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Objective To investigate the effect of soluble receptor for advanced glycation end-products (sRAGE) on inflammation in myocardial ischemia/reperfusion ( I/R ) mice and its mechanism. Methods Myocardial I/R injury model was conducted by left anterior descending ligation for 30 minutes and reperfusion for 2 weeks in male C57BL/6 mice aged 6-8 weeks. The mice were randomly divided into four groups with five C57BL/6 mice in each group. The cardiac function was detected by echocardiography, the inflammatory cells infiltration was observed by HE staining, the myocardial fibrosis was detected by Masson and Sirius red staining, the expression of galectin-3 was detected by immunohistochemical staining. Results Compared with the sham group, the cardiac function decreased, the inflammatory cells infiltrated increased among the myocardial tissue, the percentage of myocardial fibrosis area increased, and the expression of galectin-3 increased in I/R groups. After exogenous sRAGE treatment, the cardiac function of mice was significantly improved, the inflammatory cells infiltration decreased, the myocardial fibrosis area decreased, and the expression of galectin-3 decreased as well. Conclusion sRAGE may reduce inflammatory cells infiltration in mice heart by inhibiting the expression of galectin-3, and then alleviating myocardial fibrosis during myocardial ischemia/reperfusion injury.
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Objective::To investigate the effect of betulic acid(BA) on steatosis LO2 cells. Method::LO2 cells were intervened with BA at different gradient concentrations (0, 10, 20, 40, 80, 160, 250 μmol·L-1) for 24 hours. methyl thiazolyl tetrazolium(MTT) staining was used to observed cell viability to determine the final concentration of BA. The cells were divided into control, model, dimethylsulfoxide (DMSO) and BA groups, as well as BA groups intervened with low, middle and high concentrations. First, model, DMSO and BA group's cells were cultured in 10% Lipid Mix 1 medium for 24 hours to establish a nonalcoholic fatty liver model. Then, DMSO group and low, medium and high-concentration groups were separately cultured with 0.1%DMSO medium and 20, 40, 80 μmol·L-1 BA medium for 24 hours. And control and model groups were cultured in drug-free medium for 24 hours. Oil red O staining and Nile red staining were used to observe the intracellular lipid droplets. Immunofluorescence was used to detect the protein expression of inducible nitric oxide synthase (iNOS). Western blot was used to detect the protein expression levels of receptor for advanced glycation end-products (RAGE), nuclear factor κB p65 (NF-κB p55) and iNOS. Result::BA within the concentration of 80 μmol·L-1 had no significant toxicity on LO2 cells. Compared with control group, the intracellular lipid droplets were significantly increased in the model group, and the expressions of oxidative stress-related proteins RAGE, NF-κB p65 and iNOS also increased significantly(P<0.05). Compared with model group, the intracellular lipid droplets in DMSO group were similar to those in model group, with no significant difference in the three protein expressions between the two groups. However, the intracellular lipid droplets deposition in the BA group was significantly decreased. And the expressions of RAGE, NF-κB p65 and iNOS proteins in high-concentration BA group were significantly decreased(P<0.05, P<0.01). Conclusion::BA can significantly improve the intracellular fat deposition in LO2 cells, which was probably related to the inhibition of the expressions of oxidative stress-related proteins RAGE, NF-κB p65 and iNOS.
