Asthenozoospermia (AZS) is responsible for about 80 % of male infertility cases. Oxidative stress (OS) seems to be involved in cases of AZS otherwise termed "idiopathic," so antioxidant molecules have gained increasing interest in the treatment of infertility. In the present study, the in vitro effects of two different concentrations (12 and 30 µM) of resveratrol (RSV), a potent natural antioxidant, on sperm motility and OS counteragent of 154 subjects with AZS were evaluated. After 1 hour at 37 °C, the control group and the group treated with 12 µM of RSV showed a slight increase in progressive motility (PM) and a simultaneous decrease in non-progressive motility (NP). Conversely, the group treated with 30 µM of RSV showed a significant decrease in all motility parameters. Moreover, a significant decrease in Dichlorofluorescein (DCF) fluorescence intensity from controls (248.14 ± 111.16 a.u.) was observed both in group treated with 12 µM (152.47 ± 110.59 a.u., p < 0.0001) and 30 µM of RSV (128.06 ± 94.21 a.u., p < 0.0001). These findings support the hypothesis that excessive ROS reduction may lead to redox unbalance that could paradoxically worsen the seminal parameters of subjects with AZS when treated with excessive doses of antioxidants.

The interaction between metals and catecholamines plays a pivotal role in the generation of reactive oxygen species (ROS), leading to oxidative stress and DNA damage. ROS are linked to several diseases, including neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. This review examines how essential metals (iron, copper, zinc, manganese) and a few non-essential metal(loid)s (mercury, chromium, arsenic, aluminum, cadmium, and nickel) contribute to oxidative stress in the presence of catecholamines. In the presence of metals, catecholamines can cause oxidative DNA modification, possibly resulting in cell apoptosis, by taking part in redox reactions and oxidizing to the corresponding aminochrome with simultaneous ROS production. Essential metals are vital for physiological functions, but imbalances in their homeostasis can be harmful. Furthermore, non-essential metals, commonly encountered through environmental or occupational exposure, can exhibit significant toxicity. Previous studies on catecholamine-induced oxidative stress focused on copper and iron, but this review emphasizes the need to investigate other neurotoxic metals and expand existing knowledge on the interactions between metals, catecholamines, and DNA damage. Results from such research could help prioritizing the development of new assessment methods associated with adverse outcome pathways, to reliably predict harmful effects on human health, aiding in the development of therapeutical strategies. The present work will help to shed light on the interplay of metals, catecholamines, and DNA damage in different diseases hopefully fostering new research in this still understudied topic. Future research should investigate the molecular mechanisms through which these metals affect neuronal health and contribute to disease pathogenesis.

In this study, a dual-mode sensing system was developed for the determination of total antioxidant capacity (TAC) using the Fe(III)-phenanthroline (Fe(III)-phen) reagent. The first detection mechanism of the system is based on the reduction of the Fe(III)-phen reagent by antioxidants, leading to the formation of the orange-red Fe(II)-phen chelate, which is quantified by the absorbance change at 510 nm. The second mechanism exploits the oxidase-like activity of the Fe(III)-phen complex. This complex generates superoxide anion radicals that oxidize 3,3',5,5'-tetramethylbenzidine (TMB) to produce a blue-colored oxidized TMB (ox-TMB) charge-transfer complex. In the presence of antioxidants, this reaction is inhibited, resulting in a decrease in ox-TMB formation, and the absorbance change at 652 nm correlates with the TAC of the tested sample. The proposed system was successfully applied to standard antioxidants, synthetic antioxidant mixtures, and real food extracts, demonstrating its applicability and sensitivity for TAC analysis. The linear equation of the calibration graphs obtained for different trolox (TR) concentrations were found to be A510 = 0.0221CTR + 0.0223 (A: absorbance and C: concentration in μM) and ΔA = 0.0301CTR + 0.0583 (ΔA: the difference of absorbance resulting from decreasing ox-TMB formation in the presence of TR, and C: concentration in μM) for the reduction-based Fe(III)-phen method and the TMB-based Fe(III)-phen method, respectively. The limits of detection (LOD) for the reduction based Fe(III)-phen method and the TMB-based Fe(III)-phen method were found to be 0.45 and 0.87 μM, respectively, for trolox. The LOD was calculated using the equation; LOD = 3 sbl/m (sbl: standard deviation of a blank, m: slope of the calibration line). This study presents an innovative approach by utilizing the same probe, Fe(III)-phen, through two distinct mechanisms for the simple, rapid, and sensitive determination of TAC.

Prussian blue (PB) has garnered considerable scholarly interest in the field of biomedical research owing to its notably high biocompatibility, formidable multi-enzyme mimetic capabilities, and established clinical safety profile. These properties in combination with its reactive oxygen species (ROS) scavenging activity have facilitated significant progress in disease diagnosis and therapy for various ROS-mediated pathologies, where overproduced ROS exacerbates disease symptoms. Additionally, the underlying ROS-associated mechanisms are disease-specific. Hence, we systematically examined the role of ROS and its basic underlying mechanisms in representative disease categories and comprehensively reviewed the effect of PB-based materials in effectively alleviating pathological states. Furthermore, we present a thorough synthesis of disease-specific design methodologies and prospective directions for PB as a potent ROS-scavenging biotherapeutic material with emphasis on its applications in neurological, cardiovascular, inflammatory, and other pathological states. Through this review, we aim to accelerate the progress of research on disease treatment using PB-based integrated therapeutic system.

Depression is a chronic and recurrent neuropsychiatric disorder with complex pathophysiology. Dihydromyricetin (DMY), a bioactive flavonoid compound isolated from Ampelopsis grossedentata (commonly known as rattan tea), has demonstrated multiple pharmacological properties including anti-inflammatory, antioxidant, antitumor, and antimicrobial activities. In the present study, a well-established rodent model of depression was generated through chronic unpredictable mild stress (CUMS) paradigm combined with social isolation. Following eight weeks of DMY intervention, comprehensive behavioral assessments were conducted to validate both the successful establishment of the depression model and the therapeutic efficacy of DMY treatment. We employed network pharmacology approaches to systematically predict potential antidepressant targets of DMY. Further mechanistic investigations were performed to elucidate the underlying molecular pathways, providing novel perspectives for developing innovative antidepressant therapeutics.Integrating network pharmacology prediction with molecular biology validation, our findings revealed that DMY exerts significant antidepressant-like effects through suppression of the advanced glycosylation end products (AGEs)-RAGE signaling pathway, activation of the nuclear factor E2-related factor 2 (NRF2)-mediated antioxidant defense system, and upregulation of synaptic plasticity-related proteins including postsynaptic density protein 95 (PSD95) and synaptophysin (SYP). These results suggest that DMY may represent a promising natural therapeutic candidate for depression treatment.

