Cardioprotection against ischaemia/reperfusion by vitamins C and E plus n−3 fatty acids: molecular mechanisms and potential clinical applications

2012 ◽  
Vol 124 (1) ◽  
pp. 1-15 ◽  
Author(s):  
Ramón Rodrigo ◽  
Juan C. Prieto ◽  
Rodrigo Castillo
Keyword(s):  
Oxidative Stress ◽  
Heart Disease ◽  
Vitamin C ◽  
Ischaemic Heart Disease ◽  
Molecular Mechanisms ◽  
Cellular Damage ◽  
Related Factor ◽  
Nuclear Factor ◽  
Ros Scavenging ◽  
Ischaemia Reperfusion

The role of oxidative stress in ischaemic heart disease has been thoroughly investigated in humans. Increased levels of ROS (reactive oxygen species) and RNS (reactive nitrogen species) have been demonstrated during ischaemia and post-ischaemic reperfusion in humans. Depending on their concentrations, these reactive species can act either as benevolent molecules that promote cell survival (at low-to-moderate concentrations) or can induce irreversible cellular damage and death (at high concentrations). Although high ROS levels can induce NF-κB (nuclear factor κB) activation, inflammation, apoptosis or necrosis, low-to-moderate levels can enhance the antioxidant response, via Nrf2 (nuclear factor-erythroid 2-related factor 2) activation. However, a clear definition of these concentration thresholds remains to be established. Although a number of experimental studies have demonstrated that oxidative stress plays a major role in heart ischaemia/reperfusion pathophysiology, controlled clinical trials have failed to prove the efficacy of antioxidants in acute or long-term treatments of ischaemic heart disease. Oral doses of vitamin C are not sufficient to promote ROS scavenging and only down-regulate their production via NADPH oxidase, a biological effect shared by vitamin E to abrogate oxidative stress. However, infusion of vitamin C at doses high enough to achieve plasma levels of 10 mmol/l should prevent superoxide production and the pathophysiological cascade of deleterious heart effects. In turn, n−3 PUFA (polyunsaturated fatty acid) exposure leads to enhanced activity of antioxidant enzymes. In the present review, we present evidence to support the molecular basis for a novel pharmacological strategy using these antioxidant vitamins plus n−3 PUFAs for cardioprotection in clinical settings, such as post-operative atrial fibrillation, percutaneous coronary intervention following acute myocardial infarction and other events that are associated with ischaemia/reperfusion.

scholarly journals Crosstalk between Long-Term Sublethal Oxidative Stress and Detrimental Inflammation as Potential Drivers for Age-Related Retinal Degeneration

Antioxidants ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 25
Author(s):  
Lara Macchioni ◽  
Davide Chiasserini ◽  
Letizia Mezzasoma ◽  
Magdalena Davidescu ◽  
Pier Luigi Orvietani ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Age Related Macular Degeneration ◽  
Inflammasome Activation ◽  
Related Factor ◽  
Nuclear Factor ◽  
Rpe Cells ◽  
Age Related ◽  
Oxidative Insult

Age-related retinal degenerations, including age-related macular degeneration (AMD), are caused by the loss of retinal pigmented epithelial (RPE) cells and photoreceptors. The pathogenesis of AMD, deeply linked to the aging process, also involves oxidative stress and inflammatory responses. However, the molecular mechanisms contributing to the shift from healthy aging to AMD are still poorly understood. Since RPE cells in the retina are chronically exposed to a pro-oxidant microenvironment throughout life, we simulated in vivo conditions by growing ARPE-19 cells in the presence of 10 μM H2O2 for several passages. This long-term oxidative insult induced senescence in ARPE-19 cells without affecting cell proliferation. Global proteomic analysis revealed a dysregulated expression in proteins involved in antioxidant response, mitochondrial homeostasis, and extracellular matrix organization. The analyses of mitochondrial functionality showed increased mitochondrial biogenesis and ATP generation and improved response to oxidative stress. The latter, however, was linked to nuclear factor-κB (NF-κB) rather than nuclear factor erythroid 2–related factor 2 (Nrf2) activation. NF-κB hyperactivation also resulted in increased pro-inflammatory cytokines expression and inflammasome activation. Moreover, in response to additional pro-inflammatory insults, senescent ARPE-19 cells underwent an exaggerated inflammatory reaction. Our results indicate senescence as an important link between chronic oxidative insult and detrimental chronic inflammation, with possible future repercussions for therapeutic interventions.

