Search Results (662)

Ischemic stroke is a major cause of long-term disability and death, with oxidative stress contributing substantially to post-ischemic injury. Reperfusion restores oxygen supply but simultaneously increases reactive oxygen species (ROS), amplifying secondary neuronal damage. This study examined time-dependent changes in systemic thiol redox status following transient middle cerebral artery occlusion (tMCAO) in rats. Plasma concentrations of cysteine (CySH), cystine (CySS), glutathione (GSH), and glutathione disulfide (GSSG), along with corresponding CySS/CySH and GSSG/GSH ratios and redox potentials (Eh), were evaluated 24 and 48 h after occlusion. At 24 h, thiol concentrations and redox ratios showed no significant differences between sham and tMCAO groups. By 48 h, a marked oxidative shift emerged, characterized by reduced CySH, elevated GSSG, and significant increases in both CySS/CySH and GSSG/GSH ratios. Redox potentials also demonstrated substantial oxidation at this time point. These findings indicate that prolonged ischemia–reperfusion induces systemic oxidative stress, with plasma redox status serving as a sensitive indicator of reperfusion-related injury. The results underscore the plasma redox status as a potentially sensitive biomarker of reperfusion-induced oxidative injury and support the therapeutic value of targeting redox imbalance to mitigate oxidative damage following stroke. Full article

Type 2 diabetes mellitus (T2DM) involves chronic hyperglycemia, insulin resistance, low-grade inflammation, and oxidative stress that drive cardiometabolic and renal damage despite current therapies. Sodium–glucose cotransporter (SGLT) inhibitors have reshaped the treatment landscape, but residual risk and safety concerns highlight the need for new agents that combine glucose-lowering efficacy with redox–inflammatory modulation. LASSBio-1986 is a synthetic N-acylhydrazone (NAH) derivative designed as a gliflozin-like scaffold with the potential to interact with SGLT1/2 while also influencing oxidative and inflammatory pathways. Here, we integrated in silico and in vivo approaches to characterize LASSBio-1986 as a multifunctional antidiabetic lead in murine models of glucose dysregulation. PASS and target class prediction suggested a broad activity spectrum and highlighted transporter- and stress-related pathways. Molecular docking indicated high-affinity binding to both SGLT1 and SGLT2, with a modest energetic preference for SGLT2, and ADME/Tox predictions supported favorable oral drug-likeness. In vivo, intraperitoneal LASSBio-1986 improved oral glucose tolerance and reduced glycemic excursions in an acute glucose challenge model in C57BL/6 mice, while enhancing hepatic and skeletal muscle glycogen stores. In a dexamethasone-induced insulin-resistance model, LASSBio-1986 improved insulin sensitivity, favorably modulated serum lipids, attenuated thiobarbituric acid-reactive substances (TBARS), restored reduced glutathione (GSH) levels, and rebalanced pro- and anti-inflammatory cytokines in metabolic tissues, with efficacy broadly comparable to dapagliflozin. These convergent findings support LASSBio-1986 as a preclinical, multimodal lead that targets SGLT-dependent glucose handling while mitigating oxidative and inflammatory stress in models relevant to T2DM. Chronic disease models, formal toxicology, and pharmacokinetic studies, particularly with oral dosing, will be essential to define its translational potential. Full article

Oxidative stress is a defining feature of stroke pathology, but the magnitude, timing and impact of redox imbalance are not static. Emerging evidence indicates that physiological contexts, such as aging, metabolic stress, and circadian disruption, continuously reshape oxidative status and determine the brain’s vulnerability to ischemic and reperfusion injury. This review integrates recent insights into how these intrinsic modulators govern the transition from adaptive physiological redox signaling to pathological oxidative stress during stroke. Aging compromises mitochondrial quality control and blunts NRF2-driven antioxidant responses, heightening susceptibility to ROS-driven damage. Metabolic dysfunction, as seen in obesity and diabetes, amplifies oxidative burden through NADPH oxidase activation, lipid peroxidation, and impaired glutathione recycling, further aggravating post-ischemic inflammation. Circadian misalignment, meanwhile, disrupts the rhythmic expression of antioxidant enzymes and metabolic regulators such as BMAL1, REV-ERBα, and SIRT1, constricting the brain’s temporal window of resilience. We highlight convergent signaling hubs, NRF2/KEAP1, SIRT–PGC1α, and AMPK pathways, as integrators of these physiological inputs that collectively calibrate redox homeostasis. Recognizing oxidative stress as a dynamic, context-dependent process reframes it from a static pathological state to a dynamic outcome of systemic and temporal imbalance, offering new opportunities for time-sensitive and metabolism-informed redox interventions in stroke. Full article

