The effect of endogenous oxidative stress induced by gamma-glutamyl cysteinesynthetase inhibitor D,L-buthionine sulfoximine (BSO) on the functioning of hypoxia-induced factor 1a (HIF-1alpha) was ...studied on Caco-2 cells. BSO was added for 24 h in concentrations of 5, 10, 50, 100, and 500 microM. It was shown that BSO in concentrations of 10, 50, and 100 microM induced endogenous oxidative stress and increased the content of HIF-1alpha; this effect was regulated through nuclear factor of erythroid origin 2 (Nrf2). Activation of HIF-1alpha had an independent protective effect, as evidenced by the decrease in cell viability after HIF-1alpha inhibition under these conditions. When the concentration of BSO was increased to 500 microM the content of HIF-1alpha did not change, and cell viability decreased. Key Words: hypoxia-induced factor 1a (HIF-1alpha); D,L-buthionine sulfoximine; erythroid-derived nuclear factor 2 (Nrf2); oxidative stress
Diabetes-induced oxidative stress is one of the major contributors to dysfunction of endothelial progenitor cells (EPCs) and impaired endothelial regeneration. Thus, we tested whether increasing ...antioxidant protein metallothionein (MT) in EPCs promotes angiogenesis in a hind limb ischemia (HLI) model in endothelial MT transgenic (JTMT) mice with high-fat diet- and streptozocin-induced diabetes. Compared with littermate wild-type (WT) diabetic mice, JTMT diabetic mice had improved blood flow recovery and angiogenesis after HLI. Similarly, transplantation of JTMT bone marrow-derived mononuclear cells (BM-MNCs) stimulated greater blood flow recovery in
mice with HLI than did WT BM-MNCs. The improved recovery was associated with augmented EPC mobilization and angiogenic function. Further, cultured EPCs from patients with diabetes exhibited decreased MT expression, increased cell apoptosis, and impaired tube formation, while cultured JTMT EPCs had enhanced cell survival, migration, and tube formation in hypoxic/hyperglycemic conditions compared with WT EPCs. Mechanistically, MT overexpression enhanced hypoxia-inducible factor 1α (HIF-1α), stromal cell-derived factor (SDF-1), and vascular endothelial growth factor (VEGF) expression and reduced oxidative stress in ischemic tissues. MT's pro-EPC effects were abrogated by siRNA knockdown of HIF-1α without affecting its antioxidant action. These results indicate that endothelial MT overexpression is sufficient to protect against diabetes-induced impairment of angiogenesis by promoting EPC function, most likely through upregulation of HIF-1α/SDF-1/VEGF signaling and reducing oxidative stress.
The human skin is exposed to various environmental factors including solar radiation and ambient air pollutants. Although, due to its physical and biological properties, the skin efficiently protects ...the body against the harm of environmental factors, their excessive levels and possible synergistic action may lead to harmful effects. Among particulate matter present in ambient air pollutants, PM
is of particular importance for it can penetrate both disrupted and intact skin, causing adverse effects to skin tissue. Although certain components of PM
can exhibit photochemical activity, only a limited amount of data regarding the interaction of PM
with light and its effect on skin tissue are available. This study focused on light-induced toxicity in cultured human keratinocytes, which was mediated by PM
obtained in different seasons. Dynamic Light Scattering (DLS) and Atomic Force Microscopy (AFM) were employed to determine sizes of the particles. The ability of PM
to photogenerate free radicals and singlet oxygen was studied using EPR spin-trapping and time-resolved singlet oxygen phosphorescence, respectively. Solar simulator with selected filters was used as light source for cell treatment to model environmental lightning conditions. Cytotoxicity of photoexcited PM
was analyzed using MTT assay, PI staining and flow cytometry, and the apoptotic pathway was further examined using Caspase-3/7 assay and RT-PCR. Iodometric assay and JC-10 assay were used to investigate damage to cell lipids and mitochondria. Light-excited PM
were found to generate free radicals and singlet oxygen in season-dependent manner. HaCaT cells containing PM
and irradiated with UV-Vis exhibited oxidative stress features-increased peroxidation of intracellular lipids, decrease of mitochondrial membrane potential, enhanced expression of oxidative stress related genes and apoptotic cell death. The data indicate that sunlight can significantly increase PM
-mediated toxicity in skin cells.
Excessive iron contributes to oxidative stress after central nervous system injury. NADPH oxidase (NOX) enzymes are upregulated in microglia after pro-inflammatory activation and contribute to ...oxidative stress. The relationship between iron, microglia, NOX, and oxidative stress is currently unclear.
