Oxidative Medicine and Cellular Longevity最新文献

Background: Aging is characterized by the progressive decline of physiological functions and is associated with an increasing risk for developing multiple age-related diseases. UDP-glucuronosyltransferase (UGT)1A enzymes detoxify a variety of endo- and xenobiotic reactive metabolites, thereby acting as indirect antioxidants. A common genetic UGT1A haplotype was shown to affect redox balance in humanized transgenic (htg) UGT1A mice. Since oxidative stress is a main activator of cellular senescence, we aimed to investigate the role of genetic UGT1A variants in the process of aging. Methods: HtgUGT1A-WT and htgUGT1A-SNP mice were harvested at the age of either 12 weeks (young) or 18 months (aged). The effect of aging was examined by analyzing UGT1A expression and activity, expression of senescence markers, and senescence-associated secretory phenotype (SASP) factors, as well as blood counts, serum parameter, and histological staining. Results: In comparison to aged htgUGT1A-WT mice, hepatic UGT1A mRNA and protein expression as well as UGT activity were significantly reduced in aged htgUGT1A-SNP mice. Moreover, elderly htgUGT1A-SNP mice exhibited increased levels of oxidative stress, senescence markers, SASP factors, and peripheral leukocyte counts compared to the respective htgUGT1A-WT mice. Consistent with these findings, we observed higher amounts of collagen and amyloid fibrils as well as an elevated senescence-associated β-galactosidase (SA-β-gal) activity in histological sections of the liver obtained from aged htgUGT1A-SNP mice. Conclusion: Our data suggest an accelerated aging process caused by a common UGT1A haplotype. Moreover, elderly individuals carrying the UGT1A haplotype might exhibit an altered metabolism of drugs, which could necessitate dose adjustments.

This study intends to investigate the green synthesis of silver (Ag) and gold (Au) nanoparticles (NPs) using Echinophora platyloba extract and to evaluate the antioxidant and anti-inflammatory effects of the synthesized NPs and the extract. In this study, aqueous and hydroalcoholic extracts of E. platyloba were prepared, which were used for the biosynthesis of Ag and Au NPs. Dynamic light scattering (DLS), zeta potential analysis, transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) spectroscopy, UV-Vis spectroscopy, and X-ray diffraction (XRD) methods were used to characterize the green NPs. The antioxidant effect of the NPs was estimated using in vitro methods, including reducing power (RP), ferric reducing/antioxidant power (FRAP), and 2,2-diphenyl-1-picrylhydrazyl (DPPH). To evaluate the anti-inflammatory and antioxidant activity of E. platyloba extract and Ag and Au NPs, we used the carrageenan method. In our experiment, the extract and the synthesized NPs were administered orally to the mice 2 h before the carrageenan injection. The subsequent inhibition of inflammation and reduction of paw thickness were quantified. To evaluate their antioxidant effect, malondialdehyde (MDA), and total antioxidant capacity (TAC) levels were measured. Levels of pro-inflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), were also quantified. In this study, the results indicate that the synthesized Ag and Au NPs have antioxidant and anti-inflammatory effects. The most promising results were observed in the groups that received the Ag NPs.

Background: The present study reports the protective effect conferred by scavenging mitochondrial oxidative stress (mtOS) in 5-fluorouracil (5-FU)-induced renal injury. Methods: 5-FU renal toxicity model was created by administering 5-FU (12 mg/kg b.w. intraperitoneally [i.p.], for 4 days) to male BALB/c mice. The protective effect of mitochondria-targeted antioxidant (MTA), Mito-TEMPO coadministered at a dosage of 0.1 mg/kg b.w. i.p., was established in terms of levels/expressions of renal injury markers, histopathological alterations, oxidative DNA damage, proinflammatory markers, mtOS, mitochondrial dysfunction, and modulation of apoptotic proteins and apoptotic cell death. Results: A significant rise in the levels of serum urea, uric acid, and creatinine was noted after 5-FU administration to the animals. Immunohistochemical and ELISA findings demonstrated significant decrease in podocin and conversely a significant increase in neutrophil gelatinase-associated lipocalin (NGAL) expression after 5-FU challenge. The histopathological analysis further revealed Bowman's capsule dilation, glomerular condensation, and vacuolar degeneration. Mito-TEMPO treatment significantly lowered renal injury markers, reversed the expressions of podocin and NGAL to normal, and restored normal histoarchitecture of renal tissue. Mitochondrial reactive oxygen species (mtROS), mtLPO, activity of mitochondrial enzyme complexes, and mitochondrial antioxidant defense status were significantly improved in Mito-TEMPO protected group as compared to the 5-FU group. Further, significantly decreased expression of 8-OHdG, reduction in apoptotic cell death, and modulation of apoptotic proteins Bax, Bcl-2, and caspase-3 were noted in Mito-TEMPO protected group, indicating its protective effect against 5-FU-induced renal injury. Conclusion: The approach of targeting mtOS using MTA, Mito-TEMPO, may prove as safe adjuvant in alleviating renal toxicity during 5-FU chemotherapy.