Parkinson's disease (PD) is a multifactorial neurodegenerative disorder driven by genetic predisposition and environmental exposure. Given its well-documented antioxidative and neuroprotective properties, resveratrol is increasingly being considered for its potential to counteract the neuronal damage characteristic of Parkinson's disease. Here, we investigated the therapeutic action of resveratrol in a transgenic Drosophila melanogaster model expressing human α-synuclein (SNCA, PD flies), in combination with network pharmacology and molecular docking analyses. The PD flies were fed diet supplemented with resveratrol (15, 30, and 60 mg/kg diet, approximately 6.57, 13.14 and 26.28 mM, respectively), to evaluate lifespan. This was followed by a 21-day treatment of PD flies with similar concentrations of resveratrol in the diet to evaluate cognitive function, oxidative stress, and antioxidant biomarkers, using Levodopa (0.1 mM) as positive control. The results showed that resveratrol supplementation in the diet significantly improved lifespan, locomotor activity, acetylcholinesterase and catalase activities, and thiol content compared to untreated PD flies. Furthermore, resveratrol reduced nitric oxide (nitrite/nitrate), malondialdehyde, and total hydroperoxide levels, and enhanced cellular metabolic activity and upregulated Sod1 mRNA expression (p < 0.05). The network pharmacology and molecular docking analyses identified key molecular targets that may account for the therapeutic action of resveratrol, including B-Cell Lymphoma 2, Monoamine Oxidase (MAO); in flies, MAO-Like, Dopa Decarboxylase, Protein Kinase A and Glycogen Synthase Kinase-3 (GSK-3). Among these, MAO and GSK-3 emerged as top targets as indicated by network prominence and strong binding interactions. Additionally, the binding interaction of resveratrol to SNCA at specific sites suggests a potential role in inhibiting its aggregation, which is a hallmark of PD pathology. Quantum mechanics calculations revealed that resveratrol functions as both a proton donor and acceptor, contributing to its strong target binding interactions and antioxidant potential. Overall, resveratrol supplementation in the diet may be beneficial for PD management by modulating dopamine metabolism, apoptosis, oxidative stress, and cell survival. The study provides valuable experimental and computational insights into the underlying therapeutic mechanisms of action of resveratrol and supports its potential use in PD management.

This study aimed to investigate autophagy and its associated mechanisms in periodontal ligament stem cells (PDLSCs) within the inflammatory microenvironment of type 2 diabetes mellitus (T2DM) and periodontitis. Periodontal ligament tissues were obtained from healthy individuals, individuals with T2DM, individuals with chronic periodontitis, and individuals with both T2DM and periodontitis. PDLSCs were isolated, cultured, and treated with the autophagy inhibitor 3-methyladenine (3-MA) and the autophagy activator rapamycin (Rapa). Cell proliferative capacity was evaluated, autophagic activity and organelle damage were assessed using transmission electron microscopy, and the relative expression levels of autophagy-related genes (Beclin-1, LC3 II, P62) were measured using real-time quantitative PCR. Compared to PDLSCs derived from healthy individuals, those from individuals with chronic periodontitis or T2DM exhibited no significant morphological differences but demonstrated reduced proliferative capacity. Treatment with 3-MA and Rapa did not significantly alter proliferative capacity across groups. PDLSCs from individuals with chronic periodontitis and T2DM displayed increased autophagosome formation, more severe organelle damage, and upregulated expression of autophagy-related genes Beclin-1 and LC3 II, while P62 expression was downregulated, compared to PDLSCs from healthy individuals. PDLSCs from individuals with T2DM and periodontitis exhibit excessive autophagy and organelle damage. Autophagy dysregulation in PDLSCs within a diabetic and inflammatory microenvironment may contribute to the severity of periodontal destruction observed in individuals with T2DM.

The accumulation of reactive oxygen species (ROS) in the skin following UVB exposure is a key contributor to ultraviolet-induced skin photodamage. Orientin, a bioactive flavonoid, has demonstrated antioxidant properties in previous studies. However, its efficacy in treating skin photodamage remains inadequately understood. This study investigates the effects of orientin in preventing UVB-induced immortalized human keratinocytes (HaCaT cells) and BALB/c mouse skin photodamage by activating the AMPK/Nrf2 axis. Results show that orientin protects HaCaT cell viability after UVB exposure, reduces ROS levels, and upregulates antioxidant enzymes, including SOD1, HO-1, and NQO-1, while concurrently suppressing the expression of inflammatory mediators such as COX-2, IL-6, and IL-8. Additionally, orientin promotes AMPK phosphorylation, which facilitates Nrf2 nuclear translocation, thereby enhancing the antioxidant defense of cells. This effect is diminished upon inhibition of AMPK or Nrf2. In the BALB/c mouse model of photodamage, topical application of orientin alleviates symptoms like skin roughness, scaling, and erythema induced by UVB irradiation, while also elevating antioxidant enzyme expression in skin tissues. These findings suggest that orientin mitigates ultraviolet-induced skin photodamage both in vitro and in vivo, boosts cellular antioxidant capacity, and diminishes inflammatory responses, suggesting its potential for further exploration in skin photodamage management.

Wilson disease (WD), a rare autosomal-recessive disorder caused by impaired copper metabolism, leads to hepatic dysfunction and copper overaccumulation, debilitating neurological symptoms. Current treatments, primarily metal chelating agents and antioxidants, have limitations like sub-optimal efficacy, limited blood-brain barrier transport, and systemic side effects. This study aims to deliver monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA), a novel next-generation chelator encapsulated in a liposomal nanocarrier coated with apolipoprotein E (ApoE) to enhance brain targeting and copper chelation. ApoE-coated liposomal formulation is optimized using the Box-Behnken design (BBD). This was followed by comprehensive characterization like dynamic light scattering, scanning electron microscopy, drug-excipient compatibility studies, and in vitro drug release kinetics. Additionally, the developed formulation was investigated on the human neuroblastoma cells (SH-SY5Y) demonstrating safety, biocompatibility, and cell internalization efficacy within 24 h. Bioimaging studies further demonstrated significant brain permeability of the ApoE-coated MiADMSA liposomes, comparable to uncoated MiADMSA liposomes, followed by pharmacodynamic evaluations. Morphometric analysis, behavioral studies, biochemical estimations, and histopathological assessments confirmed the efficacy of ApoE-coated MiADMSA liposomes. The optimized formulation demonstrated sustained release, excellent encapsulation efficiency of up to 90.29%, and a nanosized spherical shape (141.3 ± 1.26 nm). Effective internalization, biocompatibility, and neuroprotection were validated by cellular investigations. ApoE-MiADMSA-LPS showed notable BBB penetration in in vivo imaging. Biochemical examination indicated less oxidative stress (lower MDA, higher SOD, CAT, and GSH levels), while behavioral investigations demonstrated enhanced cognitive and motor abilities. The optimized liposomal formulation demonstrated enhanced brain targeting, cellular uptake, and neuroprotection, making it a promising therapeutic approach for Wilson disease.

