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RAGE-Specific Inhibitor FPS-ZM1 Attenuates AGEs-Induced Neuroinflammation and Oxidative Stress in Rat Primary Microglia
Shen, C;Ma, YJ;Zeng, ZL;Yin, QQ;Hong, Y;Hou, XY;Liu, XP
NEUROCHEMICAL RESEARCH 2017年 42卷10期 页码:2902-2911
GLYCATION END-PRODUCTS; ALZHEIMERS-DISEASE; NADPH OXIDASE; CORTICAL-NEURONS; CELL-DEATH; ENDPRODUCTS; EXPRESSION; CYTOKINES; PATHOLOGY; PATHOPHYSIOLOGY
Advanced glycation end products (AGEs) enhance microglial activation and intensify the inflammatory response and oxidative stress in the brain. This process may occur due to direct cytotoxicity or interacting with AGEs receptors (RAGE), which are expressed on the surface of microglia. FPS-ZM1 is a high-affinity but nontoxic RAGE-specific inhibitor that has been recently shown to attenuate the A beta-induced inflammatory response by blocking the ligation of A beta to RAGE. In this study, we further investigated the effect of FPS-ZM1 on the AGEs/RAGE interaction and downstream elevation of neuroinflammation and oxidative stress in primary microglia cells. The results suggested that FPS-ZM1 significantly suppressed AGEs-induced RAGE overexpression, RAGE-dependent microglial activation, nuclear translocation of nuclear factor kappaB p65 (NF-kappa B p65), and the expression of downstream inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) and inducible nitric oxide synthase (iNOS)/nitric oxide (NO). Furthermore, FPS-ZM1 attenuated AGEs-stimulated NADPH oxidase (NOX) activation and reactive oxygen species (ROS) expression. Finally, FPS-ZM1 elevated the levels of transcription factors nuclear-factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1), as well as decreased antioxidant capacity and increased production of oxidative species. Our results suggest that FPS-ZM1 may be neuroprotective through attenuating microglial activation, oxidative stress and inflammation by blocking RAGE.
Circulating FABP4 (Fatty Acid-Binding Protein 4) Is a Novel Prognostic Biomarker in Patients With Acute Ischemic Stroke
Tu, WJ;Zeng, XW;Deng, AJ;Zhao, SJ;Luo, DZ;Ma, GZ;Wang, H;Liu, Q
STROKE 2017年 48卷6期 页码:1531-+ 影响因子:5.787
NATRIURETIC PEPTIDE; CHINESE PATIENTS; SERUM; MORTALITY; MARKER; EXPRESSION; DISEASE; ATHEROSCLEROSIS; HYPERTENSION; ADIPONECTIN
Background and Purpose-FABP4 (fatty acid-binding protein 4) is an intracellular lipid chaperone involved in coordination of lipid transportation and atherogenesis. This study aimed at observing the effect of FABP4 on the 3-month outcomes in Chinese patients with acute ischemic stroke.;-;Methods-In a prospective multicenter observational study, serum concentrations of FABP4 were on admission measured in plasma of 737 consecutive patients with acute ischemic stroke. Serum concentrations of FABP4, National Institutes of Health Stroke Scale score, and conventional risk factors were evaluated to determine their value to predict functional outcome and mortality within 3 months.;-;Results-During follow-up, an unfavorable functional outcome was found in 260 patients (35.3%), and 94 patients (12.8%) died. In multivariate models comparing the third and fourth quartiles to the first quartile of FABP4, the concentrations of FABP4 were associated with poor functional outcome and mortality. Compared with the reference category (Q1-Q3), the concentrations of FABP4 in Q4 had a relative risk of 4.77 (95% confidence interval [CI], 2.02-8.15; P<0.001) for poor functional outcome and mortality (odds ratio, 6.15; 95% CI, 3.43-12.68) after adjusting for other significant outcome predictors in univariate logistic regression analysis. Receiver-operating characteristic curves to predict poor functional outcome and mortality demonstrated areas under the curve of FABP4 of 0.78 (95% CI, 0.75-0.82) and 0.83 (95% CI, 0.79-0.88), which improved the prognostic accuracy of National Institutes of Health Stroke Scale score with combined areas under the curve of 0.83 (95% CI, 0.76-0.89; P<0.01) and 0.86 (95% CI, 0.81-0.92), respectively.;-;Conclusions-Data show that FABP4 is a novel independent prognostic marker improving the currently used risk stratification of stroke patients.