Introduction: High-intensity interval training (HIIT) is a form of interval exercise that enhances capacity and benefits well-being. Resveratrol is a naturally occurring polyphenol prevalent in grapes and red wine, demonstrating significant health effects on the body. This study sought to evaluate the synergistic effects of swimming HIIT and resveratrol intake on the expression of SIRTs 4, SIRTs 5, and superoxide dismutases (SOD1 and SOD2) in the frontal lobe of elderly rats. Materials and Methods: Forty-five male Wistar rats, aged 22 months, were categorized into five groups: the control group (CTL), the swimming HIIT group (Ex: Exercise), the swimming HIIT with resveratrol group (R + Ex), the resveratrol group (R), and the solvent control group (vehicle). The R + Ex group engaged in high-intensity interval swimming and ingested resveratrol (10 mg/kg/day via gavage) for 6 weeks. During the initial and final sessions of each week, blood samples from the rats in the Ex and R + Ex groups were collected for lactate analysis. The proteins SIRTs 4 and 5, as well as SODs 1 and 2, were quantified using the western blot approach. Results: Integrating HIIT with resveratrol markedly enhanced the expression of SIRT4, SIRT5, and antioxidant enzymes in the frontal lobe of elderly rats. Conclusion: Resveratrol and HIIT, particularly their synergistic effects, provide antioxidant and antiaging benefits on the frontal lobe of aged rats.

Hypertension is a risk factor for vascular injury and thrombotic complications, and smoking tobacco is a risk factor for the development and exacerbation of hypertension. The influence of waterpipe smoke (WPS) on coagulation and vascular injury in hypertension is not fully understood. Here, we evaluated the effects of WPS in mice made hypertensive (HT) by infusing angiotensin II (Ang II) for 42 days. On day 14 of the infusion of Ang II or vehicle (normotensive; NT), mice were exposed either to air or WPS for four consecutive weeks. Each session was 30 min/day for 5 days/week. The concentrations of tissue factor, von Willebrand factor, fibrinogen, and plasminogen activator inhibitor-1 were elevated in the HT + WPS group versus either HT + air or NT + WPS groups. Similarly, in the HT + WPS group, thrombogenicity was increased both in vivo and in vitro, compared with either HT + air or NT + WPS groups. In aortic tissue, adhesion molecules including P-selectin, E-selectin, intercellular adhesion molecule-1, and vascular adhesion molecule-1 were increased in the HT + WPS group versus the controls. Likewise, various proinflammatory cytokines and markers of oxidative stress augmented in the HT + WPS group compared with either HT + air or NT + WPS. DNA damage, cleaved caspase-3, and cytochrome C were increased in the HT + WPS group versus the controls. The immunohistochemical expression of nuclear factor erythroid 2-related factor 2 was increased in the HT + WPS group versus either HT + air or NT + WPS. Taken together, our findings show that WPS exposure intensified thrombogenicity and vascular damage in experimentally induced hypertension. Our data suggest that vascular toxicity of WPS may be exaggerated in hypertensive patients.

Oxidative stress, driven by an imbalance between oxidants and antioxidants, disrupts redox homeostasis and contributes to the development of chronic diseases, including cancer, diabetes, neurodegenerative disorders, and aging. The NRF2-KEAP1 pathway is a pivotal cellular defense mechanism against oxidative stress, regulating the transcription of cytoprotective genes. Pharmacological NRF2 activation has emerged as a promising strategy to mitigate oxidative stress-related pathologies; however, challenges regarding target specificity, pharmacodynamics, efficacy, and safety remain unresolved. Isoeugenol, a phenylpropanoid found in essential oils, has traditionally been recognized as a skin allergen but is now gaining attention for its potential as an NRF2 activator. Emerging evidence suggests that isoeugenol exerts antioxidant, anti-inflammatory, and neuroprotective effects and modulates metabolic disorders such as diabetes mellitus. Despite its therapeutic potential, the direct correlation between isoeugenol's effects and NRF2 activation remains underexplored. Existing studies indicate that isoeugenol may activate NRF2 through multiple mechanisms, including covalent modification of KEAP1 cysteine residues, increased AKT activation and GSK3β inactivation, and glutathione depletion leading to reactive oxygen species (ROS) generation. Understanding these activation pathways is critical for leveraging isoeugenol as a therapeutic agent. This review provides a comprehensive analysis of isoeugenol's role in modulating NRF2 activity and its implications for treating oxidative stress-driven diseases. By integrating current findings, this review highlights new insights into the therapeutic potential of isoeugenol in translational medicine. We propose future research directions to optimize its application in clinical settings, paving the way for more targeted and effective NRF2-based interventions in chronic disease management.

