Oxidative Stress Mechanisms Research Articles

Prohibitin 2 confers NADPH oxidase 1 -mediated cytosolic oxidative signaling to promote gastric cancer progression by ERK activation

Oxidative signaling plays a dual role in tumor initiation and progression to malignancy; however, the regulatory mechanisms of Oxidative stress in gastric cancer remain to be explored. In this study, we discovered that Prohibitin 2 (PHB2) specifically regulates cytosolic reactive oxygen species production in gastric cancer and facilitates its malignant progression. Previously, we found that PHB2 is upregulated in gastric cancer, correlating with increased tumorigenicity of gastric cancer cells and poor patient prognosis. Here, we discovered that PHB2 expression correlates with the activation of the ERK/MAPK cascade, positively regulating the top gene NADPH oxidase 1 (NOX1) within this pathway. Further mechanistic investigation reveals that PHB2 enhances NOX1 transcription by interacting with the transcription factor C/EBP-beta and promoting its translocation into the nucleus, resulting in elevated intracellular oxidative signaling driven by NOX1, which subsequently activates ERK. Therefore, we propose that targeting PHB2-C/EBP-beta-NOX1-mediated cytosolic oxidative stress could offer a promising therapeutic avenue for combating gastric cancer malignant progression.

Evaluation of oxidative stress biomarkers for differentiating bacterial and viral infections: a comparative study of glutathione disulfide (GSSG) and reduced glutathione (GSH)

Background and aims. This study evaluates the potential of oxidative stress biomarkers, specifically glutathione disulfide (GSSG) and reduced glutathione (GSH), for differentiating bacterial and viral infections. Oxidative stress plays a crucial role in the immune response, and glutathione is a key regulator of cellular redox balance. The aim was to assess whether differences in GSH and GSSG levels could be used as diagnostic markers for infection type. Methods. A chemiluminescence-based method evaluated GSH and GSSG as potential biomarkers for distinguishing between bacterial and viral infections. The GSH and GSSG concentrations were analyzed across bacterial, viral, and control groups. Results. Our data revealed significant differences in the GSH/GSSG ratio between the analyzed groups, with bacterial infections showing higher oxidative stress markers compared to viral infections. A combined analysis of GSH and GSSG concentrations, visualized through heatmaps and ROC curves, improved diagnostic accuracy, with clustering patterns distinguishing infection types. Conclusions. These findings suggest that the GSH/GSSG ratio could be used as a biomarker in distinguishing between bacterial and viral infections, offering potential clinical applications for more accurate diagnosis. Further research is required to validate these results in larger cohorts and to explore the underlying mechanisms of oxidative stress in pathogen-specific immune responses.

Oxidative stress mechanism by gold compounds: a close look at total ROS increase and the inhibition of antioxidant enzymes.

The antitumor activity of various gold compounds is a promising field of investigation, attracting researchers seeking potential clinical candidates. To advance this research, they explore the complex mechanisms of action of these compounds. Since the discovery of the strong inhibition of thioredoxin reductase by auranofin, the primary mechanism explored has been the inhibition of this enzyme. This inhibition disrupts the redox balance in cells, promoting oxidative stress and triggering cell death. In this review, we analyzed studies from the past decade that measured cellular ROS increase and examined the coordination structures of gold compounds. We also correlate ROS increase with the inhibition of redox-regulating enzymes, thioredoxin reductase and glutathione reductase, to elucidate the relationship between these cellular effects and chemical structures. Our data compilation reveals that different structures exhibit varying efficacy: some significantly increase ROS production and inhibit thioredoxin reductase or glutathione reductase, while others elevate ROS levels without affecting these target enzymes, suggesting alternative mechanisms of action. This review consolidates critical evidence, enhancing our understanding of the mechanisms by which these gold complexes act and providing valuable insights for developing new therapeutic strategies against tumor cells.

