Soluble RAGE, diabetic nephropathy and genetic variability in the AGER gene

Diabetes mellitus, especially when complicated with decline of renal function due to diabetic nephropathy (DN), is associated with accumulation of advanced glycation end products (AGEs) exerting their adverse effects via receptor of AGE (RAGE). Soluble RAGE (sRAGE) is a truncated form of RAGE functioning as an inhibitor of AGE-mediated signalling. We studied relationships between sRAGE, renal function and genetic variability in the AGER gene in diabetic subjects. Study comprised a total of 265 diabetics (type 1 or 2 or LADA) with normoalbuminuria (n = 94) or DN (n = 171). sRAGE (assessed by ELISA) was significantly higher in DN than normoalbuminuria subjects (P = 0.007) and positively correlated with age, S-urea, S-creatinine and albuminuria and AGEs (determined spectrofluorimetrically), negatively with GFR (all P < 0.05); however, multivariate regression revealed that GFR was the only independent variable associated with sRAGE (P = 0.047). sRAGE did not correspond with carrier state of risk-haplotype copies (RAGE2) (P > 0.05). In conclusion, GFR is a principal determinant of sRAGE concentration and gradual sRAGE increase in subjects with advancing impairment of renal function is paralleled by AGEs.     

Serum levels of sRAGE, the soluble form of receptor for advanced glycation end products, are associated with inflammatory markers in patients with type 2 diabetes

Advanced glycation end products (AGEs) and their receptor (RAGE) play an important role in accelerated atherosclerosis in diabetes. We have recently found that the soluble form of RAGE (sRAGE) levels are significantly higher in type 2 diabetic patients than in nondiabetic subjects and positively associated with the presence of coronary artery disease in diabetes. In this study, we examined whether serum levels of sRAGE correlated with inflammatory biomarkers in patients with type 2 diabetes. Eighty-six Japanese type 2 diabetic patients (36 men and 50 women, mean age 68.4+/-9.6 years) underwent a complete history and physical examination, determination of blood chemistries, sRAGE, monocyte chemotactic protein-1 (MCP-1), adiponectin, tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6). Univariate regression analysis showed that serum levels of sRAGE positively correlated with alanine aminotransferase (ALT) (r=0.437, P=0.0001), MCP-1 (r=0.359, P=0.001), TNF-alpha (r=0.291, P=0.006), and hyperlipidemia medication (r=0.218, P=0.044). After multiple regression analyses, ALT (P<0.0001), MCP-1 (P=0.007), and TNF-alpha (P=0.023) remained significant. The present study demonstrates for the first time that serum levels of sRAGE are positively associated with MCP-1 and TNF-alpha levels in type 2 diabetic patients. These observations suggest the possibility that sRAGE level may become a novel biomarker of vascular inflammation in type 2 diabetic patients.     

晚期糖基化终产物通过其受体促进内皮细胞分泌IL-8的研究

探讨晚期糖基化终产物(AGE)修饰蛋白对内皮细胞生成白介素8(IL-8)的作用,及晚期糖基化终产物受体(RAGE)在此病理过程中的作用.内皮细胞来自培养的人脐静脉内皮细胞(HUVEC).将内皮细胞与不同浓度的AGE修饰人血清白蛋白(AGE-HSA)在体外共同培养,或以可溶性晚期糖基化终产物受体(sRAGE)对AGE-HSA进行预处理后再与HUVEC共同培养.用蛋白质液相芯片法检测HUVEC培养上清中IL-8水平,并提取细胞RNA,进行RT-PCR反应,检测细胞中IL-8 mRNA的表达水平.结果表明,AGE-HSA以时间和剂量依赖的方式刺激HUVEC生成IL-8,未经修饰的HSA无此作用.AGE-HSA用sRAGE预处理后,刺激HUVEC生成IL-8的作用被抑制,并且此抑制作用呈剂量依赖的方式.AGE-HSA刺激HUVEC使IL-8 mRNA表达增高,未经修饰的HSA无此作用.sRAGE能够阻断AGE-HSA诱导HUVEC表达IL-8mRNA的作用.整个变化趋势与蛋白质水平一致.研究首次证实,AGE-HSA与细胞表面受体RAGE相互作用可刺激内皮细胞分泌IL-8,并上调IL-8 mRNA的表达.这为研究加速型血管病变的发病机制提供了新视角,也为治疗由AGE增多和潴留所引起的病理损害提供了新靶点.     

