Search Results (1,004)

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

Glutathione S-transferases (GSTs) are phase II detoxification enzymes that display several enzymatic activities, including transferase, peroxidase, reductase, and isomerase functions, as well as non-enzymatic roles (e.g., serving as binding proteins). Their complex functionality lies in the biotransformation of xenobiotics (e.g., pesticides, drugs) and certain endogenous compounds, primarily metabolites produced by phase I detoxification enzymes. Several plant-derived compounds have been shown to modulate the activity and expression levels of these enzymes. Phytochemical activators of GSTs are potentially beneficial for detoxification in cases of exposure to various toxic compounds, whereas inhibitors of GSTs could have positive effects as adjuvant treatments for cancers that express high levels of GSTs associated with drug resistance. Full article

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disorder characterized by excessive scarring of lung tissue, predominantly affecting middle-aged and elderly populations. Oxidative stress plays a pivotal role in the pathogenesis of pulmonary fibrosis, disrupting redox homeostasis and driving fibrotic progression. Glutathione reductase (GSR), a key antioxidant enzyme, is essential for maintaining cellular glutathione (GSH) levels and mitigating oxidative damage. However, the specific involvement of GSR in IPF remains poorly understood. This study found that GSR levels were downregulated in IPF patients and mice treated with bleomycin (BLM). GSR knockdown enhanced epithelial-to-mesenchymal transition (EMT) in A549 cells and promoted the activation of MRC5 cells. Additionally, GSR depletion promoted cellular migration and senescence in both A549 and MRC5 cells. Mechanistically, silencing GSR in A549 and MRC5 cells led to a marked reduction in intracellular GSH levels, resulting in elevated reactive oxygen species (ROS) accumulation, thereby promoting the activation of the TGF-β/Smad2 signaling pathway. In conclusion, our findings demonstrate that GSR deficiency aggravates pulmonary fibrosis by impairing antioxidant defense mechanisms, promoting EMT, and activating fibroblasts through the TGF-β/Smad2 signaling. These findings suggest that GSR may be essential in reducing the fibrotic progression of IPF. Full article

MicroRNA-based regulatory mechanisms show disturbances related to oxidative stress (OS) interconnected with inflammation (IFM), as well as impairments associated with gestational diabetes (GDM). The aim of this study was to assess the diagnostic and prognostic significance of the OS/IFM-related microRNA in GDM by using peripheral blood mononuclear cells (PBMCs) and serum-derived extracellular vesicles (EVs) as biological samples. We selected the known OS/IFM-associated microRNAs miR-146a-5p, miR-155-5p, and miR-21-5p as candidates for our GDM biomarker analysis. Quantitative RT-PCR was employed for relative quantification of the selected microRNAs from paired samples of PBMCs and EVs derived from patients with GDM and healthy controls (n = 50 per group). The expression levels were analyzed for correlations with lipid and glycemic status indicators; metal ion-related parameters; serum thiol content; protein carbonyl and thiobarbituric acid-reactive substances’ (TBARS) levels; glutathione reductase (GR), Superoxide dismutase (SOD), and catalase (CAT) activity; and NRF2 expression. MiR-146a-5p and miR-21-5p were significantly upregulated in both PBMCs and EVs obtained from GDM patients. EVs-miR-21-5p showed a positive correlation with glycemic status in GDM patients, while miR-155-5p from PBMCs demonstrated correlation with iron-related parameters. The expression of selected microRNAs was found to correlate with NRF2 expression and SOD activity. The level of miR-146a-5p negatively correlated with neonatal anthropometric characteristics, while a higher level of PBMCs-miR-21-5p expression was determined in GDM patients with adverse pregnancy outcomes (p = 0.012). Our data demonstrate a disturbance of OS/IFM-microRNAs in GDM and illustrate their potential to serve as indicators of the associated OS-related changes, neonatal characteristics, and adverse pregnancy outcomes. Full article

