Search Results (117)

Membrane rupture, induced by lipid peroxidation, is a severe threat to osmotic balance, as membrane pores contribute to ferroptosis, an iron-dependent cell death. To alleviate osmotic stress, membrane constituents dynamically reconstruct the membrane and interact with intracellular molecules. Tumor-derived acidosis shift glycolysis-dependent metabolism toward lipid metabolism, increasing polyunsaturated fatty acids (PUFAs). PUFAs enhance membrane fluidity but make cancer susceptible to lipid peroxidation. Also, the ionization of phospholipids under low pH can accelerate membrane rupture. This stress can be mitigated by the redistribution of cholesterol, which maintains tension–compression balance and acts as antioxidants. When excessive reactive aldehydes—byproducts of lipid peroxidation—overwhelm cholesterol’s protective role, lipid peroxides promote membrane cracks. Moreover, a deficiency in glutathione can alter cholesterol’s function, turning it into a pro-oxidant. In contrast, ceramide, derived from membrane lipids, indirectly prevents ferroptosis by facilitating cytochrome c release. This review integrates recent findings on how membrane components and environmental stressors influence ferroptosis. It also suggests potential therapeutic strategies. This could advance our understanding of ferroptosis in cancer. Full article

Background/Objectives: Cognitive decline in older people is greatly affected by various risk factors, especially imbalances in trace elements. This study aimed to examine the relationships between serum levels of selenium, zinc, and copper and cognitive impairment. This study included 854 participants aged 63 to 85 years. Methods: We conducted clinical assessments of metabolic disorders and measured serum levels of selenium, zinc, and copper. Cognitive impairment was evaluated using the Mini-Cog test. Results: The primary analysis identified significant differences (all p < 0.05) in age, body mass index, waist circumference, various metabolic parameters (such as fasting plasma glucose, glycated hemoglobin, and plasma triglyceride levels) and some cardiometabolic indices between the groups with and without cognitive impairment. Further assessments using multiple logistic regression and receiver operating characteristic analysis showed an association between increased serum selenium and zinc levels and a protective effect against cognitive impairment. In contrast, elevated serum copper levels were identified as a risk factor for cognitive impairment. This analysis also demonstrated high sensitivity and specificity, along with established cut-off levels for all of the trace elements studied. Conclusions: The Mini-Cog test is an effective cognitive screening test for the older population. Our findings establish a significant association between the balanced status of key antioxidant trace elements and cognitive health. Specifically, adequate serum selenium and zinc levels are associated with enhanced cognitive performance, while elevated copper may indicate a pro-oxidant state detrimental to cognitive function. Consequently, these three elements offer promise as practical, accessible biomarkers for the early identification and risk stratification of individuals susceptible to cognitive impairment. Future research should prioritize clinical trials focused on targeted nutritional strategies—specifically optimizing dietary intake and/or supplementation of selenium and zinc while carefully managing copper balance—as a viable primary prevention approach to reduce the global burden of cognitive decline. Full article

Oxidative stress reflects an imbalance between pro-oxidants and antioxidants arising from physiological or environmental factors. Here, we applied our previously developed in situ microplate method for the simultaneous determination of antioxidant and pro-oxidant activities to compounds produced by plant cell cultures in vitro. The primary aim was to evaluate the added value of these compounds, which are widely used as additives in food, cosmetic, and pharmaceutical products. The secondary aim was to assess whether a predominance of pro-oxidant activity could limit their biotechnological production. Thirty-three compounds known to be produced by in vitro cultures (polyphenolic acids, flavonoids, quinones, alkaloids, etc.) were tested, and the pro-oxidant–antioxidant balance index (PABI) was calculated. Sixteen compounds showed measurable activities with DPPH₅₀/FRAP₅₀ values below 2 mM. Within this set, rosmarinic acid exhibited pronounced pro-oxidant behavior, whereas gallic acid, chlorogenic acid, and the anthocyanin cyanidin showed higher antioxidant potency and favorable PABI values. Such compounds may deliver added benefits when incorporated into food or cosmetic products and are unlikely to limit production in cell culture. Full article

