Search Results (4,812)

This study aimed to investigate the protective effects of fenofibrate against sepsis-induced acute lung injury using a feces-induced peritonitis (FIP) rat model, with particular emphasis on the modulation of HSP70 and Nrf2 as key cellular defense mechanisms. The FIP model was employed to mimic colon-origin abdominal sepsis, frequently encountered in general surgery, including conditions such as colonic perforation and anastomotic leakage. Thirty male Wistar albino rats were randomly assigned to control, FIP, and FIP + fenofibrate groups. Sepsis was induced by intraperitoneal injection of a fecal-saline suspension. Fenofibrate (100 mg/kg) was administered intraperitoneally after the FIP procedure. After 24 h, lung tissues and blood samples were collected. Assessments included histopathology (H&E staining), thoracic CT imaging, arterial blood gas analysis, ELISA-based quantification of plasma cytokines (IL-6, IL-1β, TNF-α), MDA for oxidative stress, and lung tissue levels of HSP70 and Nrf2. Feces-induced peritonitis caused severe acute lung injury, evidenced by increased histopathological damage (p < 0.001), impaired gas exchange (PaO₂ and PaCO₂, p < 0.01), elevated inflammatory cytokines (IL-6, IL-1β, TNF-α; p < 0.001), increased oxidative stress (MDA, p < 0.001), and suppressed lung Nrf2 and HSP70 expression (p < 0.001). Fenofibrate significantly attenuated lung injury, improved gas exchange (p < 0.05), reduced inflammation (p < 0.01–p < 0.001), decreased MDA (p < 0.001), and increased Nrf2 (p < 0.001) and HSP70 (p < 0.01). Fenofibrate attenuates sepsis-induced acute lung injury by reducing inflammation and oxidative stress while preserving HSP-70 and Nrf2-mediated cytoprotective pathways. These findings are clinically relevant to general surgery, as septic lung injury commonly arises from colon-origin abdominal sepsis, including colonic perforation and anastomotic leakage. Full article

Introduction: Oxidative stress and inflammation are major factors linked to obesity and metabolic dysfunction, leading to a significantly higher risk of related diseases. Atorvastatin and liraglutide possess lipid-lowering, antioxidant, and anti-inflammatory effects that could synergistically improve obesity-related perturbations through modulation of the Nrf2/HO-1 signaling pathway. Methodology: We assessed liraglutide’s pharmacological potential in extending atorvastatin’s benefit on obesity, hyperlipidemia, and fatty liver in rats fed a high-fat diet (HFD) for 12 weeks. We specifically evaluated the effects of liraglutide treatment on atorvastatin-induced anti-inflammatory and antioxidant mechanisms, with a particular focus on Nrf2/HO 1 modulation in adipose and hepatic tissue. In silico analyses, including molecular docking and AlphaFold- Multimer modeling, evaluated the binding affinities of atorvastatin and liraglutide to Nrf2 and HO 1. Results: Compared to ND, the HFD-fed rats had a significantly higher final body weight (362.4 ± 12.7 g vs. 245.6 ± 9.8 g in ND, p < 0.05). There was a marked increase in serum total cholesterol (178.6 ± 9.2 mg/dL vs. 98.3 ± 6.4), fasting glucose (340.1 ± 8.2 mg/dL vs. 82.3 ± 3.1), HbA1c (7.8 ± 0.3 vs. 4.5 ± 0.2), and hepatic COX-2 expression (99.9 ± 6.3 vs 19.6 ± 2.4). The oxidative stress markers were also disturbed, as indicated by SOD (42.5 ± 3.1 vs. 95.2 ± 4.6 U/mg protein), GSH (18.3 ± 1.5 vs. 42.7 ± 2.8 nmol/mg), and p62 (0.005 ± 0.001 vs. 0.125 ± 0.01). Atorvastatin lowered cholesterol (121.2 ± 7.5 mg/dL), COX-2 (61.3 ± 3.3), and body weight (301.7 ± 11.5 g) compared to HFD. Meanwhile, liraglutide caused a greater reduction in body weight (268.5 ± 10.3 g), glucose (112.5 ± 6.7 mg/dL), and COX-2 (42.2 ± 2.9) than atorvastatin. The combination therapy produced the most significant effects, returning body weight (253.6 ± 9.1 g) to baseline, normalizing glucose and lipids, reducing COX-2 to 22.9 ± 2.0, and reactivating the Nrf2/HO-1 pathway, as shown by increased HO-1 expression and the restoration of p62 levels (0.078 ± 0.004). In silico analyses suggest that atorvastatin favorably binds to Nrf2 and HO-1, while liraglutide interacts with structurally relevant interfaces on these proteins, providing a mechanistic basis for their complementary antioxidant and cytoprotective effects. Conclusions: Our findings support targeting the Nrf2/HO-1 signaling pathway as a potential therapy for reversing hyperlipidemia and preventing mediators of inflammation and oxidative stress damage in the liver tissue. The evidence of increased efficacy observed with the combined atorvastatin and liraglutide supports a potential novel understanding of the complementary effects of atorvastatin and liraglutide. This finding requires further investigation to elucidate the combination’s therapeutic advantages in treating metabolic disorder scenarios. Full article