Physiological, biochemical, and transcriptomic alterations in Castor (Ricinus communis L.) under polyethylene glycol-induced oxidative stress

BackgroundCastor is an important industrial raw material. Drought-induced oxidative stress leads to slow growth and decreased yields in castor. However, the mechanisms of drought-induced oxidative stress in castor remain unclear. Therefore, in this study, physiological, biochemical, and RNA-seq analyses were conducted on the roots of castor plants under PEG-6000 stress for 3 d and 7 d followed by 4 d of hydration.ResultsThe photosynthetic rate of castor leaves was inhibited under PEG-6000 stress for 3 and 7 d. Biochemical analysis of castor roots stressed for 3 d and 7 d, and rehydrated for 4 d revealed that the activities of APX and CAT were highest after only 3 d of stress, whereas the activities of POD, GR, and SOD peaked after 7 d of stress. RNA-seq analysis revealed 2926, 1507, and 111 differentially expressed genes (DEGs) in the roots of castor plants under PEG-6000 stress for 3 d and 7 d and after 4 d of rehydration, respectively. GO analysis of the DEGs indicated significant enrichment in antioxidant activity. Furthermore, KEGG enrichment analysis of the DEGs revealed significantly enriched metabolic pathways, including glutathione metabolism, fatty acid metabolism, and plant hormone signal transduction. WGCNA identified the core genes PP2C39 and GA2ox4 in the navajowhite1 module, which was upregulated under PEG-6000 stress. On the basis of these results, we propose a model for the response to drought-induced oxidative stress in castor.ConclusionsThis study provides valuable antioxidant gene resources, deepening our understanding of antioxidant regulation and paving the way for further molecular breeding of castor plants.

Particulate Matter-Induced Emerging Health Effects Associated with Oxidative Stress and Inflammation.

Environmental pollution continues to increase with industrial development and has become a threat to human health. Atmospheric particulate matter (PM) was designated as a Group 1 carcinogen by the International Agency for Research on Cancer in 2013 and is an emerging global environmental risk factor that is a major cause of death related to cardiovascular and respiratory diseases. PM is a complex composed of highly reactive organic matter, chemicals, and metal components, which mainly cause excessive production of reactive oxygen species (ROS) that can lead to DNA and cell damage, endoplasmic reticulum stress, inflammatory responses, atherosclerosis, and airway remodeling, contributing to an increased susceptibility to and the exacerbation of various diseases and infections. PM has various effects on human health depending on the particle size, physical and chemical characteristics, source, and exposure period. PM smaller than 5 μm can penetrate and accumulate in the alveoli and circulatory system, causing harmful effects on the respiratory system, cardiovascular system, skin, and brain. In this review, we describe the relationship and mechanism of ROS-mediated cell damage, oxidative stress, and inflammatory responses caused by PM and the health effects on major organs, as well as comprehensively discuss the harmfulness of PM.

Metformin-mediated protection against doxorubicin-induced cardiotoxicity

BackgroundA phase II clinical trial of metformin (MET) for the treatment of doxorubicin (DOX)-induced cardiotoxicity (NCT02472353) failed. ObjectivesThe aims of this study were to confirm MET-mediated protection against DOX-induced cardiotoxicity and its mechanism using H9C2 cells, and to establish a Wistar rat model of DOX-induced cardiotoxicity. Subsequently, Wistar rats were utilized to identify clinically relevant indicators for evaluating MET-mediated protection against DOX-induced cardiotoxicity, thereby facilitating early transition towards successful clinical trials. MethodsMET-mediated protection was assessed using cell viability and cytotoxicity experiments. Additionally, intramitochondrial reactive oxygen species (ROS) levels were measured using an ROS fluorescent probe (dihydroethidium) to confirm the oxidative stress mechanism. Eighteen Wistar rats were randomly allocated to the control, DOX, and DOX+MET groups; and the body weight, adverse drug reactions (ADRs), myocardial injury, cardiac function, oxidative stress, and histopathology of heart tissues were compared between groups. ResultsH9C2 cells treated with MET/Dexrazoxane demonstrated dose-dependent protection against DOX-induced cardiotoxicity. The fluorescence intensity of H9C2 cells suggested DOX-induced cardiomyocyte toxicity and MET-mediated protection against DOX-induced cardiotoxicity. In vivo experiments confirmed that a rat model of DOX-induced cardiotoxicity was successfully established, but MET-mediated protection against DOX-induced cardiotoxicity was not demonstrated. This was attributed to insufficient energy intake because of ADRs, such as vomiting. ConclusionsWe confirmed the MET-mediated protection against DOX-induced cardiomyocyte toxicity and its mechanism involving the inhibition of oxidative stress in vitro experiments. It is imperative to investigate the optimal conditions for MET-mediated protection against DOX-induced cardiotoxicity in vivo or clinical trials.

