Search Results (635)

Polybrominated diphenyl ethers (PBDEs), widely used as brominated flame retardants, are known to exert persistent adverse effects on the immune systems of humans and other organisms. Previous studies have demonstrated that 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), a prevalent congener, induces apoptosis, impairs phagocytic function, and triggers aberrant immune-inflammatory reactions in RAW264.7 macrophages via the induction of elevated intracellular reactive oxygen species (ROS). However, the underlying regulatory mechanism remains unclear. The nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway is a key cellular defense system against oxidative stress. In this study, we investigated the role of the Nrf2/ARE pathway in BDE-47-induced macrophage immunotoxicity. Network toxicology analysis identified Nrf2 as a hub gene within the BDE-47-associated immunotoxicity network. Molecular docking and molecular dynamics simulations suggested a potential interaction between BDE-47 and the Keap1-Nrf2 complex, with moderate binding affinity. Experimental studies in RAW264.7 cells showed that BDE-47 exposure activated the Nrf2/ARE pathway, as evidenced by Nrf2 nuclear translocation and the differential upregulation of downstream genes (GCLC, GCLM, HO-1, NQO1, SOD1, and CAT). Importantly, Nrf2 knockdown via lentiviral shRNA or pharmacological inhibition with brusatol significantly exacerbated BDE-47-induced apoptosis and immune dysfunction, including enhanced pro-inflammatory cytokine production and impaired phagocytosis. These results demonstrate that Nrf2/ARE pathway activation represents an adaptive antioxidant response and contributes to limiting BDE-47-induced cytotoxicity and immune impairment in macrophages. Full article

Cutaneous disorders such as atopic dermatitis, psoriasis, acne vulgaris, and rosacea, together with UV-induced skin injury and photoaging, are highly prevalent conditions that involve varying contributions from dysregulated immune responses, cutaneous inflammation, oxidative stress, barrier dysfunction, microbiome alteration, and exogenous injury. However, these conditions are biologically heterogeneous and should not be regarded as a single mechanistic class. Sulforaphane, a naturally occurring isothiocyanate found primarily in broccoli and other cruciferous vegetables, has attracted interest in dermatology because of its antioxidant, cytoprotective, and context-dependent anti-inflammatory properties. Sulforaphane exerts its biological effects by modulating key signaling pathways, particularly the Keap1/Nrf2 pathway and, in some settings, NF-κB-related signaling, thereby reducing oxidative stress and inflammation, regulating immune responses, enhancing skin barrier function, and potentially influencing the cutaneous microbiome. Preclinical studies and limited human data suggest that sulforaphane may reduce erythema, edema, and other markers of cutaneous damage in selected settings. This comprehensive review explores the role of sulforaphane across heterogeneous cutaneous conditions, with emphasis on molecular mechanisms, disease-specific differences, current evidence, and discusses key translational constraints including formulation, delivery, lack of standardized dosing, and the limitations of cell culture and animal models for predicting human efficacy. Overall, sulforaphane should presently be regarded as a promising but still early-stage translational candidate in dermatology. Robust human efficacy data remain lacking for chronic inflammatory dermatoses such as psoriasis, atopic dermatitis, acne, and rosacea, whereas the strongest current human evidence relates to UV-associated skin outcomes and photoprotection. Full article

5-Fluorouracil (5-FU) is a cornerstone chemotherapeutic agent that is extensively utilized in the management of malignancies; however, its clinical utility is constrained by its narrow therapeutic index and dose-limiting toxicities. The study aimed to study the hepato-nephroprotective effects of epigallocatechin gallate (EGCG) and EGCG mediated selenium nanoparticles and their effect in mitigating the toxicity induced by 5-FU. EGCG-functionalized selenium nanoparticles (EGCG-SeNPs) were produced by mixing sodium selenite, with EGCG acting as both the reducing and stabilizing agent. Nanoparticles were characterized using UV-vis spectroscopy, FT-IR, dynamic light scattering, zeta potential analysis, and transmission electron microscopy. 35 adult rats were randomly assigned to control, 5-FU, 5-FU + Na₂SeO₃, 5-FU + EGCG, and 5-FU + EGCG-SeNPs groups. Hepatorenal toxicity was induced by intraperitoneal 5-FU administration during the final five days of the experiment. Serum biochemical markers, tissue oxidative stress, antioxidant enzyme, inflammatory cytokine levels, and apoptosis-related gene expression were evaluated. Immunohistochemical analysis of Nrf2 and Keap1 and histopathological examination of tissues were performed. 5-FU induced severe hepatorenal toxicity, evidenced by marked elevations in liver and kidney function biomarkers, excessive oxidative stress, inflammatory cytokine overproduction, NF-κB activation, and apoptotic signaling. Treatment with EGCG-SeNPs markedly ameliorated 5-FU-induced hepatic and renal dysfunction, restoring liver enzyme and kidney biomarker levels to near-normal levels more effectively than EGCG or sodium selenite alone. EGCG-SeNPs significantly suppressed lipid peroxidation, NGAL, and inflammatory mediators while robustly enhancing antioxidant defenses and activating the Nrf2/HO-1 pathway with concomitant Keap-1 downregulation, strongly inhibited NF-κB signaling, normalized cytokine balance, reduced poly (ADP-ribose) (PAR) activation, and attenuated apoptosis. EGCG–SeNPs confer superior protection against 5-FU–induced hepatorenal toxicity compared to EGCG or inorganic selenium alone. The potent protective effects of EGCG–SeNPs are mediated through coordinated antioxidant, anti-inflammatory, and anti-apoptotic mechanisms, primarily via activation of the Nrf2/HO-1 axis and suppression of NF-κB signaling. Full article

