Search Results (282)

Aging is a complex, universal biological process characterized by the progressive and irreversible decline of physiological functions across multiple organ systems. This deterioration is primarily driven by cumulative cellular damage arising from both intrinsic and extrinsic stressors. The free radical theory of aging, first proposed by Denham Harman in 1956, highlights the role of reactive oxygen species (ROS), byproducts of normal metabolism, in driving oxidative stress and age-related degeneration. Emerging evidence emphasizes the importance of redox imbalance in the onset of neurodegenerative diseases and aging. Among the critical cellular defenses against oxidative stress are sulfur-containing amino acids, namely cysteine (Cys) and selenocysteine (Sec). Cysteine serves as a precursor for glutathione (GSH), a central intracellular antioxidant, while selenocysteine is incorporated into key antioxidant enzymes such as glutathione peroxidases (GPx) and thioredoxin reductases (TrxR). These molecules play pivotal roles in neutralizing ROS and maintaining redox homeostasis. This review aims to provide an updated and critical overview of the role of thiol-containing amino acids, specifically cysteine and selenocysteine, in the regulation of redox homeostasis during aging. Full article

Oxidative stress, mitochondrial dysfunction, and inflammatory responses cause acute liver failure in most cases of acetaminophen (APAP) overdose. Tamarixetin (Trx), an antioxidant and anti-inflammatory flavonoid, has not yet been studied in models of APAP-induced hepatotoxicity. Trx was tested for its protective effects on APAP-induced liver injury in rats using biochemical, histopathological, and oxidative stress parameters. Three groups of 30 male Wistar rats were randomly assigned to the following groups: control, APAP + Saline, and APAP + Trx (3 mg/kg/day, intraperitoneally for 3 days). A single 300 mg/kg intraperitoneal APAP dose caused hepatotoxicity. ALT, MDA, GSH, HSP-70, and thioredoxin were measured in blood and liver tissues. Liver sections were histopathologically examined. APAP depleted hepatic GSH and Trx and increased serum ALT and MDA. Trx treatment significantly reduced ALT (201.2 → 105.1 U/L), MDA (5.5 → 3.4 nmol/mg), and the percentage of histologically damaged hepatocytes (58.5% → 9.5%), while restoring GSH and thioredoxin levels. Notably, HSP-70 expression exceeded that of APAP and control levels, suggesting the modulation of the stress response. The Trx group showed significant hepatoprotection histologically. Trx reduces APAP-induced hepatic damage, likely through antioxidant and anti-inflammatory mechanisms. These findings suggest that Trx may be a natural hepatoprotectant, warranting clinical trials. Full article

Hioredoxins are small proteins crucial for maintaining cellular redox balance and are involved in various biological processes, including growth, photosynthesis, development, and stress responses. This study aims to conduct a genome-wide analysis of the typical Thioredoxin (TRX) gene family in hexaploid Camellia oleifera and explore the role of the CoTRX25 gene in flowering. Through bioinformatics approaches, we identified 27 typical TRX gene family members in the C. oleifera genome and analyzed their phylogenetic relationships, gene structures, conserved motifs, and chromosomal distributions. Transcriptomic analysis across different tissues was performed to determine the expression patterns of these genes. Additionally, the CoTRX25 gene was cloned and heterologously overexpressed in Arabidopsis thaliana to investigate its functional role in flowering. The 27 TRX genes were mainly located on 11 chromosomes, with multiple gene duplication events identified, indicating that gene duplication has played a significant role in the expansion of the TRX family. Transcriptomic analysis revealed that most typical TRX genes are highly expressed in embryos, suggesting their potential importance in seed development. Overexpression of CoTRX25 in A. thaliana led to delayed flowering, implying that this gene may be involved in flowering regulation. This study provides a theoretical basis for understanding the functions of typical TRX genes in C. oleifera growth and development, particularly highlighting the role of CoTRX25 in flowering regulation. Full article