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Objective To explore the role of receptor for advanced glycation end products (RAGE) in HMGBl-mediated CD4+ T cells differentiation to Th1/Th2.Methods CD4+ T lymphocytes isolated from the spleens of male BALB/C mice by magnetic beads were suspended in RPMI-1640 with 10％ FCS in 2× 106cell/well on 96-well cell culture plates in vitro.The cells were randomly divided 4 groups according to concentration of HMGB1 treatment:control group,10 ng/mL group,100 ng/mL group,1 000 ng/mL group after stimulation with ConA in 3 μg/mL for 12 hours.IL-4 and IFN-γ levels in culture supernatants were quantitated by ELISA kits after HMGB1 stimulation for 12,24,and 48 h.According to the results,cultured cells were exposed to HMGB1 in 100 ng/mL for 24 h in the following experiments.The cells were randomly divided into 4 groups:control group,A group,B group,C group,and each group were cultured with ConA in 3 μg/mL for 24 h.The cells of control group and other three groups were stimulated with PBS or 100 μg/L HMGB1 for 24 h.The cells of B,C groups were incubated with 1/200 diluted 5 μg/L anti-RAGE Abs (anti-bodies) or PBS for 2 h before HMGB1 stimulation.The cell suspension was obtained to detect the levels of IL-4 and IFN-γ by EILSA and the protein levels and mRNA expressions of RAGE,CATA-3 were detected by western-blot and real-time fluorescent quantitative PCR,respectively.ResuRs Compared with control group,CD4+ T cells incubated with increasing concentrations of HMGB1 (100,1 000 ng/mL) for 24 h resulted in a decrease in IFN-γ/IL-4 ratio (P＜0.05).When CD4+ T cells were exposed to 100 ng/mL HMGB1 for 12 h,IFN-γ/IL-4 ratio was markedly increased.However,CD4+ T cells treated with 100 ng/mL HMGB1 for 24,48 h,IFN-γ/IL-4 ratio was markedly inhibited (P＜0.05).Compared with control group,protein levels and mRNA expressions of RAGE and GATA3 of cells in A group were significantly increased (P＜0.05),and IFN-γ/IL-4 ratio of cell suspension in A group and B group was significantly down-regulated (P＜0.05).Compared with A group,IFN-γ/IL-4 ratio of cell suspension in C group was increased (P＜0.05),and expression of GATA3 mRNA was down-regulated (P＜0.05).Compared with A group,protein level of RAGE of cells in C group was significantly down-regulated (P＜0.05),but protein level of RAGE of cells in C group was still increased compared with control group (P＜0.05).Conclusion Th1/Th2 differentiation induced by HMGB1 on CD4+ T lymphocytes in vitro was at least partly mediated by over-activating RAGE/GATA3 pathway.
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BACKGROUND: Airway remodeling is a key feature of asthma, characterized by increased proliferation of airway smooth muscle cells (ASMCs). S100A8 is a calcium-binding protein with a potential to regulate cell proliferation. Here, the effect of exogenous S100A8 protein on the proliferation of ASMCs induced by platelet-derived growth factor (PDGF) and the underlying molecular mechanism was investigated. METHODS: Rat ASMCs were cultured with or without a neutralizing antibody to the receptor for advanced glycation end-products (RAGE), a potential receptor for S100A8 protein. Purified recombinant rat S100A8 protein was then added into the cultured cells, and the proliferation of ASMCs induced by PDGF was detected by colorimetric-based WST-8 assay and ampedance-based xCELLigence proliferation assay. The expression levels of RAGE in ASMCs were analyzed using western blotting assay. RESULTS: Results showed that exogenous S100A8 inhibited the PDGF-induced proliferation of rat ASMCs in a dose- dependent manner with the maximal effect at 1 µg/ml in vitro. Furthermore, when ASMCs was pre-treated with anti-RAGE neutralizing antibody, the inhibitory effect of S100A8 on PDGF-induced proliferation was significantly suppressed. In addition, neither the treatment with S100A8 or PDGF alone nor the pre-treatment with rS100A8 followed by PDGF stimulation affected the expression levels of RAGE. CONCLUSIONS: Our study demonstrated that S100A8 inhibits PDGF-induced ASMCs proliferation in a manner dependent on membrane receptor RAGE.
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Animals , Rats , Platelet-Derived Growth Factor/agonists , Myocytes, Smooth Muscle/drug effects , Calgranulin A/administration & dosage , Cell Proliferation/drug effects , Receptor for Advanced Glycation End Products/drug effects , Cells, CulturedABSTRACT
@#To investigate the effect of block of AGEs-RAGE pathway on the migration of aortic vascular smooth muscle in diabetic rats and its possible mechanisms, vascular smooth muscle cells(VSMCs)cells were pre-stimulated by antibody of RAGE, and then stimulated by AGEs. Transwell assay was adopted to assay migration of VSMCs. Proliferation of VSMCs and expression of p27 were analyzed by MTT and ELISA, respectively. The change of ROS level in VSMCs was defermined by DCFH assay, the expression of NOX1 mRNA was determined by RT-PCR assay. Results indicated that the AGEs induction for migration of VSMCs was significantly inhibited after treatment by RAGE antibody(P< 0. 01), which blocked the AGEs-RAGE pathway, and the inhibition of migration was stronger than that of proliferation. The ROS level was decreased(P< 0. 01), and the expression of NOX1 mRNA was decreased, yet the expression of P27 protein was not changed greatly. Block of AGEs-RAGE pathway by antibody of RAGE can inhibit the migration of VSMCs, and the mechanism may be related with the decrease of NOX1 mRNA and then down to the level of intracellular oxidative stress in VSMCs.
