Search Results (1,881)

MYO16 has previously been identified as a candidate gene in studies of meat productivity in sheep, but its complete sequence and the potential impact of polymorphisms on the functional properties of the gene in sheep remain understudied. The aim of this study was to analyze genetic variation in the MYO16 gene region in sheep and to identify polymorphisms that, according to bioinformatic prediction, are capable of changing the amino acid sequence of the protein or are associated with allele-specific differences in transcription factor binding motifs potentially significant for gene regulation or protein structure. Whole-genome sequencing was performed for genomic DNA from Manych Merino rams (n = 30) on an Illumina NovaSeq 6000 platform. Variants within the MYO16 region were extracted and annotated. For each variant, ±30 bp reference and alternative sequences were scanned with FIMO using the JASPAR 2020 Vertebrates PWMs to detect allele-specific gain or loss of significant motif hits. TFLink (Mus musculus) was used to retain only TFs with MYO16 listed as a target. In the MYO16 gene region, 10,318 variants were detected. The coding region contained 54 SNPs, including 15 missense variants. In silico TFBS scanning identified 23 variants showing allele-specific gain or loss of significant motif hits, involving motifs for EBF1, CTCF, NRF1, SPI1, NFE2L2, JUN, and GFI1. We examined polymorphism in the ovine MYO16 gene region and identified candidate variants to be tested for association with productivity traits in future genotype–phenotype studies. 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

Periodontitis represents a primary etiological factor in tooth mobility, with oxidative stress contributing critically to periodontal tissue destruction. Evodiamine (EVO), a quinazolinocarboline alkaloid, exhibits multiple biological activities; however, its antioxidant effects and mechanism in periodontitis have not been elucidated. The aim of this study was to investigate the regulatory effect of EVO on oxidative stress in periodontitis and to explore the associated molecular mechanism. The results indicate that EVO exhibits potent antimicrobial activity against key periodontal pathogens and suppresses pathogen-induced ROS generation as well as the release of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) under periodontitis conditions. EVO binds specifically to the Kelch domain of KEAP1 with a strong binding energy (−11.67 kcal/mol), inhibits KEAP1–NRF2 interaction, and consequently upregulates the expression of antioxidant enzymes (HO-1, NQO1, GCLC, and SOD2), while downregulating the expression of iNOS, COX2, and NOX2. Furthermore, EVO inhibits the pro-apoptotic effect of the JAK2/STAT3 signaling axis and mitigates inflammation, alleviates cell cycle arrest, and promotes the migration and repair of periodontal ligament cells. Collectively, these findings suggest that EVO acts as a potential binder of KEAP1 that alleviates periodontal inflammation through modulation of oxidative stress and regulation of the JAK2/STAT3 pathway. Full article

Neurodegenerative diseases involve progressive neuronal loss associated with oxidative stress (OS) and inflammation. Given the limited efficacy of current therapies, natural compounds with multitarget neuroprotective potential are of growing interest. In this study, we investigated the neuroprotective effects of a standardized Magnolia officinalis (L.) bark extract (MOE) in rat brain cortical slices exposed to hydrogen peroxide-induced OS. MOE significantly recovered tissue viability and reduced ROS and malondialdehyde levels caused by OS while attenuating caspase-3, -8, and -9 activation, suggesting modulation of intrinsic and extrinsic apoptotic pathways. Shotgun proteomics using LC-HRMS/MS identified OS-induced protein expression changes reversed by MOE, with fourteen of thirty-three altered proteins rescued by MOE co-treatment. These proteins participate in several processes, including neuronal survival, OS response, and proteostasis. Bioinformatic analysis demonstrated that genes responsible for protein synthesis regulated by MOE are subjected to transcriptional regulation by factors associated with OS, including FOXO4, NRF2, and SP1. The present findings support the hypothesis that MOE exerts multitarget neuroprotective effects by modulating key proteins involved in OS responses and neuronal survival in an acute ex vivo oxidative injury model, suggesting potential relevance for mechanisms associated with NDs. Full article