scholarly journals Isoliquiritigenin Confers Neuroprotection and Alleviates Amyloid-β42-Induced Neuroinflammation in Microglia by Regulating the Nrf2/NF-κB Signaling

2021 ◽  
Vol 15 ◽  
Author(s):  
Yue Fu ◽  
Jianping Jia
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Response ◽  
Molecular Mechanisms ◽  
Morphological Changes ◽  
No Production ◽  
Related Factor ◽  
Nuclear Factor ◽  
Qrt Pcr ◽  
Bv2 Cells ◽  
And Oxidative Stress

BackgroundNeuroinflammation and oxidative stress are two major pathological characteristics of Alzheimer’s disease (AD). Amyloid-β oligomers (AβO), a toxic form of Aβ, promote the neuroinflammation and oxidative stress in the development of AD. Isoliquiritigenin (ISL), a natural flavonoid isolated from the root of liquorice, has been shown to exert inhibitory effects on inflammatory response and oxidative stress.ObjectivesThe main purpose of this study is to assess the influence of ISL on inflammatory response and oxidative stress in BV2 cells stimulated with AβO, and to explore the underlying molecular mechanisms.Methods3-(4,5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H- tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) cytotoxicity assays were used to assess the toxic or protective effects of ISL. The expression levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assays. Morphological changes in BV2 cells were assessed by immunofluorescence method. Nitric oxide (NO) assay kit was used to determinate the NO production. Western blot, qRT-PCR and immunofluorescence were used to explore the underlying molecular mechanisms.ResultsISL treatment reduced the production of inflammatory cytokines and NO, and alleviated the morphological changes in BV2 cells induced by AβO. ISL treatment further protected N2a cells from the toxic medium of AβO-stimulated BV2 cells. ISL activated nuclear factor erythroid-2 related factor 2 (Nrf2) signaling and suppressed nuclear factor-κB (NF-κB) signaling in BV2 cells.ConclusionISL suppresses AβO-induced inflammation and oxidative stress in BV2 cells via the regulation of Nrf2/NF-κB signaling. Therefore, ISL indirectly protects neurons from the damage of toxic conditioned media.

scholarly journals Anemopsis californica Attenuates Photoaging by Regulating MAPK, NRF2, and NFATc1 Signaling Pathways

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1882
Author(s):  
Quynh T. N. Nguyen ◽  
Minzhe Fang ◽  
Nhung Quynh Do ◽  
Jeehaeng Jeong ◽  
Sarang Oh ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Inflammation ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Biological Effects ◽  
Dermal Fibroblasts ◽  
Related Factor ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Anemopsis Californica

Long-term exposure of the skin to solar radiation causes chronic inflammation and oxidative stress, which accelerates collagen degradation. This contributes to the formation of wrinkles and dark spots, skin fragility, and even skin cancer. In this study, Anemopsis californica (AC), a herb from North America that is well known for treating microorganism infection and promoting wound healing, was investigated for its photoprotective effects. The biological effects of AC were studied on two in vitro models, namely, lipopolysaccharide (LPS)-induced macrophages and ultraviolet B (UVB)-irradiated dermal fibroblasts, to characterize its underlying molecular mechanisms. The results showed that AC decreased the mRNA levels of inflammatory mediators in sensitized macrophages, including cytokines, inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX-2). Moreover, AC alleviated UVB-induced photoaging in dermal fibroblasts by restoring procollagen synthesis. This resulted from the regulation of excessive reactive oxygen species (ROS) by AC, which was mediated by the activation of the antioxidative system nuclear factor erythroid 2-related factor 2 (NRF2). AC also alleviated oxidative stress and inflammatory responses by inhibiting the phosphorylation of mitogen-activated protein kinase (MAPK) and interfering with the nuclear translocation of the immune regulator nuclear factor of activated T-cells 1 (NFATc1). In conclusion, the protective effects of AC on skin cellular components suggested that it has the potential for use in the development of drugs and cosmetics that protect the skin from UVB-induced chronic inflammation and aging.

scholarly journals Effects of Lespedeza Bicolor Extract on Regulation of AMPK Associated Hepatic Lipid Metabolism in Type 2 Diabetic Mice