Background: Thioredoxin-interacting protein (TXNIP) is a major inhibitor of the thioredoxin (TRX) antioxidant system and an important player in the development and aggravation of intracellular oxidative stress. Although first recognized as a metabolic regulator, recent studies have identified the multifaceted role of this protein in other molecular pathways involving inflammation, apoptosis, and glucose metabolism. Methods: This review aims to highlight the importance of TXNIP in diabetes-related pathophysiology and explore the existing evidence regarding TXNIP’s role in GDM-associated pathogenetic mechanisms, revealing common regulatory pathways. Results: Among other complex diseases, TXNIP has been found upregulated in diabetic pancreatic beta cells, thus contributing to diabetes pathogenesis and its related complications. In addition, depletion of TXNIP has been shown to decrease the negative consequences of excessive stress in various cellular systems and diseases, pointing towards a potential therapeutic target. In line with these findings, TXNIP has been investigated in the pathogenesis of Gestational Diabetes Mellitus (GDM), a common pregnancy complication affecting the mother and the neonate. Overexpression of TXNIP has been found in GDM placentas or trophoblast cell lines mimicking GDM conditions and has been associated with key dysregulated mechanisms of GDM pathophysiology, like oxidative stress, inflammation, apoptosis, impaired autophagy, altered trophoblast behavior, and placental morphology. Interestingly, TXNIP has been found upregulated in GDM maternal serum and downregulated in umbilical cord blood, indicating potential compensatory protective mechanisms to GDM-related oxidative stress. Conclusions: Due to its contribution to the regulation of critical cellular processes such as inflammation, metabolism, and apoptosis, TXNIP finds its place in the pathophysiology of gestational diabetes through a currently limited number of scientific reports. Full article

The increasing resistance of Trichomonas vaginalis to the only approved chemical family of drugs for treatment, the 5-nitroimidazoles, has prompted the exploration of new therapeutic agents against this prevalent non-viral sexually transmitted infection. Natural products have emerged as a significant source of novel treatments for trichomoniasis. The aim of this study was to evaluate the anti-T. vaginalis activity of citral (3,7-dimethyl-2,6-octadienal), the main constituent of the essential oil of Cymbopogon species, commonly known as lemongrass. Our findings indicate that citral exhibits a minimum inhibitory concentration (MIC) of 100 μM, effectively inhibiting the growth of T. vaginalis trophozoites within 12 h of exposure, and a 50% inhibitory concentration (IC₅₀) of approximately 40 μM after 24 h. Furthermore, the evaluation of nitric oxide (NO) levels suggests that citral possesses antioxidant properties. Molecular docking studies reveal a weak interaction with three parasite proteins: thioredoxin reductase (TvTrxR), purine nucleoside phosphorylase (TvPNP), and methionine gamma lyase (TvMGL). The present study highlights the potential of citral as a candidate for the development of no-nitroimidazole drugs, offering new avenues for trichomoniasis treatment and underscoring the importance of further investigation into citral’s mechanism of action. Full article

Background: The thioredoxin system (TrxS) is crucial for maintaining redox balance by regulating cellular thiol levels and is involved in various biological processes, including cancer progression. Thioredoxin reductase (TrxR), a key component of TrxS, reduces oxidized thioredoxin (Trx) using NADPH. This study investigates the inhibitory effects of 2-bromo-2-nitro-1,3-propanediol (Bronopol, BP), a preservative, on TrxR activity and its impact on cellular thiols and cell viability. Methods: Purified recombinant TrxR and noncancer and cancer cells were treated with different concentrations of BP and TrxR activity measured. BP-treated cells were examined for effects of BP on total cellular thiol level and GSH/GSSG ratio. Results: BP effectively inhibited TrxR in a dose-dependent manner, an effect that was reversible with dithiothreitol (DTT). BP treatment significantly reduced total thiol levels, decreased the GSH/GSSG ratio, and increased reactive oxygen species (ROS) in cells. Additionally, BP decreased cell viability and induced apoptosis, as indicated by morphological changes and increased c-fos mRNA expression. Conclusions: These findings highlight BP’s potential as a TrxR inhibitor and its cytotoxicity toward both noncancer and cancer cells. The observed effects—TrxR inhibition, thiol oxidation, GSH/GSSG imbalance, and ROS accumulation—may underlie BP’s cytotoxicity. Further research is needed to explore the precise molecular mechanisms by which BP exerts these effects. Full article

Cataracts, the leading cause of blindness globally, are caused by oxidative stress and inflammation, which disrupt lens transparency due to increased accumulation of reactive oxygen species (ROS) as well as protein and DNA damage during aging. Using in vitro, ex vivo, and in vivo models, we determined the protective efficacy of N-acetylcysteine amide (NACA) against oxidative stress-induced and aging-induced cataractogenesis. We found that lens epithelial cells exposed to the oxidative stress inducers hydrogen peroxide (H₂O₂) or tert-butyl hydroperoxide showed significant ROS accumulation and reduced cellular viability. These effects were inhibited by NACA via the suppression of ROS and thioredoxin-interacting protein (Txnip) expression, a regulator of oxidative stress-related cellular damage and inflammation. In ex vivo lens experiments, NACA significantly reduced H₂O₂-induced lens opacity and preserved lens integrity. Similarly to NACA-treated lenses ex vivo, the integrity and opacity of aged mouse lenses, when topically instilled with NACA, were preserved and reduced, respectively, and are directly related to reduced Txnip and increased thioredoxin (Trx) expression levels. Overall, our findings demonstrated the protective ability of NACA to abate aberrant redox-active pathways, particularly the ROS/TRX/TXNIP axis, thereby preventing cataractogenesis and preserving eye lens integrity and ultimately impeding aging-related cataracts. Full article