Effects of Diet and Supplements on Parameters of Oxidative Stress, Inflammation, and Antioxidant Mechanisms in Patients with Chronic Renal Failure Undergoing Hemodialysis.

The prevalence of chronic kidney disease (CKD) worldwide increases as the population ages. The progression of the disease increases the risk of complications and death and leads to end-stage renal failure, requiring renal replacement therapy. Despite the positive effect of hemodialysis (HD), patients are at risk of developing malnutrition, inflammation, oxidative stress, or cardiovascular disease, which worsens quality of life and can lead to organ dysfunction. The occurrence of the mentioned disorders depends largely on the diet, so changes in diet composition are an important part of the treatment of kidney disease. This study aimed to evaluate the effects of a balanced diet on some parameters of oxidative stress, immune response, and nutritional status in patients. This study included 57 HD patients (19 women and 38 men). In all of them, nutritional status and diet were initially determined, and then, they were divided into six groups, which received different diets and supplements. Serum levels of albumin, total protein, MDA, and the cytokines Il-1, IL-6, IL-8, TNF-α, and IL-10 were determined, and the activity of the enzymes such as CAT, SOD, and GSH-Px were determined in erythrocytes by spectrophotometry. Based on the results of BMI, albumin, and total protein, it can be concluded that a well-balanced diet can reduce weight loss. This study shows that a well-balanced diet can reduce the secretion of pro-inflammatory cytokines, and ensure the normal activity of antioxidative enzymes in the blood of HD patients.

The oxidative stress mechanism of Bacillus cereus spores induced by atmospheric pressure plasma jet

Emerging plasma technology has demonstrated its effectiveness in inactivating bacteria and spores, showing wide applicability in environment cleaning and in the food supply chain. Studies have revealed that the main reason of plasma-mediated bacterial inactivation were contributed to the oxidative damage on inner membranes (IMs) of cell, while few research paid attention to the oxidation stress process of lipid in spores’ IMs. This study investigated the impact of atmospheric pressure plasma jet (APPJ) treatment on spore inactivation, focusing on oxidative stress mechanisms and changes in membrane lipid composition. Results demonstrated that APPJ treatment induced significant oxidative stress within spores, characterized by elevated levels of reactive oxygen and nitrogen species (RONS). This oxidative stress led to the peroxidation of glycerophospholipids, particularly phosphatidylglycerol, phosphatidylcholine, and cardiolipin, major components of spore membranes. Subsequently, the rearrangement of membrane lipid and the formation of lipid hydroperoxide, caused by the released cations and RONS, accelerated membrane instability. These changes correlated with increased membrane permeability and structural damage observed via flow cytometry, indicating the critical role of membrane lipid peroxidation in spore inactivation. Furthermore, the study highlighted the potential of APPJ as a robust technology for enhancing food safety by targeting spore-forming pathogens throughout the food supply chain.

