Effect of green tea extract on arterial stiffness,lipid profile and sRAGE in patients with type 2 diabetes mellitus: a randomised,double-blind,placebo-controlled trial

Abstract

Type 2 diabetes mellitus (T2DM) is associated with premature atherosclerosis and arterial stiffening due to the accumulation of advanced glycation end-products in vessel walls. Green tea polyphenols are considered cardio-protective substances. In this randomised double-blind placebo-controlled trial (NCT02627898), we evaluated the effect of Green tea extract on arterial stiffness parameters, lipids, body composition and sRAGE levels. Twenty normotensive patients with T2DM treated with the standard therapy and statins, mean age 53.2?±?9.4 years and mean BMI 30.1?±?4.5?kg/m², were randomised to receive a daily dose of 400?mg of green tea extract (polyphenols ≥90%, EGCG ≥45%) or placebo for 12 weeks. Compared to placebo, administration of green tea extract decreased central augmentation index (–3.05?±?10.8% vs. 6.7?±?0.1%, p?=?.04). These findings suggest that green tea extract could be used as an adjunct to the standard therapy to improve arterial stiffness in T2DM.     

Decreased levels of soluble receptor for advanced glycation end products in patients with primary Sjögren’s syndrome

The purpose of this study was to evaluate the levels of sRAGE in primary Sjögren’s syndrome (SS), and to assess whether there is an association between sRAGE levels and disease characteristics. Thirteen patients were randomly selected from three subgroups: primary SS, (n = 6), secondary Sjögren’s, (n = 4), and ANA(+) but lacking criteria for further disease classification (n = 3). Levels of serum sRAGE were measured in triplicate using an enzyme-linked immunosorbent assay kit. Mean sRAGE levels were significantly lower in the primary Sjögren’s group. Logistic regression analysis indicated that plasma sRAGE level was a significant predictor of diagnostic status. Analyses using routine serological tests for diagnosing autoimmune disorders failed to reach statistical significance. This preliminary study supports the hypothesis that the RAGE system might participate in the disease pathway of primary SS, and that sRAGE may be a potential biomarker to aid in the diagnosis of primary SS.     

Receptor for advanced glycation end products (RAGE) in vascular and inflammatory diseases

Historically, the receptor for advanced glycation end products (RAGE) was thought to exclusively play an important role under hyperglycemic conditions. However, more and more evidence suggests that RAGE in fact is an inflammation perpetuating multi-ligand receptor and participates actively in various vascular and inflammatory diseases even in normoglycaemic conditions. Various ligands include advanced glycation end products (AGEs), S100 proteins and amphoterins etc. Besides full-length RAGE, numerous truncated forms of the receptor have also been described including the well-characterized soluble RAGE (sRAGE). sRAGE has an ability to act as a decoy to avoid interaction of RAGE with its pro-inflammatory ligands. Ligand engagement of RAGE activates multiple signaling pathways and also forms a positive feedback loop for its own enhanced expression. This review will discuss the role of multi-ligand receptor i.e. RAGE in context to various vascular diseases, which have a pathophysiologically important inflammatory component in normoglycaemic conditions.     

