Search Results (717)

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

Background: Varicocele is a common condition involving the dilation of veins in the scrotum, often linked to male infertility and testicular dysfunction. This study aimed to elucidate the molecular effects of successful varicocele treatment on sperm proteomes following percutaneous sclero-embolization. Methods: High-resolution tandem mass spectrometry was performed for proteomic profiling of pooled sperm lysates from five patients exhibiting improved semen parameters before and after (3 and 6 months) varicocele sclero-embolization. Data were validated by Western blot analysis. Results: Seven proteins were found exclusively in varicocele patients before surgery—such as stathmin, IFT20, selenide, and ADAM21—linked to inflammation and oxidative stress. After sclero-embolization, 55 new proteins emerged, including antioxidant enzymes like selenoprotein P and GPX3. Thioredoxin (TXN) and peroxiredoxin (PRDX3) were upregulated, indicating restoration of key antioxidant pathways. Additionally, the downregulation of some histones and the autophagy-related protein ATG9A suggests a shift toward an improved chromatin organization and a healthier cellular environment post-treatment. Conclusions: Varicocele treatment that improves sperm quality and fertility parameters leads to significant proteome modulation. These changes include reduced oxidative stress and broadly restored sperm maturation. Despite the limited patient cohort analyzed, these preliminary findings provide valuable insights into how varicocele treatment might enhance male fertility and suggest potential biomarkers for improved male infertility treatment strategies. Full article

The regulation of oxidative stress is an effective strategy for treating cancers. Therapeutic strategies for modulating an undesirable redox balance against cancers have included the enhancement of oxidative components, reducing the action of antioxidant systems, and the combined application of radiation and redox-modulating drugs. A precise understanding of redox regulation is required to treat different kinds of cancer. This review focuses on the redox regulation and oxidative stress defense systems of lung cancers. Thus, we highlighted several enzymatic antioxidant components, such as superoxide dismutase, catalase, heme oxygenase-1, peroxiredoxin, glutaredoxin, thioredoxin, thioredoxin reductase, glutathione peroxidase, and antioxidant components, including glutathione, nuclear factor erythroid 2–related factor 2, 8-oxo-7,8-dihydro-2′-deoxyguanosine, and mitochondrial citrate carrier SLC25A1, based on PubMed and Scopus-indexed literature. Understanding the oxidative stress defense system in lung cancer would be beneficial for developing and expanding therapeutic strategies, such as drug development, drug design, and advanced delivery platforms. 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

CD38, a nicotinamide adenine dinucleotide (NAD⁺) glycohydrolase, increases in old murine macrophages after infection compared to young controls. We aimed to determine whether the increase in CD38 in old murine macrophages after infection is directly associated with enhanced inflammation induced by the oral pathogens Aggregatibacter actinomycetemcomitans (Aa) or Porphyromonas gingivalis (Pg) when compared to young controls. Additionally, we determined the effects of a specific CD38 inhibitor (78c) on CD38, NAD⁺, interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α expressions, and anti-oxidative responses in old murine macrophages induced by oral pathogens. Old and young murine macrophages were either uninfected or infected with the oral pathogens Aa or Pg for 1 to 24 h. Protein levels of CD38 and protein kinases, including nuclear factor kappa-B (NF-κB), phosphoinositide 3-kinase (PI3K), and mitogen-activated protein kinases (MAPKs), NAD⁺, and inflammatory cytokine (IL-1β, IL-6, TNF-α) levels were evaluated. Additionally, old murine macrophages were treated with a vehicle or a CD38 inhibitor (78c) and cells were either uninfected or infected with Aa or Pg. CD38, NAD⁺, cytokine (IL-1β, IL-6, TNF-α) levels, reactive oxygen species (ROS), NAPDH oxidase 1 (Nox1), and anti-oxidative enzymes, including superoxide dismutase1 (Sod1), glutathione peroxidase 4 (Gpx4), Peroxiredoxin 1 (Prdx1), thioredoxin reductase 1 (Txnrd1), and catalase (Cat), were evaluated. The results showed that old murine macrophages significantly enhanced CD38 and reduced NAD⁺ levels 24 h after Aa or Pg infection compared to young controls. This enhanced CD38 in old murine macrophages was not directly correlated with the activation of protein kinases (NF-κB, PI3K, and MAPKs), nor the (IL-1β, IL-6, TNF-α) levels in macrophages. The inhibition of CD38 by 78c reduced CD38, enhanced NAD⁺ levels, attenuated IL-1β, IL-6 and TNF-α pro-inflammatory cytokine levels, reduced ROS and Nox1 expressions, and enhanced expressions of Sod1, Gpx4, Prdx1, Txnrd1, and Cat in old murine macrophages infected with Aa or Pg. These results suggest that the inhibition of CD38 by 78c is a promising therapeutic strategy to treat aging-associated periodontitis. Full article