Exploring the detrimental effects of microplastics on Asian seabass (Lates calcarifer) fingerlings survival and health

Microplastics (MPs) are widely used and disposed of indiscriminately, posing a potential threat to aquatic life. Herein, Asian seabass (Lates calcarifer) fingerlings were exposed to various concentrations (1, 10 and 100 ppt or g/kg) of dietary polyethylene MPs for 16 days. The results indicated a significant increase in mortality among the fish fed with dietary MPs compared to the control. Furthermore, histological analysis of the liver revealed moderate-to-severe morphological alterations, hepatocyte necrosis and vacuolisation as the concentration gradient of MPs increased. The severity of the alterations was highest at a concentration of 100 ppt, indicating a direct correlation between MP and liver damage. In addition, RNA sequencing and Gene Ontology term enrichment analysis revealed that a total of 4137 genes were significantly differentially expressed, with 1958 upregulated and 2179 downregulated genes. The significantly enriched terms included ‘oxidoreductase activity’, ‘endocytosis’, ‘mitochondrial’, ‘immune system process’ and ‘lipid catabolic process’. Moreover, the Kyoto Encyclopaedia of Genes and Genomes enrichment analysis demonstrated that dietary MPs triggered oxidative stress, immune response and adaptive mechanism pathways in fish. Thus, MPs can induce metabolic disorders in L. calcarifer, highlighting their potential threat to aquatic organisms.

The effect of a new 3-hydroxypyridine derivative LHT-2-20 on free radical oxidation in experimental periodontitis

Aim. To study the effect of a new complex compound LHT-2-20 (2-ethyl-6-methyl-3-hydroxypyridine-2-(3benzoyl phenyl)-propanoate) on free radical oxidation in experimental periodontitis.Materials and methods. The experimental study was performed on 195 white mongrel mice weighing 19–23 g and 137 white mongrel rats weighing 180–220 g. The effect of a new complex compound LHT-2-20 (2-ethyl-6methyl-3-hydroxypyridine-2-(3-benzoyl phenyl)-propanoate) on the intensity of free radical oxidation and the local state of periodontal tissues during a course of intragastric administration was studied on the experimental model of periodontitis. Statistical processing of the results was carried out using the SPSS Statistics 20.0 software package with the analysis of variance (ANOVA) and the parametric Tukey’s test.Results. The LHT-2-20 compound reduced elevated levels of primary and secondary lipoperoxidation products (conjugated dienes, malondialdehyde in plasma and in erythrocytes during spontaneous and iron-induced oxidation) already at the early stages of the experiment, bringing the studied parameters closer to the reference values by the end of the course of treatment. The use of the compound LHT-2-20 contributed to an increase in the activity of the main antioxidant enzymes (catalase and superoxide dismutase), normalizing them to baseline values by the end of the experiment. With the correction of free radical processes, the use of LHT-2-20 limited the local inflammatory response in periodontal tissues, which was confirmed by a decrease in gingival edema and hyperemia, bleeding, depth of periodontal pockets, and tooth mobility.Conclusion. The results of this study confirm the anti-inflammatory potential of the compound and the multiplicity of its effects due to the impact on the mechanisms of oxidative stress. The expediency of further study of the drug is justified by the prospect of creating a new drug and its subsequent wide clinical application as part of the complex therapy of periodontal inflammation.

Mechanistic studies on the alleviation of lipid accumulation and oxidative stress by Majia pomelo seed oil

In this study, hot-pressed Majia pomelo seed oil (MPSO), which has high oxidative stability and antioxidant capacity, was used to study the effects and potential mechanisms of lipid accumulation and oxidative stress. The results indicated that the low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TG) levels in HepG2 cells were lowest when the MPSO concentration was 0.5 mg/mL. At this concentration, MPSO could alleviate oleic acid (OA)-induced lipid accumulation, reduce intracellular lipid level, and decrease lipid and cholesterol synthesis by increasing AMPK phosphorylation and down-regulating the expression levels of genes and proteins of ACC, SREBP-1c, PPAR-γ, and FAS. Meanwhile, MPSO can reduce reactive oxygen species (ROS) and malondialdehyde (MDA) content and enhance superoxide dismutase (SOD) content in HepG2 cells by down-regulating the expression levels of Nrf2, γ-GCS, and HO-1 genes and proteins, thus acting as an anti-oxidative stress. In addition, molecular docking results indicated that the active ingredients of MPSO could effectively bind AMPK protein and Keap1 protein, which further demonstrated that MPSO could alleviate lipid accumulation and oxidative stress.

