Search Results (470)

Cancer metastasis, characterized by the dissemination of malignant cells from the primary tumor to distant organs, remains the leading cause of cancer-related mortality in solid tumors. In colorectal cancer (CRC), increasing attention has been directed toward therapeutic strategies aimed at suppressing cancer cell migration and invasion rather than solely reducing tumor mass, giving rise to the concept of migrastatic therapies. In the present study, green-synthesized silver nanoparticles (AgNPs), previously obtained using aqueous extracts of Filipendula ulmaria (L.) Maxim. and Salvia verticillata L., were evaluated for their antimigratory and anti-inflammatory potential in human colorectal carcinoma HCT-116 cells. Treatment with AgNPs induced considerable perturbations in cellular redox homeostasis, as evidenced by increased intracellular reactive oxygen species (ROS), lipid peroxidation (LPO), glutathione (GSH), and nitric oxide (NO) levels. These redox alterations were accompanied by a significant inhibition of cancer cell migration, together with reduced expression of matrix metalloproteinases MMP-2 and MMP-9, key mediators of extracellular matrix remodeling associated with tumor progression. AgNP exposure was associated with activation of the cytoprotective transcription factor Nrf-2 and suppression of the pro-inflammatory NF-κB/COX-2 signaling axis, indicating coordinated modulation of redox-sensitive pathways linked to tumor cell motility and inflammatory responses. Collectively, these findings demonstrate that green-synthesized AgNPs derived from F. ulmaria and S. verticillata exert multi-level regulatory effects on redox balance, inflammatory signaling, and migration-associated molecular markers in colorectal cancer cells. This study supports their potential as promising migrastatic nanocarriers for further investigation in colorectal cancer research. Full article

Selenium (Se) is an essential trace element for humans and animals, with nutritional functions and abiotic stress regulation capacity, and has been confirmed to alleviate heavy metal toxicity and inhibit its accumulation in crops. Soil lead contamination has become a prominent environmental safety problem in agricultural production, particularly in South China, and lead over-standard in edible crops poses irreversible threats to the human nervous system and blood circulation through food chain transmission. As an efficient exogenous antagonist, Se can comprehensively regulate the absorption, translocation, and compartmentalization of lead in soil–plant systems. This review systematically summarizes the interactive effects of soil physicochemical properties, crop genotypes, and Se speciation on plant lead uptake, and focuses on phytochelatin synthase (PCS), the core rate-limiting enzyme for intracellular heavy metal chelation, to elucidate the molecular cascade of Se-mediated PCS-dependent lead detoxification. We further outline multi-pathway agronomic Se applications for lead reduction; analyze key limiting factors, including Se concentration, application method, and rhizosphere microbial community; and discuss contradictory results and unresolved questions in existing studies. Current evidence confirms that appropriate Se treatment increases glutathione (GSH) content via antioxidant system regulation, upregulates PCS gene transcription and activity, promotes phytochelatins (PCs) polymerization, and forms stable PC-Pb complexes sequestered in vacuoles to reduce cytoplasmic lead mobility. Additionally, Se reshapes rhizosphere microbial community composition to lower soil Pb²⁺ bioavailability and enhances lignin and pectin biosynthesis in root cell walls to physically block root Pb²⁺ influx. Nevertheless, critical knowledge gaps remain unaddressed: (1) upstream signal transduction cascades triggering Se-induced differential PCS expression; (2) precise Pb²⁺ binding sites and affinity of PC oligomers; (3) valence-dependent disparities in selenate, selenite, and nano-Se (SeNPs) modulating PCS activity; and (4) standardized field Se fertilization protocols tailored to staple and tropical tuber crops such as cassava. This review provides systematic theoretical reference and technical foundations for dissecting Se-Pb antagonistic molecular networks, developing Se-enriched low Pb²⁺ functional fertilizers, and mitigating Pb²⁺ contamination risk in agricultural commodities. Full article