Soluble Forms and Ligands of the Receptor for Advanced Glycation End-Products in Patients with Acute Respiratory Distress Syndrome: An Observational Prospective Study

Background

The main soluble form of the receptor for advanced glycation end-products (sRAGE) is elevated during acute respiratory distress syndrome (ARDS). However other RAGE isoforms and multiple ligands have been poorly reported in the clinical setting, and their respective contribution to RAGE activation during ARDS remains unclear. Our goal was therefore to describe main RAGE isoforms and ligands levels during ARDS.

Methods

30 ARDS patients and 30 mechanically ventilated controls were prospectively included in this monocenter observational study. Arterial, superior vena cava and alveolar fluid levels of sRAGE, endogenous-secretory RAGE (esRAGE), high mobility group box-1 protein (HMGB1), S100A12 and advanced glycation end-products (AGEs) were measured in duplicate ELISA on day 0, day 3 and day 6. In patients with ARDS, baseline lung morphology was assessed with computed tomography.

Results

ARDS patients had higher arterial, central venous and alveolar levels of sRAGE, HMGB1 and S100A12, but lower levels of esRAGE and AGEs, than controls. Baseline arterial sRAGE, HMGB1 and S100A12 were correlated with nonfocal ARDS (AUC 0.79, 0.65 and 0.63, respectively). Baseline arterial sRAGE, esRAGE, S100A12 and AGEs were associated with severity as assessed by PaO₂/FiO₂.

Conclusions

This is the first kinetics study of levels of RAGE main isoforms and ligands during ARDS. Elevated sRAGE, HMGB1 and S100A12, with decreased esRAGE and AGEs, were found to distinguish patients with ARDS from those without. Our findings should prompt future studies aimed at elucidating RAGE/HMGB1/S100A12 axis involvement in ARDS.

Trial Registration

clinicaltrials.gov Identifier: NCT01270295.     

Soluble RAGE in type 2 diabetes: association with oxidative stress

Advanced glycation end products (AGEs) contribute to diabetic vascular complications by engaging the AGE receptor (RAGE). A soluble RAGE form (sRAGE) acts as a decoy domain receptor, thus decreasing AGE cellular binding. A cross-sectional comparison of sRAGE, asymmetric dimethylarginine (ADMA) plasma levels (index of endothelial dysfunction), and urinary 8-iso-prostaglandin (PG)F(2alpha) (marker of oxidative stress) was performed between 86 diabetic patients and 43 controls. Plasma sRAGE levels were significantly lower and ADMA levels were significantly higher in diabetic patients as compared to controls (P<0.0001). HbA1c and urinary 8-iso-PGF(2alpha) were correlated inversely with sRAGE and directly with ADMA. On multivariate analysis HbA1c was independently related to sRAGE levels in diabetic patients. Twenty-four of 86 patients with newly diagnosed diabetes and 12 patients in poor metabolic control were reevaluated after treatment with a hypoglycemic agent or insulin, respectively. Improvement in metabolic control by oral agents or insulin resulted in a significant increase in sRAGE and decrease in ADMA levels (P<0.0001). Thus, poor glycemic control reduces sRAGE levels, in association with enhanced oxidative stress and endothelial dysfunction in diabetes. These abnormalities are susceptible to modulation by improvement in metabolic control.     