Antioxidants ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 599 ◽  
Author(s):  
Younmi Kim ◽  
Heaji Lee ◽  
Sun Yeou Kim ◽  
Yunsook Lim
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Smooth Muscle Actin ◽  
Lipid Synthesis ◽  
Hepatic Damage ◽  
Related Factor ◽  
Nuclear Factor ◽  
Diabetic Mice ◽  
Lespedeza Bicolor

Lespedeza bicolor (LB) is one of the ornamental plants used for the treatment of inflammation caused by oxidative damage. However, its beneficial effects on hyperglycemia-induced hepatic damage and the related molecular mechanisms remain unclear. We hypothesized that Lespedeza bicolor extract (LBE) would attenuate hyperglycemia-induced liver injury in type 2 diabetes mellitus (T2DM). Diabetes was induced by a low dosage of streptozotocin (STZ) injection (30 mg/kg) with a high fat diet in male C57BL/6J mice. LBE was administered orally at 100 mg/kg or 250 mg/kg for 12 weeks. LBE supplementation regardless of dosage ameliorated plasma levels of hemoglobin A1c (HbA1c) in diabetic mice. Moreover, both LBE supplementations upregulated AMP-activation kinase (AMPK), which may activate sirtuin1 (SIRT) associated pathway accompanied by decreased lipid synthesis at low dose of LBE supplementation. These changes were in part explained by reduced protein levels of oxidative stress (nuclear factor erythroid 2-related factor 2 (Nrf2) and catalase), inflammation (nuclear factor kappa B (NF-κB), interleukin-1β (IL-1β), interleukin-6 (IL-6), and nitric oxide synthases (iNOS)), and fibrosis (α-smooth muscle actin (α-SMA) and protein kinase C (PKC)) in diabetic liver. Taken together, LBE might be a potential nutraceutical to ameliorate hepatic damage by regulation of AMPK associated pathway via oxidative stress, inflammation, and fibrosis in T2DM.

scholarly journals Oxidative Damage and Nrf2 Translocation Induced by Toxicities of Deoxynivalenol on the Placental and Embryo on Gestation Day 12.5 d and 18.5 d

Toxins ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 370 ◽  
Author(s):  
Miao Yu ◽  
Zhi-Yuan Wei ◽  
Zhou-Heng Xu ◽  
Jia-Qi Pan ◽  
Jian-Huan Chen
Keyword(s):  
Oxidative Stress ◽  
Superoxide Dismutase ◽  
Oxidative Damage ◽  
Elevated Level ◽  
Molecular Mechanisms ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Pathway Activation ◽  
Different Doses

Deoxynivalenol (DON) is a kind of natural pollutant belonging to the trichothecenes family. The aim of this study is to use diverse assays to evaluate oxidative damage as well as translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), and to investigate their mechanisms in DON-induced toxicities on a placenta and embryo. Pregnant C57BL/6 mice were randomly assigned to three groups with different doses of DON: 0, 1.0, 2.5 mg/(kg·day). In gestation day (GD) 12.5 d and 18.5 d, DON induced an elevated resorption rate of the embryos as well as structural and functional damage of the placenta. In the placenta, altered levels of the antioxidant enzymes malondialdehyde, superoxide dismutase and glutathione indicated remarkable oxidative stress. Furthermore, an elevated level of heme oxygenase-1 (HO-1) and the translocation of Nrf2 from nucleus to cytoplasm indicated Nrf2/HO-1 pathway activation in DON-L group (1.0 mg/(kg·day)). It is noteworthy that the results in this experiment in GD 12.5 d were similar to those in GD 18.5 d. In conclusion, DON-induced placental oxidative damage and Nrf2 translocation were similar in GD 12.5 d and GD 18.5 d. Oxidative stress is one of the most important molecular mechanisms for embryotoxicity induced by DON, and Nrf2 translocation may play a substantial role against it.

scholarly journals Astaxanthin as a Modulator of Nrf2, NF-κB, and Their Crosstalk: Molecular Mechanisms and Possible Clinical Applications

Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 502
Author(s):  
Sergio Davinelli ◽  
Luciano Saso ◽  
Floriana D’Angeli ◽  
Vittorio Calabrese ◽  
Mariano Intrieri ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Nuclear Factor Κb ◽  
Protective Role ◽  
Related Factor ◽  
Nuclear Factor ◽  
Molecular Features ◽  
Wide Range ◽  
Pharmaceutical Industries

