Counteracting role of nuclear factor erythroid 2-related factor 2 pathway in Alzheimer's disease

Sharma, Veerta; Kaur, Amandeep; Singh, Thakur Gurjeet

doi:10.1016/j.biopha.2020.110373

Cited by 81 publications

(31 citation statements)

References 175 publications

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“…The Keap1‐Nrf2 pathway is the major regulator of cytoprotective responses to oxidative stresses, thereby is responsible for cell defense against apoptosis in nervous system disorders like cognitive impairment (Baird & Yamamoto, 2020; Sharma et al., 2020). Molecular docking is a computational approach to identify possible binding modes of the selected compound against its biological target (Pingaew et al., 2018).…”

Section: Resultsmentioning

confidence: 99%

“…The top 14 significantly enriched terms (Count ≥ 60 and p values ≤ 1 × 10 -30 ) in BP were shown in Figure 3b, which indicated that resveratrol may regulate neuron function via apoptosis process, programmed cell death, response to oxygen-containing compound to exert its therapeutic effects on METH-induced memory impairment. The Keap1-Nrf2 pathway is the major regulator of cytoprotective responses to oxidative stresses, thereby is responsible for cell defense against apoptosis in nervous system disorders like cognitive impairment(Baird & Yamamoto, 2020;Sharma et al, 2020).Molecular docking is a computational approach to identify possible binding modes of the selected compound against its biological target(Pingaew et al, 2018). Therefore, Autodock software was used to do molecular docking between resveratrol and Keap1 and analyze the possible interaction between them.…”

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confidence: 99%

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Resveratrol attenuates methamphetamine‐induced memory impairment via inhibition of oxidative stress and apoptosis in mice

et al. 2021

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Methamphetamine (METH) abuse produces serious neurotoxicity to the central nervous system along with long-term cognitive dysfunction. Resveratrol, a natural polyphenol, has broad application prospects in the treatment of neurodegenerative diseases. Therefore, this study was conducted to investigate whether resveratrol might alleviate METH-induced memory deficits in vivo. We found that multiple exposures to METH significantly impaired cognitive functions and caused long-lasting memory deficits (p < .05). Pretreatment of resveratrol (10 or 100 mg/kg) remarkably attenuated METH-induced memory impairment in mice (p < .05). Bioinformatics analysis results showed that resveratrol might alleviate memory deficits by inhibiting METH-induced oxidative damage and apoptosis. Molecular docking showed that resveratrol had hydrogen bonding interactions with Kelch-like ECH associated protein 1 (Keap1), a repressor protein of the classic antioxidant Keap1-Nrf2 pathway. Further results validated oxidative stress parameters, apoptosis, and expression of Keap1 were significantly increased, while the translocation and activation of nuclear factor erythroid 2-related factor 2 (Nrf2) into the nucleus and expression of its downstream proteins were greatly decreased in the hippocampus after METH exposure (p < .05). These changes caused by METH could be prevented by resveratrol (p < .05). Therefore, these findings suggested that the prevention of resveratrol on memory dysfunction induced by METH was possibly related to the activation of the Keap1-Nrf2 pathway and reduction of apoptosis. Supplementation of resveratrol could be a potential treatment for preventing the neurotoxicity of METH in the future. Practical applications As one of the worst commonly abused psychostimulants, methamphetamine (METH) addiction produces serious complications including cognitive impairment and memory deficits. Resveratrol is a natural polyphenol that has important nutritional supplements and protective effects in the treatment of many neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Resveratrol attenuates methamphetamine‐induced memory impairment via inhibition of oxidative stress and apoptosis in mice

et al. 2021

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“…37 Nrf2 binds with Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm and will be degraded through ubiquitination if inactivated. 38 Nrf2 activity is controlled by Keap1 in a stress-dependent manner, and once Nrf2 is activated following various stimuli, it detaches from Keap1, translocates into the nucleus, and then binds to the antioxidant response element (ARE), initiating the synthesis of antioxidant proteins including NQO1, HO-1, SOD, glutamate cysteine ligase catalytic subunit (GCLC), and glutathione-S-transferases (GST). [39][40][41] We treated NPCs with acacetin and analyzed the intranuclear content of the Nrf2 protein, demonstrating that acacetin also activated the Nrf2 pathway in NPCs.…”

Section: Discussionmentioning

confidence: 99%

<p>Acacetin Alleviates Inflammation and Matrix Degradation in Nucleus Pulposus Cells and Ameliorates Intervertebral Disc Degeneration in vivo</p>