Glutinous rice huangjiu, a non-distilled wine variety unique to China, is rich in nutrients. However, systematic research on the differences in its non-volatile functional components remains scarce, despite these variations being key factors influencing its antioxidant effects. This study employed non-targeted metabolomics to systematically analyze the non-volatile metabolite profiles of 16 glutinous rice huangjiu brands, identifying 1450 metabolites. An alcohol-induced hepatocyte injury model was established, combining cell viability and reactive oxygen species (ROS) level assays to screen for samples (G10 and G11) exhibiting significant efficacy across varying alcohol concentrations. Differential metabolite analysis further identified key bioactive compounds including L-proline, dihydroferulic acid, chalcones, and multiple phenolic derivatives. Using molecular docking technology, we preliminarily revealed that these components may exert antioxidant and hepatoprotective effects either by directly scavenging free radicals or indirectly through mechanisms such as participating in glutathione metabolism and regulating the KEAP1-Nrf2 signaling pathway. This study elucidates the differences among glutinous rice huangjiu at the metabolomic and cellular model levels, providing a scientific basis for evaluating the health benefits and developing new products of huangjiu. Full article

Quercetagetin (QG), a principal flavonol from marigold (Tagetes erecta L.), is recognized for its potent antioxidant properties. However, its efficacy in mitigating intestinal injury under heat stress (HS) conditions remains unclear. We investigated the protective effects of QG using a mouse model of HS (41 °C, 70% humidity). Mice received oral QG (100 mg/kg/day) or saline for seven consecutive days before and during HS exposure. We assessed jejunal histopathology, oxidative stress markers, inflammatory cytokines, gene expression, and gut microbiota composition via 16S rRNA sequencing. QG supplementation significantly ameliorated HS-induced jejunal damage. It enhanced the activities of superoxide dismutase (SOD) and catalase (CAT) while reducing malondialdehyde (MDA) and pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). QG downregulated the mRNA expression of heat shock proteins (Hsp70, Hsp90) and upregulated antioxidant-related genes (SOD1, GPX4, CAT, NQO1, Nrf2). Furthermore, QG preserved intestinal barrier integrity by upregulating tight junction proteins (Occludin, Zo-1, Claudin). 16S rRNA analysis revealed that QG significantly reshaped the gut microbiota, marked by an increased relative abundance of Lactobacillus and a decrease in potentially harmful taxa such as Allobaculum, Oscillibacter, and Colidextribacter. QG effectively alleviates HS-induced intestinal injury by enhancing antioxidant capacity, suppressing inflammation, and modulating the gut microbiota. These findings provide a scientific basis for the potential application of QG as a functional feed additive to improve animal health under heat stress conditions. Full article

