Search Results (509)

Oxidative stress (OS) is increasingly recognized as a dynamic disturbance of cellular redox networks rather than a simple imbalance between oxidants and antioxidants. In this context, ferroptosis and cuproptosis—two regulated and metal-dependent forms of cell death—emerge as key mechanisms linking OS to metabolic dysfunction, inflammation, and tissue injury. This review integrates findings from biochemical, lipidomic and metallomic studies to describe how lipid peroxidation (LPO), glutathione (GSH)–Glutathione Peroxidase 4 (GPX4) activity, ferritinophagy, copper-induced mitochondrial protein lipoylation, and altered communication between organelles generate distinct redox signatures across diseases. By examining cutaneous, metabolic, cardiovascular, infectious, neurodegenerative, and oncologic conditions, we outline the shared redox pathways that connect iron- and copper-dependent cell death to systemic inflammation, immune dysregulation, and chronic tissue damage. Common oxidative markers—such as oxidized phospholipids, lipid aldehydes including 4-Hydroxynonenal (4-HNE) and malondialdehyde (MDA), and systemic metal imbalance—are highlighted as potential indicators of disease severity and as emerging therapeutic targets. We also discuss innovative analytical tools, including redox lipidomics, metallomic profiling and artificial-intelligence (AI)-based classification approaches, which improve the characterization of redox vulnerability and may guide the development of precision redox therapies. Overall, ferroptosis and cuproptosis represent unifying mechanisms that connect OS to multisystem disease and provide new opportunities for diagnostic refinement and targeted antioxidant-based interventions. Full article

Mesenchymal stromal cells (MSCs) are promising therapeutic agents, largely due to their capacity for self-renewal, differentiation, and immunomodulation. Importantly, these beneficial effects are frequently mediated by the MSC secretome, which contains factors with anti-inflammatory, anti-apoptotic, and pro-regenerative properties. However, cellular senescence can impair these critical functions. To identify senescence-associated changes in the MSC secretome that may regulate aging and intercellular communication, we performed a mass spectrometry-based proteomic analysis of the conditioned medium from MSCs undergoing stress-induced senescence. Our analysis confirmed the upregulation of established aging markers, such as IL-6, PAI-1, and IGFBP7. Furthermore, we identified a significant increase in lesser-known senescence-associated secretory phenotype (SASP) components, including INHBA—a known inhibitor of proliferation—and DKK3, which blocks stromal cell pluripotency. Pathway analysis revealed that stress-induced senescence broadly affected proteins involved in glycolysis, immune response, hemostasis, and the regulation of cell death and the cell cycle. These alterations are likely to negatively impact the MSC microenvironment. Interestingly, the cellular response to senescence was dualistic. Alongside detrimental SASP factors, we observed an increase in protective proteins such as annexins (ANXA1, ANXA2), antioxidants (TXN, PRDX1, PRDX6), and the heat shock protein HSPB1, which collectively defend neighboring cells from inflammation and oxidative stress. These findings underscore the complex etiology of cellular senescence and the paradoxical nature of the SASP. The obtained data also emphasize the necessity of comprehensive proteomic profiling of the MSC secretome across different aging models to harness the full therapeutic potential of MSCs and their secretomes for regenerative medicine. Full article

Dry Anophthalmic Socket Syndrome (DASS) is a multifactorial condition that affects roughly half of all prosthetic eye wearers and remains frequently underrecognized. It is characterised by symptoms such as dryness, discomfort, discharge, and inflammation of the socket surface. Diagnostic criteria include validated symptom questionnaires (e.g., OSDI, DEQ-5, SANDE) and at least one clinical sign such as conjunctival staining, blepharitis, or reduced tear meniscus height. This review describes the anatomical, cellular, and molecular changes associated with DASS. Meibomian gland dysfunction is common, with a significant reduction in gland density and structure. Goblet cell density is also often decreased, particularly in the tarsal and bulbar conjunctiva, although findings may be affected by topical treatments. Increased conjunctival inflammation—evidenced by immune cell infiltration and elevated markers such as MMP-9 and ICAM-1—is frequently observed, particularly in the posterior socket lining. Oxidative stress, mediated by dysregulated NOX4, KEAP1, and NRF2 expression, appears to play a contributory role. Additional factors influencing DASS include eyelid malpositions such as entropion and ectropion, prosthesis smoothness and amount of tear film production. Poor hygiene practices and environmental factors may exacerbate symptoms. Given its multifactorial aetiology, DASS requires a complex management strategy targeting inflammation, tear film instability, mechanical irritation, eyelid position and patient education. Increased awareness, standardised diagnostics, and evidence-based care protocols are critical to improving outcomes for prosthetic eye wearers. Full article