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Amyloid beta-peptides ( Aβ) is the key pathological feature of Alzheimer’s Disease (AD). Various factors contrib-ute to the accumulations of Aβ in the brains of patients. Among them, blood-brain barrier ( BBB) plays a crucial role in trans-porting Aβ between the brain and the bloodstream while this transfer function is mediated by the receptor of Aβon BBB. The abnormality of Aβ transport and related receptor expression can be detected in the brains of patients with AD, resulting in an un-usual increase in Aβlevels unusually increased . This review e-laborates the structure and function of BBB, the transport of Aβand the expression and transport mechanism of the related recep-tor, as well as summarizes the possible clearance strategy of Aβacross the BBB.
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Objective To explore the molecular mechanism of S100A9-induced secretion of vascular endothelial growth factor-A (VEGF-A)by monocytes.Methods Peripheral blood specimen were collected from healthy individuals undergoing physical exami-nation and the CD14 + monocytes were purified by using immunomagnetic beads and the expression of the receptor for advanced gly-cation endproducts (RAGE)was detected by flow cytomertry.In vitro CD14 + monocytes were stimulated by S100A9,and anti-RAGE antibody or NK-κB signal pathway inhibitor were pre-incubated for 1 hour and then stimulated by S100A9,the levels of VEGF-A were detected by using enzyme-linked immunosorbent assay.Results The high level of RAGE was expressed by isolated CD14 + monocytes,after S100A9 stimulation,the secretion of VEGF-A by CD14 + monocytes was significantly increased in a dose and time dependent manner.However,the inducing VEGF-A was significantly decreased(P <0.01 ),while pre-treated with anti-RAGE antibody or NK-κB inhibitor (P <0.01).Conclusion S100A9 inducing the secretion of VEGF-A by monocytes and is de-pended on RAGE-NK-κB signal pathway,suggesting that S100A9 might promote angiogenesis.
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Objective To observe the effect of propofol on cognitive functions and hippocampus tissue in hyperlipidemia aged rats.Methods Seventy-six aged male SD rats were selected and randomly divided into basal diet with propofol injection (group PI), basal diet with normal saline injection(group N1), high-fat diet with propofol injection (group P2) and high-fat diet with normal saline injection (group P2), with 19 rats in each group.Eight weeks later,group P1 and P2 received intraperitoneal injection of propofol 100 mg · kg-1 · d-1 for 5 days.While in group N1 and N2, rats received the same intraperitoneal injection of equal volume normal saline.One day after the last injection, escape latency and space exploration were detected by Morris water maze in the next six days.One hour after the last water maze test, the serum and hippocampus were sampled to detect the expression of beta-amyloid protein and receptor for advanced glycation endproducts(RAGE) by immunohistochemical method and ELISA respectively.Results In place navigation tests,the escape incubation period(98.20±25.40)s in group P1 was obviously longer than that in N 1 group (47.50± 11.08) s (P＜ 0.01).Compared with P2 (99.79 ± 20.38) s, escape incubation period was shortened in N2 (50.70± 20.55) s (P＜ 0.05).There was no significantly difference between N2 and N1 (P＞0.05), while the escape incubation period in group P2 was longer than P1 (P＜ 0.05).In spatial probe test,platform passing number ((2.86 ±1.46)times) in group P1 were less than that in N1 group ((7.50± 1.70) times, P＜0.05).In group N2, the platform passing number ((6.60 ±3.91) times) were more than those in group P2 ((1.16 ±1.16)times, P＜0.05) while there was no significant difference between group N1 and N2 (P＞0.05).Times of crossing platform in group P2 were less than that in P1 group (P＜0.05).Compared with group N1((147.83±60.88) ng/L) and N2((152.73±87.50) ng/L) ,the expression of RAGE protein was increased in group P1((629.89±110.33) ng/L) and P2((229.89±53.20) ng/L) (P＜0.05).There was no significant difference between N1 and N2 groups(P＞0.05) ,while the expression of RAGE protein in P1 group was lower than that of P2(P＜0.05).In immunohistochemical test, positive expression cells in P1 ((18.49± 1.53) and P2 (25.67±3.08)) were higher than that in group N1(9.33±2.31) and group N2(12.14±2.52) (P＜0.05) ,while there was no significant difference between group N1 and N2(P＞0.05).Conclusions Anesthetic dose of propofol can injure spatial learning and memory ability in aged rats.Hyperlipidemia might act synergistically with propofol.