Sarcopenia is an age-related pathological syndrome characterized by progressive and generalized loss of skeletal muscle mass and function, with muscle atrophy representing its cardinal pathological hallmark. Ferroptosis, an iron-dependent regulated cell death, has been implicated in the pathogenesis of muscle atrophy; however, the precise role of iron dysregulation in sarcopenia remains incompletely understood. In the present study, we identified ferroptosis in D-galactose (D-gal)-induced senescent myoblasts, as evidenced by elevated intracellular iron levels and lipid peroxidation, increased malondialdehyde (MDA) content, and upregulated expression of prostaglandin endoperoxide synthase 2 (PTGS2), 4-hydroxynonenal (4-HNE), and long-chain acyl-CoA synthetase 4 (ACSL4), accompanied by diminished glutathione peroxidase 4 (GPX4), SLC7A11 (xCT), and glutathione (GSH) levels, as well as pronounced mitochondrial damage. Notably, treatment with the iron chelator deferoxamine (DFO) significantly attenuated senescence-associated ferroptosis. Moreover, D-gal-induced senescence in myoblasts was accompanied by reduced ferritin expression and elevated nuclear receptor coactivator 4 (NCOA4) levels, both of which were reversed by autophagy inhibition with 3-methyladenine (3-MA) or NCOA4 knockdown, suggesting that NCOA4-mediated ferritinophagy is involved in senescence-induced iron overload and ferroptosis. Furthermore, senescent myoblasts exhibited increased reactive oxygen species (ROS) generation and mitochondrial impairment, which were attributed to cytosolic iron overload-mediated upregulation of mitoferrin 2 (Mfrn2), thereby promoting mitochondria iron import. Finally, pharmacological inhibition of iron overload or ferroptosis by DFO or ferrostatin-1 (Ferr-1) effectively ameliorated skeletal muscle atrophy and functional decline in aged sarcopenia mice. Collectively, these findings elucidate the mechanistic basis of sarcopenia and highlight potential therapeutic avenues targeting iron dysregulation and ferroptosis. Full article

Schizophrenia is a heterogeneous neurodevelopmental disorder in which genetic liability, developmental exposures, illness stage, treatment, and metabolic or inflammatory comorbidity may shape redox biology. This narrative review evaluates the human and mechanistic evidence for impaired redox adaptation as a convergence mechanism linking glutathione (GSH) regulation, N-methyl-D-aspartate receptor hypofunction, parvalbumin-interneuron and perineuronal-net vulnerability, mitochondrial–glial dysfunction, and neuroimmune signalling. The findings do not support a uniform oxidative abnormality across all patients or compartments: the peripheral biomarkers are heterogeneous, the group-level brain GSH magnetic resonance spectroscopy findings are largely null, and treatment-related changes vary by marker and illness phase. Beyond the established GSH–NMDA–redox–immune models, we integrate iron–lipid redox regulation as a conditional, hypothesis-generating extension and apply a deliberately conservative evidence hierarchy. Human studies more often report a lower peripheral iron and reduced or redistributed brain iron than a uniform iron excess; the plasma signals for predominantly intracellular proteins remain analytically unvalidated, and ferroptotic neuronal death has not been demonstrated. Longitudinal, sex-aware, multi-compartment, and challenge-based studies are needed to define meaningful redox subgroups; no redox- or ferroptosis-related biomarker is currently validated to guide treatment selection. Full article

Despite the traditional application of Sophora moorcroftiana seeds (SMS) in Tibetan medicine for heat-clearing, damp-drying, anti-inflammatory and detoxifying properties, the anti-inflammatory mechanisms of SMS remain insufficiently understood and warrant systematic investigation. This study evaluated the protective effects of an ethanolic SMS extract against lipopolysaccharide (LPS)-induced oxidative stress and inflammation in RAW 264.7 macrophages, with emphasis on the p62/Keap1/Nrf2 signaling pathway. In vitro, the extract exhibited significant DPPH, ABTS and ·OH radical scavenging activities, as well as ferric-reducing antioxidant power, in a clear concentration dependent manner. An inflammatory model was established by stimulating RAW 264.7 cells with LPS, followed by treatment with graded concentrations of the ethanolic SMS extract. The extract significantly reduced LPS-induced nitric oxide production and decreased the secretion of TNF-α, IL-6 and IL-1β, while suppressing iNOS and COX-2 expression at both mRNA and protein levels. In parallel, the extract alleviated oxidative stress, as evidenced by reduced intracellular reactive oxygen species (ROS) and MDA levels, increased antioxidant defenses including SOD, GSH and CAT, and decreased LDH release. At the protein-expression level, SMS treatment was accompanied by differential changes in p62, Keap1, total Nrf2 and HO-1 expression, suggesting that its effects may involve regulatory processes associated with cellular stress and antioxidant defense. Collectively, the ethanolic extract of SMS attenuated LPS-induced inflammatory and oxidative stress responses in RAW 264.7 macrophages. These effects may be associated with the suppression of inflammatory mediator production, reduction in the cellular oxidative stress burden and modulation of proteins involved in cellular stress responses and antioxidant defense. Full article

