scholarly journals Propofol Protects Hippocampal Neurons from Hypoxia-Reoxygenation Injury by Decreasing Calcineurin-Induced Calcium Overload and Activating YAP Signaling

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Xiaojun Li ◽  
Li Yao ◽  
Qianlei Liang ◽  
Hangyin Qu ◽  
Hui Cai
Keyword(s):  
Flow Cytometry ◽  
Cell Viability ◽  
Intracellular Calcium ◽  
Cell Apoptosis ◽  
Hippocampal Neurons ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion ◽  
Colorimetric Method ◽  
Calcium Overload ◽  
Dependent Manner

Objectives. Propofol is a popular anesthetic drug that is neuroprotective. However, the mechanisms of propofol for hippocampal neuroprotection remain elusive. This study is aimed at investigating the neuroprotective effect and mechanism of propofol in hippocampal neurons exposed to ischemia-reperfusion (I/R) injury. Methods. Hypoxia-reoxygenated (H/R) HT-22 cells were used to mimic I/R injury of the hippocampus in vitro. An MTT assay was used to determine cell viability. Cell apoptosis was detected by a TUNEL assay and a flow cytometry cell apoptosis assay. Expression levels of proteins were measured by Western blotting. Intracellular calcium was assessed by Fura-2/AM staining. Flow cytometry was used to determine the mitochondrial membrane potential (MMP). Coimmunoprecipitation was used to evaluate the stability of the FKBP-RyR complex. Calcineurin enzymatic activity was measured with a colorimetric method. YAP nuclear translocation was tested by immunofluorescence staining. Results. H/R induced HT-22 cell viability depression, and apoptosis was reversed by propofol treatment. Propofol could alleviate H/R-induced intracellular calcium accumulation and MMP loss by inhibiting calcineurin activity and FKBP12.6-RyR disassociation in a concentration-dependent manner. In addition, YAP expression was crucial for propofol to protect HT-22 cell apoptosis from H/R injury. Propofol could activate YAP through dephosphorylation. Activated YAP stimulated the transcription of the Bcl2 gene, which promotes cellular survival. Our data also demonstrated that propofol activated YAP through the RhoA-Lats1 pathway without large G proteins or MST involvement. In addition, we showed that there was no interaction between calcineurin signaling and YAP activation in HT-22 cells. Conclusions. Propofol protected hippocampal neurons from I/R injury through two independent signaling pathways, including the calcineurin/FKBP12.6-RyR/calcium overload pathway and the RhoA/Lats1/YAP/Bcl-2 pathway.

scholarly journals Modulation of Preactivation of PPAR-βon Memory and Learning Dysfunction and Inflammatory Response in the Hippocampus in Rats Exposed to Global Cerebral Ischemia/Reperfusion

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Ge Kuang ◽  
Qin He ◽  
Yunmei Zhang ◽  
Ruichun Zhuang ◽  
Anling Xiang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Hippocampal Neurons ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion Injury ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Global Cerebral Ischemia ◽  
Dependent Manner ◽  
Neuroprotective Effects ◽  
Cerebral Ischemia Reperfusion

The aim of this study is to investigate the neuroprotective effects and relevant mechanism of GW0742, an agonist of PPAR-β, after global cerebral ischemia-reperfusion injury (GCIRI) in rats. The rats showed memory and cognitive impairment and cytomorphological change in the hippocampus neurons following GCIRI. These effects were significantly improved by pretreatment with GW0742 in the dose-dependent manner. The expressions of IL-1β, IL-6, and TNF-αwere increased after GCIRI, while the increases in these proinflammatory cytokines by GCIRI were inhibited by GW0742 pretreatment. Similarly, GW0742 pretreatment also improved the GCIRI-induced decrease in the expression of IL-10, which can act as an inhibitory cytokine to reduce cerebral ischemic injury. For another, NF-κB p65 expression was significantly increased in hippocampal neurons with apparent nuclear translocation after global cerebral IRI, and these phenomena were also largely attenuated by GW0742 pretreatment. Moreover, the mRNA and protein expressions of PPAR-βwere significantly decreased in GCIRI + GW0742 groups when compared with those in GCIRI group. Our data suggests that the PPAR-βagonist GW0742 can exert significant neuroprotective effect against GCIRI in rats via PPAR-βactivation and its anti-inflammation effect mediated by the inhibition of expression and activation of NF-κB in the hippocampus.

