Anti-atherosclerotic effects of Polygonum aviculare L. ethanol extract in ApoE knock-out mice fed a Western diet mediated via the MAPK pathway

Ethnopharmacological relevance

Polygonum aviculare L. has been used in traditional Korean medicine to treat obesity and symptoms associated with hypertension. The effectiveness or mechanism of Polygonum aviculare L. ethanol extract (PAE) on atherosclerosis disease has not been examined experimentally. This study investigated the protective effect of PAE in atherosclerotic mice.

Materials and methods

ApoE KO mice were fed a Western diet (WD) alone or with PAE or a statin for 12 weeks, followed by analysis of bodyweight, serum lipid levels, and blood pressure. Staining of the aorta and adipose tissue, expression levels of adhesion molecules, and the MAPK pathway were also examined. Cell viability, NF-κB activity, and protein levels of adhesion molecules were assessed in vitro.

Results

ApoE KO mice fed PAE (50 and 100 mg/kg) or statin (10 mg/kg) gained less body weight, and has less adipose tissue and lower serum lipid levels and blood pressures than the WD group. Aorta ICAM-1, VCAM-1, and NF-κB levels were decreased by PAE in a dose-dependent manner, consistent with the in vitro observations. PAE and statin decreased atherosclerotic plaque and adipocyte size versus the WD group. Furthermore, PAE decreased phosphorylation of MAPK pathway components in the aorta of PAE-treated mice, suggesting that PAE's anti-atherosclerotic effects are mediated via a MAPK pathway-dependent mechanism.

Conclusions

PAE may protect against the development of atherosclerotic disease. The beneficial effects are associated with lowering bodyweight, serum lipids, blood pressure, adhesion molecular protein levels, atherosclerotic plaque, and adipocyte size, involving the MAPK pathway.     

Altered red cell and platelet adhesion in hemolytic diseases: Hereditary spherocytosis,paroxysmal nocturnal hemoglobinuria and sickle cell disease

Objectives

Intravascular hemolysis may have important pathophysiological consequences, such as the induction of cellular adhesion and vasculopathy. We compared the adhesive properties of red cells (RBC) and platelets in hereditary spherocytosis (HS), paroxysmal nocturnal hemoglobinuria (PNH) and sickle cell disease (SCD) patients.

Design and methods

The adhesion of RBC and platelets, from patients and healthy subjects, was determined using static adhesion assays. RBC surface markers were characterized by flow cytometry and lactate dehydrogenase (LDH), plasma hemoglobin (pHb) and TNF-α were assayed in serum/plasma samples.

Results

pHb levels were elevated in all three hemolytic diseases, indicating the incidence of intravascular hemolysis. RBC adhesion and TNF-α were augmented in HS and SCD, but not in PNH. Reticulocyte counts were raised in the three diseases, but were higher in HS and SCD than in PNH; high expressions of CD71, CD36 and CD49d were observed on SCD RBC, while CD71 alone was increased on HS and PNH RBC. Splenectomy was associated with reversals of increased pHb, RBC adhesion, reticulocytes, RBC marker expression and inflammation in HS. In contrast, platelet adhesion was elevated in SCD and PNH, but not HS. Platelet adhesion correlated significantly with serum LDH, but not pHb, in the hemolytic disease cohort; interestingly, LDH did not correlate with reticulocytes or pHb levels.

Conclusions

Results indicate that extravascular, rather than intravascular, hemolysis (and ensuing RBC production) may contribute to elevations in RBC adhesive properties in HS and SCD, while mechanisms peculiar to each disease may augment platelet adhesion in SCD and PNH.     

Increased urinary orosomucoid excretion: a proposed marker for inflammation and endothelial dysfunction in patients with type 2 diabetes

