ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease

Antioxidants, Год журнала: 2020, Номер 9(8), С. 743 - 743

Опубликована: Авг. 13, 2020

Neurodegenerative disorders, such as Alzheimer’s disease, are a global public health burden with poorly understood aetiology. Neuroinflammation and oxidative stress (OS) undoubtedly hallmarks of neurodegeneration, contributing to disease progression. Protein aggregation neuronal damage result in the activation disease-associated microglia (DAM) via damage-associated molecular patterns (DAMPs). DAM facilitate persistent inflammation reactive oxygen species (ROS) generation. However, mechanisms linking OS have not been well-defined; thus targeting these cells for clinical benefit has possible. In microglia, ROS generated primarily by NADPH oxidase 2 (NOX2) NOX2 is associated DAMP signalling, amyloid plaque deposition, especially cerebrovasculature. Additionally, originating from both NOX mitochondria may act second messengers propagate immune activation; intracellular signalling underlie excessive OS. Targeting key kinases inflammatory response could cease promote tissue repair. Expression antioxidant proteins dehydrogenase 1 (NQO1), promoted transcription factor Nrf2, which functions control limit Lipid droplet accumulating (LDAM) also represent double-edged sword neurodegenerative sequestering peroxidised lipids non-pathological ageing but becoming dysregulated pro-inflammatory disease. We suggest that future studies should focus on targeted manipulation understand driving inflammatory-related activation. Finally, we discuss recent evidence therapeutic target identification be unbiased founded relevant pathophysiological assays discovery translatable anti-inflammatory therapeutics.

Язык: Английский

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Role of oxidative stress in depression

Drug Discovery Today, Год журнала: 2020, Номер 25(7), С. 1270 - 1276

Опубликована: Май 8, 2020

Язык: Английский

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NRF2 and NF-қB interplay in cerebrovascular and neurodegenerative disorders: Molecular mechanisms and possible therapeutic approaches

Redox Biology, Год журнала: 2018, Номер 21, С. 101059 - 101059

Опубликована: Ноя. 28, 2018

Electrophiles and reactive oxygen species (ROS) play a major role in modulating cellular defense mechanisms as well physiological functions, intracellular signaling. However, excessive ROS generation (endogenous exogenous) can create state of redox imbalance leading to tissue damage (Ma He, 2012) [1]. A growing body research data strongly suggests that imbalanced electrophile overproduction are among the prodromal factors onset progression several cerebrovascular neurodegenerative disorders such amyotrophic lateral sclerosis (ALS), stroke, Alzheimer's disease (AD), Parkinson's (PD), aging 2012; Ramsey et al., 2017; Salminen Sandberg 2014; Sarlette 2008; Tanji 2013) [1–6]. Cells offset oxidative stress by action housekeeping antioxidative enzymes (such superoxide dismutase, catalase, glutathione peroxidase) direct indirect antioxidants (Dinkova-Kostova Talalay, 2010) [7]. The DNA sequence responsible for cytoprotective responses cells has been identified antioxidant response element (ARE), while nuclear factor erythroid 2-related (NRF2) is regulator xenobiotic-activated receptor (XAR) activating ARE-pathway, thus defined NRF2-ARE system In addition, interplay between kappa-light-chain-enhancer activated B (NF-ĸB, protein complex controls cytokine production cell survival), further investigated relation neuroinflammatory disorders. On these premises, we provide review analysis current understanding NRF2-NF-ĸB interplay, their specific CNS disorders, consequent therapeutic implication treatment diseases.