scholarly journals CD82 Aggravates Sevoflurane - Induced Neurotoxicity by Regulating TRPM7 in Developing Neurons

2020 ◽  
Keyword(s):  
Protein Expression ◽  
Cell Viability ◽  
Cell Apoptosis ◽  
Hippocampal Neurons ◽  
Transient Receptor Potential ◽  
Time Dependent ◽  
Dependent Manner ◽  
Over Expression ◽  
Transient Receptor Potential Melastatin ◽  
Developing Neurons

Background: Sevoflurane, a commonly used anesthetic in neonatal, could induce neurotoxicity in newborn animals. CD82 was found to be involved in age-related cognitive impairment. However, the role of CD82 in sevoflurane-induced neurotoxicity remains elusive. Methods: Hippocampal neurons were isolated from neonatal rats (postnatal day 1 or 2), and then exposed to 1.8 % sevoflurane for 6, 12, 24 or 48 hours. Neurons were pre-transfected with siRNA targeting CD82 (siCD82) or co-transfected with siTRPM7 (transient receptor potential melastatin 7) and pcDNA 3.1-CD82, and then exposed with sevoflurane (1.8%, 12 hours). Cell viability of the neurons was analyzed with MTT assay, and cell apoptosis was determined by flow cytometry. Protein expression was analyzed by western blot. Results: Sevoflurane exposure decreased cell viability of the developing hippocampal neurons in a time-dependent manner. Protein expressions of CD82 and TRPM7 were increased in neurons post sevoflurane exposure in a time-dependent manner. Pre-transfection of siCD82 attenuated sevoflurane-induced decrease in cell viability and increase in cell apoptosis in the neurons. Moreover, knockdown of CD82 reversed the promoting effects of sevoflurane on protein expression of cleaved TRPM7 and cleaved caspase-3. Over-expression of CD82 aggravated sevoflurane-induced decrease in cell viability and increase in cell apoptosis in neurons, while knockdown of TRPM7 counteracted with the effects of CD82 over-expression on sevoflurane-induced developing neurons. Conclusion: Sevoflurane exposure increased the expression of CD82 and TRPM7 in developing hippocampal neurons, decreased cell viability and promoted the cell apoptosis. Knockdown of CD82 partially ameliorated sevoflurane-induced neurotoxicity by down-regulation of cleaved TRPM7 in the developing neurons.

scholarly journals Overexpression of IκBα in cardiomyocytes alleviates hydrogen peroxide-induced apoptosis and autophagy through inhibiting NF-κB translocation

2020 ◽  
Author(s):  
Min Han ◽  
Xiao-Cui Chen ◽  
Ming-Hui Sun ◽  
Min-Tao Gai ◽  
Yi-Ning Yang ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Cell Viability ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion ◽  
Annexin V ◽  
Neonatal Rat ◽  
Cell Counting ◽  
Pyrrolidine Dithiocarbamate ◽  
Dependent Manner ◽  
Induced Apoptosis

