Search Results (147)

Reactive oxygen species (ROS) function as critical signaling molecules in cancer biology, promoting proliferation, angiogenesis, and metastasis at controlled levels while inducing lethal damage when exceeding the cell’s buffering capacity. To survive under this state of chronic oxidative stress, cancer cells become dependent on a hyperactive antioxidant shield, primarily orchestrated by the Nrf2, glutathione (GSH), and thioredoxin (Trx) systems. These defenses maintain redox homeostasis and sustain oncogenic signaling, notably through the oxidative inactivation of tumor-suppressor phosphatases, such as PTEN, which drives the PI3K/AKT/mTOR pathway. Targeting this addiction to a rewired redox state has emerged as a compelling therapeutic strategy. Pro-oxidant therapies aim to overwhelm cellular defenses, with agents like high-dose vitamin C and arsenic trioxide (ATO) showing significant tumor-selective toxicity. Inhibiting the master regulator Nrf2 with compounds such as Brusatol or ML385 disrupts the core antioxidant response. Disruption of the GSH system by inhibiting cysteine uptake with sulfasalazine or erastin potently induces ferroptosis, a non-apoptotic cell death driven by lipid peroxidation. Furthermore, the thioredoxin system is targeted by the repurposed drug auranofin, which irreversibly inhibits thioredoxin reductase (TrxR). Extensive preclinical data and ongoing clinical trials support the concept that this reliance on redox adaptation is a cancer-selective vulnerability. Moreover, novel therapeutic strategies, including the expanding field of redox-active metal complexes, such as manganese porphyrins, which strategically leverage the differential redox state of normal versus cancer cells through both pro-oxidant and indirect Nrf2-mediated antioxidative mechanisms (triggered by Keap1 oxidation), with several agents currently in advanced clinical trials, have also been discussed. Essentially, pharmacologically tipping the redox balance beyond the threshold of tolerance offers a rational and powerful approach to eliminate malignant cells, defining a novel frontier for targeted cancer therapy. Full article

Mycobacterium marinum and Mycobacterium leprae are zoonotic mycobacteria causing chronic cutaneous infections that challenge host immunity and tissue integrity. Reactive oxygen species (ROS) play a complex role in the host defense system. While essential for pathogen elimination and intracellular signaling, excessive ROS can lead to immune dysregulation and impaired tissue healing. This review explores M. marinum and M. leprae pathogenesis through the role of ROS in redox imbalances, immunity, and cutaneous wound healing. Physiological ROS levels are vital for T-cell activation and differentiation. However, excessive ROS production, particularly in innate immune cells, can lead to T-cell suppression. M. leprae infection is associated with a significant reduction in key antioxidants such as glutathione (GSH), GSH peroxidase (GSH-Px), and GSH reductase (GR), a reduction that correlates with disease severity. For M. marinum, disrupting the pathogen’s redox balance through thioredoxin reductase (TrxR) inhibition sensitizes bacteria to ROS damage, reducing bacterial load. Overall, redox imbalance is central to the pathogenesis and persistence of cutaneous mycobacterial infections, compromising host defense and impairing tissue repair. Restoring and maintaining proper redox homeostasis, potentially by exploring the role of GSH as an antioxidant, represents a promising adjunct treatment to improve host outcomes in these challenging dermatological conditions. Full article