Sphingolipids are essential for cellular structure and signaling, and recent evidence implicates them in chronic inflammation. We hypothesized that altered sphingolipid metabolism contributes to the disease activity of systemic lupus erythematosus (SLE). Serum sphingolipids were quantified by liquid chromatography–tandem mass spectrometry in 38 female SLE patients (11 with lupus nephritis [LN], 27 without LN) and 30 age-matched healthy controls (HCs). Serum ceramide (Cer)16/sphingosine-1-phosphate (S1P) ratios were elevated in SLE compared to HCs (0.33 [0.26–0.38] vs. 0.25 [0.21–0.3], p = 0.019). Notably, Cer16/S1P levels were significantly higher in the LN group (0.33 [0.26–0.38]) than in non-LN SLE (0.27 [0.2–0.34], p = 0.027). ROC analysis showed good diagnostic potential for LN (AUC = 0.739). Cer16/S1P correlated positively with disease activity markers, including erythrocyte sedimentation rate (r = 0.519, p = 0.001), SLE Disease Activity Index 2000 (SLEDAI-2k) score (r = 0.547, p < 0.001), anti-double stranded DNA antibody levels (r = 0.359, p = 0.027), and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (r = 0.327, p = 0.045). The serum Cer16/S1P ratio may serve as a surrogate marker of disease activity in patients with LN. Full article

Aging is a critical factor influencing susceptibility to hepatic injury. In this study, the spontaneous development of liver injury with advancing age and potential sex-related differences in these processes are examined. This study focuses on key mechanisms such as fatty acid metabolism, immune response, and cellular stress in male and female C57BL/6 mice. Aged male and female mice (20 to 22 months old) exhibited higher body weight and an altered metabolic profile and fatty acid metabolism compared to their younger counterparts (8 to 10 weeks old). In addition, increased oxidative stress, cellular senescence, expression of inflammatory markers, and cytokines/chemokines levels were also observed in aged male and female mice compared to younger mice. Furthermore, the aged mice exhibited increased indices of hepatic fibrosis, evident from the upregulation of smooth muscle actin-α, collagen, and transforming growth factor-β. In conclusion, aging promotes spontaneous liver injury by increasing indices of oxidative stress, steatosis, inflammation, and fibrosis. These results highlight the impact of chronological age on the liver that can increase its susceptibility to secondary hepatic stressors such as alcohol, high-calorie diet, or hepatotropic infections. Understanding how metabolic and inflammatory pathways change with aging in males and females is essential for elucidating the mechanisms that drive chronic liver disease progression. These insights are particularly important for developing targeted, sex-specific prevention and therapeutic strategies for the aging population. Full article