Язык: Английский

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Melatonin as a mitochondria-targeted antioxidant: one of evolution’s best ideas

Cellular and Molecular Life Sciences, Год журнала: 2017, Номер 74(21), С. 3863 - 3881

Опубликована: Сен. 1, 2017

Язык: Английский

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Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Translational Neurodegeneration, Год журнала: 2020, Номер 9(1)

Опубликована: Апрель 3, 2020

The homeostasis of metal ions, such as iron, copper, zinc and calcium, in the brain is crucial for maintaining normal physiological functions. Studies have shown that imbalance these ions closely related to onset progression Alzheimer's disease (AD), most common neurodegenerative disorder elderly.Erroneous deposition/distribution different regions induces oxidative stress. stress together or independently promote amyloid-β (Aβ) overproduction by activating β- γ-secretases inhibiting α-secretase, it also causes tau hyperphosphorylation protein kinases, glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase-5 (CDK5), mitogen-activated kinases (MAPKs), etc., phosphatase 2A (PP2A). imbalances can directly indirectly disrupt organelles, causing endoplasmic reticulum (ER) stress; mitochondrial autophagic dysfunctions, which cause aggravate Aβ aggregation/accumulation, impair synaptic Even worse, imbalance-induced alterations reversely exacerbate misdistribution deposition. vicious cycles between Aβ/tau abnormalities will eventually lead a chronic neurodegeneration cognitive deficits, seen AD patients.The pathologies affecting multiple cellular/subcellular pathways, disrupted transportation/deposition. Therefore, adjusting balance supplementing chelating may be potential ameliorating pathologies, provides new research directions treatment.

Язык: Английский

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Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1/Nrf2/HO-1/Gpx4 pathway

Journal of Neuroinflammation, Год журнала: 2022, Номер 19(1)

Опубликована: Фев. 7, 2022

The inflammation and oxidative stress (OS) have been considered crucial components of the pathogenesis depression. Edaravone (EDA), a free radical scavenger, processes strong biological activities including antioxidant, anti-inflammatory neuroprotective properties. However, its role potential molecular mechanisms in depression remain unclear. present study aimed to investigate antidepressant activity EDA underlying mechanisms.A chronic social defeat (CSDS) model was performed explore whether could produce effects. Behaviors tests were carried out examine depressive, anxiety-like cognitive behaviors interaction (SI) test, sucrose preference test (SPT), open field (OFT), elevated plus maze (EPM), novel object recognition (NOR), tail suspension (TST) forced swim (FST). Hippocampal medial prefrontal cortex (mPFC) tissues collected for Nissl staining, immunofluorescence, targeted energy metabolomics analysis, enzyme-linked immunosorbent assay (ELISA), measurement MDA, SOD, GSH, GSH-PX, T-AOC transmission electron microscopy (TEM). Western blotting (WB) quantitative real-time polymerase chain reaction (qRT-PCR) detected Sirt1/Nrf2/HO-1/Gpx4 signaling pathway. EX527, Sirt1 inhibitor ML385, Nrf2 injected intraperitoneally 30 min before injection daily. Knockdown experiments determine effects Gpx4 on CSDS mice with treatment by an adeno-associated virus (AAV) vector containing miRNAi (Gpx4)-EGFP infusion.The administrated dramatically ameliorated CSDS-induced depressive behaviors. In addition, notably attenuated neuronal loss, microglial activation, astrocyte dysfunction, damage, metabolism pro-inflammatory cytokines activation hippocampus (Hip) mPFC mice. Further examination indicated that application after significantly increased protein expressions Sirt1, Nrf2, HO-1 Hip. EX527 abolished effect as well levels Gpx4. Similarly, ML385 reversed anxiolytic via decreased knockdown EDA-generated efficacy behaviors.These findings suggest possesses potent properties through axis Gpx4-mediated ferroptosis may play key this effect.

