Search Results (354)

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

Prostate adenocarcinoma (PRAD) poses a significant challenge due to therapy resistance and an immunosuppressive tumor microenvironment (TME). Ferroptosis has emerged as a therapeutic vulnerability, yet its immunomodulatory role in PRAD remains elusive. Here, we employed a multi-omics approach—integrating bulk RNA-seq (498 tumors), single-cell RNA-seq (68,322 cells), and spatial transcriptomics (19,483 spots)—to decode the ferroptosis-immune landscape. We derived a robust 16-gene ferroptosis signature that predicted biochemical recurrence (C-index = 0.76) and validated it in two independent cohorts. Crucially, high-risk tumors exhibited a “cold” immunosuppressive TME enriched in regulatory T cells and M2 macrophages, alongside elevated immune checkpoints (HAVCR2, CTLA4, PDCD1). Single-cell and virtual knockout analyses revealed that cancer epithelial cells evade ferroptosis via NFE2L2-associated antioxidant defenses, which strongly correlates with immune exclusion. Spatial transcriptomics further demonstrated spatially organized vulnerabilities, with ferroptosis-resistant tumor cores and immune-infiltrated invasive margins. To identify therapeutic interventions, we utilized drug response modeling and molecular docking, prioritizing RSL3, Atovaquone (targeting NOX4 (NADPH oxidase 4)/DHODH), and Sorafenib (targeting TrxR1 (thioredoxin reductase 1, encoded by TXNRD1)) as potent agents with potential ferroptosis-modulatory activity. Collectively, our findings demonstrate that NFE2L2-associated ferroptosis resistance shapes immune evasion in PRAD. Targeting ferroptosis regulators provides a compelling therapeutic rationale to remodel the TME and synergize with immune checkpoint blockade. Full article

Background/Objectives: Phillygenin (PHI), a natural lignan derived from Forsythia suspensa, has garnered attention for its potential to alleviate chronic diseases, including chronic colitis, pulmonary fibrosis, and diabetes. Chronic kidney disease (CKD) poses a global health challenge, characterized by high morbidity and mortality rates and associated with a spectrum of secondary complications. In this study, we aim to investigate the therapeutic effectiveness of PHI on CKD and also identify molecular signals by using a unilateral ureteral obstruction (UUO) mouse model and in vitro experiments. Methods: C57BL/6 mice were administered PHI at 50 mg/kg/day to assess its therapeutic effectiveness. In vitro, lipopolysaccharide (LPS) and adenosine triphosphate (ATP) were used to induce pyroptosis, also known as pyroptosis, in renal proximal tubular cells (NRK52E). Results: After PHI treatment for 14 consecutive days, the collagen deposition and extracellular matrix (ECM) accumulation, the expression of oxidative stress response proteins (catalase, superoxide dismutase 2, NADPH oxidase 4, and thioredoxin reductase 1), pro-inflammatory markers (TNF-α and Cyclooxygenase-2(COX-2), and infiltration of neutrophils and macrophages were significantly ameliorated in the UUO mice. Interestingly, the pyroptosis-related proteins (NLRP3/Caspase-1/GSDMD/IL-1β) and cell apoptotic death were also conspicuously relieved after treatment with PHI. Furthermore, PHI administration significantly attenuated the ATP/LPS-induced NF-κB/NLRP3/Caspase-1/GSDMD pyroptosis signal pathway in NRK52E cells. Conclusions: These results demonstrate, for the first time, that PHI treatment ameliorates inflammation and the related pyroptosis via inhibitory regulation of the NF-κB/NLRP3/Caspase-1/GSDMD axis, leading to attenuated renal fibrosis and progressive CKD in UUO mice and in vitro. Our findings suggest that PHI could be a nutraceutical candidate for attenuating CKD progression. Full article

Ruthenocene (Rc) and its derivatives form a structurally versatile class of metallocenes with unique and multifunctional applicability. This review presents a detailed analysis of Rc chemistry including the structural comparison with ferrocene, its redox behavior, and substituent effects. We also discuss its applications in sensing, energy storage, photochemistry, and biomedicine. Rc exhibits unique conformational and adaptive electronic properties based on one and two-electron oxidation processes. Electrochemical investigations of Rc to date indicate that its redox behavior is strongly dependent on the electrolyte system, exhibiting quasi-Nernstian characteristics, the formation of stabilized dimeric species [Rc₂]²⁺, and interconversion among Ru(II), Ru(III), and Ru(IV) oxidation states. Rc-based systems exhibit superior performance as redox mediators and labels in electrochemical sensing systems in terms of electron-transfer kinetics, signal amplification, and surface immobilization. In the field of energy storage, Rc decreases the charging overpotential and increases the cycle life of Li-O₂ batteries. Rc further acts as a photoinitiator via charge-transfer-to-solvent and efficient photoinduced electron transfer in metalloporphyrin and fullerene dyads. In biomedical research, Rc derivatives as well as bioconjugates possess promising anticancer activities, displaying reactive oxygen species generation, topoisomerase inhibition, thioredoxin reductase inhibition, receptor-mediated uptake, and target peptide conjugation. Given its flexible ligand design, electrolyte driven redox behaviors, and antiproliferative properties, Rc exhibits a very adaptive molecular scaffold for next generation electrochemical technologies as well as metallodrug design. Full article