Freshwater cladocerans such as Daphnia magna (D. magna) are keystone grazers whose hormone-regulated life history traits make them sensitive sentinels of endocrine-disrupting chemicals (EDCs). The organophosphate flame-retardant tris(2-butoxyethyl) phosphate (TBOEP) and perfluoroethylcyclohexane sulfonate (PFECHS) now co-occur at ng L⁻¹–µg L⁻¹ in surface waters, yet their chronic sub-lethal impacts on invertebrate endocrine networks remain unclear. We analysed two publicly available 21-day microarray datasets (TBOEP: GSE55132; PFECHS: GSE75607) using gene ontology enrichment, STRING protein interaction networks, Drosophila phenotype mapping, and KEGG (Kyoto Encyclopaedia of Genes and Genomes)-anchored frameworks to build putative adverse outcome pathways (AOPs) for D. magna. Differentially expressed genes were clustered into functional modules and hub nodes were ranked by degree and betweenness. TBOEP suppressed moulting and growth, altering 1157 genes enriched for metabolism and membrane processes; hubs VRK1, MIB2, and adenylosuccinate synthetase formed a muscle anatomical development sub-network. PFECHS down-regulated vitellogenin and shifted 879 genes dominated by oxidative-stress and glutathione-metabolism signatures; central nodes UBC9, eIF4A-III, Tra-2α, and HDAC1 linked meiotic-cycle, oogenesis, and cyclic-compound binding. Despite chemical dissimilarity, both compounds converged on Wnt-signalling nodes—TBOEP via presenilin-1, and PFECHS via CK1ε/CK2—thereby reducing TCF/LEF-dependent transcription. Predicted outcomes include impaired oocyte maturation, reduced fecundity, and stunted body size, consistent with observed decreases in length and vitellogenin protein. Our network analysis, based on high-dose, sub-lethal exposures used in the underlying microarray studies, indicates that TBOEP- and PFECHS-induced perturbations can destabilise endocrine, developmental, and metabolic pathways in D. magna without overt lethality, and highlights Wnt-centred key events and hub genes as candidate biomarkers to be evaluated in future low-dose studies that use environmentally realistic exposure scenarios. Hub genes and Wnt-mediated key events emerge as sensitive biomarkers for monitoring mixed EDC exposure. Full article

Glutamine synthetase (GS; EC 6.3.1.2) is a key enzyme for primary assimilation and re-assimilation of ammonium in higher plants. Although several GS gene families have been reported for several cereal crops, systematic studies for barley (Hordeum vulgare) under different nitrogen treatment conditions are still lacking. In this study, we combined genome-wide bioinformatics mining with transcriptome analysis to characterize the HvGS gene family in two different genotypes of barley (nitrogen-efficient W26 and nitrogen-sensitive W20) and their responses to low nitrogen stress. Four HvGS genes were retrieved from the barley genome and named HvGS1–HvGS4. These genes were comprehensively analyzed in terms of chromosomal distribution, physicochemical properties, subcellular localization, intron-exon structure, conserved motifs, promoter cis-acting elements, evolutionary relationships, and predicted protein–protein interactions. Leaves and roots were sampled and subjected to RNA-seq analysis at 3, 18, and 21 days of low-nitrogen stress, which revealed significant expression differences among genotypes and tissues. In W26, low nitrogen (0.4 mmol·L⁻¹) induced synergistic expression of HvGS1 and HvGS4 and suppressed expression of plastidic HvGS2, whereas W20 up-regulated the expression of HvGS1 and HvGS3 mainly in the root system. Combined GO/KEGG enrichment analysis and metabolomic characterization of the differentially expressed genes highlighted nitrogen metabolism, glutathione turnover, and amino acid biosynthesis as key hubs in the tolerant genotypes. Our results provide a genome-wide analysis of the barley GS family and highlight HvGS1 and HvGS4 as candidate genes for functional validation toward improved nitrogen use efficiency. Full article