Reactive oxygen species (ROS) play a key role in cancer progression and antitumor therapy. Glioblastoma is a highly heterogeneous tumor with different cell populations exhibiting various redox statuses. Elevated ROS levels in cancer cells promote tumor growth and simultaneously make them more sensitive to anticancer drugs, but further elevation leads to cell death and apoptosis. Meanwhile, various subsets of tumor cells, such a glioblastoma stem cells (GSC) or the cells in tumor microenvironment (TME), demonstrate adaptive mechanisms to excessive ROS production by developing effective antioxidant systems such as glutathione- and thioredoxin-dependent. GSCs demonstrate higher chemoresistance and lower ROS levels than other glioma cells, while TME cells create a pro-oxidative environment and have immunosuppressive effects. Both subpopulations have become an attractive target for developing therapies. Increased expression of thioredoxin reductase (TrxR) is often associated with tumor progression and poor patient survival. Various TrxR inhibitors have been investigated as potential anticancer therapies, including nitrosoureas, flavonoids and metallic complexes. Gold derivatives are irreversible inhibitors of TrxR. Among them, auranofin (AF), a selective TrxR inhibitor, has proven its effectiveness as a drug for the treatment of rheumatoid arthritis and its efficacy as an anticancer agent has been demonstrated in preclinical studies in vitro and in vivo. However, further clinical application of AF could be challenging due to the low solubility and insufficient delivery to glioblastoma. Different delivery strategies for hydrophobic drugs could be used to increase the concentration of AF in the brain. Combining different therapeutic approaches that affect the redox status of various glioma cell populations could become a new strategy for treating brain tumor diseases. Full article

Thioredoxin-1 (Trx-1) is an important redox protein found in almost all prokaryotic and eukaryotic cells, which has a highly conserved active site sequence: Trp-Cys-Gly-Pro-Cys. To investigate whether the Trp31 residue is essential for the antioxidant activity of human Trx-1 (hTrx-1), we mutated Trx-1 by replacing Trp31 with Ala31 (31Ala) or deleting Trp31 residue (31Del). We introduced 31Ala and 31Del mutations into prokaryotic cells for hTrx-1 protein expression, protein purification and evaluation of antioxidant activity. The results showed that neither the replacing mutation to Ala31 nor the deletion of Trp31 residue affected the efficient expression of hTrx-1 protein in prokaryotic cells, indicating that neither form of Trp31 mutation would disrupt the folded structure of the Trx-1 protein. Comparison of the antioxidant activity of purified hTrx-1 proteins of wild-type, 31Ala and 31Del forms revealed that both mutant forms significantly decreased the antioxidant capacity of hTrx-1. Further investigations on eukaryotic cells showed that H₂O₂ treatment caused massive cell death in EA.Hy926 human endothelial cells with 31Ala and 31Del mutations compared to wild-type cells, which was associated with increased ROS production and downregulation of antioxidant Nrf2 and HO-1 expression in the mutant cells. These results suggested that mutations in the Trp31 residue of hTrx-1 remarkably disrupted cellular redox defense against oxidative stress. The antioxidant activity of hTrx-1 relies on the thiol–disulfide exchange reaction, in which the content of thiol groups forming disulfide bonds in hTrx-1 is critical. We found that the content of free thiol groups specifically participating in disulfide bond formation was significantly lower in Trp31 mutant hTrx-1 than in wild-type hTrx-1; that was speculated to affect the formation of disulfide bonds between Cys32 and Cys35 by virtual analysis, thus abolishing the antioxidant activity of hTrx-1 in cleaving oxidized groups and defending against oxidative stress. The present study provided valuable insights towards understanding the importance of Trp31 residue of hTrx-1 in maintaining the correct conformation of the Trx fold structure, the antioxidant functionality of hTrx-1 and the cellular redox defense capability against oxidative stress. Full article