Septic shock is associated with receptor for advanced glycation end products ligation of LPS

Septic shock is a severe systemic response to bacterial infection. Receptor for advanced glycation end products (RAGE) plays a role in immune reactions to recognize specific molecular patterns as pathogen recognition receptors. However, the interaction between LPS, the bioactive component of bacterial cell walls, and RAGE is unclear. In this study, we found direct LPS binding to RAGE by a surface plasmon resonance assay, a plate competition assay, and flow cytometry. LPS increased TNF-α secretion from peritoneal macrophages and an NF-κB promoter-driven luciferase activity through RAGE. Blood neutrophils and monocytes expressed RAGE, and TLR2 was counterregulated in RAGE(-/-) mice. After LPS injection, RAGE(+/+) mice showed a higher mortality, higher serum levels of IL-6, TNF-α, high mobility group box 1, and endothelin-1, and severe lung and liver pathologies compared with RAGE(-/-) mice without significant differences in plasma LPS level. Administration of soluble RAGE significantly reduced the LPS-induced cytokine release and tissue damage and improved the LPS-induced lethality even in RAGE(-/-) as well as RAGE(+/+) mice. The results thus suggest that RAGE can associate with LPS and that RAGE system can regulate inflammatory responses. Soluble RAGE would be a therapeutic tool for LPS-induced septic shock.     

The association of receptor of advanced glycated end products and inflammatory mediators contributes to endothelial dysfunction in a prospective study of acute kidney injury patients with sepsis

The pathogenesis of acute kidney injury (AKI) occurring due to sepsis is incompletely understood. Endothelial activation, defined as up-regulation of adhesion molecules by proinflammatory cytokines, may be central to the development of sepsis-induced AKI. Our aim was to determine levels of circulating adhesion molecules endothelial (E)-selectin, intercellular adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM), inflammatory mediators; tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β), vasoactive mediators; endothelin-1 (ET-1) and nitric oxide (NO), soluble receptor for advanced glycated end products (sRAGE) and serum fetuin-A in septic AKI patients before and after antibiotic therapy. Nineteen AKI patients with sepsis and fifteen healthy controls were enrolled in this prospective study. Results revealed that 12 weeks of therapy caused amelioration of endothelial and inflammatory injuries as well as renal function markers. Moreover, the positive correlations between levels of RAGE and E-selectin (r=0.88), ET-1 (r=0.90), and TNF-α (r=0.94) and negative with NO (r=-0.75-0.95) suggest that possible interaction of RAGE and inflammation may contribute to endothelial dysfunction in septic AKI patients.     

AGEs-RAGE mediated up-regulation of connexin43 in activated human microglial CHME-5 cells

Microglial activation is a significant contributor to the pathogenesis of many neurodegenerative diseases. Microglia respond to a range of stimuli including pathogenic protein deposits such as advanced glycation endproducts (AGEs). AGEs are prominent inflammatory stimuli that accumulate in the ageing brain. AGEs can activate microglia, leading to the production of excessive amounts of inflammatory cytokines and coupling via gap junction proteins especially connexin43 (Cx43). The literature on the expression of microglial Cx43 during inflammation is controversial. Many cellular effects of AGEs are thought to be mediated by the receptor RAGE. There is however, no evidence suggesting Cx43 is a downstream effector of AGEs-RAGE interaction in microglia. In addition, most of the AGEs-related studies have been undertaken using rodent microglia; the information on human microglia is sparse. Microglia of human and rodent origin respond differently to certain stimuli. The aims of this study were to investigate the AGEs-RAGE-mediated activation of human microglia and establish if Cx43 is one of the downstream effectors of AGEs-RAGE interaction in these cells. Human microglial CHME-5 cells were treated with different doses of AGEs for a selected time-period and microglial activation studied using specific markers. The protein expression of RAGE, Cx43 and TNF-α-receptors (RI and RII) was analysed in response to AGEs in the absence/presence of various doses of anti-RAGE Fabs. TNF-α levels in media were measured using ELISA. TNF-α-induced opening of gap junctional channels was assessed by dye uptake assays and the effect of neutralising TNFRII on Cx43 levels was also studied. CHME-5 cells showed an up-regulation of RAGE, TNF-α, TNFRs (especially TNFRII) and Cx43 upon AGEs treatment and a significant dose-dependent drop in the levels of TNF-α, TNFRII and Cx43 in the presence of anti-RAGE Fabs. TNF-α induced gap junctional/hemichannel opening whereas blocking TNFRII inhibited TNF-α-induced increase in Cx43 levels. Results suggested that TNF-α, TNFRII and Cx43 are downstream effectors of the AGEs-RAGE interaction in human microglial CHME-5 cells.     