We evaluated the effects of iron on lipopolysaccharide (LPS)-activated microglia and its secondary effect within neuronal co-cultures. Further, NOX2 and four specific inhibitors were tested to evaluate the relationship with the reactive oxygen species (ROS)-producing enzymes.
An iron dose-dependent increase in ROS production among microglia treated with LPS was identified. Interestingly, despite this increase in ROS, inflammatory polarization alterations were not detected among the microglia after exposure to iron and LPS. Co-culture experimentation between primary neurons and exposed microglia (iron and LPS) significantly reduced neuronal cell number at 24 h, suggesting a profound neurotoxic effect despite the lack of a change in polarization phenotype. NOX2 and NOX4 inhibition significantly reduced ROS production among microglia exposed to iron and LPS and reduced neuronal damage and death in response to microglial co-culture.
In conclusion, iron significantly increased ROS production and neurotoxicity without exacerbating LP-activated microglia phenotype in vitro, suggesting that iron contributes to microglia-related oxidative stress, and this may be a viable therapeutic target for injury or neurodegeneration. Further, this study highlights both NOX2 and NOX4 as potential therapeutic targets in the treatment of iron-induced microglia-related inflammation and neurotoxicity.
Particulate matter (PM) pollutant exposure, which induces oxidative stress and inflammation, and vitamin D insufficiency, which compromises immune regulation, are detrimental in asthma.
Mechanistic ...cell culture experiments were undertaken to ascertain whether vitamin D abrogates PM-induced inflammatory responses of human bronchial epithelial cells (HBECs) through enhancement of antioxidant pathways.
Transcriptome analysis, PCR and ELISA were undertaken to delineate markers of inflammation and oxidative stress; with comparison of expression in primary HBECs from healthy and asthmatic donors cultured with reference urban PM in the presence/absence of vitamin D.
Transcriptome analysis identified over 500 genes significantly perturbed by PM-stimulation, including multiple pro-inflammatory cytokines. Vitamin D altered expression of a subset of these PM-induced genes, including suppressing IL6. Addition of vitamin D suppressed PM-stimulated IL-6 production, although to significantly greater extent in healthy versus asthmatic donor cultures. Vitamin D also differentially affected PM-stimulated GM-CSF, with suppression in healthy HBECs and enhancement in asthmatic cultures. Vitamin D increased HBEC expression of the antioxidant pathway gene G6PD, increased the ratio of reduced to oxidised glutathione, and in PM-stimulated cultures decreased the formation of 8-isoprostane. Pre-treatment with vitamin D decreased CXCL8 and further decreased IL-6 production in PM-stimulated cultures, an effect abrogated by inhibition of G6PD with DHEA, supporting a role for this pathway in the anti-inflammatory actions of vitamin D.
In a study using HBECs from 18 donors, vitamin D enhanced HBEC antioxidant responses and modulated the immune response to PM, suggesting that vitamin D may protect the airways from pathological pollution-induced inflammation.
Display omitted
At present, ischemic heart failure (HF) caused by coronary heart disease (CHD) has a high morbidity and mortality, placing a heavy burden on global human health. L-Proline (Pro), a ...nonessential amino acid and the foundation of proteins in the human body, was found to be protective against oxidative stress in various diseases. However, the role of Pro in cardiovascular disease (CVD) remains unclear. In vivo, adult mice were subjected to left anterior descending (LAD) artery ligation for 4 weeks with or without Pro treatment. In vitro, H9c2 cardiomyocytes were pretreated with or without Pro, followed by treatment with hydrogen peroxide (H2O2) (200 μM) for 6 and 12 h. Our data showed that Pro metabolism was disturbing after myocardial infarction (MI). Pro treatment improved cardiac remodeling, reduced infarct size, and decreased oxidative stress and apoptosis in mouse hearts after MI. Pro inhibited the H2O2-induced increase in reactive oxygen species (ROS) in H9c2 cells and protected against H2O2-induced apoptosis. Mechanistically, by RNA sequencing (RNA-seq) and pathway analysis, Pro was shown to exert a protective effect through H2O2 catabolic processes and apoptotic processes, especially oxidative phosphorylation (OXPHOS). Taken together, our findings suggested that Pro protects against MI injury at least partially via redox regulation, highlighting the potential of Pro as a novel therapy for ischemic HF caused by CHD.