The beneficial effects of ammonium nitrate and potassium humate on carrots are well-documented. However, their impact on physiological and biochemical mechanisms under varying irrigation conditions still needs to be explored. Here, we investigated the effects of soil-applied ammonium nitrate and foliar-applied potassium humate on the physio-chemical characteristics and water use efficiency of carrot plants under three irrigation levels: 100%, 80%, and 60% of crop evapotranspiration (ETc). Carrot plants were treated with two rates of soil ammonium nitrate (200 and 250 kg N ha- 1), foliar potassium humate (200 and 400 g 100 L- 1), and four combinations of these treatments. Under 80% of ETc, the combined applications of soil ammonium nitrate and foliar potassium humate significantly influenced the leaf contents of chlorophyll a, nitrate, ammonium, catalase, carbohydrate, and soluble sugar patterns, enhancing osmotic regulation under water deficit conditions. Interestingly, when carrots were irrigated by 100% of ETc instead of 80 and 60% and sprayed with 400 g 100 L- 1 of potassium humate in combination with 250 kg N ha- 1 of ammonium nitrate, water use was decreased by 49.2 and 30.7%, respectively. We attributed that to: a), the observed increments in NH4 concentrations in the leaves under 100% ETc which caused negative physiological impacts on chlorophyll, and b) the change in C/N and N/P ratios. This highlights the importance of choosing a suitable irrigation pattern for carrot crops when the potassium humate in combination with ammonium nitrate is adapted. Overall, using foliar potassium humate at a rate of 200 g 100 L- 1 with soil ammonium nitrate applications at 250 kg N ha- 1 under 80% ETc attained the highest yield and water use efficiency.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting millions worldwide and imposing a significant social and economic burden. Despite extensive research, there is still no effective cure for this disease. AD is multifactorial and involves multiple etiopathogenic mechanisms, one of which is oxidative stress. Consequently, the Nrf2/ARE pathway, which regulates the expression of cellular defense genes, including those for antioxidant enzymes, is considered to be a prospective therapeutic target for AD. Meanwhile, multitarget-directed ligands (MTDLs) are a promising approach for developing effective AD medications. In this regard, we evaluated the antioxidant potential of eight chromone-containing MTDLs in vitro, including Nrf2 transcriptional activation potencies, Nrf2/ARE downstream genes activation, and antioxidant effects in vitro. All tested compounds effectively activated the Nrf2/ARE pathway. Notably, compounds 4b, 4c, 4f, and 4h demonstrated the highest Nrf2 activation potencies, while compounds 4b, 4c, 4d, and 4g significantly induced the expression of Nrf2-target antioxidant genes, specifically NQO1 and HO1. Additionally, compound 4d exhibited a significant antioxidant effect in vitro. These findings encourage further investigation of the studied compounds, with particular emphasis on compound 4d as the most promising candidate.

Doxorubicin is a commonly used chemotherapy that rapidly accumulates in skeletal muscle and disrupts nitric oxide (NO) formation. However, studies investigating these effects have largely been performed in tumour-free models, therefore it remains unknown whether intramuscular accumulation and disruptions to NO content persist during tumour growth. Female C57bl/6 mice (n = 8/group) were randomly assigned to true control, doxorubicin control, tumour only, or tumour plus doxorubicin groups. Tumours were grown for 21, 24, or 28 days using E0771 cells. Doxorubicin was administered as a single 10 mg/kg intraperitoneal dose on day 21. Doxorubicin accumulation was similar in muscle with and without tumours present. Doxorubicinol, a metabolite of doxorubicin, was elevated (p < 0.05) in 24-day tumour + doxorubicin compared to doxorubicin alone. NO was similar across all groups in muscle; however, tumour NO was 15-fold higher at day 21 compared to 24, or 28 days (p < 0.05). The results confirm that doxorubicin is sequestered in skeletal muscle when a tumour is present, which may impact bioavailability. Tumour growth transiently increased intramuscular doxorubicinol, potentially exacerbating the toxicity of the drug. Earlier stage tumour growth appeared to profoundly elevate NO, which could suggest temporal angiogenesis and vasodilation to facilitate growth.

Multiple sclerosis is an inflammatory disease of the central nervous system (CNS), characterized by oligodendrocyte loss and demyelination of axons leading to neurodegeneration and severe neurological disability. Despite the existing drugs that have immunomodulatory effects an adequate therapy that slow down or stop neuronal death has not yet been found. Oxidative stress accompanied by excessive release of iron into the extracellular space, mitochondrial damage and lipid peroxidation are important factors in the controlled cell death named ferroptosis, latterly recognized in MS. As the fullerenols exhibit potent antioxidant activity, recent results imply that they could have protective effects by suppressing ferroptosis. Based on the current knowledge we addressed the main mechanisms of the protective effects of fullerenols in the CNS in relation to ferroptosis. Inhibition of inflammation, iron overload and lipid peroxidation through the signal transduction mechanism of Nuclear Factor Erythroid 2-Related Factor 2 (NRF2), chelation of heavy metals and free radical scavenging using fullerenols are proposed as benefitial strategy preventing MS progression. Current review connects ferroptosis molecular targets and important factors of MS progression, with biomedical properties and mechanisms of fullerenols' actions, to propose new treatment strategies that could be addaptobale in other neurodegenerative diseases.

The fungal genus Trichoderma contains a vast array of species well known for their high opportunistic potential and adaptability to various ecological niches. The ability of many Trichoderma species to both colonize the rhizosphere and parasitize plant pathogenic fungi has led to their use in biological pathogen control for several decades. Reactive oxygen species (ROS) are linked to both the antagonism imposed by the mycoparasite Trichoderma and the elicited defence reaction by its fungal hosts during the mycoparasitic interaction. Trichoderma spp. likely tolerate higher levels of ROS compared with some of their host species, thereby giving them an advantage during the mycoparasitic interaction. In the present study, we investigated glutathione redox dynamics using the fluorescent reporter Grx1-roGFP2 stably expressed in Trichoderma asperellum following electrotransformation. Grx1-roGFP2 undergoes reversible changes in its excitation spectrum in response to variations in the cellular glutathione redox potential, providing a real-time indication of intracellular oxidative load. Considering the putative importance of ROS in mycoparasitic interactions, we performed live-cell imaging of the T. asperellum reporter strain interacting with the cereal pathogen Fusarium graminearum. Surprisingly, the glutathione redox potential did not change during this mycoparasitic interaction. We found no evidence that host-induced tip growth arrest within T. asperellum hyphae is induced by intracellular ROS accumulation. Furthermore, we show that the F. graminearum mycotoxins deoxynivalenol and zearalenone do not induce detectable changes in glutathione redox potential, even at very high concentrations. We infer that T. asperellum has a robust anti-oxidant defence system, supported by the observation that high concentrations of H2O2 are required to fully oxidize the reporter during in vivo calibration. We cannot rule out a role for ROS as a signal during mycoparasitic interactions, but, if present, this does not appear to be mediated by glutathione redox potential.