Tempol, a synthetic nitroxide, exhibits dual antioxidant and pro-oxidant activity, requiring millimolar concentrations to induce oxidative stress, which limits its therapeutic use. Glutathione Peroxidase 4 (GPX4) is a critical lipid peroxidase that prevents ferroptosis, and its inhibition has emerged as a strategy to sensitize cancer cells to oxidative stress. To enhance Tempol’s efficacy, we investigated its interaction with ML210, a GPX4 inhibitor, in human colon (HT29) and gastric (CRL-1739) cancer cell lines. We quantified cell viability, oxidative stress markers (H₂O₂, Total Oxidant Status (TOS), and Total Antioxidant Status (TAS)) and endoplasmic reticulum (ER) stress proteins (ATF6, GRP78, and IRE1α) in in vitro assays. Synergy was assessed using Bliss independence analysis. The combination of Tempol (2 mM) and ML210 (0.05 μM) markedly reduced viability in both cell lines. Bliss analysis revealed slight/moderate synergy for cytotoxicity (Δ = +0.15 in HT29; Δ = +0.26 in CRL-1739) and strong synergy for H₂O₂ accumulation (Δ = +1.92–2.23 across replicates). In contrast, TOS showed moderate-to-strong antagonism across both cell lines, and TAS demonstrated slight synergistic or antagonistic effects. ER stress markers exhibited marker and cell line specific synergy: ATF6 showed strong synergy, IRE1α slight synergy in both lines, and GRP78 activation was highly variable, showing strong synergy in CRL-1739 cells but moderate antagonism in HT29 cells. These findings indicate that the cooperative action of Tempol and ML210 is ROS-pool–specific and pathway-selective in the ER. These findings demonstrate that ML210 potentiates Tempol’s pro-oxidant pressure by targeting GPX4, selectively amplifying H₂O₂ accumulation and ER stress engagement without collapsing global redox balance. This study provides mechanistic rationale for redox–proteostasis co-targeting in gastric and colon cancers and establishes a foundation for in vivo validation. Full article

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

Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality worldwide, arising from complex interactions among metabolic, genetic, and environmental factors. Nicotinamide N-methyltransferase (NNMT) has recently emerged as a key metabolic regulator in CVD pathogenesis. By consuming nicotinamide and methyl groups, NNMT perturbs epigenetic, metabolic, and redox pathways that are critical for cardiovascular health. NNMT-mediated NAD⁺ depletion impairs mitochondrial function, sirtuin (SIRT) activity, redox balance, and energy metabolism, thereby creating a pro-atherogenic environment. NNMT and its product 1-methylnicotinamide (1-MNA) show a complex duality: they modulate SIRT activity—particularly SIRT1 and SIRT3—to influence gluconeogenesis, cholesterol synthesis, lipogenesis, and mitochondrial antioxidant defenses. NNMT upregulation also elevates homocysteine levels, activating pro-inflammatory and pro-oxidative cascades (e.g., TLR4–NF-κB and STAT3–IL-1β). Growing evidence links NNMT to major CVD risk factors, including hyperlipidemia, hypertension, diabetes mellitus, and obesity. Thus, NNMT has a multifaceted role in cardiovascular health: while its enzymatic activity is often pathogenic (via NAD⁺/SAM consumption and homocysteine production), its metabolite 1-MNA can exert protective effects (via NRF2 activation and anti-thrombotic mechanisms). This duality highlights the need to delineate the molecular processes that balance these opposing actions. Experimental studies using small-molecule NNMT inhibitors and RNA interference have shown promising cardiometabolic benefits in preclinical models, including improved insulin sensitivity, reduced atherosclerosis, and attenuated cardiac dysfunction. However, no clinical trials have yet targeted NNMT specifically in CVD. Future research should clarify the tissue-specific functions of NNMT and translate these insights into novel therapeutic strategies. Full article