Wang

Jiang

Pang

et al. 2020

DDDT

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Purpose Intervertebral disc degeneration (IDD) is one of the most prevalent musculoskeletal disorders. The nucleus pulposus is the major component of the intervertebral disc, and nucleus pulposus cells (NPCs) play a significant role in the normal functioning of the intervertebral disc. Reactive oxygen species (ROS) generation, inflammation and extracellular matrix degradation in NPCs contribute to the degeneration of intervertebral discs. Acacetin is a drug that exerts antioxidant and anti-inflammatory effects on many types of cells. However, whether acacetin can relieve the degeneration of NPCs remains unknown. Methods NPCs were extracted from rat intervertebral discs. The NPCs were treated with tert-butyl peroxide (TBHP) to simulate a high-ROS environment, and acacetin was subsequently added. The contents of ROS, inflammatory mediators (COX-2, iNOS) and extracellular matrix components (aggrecan, collagen II, MMP13, MMP9, MMP3) were measured. Components of related signaling pathways (Nrf2, MAPK) were also evaluated. To determine the effect of acacetin in vivo, we simulated disc degeneration via needle puncture. Acacetin was then applied intraperitoneally, and the degenerative status was evaluated using MRI and histopathological analysis. Results In vitro, acacetin alleviated TBHP-induced ROS generation and upregulated the expression of antioxidant proteins, including HO-1, NQO1, and SOD. In addition, acacetin relieved the TBHP-induced generation of inflammatory mediators (COX-2, iNOS) and degradation of the extracellular matrix (aggrecan, collagen II, MMP13, MMP9, and MMP3). Acacetin exerted its effect by activating the Nrf2 pathway and inhibiting p38, JNK and ERK1/2 phosphorylation. In vivo, acacetin ameliorated puncture-induced disc degeneration in a rat tail model, which was evaluated using MRI and histopathological analysis. Conclusion Acacetin alleviated IDD in vitro and in vivo and may have the potential to be developed as an effective treatment for IDD.

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“…Thus, by influencing neurotransmitter signaling, receptor expression, and neuromodulatory activities, microbiota may influence cognitive functions closely [ 54 ]. The infection of H. pylori in AD patients signals inflammation, the formation of tangles, and cognitive decline, and increased deposition of senile plaques has been reported in the presence of Orrelia burgdorferi and Chlamydia pneumonia beside pylori infection [ 12 , 55 ]. Blood analyses of AD patients having amyloid load and inflammatory markers have also shown an increased presence of bacteria which instigate inflammation ( Escherichia/Shighella ) and an abridged existence of anti-inflammatory ( Escherichia rectale ) microbes [ 56 ].…”

Section: Microbiota In Admentioning

confidence: 99%

“…Some studies have tied cognitive decline and AD risk with exposure to common pathogens including Cytomegalovirus, Herpes simplex virus type 1, Helicobacter pylori, etc. which have shown abundance in AD patients [ 12 ]. Additionally, gut microbes influence brain attributes through various ways, which include dysbiosis-related inflammation, the involvement of altered microbiota in oxidative stress, altered permeability, resultant immune activity, age-related reduction in beneficial microbiota, dysbiosis induced insulin-resistant state, etc.…”

Section: Introductionmentioning

confidence: 99%

Dysbiosis and Alzheimer’s Disease: A Role for Chronic Stress?

et al. 2021

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Alzheimer’s disease (AD) is an incurable, neuropsychiatric, pathological condition that deteriorates the worth of geriatric lives. AD is characterized by aggregated senile amyloid plaques, neurofibrillary tangles, neuronal loss, gliosis, oxidative stress, neurotransmitter dysfunction, and bioenergetic deficits. The changes in GIT composition and harmony have been recognized as a decisive and interesting player in neuronal pathologies including AD. Microbiota control and influence the oxidoreductase status, inflammation, immune system, and the endocrine system through which it may have an impact on the cognitive domain. The altered and malfunctioned state of microbiota is associated with minor infections to complicated illnesses that include psychosis and neurodegeneration, and several studies show that microbiota regulates neuronal plasticity and neuronal development. The altered state of microbiota (dysbiosis) may affect behavior, stress response, and cognitive functions. Chronic stress-mediated pathological progression also has a well-defined role that intermingles at various physiological levels and directly impacts the pathological advancement of AD. Chronic stress-modulated alterations affect the well-established pathological markers of AD but also affect the gut–brain axis through the mediation of various downstream signaling mechanisms that modulate the microbial commensals of GIT. The extensive literature reports that chronic stressors affect the composition, metabolic activities, and physiological role of microbiota in various capacities. The present manuscript aims to elucidate mechanistic pathways through which stress induces dysbiosis, which in turn escalates the neuropathological cascade of AD. The stress–dysbiosis axis appears a feasible zone of work in the direction of treatment of AD.

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Counteracting role of nuclear factor erythroid 2-related factor 2 pathway in Alzheimer's disease

Cited by 81 publications

References 175 publications

Resveratrol attenuates methamphetamine‐induced memory impairment via inhibition of oxidative stress and apoptosis in mice

Resveratrol attenuates methamphetamine‐induced memory impairment via inhibition of oxidative stress and apoptosis in mice

<p>Acacetin Alleviates Inflammation and Matrix Degradation in Nucleus Pulposus Cells and Ameliorates Intervertebral Disc Degeneration in vivo</p>

Dysbiosis and Alzheimer’s Disease: A Role for Chronic Stress?

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