Microcystin-LR (MC-LR), a cyclic heptapeptide produced by freshwater cyanobacteria, induces a range of liver injuries. However, the mechanisms underlying MC-LR toxicity in primary hepatocytes of aquatic organisms remains poorly understood. In this study, we investigated the effects of MC-LR on oxidative stress and mitochondrial function using primarily cultured grass carp hepatocytes. The results revealed that IC50 of MC-LR on grass carp primary liver cells for 24 hours was 2.40 μmol/L. Based on 24h-IC50, concentrations of 0, 0.30, 0.60, and 1.20 μmol/L were used in subsequent experiments. MC-LR exposure led to a significant reduction in cell viability, induced abnormal cell morphology, and caused plasma membrane rupture, as indicated by elevated LDH activity in a concentration-dependent manner. Additionally, MC-LR exposure induced oxidative stress, resulting in increased ROS levels and downregulation of genes associated with oxidative stress, including keap1, nrf2, cat, sod1, gpx, gst, and gr (P<0.05). Furthermore, the electron microscopy results showed that MC-LR caused damage to the ultrastructure of primary hepatocytes, including mitochondrial membrane rupture, vacuolation, and induction of mitochondrial autophagy. Moreover, MC-LR exposure elevated intracellular Ca2+ concentration, reduced MMP and ATP levels, and inhibited mitochondrial respiratory chain complex I activity (P<0.05). qRT-PCR analysis demonstrated that MC-LR treatment significantly decreased the transcriptional levels of genes related to mitochondrial quality control including pgc-1α, tfam, nrf1, drp1, opa1, mfn1, and mfn2 (P<0.05). Collectively, our findings highlight that MC-LR causes oxidative stress and impairs mitochondrial function, leading to further hepatocyte damage, which provides insights into the mechanisms of MC-LR-induced hepatotoxicity and offers valuable references for further investigations.

Longevity is influenced by various factors, including fatty acid composition and free radical stress, which relate to the membrane pacemaker and rate of living hypotheses. While these aspects are well-documented in some long-lived species, they remain largely unexplored in tree squirrels. This study aimed to compare oxidative stress, antioxidant activity, nitrosative stress, and lipid composition between the long-lived Persian squirrel (Sciurus anomalus) and the short-lived Wistar rat across age cohorts (younger and older). Tissue homogenates from skin, liver, skeletal muscle, spleen, lung, and kidney were analysed for lipid composition (monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), arachidonic to linoleic acid ratio, peroxidation index, and unsaturation index. Oxidative, nitrosative, and antioxidant markers were assessed, including NADPH oxidase, superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase (GST), nitric oxide synthase, superoxide, hydrogen peroxide, nitric oxide, malondialdehyde, 4-hydroxynonenal, and total antioxidant capacity (TAC). Squirrels demonstrated higher GST activity, lower free radical stress, lower PUFA, and higher MUFA compared to rats. Antioxidant activities, except for TAC were negatively correlated with longevity. Older squirrels exhibited similar oxidative, nitrosative, and antioxidant profiles to younger squirrels, whereas younger rats displayed highly susceptible fatty acids, similar to older rats. The Persian squirrel's longevity appears closely linked to fatty acid composition and free radical resistance, likely due to increased GST activity. We propose GST's multifunctional role in reducing inflammation, enhancing immune response, providing disease resistance, and antioxidant activity contributes significantly to the longevity of the Persian squirrel.

The majority of oral and topical skin-whitening products, as well as chemical peels, are commonly used to treat chloasma, a challenging skin pigmentation disorder. However, the therapeutic efficacy of these treatments often falls short of patients' expectations and is accompanied by notable side effects. Oxidative stress, characterized by an imbalance between oxidation and antioxidation, plays a crucial role in various clinical conditions and leads to oxidative damage, including cellular dysfunction, DNA damage, protein and lipid peroxidation, and even irreversible cell death. Recent research has shown that the onset of chloasma is closely associated with oxidative stress. This review explores the role of oxidative stress in the pathogenesis of chloasma and examines the related signaling pathways and biomarkers. Our findings suggest that antioxidant therapy can enhance the effectiveness of chloasma treatment by inhibiting tyrosinase activity and reducing melanin production. We hope this review will provide a theoretical foundation for future antioxidant-based treatments for chloasma.

Little is known regarding the pulmonary effects induced by the inhalation of menthol-flavored e-cigarette aerosols on asthma exacerbation, despite the popularity of these devices and flavors among youth and young adults. In the lungs, matrix metalloproteinase 12 (MMP12) expressed and secreted by both alveolar macrophages and bronchial epithelial cells plays an essential role in airway remodeling, a key feature of severe asthma. In this study, we investigated the role of MMP12 in menthol-flavored e-cigarette aerosol exposures plus house-dust mite (HDM)-induced asthmatic responses.

We exposed wild-type (WT) and MMP12 knockout (KO) juvenile female mice to well-characterized menthol-flavored e-cigarette aerosols followed by either PBS or HDM treatment, and evaluated pulmonary outcomes in terms of iron metabolism, oxidative stress responses and pulmonary inflammation.

We found high levels of iron in the menthol-flavored e-cigarette aerosol. This correlated with e-cigarette + HDM WT mice exhibiting disruption of pulmonary iron metabolism, suggesting a defense mechanism against iron-mediated toxicity. This was evidenced by altered lung protein concentrations of ferroportin, ferritin, lactoferrin, and transferrin, activation of the antioxidant response element (ARE) pathway and up-regulated expression of NQO1 in e-cigarette + HDM WT mice. Further, despite decreased neutrophilic inflammation, MUC5AC, an oxidative stress inducible mucin, was increased in the e-cigarette + HDM WT mice. In contrast, MMP12 KO mice were protected against iron-induced oxidative stress responses, highlighting a crucial role of MMP12 in this model.

These findings revealed in vivo evidence supporting a crucial role for iron metabolism in nicotine salt iron-rich ENDS aerosol toxicity.

Reactive oxygen species (ROS) are mainly generated as a result of cellular metabolism in plants and animals, playing a crucial role in cellular signaling mechanisms. The excessive generation of ROS leads to oxidative stress, which is associated with numerous diseases such as cancer, diabetes, and neurodegenerative disorders. Superoxide (O2˙-), hydrogen peroxide (H2O2), and hydroxyl radicals (˙OH) are the most common ROS involved in a wide range of human diseases. Therefore, sensitive and selective detection of these ROS is of paramount importance for understanding their roles in biological systems and for disease diagnosis. Among the various detection methods, electrochemical techniques have gained significant attention due to their high sensitivity, selectivity, and real-time monitoring capabilities. Electrochemical methods incorporate both organic and inorganic molecules to detect and monitor ROS, facilitating a deeper understanding of how their levels influence diseases linked to oxidative stress. This review aims to provide a critical discussion on the recent advances in electrochemical methods for detecting O2˙-, H2O2, and ˙OH. The review also highlights the application of these electrochemical techniques in detecting ROS in living cells and discusses the challenges and future perspectives in this field.