Copeptin and NT-proBNP for prediction of all-cause and cardiovascular death in ischemic stroke
Tu, WJ;Ma, GZ;Ni, Y;Hu, XS;Luo, DZ;Zeng, XW;Liu, Q;Xu, TT;Yu, L;Wu, BS
NEUROLOGY 2017年 88卷20期 页码:1899-1905 影响因子:8.166
NATRIURETIC PEPTIDE LEVELS; ARGININE-VASOPRESSIN; ATRIAL-FIBRILLATION; PROGNOSTIC MARKER; CAUSE MORTALITY; HEART-FAILURE; INFARCTION; RISK; BIOMARKERS; COMMUNITY
Objective: To evaluate long-term mortality in patients with acute ischemic stroke (AIS) by exploring the correlation between death and plasma concentrations of copeptin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in a cohort study.;-;Methods: In a prospective, multicenter observational study of 4,215 patients with AIS, copeptin and NT-proBNP levels were measured with a standardized method when patients were admitted to hospital. The primary endpoint was all-cause mortality or cardiovascular disease (CVD) mortality within 1 year.;-;Results: During a follow-up period, 906 patients (20.1%, 95% confidence interval [CI] 18.9-21.2) died, including 589 cases of CVD mortality (13.1%, 95% CI 12.1-14.0). With the use of a multivariate analysis, both markers were found to have prognostic value in the same model (CVD mortality: odds ratio [OR] for fourth quartile of copeptin and NT-proBNP 1.68 and 2.58, 95% CI 1.22-2.49 and 1.76-4.05, respectively; all-cause mortality: OR for fourth quartile of copeptin and NT-proBNP 1.48 and 2.47, 95% CI 1.22-2.03 and 1.68-3.95, respectively). In a receiver operating characteristics analysis of CVD mortality, the area under the curve varied from 0.80 to 0.83 (95% CI 0.79-0.87) when the index of NT-proBNP was added and increased to 0.86 (95% CI 0.83-0.90) when both markers were added.;-;Conclusions: Copeptin and NT-proBNP may be useful independent prognostic markers of allcause or CVD mortality in Chinese patients with AIS.
IGF-1 protects against A beta(25-35)-induced neuronal cell death via inhibition of PUMA expression and Bax activation
Hou, XY;Jin, Y;Chen, J;Hong, Y;Luo, DZ;Yin, QQ;Liu, XP
NEUROSCIENCE LETTERS 2017年 637卷 页码:188-194
FACTOR-I PREVENTS; ALZHEIMERS-DISEASE; HIPPOCAMPAL-NEURONS; APOPTOSIS; INSULIN; PATHWAY; BIM; FOXO3A
Amyloid-p-peptide (A beta) is considered to be the toxic species in AD and causes cell death in the affected areas of patient's brain. Insulin-like growth factor 1 (IGF-1) has been reported to attenuate A beta toxicity in neuronal cells. However, the molecular mechanisms involved in the neuroprotective function of IGF-1 remain largely unknown. In the present study, we for the first time demonstrated that IGF-1 protects against A beta-induced neurotoxicity via inhibition of PUMA expression and Bax activation. We found that IGF-1 could activate Akt, which in turn inhibited A beta-induced FOXO3a nuclear translocation and thus decreased the binding ability of FOXO3a to PUMA promoter, leading to decreased PUMA expression. In addition, IGF-1 inhibited the translocation of Bax to the mitochondria induced by A beta. Notably, addition of wortmannin, a specific inhibitor of PI3K, significantly abolished the neuroprotective effect of IGF-1, suggesting that IGF-1 exerts its anti-apoptotic effect depend on PI3K activity. Our findings may provide new insights into molecular mechanisms mediated by IGF-1 in cell survival against A beta-induced apoptosis. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
Effects of RAGE-Specific Inhibitor FPS-ZM1 on Amyloid-beta Metabolism and AGEs-Induced Inflammation and Oxidative Stress in Rat Hippocampus
Hong, Y;Shen, C;Yin, QQ;Sun, MH;Ma, YJ;Liu, XP
NEUROCHEMICAL RESEARCH 2016年 41卷5期 页码:1192-1199
GLYCATION END-PRODUCTS; ALZHEIMERS-DISEASE; MOUSE MODEL; KAPPA-B; RECEPTOR; ACTIVATION; INVOLVEMENT; EXPRESSION; NEURONS; NEUROINFLAMMATION
An increased level of advanced glycation end products (AGEs) is observed in brains of patients with Alzheimer's disease (AD). AGEs and receptor for AGEs (RAGE) play important roles in the pathogenesis of AD. FPS-ZM1 is a high-affinity RAGE-specific blocker that inhibits amyloid-beta binding to RAGE, neurological damage and inflammation in the APP(sw/0) transgenic mouse model of AD. FPS-ZM1 is not toxic to mice and can easily cross the blood-brain barrier. In this study, an AGEs-RAGE-activated rat model were established by intrahippocampal injection of AGEs, then these rats were treated with intraperitoneal administration of FPS-ZM1 and the possible neuroprotective effects were investigated. We found that AGEs administration induced an-regulation of Abeta production, inflammation, and oxidative stress, and an increased escape latency of rats in the Morris water maze test, all of these are significantly reduced by FPS-ZM1 treatment. Our results suggest that the AGEs-RAGE pathway is responsible for cognitive deficits, and therefore may be a potential treatment target. FPS-ZM1 might be a novel therapeutic agent to treat AD patients.