Endothelial dysfunction (ED) is characterized by an imbalance between vasodilatory and vasoconstrictive factors, leading to impaired vascular tone, thrombosis, and inflammation. These processes are critical in the development of cardiovascular diseases (CVDs) such as atherosclerosis, hypertension and ischemia/reperfusion injury (IRI). Reduced nitric oxide (NO) production and increased oxidative stress are key contributors to ED. Aging further exacerbates ED through mitochondrial dysfunction and increased oxidative/nitrosative stress, heightening CVD risk. Antioxidant systems like superoxide-dismutase (SOD), glutathione-peroxidase (GPx), and thioredoxin/thioredoxin-reductase (Trx/TXNRD) pathways protect against oxidative stress. However, their reduced activity promotes ED, atherosclerosis, and vulnerability to IRI. Metabolic syndrome, comprising insulin resistance, obesity, and hypertension, is often accompanied by ED. Specifically, hyperglycemia worsens endothelial damage by promoting oxidative stress and inflammation. Obesity leads to chronic inflammation and changes in perivascular adipose tissue, while hypertension is associated with an increase in oxidative stress. The NLRP3 inflammasome plays a significant role in ED, being triggered by factors such as reactive oxygen and nitrogen species, ischemia, and high glucose, which contribute to inflammation, endothelial injury, and exacerbation of IRI. Treatments, such as N-acetyl-L-cysteine, SGLT2 or NLRP3 inhibitors, show promise in improving endothelial function. Yet the complexity of ED suggests that multi-targeted therapies addressing oxidative stress, inflammation, and metabolic disturbances are essential for managing CVDs associated with metabolic syndrome. Full article

The thioredoxin (Trx) system is one of the most significant systems in living organisms as it regulates cellular redox reactions and plays a pivotal protective role within the cell by promoting redox homeostasis. Trx and thioredoxin reductase (TrxR) are the core oxidoreductases of the Trx system. In this study, the novel full-length cDNAs of LvTrx2 and LvTrxR were cloned from Litopenaeus vannamei. The ORFs of LvTrx2 and LvTrxR were 453 bp and 1785 bp, encoding polypeptides consisting of 150 and 596 amino acids. Sequence alignment analysis revealed that the amino acid sequence of LvTrx2 shared a high degree of identity (93%) with that of Penaeus chinensis, while in LvTrxR, it exhibited a similarity level of 95% with previously submitted Penaeus chinensis and Penaeus monodon sequences. Regarding tissue-specific expression patterns, LvTrx2 showed its highest expression levels in hepatopancreas and gill. For LvTrxR, the highest expression was observed in gill followed by hepatopancreas and intestine. During exposure to ammonia-N, there was a significant upregulation in the relative mRNA levels of LvTrx2 and LvTrxR in hepatopancreas and gill, with the peak values occurring at 24 h or 48 h of exposure. After LPS injection, the LvTrx2 and LvTrxR transcripts in hepatopancreas and gill had different upregulated levels. These findings suggest that LvTrx2 and LvTrxR play pivotal roles in enhancing stress resistance and bolstering antibacterial defense mechanisms in L. vannamei. To explore the roles, LvTrx2 expression was knocked down in vivo to verify the defense mechanism against 4-NP stress. LvTrx2 silencing in 4-NP-challenged shrimp could significantly induce the gene expression of antioxidant-related genes (except for LvTrxR) and aggravate the oxidative damage of lipids. This study suggests that the Trx system is involved in regulating the antioxidant processes, and LvTrx2 and LvTrxR play a vital role in defense responses against environmental stress. Full article

(1) Context: Cancer is still a major problem worldwide, and traditional therapies like radiation and chemotherapy often fail to alleviate symptoms because of side effects, systemic toxicity, and mechanisms of resistance. Beneficial anticancer effects that spare healthy tissues are made possible by the distinctive redox characteristics of noble metal complexes, especially those containing palladium, gold, silver, and platinum. (2) Methods: The redox processes, molecular targets, and therapeutic uses of noble metal complexes in cancer have been the subject of much study over the last 20 years; novel approaches to ligand design, functionalization of nanoparticles, and tumor-specific drug delivery systems are highlighted. (3) Results: Recent developments include Pt(IV) prodrugs and terpyridine-modified Pt complexes for enhanced selectivity and decreased toxicity; platinum complexes, like cisplatin, trigger reactive oxygen species (ROS) production and DNA damage. Functionalized gold nanoparticles (AuNPs) improve targeted delivery and theranostic capabilities, while gold complexes, particularly Au(I) and Au(III), inhibit redox-sensitive processes such as thioredoxin reductase (TrxR). (4) Conclusions: Ag(I)-based compounds and nanoparticles (AgNPs) induce DNA damage and mitochondrial dysfunction by taking advantage of oxidative stress. As redox-based anticancer medicines, noble metal complexes have the ability to transform by taking advantage of certain biochemical features to treat cancer more effectively and selectively. Full article