Branch retinal vein occlusion (BRVO) is a retinal vascular disorder characterized by ischemia and hypoxia. These pathological conditions contribute to retinal pigment epithelial (RPE) cell injury through oxidative stress and ferroptosis. However, whether baicalin (BC) protects against hypoxia-induced RPE injury remains unclear. CoCl₂-induced hypoxic ARPE-19 cells were used to evaluate the protective effects and potential mechanisms of BC. BC improved cell viability and reduced LDH release under hypoxic conditions. BC markedly suppressed hypoxia-induced inflammatory responses, as evidenced by reduced p65 and ICAM-1 expression and decreased release of pro-inflammatory cytokines. Moreover, BC alleviated oxidative stress by reducing ROS and MDA accumulation and restoring SOD and GSH activity. BC attenuated mitochondrial dysfunction, accompanied by restoration of mitochondrial membrane potential, oxygen consumption rate (OCR), and ATP production. Transmission electron microscopy (TEM) results further confirmed the protective effect of BC on mitochondrial integrity. Mechanistically, BC suppressed ferroptosis by reducing intracellular Fe²⁺ accumulation and lipid peroxidation, accompanied by downregulation of TFR1, ACSL4, and p53, as well as upregulation of SLC7A11 and GPX4. These findings suggest that BC protects ARPE-19 cells against hypoxia-induced injury through preservation of mitochondrial function and inhibition of ferroptosis. Full article

Chickpea is an important source of plant flavonoids in the diet, and flavonoids from chickpea have hypoglycemic activity. In this study, a male SD rat model of type 2 diabetes mellitus (T2DM) induced by a high-fat high-sugar diet combined with streptozotocin (STZ) was used to investigate the inhibitory effects on the polyol pathway (a branch of glucose metabolism) by chickpea flavonoid extract (CFE). The results demonstrated that CFE significantly lowered fasting blood glucose (FBG) level, and reduced insulin resistance in diabetic rats by elevating the homeostasis model assessment of insulin sensitivity (HOMA-IS) and decreasing the homeostasis model assessment of insulin resistance (HOMA-IR). And CFE relieved oxidative stress through reducing H₂O_2, malondialdehyde (MDA) and carbonylated protein levels, and increasing the activity of glutathione peroxidase (GSH-Px). Moreover, CFE inhibited the polyol pathway by downregulating the aldose reductase (AR) and sorbitol dehydrogenase (SDH) activities, as well as reducing the sorbitol and fructose levels. Meanwhile, CFE also enhanced the antioxidant defense capacity through increasing glutathione reductase (GR) activity and the glutathione (GSH) level, while decreasing the oxidized glutathione (GSSG) level. Further results showed that CFE mitigated reductive stress in T2DM rats via increasing intracellular NAD⁺ content and the NAD⁺/NADH ratio, due to suppressing PARP activity and upregulating Sirt3 activity. Furthermore, CFE regulated the levels of metabolites such as nicotinamide and β-aminobutyric acid, and modulated seven metabolic pathways closely associated with the improvement of diabetes and its complications. Ten key differential metabolites were reversed after CFE intervention, which were strongly correlated with the polyol pathway and oxidative stress in T2DM rats. In summary, CFE possessed hypoglycemic activity and could inhibit the polyol pathway, which was considered a promising natural product for diabetes prevention. Full article