Ferroptosis, a type of iron overload-induced cell death, is involved in diabetes-induced testicular dysfunction. Hence, this study was designed to investigate, for the first time, the impact of lipoxin A4 (LXA4) administration on testicular tissue in diabetic rats and explore its probable role in regulating ferroptosis in comparison with the standard ferroptosis inhibitor (ferrostatin-1, Fer-1). Albino rats of Wistar strain were divided into a control group, a type II diabetes mellitus (DM) group, a DM + Fer-1group, and a DM + LXA4 group. Serum levels of iron, insulin, glucose, total cholesterol, triglycerides, and testosterone were assayed. Testicular tissue markers of oxidative stress, ferroptosis, and inflammation were also assessed by different methods. Our results confirmed diabetes-induced testicular injury and disruption of its function via inducement of ferroptosis, but this was ameliorated with LXA4 and Fer-1 administration. However, Fer-1 showed a greater protective effect compared to LXA4 under the conditions of this study. We concluded that LXA4 partially secured the testicular tissue of diabetic rats against ferroptosis via augmenting the antioxidant Nrf2/SLC7A11/GPX4 pathway. Therefore, LXA4 may have a possible protective effect on the testicular tissue of diabetic patients. Full article

In the treatment of atopic dermatitis (AD), synergistic activation of the aryl hydrocarbon receptor (AHR)/nuclear factor erythroid 2-related factor 2 (NRF2) pathways represents a promising strategy. However, known dual agonists are limited, and traditional screening methods are inefficient. Therefore, this study developed machine learning models to predict AHR/NRF2 dual agonists using molecular descriptors and fingerprints. All models achieved area under the receiver operating characteristic curve (AUC) values above 0.86, indicating good classification performance. The optimal AHR model showed an accuracy (ACC) of 0.811 and an AUC of 0.878, while the best NRF2 model yielded an ACC of 0.839 and an AUC of 0.907. Based on this model, compounds with a low fraction of sp³-hybridized carbons, moderate hydrophobicity, limited alkyl chains, and highly conjugated structures tend to act as AHR/NRF2 dual agonists. Finally, this study screened 1011 potential natural AHR/NRF2 dual agonists suitable for drug development. Among these, 2-arylbenzofurans, alkaloids, phenanthrenes, flavones, and furocoumarins demonstrated particular advantages. For validation, Indirubin, imperatorin and 3′-O-Methylbutastatin III were first discovered as AHR/NRF2 dual agonists in HaCaT cells. This work provides a robust predictive tool, clarifies key molecular features of dual agonists, and may support the discovery of anti-AD agents. Full article

Adolescence is a metabolically vulnerable period, during which rapid physiological maturation coincides with the dynamic remodelling of the gut microbiome. This narrative review summarises evidence from 2015 to 2025 to clarify how disturbances to the gut–liver axis driven by dysbiosis contribute to the development and progression of non-alcoholic fatty liver disease (NAFLD) in young people. Based on a systematic search of the databases PubMed, Scopus and Web of Science, we outline the basis of bidirectional communication between the gut and liver and emphasise how microbial imbalance alters the handling of lipids in the liver by enhancing de novo lipogenesis, impairing fatty acid oxidation and disrupting AMPK signalling and mitochondrial function. Consistent findings from clinical and experimental studies show that adolescents with NAFLD exhibit reduced microbial diversity, the enrichment of ethanol- and LPS-producing taxa, and altered short-chain fatty acid profiles. Each of these is associated with hepatic inflammation and metabolic reprogramming. Microbial molecules, including LPS, secondary bile acids and branched-chain amino acid metabolites, activate TLR4–NF-κB pathways, promote Kupffer cell activation and intensify oxidative stress. These mechanisms intersect with factors specific to adolescence, such as increased adiposity, hormonal shifts and diet-induced metabolic strain. Dietary patterns emerge as key modulators of these processes. Westernised diets promote dysbiosis and endotoxemia, whereas Mediterranean, fibre-rich and plant-based diets enhance SCFA production, strengthen epithelial integrity and modulate adiponectin-dependent hepatic metabolism. Micronutrient-sensitive epigenetic regulation, particularly that involving folate, choline and polyphenols, also plays a role in shaping lipid homeostasis and inflammatory tone. We also highlight emerging evidence that the activation of cytoprotective pathways, especially Nrf2, is dependent on lifestyle factors and links antioxidant-rich functional foods and physical activity to improved mitochondrial resilience and microbiome stability. We evaluate therapies targeting the microbiome, including probiotics, prebiotics, synbiotics and postbiotics, which reduce endotoxemia, restore microbial balance and complement dietary strategies. Thus, these findings emphasise the importance of age-specific, mechanistically informed interventions that integrate diet quality, microbial ecology, and the molecular pathways that govern metabolic health in adolescents with NAFLD. Full article