Abstract Background: Inflammation and oxidative stress play a predominant role in the initiation and progression of ischemia/reperfusion (I/R) injury, of which nuclear factor kappa B (NF-κB) is considered to be a crucial mediator. Inactivation of NF-κB could benefit cardiomyocytes through inhibiting apoptosis. IκBα, an inhibitor of NF-κB, is hypothesized to protects cardiomyocytes from H2O2-induced apoptosis and autophagy through inhibiting the NF-κB pathway.Methods: We designed an AAV9-delivered mutated IκBαS32A, S36A and investigated its effect on neonatal rat ventricular cardiomyocytes (NRVMs) in response to hydrogen peroxide (H2O2). NRVMs were divided into Normal (blank), Control (H2O2), GFP +H2O2, IκBα+H2O2, and Pyrrolidine dithiocarbamate (PDTC)+H2O2 groups. NF-κB p65 nuclear translocation was evaluated by immunofluorescence and western blot. Cell viability was assessed by a cell counting kit-8 kit. Supernatant lactate dehydrogenase (LDH) and intracellular malondialdehyde (MDA) were measured to identify H2O2-stimulated cytotoxicity. Apoptosis was determined by Annexin V-PE/7-AAD, and the mitochondrial membrane potential (△Ψm) was detected by JC-1. Western bolt was used to detect apoptosis and autophagy related proteins.Results: Consequently, H2O2-treated NRVMs showed reductions in cell viability but increased IκBα degradation and NF-κB p65 nuclear translocation in a time-dependent manner. Furthermore, LDH and MDA content, LC3-Ⅱ/LC3-Ⅰ ratio, Bax and Beclin-1 expressions, and apoptotic cells were upregulated in NRVMs exposed to H2O2, whereas △Ψm and Bcl-2 expression were downregulated. Additionally, IκBα transduction or PDTC pretreatment both attenuated the nuclear translocation of the p65 subunit and reversed the H2O2-stimulated effects in NRVMs.Conclusion: These findings suggest that IκBα could ameliorate H2O2-induced apoptosis and autophagy through targeted inhibition of NF-κB activation, which may guide strategies to prevent cardiac I/R jury.

The Effects of Butyric Acid on the Differentiation, Proliferation, Apoptosis, and Autophagy of IPEC-J2 Cells

2020 ◽  
Vol 20 (4) ◽  
pp. 307-317
Author(s):  
Yuan Yang ◽  
Jin Huang ◽  
Jianzhong Li ◽  
Huansheng Yang ◽  
Yulong Yin
Keyword(s):  
Cell Viability ◽  
P38 Mapk ◽  
Butyric Acid ◽  
Cell Apoptosis ◽  
Mapk Pathway ◽  
Mrna Level ◽  
Dependent Manner ◽  
M Phase ◽  
High Concentrations ◽  
Underlying Mechanisms

Background: Butyric acid (BT), a short-chain fatty acid, is the preferred colonocyte energy source. The effects of BT on the differentiation, proliferation, and apoptosis of small intestinal epithelial cells of piglets and its underlying mechanisms have not been fully elucidated. Methods: In this study, it was found that 0.2-0.4 mM BT promoted the differentiation of procine jejunal epithelial (IPEC-J2) cells. BT at 0.5 mM or higher concentrations significantly impaired cell viability in a dose- and time-dependent manner. In addition, BT at high concentrations inhibited the IPEC-J2 cell proliferation and induced cell cycle arrest in the G2/M phase. Results: Our results demonstrated that BT triggered IPEC-J2 cell apoptosis via the caspase8-caspase3 pathway accompanied by excess reactive oxygen species (ROS) and TNF-α production. BT at high concentrations inhibited cell autophagy associated with increased lysosome formation. It was found that BT-reduced IPEC-J2 cell viability could be attenuated by p38 MAPK inhibitor SB202190. Moreover, SB202190 attenuated BT-increased p38 MAPK target DDIT3 mRNA level and V-ATPase mRNA level that were responsible for normal acidic lysosomes. Conclusion: In conclusion, 1) at 0.2-0.4 mM, BT promotes the differentiation of IPEC-J2 cells; 2) BT at 0.5 mM or higher concentrations induces cell apoptosis via the p38 MAPK pathway; 3) BT inhibits cells autophagy and promotes lysosome formation at high concentrations.

MicroRNA-16-5p Aggravates Myocardial Infarction Injury by Targeting the Expression of Insulin Receptor Substrates 1 and Mediating Myocardial Apoptosis and Angiogenesis

2020 ◽  
Vol 17 (1) ◽  
pp. 11-17 ◽  
Author(s):  
Xiancan Wang ◽  
Yuqiang Shang ◽  
Shilin Dai ◽  
Wei Wu ◽  
Fan Yi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cell Viability ◽  
Insulin Receptor ◽  
Cell Apoptosis ◽  
Ischemia Reperfusion ◽  
Nuclear Antigen ◽  
Minichromosome Maintenance ◽  
Protein Levels ◽  
Insulin Receptor Substrates ◽  
Creatine Kinase Mb