Advanced glycation end product ligands for the receptor for advanced glycation end products: biochemical characterization and formation kinetics

Advanced glycation end products (AGEs) accumulate with age and at an accelerated rate in diabetes. AGEs bind cell-surface receptors including the receptor for advanced glycation end products (RAGE). The dependence of RAGE binding on specific biochemical characteristics of AGEs is currently unknown. Using standardized procedures and a variety of AGE measures, the present study aimed to characterize the AGEs that bind to RAGE and their formation kinetics in vitro. To produce AGEs with varying RAGE binding affinity, bovine serum albumin (BSA) AGEs were prepared with 0.5M glucose, fructose, or ribose at times of incubation from 0 to 12 weeks or for up to 3 days with glycolaldehyde or glyoxylic acid. The AGE-BSAs were characterized for RAGE binding affinity, fluorescence, absorbance, carbonyl content, reactive free amine content, molecular weight, pentosidine content, and N-epsilon-carboxymethyl lysine content. Ribose-AGEs bound RAGE with high affinity within 1 week of incubation in contrast to glucose- and fructose-AGE, which required 12 and 6 weeks, respectively, to generate equivalent RAGE ligands (IC50=0.66, 0.93, and 1.7 microM, respectively). Over time, all of the measured AGE characteristics increased. However, only free amine content robustly correlated with RAGE binding affinity. In addition, detailed protocols for the generation of AGEs that reproducibly bind RAGE with high affinity were developed, which will allow for further study of the RAGE-AGE interaction.     

Thyroid dysfunction in obese pre-pubertal children: oxidative stress as a potential pathogenetic mechanism

Although a relationship between obesity and hyperthyrotropinemia has been hypothesized in obese children, the underlying pathogenesis is not completely known. In the current cross-sectional study, we evaluated the thyroid function in a group of 80 obese pre-pubertal children compared to 41 healthy normal weight peers, exploring the possible association between hyperthyrotropinemia and oxidative stress. In all children, thyrotropin (TSH), free T4 (fT4), free T3 (fT3) and anti-thyroid antibodies were evaluated. Homeostatic model assessment of insulin resistance (HOMA-IR) level was evaluated as index of insulin resistance. We measured the endogenous secretory receptor for advanced glycation end products (esRAGE) and soluble RAGE (sRAGE) and the urinary prostaglandin F2α (PGF-2α) as markers of oxidative stress. We found that TSH levels were significantly higher in obese children than controls. TSH significantly correlated with body mass index-standard deviation score (BMI-SDS), HOMA-IR, PGF-2α, esRAGE and sRAGE. The multiple linear regression showed that in obese children HOMA-IR, PGF-2α, esRAGE and sRAGE were significantly related to TSH, independently of BMI-SDS, age and gender. In obese children, hyperthyrotropinemia could be detected already in pre-pubertal age. The increased oxidative stress might represent one of the key regulators of TSH levels, early in life.     

Effects of RAGE-Specific Inhibitor FPS-ZM1 on Amyloid-β Metabolism and AGEs-Induced Inflammation and Oxidative Stress in Rat Hippocampus

Neurochemical Research - 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...     