Ferroptosis is a non-apoptotic form of cell death that is driven by iron and reactive oxygen species (ROS). This process is characterised by lipid peroxidation, which damages cell membranes and distinguishes it from other types of cell death. Excess iron promotes ferroptosis through Fenton chemistry, leading to increased ROS production. While glutathione peroxidase 4 has been identified as a key regulator of this process, other factors, such as the ferroptosis suppressor protein 1 (FSP1), suggest that regulation is more complex. Ferroptosis has been associated with several degenerative diseases, including Alzheimer’s disease, Parkinson’s disease, acute kidney injury, liver disorders, and cancer. The enzyme haemoxygenase-1 (HO-1) plays dual roles: it can promote ferroptosis by releasing iron or provide protection through its antioxidant effects in various organs and tissues. HO-1 increases iron levels through the catabolism of haem which can heighten sensitivity to ferroptosis by influencing iron trafficking and ferritin expression. Conversely, HO-1 has demonstrated nephroprotective effects in cases of renal injury and other disorders. HO-1′s involvement in regulating iron metabolism and its antioxidant capabilities can lead to differing outcomes, highlighting key players in the ferroptosis process. The Nrf2/HO-1 axis is crucial for its antioxidant properties in various disorders. Moreover, dietary sources can enhance HO-1 induction through Nrf2 regulation. Hence, HO-1 acts as both a modulator and a mediator, presenting new therapeutic targets for cancer, neurodegeneration, and kidney and liver diseases. Full article

Multidrug resistance (MDR) presents a significant challenge in the treatment of glioblastoma. We evaluated six novel adamantane–sclareol hybrids that integrate a natural labdane diterpene scaffold with an adamantane moiety to address this issue. Compounds 2, 5, and 6 demonstrated the ability to bypass P-glycoprotein (P-gp)-mediated resistance in resistant U87-TxR cells and induced collateral sensitivity, with compound 2 exhibiting the highest selectivity for glioblastoma compared to normal glial cells. Mechanistic studies revealed that compounds 2 and 5 selectively triggered early apoptosis in MDR cells, significantly elevated levels of H₂O₂ and peroxynitrite, and disrupted mitochondrial membrane potential. Additionally, these compounds altered the expression of key genes involved in glutathione (GSH) and thioredoxin (Trx) antioxidant defense systems and increased ASK1 protein levels, indicating the activation of ROS-driven apoptotic signaling. Both compounds inhibited P-gp function, leading to enhanced intracellular accumulation of rhodamine 123 (Rho 123) and synergistically sensitized U87-TxR cells to paclitaxel (PTX). A preliminary Rag1 xenograft study demonstrated that compound 5 effectively suppressed tumor growth without causing significant weight loss. Collectively, these findings position adamantane–sclareol hybrids, particularly compounds 2 and 5, as promising strategies that exploit an MDR-associated reactive oxygen species (ROS) vulnerability, combining selective cytotoxicity, redox disruption, and P-gp modulation to eliminate resistant glioblastoma cells and enhance the efficacy of chemotherapeutics. Full article

Drought is one of the most severe abiotic stresses limiting agricultural productivity and threatening global food security. As the central organelle responsible for photosynthesis and stress perception, the chloroplast is highly sensitive to drought, and its structural and functional stability directly determines plant adaptability. Recent studies have revealed that chloroplasts undergo pronounced ultrastructural alterations under drought stress, including thylakoid membrane shrinkage, disorganization of grana stacks, and accumulation of reactive oxygen species (ROS). Excessive ROS production causes oxidative damage to lipids, proteins, and nucleic acids, whereas moderate ROS levels act as retrograde signals to regulate nuclear gene expression. In parallel, calcium (Ca²⁺) oscillations and retrograde signaling pathways—such as those mediated by GENOMES UNCOUPLED PROTEIN1 (GUN), 3′-phosphoadenosine-5′-phosphate (PAP), and Methylerythritol cyclodiphosphate (MecPP)—integrate chloroplast-derived stress cues with nuclear responses. To counteract drought-induced damage, plants activate a series of antioxidant systems—both enzymatic (Superoxide Dismutase (SOD), Ascorbate Peroxidase (APX), Catalase (CAT)) and non-enzymatic (Ascorbic Acid (ASA), (Glutathione) GSH, tocopherols, carotenoids)—along with protective proteins such as fibrillins (FBNs) and WHIRLYs that stabilize thylakoid and membrane structures. In addition, autophagy and plastid degradation pathways selectively remove severely damaged chloroplasts to maintain cellular homeostasis. Exogenous substances, including melatonin, 5-aminolevulinic acid (ALA), and Zinc oxide (ZnO) nanoparticles, have also been shown to enhance chloroplast stability and antioxidant capacity under drought stress. In this review, we discuss the structural and functional changes in chloroplasts, signaling networks, and protective repair mechanisms under drought stress. Furthermore, we highlight future research prospects for enhancing plant stress resilience through multi-omics integration, application of functional regulators, and molecular design breeding. Full article