Chronic liver diseases, including fibrosis and hepatocellular carcinoma (HCC), are primarily driven by oxidative stress, yet traditional antioxidant therapies often lack the specificity and efficacy required for clinical success. This review evaluates the emerging therapeutic potential of two atypical globins, cytoglobin (CYGB) and neuroglobin (NGB), exploring their unique hexacoordinated heme structures that enable potent reactive oxygen and nitrogen species (ROS/RNS) scavenging and redox-regulated signaling. We summarize a broad range of in vitro and in vivo evidence demonstrating that these globins deactivate hepatic stellate cells, reduce extracellular matrix accumulation, and function as tumor suppressors by modulating pathways such as Raf/MEK/ERK and NRF2. In human cohorts, CYGB expression levels inversely correlate with the progression of Metabolic Dysfunction-Associated Steatohepatitis (MASH) and HCC, highlighting its potential as a clinical biomarker. Furthermore, recombinant protein therapies involving CYGB and NGB show promise in promoting collagen degradation and inhibiting malignant transformation. We conclude that CYGB and NGB represent sophisticated catalytic redox regulators that offer a novel therapeutic paradigm for restoring redox homeostasis. While delivery and pharmacokinetic barriers remain, these globins are highly promising candidates for first-in-class biologics in hepatology. Full article

Ultraviolet B (UVB), as a major component of solar radiation, is a key factor in inducing skin photoaging. The epidermis serves as the primary defensive barrier of the skin and absorbs the majority of UVB. This study aims to elucidate the protective effect of Alk against UVB-induced photoaging and further uncover its underlying molecular mechanisms. In vitro, Alk-pretreated HaCaT cells were exposed to UVB. Cell viability, ROS, senescence, antioxidant enzymes, and protein expression were analyzed. Mechanisms were examined using CETSA, DARTS, Co-IP, and NRF2 knockout. In vivo, Alk hydrogel was tested in UVB-exposed BALB/c mice, with protection assessed via histology and immunohistochemistry. In vitro, Alk directly binds to Keap1, disrupts Keap1–Nrf2 interaction, promotes nuclear translocation of Nrf2, and upregulates the expression of its downstream target HO-1. Consequently, intracellular ROS generation is reduced, cellular senescence is alleviated, and the expression of inflammatory factors (TNF-$\alpha$, COX-2) and MMP-9 is suppressed. In vivo, topical application of the Alk hydrogel prevented UVB-induced skin thickening and collagen degradation. Alk exerts a preventive effect on UVB-induced photoaging in HaCaT cells and skin, providing strong support for developing Alk as a potential plant-derived active ingredient for preventing skin photoaging. Full article

Silymarin (Silybum marianum (L.) Gaertn. extract) is a widely used botanical for liver disease, yet clinical results remain inconsistent. Most mechanistic work uses supraphysiological aglycones, whereas humans are exposed predominantly to phase II conjugates that are strongly protein-bound and routed by transporters toward bile and the intestinal mucosa. We reframe silymarin activity through a spatial pharmacology lens, proposing three post-intake windows: early (0–2 h) conjugate-dominant exposure with localised β-glucuronidase-mediated reactivation; intermediate (2–8 h) enterohepatic recirculation pulses; and late (8–48 h) microbial catabolite contributions. Each window engages distinct signalling modules—Keap1/NRF2, NF-κB, and AMPK-mTOR-TFEB—via transient redox events (quinone cycling, micro-H₂O₂ relays) and proteostatic remodelling (autophagy/mitophagy). We synthesise human pharmacokinetic and clinical evidence—with emphasis on MASLD and alcohol-associated liver disease—and show how formulation, meal timing, and microbiome metabotype determine which windows are engaged. Finally, we propose minimum reporting standards and falsifiable hypotheses to reduce between-study heterogeneity and enable precision use of silymarin. Full article