The tripeptide glutathione (GSH) is the most abundant cellular non-enzymatic antioxidant. The GSH system plays a crucial role in antioxidant defense against oxidative stress and in supporting cellular redox homeostasis, regulating the reduction of lipid peroxides, and protecting cells from ferroptosis depending on the GSH level, which is maintained in a state of dynamic equilibrium not only by the activities of GSH synthesis enzymes, transporters of GSH precursor amino acids, and GSH transporters, but also by the actions of GSH-related enzymes. Some GSH-related enzymes are key enzymes with antioxidant functions such as glutathione peroxidases (GPxs), especially GPx4, and glutathione S-transferases (GSTs), which use GSH as a co-substrate for the reduction of hydroperoxides to alcohols, whereas glutathione-specific gamma-glutamyl cyclotransferase 1 (ChaC1) degrades intracellular GSH, so they can correspondingly lead to suppression or induction of ferroptosis. Ferroptosis is characterized by a buildup of lipid peroxides due to excessive lipid peroxidation and iron accumulation, which results from redox imbalance between ferroptosis’s drivers and defense systems, including impaired cellular antioxidant systems, particularly disruptions of GSH metabolism. It appears pertinent to assess the influence on ferroptosis regulation by GSH-dependent enzymes that utilize the GSH pool in diverse ways. This review offers an updated exploration of the roles of GPx4, ChaC1, and GSTs in redox regulation of ferroptosis in cancer cells, with a focus on both the regulation of each enzyme’s activity and their possible interactions, considering the impact on the risk of ferroptosis induction. Full article

Mycobacterium avium (M. avium) is an opportunistic intracellular pathogen causing chronic pulmonary disease in immunocompromised individuals, particularly in those with HIV/AIDS. Current treatments present challenges due to duration, antibiotic resistance and toxicity, creating a need for novel treatments. Glutathione (GSH), a key intracellular antioxidant, is depleted in immunocompromised individuals. This study evaluated the direct and intracellular antimycobacterial activity of liposomal glutathione (L-GSH) against M. avium. Furthermore, the minimum inhibitory concentration (MIC) and depolarization effects of L-GSH were also determined. Our results indicate that L-GSH has potent direct antimycobacterial activity against M. avium through membrane depolarization and reduces intracellular survival of M. avium in human macrophages. Given the established GSH deficiency in HIV-infected individuals and the clinical need for novel Mycobacterium avium complex (MAC) therapies with favorable safety profiles, these findings support further investigation of L-GSH as a host-directed therapeutic agent for HIV-associated M. avium infections. Full article

Background/Objectives: Since redox balance is critical to colorectal cancer cell survival, and estradiol, a potent antioxidant, correlates with reduced disease incidence, understanding the redox basis of cellular responsiveness to estradiol is essential for advancing therapeutic insight. This study evaluates the adaptive and maladaptive redox responses of colorectal carcinoma cells to estradiol treatment by defining the basal redox set-point as the intracellular balance between pro-oxidants and antioxidants. Methods: Human colorectal cancer cell lines HCT-116 and SW-480 were treated for 24 h with pregnancy-range and pharmacological-range concentrations of estradiol. Redox biomarkers (superoxide anion/O₂^.−, hydrogen peroxide/H₂O₂, nitric oxide/NO, reduced glutathione/GSH and oxidized glutathione/GSSG), cell viability, and basal migration were analyzed. Correlation, network topology, PCA, and Jaccard similarity analyses were applied to characterize basal redox set-points and quantify estradiol-induced changes in redox profiles in the two cell lines. Results: HCT-116 cells exhibited an O₂^.−-centered redox set-point associated with NO and GSH. SW-480 cells displayed a H₂O₂-centered redox set-point associated with NO and GSH. In HCT-116 cells, estradiol triggered a maladaptive response associated with antioxidant activation and reduced proliferation. Conversely, SW-480 cells exhibited an adaptive response characterized by modulation of NO levels and the GSH pool and associated with increased proliferation. Conclusions: These findings identify redox set-point organization as a potential determinant of estradiol responsiveness in colorectal cancer cells. From a clinical perspective, characterizing basal redox set-points in patient-derived tumor cells may enable stratification of colorectal cancer patients by predicted responsiveness to redox-modulating therapies, informing personalized treatment. Full article

