Search Results (237)

Background: Pathological aggregation of islet amyloid polypeptide (IAPP) contributes to β-cell dysfunction in type 2 diabetes. Our previous studies demonstrated that caveolin-1 (Cav-1) deficiency protects β-cells from palmitate-induced apoptosis. Microarray profiling further indicated that Cav-1 silencing alters IAPP expression. This study aimed to investigate the effects of Cav-1 depletion on IAPP secretion and expression and to explore the potential involvement of thioredoxin-interacting protein (TXNIP). Methods: We performed lentiviral-mediated Cav-1 knockdown in NIT-1 cells and isolated murine islets, and simultaneously generated an inducible β-cell-specific Cav-1 knockout (iβ-Cav1 KO) mouse model. IAPP secretion and expression were assessed by ELISA, Western blot, qPCR and immunofluorescence. The expression of IAPP-processing enzymes (PAM, PC1, and PC2) and degradation factors (IDE and BACE2) was examined. Co-immunoprecipitation (Co-IP) and immunofluorescence were performed to investigate the interaction between Cav-1 and TXNIP. Results: Cav-1 depletion significantly reduced both IAPP secretion and expression in vitro and in vivo. High-fat-diet-fed iβ-Cav1 KO mice exhibited the lowest serum IAPP levels. Mechanistically, Cav-1 depletion was associated with downregulation of PAM, PC1, and PC2 and upregulation of IDE and BACE2. Additionally, Cav-1 depletion decreased TXNIP expression. Immunofluorescence revealed co-localization of Cav-1 and TXNIP, and co-immunoprecipitation further demonstrated their direct physical interaction. Conclusions: Cav-1 is essential for IAPP secretion and expression in β-cells. The direct physical interaction between Cav-1 and TXNIP suggests that TXNIP may mediate the regulatory effects of Cav-1 on IAPP processing or secretion. These findings identify the Cav-1–TXNIP axis as a potential target for mitigating IAPP-related β-cell dysfunction. Full article

Ultraviolet A (UVA) radiation disrupts the redox balance of melanocytes and may lead to the development of melanoma, highlighting the need for new skin protection strategies. This study assessed the effect of phytocannabinoids [cannabigerol (CBG), cannabidiol (CBD), and CBG + CBD] on redox homeostasis in control and UVA-exposed melanocytes and in melanoma cells (SK-Mel-5). UVA radiation increased the activity of prooxidant enzymes in both melanocytes and SK-Mel-5 cells and, consequently, the level of reactive oxygen species (ROS) (approx. 2-fold). It also activated nuclear factor erythroid 2 (Nrf2), as reflected by increased expression of heme oxygenase 1 (HO-1) (melanocytes approx. 2-fold; SK-Mel-5 approx. 7-fold). Concomitantly, antioxidant mechanisms were impaired, as demonstrated by reduced superoxide dismutase (SOD1/SOD2) activity and impaired glutathione and thioredoxin function. These changes were accompanied by increased levels of oxidative damage markers (isoprostanes, 4-hydroxynonenal-4-HNE, and 4-HNE-protein adducts) (43–100%) and increased inflammatory signaling, including increased expression of nuclear factor kappa B (NF-κB) subunits (melanocytes: p52 ~2-fold, p65 ~75%; SK-Mel-5: ~4–4.5-fold) and tumor necrosis factor alpha (TNF-α; ~30%). Phytocannabinoid treatment modulated these UVA-induced changes. In SK-Mel-5 cells, phytocannabinoids normalized the activity of prooxidant enzymes and consequently reduced ROS levels (~30%). They also reduced Nrf2 activation and HO-1 expression; however, CBG increased HO-1 level in melanocytes (~25–40%). Furthermore, phytocannabinoids enhanced antioxidant defense by increasing SOD activity, particularly in melanocytes (~10–40%), and restoring the glutathione and thioredoxin systems. Markers of oxidative damage were reduced by approximately 23–37% after treatment. Furthermore, phytocannabinoids attenuated NF-κB activation (p52 ~18–28%, p65 ~25–29% in melanocytes; ~20% in SK-Mel-5), while TNF-α levels remained unchanged. The effects in non-irradiated cells were modest (<15%). These results suggest that phytocannabinoid-mediated modulation of redox balance may stabilize melanocytes exposed to UVA radiation and potentially reduce the risk of neoplastic transformation. However, the observed protective effects in SK-Mel-5 cells require further investigation and detailed molecular analysis. Full article