Hydrogen peroxide (H₂O₂) plays a crucial role in cell signaling in response to physiological and environmental perturbations. H₂O₂ can oxidize typical 2-Cys peroxiredoxin (PRX) first into a sulfenic acid, which resolves into a disulfide that can be reduced by thioredoxin (TRX)/TRX reductase (TR). At high levels, H₂O₂ can also hyperoxidize sulfenylated PRX into a sulfinic acid that can be reduced by sulfiredoxin (SRX). Therefore, PRX, TRX, TR, and SRX (abbreviated as PTRS system here) constitute the coupled sulfenylation and sulfinylation cycle (CSSC), where certain oxidized PRX and TRX forms also function as redox signaling intermediates. Earlier studies have revealed that the PTRS system is capable of rich signaling dynamics, including linearity, ultrasensitivity/switch-like response, nonmonotonicity, circadian oscillation, and possibly, bistability. However, the origins of ultrasensitivity, which is fundamentally required for redox signal amplification, have not been adequately characterized, and their roles in enabling complex nonlinear dynamics of the PTRS system remain to be determined. Through in-depth mathematical modeling analyses, here we revealed multiple sources of ultrasensitivity that are intrinsic to the CSSC, including zero-order kinetic cycles, multistep H₂O₂ signaling, and a mechanism arising from diminished H₂O₂ removal at high PRX hyperoxidation state. The CSSC, structurally a positive feedback loop, is capable of bistability under certain parameter conditions, which requires embedding multiple sources of ultrasensitivity identified. Forming a negative feedback loop with cytosolic SRX as previously observed in energetically active cells, the mitochondrial PTRS system (where PRX3 is expressed) can produce sustained circadian oscillations through supercritical Hopf bifurcations. In conclusion, our study provided novel quantitative insights into the dynamical complexity of the PTRS system and improved appreciation of intracellular redox signaling. Full article

Reactive oxygen species (ROS), as signaling molecules, play a crucial role in the plant immune response. However, the mechanism(s) by which viruses affect ROS metabolism remain largely unexplored. Here, we found that wheat yellow mosaic virus (WYMV)-encoded P1 is a pathogenic protein. Transcriptomic and proteomic integrative analyses were performed on WYMV-infected overexpressing-P1 wheat and wild-type plants. A total of 9245 differentially expressed genes (DEGs) and 1383 differentially expressed proteins (DEPs) were identified in the transcriptome and proteome, respectively. At their intersection, 373 DEGs/Ps were identified. Enrichment analysis revealed that the expression of genes related to the ROS metabolism pathway in overexpressed P1 transgenic wheat (OE-P1) plants significantly increased during WYMV infection. We screened peroxidase (TaPOD) and thioredoxin reductase (TaTrxR) as they showed the most significant differences in expression. The silencing of TaPOD and TaTrxR revealed that they positively regulate WYMV infection by reducing ROS accumulation. Furthermore, hydrogen peroxide treatment induced WYMV resistance in wild-type wheat plants and OE-P1 transgenic plants. This study provides a theoretical basis for the role of P1 in plant viral infection. Full article

Traumatic brain injury (TBI) results from external mechanical forces exerted on the brain, triggering secondary injuries due to cellular excitotoxicity. A key indicator of damage is mitochondrial dysfunction, which is associated with elevated free radicals and disrupted redox balance following TBI. However, the temporal changes in mitochondrial redox homeostasis after penetrating TBI (PTBI) have not been thoroughly examined. This study aimed to investigate redox alterations from 30 min to two-weeks post-injury in adult male Sprague Dawley rats that experienced either PTBI or a Sham craniectomy. Redox parameters were measured at several points: 30 min, 3 h, 6 h, 24 h, 3 d, 7 d, and 14 d post-injury. Mitochondrial samples from the injury core and perilesional areas exhibited significant elevations in protein modifications including 3-nitrotyrosine (3-NT) and protein carbonyl (PC) adducts (14–53%, vs. Sham). In parallel, antioxidants such as glutathione, NADPH, peroxiredoxin-3 (PRX-3), thioredoxin-2 (TRX-2), and superoxide dismutase 2 (SOD2) were significantly depleted (20–80%, vs. Sham). In contrast, catalase (CAT) expression showed a significant increase (45–75%, vs. Sham). These findings indicate a notable imbalance in redox parameters over the two-week post-PTBI period suggesting that the therapeutic window to employ antioxidant therapy extends well beyond 24 h post-TBI. Full article