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Objective investigate the correlation between plasma soluble receptor for advanced glycation endproducts (sRAGE) and arterial stiffness in patients with different types of metabolic syndrome (MS).Methods A total of 180 subjects were drawn from a epidemiologic follow-up study,including 60 cases non-metabolic syndrome (NMS),60 cases metabolic syndrome without diabetes mellitus (NDMMS),60 cases metabolic syndrome with diabetes mellitus (DMMS).Carotid femoral arterial pulse wave velocity (CFPWV) was assessed by the French KangPuLe atherosclerosis measurement instrument,and plasma sRAGE levels were measured by ELISA.Comparison of mean in multiple groups was conducted by analysis of variance.Multivariate analysis was done with multiple linear stepwise regression analysis.P ＜ 0.05 was considered as statistically significant difference.Results Compared with NMS group,plasma sRAGE levels were significantly lower in DMMS and NDMMS groups [(635.07 ± 229.20) pg/mL vs.(671.17 ± 358.16) pg/mL vs.(992.99 ± 427.83) pg/mL,P =0.001].CFPWV of DMMS group was significantly higher than that of NMDMS and NMS groups (14.22 ±3.14) m/s vs.(12.15 ±2.79) m/s vs.(11.66 ± 2.52) m/s,P =0.002).Plasma sRAGE level was negatively correlated with CFPWV (r =-0.278,P =0.005).(3) Multiple linear regression analysis demonstrated that age (β =-0.091,95％ CI-0.096 ～-0.095,P =0.031),HDL-C (β =1.295,95％ CI 1.231 ～ 1.360,P =0.022) and sRAGE (β =0.119,95％ CI 0.118 ～ 0.130,P =0.032) had a significant effect on CFPWV.Conclusions The increased arterial stiffness is closely related to the discreased plasma sRAGE levels in MS.Plasma sRAGE maybe a novel target for vascular disease prevention and treatment in patients with metabolic syndrome.
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Objective To evaluate the effects of curcumin on the expression of receptor for advanced glycation end-products (RAGE) in the spinal dorsal horn and dorsal root ganglion (DRG) of the rats with type 2 diabetic neuropathic pain (DNP).Methods Male Sprague-Dawley rats,weighing 160-180 g,were used in this study.Type 2 diabetes mellitus was induced by high-fat and high-sucrose diet for 8 weeks and intraperitoneal streptozotocin (STZ) 35 mg/kg and confirmed by fasting blood glucose level ≥ 16.7 mmol/L 3 days later.Type 2 DNPwas confirmed by the mechanical paw withdrawal threshold (MWT) and thermal paw withdrawal latency (TWL) measured on day 14 after STZ administration less than 80％ of the baseline value.Eighty-one rats with type 2 DNP were randomly divided into 3 groups (n =27 each) using a random number table:DNP group,DNP + curcumin group (DCur group),and DNP+ solvent group (group DSC).In DCur and DSC groups,curcumin 100 mg· kg-1 · d-1 and corn oil 4 ml · kg-1 · d-1 were injected intraperitonally,respectively,for 14 consecutive days starting from the day 14 after STZ administration.Another 27 normal male Sprague-Dawley rats served as control group (group C) and were fed with normal forage.MWT and TWL were measured before STZ injection,at day 14 after STZ injection,and on 3,7 and 14 days after curcumin injection.RAGE positive cells were determined by immuno-histochemistry and the expression of RAGE by Western blot in the spinal dorsal horn and DRG after MWT and TWL were measured on 3,7 and 14 days after curcumin injection.Results Compared with group C,MWT was significantly decreased and TWL was shortened at 14 days after STZ injection and each time point after curcumin injection,the rate of RAGE positive cells in the spinal dorsal horn and DRG was increased at each time point after curcumin injection,and the expression of RAGE was up-regulated in the spinal dorsal horn at each time point after curcumin injection and in the DRG at 7 and 14 days after curcumin injection in group DNP.Compared with group DNP,MWT was significantly increased and TWL was prolonged at each time point after curcumin injection,the rate of RAGE positive cells in the spinal dorsal horn and DRG was significantly decreased at 7 and 14 days after curcumin injection,and the expression of RAGE was down-regulated in the spinal dorsal horn at each time point after curcumin injection and in the DRG at 7 and 14 days after curcumin injection in group DCur,and no significant change was found in the parameters mentioned above in group DSC.Conclusion The mechanism by which curcumin attenuates DNP may be related to inhibition of up-regulated expression of RAGE in the spinal dorsal horn and DRG of rats with type 2 diabetes mellitus.