A novel carbohydrazide-based ligand (L) and its binuclear Cu(II) complex were successfully synthesized and characterized. Structural analysis confirmed that the Cu(II) complex adopted a monoclinic crystal system with a distorted coordination configuration, in which the multidentate Schiff base ligand chelated and bridged two Cu(II) centers. The in vitro anti-tumor results revealed that the Cu(II) complex exhibited prominent cytotoxicity against five human cancer cell lines with much lower IC₅₀ values than the free ligand, copper chloride and cisplatin. Mechanistic studies demonstrated that the Cu(II) complex significantly increased intracellular ROS and MDA levels, decreased the GSH/GSSG ratio, and reduced ATP content, thereby disrupting cellular redox balance and bioenergetic metabolism. In addition, flow cytometry analysis verified that the complex effectively triggered tumor cell apoptosis. In contrast, free CuCl₂ showed almost no anticancer activity, indicating that the synergistic effect between the Schiff base ligand and copper ions contributed to the excellent anti-tumor performance. This work suggests that the prepared binuclear Cu(II) complex can serve as a promising candidate for developing metal-based anticancer agents. Full article

Background: Due to the serious side effects and the resistant phenotype acquired by tumors, cisplatin has limited clinical efficacy. The current study aims to investigate the potential of disulfide-bridged phthalocyanines to make breast cancer cells (MCF-7) more sensitive to cisplatin. For this purpose, a novel disulfide-bridged dimeric phthalocyanine complex with a therapeutically active wavelength absorbance value that is activatable in cancer cells was synthesized and encapsulated in liposome nanoparticles. Methods: The synthesized phthalocyanine was characterized using FTIR, UV–visible, and MALDI-TOF-MS techniques; liposome nanoparticles containing the synthesized phthalocyanine were characterized using a particle size analyzer and were tested on MCF-7 breast cancer cell lines using MTT and flow cytometric assays. Results: The results have illustrated that GSH cleavages disulfide bonds of the synthesized disulfide-bridged dimeric phthalocyanine complex with quite favorable characteristics for photodynamic therapy, such as a therapeutically active wavelength absorbance value (685 nm), and disulfide-bridged phthalocyanine (ASG20)-containing liposome nanoparticles have quite favorable characteristics (average size of 167.6 nm and polydispersity index of 0.108) for biomedical applications. As evidenced by MTT and flow cytometric assays, by causing extra decreases in the viability of breast cancer cells (p < 0.01), pre-treatment of the breast cancer cells with photodynamic therapy using the activatable liposome nanoparticles significantly (p < 0.01) enhanced the anticancer activity of cisplatin in high and low doses. Conclusions: In conclusion, the activatable liposome nanoparticles containing disulfide-bridged dimeric phthalocyanine complexes can enable much more effective cisplatin-based therapies for breast cancer by overcoming the handicaps of cisplatin, drug resistance (by decreasing intracellular GSH levels), and serious side effects (by enabling the usage of lower doses of cisplatin in chemotherapy). Full article