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of the cellular antioxidant response and a promising therapeutic target for Parkinson’s disease (PD). Resibufogenin (RBG), a bioactive bufadienolide from toad venom, has been identified as a potential Nrf2 agonist; however, its application is limited by cytotoxicity and poor drug-like properties. Herein, we report the rational design, synthesis, and biological evaluation of a series of RBG derivatives modified at the C3, C14–C15, and C17 positions. Systematic structure–activity relationship (SAR) studies identified 2-5c, featuring a C3 2-chloroacryloyl group and a C17 pyrimidine substitution, as a potential Nrf2 activator (EC₅₀ = 4.18 μM), exhibiting approximately 7-fold greater activity than RBG. Importantly, 2-5c demonstrated neuroprotective effects in MPP⁺-induced BV2 microglial cells and effectively ameliorated motor deficits in an MPTP-induced PD mouse model. These findings suggest that 2-5c represents a promising candidate for further investigation in the development of novel Nrf2-based therapies for PD. Full article

Sestrins are an evolutionarily conserved family of stress-responsive proteins that regulate cellular metabolism, redox balance, and survival. Their expression is induced by diverse cellular stresses through activation of transcription factors such as p53, NRF2, and FOXO. Through antioxidant activity and modulation of mTORC1 and mTORC2 signalling, Sestrins limit the accumulation of reactive oxygen species, regulate metabolic pathways, and promote autophagy. In this review, we analyse published studies reporting SESN1, SESN2, and SESN3 expression in human tissues, circulation, and experimental disease models. The available evidence indicates that Sestrin levels are dynamically regulated across multiple pathologies, including metabolic, ageing, cardiovascular, inflammatory, neurodegenerative, and degenerative disorders. Notably, changes in tissue Sestrin expression are often mirrored in circulation. These observations suggest that Sestrins may serve as informative biomarkers of cellular stress and disease states, and that monitoring their expression in tissues or blood could provide insight into disease progression and therapeutic response. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most prevalent chronic liver disease worldwide with complex pathogenesis and no approved specific therapy. Siraitia grosvenorii is a widely used medicinal and edible herb, yet its efficacy and underlying mechanisms against MAFLD remain poorly defined. This study explored the protective effects and potential mechanisms of aqueous extract of Siraitia grosvenorii (AESG) on MAFLD. Based on ultra-high-performance liquid chromatography-linear trap quadrupole orbitrap mass spectrometry (UHPLC-LTQ-Orbitrap-MS) analysis, 38 components in AESG were tentatively assigned, with tetracyclic triterpene saponins being the most abundant. In high-fat diet (HFD)-induced MAFLD mice, AESG significantly attenuated body weight gain, reduced plasma total cholesterol (T-CHO) and low-density lipoprotein cholesterol (LDL-C) levels, and dramatically decreased hepatic triglyceride (TG) accumulation from 0.0141 mmol/g in the model group to 0.0063 mmol/g in the low-dose AESG group, corresponding to a reduction of 55.00%. AESG also alleviated plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, and improved hepatocyte steatosis. Furthermore, AESG restored HFD-induced gut dysbiosis by enriching beneficial bacteria including Akkermansia and suppressing harmful bacteria such as Ruminococcus. In free fatty acids (FFA) stimulated HepG2 cells, AESG suppressed de novo lipogenesis via downregulating Fatty Acid Synthase (FASN), Acetyl-CoA Carboxylase (ACC) and Sterol Regulatory Element-Binding Protein 1c (SREBP1c), and enhanced antioxidant capacity via activating the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)/Heme Oxygenase 1 (HO-1)/Sirtuin 1 (SIRT1) pathway, thereby attenuating lipid accumulation and oxidative stress. In conclusion, AESG ameliorates MAFLD by inhibiting lipogenesis, improving oxidative stress, and regulating gut microbiota. These findings support Siraitia grosvenorii as a promising natural dietary intervention for MAFLD prevention and adjuvant therapy. Full article