Arsenic-mediated neurodegenerative disorders affect millions of individuals globally, but the specific impact of environmental arsenic on adult cerebellar degeneration and neurogenesis is incompletely understood. Of particular concern is arsenic-induced apoptosis-driven neurodegeneration. Our major objective was to investigate the molecular signaling intricacies associated with arsenic-induced death of cerebellar neurons and to propose folic acid as a possible intervention. Swiss albino mice were treated with sodium arsenite (orally: 0.05 mg/L) and folic acid (orally:10 mg/kg) for 28 days. We observed that arsenic caused noticeable cell loss with morphological alterations in cerebellum, which was remarkably restored by folic acid. Arsenic-induced morphological alterations consequently perturbed transcriptional activities of neural stem cell factors-SOX2 and KLF9, which resulted in the suppression of pro-neurogenic mediators NeuroD1, Neurogenin2, calbindin and NeuN. Interestingly, folic acid reversed the expression of these critical pro-neurogenic mediators to mitigate these degenerative changes to promote neurogenesis. Delving deep, we found that folic acid rescued arsenic-exposed cerebellum from severe oxidative and pro-inflammatory insults by increasing antioxidants like SOD, Catalase, GSH, upregulating Nrf2 and downregulating M1 macrophages, JNK, NF-κB, and STAT3 activities. For the first time, we are reporting that arsenic induced a G1/S cell cycle arrest and triggered apoptosis in mouse cerebellum by activating the p53-p21 axis, downregulating CDKs and instigated p21-mediated suppression of SOX2 transcriptional activity. Folic acid abated such alterations by modulating the p53/p21/SOX2 axis. Collectively, the anti-apoptotic and pro-neurogenic effects of folic acid present it as a promising therapeutic candidate, warranting further research into its efficacy against metal-induced neurodegenerative disorders.

Nasopharyngeal Carcinoma (NPC) is a major public health problem in endemic zones. NPC is correlated with substantial illness and death; thus, superior treatment is desired. Rosmanol (RM) is a phenolic diterpene antioxidant extracted from the medicinal herb Rosemary (Rosmarinus officinalis). RM has been investigated for its anti-inflammatory and anti-tumor properties by numerous signaling cascades. However, the fundamental anticancer latent mechanism of RM persists as unidentified. Hence, this present research proposes to search for the anti-cancer efficacy of RM on human NPC cells CNE2 using an in vitro approach. To assess the possible molecular mechanisms of proliferation, apoptosis, cell-cycle regulatory proteins, and MAPKs/NF-κB signaling of NPC cells were administered RM (20 and 30 µM) and assayed through MTT, DCFH-DA, Rh-123 staining, AO/EB, PI, Rh-123/DAPI merge form staining, RT-PCR, and Western blot. The result was recognized that RM could reduce NPC cell viability by elevated intracellular ROS, MMP damage, and generate apoptosis. RM inhibits the Cyclin-D1, Bax, TNF-α, and NF-κB, and induces BCl-2 analyzed via RT PCR. RM attenuates the cell cycle mechanism by repressing NPC cell cycle-related proteins: CDK4/CDK6, pRB, cyclin-D1, and MAPKs/NF-κB signaling. These data established that the MAPKs/NF-κB pathway is a potential target for the remedial action of RM. In summary, RM may be an effective conventional chemotherapy drug in preventing the progression of NPC.

Acute lung injury (ALI) is a life-threatening complication of influenza A virus (IAV) infection, characterized by high morbidity and mortality. Recent studies have implicated ferroptosis, a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation, in the pathogenesis of IAV-induced ALI. However, the underlying mechanisms and key regulators of IAV-induced ferroptosis remain largely unknown. In this study, we found that IAV infection induces predominant ferroptosis in alveolar and bronchial epithelial cells, contributing to tissue damage and the development of acute lung injury. Treatment with the ferroptosis inhibitor ferrostatin-1 improved survival, mitigated weight loss, and alleviated lung injury in IAV-infected mice. Mechanistically, IAV-induced ferroptosis was associated with excess lipid peroxidation, nitrative stress, and disrupted iron metabolism. Targeted lipidomic analysis revealed that phospholipid peroxidation is a crucial mechanism in IAV-induced ferroptosis. Importantly, we identified indoleamine 2,3-dioxygenase 1 (IDO1) as a key regulator of IAV-induced ferroptosis. IDO1 knockdown inhibited IAV-induced cell death, and reduced intracellular reactive oxygen species, peroxynitrite, and inducible nitric oxide synthase expression. Furthermore, pharmacological inhibition of IDO1 with 1-methyl-tryptophan improved ALI phenotype in IAV-infected mice. These findings highlight the critical role of ferroptosis in IAV-induced ALI pathogenesis and identify IDO1 as a potential therapeutic target for the treatment of this life-threatening condition.

Uremic cardiomyopathy (UC) is a significant cardiovascular complication in individuals with end-stage renal disease. This review aims to explore the multifaceted landscape of UC, including the key pathophysiological mechanisms, diagnostic challenges, and current therapeutic approaches. The prevalence of cardiac hypertrophy, as a hallmark of UC, is highlighted and some new insights to its intricate pathogenesis, involving uremic toxins, oxidative stress, and inflammatory responses is elucidated. Diagnostic complexities, including the absence of specific biomarkers, are discussed, and the need for advanced imaging modalities and emerging diagnostic strategies are emphasized. Current therapeutic interventions, although lacking specificity, are addressed, paving its way to the potential future directions in targeted therapies. The review concludes new insights into the critical importance of ongoing research and technological advancements which will enhance early detection, precision treatment, and ultimately improve outcomes for individuals with UC.

Epilepsy, affecting approximately 50 million individuals worldwide, is a neurological disorder characterized by recurrent seizures. Mitochondrial dysfunction and oxidative stress are critical factors in its pathophysiology, leading to neuronal hyperexcitability and cell death. Because of the multiple mitochondrial pathways that can be involved in epilepsy and mitochondrial dysfunction, it is optimal to treat epilepsy with multiple antioxidants in combination. Recent advancements highlight the potential of antioxidant therapy as a novel treatment strategy. This approach involves tailoring antioxidant interventions-such as melatonin, idebenone, and plant-derived compounds-based on individual mitochondrial health, including mitochondrial DNA mutations and haplogroups that influence oxidative stress susceptibility and treatment response. By combining antioxidants that target multiple pathways, reducing oxidative stress, modulating neurotransmitter systems, and attenuating neuroinflammation, synergistic effects can be achieved, enhancing therapeutic efficacy beyond that of a single antioxidant on its own. Future directions include conducting clinical trials to evaluate these combination therapies, and to translate preclinical successes into effective clinical interventions. Targeting oxidative stress and mitochondrial dysfunction through combination antioxidant therapy represents a promising adjunctive strategy to modify disease progression and improve outcomes for individuals living with epilepsy.

Phosphorylated nitrones belong to an important class of compounds with several applications, such as their therapeutic potency to reduce oxidative stress or as spin-trapping agents. This review covers available synthetic methods for the preparation of both non-cyclic and cyclic phosphorylated nitrones, including the possibilities of the modification of structures with selected functional groups, as well as examples of their application. As reported, the incorporation of diethoxyphosphoryl function into the structure of PBN and DMPO resulted in obtaining their phosphorylated analogs, i.e., N-benzylidene-1-diethoxyphosphoryl-1-methylethylamine N-oxide (PPN) and 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline-N-oxide (DEPMPO), respectively, both forming spin adducts of improved stability in comparison to the reference non-phosphorus nitrones. Moreover, antioxidant and neuroprotective activity observed in the group of phosphorylated nitrones makes them promising candidates for therapeutics.