An observational study on variations of serum uric acid level in patients of depression and healthy controls and its correlation with hidden bipolarity

Background: Bipolar disorder (BD) is one of the most studied psychiatric disorders, this being one of the leading causes of disability in young individuals. In search for its predictive biomarker, serum uric acid (UA) level was seen to have a pathophysiologic role in the genesis of BD through oxidative stress and other mechanism. Aims and Objectives: The aim of the study was to estimate serum UA levels in patients with 1st episode depression, to compare serum UA levels between patients and matched healthy controls and to compare serum UA levels between patients with and without hidden bipolarity and therefore, and to evaluate whether it can be used as a predictor of bipolarity. Materials and Methods: A study was conducted in a tertiary care center in Eastern India for a duration of 3 months with a sample size of 92, comprising 46 cases with major depressive disorder (MDD) and 46 control groups of healthy subjects. Their serum UA levels were estimated. The study population was subjected to a mood disorder questionnaire (MDQ) and Montgomery–Asberg Depression Rating Scale (MADRS) scoring. All these data were tabulated in a master sheet and analyzed using Statistical Packages for the Social Sciences 25 software. Results: The mean age of the study population was 32 years with 46 males and 46 females. The mean UA levels for MDD group was 5.27±1.14 mg/dL and for control group was 4.6±1.2 mg/dL, which was seen to be statistically significant (P=0.001). No statistically significant association was seen between the group with a high likelihood of bipolarity versus a low chance of bipolarity with respect to UA levels. A positive correlation was seen between MDQ scores and UA levels of depressed individuals (using Spearmen’s rho: rs=0.345, P=0.019), but not with their MADRS scores. Conclusion: Serum UA levels are significantly higher in depressed patients as compared to healthy subjects. A non-statistical association was seen between UA levels and their bipolar tendencies, owing to a small sample size of comparable groups. However, a higher MDQ score was associated with high UA levels. A larger study population is needed to conclusively establish the predictive role of UA with respect to BD.

Diagnostic Challenges and Pathogenetic Differences in Biomass-Smoke-Induced versus Tobacco-Smoke-Induced COPD: A Comparative Review.

Background: Chronic Obstructive Pulmonary Disease (COPD) is a major global health challenge, primarily driven by exposures to tobacco smoke and biomass smoke. While Tobacco-Smoke-Induced COPD (TSCOPD) has been extensively studied, the diagnostic challenges and distinct pathogenesis of Biomass-Smoke-Induced COPD (BSCOPD), particularly in low- and middle-income countries, remain underexplored. Objective: To explore the differences in clinical manifestations, pulmonary function, and inflammatory profiles between BSCOPD and TSCOPD and highlight the diagnostic complexities of BSCOPD. Methods: This review analyzes the current literature comparing BSCOPD with TSCOPD, focusing on distinctive pathophysiological mechanisms, inflammatory markers, and oxidative stress processes. Results: BSCOPD presents differences in clinical presentation, with less emphysema, smaller airway damage, and higher rates of pulmonary hypertension compared to TSCOPD. BSCOPD is also characterized by bronchial hyperresponsiveness and significant hypoxemia, unlike TSCOPD, which exhibits severe airflow obstruction and emphysema. Additionally, the inflammatory profile of BSCOPD includes distinct mucous hypersecretion and airway remodeling. Conclusions: The unique genetic, epigenetic, and oxidative stress mechanisms involved in BSCOPD complicate its diagnosis and management. Biomass smoke's underrecognized impact on accelerated lung aging and exacerbation mechanisms emphasizes the need for targeted research to refine diagnostic criteria and management strategies for BSCOPD. Future directions: Further research should focus on identifying specific biomarkers and molecular pathways to enhance early diagnosis and improve clinical outcomes in populations exposed to biomass smoke.