Background/Objectives: Chronic inflammation arises from self-reinforcing immune–metabolic circuits encompassing pattern-recognition signaling, inflammasome activation, cytokine networks, immunometabolic reprogramming, barrier–microbiome disruption, cellular senescence, and neuro–immune–endocrine crosstalk. This review synthesizes these mechanistic axes across diseases and introduces an operational endotype-to-care framework designed to translate mechanistic insights into precision-based, scalable, and equitable interventions. Methods: A narrative, mechanism-focused review was performed, integrating recent literature on immune–metabolic circuits, including pattern-recognition receptors, inflammasome pathways, cytokine modules, metabolic reprogramming, barrier–microbiome dynamics, senescence, and neuro–immune–endocrine signaling. Validated, low-cost screening biomarkers (hs-CRP, NLR, fibrinogen) were mapped to phenotype-guided endotyping panels and corresponding therapeutic modules, with explicit monitoring targets. Results: We present a stepwise, pragmatic pathway progressing from broad inflammatory screening to phenotype-specific endotyping (e.g., IL-6/TNF for metaflammation; ISG/IFN for autoimmunity; IL-23/17 for neutrophilic disease; IL-1β/NLRP3 or urate for crystal-driven inflammation; permeability markers for barrier–dysbiosis). Each module is paired with targeted interventions and prespecified treat-to-target outcomes: for example, achieving a reduction in hs-CRP (e.g., ~40%) within 8–12 weeks is used here as a pragmatic operational benchmark rather than a validated clinical threshold. Where feasible, cytokine and multi-omic panels further refine classification and prognostication. A tiered implementation model (essential, expanded, comprehensive) ensures adaptability and equity across clinical resource levels. Conclusions: Distinct from prior narrative reviews, this framework defines numeric triage thresholds, minimal endotype panels, and objective monitoring criteria that make chronic inflammation management operationalizable in real-world settings. It embeds principles of precision, equity, and stewardship, supporting iterative, evidence-driven implementation across diverse healthcare environments. Full article

Traumatic brain injury has long-term detrimental effects on neurological function and general quality of life of affected individuals. Bioenergetic failure is a primary mechanism for cellular dysfunction. We used the mitochondrial activator humanin (HN) to try to normalize the disruptive action of TBI on cellular bioenergetics in the hippocampus. We found that HN supplied right after the injury counteracted the action of TBI on metabolic sensing proteins (LKB1, AMPK, and AKT). HN also counteracted cognitive function and restored the synaptic proteins (Synapsin I and PSD-95) at three weeks post-injury. Moreover, HN normalized the disruptive action of TBI on mitochondrial functioning and dynamics (fusion, fission, and mitophagy). In addition, HN treatment counteracted TBI’s effects on mitochondrial biogenesis (PGC-1α), antioxidant (SOD2), and apoptotic marker (CC3). Furthermore, HN intervention in injured animals counteracted the gene expression linked with inflammation (Itgax, SALL1, GFAP, and NLRP3), synaptic plasticity (HDAC2), and bioenergetics (mtND2, TFAM, SIRT1, and SIRT3). These observations emphasize the therapeutic potential of HN by normalizing the fundamental aspects of TBI pathogenesis central to cellular bioenergetics and synaptic plasticity. Full article

Histological healing is increasingly recognized as a sensitive marker of disease remission in ulcerative colitis (UC). However, the dynamics of mucosal T lymphocytes and proinflammatory cytokines during healing remain incompletely understood. In this paired, within-subject observational study (retrospective analysis of paired biopsies), colonic biopsy sets from 20 adult UC patients were analyzed during active inflammation and at a subsequent time point of histologic healing. Immunohistochemistry was performed for CD3, CD4, CD8, and IL-6. Lymphocyte densities were quantified in intraepithelial and lamina propria compartments, while IL-6 expression was scored semi-quantitatively. Histological activity was assessed using the Geboes score. Intraepithelial CD4⁺ T cells significantly decreased during histologic healing (mean 6.8 → 3.75 cells/100 epithelial cells, p < 0.05), whereas lamina propria CD4⁺ cells remained variably persistent, suggesting ongoing immune regulation. Intraepithelial CD8⁺ cells increased during remission, indicating a potential reparative or surveillance role. IL-6 expression markedly declined in epithelial and stromal compartments during healing, reflecting resolution of mucosal inflammation. Correlation analyses revealed enhanced coordination between CD4⁺ and CD8⁺ cells in the healing phase, consistent with immune homeostasis. Histologic healing in UC involves compartment-specific shifts in T lymphocyte populations and a marked reduction in IL-6 expression, reflecting coordinated immune regulation beyond clinical remission. These findings highlight the potential of combined cellular and cytokine biomarkers to monitor mucosal healing and guide immunomodulatory therapies. Full article