Carvacrol is a common ingredient in the pharmaceutical, cosmetic, and perfume industries. It possesses various pharmaceutical properties including pain relief, anti-cell death, antioxidant, anti-cancer, and anti-inflammatory effects. We investigated the protective impact of carvacrol on infertility caused by varicocele in rats. The animals were assigned to nine groups randomly: control, sham-operated, carvacrol alone at 10, 20, and 40 mg/kg b.w./day, varicocele-induced control, and varicocele-induced rats treated with carvacrol. After thirty days of treatment, the serum was collected to evaluate testosterone levels, and left epididymal sperm samples were obtained to assess sperm quality. Additionally, the left testis was removed for biochemical and histopathological evaluation. The findings demonstrated that carvacrol administration (20 and 40 mg/kg) notably improved sperm quality in rats with varicocele. Furthermore, carvacrol treatment (20 and 40 mg/kg) increased antioxidant levels, reduced MDA levels, decreased AQP9 expression in testicular tissue, and improved testicular tissue structure. Hence, carvacrol (20 and 40 mg/kg) may serve as a therapeutic agent for male reproductive system disorders, particularly varicocele-related infertility, due to its antioxidant properties and protective effects on testicular function.

Cisplatin is widely used in clinical cancer treatment; however, its application is often hindered by severe side effects, particularly inherent or acquired resistance of target cells. To address these challenges, an effective strategy is to modify the metal core of the complex and introduce alternative coordination modes or valence states, leading to the development of a series of metal complexes, such as platinum (IV) prodrugs and cyclometalated complexes. Recent advances in nanotechnology have facilitated the development of multifunctional nanomaterials that can selectively deliver drugs to tumor cells, thereby overcoming the pharmacological limitations of metal-based drugs. This review first explores the self-assembly of metal complexes into spherical, linear, and irregular nanoparticles in the context of biomedical applications. The mechanisms underlying the self-assembly of metal complexes into nanoparticles are subsequently analyzed, followed by a discussion of their applications in biomedical fields, including detection, imaging, and antitumor research.

Heat stress impacts all aspects of life, from evolution to global food security. Therefore, it becomes essential to understand how plants respond to heat stress, especially in the context of climate change. The heat stress response (HSR) involves three main components: sensing, signal transduction, and cellular reprogramming. Here, I focus on the heat stress sensing component. How can cells detect heat stress if it is not a signalling particle? To answer this question, I have looked at the molecular definition of heat stress. It can be defined as any particular rise in the optimum growth temperature that leads to higher-than-normal levels of reactive molecular species and macromolecular damage to biological membranes, proteins, and nucleic acid polymers (DNA and RNA). It is precisely these stress-specific alterations that are detected by heat stress sensors, upon which they would immediately trigger the appropriate level of the HSR. In addition, the work towards thermotolerance is complemented by a second type of response, here called the cellular homeostasis response (CHR). Upon mild and extreme temperature changes, the CHR is triggered by plant thermosensors, which are responsible for monitoring temperature information. Heat stress sensors and thermosensors are distinct types of molecules, each with unique modes of activation and functions. While many recent reviews provide a comprehensive overview of plant thermosensors, there remains a notable gap in the review literature regarding an in-depth analysis of plant heat stress sensors. Here, I attempt to summarise our current knowledge of the cellular sensors involved in triggering the plant HSR.

High-entropy alloy (HEA) nanoparticles possess finely tunable and multifunctional catalytic activity due to their extremely diverse adsorption sites. Their unique properties enable HEA nanoparticles to mimic the complex interactions of the redox homeostasis system, which is composed of cascade and multiple enzymatic reactions. The application of HEAs in mimicking complex enzymatic systems remains relatively unexplored, despite the importance of regulating biological redox reactions. Here, it is reported that ultra-small (<10 nm in a diameter) HEA nanozymes consisting of five platinum-group metals with tunable morphologies from planar to dendritic structures are synthesized. The synthesized HEA nanozymes exhibited higher peroxidase-like activity compared to monometallic platinum-group nanoparticles. Additionally, HEA nanoparticles effectively mimicked RONS-regulation metabolism in cascade reactions involving superoxide dismutase and catalase, as well as in multiple reactions including HORAC and NO scavenging. As a result, the HEA nanozyme exhibited superior anti-inflammatory efficacy both in vitro and in vivo. The findings underscore the effectiveness of the high-entropy alloy structure in restoring in vivo enzymatic systems through intrinsic activity enhancements and cascade reaction mechanisms.

Oleanolic acid (OA) is a pentacyclic triterpenoid with antioxidant activity that can be an effective scavenger of free radicals in cells. This study was designed to investigate the effects of OA on porcine early embryo developmental competence in vitro and its possible mechanisms of action.

In the present study, parthenogenetically activated porcine embryos were used as models to assess the effects of OA on the in vitro developmental capacity of early porcine embryos in vitro. Zygotic genome activation, mitochondrial function, oxidative stress, cell proliferation and apoptosis in early porcine embryos were examined after supplementing the culture medium with 5 μM OA.

The results showed that 5 μM OA supplementation not only significantly increased the blastocyst diameter in early embryos on day 6 but also increased the total cell number of blastocysts. Furthermore, OA supplementation increased the blastocyst proliferation rate and decreased blastocyst apoptosis. Moreover, OA supplementation significantly increased the proportion of embryos that developed to the 4-cell stage after 48 h of in vitro culture and upregulated the expression of genes associated with zygotic genome activation (DPPA2 and ZSCAN4). Notably, OA alleviated oxidative stress by reducing the intracellular levels of reactive oxygen species and increasing the intracellular levels of reduced glutathione at the 4-cell stage and increased the activities of superoxide dismutase and catalase. Concurrently, OA significantly increased the mitochondrial membrane potential and intracellular adenosine 5'-triphosphate content.

These results suggest that OA promotes the in vitro developmental competence of parthenogenetically activated porcine embryos by reducing oxidative stress and improving mitochondrial function during in vitro culture and that OA may contribute to the efficiency of in vitro embryo production.

Aryl hydrocarbon receptor (AHR) and nuclear factor-erythroid 2-related factor 2 (NRF2) can regulate a series of genes encoding the detoxifying phase I and II enzymes, via a signaling crosstalk known as the "AHR-NRF2 gene battery". The chromatin transcriptional regulator Jun dimerization protein 2 (JDP2) plays a central role in thetranscription of AHR gene in response to the phase I enzyme ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin. It forms a transcriptional complex with AHR-AHR nuclear translocator (ARNT) and NRF2-small musculoaponeurotic fibrosarcoma proteins (sMAF), which are then recruited to the respective cis-elements, such as dioxin response elements and antioxidant response elements, respectively, in the AHR promoter. Here, we present a revised description of the AHR-NRF2 gene battery as the AHR-NRF2-JDP2 gene battery for transactivating the AHR promoter by phase I enzyme ligands. The chromatin regulator JDP2 was found to be involved in the movement of AHR-NRF2 complexes from the dioxin response element to the antioxidant response element in the AHR promoter, during its activation in a spatiotemporal manner. This new epigenetic and chromatin remodeling role of AHR-NRF2-JDP2 axis is useful for identifying new therapeutic targets for various diseases, including immunological response, detoxification, development, and cancer-related diseases.