Circadian rhythm in neurodegenerative disease: the role of RNA modifications and potential application of RNA-based therapeutics

Neurodegenerative diseases usually present as progressive impairment of the motor or mental functions of the central or peripheral nervous system, which is often linked to genetic and biochemical factors. The main features include synaptic and neuronal deficits, abnormal protein homeostasis, DNA and RNA defects, inflammation, and pathological protein aggregation. Clinical evidence suggests that circadian rhythms affect different neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, through oxidative stress, neuroinflammation, and other mechanisms. Disruptions in circadian rhythms, which are often linked to alterations in RNA modifications, contribute to disease progression. This review provides an overview of current research progress on neurodegenerative diseases and outlines their relationship in terms of aberrant circadian rhythm, highlights the role of RNA modifications in circadian rhythm-regulated neurodegenerative diseases, and presents the potential applications of RNA-based drugs for treating neurodegenerative diseases.

High dietary antioxidant intake linked to lower risk of myocardial infarction: a nested case-control study

BackgroundIn developing nations, myocardial infarction (MI) remains a significant contributor to deaths from sudden cardiac arrest, with diet playing a key role in its incidence through oxidative stress mechanisms. Although the connection between the Dietary Antioxidant Index (DAI) and cardiovascular diseases has been demonstrated in some studies, the relationship between DAI and MI has not been extensively explored. Therefore, this research aims to investigate this association.MethodsWe conducted a nested case-control study involving 156 MI cases and 312 healthy controls, utilizing data from the Fasa Adults Cohort Study (FACS), a population-based study of individuals aged 35–70 residing in Fasa, Iran, with 11,097 participants included at baseline. The DAI was determined by normalizing the intake values of six dietary vitamins and minerals, adjusting by subtracting the global mean, and then dividing by the global standard deviation. MI diagnosis was established by an experienced cardiologist using electronic medical records. Conditional logistic regression was employed to examine the association between DAI and MI.ResultsThere were no significant differences between the case and control groups in terms of age (P = 0.96), gender distribution (P = 0.98), and education level (P = 0.38). In a multiple conditional logistic regression analysis, after adjusting for key variables—including body mass index (BMI), smoking status, education level, and serum levels of triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC), fasting blood sugar (FBS), saturated fatty acids (SFA), and polyunsaturated fatty acids (PUFA)—an inverse association was found between DAI and the risk of myocardial infarction (MI) [adjusted Odds Ratio (Adj OR) = 0.88, 95% Confidence Interval (CI): 0.85–0.92; P < 0.001].ConclusionsThis study highlights the crucial role of the DAI in reducing the risk of myocardial infarction. Promoting diets rich in antioxidants presents a straightforward and effective strategy for MI prevention and the promotion of cardiovascular health, underscoring the novelty and significance of this research in dietary approaches to disease prevention.

Association of MnSOD, CAT, and GPx1 Gene Polymorphism with Risk of Diabetic Nephropathy in South Indian Patients: A Case-Control Study.