Metabolic syndrome (MetS) is a multifactorial cardiometabolic condition characterized by insulin resistance, visceral adiposity, dyslipidemia, hypertension, and chronic low-grade inflammation, collectively increasing the risk of type 2 diabetes mellitus, non-alcoholic fatty liver disease, and cardiovascular disease. Growing interest has focused on plant-derived dietary strategies capable of targeting multiple pathogenic pathways simultaneously. Opuntia ficus-indica fruits (OFIF) represent a complex food matrix containing betalains, polyphenols, carotenoids, soluble fiber, functional amino acids, vitamins, and minerals. Experimental evidence suggests that these constituents interact with key molecular networks implicated in MetS pathophysiology, including redox-sensitive pathways (NRF2), inflammatory signaling (NF-κB), energy-sensing regulators (AMPK), and lipid metabolism proliferator-activated receptor alpha (PPAR-α) dependent mechanisms. Preclinical studies consistently report associations with improvements in oxidative stress, inflammatory markers, hepatic steatosis, and glucose homeostasis following OFIF supplementation. However, human evidence remains limited by small sample size, short intervention duration, and variability in compositional standardization. This narrative review adopts a systems-level perspective to integrate mechanistic, preclinical, and early clinical evidence in the context of metabolic syndrome pathophysiology, while critically addressing translational gaps, compositional variability, and current limitations in human validation. Full article

Background/Objectives: Many chronic diseases, including cancer, can be developed in conjunction with excessive intracellular oxidative stress and persistent inflammation. The importance of preventive strategies is highlighted by the potential of phytochemical interventions to mitigate these diseases. The purpose of this study was to investigate how Citrus depressa leaf (CDL) extracts can prevent 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced carcinogenesis in JB6 P+ mouse skin epidermal cells. Methods: CDL extracts were prepared and characterized for their phenolic and flavonoid contents. Effects of the potent extract on cell viability, TPA-induced colony formation, intracellular reactive oxygen species (ROS) levels, and nuclear factor erythroid 2–related factor 2 (Nrf2)-related protein and mRNA expression, mediated by epigenetic modifications, were evaluated in JB6 P+ cells. Results: Both the water extract (CDL-WE) and the 95% ethanol extract (CDL-95EE) contain abundant flavonoids that inhibit TPA-induced cell transformation and colony formation without minimal cytotoxicity. Mechanistic studies indicated that CDL-95EE increased the gene expression of Nrf2-related detoxification and antioxidant enzymes, such as UDP-glucuronosyltransferase 1A (UGT1A) and heme oxygenase-1 (HO-1), and decreased intracellular ROS accumulation. Furthermore, CDL-95EE reduced the expression of epigenetic modifiers, including DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), suggesting involvement in epigenetic regulation. Conclusions: These findings indicate that CDL, an agricultural by-product, may be useful in cancer prevention through antioxidant and epigenetic mechanisms. Full article

Aging is closely linked to oxidative stress and inflammation. This review provides a critical overview of the antioxidant compounds present in apple pomace and explores how they may mitigate age-related oxidative damage and inflammatory responses. We focus on the nutritional profile of apple pomace including its macro- and micronutrients, with particular focus on polyphenols, such as procyanidin tannins, quercetin glycosides (rutin, quercetin-3-glucoside), phloridzin, dietary fiber, vitamins, and lipids alongside current techniques for isolating its bioactive components. Special attention is given to biological pathways through which these compounds influence aging: redox regulation via Nrf2, inflammatory modulation via NF-κB, and metabolic regulation via AMPK, SIRT1 and PI3K/Akt/mTOR. Evidence from in vitro cellular models (HepG2, CCD-986Sk fibroblasts), in vivo rodent studies and limited human pilot trials is summarized, as well as existing and emerging applications of apple pomace in functional foods, cosmeceuticals, and other sectors. Finally, we discuss the challenges and future opportunities in harnessing this by-product of the food industry. Although clinical data remain limited, preclinical findings support the repurposing of apple pomace as a sustainable functional ingredient contributing to healthier aging and circular economy goals. Future long-term randomized controlled trials are necessary to confirm efficacy in humans. Full article