Inhibitory effect of group II mGluR agonist 2R, 4R-APDC on cell proliferation in dentate gyrus in rats with epileptic seizure
Yao, H;Feng, YB;Pang, YJ;Xu, JJ;Yu, BX;Liu, XP
EUROPEAN REVIEW FOR MEDICAL AND PHARMACOLOGICAL SCIENCES 2015年 19卷15期 页码:2922-2927
METABOTROPIC GLUTAMATE RECEPTORS; TEMPORAL-LOBE EPILEPSY; GRANULE CELLS; ADULT-RAT; INDUCED NEUROGENESIS; BRAIN; ACTIVATION; INJURY; ANTAGONISTS; NEURONS
OBJECTIVE: Epileptic seizure can increase the cell proliferation in dentate gyrus in brain, but the mechanism remains unclear.;-;MATERIALS AND METHODS: In this study, using systemic bromodeoxyuridine (BrdU) to label the dividing cells, the inhibitory effect of group II metabotropic glutamate receptor (mGluR) agonist 2R, 4R-4-aminopyrrolidine-2, 4-dicarboxylate (2R, 4R-APDC) on cell proliferation in dentate gyrus in rats after pilocarpine-induced status epilepticus (SE) was investigated.;-;RESULTS: Results found that, 2R, 4R-APDC could significantly inhibit the behavioral seizure and block the seizure-induced increase of BrdU-positive cells in dentate gyrus, especially in hilus. Double-label immunofluorescence staining showed that, 2R, 4R-APDC did not affect the ability of newborn cells to differentiate into neurons or astrocytes.;-;CONCLUSIONS: 2R, 4R-APDC not only has anticonvulsant effect on adult rats with pilocarpine-induced SE, but also has neuroprotective effect by reducing the abnormal regeneration of nerves.
Puerarin attenuates cognitive dysfunction and oxidative stress in vascular dementia rats induced by chronic ischemia
Zhang, J;Guo, WS;Tian, BX;Sun, MH;Li, H;Zhou, LN;Liu, XP
INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015年 8卷5期 页码:4695-4704
CHRONIC CEREBRAL HYPOPERFUSION; RENIN-ANGIOTENSIN SYSTEM; ALZHEIMERS-DISEASE; NEURONAL DAMAGE; CNS DISEASES; BRAIN; DISORDERS; APOPTOSIS; PERMANENT; OCCLUSION
Objective: To explored the effects of puerarin on cognitive deficits and tissue oxidative stress and the underlying mechanisms. Methods: 6 to 8 week old male Wistar rats were adopted as experimental animals. Morris water maze (MWM) test was adopted to test the learning and memory function of rats. MDA, glutathione peroxidase and total thiol assessment was done to reflect the oxidative stress in the brain tissue. Cell Counting Kit-8 (CCK8) and flow cytometry (FCM) were performed to examine the cell viability and apoptosis rate. Reactive oxygen species (ROS) generation was determined by the 2', 7'-dichlorofluorescein diacetate (DCFH-DA) assay. qPCR and Western blot (WB) were adopted to test the molecular function mechanisms of puerarin. Results: Our results indicated a protective effect of puerarin on vascular dementia. Administration of puerarin could improve the impaired learning and memory function. The levels of MDA were partially decreased by puerarin. The levels of glutathione peroxidase and total thiol were partially restored. Cell viability was improved in a dose-dependent pattern (P < 0.05). Cell apoptosis rate was reduced in a dose-dependent pattern (P < 0.05). Puerarin could scavenge ROS generation induced by pre-treatment of hydrogen peroxide. The results showed up-regulated levels of Nrf2, FoxO1, FoxO3 and FoxO4 (P < 0.05). Conclusion: Puerarin is protective on the vascular dementia by reducing oxidative stress and improving learning and memory functions. On the molecular level, Nrf2, FoxO1, FoxO3 and FoxO4 were up regulated by puerarin.
