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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.
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.
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.
Administration of embryonic stem cells generates effective antitumor immunity in mice with minor and heavy tumor load
Dong, W;Du, JJ;Shen, HC;Gao, DW;Li, ZX;Wang, GH;Mu, XR;Liu, Q
CANCER IMMUNOLOGY IMMUNOTHERAPY 2010年 59卷11期 页码:1697-1705
CARCINOMA CELLS; CANCER; TRANSPLANTATION; IDENTIFICATION; IMMUNOTHERAPY; SARCOMAS; SUBPOPULATION; VACCINATION; PROGRESSION; REJECTION
The history of immunizing animals with fetal tissues to generate an antitumor response dates back a century ago. Subsequent reports supported the idea that vaccination with embryonic materials could generate cancer-specific immunity and protect animals from transplantable and chemically induced tumors. In our study, we found C57 BL/6 mice vaccinated with embryonic stem cells (ESCs) received obvious antitumor immunity, which protected them from the formation and development of lung cancer. Furthermore, we investigated the antitumor effects of administration of ESCs in mice with minor and/or heavy tumor load. The tumor growth was monitored, the proliferation of lymphocytes and secretion of cytokines were examined, and finally the tissue sections were approached by immunohistochemical and apoptosis staining. The results suggested that mice injected with ESCs received obvious tumor inhibition and retardation due to significant lymphocyte proliferation and cytokine secretion, which help to rebuild the host's immunity against cancer to some extent and comprise the main part of antitumor immunity. Moreover, mice with minor tumor load received stronger antitumor effect compared with mice with heavy tumor load, may be due to relatively intact immune system. Thus, besides their function as prophylactic vaccines, administration of ESCs could be a potential treatment for cancer, which obviously prevent and control the proliferation and development of malignant tumors.
A comparison of Twist and E-cadherin protein expression in primary non-small-cell lung carcinoma and corresponding metastases
Wang, GH;Dong, W;Shen, HC;Mu, XR;Li, ZX;Lin, XY;Liu, Y;Du, JJ
EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY 2011年 39卷6期 页码:1028-1032
EPITHELIAL-MESENCHYMAL TRANSITION; GROWTH-FACTOR RECEPTOR; TUMOR PROGRESSION; CANCER; ADENOCARCINOMAS; PATHWAYS; SURVIVAL; ADHESION
Objective: The metastasis of solid tumors is directly or indirectly responsible for most cancer-related deaths. It has already been known that in non-small-cell lung carcinoma cells, up-regulation of Twist (a highly conserved basic helix-loop-helix transcription factor) can promote epithelial-mesenchymal transition through down-regulation of E-cadherin. The main aim of this study was to determine whether the expression of Twist and E-cadherin differs between primary and metastatic lung carcinoma and to correlate Twist and E-cadherin expression in primary and metastatic non-small-cell lung carcinoma. Methods: Thirteen patients with non-small-cell lung carcinoma and hematogenous metastases were studied in retrospect, and Twist and E-cadherin were detected by immunohistochemistry in 26 tissue samples from the 13 patients. Results: We demonstrated that the expression of Twist was higher in metastatic non-small-cell lung carcinoma tissues than in primary non-small-cell lung carcinoma (p = 0.008) and discordance of Twist expression was observed in 11 (85%) patients. For E-cadherin, 12 cases (92%) showed discordance between primary tumor and metastasis (p = 0.002): E-cadherin expressed higher in the primary tumor than in the metastasis in 12 cases. We also found that increased Twist expression was correlated with decreased membranous E-cadherin expression (p = 0.009). Conclusions: Our data imply that Twist induces epithelial-mesenchymal transition in non-small-cell lung carcinoma by reducing E-cadherin, then promoting metastasis. (C) 2011 European Association for Cardio-Thoracic Surgery. Published by Elsevier B. V. All rights reserved.
Sevoflurane improves gaseous exchange and exerts protective effects in lipopolysaccharide-induced lung injury in mice models
Shen, WM;Li, C;Yuan, YH;Xu, YX;Chi, YL
TROPICAL JOURNAL OF PHARMACEUTICAL RESEARCH 2018年 17卷1期 页码:47-52
ALVEOLAR EPITHELIAL-CELLS; INFLAMMATION; ANTIOXIDANT
Purpose: To investigate the protective effect of sevoflurane against lipopolysaccharide (LPS)-induced acute liver injury (ALI) in amice model.;-;Methods: Seven week-old female BalB/C mice were used. Lung water content and cell count were estimated by standard protocols. Cytokine and chemokine analysis was performed using commercially available kits. Myeloperoxidase activity was evaluated spectrophotometrically while histopathological analysis was carried out by H and E staining.;-;Results: The results revealed that sevoflurane treatment significantly improved gaseous exchange, and reduced lung water content and lung inflammation as evidenced by a decrease in neutrophil migration into BALF (p < 0.01). Sevoflurane also significantly reversed the LPS-triggered suppression of IL-10 in the lung tissues of LPS-treated mice, when compared to saline-treated controls (p < 0.01). It reversed LPS-induced oxidative stress, as demonstrated by increase in total antioxidant capacity (T-AC), catalase (CAT) and superoxide dismutase-1 (SOD-1), as well as an increase in reduced/oxidized glutathione (GSH/GSSG) ratio. In addition, sevoflurane blocked LPS-induced lung tissue injury in ALI mice, and exerted protective effects against acute LPS-induced lung injury.;-;Conclusion: These results suggest that sevoflurane improves gaseous exchange and exerts a protective effect against LPS-triggered lung injury in mice model, most probably due to its anti-inflammatory and antioxidant properties.
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