Farmers commonly throw away tomato leaves when they harvest tomatoes, although they are a good source of vital biomolecules. ZnO nanoparticles (ZnO NPs) enhance plant growth by regulating abiotic stress and scavenging reactive oxygen species. In the current article, the activities of five antioxidant enzymes—glutathione reductase (GR), peroxidase (POX), glutathione-S-transferase (GST), superoxide dismutase (SOD), and catalase (CAT)—were determined spectrophotometrically to study the interaction between foliar fertilization of ZnO NPs and salt stress in tomato plants. We employed the next-generation sequencing (NGS) technique to investigate the gene expression. It was also used to generate a de novo supertranscript and then determine the sequences modulated by treatments. Differential expression analysis was used to identify increased and reduced gene clusters, and gene enrichment analysis was used to identify over- and under-expressed genes under the treatment. Gene Ontology (GO) was used to identify the functions and regulatory pathways of the differentially expressed genes (DEGs). It was found that ZnO nanoparticles had the capability to overcome the reduction in antioxidant enzyme production levels in the case of the salinity-stressed treatments and enhance the secretion of those enzymes in the non-stressed but sprayed treatments. The ZnO NPs also enhanced the reduction in stress-responsive genes associated with salt stress resistance. The results revealed the impact of ZnO nanoparticles on alleviating the salinity stress reductive effects in antioxidative enzymes and regulating the mechanism by which metabolically relevant genes adaptively respond to salt stress in tomato plants. So, spraying tomato plants (stressed or not) with ZnO NPs is a promising agricultural technique in improving different metabolic pathways that are responsible for plants’ resistance. 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

Contaminants such as nano-polystyrenes (NPs) and heavy metal cocktail (HMC) have been found to disrupt physiological functions in aquatic organisms. Although HMC and NPs alone induce oxidative stress, their combined effects are not well understood. This study aimed to assess the combined effects of HMC and NPs on the freshwater shrimp (Macrobrachium rosenbergii). Shrimp were divided into seven groups, including the control group, and the experimental groups co-exposed to 0, 50, 100, 150, 200, and 250 µg/L NPs combined with 0.5 mg/L HMC. After 14 days, shrimp were sampled, and their hepatopancreas and muscle tissues were analyzed for oxidative biomarkers, biochemical parameters, and metabolic profiles. Moreover, the bioaccumulation rate of heavy metals was measured. Results showed that co-exposure to NPs and HMC increased superoxide dismutase, glutathione peroxidase, glutathione reductase activities, and malondialdehyde levels, while reducing glutathione and total antioxidant capacity. The integrated biomarker response indicated that co-exposure to HMC and NPs induces oxidative stress. A significant decrease was observed in aspartate aminotransferase, gamma-glutamyl transpeptidase, and alkaline phosphatase activities, glycogen, triglyceride, and total protein levels. However, lactate dehydrogenase activity was significantly increased. Co-exposure to HMC and NPs increased heavy metal bioaccumulation, induced oxidative stress, biochemical changes, and enhanced HMC toxicity in shrimp. Full article

The advanced glycation end product (AGE)–RAGE axis has been implicated in the pathophysiology of diabetic bladder dysfunction (DBD). However, no previous studies have explored the effects of RAGE blockade on this condition. Here, we explored the effects of the selective RAGE inhibitor TTP488 (azeliragon) at the functional and molecular levels of bladder dysfunction in ob/ob leptin-deficient mice. Female B6.V-Lep ob/JUnib (ob/ob) and wild-type (WT) C57BL/6 mice were used as lean controls. Treatment with TTP488 in ob/ob mice resulted in no changes in body weight, fasting glucose, or insulin resistance; however, it reduced total AGE and MG-H1 levels without altering RAGE levels in bladder tissues. TTP488 normalized glyoxalase-1, glutathione reductase, glutathione peroxidase, and superoxide dismutase activities in bladder tissues. Marked increases in collagen intensity were also observed in ob/ob mice, an effect fully reversed by TTP488 treatment. TTP488 reduced total void volume, volume per void, and ex vivo bladder contractility in response to electrical-field stimulation and carbachol. Our finding that TTP488 mitigates DBD in ob/ob mice supports the proposal that RAGE blockade could serve as a promising therapeutic strategy for managing DBD. 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