The exposure to risk factors, such as cigarette smoke and air pollution (containing metabolic oxidants and toxic substances), leading to cellular and molecular alterations, promotes the development of lung cancer at multiple stages. The antioxidant defence system plays a critical role in counteracting the mechanisms of oxidative stress. In physiological conditions, the balance between pro-oxidant and antioxidant species is critically important for the correct performance of cellular functions. Its imbalance is accompanied by the onset and progression of various pathologic states, including lung cancer. Cell signalling pathways and non-coding RNAs play a crucial role in the mechanisms of carcinogenesis and in the development of resistance to conventional therapeutic treatments. The interplay between the oxidant/antioxidant system, transcription factors, and non-coding RNAs is involved in the development and in the pathogenesis of lung cancer. This review provides a comprehensive resource for researchers and clinicians to better understand this intricate system and its cellular interactions, with the aim of disseminating the knowledge of the mechanisms involved in both cancer development and the development of new anti-cancer therapeutic strategies. A thorough understanding of the interplay between oxidative stress mechanisms, the activity of transcription factors, and non-coding RNAs could improve the efficacy of drug treatments and open new pharmacological perspectives for the control of inflammation and disease progression in lung cancer. Full article

Background: The majority of parotid gland tumors are benign, e.g., pleomorphic adenoma (PA) and Warthin’s tumor (WT). From a biomedical point of view, oxidative stress is of significant importance due to its established association with the initiation and progression of various types of cancer, including parotid gland cancers. This study aimed to assess whether blood prooxidant–antioxidant markers could aid in diagnosing and guiding surgery for recurrent malignancies after parotid tumor treatment. Methods: We examined patients (n = 20) diagnosed with WT (n = 14) and PA (n = 6) using histopathological verification and computed tomography (CT) who qualified for surgical treatment. Blood samples were taken before the surgery and again 10 days later for biochemical analysis. The activities of the antioxidant enzymes (SOD, CAT and GPx), the non-enzymatic antioxidants (GSH and UA) and oxidative stress markers (MDA and TOS) were determined in the blood. The activities of CK and LDH and the concentrations of Cor and TAS were measured in the serum. Hb and Ht were determined in whole blood. Results: The patients’ SOD, CAT, and GPx activities after surgery did not differ significantly from their preoperative levels. However, following surgery, their serum TOS levels were significantly elevated in all the patients compared to baseline. In contrast, the plasma MDA concentrations were markedly reduced after surgery. Similarly, the GSH concentrations showed a significant decrease postoperatively. No significant changes were observed in the CK and LDH activities, TAS concentrations, or levels of Hb, Ht and Cor following surgery. Conclusions: The surgical removal of salivary gland tumors did not result in a reduction in oxidative stress at 10 days after surgery. Therefore, further studies are needed to determine the effectiveness of endogenous defense mechanisms in counteracting the oxidative stress induced by salivary gland tumors. Full article

Although emerging evidence suggests that epigenetic mechanisms contribute to the pathogenesis and progression of type 2 diabetes mellitus (T2DM), data remain limited for patients with suboptimal metabolic control. The aim of this study was to assess global DNA methylation in patients with poorly controlled T2DM and to identify diabetes-related factors associated with DNA methylation levels. The study included 107 patients and 50 healthy controls. Global DNA methylation (5mC) was measured by UHPLC-DAD method. Pro-oxidant and antioxidant biomarkers, advanced glycation end-products, high-sensitivity C-reactive protein (hsCRP) and complete blood count were determined and leukocyte indices calculated. Patients had a significantly lower 5mC than controls (3.56 ± 0.31% vs. 4.00 ± 0.68%; p < 0.001), with further reductions observed in those with longer disease duration and diabetic foot ulcers. Oxidative stress and inflammatory biomarkers were higher in the patient group. DNA hypomethylation was associated with a higher monocyte-to-lymphocyte ratio and hsCRP, pro-oxidant–antioxidant balance, ischemia-modified albumin, and advanced oxidation protein products levels. Conversely, 5mC levels showed positive correlations with total antioxidant status and total sulfhydryl groups. Principal component analysis identified five key factors: proinflammatory, pro-oxidant, aging, hyperglycemic, and antioxidant. The pro-oxidant factor emerged as the sole independent predictor of global DNA hypomethylation in T2DM (OR = 2.294; p = 0.027). Our results indicate that global DNA hypomethylation could be a biomarker of T2DM progression, reflecting the complex interactions between oxidative stress, inflammation, and epigenetic modifications in T2DM. Full article