Oxidative stress contributes to reproductive disorders, immune dysfunction, and reduced productivity in livestock during periods of high metabolic demand and environmental challenge. Selenium supports antioxidant defense systems because it is incorporated as selenocysteine into selenoproteins, including glutathione peroxidases and thioredoxin reductases that detoxify peroxides and sustain redox balance. The review summarizes selenium occurrence and chemical forms in feeds, as well as its absorption, transportation, and storage. The review also outlines the major features of selenoprotein biosynthesis and its prioritized allocation, with an emphasis on cattle, pigs, sheep, and goats. Evidence from multiple sources indicates that selenium status and supplementation interacts with antioxidant capacity, immune competence, thyroid hormone metabolism, reproductive performance, and the transfer of selenium to milk and offspring. In ruminants, rumen microbial transformations can reduce the bioavailability of inorganic selenium salts, and organic sources, such as selenium-enriched yeast, hydroxy-selenomethionine, and selenitetriglycerides, often increase blood and milk selenium more effectively. In pigs, organic selenium is commonly associated with enhanced antioxidant and immune indices in sows and piglets during late gestation, lactation, and weaning, whereas effects on growth performance are inconsistent. The review emphasizes the narrow margin between adequacy and excess and outlines practical considerations for supplementation and monitoring, alongside research needs for emerging selenium forms and functional biomarkers. Full article

Selenium (Se) is a trace element with a narrow margin between beneficial effects and stress from toxic effects. The determinants of the transition from selenium adequacy to toxicity remain unknown. Moreover, the roles of selenoproteins and other adaptive responses also remain unclear. The effects of dynamic and localized redox fluctuations on survival and neurodegeneration also require further investigation. To better understand the underlying mechanisms, several studies utilized the nematode Caenorhabditis elegans (C. elegans) as a model. This review systematically addresses pivotal mechanistic controversies. Thioredoxin reductase-1 (TRXR-1) is the only protein in a small amount of the selenoproteome, and it also has a fully conserved selenocysteine insertion mechanism. Moreover, this systematic review also incorporates the current understanding of the molecular factors that determine selenium homeostasis, ranging from neurotoxicological diseases to biosynthetic circumstances. TRXR-1 supports health benefits such as enhance lipid metabolism, longevity, and stress response. During acute selenium toxicity, TRXR-1 is not needed for survival. Instead, cells defend against adverse effects by using the HIF-1 pathway. Reactive oxygen species (ROS) and hydrogen sulfide (H₂S) inhibit the prolyl hydroxylase EGL-9 in high-selenium conditions, stabilizing HIF-1 and initiating a transcriptional detoxification process independent of the selenoprotein mechanism. Finally, this review also discuss selective neurotoxicity, a condition in which degeneration that occurs solely in cholinergic ventral cord motor neurons plays a distinctive and precarious role among trace elements. 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

Glutathionyl-hemoglobin (HbSSG) reversibly forms under oxidative stress in erythrocytes, where it constitutes the main redox buffer, in a dynamic equilibrium with the thiol (GSH) and disulfide (GSSG) forms of glutathione, that quickly revert to the reduced thiols when oxidative pressure is relieved. Under acute challenge, the “oxidized” GSH pool distributes between GSSG and HbSSG. Recalculation with electrochemical metrics based on redox potentials of the GSSG/GSH and HbSSG/HbSH pairs, plotted in their phase space, improves the understanding of the competing reduction processes. The first process is reduction of the GSSG pool, while, later, HbSSG reduction occurs as a two-step process. HbSSG accumulation in chronic oxidative stress follows an impairment of these steps. In 30 strong smokers, homogeneous levels of HbSSG are in the range of 2.4–11.7% (E_h −120–−95 mV), but the E_h of the GSSG/GSH redox pair is wider (−160–−240 mV), suggesting that HbSSG accumulation does not depend on GSH availability but on enzyme activity impaired by exogenous and endogenous electrophiles. As hinted by HbSSG measurements, one such species is the dehydro-alanine analog of GSH, produced both from butadiene in exposed petrochemical workers and from the drug busulfan in a treated patient. Inactivation of the low-copy recycling enzymes can thus explain the increase of HbSSG. Full article