Celastrol (CSL), a natural triterpenoid extracted from Tripterygium wilfordii, demonstrates a wide range of biological activities. In this study, we explored whether CSL alleviates kidney damage in spontaneously hypertensive rats (SHRs) through the modulation of the Nrf2/Ho-1 pathway, a crucial target in renal injury models. A total of 40 male SHRs, aged 6–8 weeks, were randomly allocated to four groups: the control group (CON, serving as the healthy control), the spontaneously hypertensive rat group (SHR), the SHR group treated with low-dose CSL (L-CSL + SHR, 0.5 mg/kg/d), and the SHR group treated with high-dose CSL (H-CSL + SHR, 1 mg/kg/d). All drugs were formulated using physiological saline as the solvent and administered via intraperitoneal injection. The control group received an equivalent volume of physiological saline via intraperitoneal injection, and all groups underwent continuous daily administration for 6 weeks. The results indicated that, in comparison with the control group, the serum levels of angiotensin, angiotensin-converting enzyme, and aldosterone in the SHR group were relatively high, and CSL treatment further downregulated these indices. Simultaneously, CSL downregulated pro-inflammatory factors (tumor necrosis factor-α and interleukin-1β) and upregulated interleukin-6. Regarding renal function-related indicators, CSL reduced malondialdehyde levels and enhanced the activities of antioxidant enzymes, such as superoxide dismutase, glutathione peroxidase, and catalase. Moreover, CSL inhibited the overexpression of Keap1. Significantly, the mRNA levels of Nrf2, Nqo1, and Ho-1 in the CSL-treated groups were notably higher than those in the SHR group. These findings suggest that CSL mitigates renal pathological damage in SHR by activating the Nrf2/Ho-1 pathway, offering a potential therapeutic approach for hypertension-induced renal injury. Full article

Astragalin (AST), a natural flavonoid found in various plants, possesses antioxidant and anti-inflammatory properties. However, its protective efficacy against ultraviolet B (UVB)-induced cutaneous damage remains unclear. This study investigated the photoprotective effects of AST against UVB-induced photodamage using HaCaT keratinocytes and Kunming mice. In vitro, AST mitigated UVB-induced cytotoxicity and apoptosis in HaCaT cells. In vivo, topical application of AST attenuated UVB-induced erythema, epidermal hyperplasia, and collagen degradation in mouse skin. Additionally, AST reduced reactive oxygen species accumulation and enhanced antioxidant enzyme activity via activation of the Keap1/Nrf2 pathway. Furthermore, AST suppressed the expression of proinflammatory cytokines by inhibiting the TLR4/NF-κB signaling pathway. These findings demonstrate the photoprotective properties of AST and support its potential as a natural therapeutic agent for preventing UVB-induced skin damage. Full article