Diabetic nephropathy (DN) is one of the common complications of type 2 diabetes mellitus (T2DM), and oxidative stress plays a key role in the pathogenesis of DN. Studies have demonstrated that antioxidants (MnSOD, CAT, and GPx1) may reduce the complications associated with T2DM. The purpose of the study is to correlate the role of antioxidant gene polymorphisms in the pathogenesis of DN among T2DM individuals in the South Indian population. It clarifies the importance of early manifestation and reliable genetic indicators modulating the oxidative stress mechanism in DN.The study participants were divided and grouped as Group 1: Control, Group 2: T2DM without DN, and Group 3: T2DM with DN (n = 100 in each group). The levels of plasma glucose, HbA1c, renal profile, SOD, CAT, GPx1, MDA, and TAS were assessed. MnSOD (rs4880), CAT (rs1049982), and GPx1 (rs1050450) polymorphisms were genotyped via Tetra-arms PCR.The genotypes of GPx1 depict a significant role in the progression of DN in T2DM patients (co-dominant [OR: 2.134; 95% CI (1.202-3.788), p < 0.01], dominant [OR: 2.015; 95% CI (1.117-3.634), p = 0.02], and recessive model [OR: 2.215; 95% CI (1.235-3.972), p = 0.008]); whereas rs4880 and rs1049982 polymorphisms are not associated with DN progression. As a result, GPx1 (rs1050450) polymorphism could be a diagnostic risk factor for developing DN in T2DM patients. Moreover, the genotypes of rs4880 and rs1049982 polymorphism show significant difference in the antioxidant parameters compared to the genotypes of rs1050450.In contradiction to earlier studies, the current study demonstrates that the genotypes of rs1050450 (GPx1) can be considered as an influential component for higher susceptibility and risk of developing DN in T2DM patients among the South Indian population.

The Neuroprotective Effects of Agmatine on Parkinson's Disease: Focus on Oxidative Stress, Inflammation and Molecular Mechanisms.

Agmatine (AGM), a naturally occurring polyamine derived from L-arginine, has shown significant potential for neuroprotection in Parkinson's Disease (PD) due to its multifaceted biological activities, including antioxidant, anti-inflammatory, and anti-apoptotic effects. This review explores the therapeutic potential of AGM in treating PD, focusing on its neuroprotective mechanisms and evidence from preclinical studies. AGM has been demonstrated to mitigate the neurotoxic effects of rotenone (ROT) by improving motor function, reducing oxidative stress markers, and decreasing levels of pro-inflammatory cytokines in animal models. Additionally, AGM protects against the loss of TH + neurons, crucial for dopamine synthesis. The neuroprotective properties of AGM are attributed to its ability to modulate several key pathways implicated in PD pathogenesis, such as inhibition of NMDA receptors, activation of Nrf2, and suppression of the HMGB1/ RAGE/ TLR4/ MyD88/ NF-κB signaling cascade. Furthermore, the potential of agmatine to promote neurorestoration is highlighted by its role in enhancing neuroplasticity elements such as CREB, BDNF, and ERK1/2. This review highlights agmatine's promising therapeutic potential in PD management, suggesting that it could offer both symptomatic relief and neuroprotective benefits, thereby modifying the disease course and improving the quality of life for patients. Further research is warranted to translate these preclinical findings into clinical applications.

Role of serum cd4+, cd25+, and foxp3+ cells’ segmental and nonsegmental vitiligo

Background Vitiligo is an autoimmune skin disease presented with depigmented macules and patches. Vitiligo has an impact on the quality of life. The etiopathogenesis of vitiligo is multifactorial, including genetic, immune dysregulation, and oxidative stress mechanisms. Lately, several researches have underlined the pivotal function of regulatory T cells (Tregs) in the vitiligo pathogenesis with lack of data regarding their role in segmental vitiligo (SV). Objective To investigate the role of Tregs in SV and nonsegmental vitiligo (NSV) pathogenesis and its correlation with disease activity and severity. Patients and methods This case–control study included 20 cases with NSV and 10 cases with SV in addition to 10 healthy volunteers. Vitiligo Area Scoring Index and Vitiligo Disease Activity scores were estimated for vitiligo cases and all the included participants were assessed for the percentage of serum CD4+, CD25+, and FOXP3+ T cells using flow cytometry staining buffer. Results There was significant reduction of the peripheral Tregs in NSV cases in comparison with healthy participants and negative correlation with their percentage to disease activity. On the other hand, there was insignificant difference between the percentage of peripheral Tregs in SV cases and healthy participants. Also, there was insignificant correlation between peripheral Tregs and both severity and activity of the disease among SV cases. Conclusion NSV cases showed significant reduction of the peripheral Tregs and negative correlation with disease activity, indicating the importance of Tregs in the etiopathogenesis of NSV and hence future targeting therapy. On the other hand, in SV cases, there was insignificant reduction of peripheral Tregs and insignificant correlation between their percentage and both severity and activity indicating mosaic etiopathogenesis.