Background: Dithiolopyrrolones (DTPs), such as holomycin and thiolutin, exhibit potent antibacterial activities. DTPs contain a disulfide within a unique bicyclic scaffold, which may chelate metal ions and disrupt metal-dependent cellular processes once the disulfide is reductively transformed to thiols. However, the contribution of the intrinsic redox mechanism of DTPs to their antibacterial activity remains unclear. Herein we used pyrroloformamide (Pyf) A, a DTP with a unique formyl substituent, as a prototype to study the antibacterial potential and mechanism against ESKAPE pathogens, in particular carbapenem-resistant Klebsiella pneumoniae (CRKP). Methods: The antibacterial and anti-biofilm activities of Pyf A were mainly assessed against clinical CRKP isolates. Propidium iodide staining, scanning electron microscopy, glutathione (GSH) quantification, and reactive oxygen species (ROS) analysis were utilized to infer its anti-CRKP mechanism. The synergistic antibacterial effects of Pyf A and AgNO₃ were evaluated through checkerboard and time-kill assays, as well as in vivo murine wound and catheter biofilm infection models. Results: Pyf A exhibited broad-spectrum antibacterial activity against ESKAPE pathogens with minimum inhibitory concentrations ranging from 0.25 to 4 μg/mL. It also showed potent anti-biofilm effects against CRKP. Pyf A disrupted the cell membranes of CRKP and markedly depleted intracellular GSH without triggering ROS accumulation. Pyf A and AgNO₃ showed synergistic anti-CRKP activities in vitro and in vivo, by disrupting both GSH- and thioredoxin-mediated redox homeostasis. Conclusions: Pyf A acts as a GSH-depleting agent and, when combined with AgNO₃, achieves dual-targeted disruption of bacterial thiol redox systems. This dual-targeting strategy enhances antibacterial efficacy of Pyf A and represents a promising therapeutic approach to combat CRKP infections. Full article

Chronic exposure to arsenic via drinking water can induce bladder cancer in humans. Nevertheless, there is little knowledge about the precise mechanisms of this. Abnormal elevations in cell proliferation and migration have repeatedly been identified as the first cellular traits of carcinogenesis. The aims of this study are to uncover the molecular mechanisms underlying arsenic-induced aberrant proliferation and migration of uroepithelium cells by exploring the role of cellular redox modulation. Our results show significant elevations in the levels of ROS and GSH, Trx1, components of the Nrf2 system, and NLRP3 inflammasome activity in the cells chronically treated with arsenite, which also experienced markedly enhanced proliferation and migration capacities. Additionally, ROS inhibitors, NLRP3, and the above antioxidant system could suppress this enhancement of the proliferation and migration capacities and reverse overexpression in these cells. However, only the AKT and ERK inhibitors were capable of reversing EGF, TGFα, and HSP90 overexpression. In conclusion, our findings indicate that the cellular redox status in the uroepithelium following chronic treatment with low-level arsenite was rebalanced due to ROS overproduction and compensatory upregulation of the redox control systems, which may allow ROS and Trx1 to be maintained at higher levels to facilitate cell proliferation and migration via overstimulation of the related signaling pathways. Full article

Schistosomiasis mansoni is a neglected tropical disease caused by the parasite Schistosoma mansoni, affecting approximately 200 million people annually. Currently, treatment relies primarily on a single drug, praziquantel (PZQ), which shows limited efficacy against the parasite’s immature forms. As a result, Thioredoxin Glutathione Reductase from S. mansoni (SmTGR) has emerged as a promising target for novel drug development. This study presents the development of integrated in silico methods to identify alkaloids from medicinal plants with potential activity against S. mansoni. Fourteen alkaloids were identified, with predicted activity ranging from 61.3 to 85.2%. Among these, lindoldhamine and daibucarboline A demonstrated, for the first time, potential SmTGR inhibition, with probabilities of 85.2% and 75.8%, respectively. These findings highlight the potential of these alkaloids as promising candidates for the development of new therapies against schistosomiasis. Full article