Astaxanthin (AST) is a dietary xanthophyll predominantly found in marine organisms and seafood. Due to its unique molecular features, AST has an excellent antioxidant activity with a wide range of applications in the nutraceutical and pharmaceutical industries. In the past decade, mounting evidence has suggested a protective role for AST against a wide range of diseases where oxidative stress and inflammation participate in a self-perpetuating cycle. Here, we review the underlying molecular mechanisms by which AST regulates two relevant redox-sensitive transcription factors, such as nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor κB (NF-κB). Nrf2 is a cellular sensor of electrophilic stress that coordinates the expression of a battery of defensive genes encoding antioxidant proteins and detoxifying enzymes. Likewise, NF-κB acts as a mediator of cellular stress and induces the expression of various pro-inflammatory genes, including those encoding cytokines, chemokines, and adhesion molecules. The effects of AST on the crosstalk between these transcription factors have also been discussed. Besides this, we summarize the current clinical studies elucidating how AST may alleviate the etiopathogenesis of oxidative stress and inflammation.

scholarly journals Thymol Mitigates Monosodium Glutamate-Induced Neurotoxic Cerebral and Hippocampal Injury in Rats through Overexpression of Nuclear Erythroid 2-Related Factor 2 Signaling Pathway as Well as Altering Nuclear Factor-Kappa B and Glial Fibrillary Acidic Protein Expression

2021 ◽  
Vol 9 (A) ◽  
pp. 716-726
Author(s):  
Rasha Mostafa ◽  
Azza Hassan ◽  
Abeer Salama
Keyword(s):  
Oxidative Stress ◽  
Cerebral Cortex ◽  
Glial Fibrillary Acidic Protein ◽  
Brain Tissue ◽  
Molecular Mechanisms ◽  
Monosodium Glutamate ◽  
Acidic Protein ◽  
Behavioral Activity ◽  
Related Factor ◽  
Nuclear Factor

BACKGROUND: Monosodium glutamate (MSG) is commonly used in various food industries as a flavor enhancer. MSG is reported to cause increased neurotoxicity. AIM: The study investigates the molecular mechanisms underlying the neuroprotective effect of thymol against MSG-induced neurotoxic cerebral and hippocampal injury in rats. MATERIALS AND METHODS: Forty rats were allocated to four Groups: I (Normal); II MSG-control (2 g/kg; i.p.); III-IV MSG + Thymol (400 and 800 mg/kg/day; p.o.). All groups were treated for 15 days. RESULTS: MSG-control group showed a significant reduction in behavioral activity, elevated brain tissue oxidative stress, inflammatory parameters, Nuclear Erythroid 2-Related Factor 2 (Nrf2) gene upregulation, overexpression of nuclear factor-kappa β _(NF-kβ), glial fibrillary acidic protein (GFAP) along with neuronal damage in the cerebral cortex, and hippocampus. Thymol ameliorated MSG-induced brain injury through overexpression of Nrf2 gene, thus increasing the cellular defense and resulting in organized anti-oxidant and anti-inflammatory effects. Thymol improved behavioral activity and brain tissue glutathione content. Thymol also decreased brain contents of malondialdehyde, nitric oxide, tumor necrosis factor-alpha, and interleukin-6. Moreover, Thymol improved NF-kβ _and GFAP immunohistochemical expression besides histopathological picture in cerebral cortex and hippocampus as compared to MSG control rats. CONCLUSION: These results suggest that thymol exhibits promising neuroprotective effects. The study elucidates the molecular mechanisms linking Nrf2 pathway signaling to oxidative stress, inflammation and NF-kβ _expression underlying thymol’s protection against MSG-induced neurotoxicity. The study also highlights the role of GFAP expression in MSG-induced astrocyte injury of cerebrum and hippocampus of rats and the promising protective effects of thymol in ameliorating astrocyte injury.

scholarly journals Drug Delivery Strategies for Curcumin and Other Natural Nrf2 Modulators of Oxidative Stress-Related Diseases

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2137
Author(s):  
Nina Katarina Grilc ◽  
Matej Sova ◽  
Julijana Kristl
Keyword(s):  
Oxidative Stress ◽  
Drug Delivery ◽  
Oral Bioavailability ◽  
Drug Delivery Systems ◽  
Molecular Mechanisms ◽  
Delivery Systems ◽  
Cellular Damage ◽  
Related Factor ◽  
Wide Range