Leishmaniasis remains a major neglected tropical disease with limited therapeutic options, challenged by drug toxicity and emerging resistance to current treatments like miltefosine. In this study, a virtual library of approximately 150 azole-derived compounds was screened in silico to identify promising thiazole and imidazole scaffolds, leading to the rational design of novel hybrid molecules. Molecular docking against thioredoxin reductase (PDB ID: 4CBQ), a key enzyme in the redox metabolism of Leishmania mexicana, showed improved binding affinity compared to miltefosine, with compound 3f showing the most favourable interaction profile. Among the synthesized series 3a–f, compound 3f (4-NO₂Ph) exhibited the most favourable predicted binding parameters within the series (∆G = −16.08, Ki = 0.0019 nM). Biological evaluation was performed against L. mexicana promastigotes as an early-stage phenotypic screening model to identify active compounds with potential relevance during the initial infective phase, and a markedly improved in vitro inhibitory effect (IC₅₀ = 22.41 µM) compared to miltefosine (IC₅₀ = 132.42 µM), representing a six-fold increase in molar potency. Furthermore, hybrid thiazolyl–imidazole systems (series 3) consistently outperformed single-core analogues, likely due to enhanced molecular planarity and lipophilicity provided by the imine linkage. Cytotoxicity assays in Vero cells revealed a high safety margin for the lead compounds, with compound 3f achieving a Selectivity Index (SI) of around 89, significantly outperforming the reference drug. Acute toxicity studies (LD₅₀) in murine models further confirmed the safety profile, with values exceeding 2000 mg/kg for the most active derivatives. These findings identify thiazolyl–imidazole hybrids as promising early-stage scaffolds for antileishmanial drug discovery, particularly for early infection/prophylactic screening. Full article

Metabolic syndrome (MeS) is a multifactorial disorder characterized by insulin resistance, dyslipidemia, hypertension, and obesity, and oxidative stress plays a key role in tissue damage in this syndrome. This study aimed to investigate this role in Na⁺/K⁺-ATPase (NKA) expression in skeletal muscle and to evaluate the effects of quercetin. A high-sucrose-diet-induced MeS model was established in Wistar albino rats (n = 32), and skeletal muscle tissues were analyzed. Biochemical parameters were measured, including aspartate aminotransferase (AST), lactate dehydrogenase (LDH), total antioxidant status (TAS), total oxidant status (TOS), superoxide dismutase (SOD), and malondialdehyde (MDA). In addition, thioredoxin-1 (TRX1) and NKA protein expression levels were evaluated using Western blot analysis. In the MeS group, AST, TAS, TRX1, and NKA expression significantly decreased, while LDH, TOS, SOD, and MDA levels increased, indicating disrupted redox balance, elevated oxidative stress, and impaired antioxidant defense. Increased MDA and TOS levels reflected enhanced lipid peroxidation, whereas decreased TAS and TRX1 suggested reduced antioxidant capacity. Elevated SOD activity may indicate a compensatory response to excessive reactive oxygen species (ROS). The reduction in NKA expression may contribute to impaired ion transport and potential skeletal muscle dysfunction. Quercetin administration improved oxidative stress markers and partially restored NKA expression. These findings suggest that oxidative stress contributes to NKA dysfunction in MeS, and quercetin may have therapeutic potential by modulating oxidative stress and preserving enzyme function. Full article