Purpose: Myocardial infarction is a common cardiovascular disease. MicroRNA-16-5p (miR-16-5p) was upregulated in heart and kidney hypoxia/reoxygenation (H/R) injury. However, the role of miR-16-5p in myocardial infarction injury is still unclear. Methods: Human adult ventricular cardiomyocytes (AC16) were treated with ischemia/reperfusion (H/R). The miR-16-5p level was evaluated through real-time PCR. The activity of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) was detected via LDH and CK-MB monitoring kits. Cell viability was examined with 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetra-zolium bromide (MTT) assay. Western blotting was used to analyze the protein levels. The luci-ferase report assay confirmed the relative luciferase activity. Results: miR-16-5p was elevated in H/R-treated AC16 cells. miR-16-5p overexpression and knockdown were carried out. miR-16-5p knockdown repressed cell apoptosis, attenuated LDH and CK-MB activities, and enhanced cell viability in H/R-treated AC16 cells. Moreover, miR-16-5p knockdown promoted angiogenesis in human microvascular endothelial cells (HMVEC), causing elevation of vascular endothelial growth factor (VEGF), insulin receptor substrates 1 (IRS1), minichromosome maintenance complex component 2 (MCM2) and proliferating cell nuclear antigen (PCNA) protein levels. Moreover, miR-16-5p was testified to target IRS1. IRS1 silencing alleviated miR-16-5p knockdown-mediated inhibition of apoptosis in AC16 cells. Conclusion: miR-16-5p knockdown increased cell viability and angiogenesis, as well as inhibited cell apoptosis by increasing IRS1. These findings indicated that miR-16-5p knockdown may be a new therapeutic target for myocardial infarction.

Overexpression of miR-431 attenuates hypoxia/reoxygenation-induced myocardial damage via autophagy-related 3

2020 ◽  
Author(s):  
Kang Zhou ◽  
Yan Xu ◽  
Qiong Wang ◽  
Lini Dong
Keyword(s):  
Cell Viability ◽  
Cell Apoptosis ◽  
Myocardial Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Myocardial Damage ◽  
Protective Role ◽  
Human Cardiomyocytes ◽  
Hypoxia Reoxygenation

Abstract Myocardial injury is still a serious condition damaging the public health. Clinically, myocardial injury often leads to cardiac dysfunction and, in severe cases, death. Reperfusion of the ischemic myocardial tissues can minimize acute myocardial infarction (AMI)-induced damage. MicroRNAs are commonly recognized in diverse diseases and are often involved in the development of myocardial ischemia/reperfusion injury. However, the role of miR-431 remains unclear in myocardial injury. In this study, we investigated the underlying mechanisms of miR-431 in the cell apoptosis and autophagy of human cardiomyocytes in hypoxia/reoxygenation (H/R). H/R treatment reduced cell viability, promoted cell apoptotic rate, and down-regulated the expression of miR-431 in human cardiomyocytes. The down-regulation of miR-431 by its inhibitor reduced cell viability and induced cell apoptosis in the human cardiomyocytes. Moreover, miR-431 down-regulated the expression of autophagy-related 3 (ATG3) via targeting the 3ʹ-untranslated region of ATG3. Up-regulated expression of ATG3 by pcDNA3.1-ATG3 reversed the protective role of the overexpression of miR-431 on cell viability and cell apoptosis in H/R-treated human cardiomyocytes. More importantly, H/R treatments promoted autophagy in the human cardiomyocytes, and this effect was greatly alleviated via miR-431-mimic transfection. Our results suggested that miR-431 overexpression attenuated the H/R-induced myocardial damage at least partly through regulating the expression of ATG3.

scholarly journals Modulation of cardiac Na+,K+-ATPase cell surface abundance by simulated ischemia-reperfusion and ouabain preconditioning

2013 ◽  
Vol 304 (1) ◽  
pp. H94-H103 ◽  
Author(s):  
Aude Belliard ◽  
Yoann Sottejeau ◽  
Qiming Duan ◽  
Jessa L. Karabin ◽  
Sandrine V. Pierre
Keyword(s):  
Cell Surface ◽  
Atpase Activity ◽  
Ion Transport ◽  
Cell Viability ◽  
Ischemia Reperfusion ◽  
Resistant Mutant ◽  
Surface Expression ◽  
Live Cells ◽  
Mutant Form ◽  
Dependent Manner