Reactive oxygen species (ROS) are highly reactive chemical species containing oxygen, controlled by both enzymatic and nonenzymatic antioxidant defense systems. In the heart, ROS play an important ...role in cell homeostasis, by modulating cell proliferation, differentiation, and excitation-contraction coupling. Oxidative stress occurs when ROS production exceeds the buffering capacity of the antioxidant defense systems, leading to cellular and molecular abnormalities, ultimately resulting in cardiac dysfunction. In this review, we will discuss the physiological sources of ROS in the heart, the mechanisms of oxidative stress-related myocardial injury, and the implications of experimental studies and clinical trials with antioxidant therapies in cardiovascular diseases.
Catechins are polyphenolic compounds—flavanols of the flavonoid family found in a variety of plants. Green tea, wine and cocoa-based products are the main dietary sources of these flavanols. ...Catechins have potent antioxidant properties, although in some cases they may act in the cell as pro-oxidants. Catechins are reactive oxygen species (ROS) scavengers and metal ion chelators, whereas their indirect antioxidant activities comprise induction of antioxidant enzymes, inhibition of pro-oxidant enzymes, and production of the phase II detoxification enzymes and antioxidant enzymes. Oxidative stress and ROS are implicated in aging and related dysfunctions, such as neurodegenerative disease, cancer, cardiovascular diseases, and diabetes. Due to their antioxidant properties, catechins may be beneficial in preventing and protecting against diseases caused by oxidative stress. This article reviews the biochemical properties of catechins, their antioxidant activity, and the mechanisms of action involved in the prevention of oxidative stress-caused diseases.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular senile plaques and intracellular neurofibrillary tangles in the brain. Amyloid-β peptides (Aβ) are considered ...to play a critical role in the onset and progression of AD. Apigenin (4',5,7-trihydroxyflavone) is a pharmacologically active agent. Even though some evidence suggests that it has potential neuroprotective effects, no preexisting study has reported any therapeutic effects of apigenin in AD models. In the present study, we examined the effects of apigenin on cognitive function in APP/PS1 double transgenic AD mice and explored its mechanism(s) of action. Three-month oral treatment with apigenin rescued learning deficits and relieved memory retention in APP/PS1 mice. Apigenin also showed effects affecting APP processing and preventing Aβ burden due to the down-regulation of BACE1 and β-CTF levels, the relief of Aβ deposition, and the decrease of insoluble Aβ levels. Moreover, apigenin exhibited superoxide anion scavenging effects and improved antioxidative enzyme activity of superoxide dismutase and glutathione peroxidase. In addition, apigenin restored neurotrophic ERK/CREB/BDNF pathway in the cerebral cortex. In conclusion, apigenin may ameliorate AD-associated learning and memory impairment through relieving Aβ burden, suppressing amyloidogenic process, inhibiting oxidative stress, and restoring ERK/CREB/BDNF pathway. Therefore, apigenin appears to represent an alternative medication for the prevention and/or therapy of AD.
Current oxidative stress amplifying strategies for immunogenic cell death (ICD) promotion are mainly restricted to immune tolerance induced by adaptive cellular antioxidation, limited ...tumor-selectivity, and tumoral immunosuppression. Herein, a facile and efficient scenario of genetically engineering transferrin-expressing cell membrane nanovesicle encapsulated IR820-dihydroartemisinin nanomedicine (Tf@IR820-DHA) was developed to boost a-PD-L1-mediated immune checkpoint blocking (ICB) via synergetic triple stimuli-activated oxidative stress-associated ICD. We demonstrate that the engineered transferrin of Tf@IR820-DHA has excellent tumor targeting and Fe(III)-loading properties and thus delivered Fe(III) and IR820-DHA nanoparticles (NPs) to the lesion location effectively. We found that the self-carrying Fe(III)-mediated programmable catalysis of DHA and glutathione (GSH) depletion generated plenty of reactive oxygen species (ROS). Moreover, DHA also acted as an immunomodulator to decrease the number of T regulatory cells, thereby remodeling the tumor immune microenvironment and achieving double T cell activation. Furthermore, the IR820 molecule served as a competent sonosensitizer to produce ROS under ultrasound activation and guide precise immunotherapy via fluorescent/photoacoustic (FL/PA) imaging. Through its three-pronged delivery of stimuli-activated oxidative stress (DHA-induced chemodynamic therapy, catalysis-conferred GSH depletion, and IR820-mediated sonodynamic therapy), Tf@IR820-DHA caused high levels of targeted ICD. This significantly increased the proportions of IFN-γ-secreting T cells (CD4+ T and CD8+ T) and enhanced a-PD-L1-mediated ICB against primary and distant tumors, which represents a promising approach for cancer nanoimmunotherapy.
PDF