In the present study, five novel dexketoprofen amide derivatives with a free carboxyl group in their side chains were synthesized. The in vivo anti-inflammatory potential of dexketoprofen derivatives was evaluated using a carrageenan-induced paw edema model of acute inflammation. Additionally, the local and systemic redox status in rats following acute administration of the compounds was assessed by measuring levels of pro-oxidative markers and the activity of antioxidant enzymes. Among the analyzed molecules, derivatives 2 and 4 exhibited the most potent in vivo anti-inflammatory activity, showing effects comparable to those of the parent compound dexketoprofen. In vitro results revealed that all newly synthesized compounds exhibited low inhibitory activity toward COX-1, whereas only compound 4 showed significant COX-2 inhibition. The stronger binding affinity of derivative 4 for COX-2 in comparison to other tested compounds is likely attributed to its ability to form multiple electrostatic interactions within the enzyme’s active site. Furthermore, compounds 2 and 5 demonstrated efficacy comparable to the parent drug in restoring redox balance, indicating their potential antioxidant properties under acute inflammatory conditions. The findings of this study underscore the therapeutic potential of the novel dexketoprofen amide derivatives as dual-function agents with the capacity to modulate both inflammatory responses and oxidative stress. Full article

Pemphigus-associated interstitial lung disease (P-ILD) is a severe complication observed in pemphigus patients that is characterized by pulmonary interstitial inflammation and fibrosis. This study investigated the role of anti-desmoglein (Dsg) 1/3 antibodies in P-ILD pathogenesis and evaluated the therapeutic potential of molecular hydrogen (H₂). Using a BALB/cJGpt mouse model, we demonstrated that anti-Dsg 1 antibodies, but not anti-Dsg 3 antibodies, induced interstitial inflammation and fibrosis. Immunofluorescence staining confirmed IgG deposition in the alveolar epithelium, suggesting immune complex formation and epithelial damage. Gene expression analysis revealed elevated pro-inflammatory cytokines (IL-1β, IL-13) and upregulated pro-fibrotic markers (α-SMA, S100A4, TGF-β, and collagen genes) in P-ILD progression. Elevated oxidative stress and impaired ROS metabolism further implied the role of oxidative damage in disease pathogenesis. To assess H₂’s therapeutic potential, hydrogen-rich water was administered to P-ILD mice. H₂ treatment significantly reduced oxidative stress, attenuated interstitial inflammation, and prevented pulmonary fibrosis. These protective effects were attributed to H₂’s antioxidant properties, which restored the pro-oxidant–antioxidant balance. Our findings underscore the critical role of anti-Dsg 1 antibodies and oxidative stress in P-ILD and highlight H₂ as a promising therapeutic agent for mitigating anti-Dsg 1 antibody-induced lung injury. Full article

Oxidative stress (OS) is an established hallmark of cancer and neurodegenerative disorders (NDDs), which contributes to genomic instability and neuronal loss. This review explores the contrasting role of OS in cancer stem cells (CSCs) and NDDs. Elevated levels of reactive oxygen species (ROS) contribute to genomic instability and promote tumor initiation and progression in CSCs, while in NDDs such as Alzheimer’s and Parkinson’s disease, OS accelerates neuronal death and impairs cellular repair mechanisms. Both scenarios involve disruption of the delicate balance between pro-oxidant and antioxidant systems, which leads to chronic oxidative stress. Notably, CSCs and neurons display alterations in redox-sensitive signaling pathways, including Nrf2 and NF-κB, which influence cell survival, proliferation, and differentiation. Mitochondrial dynamics further illustrate these differences: enhanced function in CSCs supports adaptability and survival, whereas impairments in neurons heighten vulnerability. Understanding these common mechanisms of OS-induced redox imbalance may provide insights for developing interventions, addressing aging hallmarks, and potentially mitigating or preventing both cancer and NDDs. Full article