Microbial reduction of soluble selenium oxyanions is a sustainable strategy for remediating selenium-contaminated environments, yet the molecular mechanisms underlying selenite tolerance in the genus Rhodococcus remain poorly understood. In this study, we investigated the proteomic adaptation of the highly tolerant strain Rhodococcus qingshengii PM1 under high-concentration selenite stress (50 mM Na₂SeO₃) using a data-independent acquisition (DIA)-based quantitative proteomics approach. A total of 3335 proteins were identified, and 3310 proteins were retained for downstream analysis. Comparative proteomics revealed 1411 differentially expressed proteins, including 972 upregulated and 439 downregulated proteins in the selenite-treated group. These changes indicate extensive systems-level proteomic reprogramming and support a growth–defense trade-off strategy. Strain PM1 strongly upregulated ferredoxin and multiple respiratory-chain- and oxidoreductase-associated proteins, suggesting a ferredoxin-associated electron-transfer network that may contribute to Se(IV) transformation and intracellular redox adjustment. In parallel, proteins involved in sulfur assimilation, cysteine/methionine and selenocompound metabolism, ergothioneine biosynthesis, GSH-associated metabolism, Trx/MSH thiol-redox systems, peroxidase/Ohr-Prx detoxification, metalloid/oxyanion resistance, urease-associated pH adaptation, DNA repair, and cell-envelope remodeling were induced, indicating activation of multilayered defense and homeostasis mechanisms. Conversely, proteins associated with central carbon metabolism, carbohydrate uptake, and ribosome-dependent translation were repressed, suggesting reduced growth investment and energy conservation under severe selenite pressure. Overall, this study provides a systems-level proteomic framework for understanding Se(IV) resistance in R. qingshengii PM1 and identifies candidate targets for future functional validation, strain engineering, and selenium/metal(loid) bioremediation. Full article

Hepatocellular carcinoma (HCC) remains a malignancy with poor prognosis and limited therapeutic targets. Emerging evidence suggests a critical role for iron metabolism and ferroptosis in tumor progression. However, the involvement of hematopoietic lineage cell-specific protein 1 (HAX1) in HCC, particularly its regulatory role in ferroptosis, remains largely unknown. Here, we report that HAX1 is significantly upregulated in HCC tissues and correlates with advanced pathological stages and poor patient survival, suggesting its potential as an oncogene. Functionally, HAX1 overexpression promotes the proliferation and migration of HCC cells, while its knockdown inhibits these malignant phenotypes. Mechanistically, we demonstrate that HAX1 acts as a negative regulator of ferroptosis. Silencing HAX1 sensitizes HCC cells to the ferroptosis inducer IKE, leading to abnormal accumulation of intracellular ferrous iron (Fe²⁺) and increased lipid reactive oxygen species (ROS). Conversely, HAX1 overexpression suppresses iron overload and lipid peroxidation. Furthermore, we reveal that HAX1 maintains redox homeostasis by regulating the GSH/GPX4 antioxidant pathway. Knockdown of HAX1 depletes reduced glutathione (GSH), reduces glutathione peroxidase activity, and downregulates key ferroptosis defense proteins, including GPX4, FSP1, and SLC7A11. Our findings identify HAX1 as a critical promoter of HCC progression that functions by inhibiting ferroptosis through the modulation of iron homeostasis and the GSH/GPX4 pathway. Targeting the HAX1-mediated anti-ferroptotic mechanism may represent a promising therapeutic strategy for HCC treatment. Full article

Glutathione (GSH), the most abundant intracellular antioxidant, plays a central role in maintaining redox homeostasis, regulating immune responses, and protecting cellular integrity. In chronic diseases such as type 2 diabetes mellitus (T2DM), GSH deficiency is a consistent hallmark, contributing to oxidative stress, mitochondrial dysfunction, inflammation, and progressive organ damage. This review critically examines the efficacy and safety of GSH supplementation and precursor strategies, synthesizing evidence across mechanistic studies, clinical trials, and translational research. In T2DM, GSH augmentation has been linked to improved insulin sensitivity, reduced oxidative damage, and better microvascular outcomes, although findings remain preliminary and heterogeneous. Safety profiles across populations are highly favorable, with gastrointestinal discomfort being the most reported adverse effect and serious toxicities rare. Importantly, both acute and chronic studies reinforce the compatibility of GSH and its precursors with standard antiretroviral and antidiabetic therapies. Despite this encouraging data, significant research gaps remain. Standardization of biomarkers, dose–response mapping, and long-term outcomes are urgently needed to move from proof-of-concept to clinical trials. Future directions include integrating mechanistic endpoints such as mitochondrial function and multi-omic profiling, exploring targeted delivery systems, and embedding implementation science to ensure real-world feasibility and equity. Collectively, the emerging evidence supports GSH-centered strategies as promising adjuncts for oxidative stress-driven chronic disease. Rigorous, well-designed trials are now required to define their definitive role in clinical care. Full article