Reactive oxygen species (ROS) act as double-edged swords in cancer biology—facilitating tumor growth, survival, and metastasis at moderate levels while inducing oxidative damage and cell death when exceeding cellular buffering capacity. To survive under chronic oxidative stress, cancer cells rely on robust antioxidant systems such as the glutathione (GSH) and thioredoxin (Trx), and superoxide dismutases (SODs). These systems maintain redox homeostasis and sustain ROS-sensitive signaling pathways including MAPK/ERK, PI3K/Akt/mTOR, NF-κB, STAT3, and HIF-1α. Targeting the antioxidant defense mechanisms of cancer cells has emerged as a promising therapeutic strategy. Inhibiting the glutathione system induces ferroptosis, a non-apoptotic form of cell death driven by lipid peroxidation, with compounds like withaferin A and altretamine showing strong preclinical activity. Disruption of the Trx system by agents such as PX-12 and dimethyl fumarate (DMF) impairs redox-sensitive survival signaling. Trx reductase inhibition by auranofin or mitomycin C further destabilizes redox balance, promoting mitochondrial dysfunction and apoptosis. SOD1 inhibitors, including ATN-224 and disulfiram, selectively enhance oxidative stress in tumor cells and are currently being tested in clinical trials. Mounting preclinical and clinical evidence supports redox modulation as a cancer-selective vulnerability. Pharmacologically tipping the redox balance beyond the threshold of cellular tolerance offers a rational and potentially powerful approach to eliminate malignant cells while sparing healthy tissue, highlighting novel strategies for targeted cancer therapy at the interface of redox biology and oncology. Full article

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

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

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 genus Acidithiobacillus has been widely used in bioleaching, and novel strains in this genus, such as A. ferriphilus, have also been confirmed to possess bioleaching capabilities. In this study, an Acidithiobacillus ferriphilus strain, QBS3, was isolated from zinc-rich sulfide mine drainage using the gradient dilution method. QBS3 is a Gram-negative, 1.3 µm rod-shaped bacterium with small red colonies. It showed a high iron oxidation efficiency of 0.361 g/(L·h) and a sulfur oxidation efficiency of 0.206 g/(L·d). QBS3 has sphalerite bioleaching ability; using QBS3 for pure sphalerite bioleaching, 18.8% of zinc was extracted in 14 days at 1% pulp density. Whole genome sequencing was performed on QBS3. Functional prediction showed that 9.13% of the genes were involved in replication, recombination, and repair. Bioleaching-related genes were analyzed, including iron and sulfur oxidation genes, and carbon and nitrogen fixation genes. For iron oxidation, the Cyc2→RusA pathway and Iro→RusB pathway were found in QBS3. In terms of sulfur oxidation, QBS3 has an incomplete SOX system and lacks the SDO gene, but Rho and Trx may complement the SOX system, enabling QBS3 to oxidize sulfur. QBS3 has multiple sets of carbon fixation genes, and nitrogen fixation genes were also identified. A hypothetical sphalerite bioleaching model is proposed; this study provides a theoretical basis for the zinc sulfide ore bioleaching industry. 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

The behavior of the soils under dynamic loads is of great importance for the structures to be built in earthquake zones. As a result of the determination of the site-specific dynamic parameters of the soils and the analyzes to be made with these parameters, the ground response that will occur on the surface during the earthquake will be determined. Turkey is located in one of the important earthquake belts of Europe. Studies are carried out on the North Anatolian Fault Zone (NAFZ), which is one of the important and active fault lines here. In this study, as a result of 4 drilling studies on NAFZ, firstly, dynamic triaxial (TRX) and resonant column (RC) test systems were used to obtain site-specific shear modulus and damping curves depending on depth. 11 earthquake acceleration records reflecting the seismic characteristics of the region were selected and scaled in both time-history and frequency-time domains. Two different scaling methods were compared with the nonlinear soil amplification analysis. In addition, surface response spectra were examined according to the Turkish Building Earthquake Code (TEC 2018). Although there is not a big difference in amplification values in two different scaling methods, it has been determined that the design spectrum values are very different. 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

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

The oxidative modification of specific cysteine residues to persulfides is thought to be the main way by which hydrogen sulfide (H₂S) exerts its biological and signaling functions. Therefore, protein persulfidation represents an important thiol-switching mechanism as other reversible redox post-translational modifications. Considering their reductase activity but also their connections with proteins that generate H₂S and its related molecules, the glutaredoxin (GRX) and thioredoxin (TRX)-reducing systems have potential dual roles in both protein persulfidation and depersulfidation. In this review, we will first focus on recent advances describing the physiological pathways leading to protein persulfidation before discussing the dual roles of the physiological TRX and glutathione/GRX-reducing systems in protein persulfidation/depersulfidation. Full article