The present study aimed to evaluate blood redox status and acute phase protein profile throughout two pharmacological treatment protocols for pyometra bitches, employing aglepristone either as a monotherapy or in combination with prostaglandin. A prospective study was conducted in 10 open-cervix pyometra bitches assigned to two groups: aglepristone (n = 5; subcutaneous injections of aglepristone on days 1, 2, and 8 after diagnosis) and aglepristone + prostaglandin (n = 5, aglepristone coupled with daily injections of cloprostenol from days 1 to 7). Blood samples were collected daily for the liver profile (alanine aminotransferase—ALT, alkaline phosphatase, and albumin), acute phase proteins (C-reactive protein-CRP, haptoglobin, and serum amyloid-A), and redox analysis [antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx) and reduced glutathione (GSH), oxidative stress (TBARS), and protein oxidation]. In the aglepristone group, there was increase in albumin concentration and SOD, while protein oxidation and GSH decreased progressively throughout treatment. The aglepristone + prostaglandin group had lower ALT levels but higher lipid peroxidation, GPx, and CRP. In conclusion, the combined use of prostaglandin modified the profile of oxidative markers, antioxidant enzymes, and C-reactive protein, thereby preventing the assessment of treatment efficacy. Conversely, albumin concentration proved a sensitive marker of therapeutic effectiveness in both treatment protocols for pyometra bitches. Full article

Potato is globally recognized as the fourth most crucial staple food crop, trailing behind wheat, rice, and maize. Cadmium (Cd), a predominant heavy-metal pollutant in agricultural soils, demonstrates high biological toxicity and mobility. Therefore, exploring the genetic and molecular mechanisms underpinning cadmium tolerance in potato is of substantial theoretical and practical significance. In this research, an F₂ population composed of 170 families was established through the cross-breeding of homozygous diploid potato lines HD-5 (highly cadmium-tolerant) and M9 (cadmium-sensitive). Employing hydroponic cultivation, six traits, namely plant height (PH), root length (RL), shoot fresh weight (SFW), root fresh weight (RFW), chlorophyll content (SPAD), and nitrogen content (LNC), were measured in potato seedlings following a 9-day treatment with 40 mg·L⁻¹ CdCl₂. By utilizing the high-density genetic map of this population for QTL mapping, a total of 35 genetic loci associated with cadmium tolerance in potato seedlings were identified. Notably, loci21 and loci22 on chromosome 9, loci29 on chromosome 10, and loci31 and loci33 on chromosome 12 were consistently detected across multiple environmental conditions. This reproducibility across environments suggests the phenotypic stability of these five loci, which are thus considered reliable and robust genetic determinants. In addition, transcriptome sequencing analysis of roots from parental lines HD-5 and M9 after cadmium treatment revealed that significantly differentially expressed genes between the two parents were associated with glutathione metabolism and photosynthesis. By integrating QTL mapping, transcriptome analysis, and gene annotation, we screened four candidate genes involved in cadmium tolerance regulation: DM8C09G01000 (GST), DM8C09G01060 (GST), DM8C09G02130 (OXP1), and DM8C06G22960 (PsaH). These findings provide molecular targets and a genetic basis for molecular breeding of cadmium-tolerant potato varieties. Full article