Lentils (Lens culinaris; family: Fabaceae) are increasingly recognized as functional legumes with potential benefits for gut health because they provide bioactive peptides, resistant starch, and polyphenol-rich fractions within a shared food matrix. However, most existing studies have focused on individual lentil-derived compounds, and their matrix-dependent complementary interactions during digestion and fermentation remain insufficiently resolved. This review synthesizes current evidence on lentil-derived peptides, resistant starch, and polyphenols, with particular emphasis on their matrix-dependent complementary relationships, digestion-dependent transformation, microbial co-metabolism, and implications for intestinal barrier function. During gastrointestinal digestion and colonic fermentation, lentil proteins, resistant starch, and phenolic compounds undergo sequential transformation, yielding bioactive peptides, fermentable substrates, short-chain fatty acids (SCFAs), and phenolic metabolites that may collectively influence microbial composition and metabolic activity. Emerging evidence suggests that these interconnected processes may support gut health through microbiota–host crosstalk by modulating tight junction-related markers, reducing intestinal permeability, and maintaining epithelial homeostasis. Mechanistically, these effects have been associated with SCFA-mediated G protein-coupled receptor (GPCR) signaling, suppression of TLR4–NF-κB/MAPK inflammatory cascades, and activation of Keap1–Nrf2 antioxidant defenses, thereby attenuating oxidative stress and pro-inflammatory responses. Current evidence is more consistent with matrix-dependent complementary or convergent actions than with demonstrated synergy. At present, phenolic-rich fractions provide clear pathway-level evidence, whereas fermentation-linked carbohydrate effects are more strongly supported by microbiota- and in vivo-associated outcomes, and protein- or peptide-related mechanisms remain comparatively underdefined. Nevertheless, the evidence base remains limited by the scarcity of integrated studies, well-controlled human intervention trials, and factorial experimental designs capable of distinguishing complementary, additive, and truly synergistic effects among lentil bioactives. This review therefore highlights the need to move from describing coexisting beneficial effects toward formally testing interaction effects within physiologically relevant lentil matrices. Full article

This study aimed to investigate the effects of pterostilbene (PTE) on the intestinal barrier function, antioxidant capacity, lipid metabolism, and microbial and metabolite homeostasis of suckling piglets via its action on breast milk. Findings indicate that PTE supplementation enhanced the antioxidant status of mature milk and strengthened intestinal barrier function in piglets. Specifically, PTE enhanced intestinal antioxidant status and fatty acid β-oxidation in piglets by regulating the PI3K-AKT and SIRT1-Nrf2/Keap1 signaling pathways. 16S rDNA sequencing and Liquid Chromatography–Mass Spectroscopy (LC–MS) identified breast milk and gut microbiota and their metabolites, respectively. Results indicate that PTE significantly elevated levels of amino acid derivatives in colostrum (Glutathione Reducedform (GSH) and N-acetyl-L-glutamate (NAG)), whilst concurrently reducing levels of glycerophospholipid-related metabolites in both colostrum and mature milk (p < 0.05). Moreover, PTE supplementation markedly altered the composition of the colonic mucosal microbiota in piglets, with Faecalibacterium, Mucispirillum and Ruminococcus identified as key beneficial microbial markers of the colonic mucosa. Combined multi-omics revealed strong correlations in microbial community composition between mature milk and the colon, identifying glycerophospholipid metabolism as a key metabolic pathway that may be associated with the regulatory effects of PTE on milk and the piglet colon. In conclusion, the PTE supplement can improve the quality of breast milk and have a positive impact on the intestinal homeostasis of the offspring. Full article

This study investigates the antioxidant properties of several synthetic peptides derived from milk proteins previously identified in milk permeate, a by-product of the dairy industry. The aim of the research is to identify which peptides present in milk permeate are responsible for its antioxidant activity. A comprehensive experimental strategy was employed to evaluate their antioxidant potential, including in silico selection, in vitro free radical scavenging assays and cellular models using Caco-2 and HCT116 cell lines. The peptides were screened using a molecular docking approach for their potential interaction with the Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (Keap1/Nrf2) pathway, and eight out of twenty-eight were selected and synthesized for further analyses. In vitro, six of the selected peptides demonstrated significant direct antioxidant activity in the DPPH scavenging assay, and two in the ABTS scavenging test. In cellular environments, three peptides (LPAPELGPRQA, LPIIQKLEPQI and NGQVWEESLKRL) effectively protect cells from oxidative stress induced by tert-butyl hydroperoxide, reducing reactive oxygen species production and partially mitigating lipid peroxidation. Further investigation showed that two of them (LPAPELGPRQA and LPIIQKLEPQI) effectively induce the Keap1/Nrf2 pathway, as evidenced by a ∼1.5-fold increase in Nrf2 levels and overexpression of downstream proteins. Permeability studies revealed that these peptides can cross the intestinal monolayer (2–3% in 2 h), suggesting potential systemic effects. Overall, these findings highlight the multifunctional antioxidant properties of the investigated peptides and support their potential application as nutraceuticals or therapeutic agents for oxidative stress-related conditions. Full article