In this study, we evaluated the antioxidant activities of esculetin and four synthesized derivatives (E1, 2-oxo-2H-1-benzopyran-6,7-diyl diacetate; E2, 7-hydroxy-2-oxo-2H-1-benzopyran-6-yl acetate; E3, 7-(methoxymethoxy)-2-oxo-2H-1-benzopyran-6-yl acetate; E4, 7-hydroxy-2-oxo-2H-1-benzopyran-6-yl 2,4-dinitrobenzene-1-sulfonate) against oxidative stress in hepatocytes. In HepG2 cells, treatment with 1 mM tert-butyl hydroperoxide (TBHP) reduced cell viability to 40%, while co-treatment with esculetin restored cell viability. Among the esculetin derivatives, E2 exhibited the most significant cytoprotective effect, while E4 showed the lowest. Furthermore, E2 at 25 µM concentration showed the similar effects to esculetin in reducing ROS generation and preventing glutathione depletion. The treatment of E2 also enhanced the expression of HO-1 and GCLC proteins against oxidative stress. On the other hand, TBHP-induced oxidative stress decreased antioxidant activities including glutathione reductase, glutathione peroxidase, and catalase; however, E2 significantly increased these antioxidant activities. These findings suggest that the esculetin derivative, particularly E2, possesses potential as an antioxidant aimed at enhancing physiological functions. Full article

While pipecolic acid (Pip) mediates morpho-physiological and molecular responses during biotic stress, its roles under drought remain an inexpressible mystery. The investigation aimed to elucidate the roles of a 30μM Pip pretreatment in alleviating drought injury on barley (Hordeum vulgare L. cv, Bülbül89) seedlings. Pip pretreatment under normal or drought conditions lowered the osmotic potential (Ψs) and water saturation deficit (WSD), while optimizing the relative water content (RWC), triggered osmotically energetic molecules (OEM) and salicylic acid (SA) accumulation, improving osmotic adjustment (OA), and boosting water retention and uptake capacity (WTC, and WUC), alongwith a considerable improvement in seedling growth over non-treated plants under such conditions. Additionally, Pip pretreatment improved chlorophyll (Chl), the chlorophyll stability index (CSI), pheophytin_a, chlorophyllide_a (chlide_a), chlorophyllide_b (chlide_b), chl_a/chlide_a, chl_b/chlide_b, protoporphyrin, Mg-protoporphyrin, protochlorophyllide, and photosynthetic performance over non-treated plants under such conditions. Pip pretreatment preserves redox homeostasis in drought-stressed plants by accumulating antioxidant solutes alongside the activation of superoxide dismutase and glutathione reductase over non-treated plants. Drought distinctly reduced Ψs (more negative), RWC, photosynthetic pigment, CSI, chlorophyll assimilation intermediate, and photosynthetic performance, with an increment in chlorophyll degradation intermediate and nonenzymatic antioxidant solutes. Drought maintains OA capacity via a hyper-accumulation of OEM and SA, which results in higher WSD, WTC, and WUC. Drought triggered an oxidative burst, which was associated with a decline in the membrane stability index. These findings highlight Pip’s capability for lessening drought stress-induced restriction in barley seedlings via bolstering oxidative homeostasis, OA capacity, and stabilizing chlorophyll biosynthesis. Future research must elucidate the precise molecular mechanisms underlying Pip’s action in alleviating drought injury. Full article