Skin aging and wound healing are the result of intricate and interconnected processes involving chronic inflammation, oxidative stress, cellular senescence and extracellular matrix degradation. Mesenchymal stem cell (MSC)-derived exosomes are rich in bioactive components, particularly microRNAs (miRNAs), which play a crucial role in regulating gene expression and key signaling pathways critical for maintaining skin homeostasis. This article reviews the current evidence regarding the roles of MSC-derived exosomal miRNAs (MSC-Exo-miRNAs) in cutaneous repair and rejuvenation. Specific exosomal miRNAs are analyzed for their ability to modulate inflammatory responses, promote fibroblast proliferation and collagen synthesis, enhance angiogenesis, and facilitate keratinocyte migration and re-epithelialization. Their roles in regulating key signaling pathways are discussed in the context of skin regeneration and aging, including nuclear factor-κB (NF-κB), PI3K/Akt, TGF-β/Smad, Wnt/β-catenin, and nuclear factor erythroid 2-related factor 2 (Nrf2). Additionally, emerging engineering strategies aimed at optimizing miRNA cargo loading, improving delivery efficiency, and advancing clinical translation are highlighted. Overall, MSC-Exo-miRNAs represent a promising cell-free therapeutic strategy for skin repair and rejuvenation; however, further mechanistic investigations and rigorous clinical studies are necessary to fully realize their translational potential. Full article

Background: Endocrine therapy with tamoxifen remains a cornerstone in the treatment of estrogen receptor-positive (ER+) breast cancer; however, the emergence of resistance to its active metabolites, 4-hydroxytamoxifen (4-OHTAM) and Endoxifen, represents a major clinical limitation. Increasing evidence suggests that drug efflux transporters, redox-adaptive signaling, and translational control mechanisms may converge to promote chemoresistance. This study aimed to investigate the coordinated expression patterns of ABCC transporters, the eukaryotic initiation factor 4F (eIF4F) complex, and NRF2 signaling in tamoxifen-metabolite-resistant MCF-7 breast cancer cells. Methods: MCF-7 cell variants resistant to 4-OHTAM (Variant B) or Endoxifen (Variant C) were established through prolonged drug exposure. Cytotoxicity assays assessed cellular viability and chemoresistance. Protein expression and molecular interactions were analyzed using Western blotting and co-immunoprecipitation. Flow cytometry was employed to evaluate transporter-associated fluorescence intensity. In silico molecular docking was performed to estimate the binding affinity of tamoxifen metabolites to ABCC transporters. Results: Endoxifen-resistant cells exhibited the most pronounced chemoresistant phenotype. Analysis of ABCC transporters revealed modest but consistent increases in fluorescence intensity across resistant variants; however, these differences did not reach statistical significance. Dysregulation of the eIF4F complex was observed, with increased eIF4E and reduced eIF4A levels, suggesting altered translational control associated with resistant phenotypes. Increased NRF2 protein expression was detected in resistant variants, consistent with enhanced redox-adaptive capacity. Analysis of ABCC transporters revealed modest but consistent increases in fluorescence intensity across resistant variants; however, these differences did not reach statistical significance. Molecular docking demonstrated strong binding affinity between Endoxifen and ABCC2, supporting a potential role for transporter-mediated efflux. Conclusions: Tamoxifen-metabolite resistance in ER+ breast cancer is associated with coordinated trends in ABCC transporter-associated signals, altered eIF4F complex expression, and sustained NRF2 signaling. These findings suggest the presence of a multifactorial adaptive network that may contribute to endocrine resistance. Targeting components of this network warrants further mechanistic investigation. Full article