Tumor oxygenation is a key determinant of cancer biology and treatment response, correlating with angiogenesis, recurrence, and malignant progression. Hypoxia is a defining feature of glioblastoma (GBM) and adult diffuse gliomas, generating low-oxygen niches that promote invasion, stem-like states, immune suppression, and resistance to radiotherapy and temozolomide, contributing to poor outcomes. Measuring tissue partial pressure of oxygen (pO₂) and mapping its spatial heterogeneity can, therefore, inform mechanistic understanding and therapeutic development, including hypoxia-activated prodrugs, hypoxia-responsive gene therapy, and optimized radiotherapy planning. Although direct pO₂ assessment is challenging, invasive probes and multimodal imaging can characterize regional hypoxia pre-operatively, support patient stratification, monitor treatment effects, and improve outcome prediction. This review summarizes oxygen dynamics in GBM; analyzes causes of hypoxia (rapid growth outpacing supply, diffusion-limited hypoxia, and abnormal/chaotic vasculature); compares methods to quantify oxygenation from direct measurements to noninvasive imaging surrogates; and evaluates preclinical and clinical strategies that target hypoxia to enhance standard therapy, including barriers to translation. We further integrate oxygenation with cell signaling and redox biology: oxygen gradients are transduced via hypoxia-inducible factor programs and redox-sensitive pathways (NRF2/KEAP1, NOX-derived ROS, nitric oxide/S-nitrosylation, and sulfur metabolic routes), shaping mesenchymal-like transitions and cell-death programs such as ferroptosis. Framing oxygenation as both a microenvironmental and redox-signaling variable positions oxygen imaging as an entry point to biomarker-guided therapies that exploit oxidative vulnerabilities. Full article

Antioxidant peptides show significant activity and can be developed into functional foods for treating chronic diseases. Cigarette smoke components can cause damage or even apoptosis of lung cells, eventually leading to chronic lung diseases. Therefore, this study aimed to investigate the protective effects and mechanisms of Skipjack tuna peptides against in vitro cigarette smoke extract (CSE)-induced chronic obstructive pulmonary disease (COPD). The results demonstrated that tuna peptides DVGRG (S1), PHPR (S5), GRVPR (S6), and SVTEV (S7) significantly enhanced the activities of SOD, CAT, and GSH-Px by upregulating the mRNA transcription levels of Keap1 and Nrf2, consequently reducing ROS and MDA levels in CSE-induced COPD model of MLE-12 cells. Molecular docking analysis revealed that S1, S6, and S7 competitively inhibited the Keap1-Nrf2 interaction by binding to the Kelch domain of Keap1, whereas S5 operated through a non-competitive mechanism. These peptides also downregulated p65 mRNA expression and upregulated IκBα mRNA expression, leading to a significant reduction in inflammatory cytokines of IL-1β, IL-6, and TNF-α, thereby alleviating inflammatory responses. Furthermore, these peptides significantly inhibited CSE-induced apoptosis by restoring mitochondrial membrane potential and upregulating the Bcl-2/Bax ratio. Additionally, S1, S5, S6, and S7 promoted MLE-12 cell migration in a concentration-dependent manner, suggesting a role in lung epithelial repair and regeneration. In conclusion, tuna peptides S1, S5, S6, and S7 exert antioxidant, anti-inflammatory, anti-apoptotic, and cell migration-promoting effects through the regulation of the Keap1/Nrf2 and NF-κB signaling pathways, as well as Bcl-2/Bax apoptotic balance, providing a promising strategy for mitigating CSE-induced lung injury. Full article

Liver diseases, including fatty liver, hepatitis, and cirrhosis, remain major global health challenges due to their disruption of metabolic homeostasis and detoxification processes. Redox imbalance plays a central role in liver disease progression by promoting inflammation, hepatic stellate cell activation, mitochondrial dysfunction, and fibrogenesis. Although flavonoids have historically been considered direct reactive oxygen species (ROS) scavengers, emerging evidence indicates that their biological effect at physiological concentrations are primarily mediated through modulation of intracellular redox signalling rather than simple radical neutralisation. This review highlights flavonoids as redox-modulating agents capable of restoring hepatic redox homeostasis through coordinated regulation of molecular pathways. Mechanistically, flavonoids activate the Nrf2-Keap1 axis to enhance endogenous antioxidant defences, including heme oxygenase-1 and glutathione biosynthesis enzyme, while suppressing NF-κB-mediated pro-inflammatory signalling and modulating MAPK and PI3K/Akt pathways. They also regulate mitochondrial redox balance, supporting mitophagy, metabolic adaptation, and cellular resilience to oxidative stress. In addition, flavonoid biotransformation by the gut microbiome improves intestinal barrier integrity, reduces endotoxin-driven hepatic inflammation, and contributes to gut–liver crosstalk. Collectively, these mechanisms position dietary flavonoids as multi-target redox modulators with promising therapeutic potential in chronic liver disease, although further studies are needed to improve their bioavailability and clinical translation. 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