With the rapid progression of global industrialization and urbanization, heavy metal contamination has emerged as a major global threat, especially cadmium pollution. Consequently, optimizing remediation measures has become a pivotal means to solve cadmium contamination. Compared to traditional physical and chemical remediation methods, microbial remediation has great potential in addressing cadmium pollution. In this study, a novel bacterial strain, Chryseobacterium sp. HGX-24, exhibiting high cadmium resistance was successfully isolated and screened from cadmium-contaminated environments. A preliminary discussion of the response mechanisms of this strain under cadmium stress is provided. Additionally, preliminarily explored the synergistic remediation of microbial-plant in cadmium-contaminated soil. Under conditions of high cadmium concentration, cadmium ions were effectively adsorbed by strain HGX-24 through extracellular polymers and functional groups on the cell wall surface, including −COOH, −CONH−, −NH, −OH, and >C=O. Extracellular proteins and polysaccharides were secreted by strain HGX-24 to regulate the adverse effects of heavy-metal cadmium ions on bacterial growth. Furthermore, the expression of genes such as antioxidant defense and ROS scavenging (katG, fabG, ybjT), Fe-S cluster assembly (sufB, sufD), sulfur metabolism (cysAU), amino acid metabolism (hisA, cysD, aspC), phenylacetic acid catabolism (paaC), and ribosomal proteins (rplC, rpsC, rpsL, rplA, rplY, rpmC) was regulated, affecting the synthesis and metabolism of membrane transporters (ABC transporters and efflux RND transporters), antioxidant enzymes (SOD, COT, POD), Fe-S clusters, thioredoxin family proteins, and ribosomal proteins, thereby enhancing resistance to cadmium toxicity. Moreover, strain HGX-24 was found to regulate the activities of redox enzymes in Zea mays L., thereby alleviating oxidative stress and reducing the negative feedback effects of reactive oxygen species in Z. mays. Full article

Abiotic stresses disrupt redox homeostasis and reduce crop productivity. Antioxidant networks support resilience by limiting excess reactive oxygen species (ROS) and maintaining redox signalling for stress perception, gene expression, and metabolic reprogramming. We summarize advances (2000–2025) in ROS generation, detoxification mechanisms, and signalling across organelles, including chloroplasts, mitochondria, peroxisomes, and the apoplast. This includes compartmentalized enzymes—superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), glutathione peroxidase (GPX), and glutathione reductase (GR)—as well as the peroxiredoxin–thioredoxin system and non-enzymatic buffers like ascorbate, glutathione, tocopherols, carotenoids, and flavonoids. We uniquely synthesize these findings in a compartment-resolved “redox rheostat” model, linking ROS concentration–time windows (signaling vs. damage) to antioxidant network design (kinetic tiers, compartmentation, and trade-offs) and identifying intervention points for breeding, genome editing, and field-scale priming. We emphasize constraints, such as NADPH supply and antioxidant recycling capacity, that lead to context-dependent outcomes. We evaluate omics, transgenic strategies, genome editing (CRISPR and Cas systems), exogenous applications, and plant–microbe associations. This synthesis clarifies how antioxidant systems protect photosynthetic and respiratory machinery while supporting signalling, thus outlining routes to climate-resilient, yield-stable crops across varied environments and stresses. Full article

This review synthesizes current evidence on the dualistic and context-dependent roles of selenium-containing antioxidant enzymes—specifically, glutathione peroxidases (GPXs) and thioredoxin reductases (TXNRDs)—in the development and progression of human cancers. We analyze how these crucial components of cellular redox homeostasis can function as either potent oncogenes or tumor suppressors depending on the tissue of origin, cancer stage, genetic background, and tumor microenvironment. The paradoxical behavior of these enzymes is governed by a complex interplay of transcriptional regulation, epigenetic modifications, and signaling pathway interactions, ultimately influencing critical processes such as apoptosis, proliferation, invasion, and therapy resistance. Special emphasis is placed on the unique role of GPX4 in regulating ferroptosis, a promising target for novel anti-cancer strategies, and on the prognostic significance of TXNRD overexpression in aggressive malignancies. By integrating data across various cancer types, this review highlights these enzyme families as central molecular switches in carcinogenesis and discusses their potential as biomarkers and targets for rational, combination-based therapeutic interventions. Full article