sRAGE is elevated in septic patients and associated with patients outcome

BACKGROUND: (1) To evaluate in septic patients the plasma levels of soluble receptor for advanced glycation end products (sRAGE), a soluble splice variant of the full length receptor RAGE, which is involved in acute inflammation (2) to determine whether sRAGE could be used as a potential diagnostic and prognostic marker in sepsis in the surgical intensive care unit. MATERIALS AND METHODS: An observational clinical noninterventional pilot study in a surgical intensive care unit with patients admitted to the intensive care unit over a 6-mo period with clinical evidence of severe sepsis or septic shock. RESULTS: Twenty-nine intensive care patients were enrolled in the study within the first 24 h after onset of severe sepsis or septic shock. Eight healthy volunteers served as controls. Plasma sRAGE concentrations were elevated in septic patients compared with healthy volunteers (1764 +/- 138 versus 1026 +/- 177 pg/mL, P < 0.05). Additionally, nonsurvivors after 28 days have had higher plasma sRAGE concentrations than survivors (2302 +/- 189 versus 1326 +/- 112 pg/mL, P < 0.001). Receiver operating characteristic curve analysis of plasma sRAGE concentrations of septic patients showed a specificity of 75% and a sensitivity of 84.6% with 1596 pg/mL as cutoff. CONCLUSIONS: This is the first study showing elevated plasma sRAGE concentrations in septic patients. It is noteworthy that nonsurvivors had higher plasma sRAGE concentrations than survivors, suggesting that sRAGE is related to severity and outcome of septic patients. Further clinical studies are required to investigate the usefulness of sRAGE as a new sepsis marker.     

大鼠脑缺血再灌注后糖基化终产物及其受体RAGE、分泌型RAGE的表达

目的:探讨大鼠脑缺血再灌注后血清分泌型RAGE、缺血脑组织糖基化终产物及其受体RAGE的表达。方法:本实验分为假手术组和脑缺血2 h后再灌注12 h、24 h、48 h组,共四个实验组,每组20只健康成年大鼠,雌雄不限。应用单侧大脑中动脉阻断法制作局灶型脑缺血模型,脑缺血2 h后再灌注。采用ELISA法检测血清分泌型RAGE水平,免疫组化法检测缺血脑组织糖基化终产物及其受体的变化,应用原位杂交法检测RAGEm-RNA。结果:与假手术组比较,脑缺血再灌注后大鼠血清分泌型RAGE水平下降。免疫组化结果显示脑组织糖基化终产物及其受体蛋白表达的阳性细胞数量与假手术组比较,呈增高趋势,再灌注24 h时,糖基化终产物及其受体蛋白表达达高峰,再灌注48 h时,表达有所下降。统计学分析提示再灌注24 h组、48 h组分别与假手术组比较,差异显著,具有统计学意义(P<0.05-0.01),而两组之间相比较,无显著差异(P>0.05)。原位杂交法检测脑缺血再灌注48 h组缺血脑组织RAGEmRNA阳性细胞数增加,与假手术组比较,差异具有统计学意义(P<0.01)。结论:脑缺血再灌注后缺血脑组织糖基化终产物及其受体的表达升高,而分泌型RAGE在大鼠脑缺血再灌注后血清中的含量及脑组织内的表达均下降。上述变化可能是脑缺血再灌注损伤的机制之一。     

清气凉营汤对脓毒症患者HMGB1、sRAGE及免疫功能的影响

目的 探析清气凉营汤对脓毒症(Sepsis)患者HMGBL、sRAGE及免疫功能的影响.方法 收集本院2019年8月至2020年2月急诊留观室、ICU收治的Sepsis患者60例,单盲试验原则,数字标注法随机分组,对照组30例,采用西医标准治疗方案,清气凉营组30例,在标准方案基础上联合清气凉营汤用药.比较两组治疗前、...     

Changes of HMGB1 and sRAGE during the recovery of COPD exacerbation

Background

Acute exacerbation of chronic obstructive pulmonary disease is associated with increased airway and systemic inflammation. However, the correlation between acute exacerbation/convalescence of chronic obstructive pulmonary disease (COPD) and simultaneous changes of high mobility group protein B1 (HMGB1) and soluble RAGE (sRAGE) levels has not been clearly clarified. The aim of this study was to assess these issues.

Methods

A total of 44 COPD patients were recruited. Following a structured interview, plasma levels of HMGB1, sRAGE, fibrinogen and serum level of high-sensitivity C-reactive protein (hsCRP) were measured in patients with acute exacerbation of COPD (AECOPD) within 24 h of hospitalization and pre-discharge (convalescence). All patients were examined with spirometry in convalescence of COPD.