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Objective To investigate the expressions of receptor for advanced glycation endproducts (RAGE) and nuclear factor κB(NF-κB) in brain hippocampus of rat with chronic fluorosis,and to reveal the mechanism of brain damage resulted from chronic fluorosis.Methods Sixty clean grade SD rats were randomly divided to three groups(20 rats in each group,10 female and 10 male) fed with different contents of fluoride,control group with normal tap-water(＜ 0.5 mg/L fluoride),small dosage of fluoride exposure group(10 mg/L fluoride in tap-water) and large dosage of fluoride exposure group(50 mg/L fluoride) for six months.Then the rats were killed by femoral artery bleeding and hippocampus was removed.Protein and mRNA levels of RAGE and NF-κB in the hippocampus were determined by Western blotting and quantitative real time PCR,respectively.Results As compared to the control groups[(100.00 ± 2.60)％,(100.00 ± 7.80)％],the expressions of RAGE and NF-κB at protein level in the hippocampus were significantly increased in the small dosage of fluoride exposure groups [(205.00 ± 15.30)％,(156.00 ± 12.20)％] and the large dosage of fluoride exposure groups[(232.00 ± 10.90)％,(162.00 ± 9.80)％,all P ＜ 0.05]; for the mRNA level of RAGE and NF-κB,the expressions were higher in the small dosage of fluoride exposure groups(1.27 ± 0.09,0.83 ± 0.15) and the large dosage of fluoride exposure groups (2.60 ± 0.19,1.27 ± 0.19) than those of the control groups(0.66 ± 0.18,0.32 ± 0.08,all P＜ 0.05).Conclusions The increased expressions of RAGE and NF-κB in the hippocampus of rat brain are caused by chronic fluorosis,and these changes may be associated with the mechanism of nerve injury.
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Objective To investigate the role of Gly82Ser polymorphism of receptor for advanced glycation end-products (RAGE) in the genesis and progression of colon cancer in Chinese population.Methods Using the method of PCR-restriction fragment length polymorphism (PCR-RFLP),the Gly82Ser genotype of RAGE were examined in 90 colon cancer patients and 78 control subjects age and sex matched.Analyses stratified by TNM and tumor differentiation were conducted to check the associations of the Gly82Ser gene polymorphisms in RAGE and development of colon cancer.Results The genotype distribution was in agreement with that predicted under Hardy-Weinberg equilibrium for both patients and controls (both P ＞ 0.05).With the GG genotype as reference,the odds ratio (OR) for heterozygous GG and carriers with S allele (GS and SS) were 2.037 (95％ CI:1.207-3.438) and 2.022 (95％ CI:1.275-3.208),respectively,which had a significantly higher risk of colon cancer.Moreover,the elevated colon cancer risk was especially evident in patients with TNM (Ⅲ + Ⅳ) and/or patients with poor differentiation by stratification analysis (OR,3.575,95％ CI:1.495-8.550 and OR,3.580,95％ CI:1.390-9.217,respectively).Conclusions The RAGE Gly82Ser polymorphism may confer not only an increased risk of colon cancer but also with invasion of colon cancer in the Chinese population.
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The carotid initima-media thickness(CIMT)in 78 cases of type 2 diabetic patients was measured.The level of plasma endogenous secretion receptor for advanced glycation end-products(esRAGE)in patients with normal CIMT was higher than those with chickened CIMT[(0.257 3±0.165 6 vs 0.155 4±0.0701)μg/L,P<0.01].esRAGE was negatively associated with CIMT(r=-0.247,P<0.05).Logistic regression analysis showed that CIMT was negatively associated with esRAGE and hish density lipoprotein cholesterol,but was positively associated with age.