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

Oxidative stress is characterised by the production of free radicals in higher amounts than the antioxidant scavenging capacity. This may cause damage to several organs especially the main site of detoxification, the liver. In this study, the antioxidant activity of five novel lipophilic fluoroquinolones (FQs) derivatives was evaluated against oxidative stress induced by acetaminophen (APAP) and carbon tetrachloride (CCl₄). Sixty-four male Wistar rats were divided into two oxidative-stress models. FQ compounds (25 mg/kg) were administered six hours after CCl₄ or APAP administration. Serum liver enzymes including aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured. Changes in antioxidant parameters were determined in the serum including measurement of total antioxidant status and reduced-glutathione levels as well as catalase, glutathione peroxidase and superoxide dismutase activities. Additionally, molecular docking analyses were performed against catalase, CYP3A4, and Keap-1 to elucidate the potential molecular interactions underlying the observed biological activities. A significant decrease in ALT and AST levels was seen following FQ compound administration in both models. In addition, FQ compounds exhibited excellent antioxidant activity, leading to increased antioxidant enzyme activity, high total antioxidant status, and elevated reduced-glutathione levels. The docking results revealed that compound 4A exhibited the highest binding affinities toward catalase, CYP3A4, and Keap-1. These interactions suggest a possible enhancement of catalase activity, modulation of CYP3A4, and activation of the Keap-1/Nrf2 signalling pathway. Overall, these findings demonstrate the promising therapeutic potential on hepatic injury and oxidative stress of the novel FQ derivatives. Full article

This study aimed to investigate the ameliorative effects of glucuronolactone (GL) as a dietary additive on high-fat diet (HFD)-induced growth suppression and metabolic disorders in turbot. A 10-week feeding trial was conducted using juvenile turbot (16.7 ± 0.03 g). Two diets with different protein (%)/lipid (%) levels were formulated: PC (54/12) and NC (47/17). Based on the NC diet, three experimental diets were prepared by supplementing 200 (G200), 400 (G400), and 600 (G600) mg/kg of GL. The present results show that compared to the PC group, HFDs significantly inhibited the growth performance of turbot and induced severe metabolic disorders, hepatointestinal damage, and gut microbiota dysbiosis. Dietary GL supplementation effectively reversed these adverse effects. Specifically, compared to the NC group, GL supplementation significantly restored growth performance, enhanced non-specific immunity, and systematically improved metabolic health. In the liver, GL notably ameliorated tissue damage and downregulated key lipogenic genes (SREBP1, ACC, FAS, PPARγ), while upregulating genes involved in lipid oxidation and catabolism (PPARα1, CPT1, ACOX1, HSL, LPL) and lipid transport (ApoB100, MTP), thereby alleviating hepatic lipid deposition. Furthermore, GL activated the Nrf2/Keap1 antioxidant pathway, up-regulating the expression of genes such as SOD, CAT, GPX, and HO-1. It also suppressed the NF-κB-mediated inflammatory response (downregulation of IL-1β, IFN-γ and TNF-α2; upregulation of IL-10 and TGF-β2) and the mitochondrial apoptosis pathway (increased Bcl-2/Bax ratio; downregulation of Caspase3/7/9), collectively mitigating oxidative damage and cellular apoptosis. Moreover, GL restored intestinal morphology, enhanced the expression of tight junction proteins (Claudin-3, Claudin-7, ZO-1, Occludin) and MUC2, and inhibited MLCK signaling. These improvements led to a reduction in serum D-LA levels, indicating strengthened intestinal barrier function. Concurrently, GL reshaped the gut microbiota composition by enriching beneficial bacteria such as Akkermansia and suppressing potential pathogens like Listeria. In summary, GL effectively alleviated HFD-induced growth suppression and metabolic damage in turbot by improving lipid metabolism and alleviating hepatic injury, while concurrently restoring intestinal barrier integrity and microbiota homeostasis. Full article