Age-related oxidative stress is a critical factor in vascular dysfunction, contributing to hypertension and atherosclerosis. Smooth muscle cells and endothelial cells are particularly susceptible to oxidative damage, which exacerbates vascular aging through cellular senescence, chronic inflammation, and arterial stiffness. Gasotransmitters-hydrogen sulfide (H2S), nitric oxide (NO), and carbon monoxide (CO)-are emerging as promising therapeutic agents for counteracting these processes. This review synthesizes findings from recent studies focusing on the mechanisms by which H2S, NO, and CO influence vascular smooth muscle and endothelial cell function. Therapeutic strategies involving exogenous gasotransmitter delivery systems and combination therapies were analyzed. H2S enhances mitochondrial bioenergetics, scavenges ROS, and activates antioxidant pathways. NO improves endothelial function, promotes vasodilation, and inhibits platelet aggregation. CO exhibits cytoprotective and anti-inflammatory effects by modulating heme oxygenase activity and ROS production. In preclinical studies, gasotransmitter-releasing molecules (e.g., NaHS, SNAP, CORMs) and targeted delivery systems show significant promise. Synergistic effects with lifestyle modifications and antioxidant therapies further enhance their therapeutic potential. In conclusion, gasotransmitters hold significant promise as therapeutic agents to combat age-related oxidative stress in vascular cells. Their multifaceted mechanisms and innovative delivery approaches make them potential candidates for treating vascular dysfunction and promoting healthy vascular aging. Further research is needed to translate these findings into clinical applications.

Dysregulated iron metabolism-induced ferroptosis is considered a key pathological mechanism in the development of osteoporosis (OP). G protein-coupled receptor 30 (GPR30, also known as Gper1) is an estrogen-binding receptor that has shown therapeutic benefits in patients with certain degenerative diseases. Moreover, several studies have demonstrated the anti-ferroptotic effects of estrogen receptor activation. However, its role in the prevention and treatment of OP remains unclear, and there are currently no reports on the anti-ferroptotic function of GPR30 in OP. Therefore, this study aimed to investigate the ferroptosis-related effects and mechanisms of GPR30 in the context of OP. In vivo and in vitro experiments were conducted using wild-type (WT) C57BL/6 female mice and GPR30-knockout (GPR30-KO) C57BL/6J female mice. The microarchitecture of the distal femur was assessed using micro-computed tomography (micro-CT), and histomorphological changes were analyzed via hematoxylin and eosin (H&E) staining. Bone marrow mesenchymal stem cells (BMSCs) were isolated and cultured to establish an iron overload model using ferric ammonium citrate (FAC). Interventions included GPR30 overexpression via transfection and BMP-6 inhibition using LDN-214117. Cell viability was evaluated with the CCK-8 assay, while osteogenic differentiation and mineralization levels were assessed using ALP and Alizarin Red S (ARS) staining. Iron accumulation was detected via Prussian blue staining, oxidative stress levels were evaluated using ROS staining, and mitochondrial membrane potential changes were analyzed using JC-1 staining. Transmission electron microscopy (TEM) was employed to observe mitochondrial ultrastructural changes. Additionally, key gene and protein expression levels were measured using immunofluorescence and Western blotting. The micro-CT analysis revealed significant bone microarchitecture deterioration and bone loss in the GPR30-KO mouse model. At the cellular level, GPR30 overexpression markedly reduced iron accumulation and oxidative stress in BMSCs, restored the mitochondrial membrane potential, and improved the mitochondrial ultrastructure. Furthermore, GPR30 enhanced osteogenic differentiation in BMSCs by promoting the activation of the BMP-6/HEP/FPN signaling pathway, leading to increased expression of osteogenic markers. The protective effects of GPR30 were reversed by the BMP-6 inhibitor LDN-214117, indicating that BMP-6 is a critical mediator in GPR30-regulated iron metabolism and ferroptosis inhibition. GPR30 inhibits ferroptosis in BMSCs and enhances osteogenic differentiation by activating the BMP-6/HEP/FPN signaling pathway. This provides new insights and potential therapeutic targets for the treatment of osteoporosis OP.

Neuropathic pain, a debilitating condition arising from somatosensory system damage, significantly impacts quality of life, leading to anxiety, self-mutilation, and depression. Oxidative and nitrosative stress, an imbalance between reactive oxygen and nitrogen species (ROS/RNS) and antioxidant defenses, plays a crucial role in its pathophysiology. While reactive species are essential for physiological functions, excessive levels can cause cellular component damage, leading to neuronal dysfunction and pain. This review highlights the complex interactions between reactive species, antioxidant systems, cell signaling, and neuropathic pain. We discuss the physiological roles of ROS/RNS and the detrimental effects of oxidative and nitrosative stress. Furthermore, we explore the potential of manganese porphyrins, compounds with antioxidant properties, as promising therapeutic agents to mitigate oxidative stress and alleviate neuropathic pain by targeting key cellular pathways involved in pain. Further research is needed to fully understand their therapeutic potential in managing neuropathic pain in human and non-human animals.

Neurons are highly dependent on mitochondrial respiration for energy, rendering them vulnerable to oxidative stress. Reactive oxygen species (ROS), by-products of oxidative phosphorylation, can damage lipids, proteins, and DNA, potentially triggering cell death pathways. This review explores the neuronal vulnerability to ROS, highlighting metabolic adaptations and antioxidant systems that mitigate oxidative damage. Balancing metabolic needs and oxidative stress defenses is critical for neurons, as disruptions are implicated in neurodegenerative diseases. Neurons uniquely modulate metabolic pathways, favoring glycolysis over oxidative phosphorylation in cell bodies, to minimize harmful ROS production. Key antioxidants, including superoxide dismutases and glutathione peroxidases, play crucial roles in neuronal protection, as evident from genetic studies linking deficiencies to neurodegeneration. Notably, neurons have the ability to adapt to oxidative conditions in compartment-specific manners and also utilize ROS as a signaling molecule to promote adaptive synaptic plasticity. Future research should aim to elucidate differential ROS signaling and antioxidant responses across neuronal compartments for improved therapeutic strategies.

Cold atmospheric plasma (CAP) has exhibited exciting potential for cancer treatment. Reactive oxygen and nitrogen species (RONS), the primary constituents in CAP, contribute to cancer cell death by elevating oxidative stress in cells. However, several intrinsic cellular antioxidant defense systems exist, such as the glutathione peroxidase 4 (GPX4) enzyme, which dampens the cell-killing efficacy of CAP. RAS-selective lethal 3 (RSL3), also known as a ferroptosis inducer, is a synthetic GPX4 inhibitor. Therefore, we hypothesized that RSL3 can amplify CAP-induced cell death by inhibition of GPX4. In this study, we showed that RSL3 loaded in poly (ethylene glycol)-block-poly(lactide-co-glycolide) (PLGA-PEG) nanoparticles can enhance CAP-induced cell deaths in 4T1 tumor cells. Furthermore, the combination of CAP and RSL3 also promoted cancer immunogenic cell death (ICD), induced dendritic cell (DC) maturation, and macrophage polarization, initiating tumor-specific T-cell mediated immune responses against tumors. For in vivo application, RSL3@NP was co-delivered with CAP via injectable Pluronic hydrogel. In 4T1-bearing mice, hydrogel-mediated delivery of CAP and RSL3-loaded nanoparticles can effectively elicit potent anti-tumor immune responses and inhibit tumor growth.