Styela plicata, an edible ascidian rich in diverse bioactive constituents, represents a promising source of marine natural products for therapeutic discovery. Here, bioactive components from a 95% ethanol extract of S. plicata (ESP) were characterized by HPLC-MS/MS, showing that the major constituents were oxygenated small molecules dominated by fatty acyls and carboxylic acid derivatives. In a mouse model of alcohol-induced liver injury, H-ESP treatment (300 mg/kg) significantly reduced serum levels of AST, ALT, and TG (p < 0.01), while effectively ameliorating pathological changes in liver tissue, reducing lipid accumulation and inflammatory responses. Transcriptome sequencing (H-ESP vs. model group) identified 1097 differentially expressed genes (172 upregulated and 925 downregulated), and KEGG analysis highlighted significant enrichment of the Toll-like receptor signaling pathway. ESP modulated hepatic metabolite expression, suppressed inflammation via TLR-4/NF-κB pathway inhibition, and boosted antioxidant defenses by activating Nrf2/HO-1 signaling, which was further confirmed by RT-qPCR and immunohistochemistry. ESP increased intestinal SCFAs (acetate, propionate, isobutyrate; p < 0.05), improved α-diversity and the Firmicutes/Bacteroidetes ratio, reversed shifts in Lactobacillus and Bifidobacterium, and partly restored Odoribacter, supporting a gut–liver axis mechanism. Overall, these findings indicate that ESP exerts hepatoprotective effects by modulating the gut–liver axis, and they provide insights for developing natural therapeutics against alcoholic liver disease. Full article

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation and oxidative stress, increasingly implicated in cancer biology. However, its molecular regulation across breast cancer subtypes and its potential systemic manifestations remain incompletely understood. The aim of this study was to identify ferroptosis-associated molecular alterations that are largely shared across subtypes and to evaluate their systemic reflection following localized tissue injury. Tumor and matched normal breast tissues representing major molecular subtypes were analyzed. Global mRNA and miRNA expression profiling was performed using microarrays, followed by validation of selected genes using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). Functional enrichment and protein–protein interaction analyses were conducted to characterize associated pathways. In addition, systemic responses were assessed in patients undergoing fibroadenoma cryoablation through longitudinal blood sampling. Six ferroptosis-related genes (SLC7A11, GPX4, FTH1, NQO1, NFE2L2, SQSTM1) demonstrated consistent upregulation across all breast cancer subtypes, with higher expression observed in more aggressive tumors. These genes are functionally linked to antioxidant defense, iron metabolism, and oxidative stress regulation, and their coordinated expression pattern is consistent with activation of NRF2-dependent cytoprotective pathways. Downregulation of selected miRNAs may contribute to this expression profile but likely represents a secondary regulatory mechanism. Survival analysis revealed heterogeneous and subtype-dependent associations, with limited and gene-specific prognostic relevance. Cryoablation induced transient increases in circulating levels of the analyzed proteins, reflecting systemic responses to localized tissue injury. In conclusion, breast cancer is characterized by a largely shared ferroptosis-associated molecular signature across subtypes; however, its clinical impact appears to be variable and context-dependent. Systemic detection of related molecular signals suggests potential utility as indicators of tissue stress responses, although their role as specific biomarkers of ferroptosis requires further validation. Full article

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide, with oxidative stress playing a major role in disease pathogenesis by promoting endothelial dysfunction, vascular inflammation, and tissue damage. Oxidative stress results from an imbalance between antioxidant defenses and reactive oxygen species (ROS) in favor of ROS. Excessive ROS damage macromolecules and may trigger a chain reaction of lipid peroxidation, protein modification, and DNA damage. Phytochemicals are naturally occurring compounds in fruits and vegetables that may modulate redox homeostasis and positively impact cardiovascular health. The flavonoid Quercetin, Resveratrol, Curcuminoids, Coenzyme Q10, Hydroxysafflor yellow A, and Vitamins C and E have shown promise in human studies for improving endothelial function, lipid profile and markers of oxidative stress and inflammation. Among the key mechanisms of protection are their antioxidant role, anti-inflammatory role or modulation of nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, all of which contribute to cardiovascular protection. However, there are challenges associated with their use for health, such as the complexity of their quality and quantity, which require standardization, as well as their mechanisms of effects. Moreover, their systemic availability and bioactivity largely depend on metabolic transformation by the host gut microbiota. This review analyzed relevant publications in PubMed, Scopus, and Web of Science, up to February 2026, and summarizes current knowledge on phyto–chemical-mediated modulation of oxidative stress and its implications for cardiovascular protection in humans. The evidence suggests that phytochemicals hold promise for CVD prevention and treatment, but more work is needed to achieve standardization in quality and quantity. Full article