Fungi regularly occur on spacecrafts, posing a serious risk to humans and equipment. In this study, we characterized how the model organism Aspergillus nidulans responds to low-intensity, short-duration proton irradiation designed to simulate a solar particle event, a common stress factor in space. The oxidative stress-sensitive ∆atfA mutant exhibited a lower survival rate than the wild-type strain. Pretreatment of the wild-type strain with menadione sodium bisulfite (MSB), which activates oxidative stress defense mechanisms, increased tolerance to proton beam radiation. These data are consistent with the idea that oxidative defense contributes to cellular responses to ionizing radiation. Unexpectedly, the applied radiation decreased the tolerance to MSB. To understand this unusual behavior, we compared the transcriptomes of the irradiated and non-irradiated mycelia. As expected, proton beam irradiation upregulated many genes involved in DNA repair but downregulated a large number of antioxidant enzyme genes. The downregulation of three key antioxidant genes—prxA (thioredoxin peroxidase), trxB (thioredoxin reductase), and gsh1 (γ-glutamylcysteine synthase)—was further confirmed by RT-qPCR analysis. One possible explanation is that, due to the rapid elimination of reactive oxygen species generated by water radiolysis, the effects of radiolysis-derived electrons could transiently dominate redox signaling. This shift may interfere with redox sensing in the fungus, resulting in reduced antioxidant gene expression and increased sensitivity to oxidative stress. Oxidative stress sensitivity caused by proton radiation may be the Achilles heel of cells that can survive this stress. Full article

Human prostamide/prostaglandin F synthase (PGFS) catalyzes the NADPH-dependent conversion of prostaglandin H₂ (PGH2) to prostaglandin F₂α that plays a key role in regulating intraocular pressure and labor. Despite its physiological importance, structural and biochemical information of the human PGFS has been limited because of difficulties in obtaining sufficient quality of PGFS wild-type crystal and short half-life of PGH2. Here, we report the crystal structure of human PGFS with two active site mutations, C44S/C47S double mutant (DM), which mimics the reduced active form of the CXXC motif of human PGFS. Structural analysis revealed that PGFS DM adopts a typical thioredoxin (Trx)-like fold. Analysis of B-factors and MD simulations reveals that Tyr108–Asp124 is an intrinsically flexible region, devoid of any stabilizing crystal contacts. Unlike canonical Trx-like proteins, Pro167 in PGFS adopts a trans-conformation, inducing a specific Arg40 side chain localization that creates a positive charge near the CXXC motif. Activation of PGFS by reduction of disulfide bond in the CXXC motif enhanced the thermal stability via core stabilization, yet an unexpected increase in the structural disorder was detected with CD spectroscopy, especially upon ligand binding. These findings collectively establish PGFS as a structurally distinct and redox-regulated enzyme. Our results provide novel molecular insights into PGFS as an underexplored but promising therapeutic target. Full article

The thioredoxin h-type (Trxh) proteins play a crucial role as convergence points within plants’ responses to abiotic and biotic stresses. Previously, we demonstrated that the protein TdTrxh2 of durum wheat (Triticum durum Desf.) has a chaperone function and it promotes tolerance to abiotic stress. The aim of this study was to evaluate the antimicrobial effect of TdTrxh2 and its role in the response of durum wheat to Fusarium graminearum attack. First, we demonstrated the involvement of TdTrxh2 in the response of durum wheat to this fungus via the analysis of its expression profile under this fungus attack. In fact, the outcomes showed that the induction of TdTrxh2 expression is spatiotemporal in leaves and roots of durum wheat under F. graminearum infection. Interestingly, this induction was accompanied by H₂O₂ accumulation under short- and long-term stress in roots and leaves, respectively. Besides, the cis elements related to the two phytohormones ET and MeJA, and those implicated in defense and wound stress, were identified in the TdTrxh2 promoter’s sequence. Second, the purified TdTrxh2 protein possessed antimicrobial effects against a diverse range of bacteria and fungi in vitro. Finally, the expression of TdTrxh2 in transgenic Arabidopsis plants enhanced their tolerance to F. graminearum attack through the activation of the two H₂O₂-scavenging enzymes, CAT and POD, and via the induction of a subset of SA- and ABA-related genes. Moreover, the exogenous SA and ABA applications improved the growth of the transgenic lines compared to the non-transformed plants. Taken together, the results highlighted that TdTrxh2 generates tolerance of durum wheat’s response to F. graminearum attack, via the regulation of H₂O₂ homeostasis and the induction of hormone-associated genes. Thus, the TdTrxh2 gene could be considered as an interesting candidate gene to improve wheat tolerance to F. graminearum attack. Full article