Pancreatic ductal adenocarcinoma (PDAC) shows substantial heterogeneity in cysteine dependence and ferroptosis sensitivity. We identify two PDAC subtypes distinguished by EMT status: mesenchymal-like cells are highly cysteine-dependent and rapidly undergo ferroptosis upon cystine deprivation or system xc⁻ inhibition, whereas epithelial-type cells are ferroptosis-resistant. Selenium supplementation protects cells from erastin-induced ferroptosis, and this protection persists even when intracellular glutathione (GSH) is depleted, supporting an additional GPX4-independent protective mechanism. Sepp1 knockdown does not alter sensitivity, indicating that selenium’s protective effect is independent of Sepp1. Instead, epithelial-type cells rely on both cytosolic and mitochondrial thioredoxin reductases (TrxR1 and TrxR2) to maintain ferroptosis resistance. Chemical inhibition of thioredoxin reductases abolishes selenium-mediated protection and sensitizes epithelial cells to ferroptosis inducers, while dual genetic suppression of TrxR1 and TrxR2 similarly restores ferroptosis sensitivity. These findings uncover a selenium–thioredoxin redox axis that functions independently of GPX4 and contributes ferroptosis resistance in epithelial-type PDAC cells. Co-targeting cysteine metabolism and thioredoxin reductases may therefore represent a rational strategy to overcome ferroptosis resistance in some PDAC subtypes. Full article

Encouraged by the promising anticancer activity of a iodidogold(I)-N-heterocyclic carbene (NHC) complex with a 1,3-diethyl-4-anisyl-5-(4-chlorophenyl)imidazol-2-ylidene ligand system, a series of new gold(I), gold(III) and platinum(II) complexes coordinated to this ligand system were designed, prepared, and characterized using NMR spectroscopy and mass spectrometry methods. A preliminary anticancer screening of the complexes using four esophageal adenocarcinoma (EAC) cell lines showed promising activities for the cationic triphenylphosphino-NHC-gold(I) and bis-NHC-gold(I) complexes, accompanied by strong antiproliferative, colony-, and spheroid-forming inhibitory effects. The compounds were relatively less toxic to the normal esophageal cell line Het-1A and the monocyte cell line THP-1. Moreover, these compounds induced caspase 3/7 activity and downregulated anti-apoptotic proteins (Bcl-XL, Bcl-2, and Mcl-1) in EAC cells. Further, the cell cycle promoter cyclin D1 was suppressed by these NHC-gold(I) complexes. Finally, we observed strong reactive oxygen species (ROS) induction in EAC cells with NHC-gold(I) complexes 8 and 11. 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

Auranofin, a gold(I)-based compound initially developed for the treatment of rheumatoid arthritis, has emerged as a promising anticancer agent with a multimodal mechanism of action. This review comprehensively examines the therapeutic potential of auranofin in oncology focusing on its ability to synergize with conventional and emerging cancer treatments. Here, we discuss the unique pharmacological properties of auranofin, including thioredoxin reductase inhibition, reactive oxygen species induction, and modulation of key apoptotic pathways. Moreover, this article highlights new recent evidence on its ability to synergize with other cancer treatments such as chemotherapy, immunotherapy, and targeted therapies. Particular emphasis is placed on the role of auranofin in overcoming drug resistance and its potential as an adjuvant in precision medicine. By analyzing both preclinical and clinical data, this review provides critical insights into the repositioning of auranofin as a versatile component in contemporary cancer treatment paradigms, while addressing current challenges and future directions for gold-based therapeutics in oncology. 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

Background: Gold (Au) complexes have emerged as promising anticancer candidates due to their distinct coordination chemistry and ability to modulate thiol-dependent and redox-regulated cellular pathways, particularly thioredoxin reductase (TrxR). In recent years, structurally diverse Au(I) and Au(III) complexes have been reported with potent in vitro anticancer activity; however, cross-study comparability and design principles remain unclear. Aim: This systematic review critically evaluates anticancer Au(I/III) complexes reported since 2016, with the specific aim of identifying how oxidation state, coordination geometry, and ligand class influence in vitro potency, selectivity, and translational potential. Methods: A PRISMA-guided literature search was performed in Scopus, Web of Science, PubMed, and ScienceDirect for studies published between January 2016 and March 2025. Two independent reviewers screened titles/abstracts and full texts according to predefined inclusion criteria. Only original studies reporting anticancer activity of structurally characterized Au(I/III) complexes in human cancer models were included. After the removal of duplicates, 1100 records were screened at the title and abstract level. Of these, 240 articles were assessed in full text for eligibility. Ultimately, 128 studies reporting anticancer activity of structurally characterized Au(I/III) complexes met the inclusion criteria and were included in the qualitative synthesis. Biological potency data were harmonized to μM units where applicable, and results were synthesized qualitatively due to heterogeneity in experimental design. Results: A total of 128 studies met the inclusion criteria. Au(I) complexes—particularly phosphine- and N-heterocyclic carbene (NHC)-based compounds—consistently showed sub-micromolar cytotoxicity in TrxR-dependent cancer cell lines, whereas Au(III) complexes displayed greater structural diversity but variable stability and redox behavior. In vivo efficacy was reported for a limited subset of compounds and was frequently constrained by solubility, systemic toxicity, or metabolic instability. Conclusions: The available evidence indicates that anticancer activity of gold complexes is strongly dependent on oxidation state, ligand environment, and redox stability. While Au(I) scaffolds show more reproducible in vitro potency, successful translation to in vivo models remains limited. This review defines structure–activity and structure–liability relationships that can guide the rational design of next-generation gold-based anticancer agents. Full article