Autophagy is a fundamental cellular process that maintains homeostasis by degrading damaged components and regulating stress responses. It plays a crucial role in cancer biology, including tumor progression, metastasis, and therapeutic resistance. Oxidative stress, similarly, is key to maintaining cellular balance by regulating oxidants and antioxidants, with its disruption leading to molecular damage. The interplay between autophagy and oxidative stress is particularly significant, as reactive oxygen species (ROS) act as both inducers and by-products of autophagy. While autophagy can function as a tumor suppressor in early cancer stages, it often shifts to a pro-tumorigenic role in advanced disease, aiding cancer cell survival under adverse conditions such as hypoxia and nutrient deprivation. This dual role is mediated by several signaling pathways, including PI3K/AKT/mTOR, AMPK, and HIF-1α, which coordinate the balance between autophagic activity and ROS production. In this review, we explore the mechanisms by which autophagy and oxidative stress interact across different hematological malignancies. We discuss how oxidative stress triggers autophagy, creating a feedback loop that promotes tumor survival, and how autophagic dysregulation leads to increased ROS accumulation, exacerbating tumorigenesis. We also examine the therapeutic implications of targeting the autophagy–oxidative stress axis in cancer. Current strategies involve modulating autophagy through specific inhibitors, enhancing ROS levels with pro-oxidant compounds, and combining these approaches with conventional therapies to overcome drug resistance. Understanding the complex relationship between autophagy and oxidative stress provides critical insights into novel therapeutic strategies aimed at improving cancer treatment outcomes. Full article

Objectives: Resveratrol (RES) is well documented for its multiple health benefits, with a notable impact on cancer prevention and therapy. This study aimed to evaluate the effect of RES supplementation on oxidative stress in patients with head and neck cancer (HNC) receiving home enteral nutrition (HEN). Methods: This randomized, single-center, open-label study involved 72 adult patients, with 40 completing the intervention. Participants in the intervention group received 400 mg of liposomal RES daily for 12 weeks alongside HEN, while the control group received HEN only. Body composition and oxidative stress markers—including total antioxidant capacity (TAC), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), and reduced glutathione (GSH)—were measured at baseline and after 12 weeks. Results: Significant increases in TAC and SOD activity were observed in both groups. GPx activity increased significantly only in the RES group. MDA levels rose in both groups but were more pronounced in the RES group. GSH levels showed no significant changes. Phase angle (PhA) increased significantly in the RES group, while no significant change was observed in the control group. Conclusions: RES supplementation may enhance antioxidant defenses, as evidenced by increased GPx activity and improvements in TAC and SOD levels, supporting oxidative balance in patients with HNC receiving HEN. The higher MDA levels in the RES group may reflect RES’s dual antioxidant and pro-oxidant activities. Additionally, the observed increase in PhA suggests potential cellular health benefits. These findings highlight the potential of RES as a complementary antioxidant intervention in clinical oncology, warranting further investigation to clarify its therapeutic effects on oxidative stress and cellular health in cancer care. Full article

Maximal physical effort induces a disturbance in the body’s energy homeostasis and causes oxidative stress. The aim of the study was to determine whether prooxidant–antioxidant balance disturbances and the secretion of adipokines regulating metabolism, induced by maximal intensity exercise, are dependent on body composition in young, healthy, non-obese individuals. We determined changes in the concentration of advanced protein oxidation products (AOPP), markers of oxidative damage to nucleic acids (DNA/RNA/ox), and lipid peroxidation (LPO); catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activity, as well as concentrations of visfatin, leptin, resistin, adiponectin, asprosin, and irisin in the blood before and after maximal intensity exercise in men with above-average muscle mass (NFAT-HLBM), above-average fat mass (HFAT-NLBM), and with average body composition (NFAT-NLBM). We corrected the post-exercise results for the percentage change in plasma volume. In all groups after exercise, there was an increase in LPO and resistin. In HFAT-NLBM, additionally, an increase in CAT and a decrease in SOD activity were noted, and in NFAT-NLBM, an increase in visfatin concentration was observed. In our study, the effect was demonstrated of a maximal effort on six (LPO, CAT, SOD, visfatin, resistin, and asprosin) of the twelve parameters investigated, while the effect of body composition on all parameters investigated was insignificant. Maximal intensity aerobic exercise induces secretion of resistin and damages lipids regardless of the exercising subjects’ body composition. Large fat tissue content predisposes to exercise-induced disorders in the activity of antioxidant enzymes. We have also shown that it is necessary to consider changes in blood plasma volume in the assessment of post-exercise biochemical marker levels. Full article