Na+,K+-ATPase and cell survival were investigated in a cellular model of ischemia-reperfusion (I/R)-induced injury and protection by ouabain-induced preconditioning (OPC). Rat neonatal cardiac myocytes were subjected to 30 min of substrate and coverslip-induced ischemia followed by 30 min of simulated reperfusion. This significantly compromised cell viability as documented by lactate dehydrogenase release and Annexin V/propidium iodide staining. Total Na+,K+-ATPase α1- and α3-polypeptide expression remained unchanged, but cell surface biotinylation and immunostaining studies revealed that α1-cell surface abundance was significantly decreased. Na+,K+-ATPase-activity in crude homogenates and 86Rb+ transport in live cells were both significantly decreased by about 30% after I/R. OPC, induced by a 4-min exposure to 10 μM ouabain that ended 8 min before the beginning of ischemia, increased cell viability in a PKCε-dependent manner. This was comparable with the protective effect of OPC previously reported in intact heart preparations. OPC prevented I/R-induced decrease of Na+,K+-ATPase activity and surface expression. This model also revealed that Na+,K+-ATPase-mediated 86Rb+ uptake was not restored to control levels in the OPC group, suggesting that the increased viability was not conferred by an increased Na+,K+-ATPase-mediated ion transport capacity at the cell membrane. Consistent with this observation, transient expression of an internalization-resistant mutant form of Na+,K+-ATPase α1 known to have increased surface abundance without increased ion transport activity successfully reduced I/R-induced cell death. These results suggest that maintenance of Na+,K+-ATPase cell surface abundance is critical to myocyte survival after an ischemic attack and plays a role in OPC-induced protection. They further suggest that the protection conferred by increased surface expression of Na+,K+-ATPase may be independent of ion transport.

Overexpression of TEL-MN1 Fusion Enhances Resistance of HL-60 Cells to Idarubicin

Chemotherapy ◽  
2018 ◽  
Vol 63 (6) ◽  
pp. 308-314 ◽  
Author(s):  
Shenglan Gong ◽  
Mengqiao Guo ◽  
Gusheng Tang ◽  
Jianmin Yang ◽  
Huiying Qiu
Keyword(s):  
Flow Cytometry ◽  
Drug Resistance ◽  
Cell Viability ◽  
Cell Apoptosis ◽  
Chromosome Abnormality ◽  
Chemotherapy Resistance ◽  
Retroviral Vector ◽  
Promote Cell Proliferation ◽  
Enhanced Resistance

Background: The translocation t(12; 22) (p13;q12) is a recurrent but infrequent chromosome abnormality in human myeloid malignancies. To date, the role of TEL-MN1 fusion in leukemogenic process and drug resistance is still largely unknown. Methods: In the present study, the TEL-MN1 fusion was transfected into HL-60 cells to upregulate TEL-MN1 expression via a retroviral vector. MTT assay was employed to examine cell viability and flow cytometry was performed to evaluate cell apoptosis. Idarubicin was used to treat HL-60 cells for estimating the effect of TEL-MN1 fusion on the chemotherapy resistance. Results: The results showed that overexpression of TEL-MN1 in HL-60 cells could promote cell proliferation, suggesting that TEL-MN1 may be involved in the leukemogenesis process. HL-60 cells treated with idarubicin showed a weakened cell viability, whereas TEL-MN1 overexpression attenuated the idarubicin-induced inhibition of cell viability and acceleration of cell apoptosis of HL-60 cells. Conclusion: Taken together, our results indicated that TEL-MN1 fusion is an oncogene involved in the leukemogenesis process and TEL-MN1 overexpression enhanced resistance of HL-60 cells to idarubicin, which may provide a useful tool for studying the mechanism of leukemogenesis and drug resistance.

scholarly journals Safflower Yellow B Protects Brain against Cerebral Ischemia Reperfusion Injury through AMPK/NF-kB Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Shibin Du ◽  
Youliang Deng ◽  
Hongjie Yuan ◽  
Yanyan Sun
Keyword(s):  
Brain Injury ◽  
Cerebral Ischemia ◽  
Pc12 Cells ◽  
Inflammatory Cytokines ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Dependent Manner ◽  
Secondary Damage