Serum levels of soluble receptor for advanced glycation end products and of S100 proteins are associated with inflammatory, autoantibody, and classical risk markers of joint and vascular damage in rheumatoid arthritis

Introduction  

The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface receptor molecules. High concentrations of three of its putative proinflammatory ligands, S100A8/A9 complex (calprotectin), S100A8, and S100A12, are found in rheumatoid arthritis (RA) serum and synovial fluid. In contrast, soluble RAGE (sRAGE) may prevent proinflammatory effects by acting as a decoy. This study evaluated the serum levels of S100A9, S100A8, S100A12 and sRAGE in RA patients, to determine their relationship to inflammation and joint and vascular damage.     

抑郁症患者血清miR-135a、miR-221表达水平与认知功能、事件相关电位P300和炎症细胞因子的相关性分析

目的:探讨抑郁症患者血清微小核糖核酸(mi R)-135a、mi R-221表达水平与认知功能、事件相关电位P300和炎症细胞因子的相关性。方法:选择2019年1月至2021年1月我院收治的216例抑郁症患者(抑郁症组)和同期于我院体检的200例健康志愿者(对照组)。检测血清mi R-135a、mi R-221表达水平及白细胞介素-6(IL-6)、超敏C反应蛋白(hs-CRP)、肿瘤坏死因子-α(TNF-α)水平。采用蒙特利尔认知评估量表(MoCA)、简易精神状态检查量表(MMSE)评估认知功能。采用全功能肌电诱发电位仪检测P3潜伏期和P3波幅。Pearson相关性分析mi R-135a、mi R-221表达水平与MoCA评分、MMSE评分、IL-6,hs-CRP,TNF-α、P3潜伏期和P3波幅的相关性。结果:抑郁症组血清mi R-221表达水平、P3潜伏期,血清IL-6、hs-CRP、TNF-α水平高于对照组(P<0.05),mi R-135a表达水平、MMSE评分、MoCA评分、P3波幅低于对照组(P<0.05)。mi R-221表达水平与P3潜伏期,血清IL-6、hs-CRP、TNF-α水平呈正相关(P<0.05),与MMSE评分、MoCA评分、P3波幅呈负相关(P<0.05);mi R-135a表达水平与P3潜伏期,血清IL-6、hs-CRP、TNF-α水平呈负相关(P<0.05),与MMSE评分、MoCA评分、P3波幅呈正相关(P<0.05)。结论:抑郁症患者血清mi R-135a表达水平降低,mi R-221表达水平增高,mi R-135a低表达和mi R-221高表达与抑郁症患者认知功能降低、机体炎症反应有关。     

脑梗塞患者血清hs—CRP、TNF-α、血脂水平的变化及其临床意义

目的：观察脑梗塞患者血清超敏C反应蛋白（hs—CRP）、肿瘤坏死因子（TNF-α）及血脂水平的变化。并探讨其临床意义。方法：选择我院2010年6月-2012年6月收治的86例急性脑梗塞患者（轻型脑梗塞组27例、中型脑梗塞组34例、重型脑梗塞组25例）为实验组和同期40例健康体检者为对照组,检测和比较两组血清超敏C反应蛋白（hs-CRP）、肿瘤坏死因子（TNF—α）、甘油三酯（TG）、总胆固醇（TC）、低密度脂蛋白（LDL-C）和高密度脂蛋白（HDL-c）的水平,并进行相关性分析。结果：与健康对照组比较,实验纽血清hs—CRP、TNF-α及TC、TG、LDL—C水平显著升高,而血清HDL-C水平显著降低,差异均具有统计学意义（P〈0．05）。与轻型脑梗塞组比较,中、重型脑梗塞组血清hs-CRP、TNF-α及TC、TG、LDL-C等血脂水平均显著升高,而血清HDL-C水平显著降低,其异均具有统计学意义（P〈0．05）;与中型脑梗塞组比较,重型脑梗塞组血清TC、TG、LDL-C等血脂水平均显著升高,血清HDL—C水平显著降低,其差异亦均具有统计学意义（P〈0．05）。脑梗塞患者血清hs—CRP与TNF-α水平呈显著正相关（P〈0．05）,与TC、TG、LDL—C等血脂水平均亦呈显著正相关（P〈0．05）,与血清HDL—C水平呈显著负相关（P〈O．05）。脑梗塞患者血清hs．CRP、TNF-α水平与病情严重程度呈显著正相关（P〈0．05）。结论：检测血清hs-CRP、TNF-α及血脂指标水平对评估脑梗塞患者病情具有重要的临床意义。     