NOX2 mediates NLRP3/ROS facilitating nasal mucosal epithelial inflammation in chronic rhinosinusitis with nasal polyps

BackgroundPrevious investigations have provided limited insight into the role of oxidative stress in nasal mucosa inflammation. The aim of this study was to investigate the mechanism of oxidative stress in the epithelial cells of chronic rhinosinusitis with nasal polyps CRSwNP utilizing single-cell RNA sequencing data. MethodsSingle-cell RNA sequencing data from HRA000772 were used to assess oxidative stress, inflammasome activation, and nicotinamide adenine dinucleotide phosphate oxidases (NOXs) expression in epithelial cells via integrative rank-based gene set enrichment analysis. The localization of reactive oxygen species (ROS) and NOX2 in nasal mucosa and cell models was visualized using fluorescent probes and immunohistochemistry, respectively. Functional studies on NOX2 involved siRNA and plasmid transfections in vitro, while Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activity was examined using the inducer TMAO and the inhibitor MCC950. ResultsSingle-cell RNA sequencing data suggested an increase of oxidative stress score and NLRP3 inflammasome score in CRSwNP epithelial cells. Vitro experiments demonstrated that lipopolysaccharide could induce ROS accumulation, NLRP3 inflammasome activation and epithelial alarmin expression. MCC950 inhibited the expression of epithelia alarmin in vitro. Elevated NOX2 in CRSwNP epithelial cells was associated with increased ROS, NLRP3 inflammasome activation, and epithelial alarmin expression. NOX2-targeted siRNA inhibited these effects in vitro. Moreover, TMAO reversed the downregulation of epithelial alarmins without impacting ROS levels. ConclusionThis study highlights the crucial role of NOX2 as a key regulator of ROS accumulation and NLRP3 inflammasome activation in CRSwNP, underscoring its potential as a valuable therapeutic target for CRSwNP.

Discovery of novel 5-phenyl-1H-pyrrole-2-carboxylic acids as Keap1-Nrf2 inhibitors for acute lung injury treatment

Oxidative stress is intricately linked to acute lung injury (ALI) and cerebral ischemic/reperfusion (I/R) injury. The Keap1 (Kelch-like ECH-Associating protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2)-ARE (antioxidant response element) signaling pathway, recognized as a crucial regulatory mechanism in oxidative stress, holds immense potential for the treatment of both diseases. In our laboratory, we initially screened a compound library and identified compound 3, which exhibited a dissociation constant of 5090 nM for Keap1. To enhance its binding affinity, we developed a novel 5-phenyl-1H-pyrrole-2-carboxylic acid Keap1-Nrf2 inhibitor through scaffold hopping from compound 3. Structure-activity relationship studies identified compound 19 as the most potent, with a KD2 of 42.2 nM against Keap1. Furthermore, compound 19 showed significant protection against LPS-induced injury in BEAS-2B cells and promoted Nrf2 nuclear translocation. Subsequently, we investigated its therapeutic effects in mouse models of ALI injury. Compound 19 effectively alleviated symptoms at doses of 15 mg/kg for ALI injury. Additionally, it facilitated Nrf2 translocation to the nucleus, increased Nrf2 levels, and upregulated the expression of HO-1 and NQO1 in affected tissues.