Inflammation had showed its important role in the pathogenesis of cerebral ischemia and secondary damage. Safflower yellow B (SYB) had neuroprotective effects against oxidative stress-induced brain injuries, but the mechanisms were still largely unknown to us. In this study, we tried to investigate the anti-inflammation effects of SYB and the possible roles of AMPK/NF-κB signaling pathway on these protective effects. In vivo, brain ischemia/reperfusion (I/R) was induced by transient middle cerebral artery occlusion for 2 h and reperfusion for 20 h. Neurofunctional evaluation, infarction area, and brain water contents were measured. Brain injury markers and inflammatory cytokines levels were measured by ELISA kits. In vitro, cell viability, apoptosis, and LDH leakage were measured after I/R in PC12 cells. The expression and phosphorylation levels of AMPK, NF-κB p65, and P-IκB-α in cytoplasm and nuclear were measured by Western blotting. SiRNA experiment was performed to certify the role of AMPK. The results showed SYB reduced infarct size, improved neurological outcomes, and inhibited brain injury after I/R. In vitro test, SYB treatment alleviated PC12 cells injury and apoptosis and inhibited the inflammatory cytokines (IL-1, IL-6, TNF-α, and COX-2) in a dose-dependent manner. SYB treatment induced AMPK phosphorylation and inhibited NF-κB p65 nuclear translocation both in brain and in PC12 cells. Further studies also showed that the inhibition of NF-κB activity of SYB was through AMPK. In conclusion, SYB protected brain I/R injury through reducing expression of inflammatory cytokines and this effect might be partly due to the inhibition of NF-κB mediated by AMPK.

scholarly journals Mini-GAGR, an intranasally applied polysaccharide, activates the neuronal Nrf2-mediated antioxidant defense system

2018 ◽  
Vol 293 (47) ◽  
pp. 18242-18269 ◽  
Author(s):  
Kelsey Murphy ◽  
Killian Llewellyn ◽  
Samuel Wakser ◽  
Josef Pontasch ◽  
Natasha Samanich ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Antioxidant System ◽  
Cortical Neurons ◽  
Hippocampal Neurons ◽  
Nuclear Translocation ◽  
Growth Factor Receptor ◽  
Antioxidant Defense System ◽  
Related Factor ◽  
Dependent Manner ◽  
Amyloid Aβ

Oxidative stress triggers and exacerbates neurodegeneration in Alzheimer's disease (AD). Various antioxidants reduce oxidative stress, but these agents have little efficacy due to poor blood–brain barrier (BBB) permeability. Additionally, single-modal antioxidants are easily overwhelmed by global oxidative stress. Activating nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) and its downstream antioxidant system are considered very effective for reducing global oxidative stress. Thus far, only a few BBB-permeable agents activate the Nrf2-dependent antioxidant system. Here, we discovered a BBB-bypassing Nrf2-activating polysaccharide that may attenuate AD pathogenesis. Mini-GAGR, a 0.7-kDa cleavage product of low-acyl gellan gum, increased the levels and activities of Nrf2-dependent antioxidant enzymes, decreased reactive oxygen species (ROS) under oxidative stress in mouse cortical neurons, and robustly protected mitochondria from oxidative insults. Moreover, mini-GAGR increased the nuclear localization and transcriptional activity of Nrf2 similarly to known Nrf2 activators. Mechanistically, mini-GAGR increased the dissociation of Nrf2 from its inhibitor, Kelch-like ECH-associated protein 1 (Keap1), and induced phosphorylation and nuclear translocation of Nrf2 in a protein kinase C (PKC)- and fibroblast growth factor receptor (FGFR1)-dependent manner. Finally, 20-day intranasal treatment of 3xTg-AD mice with 100 nmol of mini-GAGR increased nuclear p-Nrf2 and growth-associated protein 43 (GAP43) levels in hippocampal neurons, reduced p-tau and β-amyloid (Aβ) peptide–stained neurons, and improved memory. The BBB-bypassing Nrf2-activating polysaccharide reported here may be effective in reducing oxidative stress and neurodegeneration in AD.

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