Oxidative stress is associated with a wide range of diseases characterised by oxidant-mediated disturbances of various signalling pathways and cellular damage. The only effective strategy for the prevention of cellular damage is to limit the production of oxidants and support their efficient removal. The implication of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in the cellular redox status has spurred new interest in the use of its natural modulators (e.g., curcumin, resveratrol). Unfortunately, most natural Nrf2 modulators are poorly soluble and show extensive pre-systemic metabolism, low oral bioavailability, and rapid elimination, which necessitates formulation strategies to circumvent these limitations. This paper provides a brief introduction on the cellular and molecular mechanisms involved in Nrf2 modulation and an overview of commonly studied formulations for the improvement of oral bioavailability and in vivo pharmacokinetics of Nrf2 modulators. Some formulations that have also been studied in vivo are discussed, including solid dispersions, self-microemulsifying drug delivery systems, and nanotechnology approaches, such as polymeric and solid lipid nanoparticles, nanocrystals, and micelles. Lastly, brief considerations of nano drug delivery systems for the delivery of Nrf2 modulators to the brain, are provided. The literature reviewed shows that the formulations discussed can provide various improvements to the bioavailability and pharmacokinetics of natural Nrf2 modulators. This has been demonstrated in animal models and clinical studies, thereby increasing the potential for the translation of natural Nrf2 modulators into clinical practice.

scholarly journals Molecular Mechanisms That Link Oxidative Stress, Inflammation, and Fibrosis in the Liver

Antioxidants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1279
Author(s):  
Erika Ramos-Tovar ◽  
Pablo Muriel
Keyword(s):  
Oxidative Stress ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Nuclear Factor Κb ◽  
Receptor Protein ◽  
Related Factor ◽  
Nuclear Factor ◽  
Interacting Protein ◽  
Caspase 1 ◽  
Ecm Proteins

Activated hepatic stellate cells (HSCs) and myofibroblasts are the main producers of extracellular matrix (ECM) proteins that form the fibrotic tissue that leads to hepatic fibrosis. Reactive oxygen species (ROS) can directly activate HSCs or induce inflammation or programmed cell death, especially pyroptosis, in hepatocytes, which in turn activates HSCs and fibroblasts to produce ECM proteins. Therefore, antioxidants and the nuclear factor E2-related factor-2 signaling pathway play critical roles in modulating the profibrogenic response. The master proinflammatory factors nuclear factor-κB (NF-κB) and the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome may coordinate to produce and activate profibrogenic molecules such as interleukins 1β and 18, which effectively activate HSCs, to produce large amounts of fibrotic proteins. Furthermore, the NLRP3 inflammasome activates pro-caspase 1, which is upregulated by NF-κB, to produce caspase 1, which induces pyroptosis via gasdermin and the activation of HSCs. ROS play central roles in the activation of the NF-κB and NLRP3 signaling pathways via IκB (an inhibitor of NF-κB) and thioredoxin-interacting protein, respectively, thereby linking the molecular mechanisms of oxidative stress, inflammation and fibrosis. Elucidating these molecular pathways may pave the way for the development of therapeutic tools to interfere with specific targets.

scholarly journals Food-Derived Pharmacological Modulators of the Nrf2/ARE Pathway: Their Role in the Treatment of Diseases

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 1016
Author(s):  
Feijie Zhao ◽  
Xinxin Ci ◽  
Xiaxia Man ◽  
Jiajia Li ◽  
Zhentong Wei ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Antioxidant Response ◽  
Experimental Models ◽  
Vital Role ◽  
Related Factor ◽  
Nuclear Factor ◽  
Oxygen Species ◽  
Disease Treatment ◽  
Pharmacological Regulation

Oxidative stress, which refers to unbalanced accumulation of reactive oxygen species (ROS) levels in cells, has been linked to acute and chronic diseases. Nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) pathway plays a vital role in regulating cytoprotective genes and enzymes in response to oxidative stress. Therefore, pharmacological regulation of Nrf2/ARE pathway is an effective method to treat several diseases that are mainly characterized by oxidative stress and inflammation. Natural products that counteract oxidative stress by modulating Nrf2 have contributed significantly to disease treatment. In this review, we focus on bioactive compounds derived from food that are Nrf2/ARE pathway regulators and describe the molecular mechanisms for regulating Nrf2 to exert favorable effects in experimental models of diseases.

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