Isoflurane is a widely used volatile anesthetic with context-dependent effects on neuronal survival, particularly in neurodegenerative conditions. Increasing evidence suggests that brief, sublethal stress exposure can induce adaptive cellular responses through hormesis-based preconditioning mechanisms. In this study, we investigated whether isoflurane preconditioning enhances neuronal tolerance to amyloid-β (Aβ)-induced toxicity and explored the underlying redox-dependent molecular pathways. Using HT-22 murine hippocampal neuronal cells, we demonstrate that short-term exposure to low-dose isoflurane induces a delayed neuroprotective phenotype characterized by improved cell viability, reduced apoptotic signaling, and maintained mitochondrial membrane potential following Aβ challenge. Mechanistically, isoflurane preconditioning elicited a mild and transient increase in intracellular reactive oxygen species (ROS), which is critical for the activation of the PI3K/Akt signaling pathway. Pharmacological scavenging of reactive oxygen species abolished Akt phosphorylation and reduced the protective effects of preconditioning, supporting a hormetic signaling model rather than direct antioxidant action. Following Akt activation, isoflurane preconditioning promoted the inhibitory phosphorylation of glycogen synthase kinase-3β (GSK-3β), decreased Keap1 protein levels, and facilitated nuclear translocation and transcriptional activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Consequently, the expression of Nrf2-regulated antioxidant genes, including heme oxygenase-1, NAD(P)H quinone dehydrogenase 1 (NQO1), superoxide dismutase 1 and 2 (SOD1/2), and catalase, was significantly upregulated. Collectively, these findings indicate that isoflurane preconditioning confers neuroprotection through hormesis-like mild oxidative signaling and coordinated activation of endogenous antioxidant defenses rather than via direct antioxidant scavenging. Full article

Research based on the similarities between canine and human mammary tumors should extend beyond clinical, pathophysiological, epidemiological, and histopathological characteristics to include applicable molecular markers with prognostic significance. However, despite shared similarities, important differences must also be considered in comparative and translational studies. The nuclear erythroid 2-related factor (NRF2), a nuclear transcription factor that regulates the expression of antioxidant proteins, is pathologically activated during carcinogenesis. The role of NRF2 in human breast cancer is well established, making it a potential prognostic marker. Objectives: This study aimed to evaluate NRF2 tissue expression in mammary neoplasms of female dogs and its association with tumor progression, other prognostic factors, and survival. Methods: A group of 57 female dogs was studied. Tissue samples of mammary glands from 10 healthy dogs and 47 dogs with mammary neoplasms (39 malignant tumors and 8 benign tumors) were examined for NRF2 immunoexpression. Clinicopathological data and immunohistochemical expression, assessed by histochemical score (H-score), were correlated. Results: NRF2 tissue expression showed a predominantly cytoplasmic distribution and a lower H-score in tumors with higher malignancy grading. Dogs with higher NRF2 H-scores had improved survival rates (p = 0.0036). Univariate analysis revealed significant associations between H-scores < 135 and behavior (p = 0.007), tumor size (p = 0.001), and Ki-67 index (p = 0.018). Conclusions: These results suggest that NRF2 also holds prognostic value in the evaluation of canine mammary tumors. Full article

Esophageal cancer is a highly aggressive malignancy with a poor prognosis. More precise prognostic biomarkers are therefore needed. Disulfidptosis is a recently identified form of regulated cell death driven by disulfide stress. It has been implicated in tumor progression. However, its prognostic role in esophageal cancer remains largely unexplored. This study aimed to develop a disulfidptosis-related gene signature for risk stratification and outcome prediction in esophageal cancer patients. Based on 23 disulfidptosis-related genes, consensus clustering was performed to identify molecular subtypes. Differentially expressed genes (DEGs) between subtypes were subjected to functional enrichment, immune microenvironment, and drug sensitivity analyses. Univariate and multivariate Cox regression were used to construct a prognostic risk model, which was evaluated using time-dependent receiver operating characteristic (ROC) curve and Kaplan–Meier analysis. A clinical nomogram integrating the risk score and clinicopathological factors was developed and validated. Two distinct disulfidptosis-related subtypes were identified, showing significant differences in gene expression, immune infiltration, and stromal scores. A total of 1080 DEGs were enriched in pathways related to epidermal differentiation, NRF2 signaling, and glucocorticoid receptor activity. A five-gene prognostic signature was established and effectively stratified patients into high- and low-risk groups. The risk model exhibited strong discrimination for 1-, 3-, and 5-year overall survival outcomes. The predictive accuracy was further maximized through an integrated clinical nomogram, which achieved an outstanding area under the curve (AUC) of 0.94 for 5-year survival predictions. Drug sensitivity analysis revealed subtype-specific therapeutic vulnerabilities, supporting potential precision treatment strategies. This study proposes a novel disulfidptosis-related five-gene signature and nomogram that robustly predict prognosis in esophageal cancer. The findings highlight the clinical relevance of disulfidptosis in tumor biology and offer a potential tool for risk stratification and personalized therapeutic decision-making. Full article