RAGE and AGEs in Mild Cognitive Impairment of Diabetic Patients: A Cross-Sectional Study

Objective

Receptor for advanced glycation end products (AGEs; RAGE) binds to both AGEs and amyloid-beta peptides. RAGE is involved in chronic complications of type 2 diabetes and Alzheimer’s disease. We aimed to investigate the roles of RAGE, AGEs and the Gly82Ser polymorphism of RAGE in mild cognitive impairment (MCI) among type 2 diabetes patients.

Methods

Of the 167 hospitalized type 2 diabetes patients recruited, 82 satisfied the diagnostic criteria for MCI, and 85 matched control individuals were classified as non-MCI. Demographic data were collected, and the soluble RAGE (sRAGE) concentrations, serum AGE-peptide (AGE-P) levels, RAGE Gly82Ser genotype and neuropsychological test results were examined.

Results

The MCI group exhibited a decreased sRAGE level (0.87±0.35 vs. 1.05±0.52 ng/ml, p<0.01) and an increased serum AGE-P level (3.54±1.27 vs. 2.71±1.18 U/ml, p<0.01) compared with the control group. Logistic regression analysis indicated that each unit reduction in the sRAGE concentration increased the MCI risk by 54% (OR 0.46[95% CI 0.22–0.96], p = 0.04) and that each unit increase in the AGE-P level increased the MCI risk by 72% in the type 2 diabetes patients (OR 1.72[95% CI 1.31–2.28], p<0.01). The serum sRAGE level was negatively correlated with the score on the trail making test-B (TMT-B) (r = -0.344, p = 0.002), which indicates early cognitive deficits related to diabetes. Moreover, the AGE-P level was positively correlated with multiple cognitive domains (all p<0.05). No significant differences in the neuropsychological test results or serum RAGE concentrations between the different RAGE genotypes or in the RAGE genotype frequencies between the MCI and control groups were identified (all p>0.05).

Conclusions

The RAGE pathway partially mediates AGE-induced MCI in diabetic patients. The serum AGE-P level may serve as a serum biomarker of MCI in these individuals, and sRAGE represents a predictor and even a potential intervention target of early cognitive decline in type 2 diabetes patients.

Trial registration

Advanced Glycation End Products Induced Cognitive Impairment in Diabetes: BDNF Signal Meditated Hippocampal Neurogenesis ChiCTR-OCC-15006060     

Cell signaling and receptors in toxicity of advanced glycation end products (AGEs): α-dicarbonyls, radicals, oxidative stress and antioxidants

Considerable attention has been paid to the toxicity of advanced glycation end products (AGEs), including relation to various illnesses. AGEs, generated nonenzymatically from carbohydrates and proteins, comprises large numbers of simple and more complicated compounds. Many reports deal with a role for receptors (RAGE) and cell signaling, including illnesses and aging. Reactive oxygen species appear to participate in signaling. RAGE include angiotensin II type 1 receptors. Many signaling pathways are involved, such as kinases, p38, p21, TGF-β, NF-κβ, TNF-α, JNK and STAT. A recent review puts focus on α-dicarbonyl metabolites, formed by carbohydrate oxidation, and imine derivatives from protein condensation, as a source via electron transfer (ET) of ROS and oxidative stress (OS). The toxic species have been related to illnesses and aging. Antioxidants alleviate the adverse effects.     