Wheat (Triticum aestivum L.), a staple crop of global significance, faces constant biotic stress threats, with powdery mildew caused by Blumeria graminis f. sp. tritici (Bgt) being particularly damaging. In this study, a multi-year single-site experiment was conducted to minimize the environmental impacts, and a five-level classification system was used to assess powdery mildew resistance. A 660K SNP array genotyped 204 wheat germplasms, followed by GWAS. SNP loci with a −log₁₀(p) > 3.0 were screened and validated across repeats to identify those associated with powdery mildew (Pm) resistance. Twelve SNPs were consistently associated with Pm resistance across multiple years. Of these, three colocalized with previously reported Pm-resistance gene or QTL regions, and the remaining nine represented potentially novel loci. The candidate genes identified included leucine-rich repeat (LRR) and NB-ARC immune receptors, as well as pathogen-related, thioredoxin, and serine threonine-protein kinase genes. Overall, the SNP loci and candidate genes identified in this study provide a basis for further fine mapping and cloning of the genes involved in relation to Pm resistance. Full article

Hyperglycemia is a key factor in diabetic retinopathy which leads to blindness. O-linked-N-acetylglucosamine (O-GlcNAc) modification changes are linked to various diseases, including diabetic retinopathy. This research aims to study the roles of Txnip and Trx in influencing O-GlcNAc in photoreceptor cells during diabetic retinopathy. A diabetic mouse model and 661w cells, after exposure to high glucose, were employed as models. H&E staining and ERG were used to evaluate the morphology and function of the retina, respectively. Western blotting was used to analyze protein expression, a TUNEL assay was used to measure apoptosis, and a co-immunoprecipitation (CO-IP) assay was used to detect the interactions of protein. In diabetic mice, electroretinogram (ERG) amplitude wave, retinal thickness, and body weight decreased. Glial fibrillary acidic protein (GFAP), Iba1 expression, and blood glucose level increased. In vitro, the percentage of apoptotic cell, Bax, and caspase3 levels increased, and Bcl2 decreased in 661w cells under high-glucose conditions. Moreover, Txnip expression was upregulated, while Trx was downregulated. Additionally, a Western blot analysis revealed that high-glucose exposure led to increased O-GlcNAc modification both in vivo and in vitro. The CO-IP results show that Txnip interacted with O-GlcNAc modifications. S-opsin expression was significantly downregulated in vitro under high-glucose conditions. Knockdown Txnip or upregulation Trx could reverse or delay apoptosis in 661w cells under hyperglycemic conditions. Txnip/Trx is a potential element in regulating photoreceptor apoptosis in diabetic retinopathy. The underlying mechanism is linked to regulation of O-GlcNAc modification in photoreceptor cells in DR. Full article

Metarhizium anisopliae, a well-known species of entomopathogenic fungi with great potential as a biological control agent, is vulnerable to UV damage, which restricts its use in the field. To improve the fungal resistance to UV irradiation, UV-induced mutant strains of M. anisopliae s. l. were screened and compared with the wild-type (WT) strain for heat resistance, growth rate, conidial yield, and virulence. Comparative transcriptomic analysis between the selected UV-resistant mutants and the WT was carried out. The results showed that the five mutants exhibited significantly higher heat resistance and growth rates, while the conidial production remained unchanged. Among them, the mutant MaUV-22 exhibited enhanced tolerance to heat, oxidative, osmotic, and SDS stresses as well as increased virulence against Galleria mellonella. Moreover, the transcriptome analysis of MaUV-22 revealed that the expression of genes associated with the heat shock protein pathway, glutathione S-transferase, and thioredoxin reductase were increased dramatically, while the expression of genes related to the catalase and superoxide dismutase pathways was downregulated. The UV-induction technique is an effective strategy to improve fungal resistance to environmental stresses and affords some other beneficial traits such as better control efficacy of entomopathogenic fungi against pests in the field. 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 prevalence of age-related macular degeneration (AMD), a disease that can result in the loss of central vision, is an emerging problem worldwide due to aging societies. Growing patient numbers create a challenge for the healthcare system. Understanding the mechanisms of AMD pathogenesis will aid in early, personalized, and efficient intervention, helping to mitigate this issue. Current diagnostic methods rely on optical coherence tomography and angiography imaging, which identify existing damages, but do not provide information on the mechanisms behind them. In the present work, we demonstrate a difference in the serum RNA profile between neovascular AMD (nAMD) patients and controls. Moreover, the RNA profile of nAMD patients corresponded with anatomical changes in the retinal fluid compartments as well as atrophic changes of the retina. We followed two independent ways to control false positive leads, and when these approaches were combined, thioredoxin-related transmembrane protein 4 (TMX4) was observed to be differentially expressed by both approaches. This finding opens a new pathway in AMD studies, which are limited due to restricted access to live human target material and the limited value of animal models of human AMD. 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