Caffeic acid (CaA) and chicoric acid (ChA) each exhibit significant antioxidant activity when used alone, yet their combined effects on antioxidant capacity and intestinal health in zebrafish remain unclear. This study used isobolographic analysis to identify a 1:1 ratio of CaA to ChA as optimal for synergistic antioxidant activity, with its ABTS and DPPH IC₅₀ (21.65 μg/mL, 69.66 μg/mL) outperforming single monomers in vitro. In an oxazolone (Oxa)-induced zebrafish intestinal oxidative stress model, the CaA and ChA (CaA–ChA) mixture exerted antioxidant effects by upregulating the mRNA expression levels of HTR2A, Akt, Nrf2, and downstream antioxidant enzyme genes including SOD, CAT, and GPx in the zebrafish intestine, while downregulating Keap1 mRNA expression. Intestinal microbiota analysis revealed that the CaA–ChA mixture could positively regulate the intestinal microecological structure, characterized by targeted enrichment of the beneficial bacterium Cetobacterium and inhibition of the proliferation of potential pathogenic bacteria, including Bosea and Mycobacterium. Correlation analysis confirmed that the abundances of these key genera were closely associated with the expression of signaling pathway markers, suggesting that the microbiota–signaling pathway crosstalk was involved in the regulation of antioxidant processes. In conclusion, the CaA–ChA mixture (1:1) exerts a protective effect against intestinal oxidative stress, with the potential involvement of dual gut microbiota modulation and the HTR2A/Akt/Nrf2/Keap1 pathway. These findings provide experimental and theoretical support for the combined antioxidative application of CaA and ChA. Full article

Cutaneous fibrosis is characterized by aberrant wound healing with excessive extracellular matrix deposition, sustained inflammation, and oxidative stress, while currently available therapies show limited efficacy and safety. A Dual Hyaluronic Acid Compound (DHC), consisting of high-molecular-weight, low-molecular-weight, and minimally cross-linked hyaluronic acid, has demonstrated regenerative and antioxidant properties, but its anti-fibrotic effects have not been fully explored. This study investigated the anti-fibrotic potential of DHC using a bleomycin-induced murine dermal fibrosis model and a UVB-irradiated ex vivo human skin model. In C57BL/6 mice, dermal fibrosis was induced by daily bleomycin injections for three weeks, followed by intradermal DHC administration. Histological and biomechanical analyses showed that DHC significantly reduced dermal thickness, collagen deposition, and skin hardness compared with untreated fibrotic controls. DHC decreased α-SMA expression and increased MMP1 levels, indicating attenuation of myofibroblast activation and enhanced matrix remodeling. It also reduced macrophage markers (CD68, CD163) and pro-inflammatory cytokines (IL-1β, TNF-α). Furthermore, DHC restored superoxide dismutase (SOD) and catalase (CAT) activity and upregulated NRF2, HO-1, and NQO1 expression in the in vivo model. Similarly, DHC upregulated SOD and CAT activity and reduced pro-inflammatory cytokines (IL-6, TNF-α) in the ex vivo human skin model. These findings suggest that DHC exerts multimodal anti-fibrotic effects through coordinated regulation of fibroblast activation, inflammation, and oxidative stress, supporting its potential as a therapeutic approach for cutaneous fibrosis. Full article