Lycopene attenuates insulin signaling deficits, oxidative stress, neuroinflammation, and cognitive impairment in fructose-drinking insulin resistant rats
Yin, QQ;Ma, YJ;Hong, Y;Hou, XY;Chen, J;Shen, C;Sun, MH;Shang, YY;Dong, SQ;Zeng, ZL;Pei, JJ;Liu, XP
NEUROPHARMACOLOGY 2014年 86卷 页码:389-396 影响因子:4.936
TYPE-2 DIABETES-MELLITUS; ALZHEIMERS-DISEASE; PARKINSONS-DISEASE; HUMAN HEALTH; MOUSE MODEL; PPAR-GAMMA; EXPRESSION; DECLINE; GROWTH; CELLS
Fructose intake is linked with the increasing prevalence of insulin resistance, and insulin resistance links Alzheimer's disease with impaired insulin signaling, oxidative damage, neuroinflammation, and cognitive impairment. As a member of the carotenoid family of phytochemicals, lycopene is used as a potent free scavenger, and has been demonstrated to be effective in anti-oxidative stress and anti-inflammatory reaction in the models of AD and other neurodegenerative diseases. Here, we investigated the effect of lycopene on learning and memory impairment and the possible underlying molecular events in fructose-drinking insulin resistant rats. We found that long-term fructose-drinking causes insulin resistance, impaired insulin signaling, oxidative stress, neuroinflammation, down-regulated activity of cholinergic system, and cognitive impairment, which could be significantly ameliorated by oral lycopene administration. The results from this study provide experimental evidence for using lycopene in the treatment of brain damage caused by fructose-drinking insulin resistance. (C) 2014 Elsevier Ltd. All rights reserved.
Pioglitazone Improves Cognitive Function via Increasing Insulin Sensitivity and Strengthening Antioxidant Defense System in Fructose-Drinking Insulin Resistance Rats
Yin, QQ;Pei, JJ;Xu, S;Luo, DZ;Dong, SQ;Sun, MH;You, L;Sun, ZJ;Liu, XP
PLOS ONE 2013年 8卷3期 影响因子:3.057
TYPE-2 DIABETES-MELLITUS; OXIDATIVE STRESS; ALZHEIMERS-DISEASE; INTRACEREBROVENTRICULAR STREPTOZOTOCIN; ACETYLCHOLINESTERASE ACTIVITY; LIPID-PEROXIDATION; MEMORY IMPAIRMENT; PPAR-GAMMA; BRAIN; MODEL
Insulin resistance (IR) links Alzheimer's disease (AD) with oxidative damage, cholinergic deficit, and cognitive impairment. Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist pioglitazone previously used to treat type 2 diabetes mellitus (T2DM) has also been demonstrated to be effective in anti-inflammatory reaction and anti-oxidative stress in the animal models of AD and other neuroinflammatory diseases. Here, we investigated the effect of pioglitazone on learning and memory impairment and the molecular events that may cause it in fructose-drinking insulin resistance rats. We found that long-term fructose-drinking causes insulin resistance, oxidative stress, down-regulated activity of cholinergic system, and cognitive deficit, which could be ameliorated by pioglitazone administration. The results from the present study provide experimental evidence for using pioglitazone in the treatment of brain damage caused by insulin resistance.
AGEs Induce Cell Death via Oxidative and Endoplasmic Reticulum Stresses in Both Human SH-SY5Y Neuroblastoma Cells and Rat Cortical Neurons
Yin, QQ;Dong, CF;Dong, SQ;Dong, XL;Hong, Y;Hou, XY;Luo, DZ;Pei, JJ;Liu, XP
CELLULAR AND MOLECULAR NEUROBIOLOGY 2012年 32卷8期 页码:1299-1309
GLYCATION END-PRODUCTS; UNFOLDED PROTEIN RESPONSE; REACTIVE OXYGEN; ER STRESS; NEURODEGENERATIVE DISEASES; DIABETIC-NEPHROPATHY; ALZHEIMERS-DISEASE; GENE-EXPRESSION; NADPH OXIDASE; AMYLOID-BETA
Advanced glycation endproducts (AGEs) are elevated in aging and neurodegenerative diseases such as Alzheimer's disease (AD), and they can stimulate the generation of reactive oxygen species (ROSs) via NADPH oxidase, induce oxidative stress that lead to cell death. In the current study, we investigated the molecular events underlying the process that AGEs induce cell death in SH-SY5Y cells and rat cortical neurons. We found: (1) AGEs increase intracellular ROSs; (2) AGEs cause cell death after ROSs increase; (3) oxidative stress-induced cell death is inhibited via the blockage of AGEs receptor (RAGE), the down-regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and the increase of scavenging by anti-oxidant alpha-lipoic acid (ALA); (4) endoplasmic reticulum (ER) stress was triggered by AGE-induced oxidative stress, resulting in the activation of C/EBP homologous protein (CHOP) and caspase-12 that consequently initiates cell death, taurine-conjugated ursodeoxycholic acid (TUDCA) inhibited AGE-induced ER stress and cell death. Blocking RAGE-NADPH oxidase, and RAGE-NADPH oxidase-ROSs and ER stress scavenging pathways could efficiently prevent the oxidative and ER stresses, and consequently inhibited cell death. Our results suggest a new prevention and or therapeutic approach in AGE-induced cell death.
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