Background: Exercise stress test-induced hypofibrinolysis and changes in circulating levels of several interleukins have been observed in aortic stenosis (AS). However, it is unknown whether the pattern of exercise-induced changes in oxidative stress differs between AS patients and controls and if the differences are associated with changes in fibrinolysis and inflammation. Methods: We studied 32 asymptomatic patients with moderate-to-severe AS and 32 controls of similar age, sex, and body mass index. We assessed plasma protein carbonyl (PC) concentrations, a marker of oxidative stress, in relation to interleukin (IL)-10 and -6 levels and fibrinolysis capacity, expressed as plasma clot lysis time (CLT) at four time points: at baseline, at peak exercise, 1 and 24 h after a symptom-limited exercise test. Results: AS patients had 12.8% and 27% higher PC concentrations 1 and 24 h after exercise than controls (both p  < 0.05), with no differences at baseline and peak exercise. In AS patients, PC concentration was 8.3% higher at peak exercise compared to baseline followed by further PC increase (+12.8% at 1 h and +20.5% at 24 h) compared to peak exercise (all p  < 0.05). In controls, PC concentrations increased during exercise, reaching the highest values 1 h after exercise (+21.9%). In the AS group, PC concentrations at baseline correlated with AS severity measured as peak transvalvular velocity (V _max: r = 0.49, p  < 0.05), mean (PG_mean: r = 0.42, p  < 0.05), and maximal transvalvular pressure gradients (PG_max: r = 0.41, p  < 0.05). PC concentrations correlated with IL-10 levels 1 h (r = 0.37, p  < 0.05) and 24 h (r = 0.38, p  < 0.05) post exercise in AS patients, whereas in controls only at baseline (r = 0.42, p  < 0.05). No associations between PC levels and IL-6 or CLT were observed at any time point. Conclusions: Our findings show that AS patients respond differently to exercise in terms of PC compared to controls, which suggests a novel effect of hemodynamic abnormalities in this disease on intensity of oxidative stress.

Vitiligo is a skin disease that affects all ethnicities and genders and is characterized by the loss of pigment essentially due to the selective loss of melanocytes. Although it is generally considered a systemic disease associated with polymorphisms in genes involved in the immune response, vitiligo is also considered an oxidative imbalance-associated disease. It represents a multifactorial pathology in which some genetic predisposition and epigenetic factors coupled with some critical biochemical and molecular pathways could play a pivotal role. The aim of this work was thus to review some of the fine cellular mechanisms involved in the etiopathogenesis of vitiligo, mainly focusing on the nonimmunological ones, extensively highlighted elsewhere. We took into consideration, in addition to oxidative stress, both the cause and the hallmark of the pathology, some less investigated aspects such as the role of epigenetic factors, e.g., microRNAs, of receptors of catecholamines, and the more recently recognized role of the mitochondria. Sex differences associated with vitiligo have also been investigated starting from sex hormones and the receptors through which they exert their influence. From literature analysis, a picture seems to emerge in which vitiligo can be considered not just a melanocyte-affecting disease but a systemic pathology that compromises the homeostasis of a complex tissue such as the skin, in which different cell types reside playing multifaceted physiological roles for the entire organism. The exact sequence of cellular and subcellular events associated with vitiligo is still a matter of debate. However, the knowledge of the individual biological factors implicated in vitiligo could help physicians to highlight useful innovative markers of progression and provide, in the long run, new targets for more tailored treatments based on individual manifestations of the disease.

Occupational exposure to arsenic (As), cadmium (Cd), and lead (Pb) affects many sectors, necessitating research to understand their transformation mechanisms. In this study, we characterized the process of epithelial-mesenchymal transition (EMT) in a rat hepatic epithelial cell line with decreased expression of catalase and glutamate cysteine ligase catalytic (GCLC) subunit that was exposed to a mixture of As, Cd, and Pb at equimolar occupational exposure concentrations. We evaluated the expression of genes and proteins involved in EMT. Our findings revealed that cells with a decreased antioxidant barrier showed a decreased expression and abundance of epithelial genes when exposed to a mixture of metals. Additionally, we observed alterations in the expression of transcription factors (TFs) associated with EMT and an increase in the expression and abundance of mesenchymal genes. Specifically, we found that E-cadherin expression decreased by ~50% at both the gene and protein levels. In contrast, the expression of vimentin, α-smooth muscle actin, and N-cadherin genes increased by ~70%, whereas their corresponding protein levels increased by nearly 100%. Furthermore, the TFs zinc finger e-box binding homeobox 1 and snail family transcriptional repressor 1 showed a 30% increase in gene expression and an ~80% increase in protein expression. These changes enable the cells to acquire migratory capabilities. Our results confirmed that exposure to this mixture of As, Cd, and Pb can induce EMT in cells with a decreased antioxidant barrier.