This narrative review provides an analysis of the role of nitric oxide (NO) and its precursors, particularly L-arginine, in vascular regulation and health, with an emphasis on findings from our experimental research in animal models. NO serves as a critical mediator of vascular function, contributing to vasodilation, the regulation of blood flow, and the prevention of thrombosis. As a primary precursor of NO, L-arginine is essential for maintaining endothelial integrity, modulating mitochondrial function, and reducing oxidative damage. This review synthesises the data and contextualises these findings within the physiological challenges faced by blood donors, such as repeated blood donation and associated oxidative stress. It examines the effects of L-arginine supplementation on mitochondrial respiration, lipid peroxidation, and microsomal oxidation in different conditions, including differences in age, gender, and dietary interventions. The mechanisms by which L-arginine enhances NO production, improves vascular elasticity, and alleviates endothelial dysfunction caused by reduced NO bioavailability are also investigated. By integrating experimental findings with insights from the existing literature, this review provides a perspective on the potential of L-arginine supplementation to address the specific physiological needs of blood donors. It highlights the importance of personalised nutritional approaches in enhancing donor recovery and vascular resilience. In addition, this review assesses the wider implications of L-arginine supplementation in mitigating oxidative stress and preserving vascular function. The interplay between NO bioavailability, dietary factors, and physiological adaptation in blood donors is highlighted, along with the identification of current knowledge gaps and recommendations for future research. By presenting both original experimental evidence and a critical synthesis of the literature, this article highlights the therapeutic potential of NO precursors, particularly L-arginine, in promoting vascular health in the context of blood donation.

The term "oxidative stress" refers to an imbalance between reactive oxygen species (ROS) generation and the antioxidant system, resulting in the increased formation of ROS and the reduced and/or inadequate efficiency of the physiological processes responsible for their elimination and homeostasis maintenance [...].

Vascular dementia (VaD) is a progressive neurodegenerative disease characterized by cognitive decline and memory deficits. Despite its significant prevalence and impact, the pathophysiology of VaD remains poorly understood, and current treatments are limited to symptom management. Emerging evidence highlights the importance of lifestyle-associated risk factors in VaD, emphasizing the role of gene-environment interactions, particularly in the realm of epigenetics. While preclinical studies using animal models have provided valuable insights into epigenetic mechanisms, the translatability of these findings to human clinical settings remains limited, and research into VaD-specific epigenetics is still in its infancy. This review aims to elucidate the intricate interplay between epigenetics and VaD, shedding light on potential therapeutic interventions rooted in epigenetic mechanisms. By synthesizing insights from existing literature, we also discuss the challenges and opportunities in translating preclinical findings into clinically viable treatments, underscoring the need for further research to bridge the gap between animal models and human applications.

Rationale: Renal cell carcinoma (RCC) is a highly malignant and common urological tumor. In our previous study, we reported the upregulation of PRR11 in RCC, emphasizing its important role in cell cycle regulation and apoptosis. In this follow-up study, we aim to further investigate the carcinogenic mechanism of PRR11. Methods: Immunoprecipitation-mass spectrometry (IP-MS), ubiquitination assays, and in vitro phosphorylation assays were used to investigate the phosphorylation and ubiquitination-mediated degradation of PRR11 by FBXW7 and GSK3β. RNA-seq analysis of PRR11 knockdown RCC cells and cellular functional assays, including flow cytometry and comet assays, were performed to explore downstream signaling pathways and regulatory functions. Mouse subcutaneous tumor, tail vein lung metastasis, and popliteal lymph node metastasis models were established to validate PRR11's role in vivo. Results: Our results reveal that GSK3β recognizes and phosphorylates the CDC4 phosphodegron (CPD) consensus motif of PRR11, enabling FBXW7 to bind to PRR11 and catalyze its K48-linked ubiquitination and degradation. Moreover, PRR11 activates AKT signaling, which inhibits GSK3β activity. This inhibition prevents the phosphorylation of CPD motifs on PRR11, thereby obstructing FBXW7-mediated ubiquitination and degradation. The interaction between PRR11 and AKT creates a positive feedback loop that increases the level of both proteins, which ultimately accelerates RCC progression by inhibiting oxidative DNA damage. Conclusion: The FBXW7/GSK3β-PRR11-AKT axis plays a pivotal role in the development of RCC by regulating oxidative DNA damage. Targeting PRR11 may be a potential therapeutic strategy for RCC.

Neurodegenerative diseases pose significant challenges to healthcare systems globally due to their complex etiology and relentless progression, often rendering conventional treatments ineffective. Recent advances have spotlighted excitatory amino acids, particularly D-amino acids, once considered as products of metabolism of the microbiota or deriving from food intake. This review explores the role of D-amino acids in mitigating excitotoxicity-a process characterized by excessive calcium influx through aberrant N-methyl-D-aspartate receptor (NMDAR) activation, which is implicated in the pathogenesis of diseases like Alzheimer's disease. By providing alternative pathways for neuronal signaling and protecting against excitotoxic damage, D-amino acids offer a novel approach to reversing neurodegenerative trajectories. Future research should focus on elucidating the detailed mechanisms of action of these compounds, evaluating their therapeutic potential through rigorous preclinical and clinical trials, and developing effective delivery systems to optimize their neuroprotective effects. This emerging field holds promise for developing innovative treatment strategies that could significantly improve outcomes for patients with neurodegenerative disorders.

This study investigated the chemopreventive mechanisms of fish oil (FO) at different doses and administration routes in skin carcinogenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA) and croton oil (CO) in Swiss albino mice. Seventy mice were divided into 10 groups, including controls and those receiving FO either orally or topically, with or without the carcinogenesis protocol. Warts were morphologically analyzed. Anatomopathological analysis, qRT-PCR of nuclear factor kappa B (NF-қB) subunits' gene expression, and evaluation of oxidative parameters were conducted. Anatomopathological analysis revealed a presence of invasive squamous cell carcinoma (SCC) in DMBA group. Both oral (500 mg/kg/day) and topical FO treatment showed no signs of cancer, while oral administration at 50 mg/kg/day had no therapeutic effect, and 250 mg/kg/day resulted in low-grade malignancy. Both oral (250 and 500 mg/kg/day) and topical FO significantly reduced NF-кB1 gene expression, alleviated oxidative stress markers, and restored antioxidant enzyme activities compared to the DMBA group. FO shows dose-dependent chemopreventive effects, with oral administration potentially as effective as topical application when using an appropriate dosage. The development of SCC is linked to the stress status and the upregulation of the canonical NF-κB pathway, while FO's chemoprotective effects likely result from its downregulation.