Oxidative stress in retinal pigment epithelium (RPE) cells plays a key role in the development of age-related macular degeneration (AMD), a leading cause of vision loss in the elderly. Thymoquinone, a bioactive antioxidant from Nigella sativa, has shown promise in reducing cellular oxidative stress. In AMD, prolonged exposure to oxidative stress may activate the NF-κβ signalling pathway in RPE cells, contributing to chronic inflammation, and its regulation by thymoquinone remains understudied. This study investigates the effects of thymoquinone in TNFα-induced RPE cells exposed to AGEs to mimic ageing conditions relevant for AMD. Gene and protein expression levels of NF-κβ pathway markers (P65, pP65 and Iκβα) were measured using qPCR and Western blotting, and statistical analysis was performed using Student’s t-test and one-way ANOVA. Thymoquinone pretreatment at 0.1 µM and 10 µM significantly reduced the expression of these markers in TNFα-stimulated RPE cells. Notably, AGE-exposed cells demonstrated a heightened response to thymoquinone compared to non-AGE-exposed controls. These findings suggest that thymoquinone modulates NF-κβ signalling and may serve as a potential adjuvant therapeutic agent for AMD. Full article

Background: It is widely accepted that low-grade chronic inflammation in obesity worsens the metabolic state and threatens patients’ lives in a long-term manner. In fact, diet therapy is the first-line treatment in which relevant nutrients such as the omega-3 polyunsaturated fatty acids (ω-3 PUFA) must be adequately consumed to counteract the established inflammation. In particular, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been identified as agonists of cellular receptors, including the free fatty acid receptor 4 (FFAR4), which regulates anti-inflammatory pathways associated with enhanced insulin sensitivity. However, the expression and activation of this receptor in peripheral blood mononuclear cells (PBMC) remains poorly investigated in humans. Objective: This study aimed to evaluate the effect of a diet supplemented with marine ω-3 PUFA on FFAR4 receptor activation and inflammatory markers in peripheral blood mononuclear cells in subjects with obesity. Methodology: A double-blind, randomized clinical trial (NCT05068557) was conducted over two months (eight weeks) in 55 obese individuals (aged 25–59 years). Participants were randomly assigned to one of two groups: an active placebo group (1.6 g/day of alpha-linolenic acid) or a marine ω-3 group (1080 mg of EPA and 720 mg of DHA). Both groups followed a dietary regimen with progressive calorie restriction (−200 kcal/day during weeks 0–4 and −400 kcal/day during weeks 4–8) in addition to supplementation. Results: Following the intervention, both groups showed significant improvements in body composition and biochemical parameters. Supplementation with EPA and DHA enhanced FFAR4 activation at the end of the intervention. Moreover, there was a reduction in the expression of JNK and IKKβ genes, as well as in serum levels of TNF-α, IL-6, and IL-18. In contrast, IL-10 levels increased significantly both within and between the groups. Conclusions: Marine ω-3 PUFA supplementation, in the context of a dietary intervention, promotes FFAR4 activation, thereby contributing to the modulation of the inflammatory response in human PBMC. Full article

Biebersteinia heterostemon is a traditional Tibetan medicine known for its antioxidant, hypoglycemic, and anti-atherosclerotic properties. However, its therapeutic effects and mechanisms in the treatment of hyperlipidemia remain unclear. In this study, the ethyl acetate extract of B. heterostemon (BHEE) was first identified as the most effective lipid-lowering fraction through its inhibitory activity on pancreatic lipase and cholesterol esterase. Chemical characterization of BHEE by UHPLC-MS/MS revealed 108 compounds. Network pharmacology and molecular docking analyses were then employed to predict key active components and signaling pathways involved in BHEE’s lipid-lowering effects. A total of 50 active components and 623 targets were selected from the PubChem, SwissADME, and Swiss Target Prediction databases. These targets were intersected with 1606 hyperlipidemia-related targets from GeneCards, OMIM, and DrugBank, resulting in 144 common targets. The “drug-active component-intersecting target-pathway-HLP” and protein–protein interaction (PPI) networks suggested key active components such as 6-methoxytricin, vulgarin, flazin, ganhuangenin, and eupatorin, and core targets including TNF, IL6, AKT1, PPARG, and EGFR. GO and KEGG pathway enrichment analysis highlighted potential signaling pathways, such as AGE-RAGE, PPAR, insulin resistance, TNF, and lipid and atherosclerosis pathways. Molecular docking further predicted the strong binding affinity between key active components and core targets. At the cellular level, BHEE dose-dependently reduced lipid accumulation in FFA-induced HepG2 cells and improved oxidative stress (CAT, GSH, SOD, MDA) and inflammation (TNF-α, IL-6) markers. In conclusion, BHEE may exert its anti-hyperlipidemic effects through modulation of key targets like TNF, IL6, AKT1, PPARG, and EGFR. These findings suggest a multi-target mechanism, though further experimental validation is necessary to confirm these effects. This study provides valuable insights into the potential application of B. heterostemon as a natural therapeutic agent for hyperlipidemia. Full article