Hypoxia-increased RAGE expression regulates chemotaxis and pro-inflammatory cytokines release through nuclear translocation of NF-κ B and HIF1α in THP-1 cells

The potential role of hypoxia in mediating the receptor for advanced glycation end products (RAGE) expression deserves to be confirmed. And the role of RAGE in hypoxia-induced chemotaxis and inflammation is still unclear. In present study, THP-1?cells were pretreated with siRNA to block HIF1α, NF-κ B, or RAGE, followed by exposed to hypoxia (combined with H₂O₂ or SNP), and then RAGE expression, nuclear translocation of HIF1α and NF-κ B, release of TNF-α and IL-1β, as well as expression of MCP-1 and CCR2 were measured. The results revealed that RAGE mRNA and protein in THP-1?cells were significantly increased after exposed into hypoxia atmosphere, especially into the solution containing SNP or H₂O₂. Moreover, SNP or H₂O₂ exposure could further amplify hypoxia-induced nuclear translocation of HIF-1α and NF-κ B. Knockdown HIF-1α or NF-κ B by siRNAs could reduce hypoxia- and oxidative stress-induced RAGE hyper-expression. And pretreatment THP-1?cells with RAGE siRNA or NF-κ B siRNA could reduce hypoxia- and oxidative stress-induced expression of MCP-1 and CCR2, and release of TNF-α and IL-1β. Thus, hypoxia not only increases RAGE expression in THP-1?cells by promoting nuclear translocation of NF-κ B and HIF1α, but also regulates chemotaxis and pro-inflammatory cytokines release, which may be partially mediated through upregulation of RAGE expression.     

Luteolin Ameliorates Cognitive Impairments by Suppressing the Expression of Inflammatory Cytokines and Enhancing Synapse-Associated Proteins GAP-43 and SYN Levels in Streptozotocin-Induced Diabetic Rats

Luteolin, a flavonoid isolated from Cirsium japonicum, has antioxidant, anti-inflammatory and neuroprotective activities. Our previous studies brought a prospect that luteolin benefited diabetic rats with cognitive impairments. In this study, we examined whether luteolin could suppress the inflammatory cytokines, thus increasing synapse-associated proteins in streptozotocin (STZ)-induced diabetes in rat models. The model rats underwent luteolin treatment for 8 consecutive weeks, followed by assessment of cognitive performances with MWM test. Nissl staining was employed to assess the neuropathological changes in the hippocampus and the effects of luteolin on diabetic rats. With animals sacrificed, expressions of inflammatory cytokines including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) and synapse-associated proteins including growth-associated protein-43 (GAP-43) and synaptophysin (SYN) were determined. The results affirmed improvement of behavioral performances in the MWM test, downexpression of glycation end products (AGEs) in the plasma and the receptor for advanced glycation end products in the hippocampus, inhibition of IL-1β and TNF-α in both the hippocampus and plasma in diabetic rats. Furthermore, luteolin treatment upregulated the expressions of GAP-43 and SYN in the hippocampus. Thus, luteolin could ameliorate the cognitive dysfunctions in STZ-induced diabetic rat model.     

缬沙坦对人肾小球系膜细胞糖基化终产物受体表达的影响

目的：本实验探讨缬沙坦对糖基化终产物诱导的人肾小球系膜细胞氧化应激水平及糖基化终产物受体（RAGE）表达的影响。方法：体外常规培养人肾小球系膜细胞,运用糖基化修饰的牛血清白蛋白（AGE-BSA）和缬沙坦进行干预,流式细胞术检测细胞内活性氧（ROS）,RT-PCR法检测NADPH氧化酶的亚基p47^phox的mRNA表达,RT-PCR和细胞免疫化学法检测RAGE的表达量。结果：缬沙坦干预组人肾小球系膜细胞的ROS产生量、NADPH氧化酶的亚基p47^phox mRNA表达量、RAGE表达量均低于AGE-BSA组（P〈0．05）,且缬沙坦的抑制作用呈浓度和时间依赖性。结论：缬沙坦可能通过降低氧化应激水平来抑制RAGE的表达。