Vicia faba is an agriculturally and nutritionally important legume whose growth and productivity are strongly influenced by biotic stress factors. Understanding the mechanisms by which plants respond to stress is therefore essential for improving agricultural productivity and enabling the selection of stress-tolerant cultivars. This study evaluated whether biochemical and physiological parameters can serve as early indicators of stress induced by Aphis fabae infestation in young V. faba plants. Plants were exposed to two levels of aphid infestation (low- and high-stress) and compared with aphid-free controls. Low stress caused minimal alterations in antioxidant responses: catalase (CAT) activity increased by 9.9%, glutathione (GSH) content by 20%, and malondialdehyde (MDA) levels decreased by 17.6% relative to controls. Under high stress, oxidative damage and antioxidant activation were pronounced, with CAT activity rising 2.4-fold, GSH content increasing 2.6-fold, and MDA accumulating 2.6-fold compared to control plants. Superoxide dismutase (SOD) activities increased under both stress levels, though without large differences, while nitrate reductase (NR) activity showed non-significant variation. Proline accumulation remained largely unchanged, showing only a slight 13–15% increase relative to controls. Photosynthetic pigment analysis revealed that low stress reduced contents of chlorophyll a and total chlorophyll, while increasing contents of chlorophyll b and carotenoids. Stress markedly altered pigment balance, yielding a 25.4% higher chlorophyll a/b ratio compared with control plants. The results indicate that V. faba plants can tolerate low-intensity aphid stress with minimal biochemical disturbance, whereas high infestation elicits strong oxidative stress and significant physiological changes. The measured biochemical markers, particularly CAT, MDA, and GSH, proved sensitive to early stress onset, offering valuable tools for early detection of biotic stress before visible symptoms appear. The research contributes to a better understanding of plant responses to stress, enables early detection of stress factors affecting plant physiology, facilitates the assessment of their adaptive potential, and may aid in the development of strategies to improve faba bean resistance to pest infestations. This research enhances understanding of V. faba stress responses, enabling early detection of stress factors and assessment of the plant’s adaptive potential. The insights gained may support the development of strategies to improve faba bean resistance to pest infestations and contribute to more sustainable agricultural productivity. Full article

Introduction/Objectives: Ginsenoside F1, a pharmacologically active saponin derived from Panax ginseng, exhibits diverse bioactivities, but its use is limited because it is difficult to purify and has high production costs. To overcome these challenges, a ginsenoside F1-enriched extract named SGB121 was developed. This study aimed to evaluate the therapeutic efficacy of SGB121 in a high-fat, high-carbohydrate (HFHC) diet-induced metabolic dysfunction-associated fatty liver disease (MAFLD) mouse model and to elucidate its mechanism of action using F1-based cellular assays. Methods: Male C57BL/6 mice (6 weeks old) were fed an HFHC diet to induce MAFLD and were treated with SGB121. Hepatic lipid accumulation, oxidative stress markers, and metabolic parameters were analyzed. In parallel, human hepatocellular carcinoma (HepG2) cells exposed to free fatty acids (FFAs) were used to assess oxidative stress and lipid accumulation. Mechanistic studies were conducted using purified F1 to examine adenosine monophosphate-activated protein kinase (AMPK) activation and related pathways. Results: SGB121 reduced hepatic lipid accumulation, malondialdehyde (MDA) levels, and fasting insulin while restoring glutathione (GSH) content and improving the homeostasis model assessment of insulin resistance (HOMA-IR) in MAFLD mice. In FFA-treated HepG2 cells, both SGB121 and F1 decreased reactive oxygen species (ROS), suppressed sterol regulatory element-binding protein 1 (SREBP1), enhanced peroxisome proliferator-activated receptor-α (PPARα) and β-oxidation, and restored insulin receptor substrate (IRS)/protein kinase B (Akt)/glucose transporter 2 (GLUT2) signaling. Conclusions: SGB121 ameliorates MAFLD and related metabolic dysfunction through antioxidant, lipid-regulating, and insulin-sensitizing actions, highlighting its potential as a safe multifunctional nutraceutical for MAFLD management. Full article