Alcohol use disorder (AUD) predisposes individuals to pneumonia, acute respiratory distress syndrome, and chronic obstructive pulmonary disease, yet the mechanisms underlying alcohol-related lung disease (ARLD) remain unclear. Alveolar type II (AT2) epithelial cells play a central role in ethanol (EtOH) metabolism, surfactant production, alveolar repair, and pulmonary innate immunity. To examine EtOH-mediated effects, immortalized human AT2 cells were treated with 22–130 mM EtOH for 6 h (concentration-dependent) and 65 mM EtOH for 6–72 h (time-dependent). Cytotoxicity, inflammation, surfactant lipid/protein dysregulation, fatty acid ethyl ester (FAEE) formation, cellular stress responses, AMP-activated protein kinase (AMPKα) signaling, and mitochondrial function were analyzed. EtOH disrupted surfactant homeostasis by reducing dipalmitoylphosphatidylcholine and surfactant protein C (SP-C). Importantly, EtOH inactivated AMPKα, downregulated CPT1A (involved in β-oxidation of fatty acids), and upregulated lipogenic proteins ACC1 and FAS, accompanied by increased ER stress markers (GRP78, p-eIF2α, and CHOP). Expression of carboxyl ester lipase (FAEE-synthesizing enzyme) and FAEE levels increased with EtOH exposure, further exacerbating oxidative and ER stress, impairing mitochondrial energetics, ATP production, and AT2 cell function. These findings suggest that EtOH-induced FAEE formation, dysregulation of AMPKα-CPT1A signaling, and surfactant contribute to AT2 cell dysfunction and play a critical role in the pathogenesis of ARLD. Full article

Sepsis is a life-threatening condition driven by a dysregulated immune response, leading to systemic inflammation and multi-organ failure. Among the key molecular regulators, S100A8/A9 has emerged as a critical damage-associated molecular pattern (DAMP) protein, amplifying pro-inflammatory signaling via the Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE) pathways. Elevated S100A8/A9 levels correlate with disease severity, making it a promising biomarker and therapeutic target. To unravel the role of S100A8/A9 in sepsis, we integrate scRNA-seq and RNA-seq approaches. scRNA-seq enables cell-type-specific resolution of immune responses, uncovering cellular heterogeneity, state transitions, and inflammatory pathways at the single-cell level. In contrast, RNA-seq provides a comprehensive view of global transcriptomic alterations, allowing robust statistical analysis of differentially expressed genes. The integration of both approaches enables precise deconvolution of immune cell contributions, validation of cell-specific markers, and identification of potential therapeutic targets. Our findings highlight the S100A8/A9-driven inflammatory cascade, its impact on immune cell interactions, and its potential as a diagnostic and prognostic biomarker in sepsis. Eight protein targets resulted from the integrative transcriptomics studies (corresponding to S100A8, S100A9, S100A6, NAMPT, FTH1, B2M, KLF6 and SRGN) have been used to predict interaction affinities with 2958 ChEMBL approved drugs, by using a pre-trained AI models (PLAPT) in order to point directions on drug repurposing in sepsis. The strongest predicted interactions have been confirmed with molecular docking and molecular dynamics analysis. This study underscores the power of combining high-throughput transcriptomics to advance our understanding of sepsis pathophysiology and develop precision medicine strategies. Full article