Results

There was a significant decline in plasma HMGB1 (P<0.01), sRAGE (P<0.05), fibrinogen (P<0.01) and serum hsCRP (P<0.01) levels from acute exacerbation to convalescence phase of COPD. Changes of sRAGE was significantly correlated with changes of HMGB1 (r=0.4, P=0.007). COPD disease status correlated with the ratio of HMGB1/sRAGE, but not gender, age, course of disease, smoking history and FEV1% pred. Levels of HMGB1 and sRAGE were the highest in the current smoker group, and significantly decreased in ex-smoker group in both acute exacerbation and convalescence phase of COPD, however, their levels in never smoker group were higher than ex-smoker group in either phase of COPD.

Conclusions

HMGB1 and sRAGE levels were dynamically changed between exacerbation and convalescence phase of COPD, HMGB1 and sRAGE were likely not only a potential marker in COPD exacerbation but also a therapeutic target for COPD treatment.     

Circulating nucleosomes and immunogenic cell death markers HMGB1, sRAGE and DNAse in patients with advanced pancreatic cancer undergoing chemotherapy

Serum biomarkers are urgently needed for patient stratification and efficient treatment monitoring in pancreatic cancer (PC). Within a prospective diagnostic observation study, blood samples were obtained from 78 patients with advanced PC before and weekly during the course of palliative chemotherapy. Circulating nucleosomes and immunogenic cell death markers, high‐mobility group box 1 (HMGB1), soluble receptors of advanced glycation end products (sRAGE) and DNAse activity, were measured by enzyme‐linked immunosorbent assay and correlated with results of radiological staging after 2 months of treatment, with time to progression (TTP) and overall survival (OS). Median TTP and OS of PC patients were 3.9 and 7.7 months, respectively. Pretherapeutic baseline biomarker levels did not correlate with objective response; however, nucleosome levels on day (d) 28 were higher (p = 0.048) and sRAGE levels at time of staging (d56) were lower in progressive patients (p = 0.046). Concerning estimation of prognosis, high nucleosome levels (d7, d14, d21 and d56), low sRAGE levels (d56) and DNAse activity courses (d0–d7) correlated with TTP, whereas high nucleosomes (d7, d14 and d56), high HMGB1 (d21 and d56) and DNAse (d0–d7) were associated with OS. After adjustment to Karnofsky performance score, nucleosomes and HMGB1 (both d56) and DNAse (d0–d7) remained independent prognostic factors. Thus, courses of circulating nucleosomes and immunogenic cell death markers HMGB1 and sRAGE show prognostic relevance in PC patients undergoing chemotherapy.     

Decreased serum esRAGE level is associated with angiographically determined coronary plaque progression in diabetic patients

Objective

This study evaluated the relationship between serum levels of endogenous secretory receptor for advanced glycation endproducts (esRAGE) and coronary plaque progression in diabetic and nondiabetic patients.

Design and methods

Serum esRAGE level was measured and quantitative coronary angiography (QCA) was performed in 265 consecutive patients at baseline and 1-year follow-up.

Results

Comparing to baseline, serum esRAGE level was significantly increased during follow-up in nondiabetic patients without plaque progression (p = 0.014), unchanged in nondiabetic patients with plaque progression and diabetic patients without plaque progression, and decreased in diabetic patients with plaque progression (p = 0.011). Moreover, change of esRAGE levels correlated with change of QCA measurements. Multivariable regression analyses revealed that high-density lipoprotein cholesterol (OR = 0.214, p = 0.037), hypertension (OR = 2.755, p = 0.011), high-sensitivity C-reactive protein (OR = 1.083, p < 0.001) and change of esRAGE (OR = 23.477, p < 0.001) were independent risk factors for plaque progression in diabetic patients.

Conclusions

This study demonstrated an association of decreased serum esRAGE level with coronary plaque progression in patients with diabetes.