Carbohydrate consumption during pregnancy represents an important source of energy; its consumption, however, can cause gestational diabetes mellitus (GDM), body weight gain, inflammation, increased glucose transport to the fetus, adiposity, and a risk of macrosomia. The objective was to research the impact of sucrose consumption during pregnancy on the metabolic, immune, and redox profile in female mice with GDM. A total of 24 female CD1 mice were used, divided into two groups: Control and GDM. Each group was subdivided into two subgroups: (a) Without sucrose and (b) With sucrose. The females were mated, and, once pregnancy was confirmed, GDM was induced by administering 230 mg/kg of streptozotocin subcutaneously. GDM was confirmed by glucose ≥ 200 mg/dL and the presence of polyphagia, polydipsia, and change in body weight. Metabolic, immune, and redox profile parameters were determined. Sucrose consumption groups increase HOMA-IR and the secretion of insulin, adiponectin, and leptin; it also increased the secretion of proinflammatory cytokines and the production of IgA and IgG antibodies, decreased the activity of the Glutathione Reductase enzyme, and increased the production of TBARS and AGE. High sucrose consumption increases the inflammatory response mediated mainly by CD8⁺ lymphocytes and the production of proinflammatory cytokines; it can trigger a compensatory humoral response and alter redox mechanisms, causing a state of Oxidant Stress. Full article

Paratuberculosis, caused by Mycobacterium avium subspecies paratuberculosis (MAP), is a chronic granulomatous enteritis with significant implications for ruminant health, economic productivity, and potential zoonotic risk. This study investigated the expression of biomarkers of oxidative stress and apoptosis in goats naturally infected with MAP, focusing on three biological matrices: serum, intestinal mucosa, and mesenteric lymph nodes. Twenty MAP-positive goats and ten healthy controls were included. Serum and tissue levels of malondialdehyde (MDA), glutathione S-transferase (GST), glutathione peroxidase (GPX), superoxide dismutase (SOD), glutathione reductase (GSR), and caspase-3 were quantitatively assessed using ELISA tests. Gross and histopathological analyses confirmed MAP infection. Infected animals showed significantly elevated serum levels of MDA and caspase-3 (p < 0.001), along with decreased antioxidant enzyme activities (GSR, GST, GPX, SOD). Tissue analysis revealed increased MDA and caspase-3 levels, particularly in the intestinal mucosa compared to mesenteric lymph nodes, suggesting localized oxidative damage and apoptosis. Conversely, antioxidant enzyme activity was higher in mesenteric lymph nodes, indicating a compensatory response and a pronounced involvement of the intestinal tract. These findings demonstrate that MAP infection induces marked oxidative stress and apoptotic processes, especially in the intestinal mucosa. The imbalance between pro-oxidant and antioxidant systems may play a key role in the pathogenesis and chronic progression of the disease. Caspase-3 and MDA, in particular, have been identified as promising diagnostic or prognostic biomarkers for MAP infection. This study highlights the importance of developing improved diagnostic tools and therapeutic strategies targeting oxidative stress pathways in paratuberculosis. 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

Advanced glycation end-products (AGEs) and oxidative stress are recognized as central contributors to the pathogenesis of age-related or diabetic cataracts, diabetic retinopathy (DR), and age-related macular degeneration (AMD). These glycation-related diseases are characterized by impaired redox balance and decreased glutathione (GSH) levels. This review aims to examine the mechanistic links between AGEs and GSH depletion across ocular tissues by integrating in vitro, ex vivo, in vivo, and clinical studies relevant to this topic. The multiple levels of evidence highlight GSH homeostasis as both a biomarker and therapeutic target in glycation-related ocular disorders. Therapeutic strategies aimed at restoring GSH homeostasis under glycation stress are categorized into four mechanistic domains: (I) promoting GSH supply and synthesis, (II) enhancing GSH recycling, (III) mitigating glycation stress, and (IV) reducing oxidative and nitrosative stress. Most of these strategies have been explored via different approaches, and experimental findings with various interventions have shown promise in restoring GSH balance and mitigating AGE-induced damage. A pathological link between GSH depletion and vascular endothelial growth factor (VEGF) overexpression is observed in DR and wet AMD. GSH-centered interventions act upstream to modulate redox homeostasis while anti-VEGF therapies target downstream angiogenesis. This study supports the rationale for a dual-targeting strategy that combines redox-based interventions with VEGF inhibition in glycation-related ocular diseases. Full article