressive option but relapse after discontinuation is common; oteseconazole and ibrexafungerp expand prevention choices, while probiotics show inconsistent, low-certainty benefit. RVVC consistently impairs health-related quality of life, sexual function, and mental health and imposes substantial economic burden; regional data from Southeastern Europe underscore diagnostic and access gaps. We propose a multifactorial host–pathogen–microbiome model that favors individualized, diagnosis-driven management and routine incorporation of validated patient-reported outcomes. Research priorities include harmonized case definitions, head-to-head trials of new agents, validated quality-of-life instruments, longer post-treatment follow-up, and real-world cost-effectiveness evaluations. Implementation research, equitable access strategies, clinician education, and national health policy are essential to translate evidence into improved patient outcomes globally. Full article

A high-fat diet (HFD) promotes lipid metabolic disorders, chronic low-grade inflammation and skeletal muscle dysfunction. Kukoamine B (KB), a Lycium-derived polyamine alkaloid with reported anti-inflammatory and antioxidant activities, may protect against HFD-associated muscle impairment. C57BL/6J mice were fed an HFD and orally administered KB for 12 weeks. Muscle function was evaluated using inverted grid, forelimb grip strength and treadmill exhaustion tests. Histological, transcriptomic, ELISA, immunofluorescence and Western blot analyses were used to assess muscle injury and inflammatory signalling. KB reduced intramuscular lipid deposition, collagen accumulation and myofibre damage, improved muscle strength and exercise endurance, and partially restored AKT/mTOR-associated protein metabolic signalling. Transcriptomic analysis showed that KB downregulated HFD-activated inflammatory responses, chemokine signalling, lipopolysaccharide responses and Toll-like receptor-related pathways. KB also reduced plasma and skeletal muscle LPS levels, inhibited TLR4/MyD88/NF-κB signalling, and decreased TNF-α and IL-1β expression. TAK-242 mimicked the anti-inflammatory and muscle function-improving effects of KB, whereas their combination produced no statistically detectable additional effect under the conditions tested. These findings suggest that KB attenuates HFD-induced skeletal muscle dysfunction, potentially involving reduced LPS burden and suppression of TLR4/NF-κB-mediated metabolic inflammation. Full article

Medicinal plants of the genus Atractylodes, primarily including Atractylodes lancea (Thunb.) DC., Atractylodes chinensis (DC.) Koidz., and Atractylodes macrocephala Koidz., are important traditional Chinese medicinal herbs that are widely recognized for their functions of “strengthening the spleen and drying dampness” and have traditionally been used to treat digestive and metabolic disorders. In recent years, with the increasing global burden of liver diseases, Atractylodes species have attracted growing attention for their potential pharmacological value in liver disease management due to their abundant bioactive compounds and diverse pharmacological activities. This review summarizes reported biological and hepatoprotective effects and proposed mechanisms of Atractylodes medicinal plants and their bioactive compounds in liver-related experimental models, including models relevant to MASLD, ALD, hepatic fibrosis, and HCC. Preclinical studies have reported changes in lipid metabolism, oxidative-stress-related markers, inflammatory responses, fibrotic indices, and tumor-cell phenotypes, accompanied by modulation of signaling pathways including AMPK/SIRT1, PPAR, Nrf2/HO-1, TLR4/MyD88/NF-κB, NLRP3, and TGF-β1/Smad. However, much of the mechanistic evidence is based on pathway-associated changes rather than direct compound–target validation, and clinical evidence remains limited. Overall, the available findings provide a preclinical pharmacological rationale for further investigation of Atractylodes-derived compounds in liver diseases, while their clinical efficacy and therapeutic roles remain to be established. Full article

Although persistent neurological sequelae in long COVID are reportedly well associated with neuroinflammation, the underlying regulatory mechanisms remain poorly characterized. Previously, we identified dysregulated microRNA expression, including let-7a-5p, in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike S1-stimulated human microglial cells by RNA sequencing; however, how let-7a-5p regulates the S1-mediated neuroinflammatory processes remains undetermined. In the present study, we examined the functional role of let-7a-5p in alleviating S1-induced microglial inflammation in the CHME3 cell line as well as in human monocyte-derived microglia (MDMi) using a loss- and gain-of-function approach. Functional inhibition of let-7a-5p resulted in mitigating S1-induced inflammatory cytokine release and markers of pyroptosis. Mechanistically, we established SHIP-1 as a direct target of let-7a-5p using luciferase reporter assay validation. Interestingly, we noted upregulated expression of the TLR3 gene alongside TLR2/4 in S1-stimulated microglia. Although we could not establish exactly how TLR3 is stimulated in S1-induced neuroinflammatory processes, using siRNA-mediated inhibition and a pharmacological inhibitor in both CHME3 cells and MDMi, our study certainly provides evidence of TLR3 involvement during S1-induced microglial inflammation, which needs further investigation. Together, these in vitro findings demonstrate that the let-7a-5p/SHIP-1 axis regulates S1-induced inflammatory cascades in CHME3 and MDMi cells, providing mechanistic insight into its role in SARS-CoV-2-associated neuroinflammation and warranting further validation in appropriate in vivo/organoid models. Full article

Background: Enteroviruses (EVs) have been proposed as environmental triggers in type 1 diabetes (T1D), potentially through activation of innate immune pathways and type I interferon (IFN) responses. However, the relationship between detectable viral infection and IFN-related transcriptional responses remains unclear. Methods: In this cross-sectional, exploratory study, peripheral blood samples from individuals with new-onset T1D, established T1D, and healthy controls were analyzed by an enterovirus 5′NCR-targeted RT-PCR assay and for the expression of innate immune receptors (TLR3, TLR7, TLR8), interferon-stimulated genes (IFI27, IFIT1, ISG15, IFI44L, RSAD2, SIGLEC1), and FOXP3, assessed as an exploratory marker related to regulatory T-cell biology potentially influenced by type I interferon signaling. Gene expression was assessed by quantitative RT-PCR, and comparisons were performed between groups. Results: Enterovirus-targeted amplification was observed in only one T1D sample under the applied assay conditions. In the setting of limited enterovirus-targeted amplification under the applied assay conditions, TLR3 was significantly increased in established T1D, while TLR7 was increased in both new-onset and established T1D, with the highest levels in established disease; these differences remained significant after correction for multiple comparisons across the full gene panel. TLR8 was unchanged. Several of the selected interferon-stimulated genes showed group-specific expression patterns: IFI27 and RSAD2 were significantly increased in new-onset T1D, whereas IFIT1 and ISG15 were more evident in established T1D. SIGLEC1 and IFI44L showed no significant differences. FOXP3 transcript abundance was also increased in both diabetic groups, a finding that correlated with lymphocyte proportion and is interpreted with caution. Conclusions: These findings indicate group-specific differences in whole-blood transcript expression of selected RNA-sensing and IFN-related genes in T1D under conditions in which enterovirus-targeted amplification was observed in only one sample. Given the cross-sectional whole-blood design and the analytical limitations of the EV assay, these results are hypothesis-generating and do not establish the presence or absence of systemic enterovirus infection or functional pathway activation. Full article

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. Full article