Insecticide resistance in insects poses a serious problem in population control of arthropod vectors and spreaders of human and animal diseases. Metabolic resistance to insecticides is facilitated by detoxification system enzymes, including glutathione-S-transferases (GSTs) involved in phase II of xenobiotic biotransformation. The aim of this study was to analyze the glutathione-S-transferase activity and the expression level of different class GST genes in Musca domestica. The test subjects were larvae and 3–5-day-old adults of a laboratory susceptible strain (LabTY) and a field deltamethrin-tolerant population (Nik). Based on the LC50 values, the Nik strain showed sensitivity to chlorpyrifos and chlorfenapyr and tolerance to deltamethrin with a remarkable increase in the level of resistance in males compared to females. Expression analysis of eight GST genes revealed that the expression of the GST-E12 gene (Epsilon class) was significantly elevated and the GST-S1 gene (Sigma class) was significantly decreased in the Nik strain across all groups (larvae, females, and males), with the most pronounced difference in females. A pronounced sexual dimorphism was observed: the expression of most GST genes was significantly higher in males than in females in both strains. For the first time, a consistent male-specific overexpression of multiple GST genes has been demonstrated in M. domestica. Full article

Ferroptosis, a regulated cell death pathway driven by iron-dependent lipid peroxidation, is modulated by cellular antioxidant systems, particularly the glutathione (GSH)–glutathione peroxidase 4 (GPX4) axis. NAD kinase (NADK), the only enzyme converting NAD⁺ to NADP⁺ located in cytoplasm, fuels NADPH-dependent antioxidant defenses. However, its role in ferroptosis regulation remains not fully explored. Using ferroptosis-sensitive HT1080 cells, we employed pharmacological inhibition (thioNAM), siRNA-mediated knockdown, and plasmid-driven overexpression of NADK to dissect its impact on ferroptosis. Complementary interventions with nicotinamide mononucleotide (NMN), glucose-6-phosphate dehydrogenase (G6PD) and malic enzyme 1 (ME1) were used to map metabolic interactions. Cell viability, redox metabolites (NADPH and GSH), oxidative stress markers (ROS, MDA), and protein expression were quantified. ThioNAM depleted NADP(H) and sensitized cells to RSL-3-induced ferroptosis, which was reversible with Ferrostatin-1. NADK knockdown produced similar results, reducing NADP(H) levels and amplifying lipid peroxidation. Conversely, NADK overexpression restored NADPH/GSH levels and rescued ferroptosis. NADK was essential for G6PD- and ME1-mediated NADPH production and ferroptosis resistance. Administration of ThioNAM or knockdown of NADK abolished the ferroptosis-rescuing effects of NMN, whereas NADK overexpression enhanced NMN’s ability to rescue ferroptosis by maintaining redox homeostasis. NADK is a metabolic hub in ferroptosis regulation, bridging NMN-driven NAD⁺ salvage to NADPH synthesis via G6PD/ME1. Targeting NADK offers novel strategies for diseases associated with ferroptosis. Full article

Oxidative stress is a key contributor to diabetes-related cognitive decline and is intensified by diabetes distress (DD), the psychological burden of disease management. DD lowers brain levels of nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor that regulates antioxidant defense. This study examined whether chlorogenic acid (CGA), a polyphenolic NRF2 activator, could counteract oxidative and astroglial dysfunctions in adult zebrafish subjected to chronic unpredictable mild stress (CUMS) combined with dextrose, a model mimicking DD. Zebrafish were treated with CGA (50, 100, or 200 mg/kg), and the levels of NRF2 protein and mRNA, along with its regulator keap1, were quantified. Expression levels of key downstream antioxidant genes (sod1, sod2, catalase, glutathione peroxidase, and glutamate-cysteine ligase catalytic subunit) were assessed alongside glutathione (GSH) content and superoxide dismutase (SOD) and catalase activities. Astroglial integrity was evaluated via glial fibrillary acidic protein (GFAP) levels in the whole brain and stress-sensitive regions. CGA increased total brain NRF2 protein, its mRNA, and those of its downstream effectors. At 200 mg/kg, CGA restored GSH levels, boosted antioxidant enzyme activities, and mitigated DD-associated reductions in GFAP and NRF2 in stress-vulnerable areas. These findings identify NRF2 as a promising target to protect brain health under diabetic conditions. Full article