Background: Although luteolin (Lut) is well recognized for its anti-inflammatory and antioxidant effects, its potential role in preventing vascular senescence remains underexplored in primary vascular aging. This study aimed to investigate the anti-vascular-aging effects of Lut in both cellular and murine aging models and to elucidate its conserved molecular mechanisms across species. Methods: Canine and feline vascular endothelial cells (cVECs and fVECs) were subjected to doxorubicin-induced senescence, while senescence-accelerated mice prone 8 (SAMP8) received an 8-week dietary supplementation with Lut. Senescence markers, inflammatory cytokines, antioxidant activities, vascular biomechanics, and histological changes were assessed. Transcriptomic and metabolomic analyses were combined to identify molecular pathways. Statistical significance was determined by one-way analysis of variance with Tukey’s or Games–Howell post hoc tests (p < 0.05). Results: Lut markedly reduced senescence-associated β-galactosidase activity, suppressed interleukin-6 and matrix metalloproteinase expression (p < 0.05), and enhanced superoxide dismutase activity and nicotinamide adenine dinucleotide levels (p < 0.05) in cVECs, fVECs, and SAMP8 sera. In aged mice, Lut alleviated arterial wall thickening and vascular inflammation, improved vascular biomechanics and systemic oxygenation (p < 0.05), and attenuated cardiac and hepatic inflammatory infiltration. Multi-omics analyses in cVECs revealed that Lut targets aldehyde dehydrogenase 1 to increase 9-cis retinoic acid, thereby activating the retinol X receptor–peroxisome proliferator-activated receptor (PPAR) network, which accelerates lipid clearance and oxidation. Consistent activation of this pathway was validated in murine vascular transcriptomes. Conclusions: These findings demonstrate that Lut delays vascular aging by activating the retinoic acid–PPAR axis and reprogramming lipid metabolism. This conserved mechanism was consistently observed in doxorubicin-induced cVEC senescence and the SAMP8 model, underscoring the robustness of Lut’s action across distinct contexts of vascular aging. Full article

The chemical composition of the ethanol extract of Acanthopanax senticosus fruit (ASFEE) was systematically characterized using UPLC-MS/MS (Q Exactive Orbitrap), leading to the identification of 45 compounds. Through integrated network pharmacology and molecular docking analyses, the binding affinities between key bioactive constituents—such as eleutheroside E (EE) and quercetin—and core therapeutic targets were predicted and validated. A total of 125 overlapping targets were identified between ASFEE and acute kidney injury (AKI), with significant enrichment observed in critical signaling pathways, including NF-κB, IL-17, and PI3K-Akt. To evaluate the protective effects of ASFEE, both in vitro (HK-2 cells) and in vivo (murine) models of cisplatin (DDP)-induced AKI were employed. Parameters assessed included cell viability, apoptosis, reactive oxygen species (ROS) production, activation of the NF-κB signaling pathway, kidney function, histopathological alterations, and levels of inflammatory cytokines. ASFEE treatment markedly enhanced HK-2 cell viability and reduced cellular apoptosis and ROS generation. In the murine model, DDP administration resulted in significantly elevated serum creatinine (Scr) and blood urea nitrogen (BUN) levels. Both low- and high-dose ASFEE treatments significantly attenuated these increases, improved overall kidney function, and alleviated kidney tubular damage. Furthermore, ASFEE reduced serum levels of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α. Multi-omics integration analysis enabled the identification of differentially expressed genes and metabolites. ASFEE was found to reverse 4689 DDP-induced gene expression changes and 323 metabolic disturbances, with the uridine diphosphate glucuronosyltransferase (UGT)-mediated ascorbic acid metabolism pathway emerging as the central regulatory axis. Key candidate genes and proteins were further validated via real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting. DDP significantly upregulated the expression of inflammatory markers and associated signaling molecules in kidney tissues, while concurrently downregulating UGT family genes and the UGT1A1 protein involved in uronic acid metabolism. Notably, ASFEE treatment effectively counteracted these alterations, confirming its role in enhancing UGT1A1-mediated metabolic processes and suppressing the NF-κB/PI3K-Akt/IL-17 signaling cascade. These mechanisms contribute to improved antioxidant capacity, mitigation of inflammatory responses, and restoration of metabolic homeostasis, thereby conferring protection against DDP-induced AKI. ASFEE exerts a protective effect on AKI caused by DDP by enhancing antioxidant capacity, inhibiting inflammation and restoring metabolic homeostasis, providing an experimental basis for its subsequent development and application. Full article