Язык: Английский

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Oxidative Stress, Plant Natural Antioxidants, and Obesity

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(4), С. 1786 - 1786

Опубликована: Фев. 11, 2021

Oxidative stress is important in the pathophysiology of obesity, altering regulatory factors mitochondrial activity, modifying concentration inflammation mediators associated with a large number and size adipocytes, promoting lipogenesis, stimulating differentiation preadipocytes to mature regulating energy balance hypothalamic neurons that control appetite. This review discusses participation oxidative obesity groups compounds found plants antioxidant properties, which include (a) polyphenols such as phenolic acids, stilbenes, flavonoids (flavonols, flavanols, anthocyanins, flavanones, flavones, flavanonols, isoflavones), curcuminoids (b) carotenoids, (c) capsaicinoids casinoids, (d) isothiocyanates, (e) catechins, (f) vitamins. Examples are analyzed, resveratrol, quercetin, curcumin, ferulic acid, phloretin, green tea, Hibiscus Sabdariffa, garlic. The activities these depend on their reactive oxygen species (ROS) scavengers capacity prevent activation NF-κB (nuclear factor κ-light-chain-enhancer activated B cells), reduce expression target genes, including those participating inflammation. We conclude natural have therapeutic potential for diseases mediated by stress, particularly obesity. Controlled well-designed clinical trials still necessary better know effects compounds.

Язык: Английский

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Short Overview of ROS as Cell Function Regulators and Their Implications in Therapy Concepts

Cells, Год журнала: 2019, Номер 8(8), С. 793 - 793

Опубликована: Июль 30, 2019

The importance of reactive oxygen species (ROS) has been gradually acknowledged over the last four decades. Initially perceived as unwanted products detrimental oxidative stress, they have upgraded since, and now ROS are also known to be essential for regulation physiological cellular functions through redox signaling. In majority cases, metabolic demands, along with other stimuli, vital formation their actions. this review, we focus on role in regulating cell functioning communication among themselves. relevance therapy concepts is addressed here.

Язык: Английский

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Oxidative stress in biological systems and its relation with pathophysiological functions: the effect of physical activity on cellular redox homeostasis

Free Radical Research, Год журнала: 2019, Номер 53(5), С. 497 - 521

Опубликована: Май 1, 2019

The body of evidence from the past three decades demonstrates that oxidative stress can be involved in several diseases. This study aims to summarise current state knowledge on association between and pathogenesis some characteristic biological systems diseases aging process. review also presents effect physical activity redox homeostasis. There is strong studies for participation reactive oxygen nitrogen species acute chronic based animal models human studies. Elevated levels pro-oxidants various markers cells tissues damage linked with cancer, atherosclerosis, neurodegenerative hypertension, diabetes mellitus, cardiovascular disease, reproductive system diseases, were reported. Evidence confirmed inflammation contributes widely multiple closely stress. Regular moderate regulates enhancing cellular antioxidant defence mechanisms, whereas exercise not preceded by training alter homeostasis towards higher level Future are needed clarify multifaceted effects oxygen/nitrogen continue biochemical roles antioxidants prevention stress-related tissue injury.

Язык: Английский

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Neurotoxicity Linked to Dysfunctional Metal Ion Homeostasis and Xenobiotic Metal Exposure: Redox Signaling and Oxidative Stress

Antioxidants and Redox Signaling, Год журнала: 2018, Номер 28(18), С. 1669 - 1703

Опубликована: Фев. 6, 2018

Significance: Essential metals such as copper, iron, manganese, and zinc play a role cofactors in the activity of wide range processes involved cellular homeostasis survival, well during organ tissue development. Throughout our life span, humans are also exposed to xenobiotic from natural anthropogenic sources, including aluminum, arsenic, cadmium, lead, mercury. It is recognized that alterations essential an increased environmental/occupational exposure linked several neurological disorders, neurodegeneration neurodevelopmental alterations. Recent Advances: The redox key for neuronal brain function. Alterations signaling central pathological consequences dysfunctional metal ion metals. Both redox-active redox-inactive trigger oxidative stress damage nervous system, exact mechanisms starting become delineated. Critical Issues: In this review, we aim appraise determining balance by which disturb signaling. We focus on recent literature regarding their transport, metabolism, toxicity neural systems. Future Directions: Delineating specific alter understand convey chronic dysfunction neurodegenerative disorders. Antioxid. Redox Signal. 28, 1669–1703.

Язык: Английский

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