Mycobacterium tuberculosis (M. tuberculosis) relies on the thioredoxin (Trx)–thioredoxin reductase (TrxR) system to maintain intracellular redox homeostasis and to support Trx-dependent DNA synthesis and repair, making TrxR a potential target for anti-tuberculosis therapy. Gold nanoclusters have been reported to inhibit human TrxR and suppress tumor growth, suggesting that gold-based nanomaterials can modulate TrxR activity. In this study, we report a previously uncharacterized oxidized crystal structure of M. tuberculosis TrxR containing two dimers in the asymmetric unit and use this structure to investigate inhibition by a glutathione-coated gold nanocluster (GSH-AuNC). Biolayer interferometry and enzymatic assays show that GSH-AuNC binds directly to M. tuberculosis TrxR and efficiently inhibits its catalytic activity at the purified enzyme level. Molecular dynamics simulations indicate that GSH-AuNC can occupy a surface pocket proximal to the active site, providing a plausible structural basis for enzyme engagement. AlphaFold3 modeling of the M. tuberculosis TrxR-Trx heterodimeric complex defines the interaction interface required for productive electron transfer and provides a structural hypothesis for how GSH-AuNC disrupts this process. Together, these results provide structural and mechanistic insights into the biochemical modulation of M. tuberculosis TrxR by GSH-AuNC, while the antimycobacterial activity of GSH-AuNC remains to be evaluated in future studies. Full article

Fine particulate matter (PM2.5)-induced ovarian damage has attracted widespread attention, but differences in cytotoxicity and underlying mechanisms of water-soluble (WS-PM2.5) and water-insoluble (WIS-PM2.5) fractions are unclear. To investigate potential effects of PM2.5 from livestock farming environments on animal ovaries, PM2.5 samples were collected from large-scale cattle barns. There were significant differences between fractions regarding elemental composition, proportion of water-soluble ions, polycyclic aromatic hydrocarbon content, and endotoxin concentrations. Based on transcriptome sequencing results, in a cowshed PM2.5 exposure model (rats), differentially expressed ovarian mRNAs were significantly enriched in signaling pathways such as cytokine interaction and the Hippo pathway, with the expression of thioredoxin-interacting protein (Txnip) significantly increased. In vitro (primary rat ovarian granulosa cells), short-term exposure to WS-PM2.5 (12 h) significantly induced inflammatory factor release, acute oxidative stress, mitochondrial dysfunction, and intracellular Ca²⁺ overload, with characteristics of rapid acute injury. However, extended (24 h) WIS-PM2.5 exposure had greater disruptive effects on estrogen homeostasis, intracellular enzyme release (LDH), and mitochondrial structure (subacute characteristics). Furthermore, downregulating Txnip expression via inhibitors effectively mitigated cowshed PM2.5-induced ovarian granulosa cell toxicity, oxidative stress, and mitochondrial and hormonal dysfunction. In summary, solubility of cowshed PM2.5 components affected cytotoxic characteristics, and Txnip was a key factor linking oxidative stress to granulosa cell damage. The study provided a mechanistic basis and potential targets for preventing and controlling PM2.5-induced ovarian damage in livestock environments. Full article