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Objective To investigate the effect of C reactive protein on receptor of advanced glycation end-products protein (RAGE) and mRNA expression in human endothelial cells. Methods Human saphenous vein endothelial cells (HSVECs) were incubated with CRP. RAGE protein levels were determined by flow cytometry, and RAGE mRNA levels were assessed by RT-PCR. Results (1)Compared with control group (100%), CRP caused a significant increase in RAGE protein expression at a dose as low as 5 ?g/mL (175.2%?8.1%, P0.05). Conclusion C-reactive protein upregulates RAGE protein and mRNA expression in human endothelial cells in a dose and time dependent manner.
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Objective To investigate the effects of valsartan on the expression of receptors for advanced glycation end-products(RAGE) in kidneys of diabetic rats,and to explore its renoprotection mechanisms. Methods Thirty rats were divided into normal control group,diabetes control group and diabetes with valsartan group(n=10).Blood glucose,blood lipid,HbA1c,kidney to body weight ratio and 24 h urinary protein excretion were measured after 12 weeks.RAGE mRNA level was detected by real-time quantitative PCR. Results Compared with normal control group,kidney to body weight ratio,24 h urinary protein excretion and RAGE mRNA were significantly increased in diabetes control group.Compared with diabetes control group,kidney to body weight ratio,24 h urinary protein excretion and RAGE mRNA were significantly decreased in diabetes with valsartan group. Conclusion Valsartan can inhibit renal hypertrophy and decrease urinary protein excretion in diabetic rats.The renoprotective effects may be related to its inhibition on RAGE expression.
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BACKGROUND AND OBJECTIVES: The present study investigated differences in the effects of macrophages between neointimal formation after balloon (BI) and that after stent injury (SI) in hypercholesterolemic rabbits. We also studied the relationship between advanced glycation end products (AGE), the receptor for AGE (RAGE), and S100A8/A9 in the inflammatory reaction mediated by macrophages. MATERIALS AND METHODS: Male New Zealand White rabbits fed with a 1% cholesterol diet for 2 weeks underwent balloon dilatation to one iliac artery, and stenting to the contralateral artery. Arteries were harvested at 7, 14, and 28 days after injury. RESULTS: Sizes and cell numbers of neointima were higher in SI than in BI (p0.05). Sizes and cell numbers of neointima in BI and SI increased significantly till 14 days (p0.05). Macrophage numbers increased until 28 days in the media of BI (p=0.003). Macrophage numbers increased at 14 days in the neointima of SI (p=0.001), but decreased at 28 days (p=0.014). Macrophage numbers were not changed in the media of SI. Cell numbers and area were significantly correlated with macrophage numbers in the neointima and media of BI, and in the neointima of SI (p<0.05). RAGE expression was strong in cells adjacent to lumen at 7 and 14 days, and in cells of neointima and media adjacent to internal elastic lamina at 28 days. Expression of RAGE was increased in both macrophage and smooth muscle cells. Macrophages were the predominant cells observed with AGE accumulation. S100A8/A9 was not found. CONCLUSION: There seems to be a difference in effect of macrophages on the formation of neointima after injury between BI and SI. The effects of macrophages appears to be more significant in the neointima of BI. Mechanical arterial injury induces the formation of AGE and overexpression of RAGE in macrophages.
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Humans , Male , Rabbits , Arteries , Cell Count , Cholesterol , Coronary Restenosis , Diet , Dilatation , Hypercholesterolemia , Iliac Artery , Macrophages , Myocytes, Smooth Muscle , Neointima , Rage , StentsABSTRACT
OBJECTIVE:To study the regulative function of polygona-polysaccharose on the expression of RAGE mRNA in diabetic rats’brain.METHODS:Diabetic rat model was made by intraperitoneal injection of streptozotocin.RT-PCR method was used to examine the expression of RAGE mRNA in rats’brain.RESULTS:The expression of RAGE mRNA in brain tissue of diabetic rats was increased.The value of RAGE/?-actin in diabetic rats was significantly higher than that in the control group(P