Oxidative stress represents a critical threat to aquatic animal health and aquaculture productivity. Allicin, a natural plant extract, has not been systematically investigated for its antioxidant mechanisms in aquatic crustaceans. This study established in vitro and in vivo models of tert-butyl hydroperoxide (T-BHP)-induced oxidative stress in Chinese mitten crabs (Eriocheir sinensis) to evaluate the hepatoprotective effects of allicin. Integrating biochemical, transcriptomic, and ultrastructural analyses, we found that allicin significantly alleviated T-BHP-induced cytotoxicity and oxidative damage in vitro. Mechanistically, allicin up-regulated antioxidant genes including glutathione peroxidase (gpx) and thioredoxin reductase 1 (trxr1), and down-regulated pro-inflammatory cytokines such as interleukin-1 beta (il-1β), suggesting the concomitant activation of the Nrf2 signaling pathway and inhibition of the p38-MAPK/NF-κB pathway. Transcriptomics further indicated its role in restoring proteostasis and mitochondrial function. A 35-day feeding trial validated these findings in vivo; dietary supplementation with 300 mg·kg⁻¹ allicin effectively reversed T-BHP-induced disturbances in antioxidant enzyme activities and immune-related gene expression. These consistent findings demonstrate that allicin alleviates hepatopancreatic oxidative damage through multi-pathway synergism, supporting its potential as a green and effective antioxidant feed additive in aquaculture. Full article

Oxidative stress is a key contributor to the onset and progression of diverse pathological conditions, including metabolic dysfunction-associated steatotic liver disease (MASLD), neurodegeneration, cardiovascular disorders, and cancer. Conventional antioxidant therapies, such as small-molecule scavengers or systemic enzyme administration, are limited by poor stability, inefficient delivery, and off-target effects. Extracellular vesicles (EVs), particularly exosomes, are increasingly recognized as natural carriers of antioxidant enzymes (AOEs), including catalase, superoxide dismutases, glutathione peroxidases, peroxiredoxins, and thioredoxin. These vesicles not only protect enzymes from degradation but also enable targeted delivery to recipient cells, where they can actively modulate redox homeostasis. In this review, we summarize current evidence for AOEs as bona fide EV cargo, outline mechanisms that govern their selective packaging and transfer, and highlight their roles in intercellular communication under physiological and pathological conditions. We also discuss emerging therapeutic applications of both natural and engineered EVs for redox modulation, along with the challenges of quantifying enzymatic activity, ensuring reproducibility, and scaling clinical translation. By integrating insights from cell biology, redox signaling, and translational research, we propose that EV-mediated AOE delivery represents a promising next-generation strategy for combating oxidative stress-related diseases. Full article

The development of males and females of the cephalopod Amphioctopus fangsiao is asynchronous. The male produces sperm after maturity for storage in a spermatophore prior to mating. After mating, the sperm enter the female spermatheca for storage until ovulation occurs, a period that lasts for 8 months. This is a biologically uncommon phenomenon because sperm cells generally fail to maintain their ability to fertilize for a long time after being ejaculated. However, the molecular mechanisms of this phenomenon are still not clear. Sperm cells are stored in the male spermatophore and the female spermatheca, each of which provides a suitable environment. To determine the molecular basis of the sperm storage mechanisms in A. fangsiao, protein profiles from spermathecal fluid and seminal plasma were characterized separately using mass spectrometry-based proteomics. The antioxidant enzymes superoxide dismutase (SOD), glutathione S-transferase (GST), and Thioredoxin (Trx), and the glycolytic enzymes lactate dehydrogenase (LDH), hexokinase (HK), pyruvate dehydrogenase kinase (PDK), and ATP synthase were significantly enriched in the spermathecal fluid. Catalase (CAT), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), triosephosphate isomerase (TIM), phosphoglycerate kinase (PGK), and Chitinase were significantly enriched in the seminal plasma. The antimicrobial proteins transforming growth factor beta regulator 1 (TBRG1) and interleukin enhancer binding factor 2 (ILF2) and the extracellular matrix-related proteins transforming growth factor beta induced protein (TGFBIp) and thrombospondin type-1 domain-containing protein 4 (THSD4) were also significantly expressed in the spermathecal fluid. These proteins may be crucial for successful long-term sperm storage. We measured the activities of four antioxidant enzymes based on the proteomic results, supporting the antioxidant mechanism during the sperm storage process. This study enhances our understanding of the sperm storage ability of A. fangsiao. Full article