Objective. In a previous study, urinary orosomucoid excretion rate (UOER) independently predicted cardiovascular mortality in patients with type 2 diabetes. The aim of the present study was to determine whether increased UOER is associated with cardiovascular risk factors such as inflammation, impaired left ventricular function and endothelial dysfunction in patients with type 2 diabetes. Material and methods. We performed a cross‐sectional study of 41 patients with type 2 diabetes (17 patients with normal UOER and 24 with increased UOER) with no history of cardiovascular disease and 21 healthy controls. Urinary orosomucoid was measured using a particle‐enhanced immunoturbidimetric assay. Plasma interleukin‐6 (IL‐6), tissue plasminogen activator (tPA) and soluble intercellular adhesion molecule‐1 (sICAM) were measured using ELISA. Endothelial function measured as vasodilatory capacity of the brachial artery and echocardiography were done in all participants. Results. Patients with diabetes and increased UOER had subclinically increased serum orosomucoid (p<0.001), C‐reactive protein (CRP) (p<0.001), IL‐6 (p<0.001), tPA (p<0.003) and sICAM (p<0.003) compared with healthy controls. In patients with type 2 diabetes, UOER was independently associated with increasing values of IL‐6 (1.43 (1.06–1.93)) and tPA (1.82 (1.20–2.77)). Measurements by echocardiography showed no signs of cardiac dysfunction. Conclusions. Asymptomatic patients with type 2 diabetes and increased UOER displayed signs of chronic low‐grade inflammation and endothelial dysfunction. UOER was independently related to markers of proinflammation and endothelial dysfunction in patients with type 2 diabetes. The previously shown relation between increased UOER and cardiovascular mortality is proposed to be caused by chronic low‐grade inflammation and early endothelial dysfunction.     

Increased expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured endothelial cells exposed to serum from type 1 diabetic patients: no effects of high glucose concentrations

Activation of the arterial endothelium may play an important role in the development of an atherosclerosis-prone vascular wall in diabetes. The induction of the adhesion molecules VCAM-1 and E-selectin on activated endothelial cells is crucial in monocyte recruitment during the atherogenic process. In the present study, we investigated whether sera from type 1 diabetic patients and non-diabetic persons are capable of inducing expression of VCAM-1 and E-selectin in human endothelial cells cultured in vitro . First, it was found that the addition of serum from non-diabetics to the cultures resulted in expression of adhesion molecules above basal level and also increased the cellular response to the cytokine tumor necrosis factor-alpha (TNF- &#102 ), a strong inducer of both adhesion molecules. Moreover, it was found that, on average, sera from 17 diabetic males induced a higher expression of VCAM-1 in the endothelial cells after 6 h of incubation than samples from 20 non-diabetic age-matched males (p<0.05). No difference between the diabetic and non-diabetic group was seen in the expression of E-selectin. Likewise, no differences were observed between the effects of the sera to induce TNF- &#102 responsivity. A series of experiments showed that alterations in the glucose concentrations of the growth medium (5.5 - 13.5 mmol/L) did not change the cellular content of either VCAM-1 or E-selectin before and after TNF- &#102 treatment. In conclusion, it has been shown that sera from diabetic patients contain component(s), capable of inducing VCAM-1 expression in endothelial cells independent of hyperglycemia. Augmented induction of endothelial VCAM-1 expression by circulating factor(s) may play a role in the development of atherosclerosis in diabetes.     

New prognostic factors and developing therapy of cutaneous melanoma

The multiple molecular alterations underlying the neoplastic process and clinical characteristics of cutaneous melanoma are currently under intensive investigation. Recent studies have demonstrated that the levels of melanoma-associated proteins in tumor tissue or in patient serum can serve as new markers to predict disease outcome. Similarly, the expression of thousands of genes in melanoma tumors can be surveyed simultaneously using DNA arrays, allowing molecular profiling of individual tumors, which gives the possibility of classifying melanomas based on their biological diversity. Large clinical studies have also identified multiple prognostic factors, such as tumor ulceration, and led to development of a new, more precise melanoma staging system, which emphasizes the biological characteristics of the primary disease. These new findings may have an important role in earlier measurement of the clinical response and provide a basis for tailored melanoma therapy, the development of which will also be discussed in this review.     

Molecular mechanisms of adhesion,colonization, and invasion of group A streptococci

The initial step in establishing a bacterial infection is adhesion of the organism to the epithelium of the host. Group A streptococci use multiple adhesins to attach to host cells and the types of adhesins expressed by a particular strain will determine its tissue specificity. Expression of adhesins is regulated in response to changing environmental and growth conditions. Thus, the array of adhesins expressed by a group A streptococcus will depend on the complement of its adhesin genes and on the environment. Expression of some adhesins may trigger internalization of the streptococci by host cells, which may enable the streptococci to evade antibiotics and to facilitate the penetration of deeper tissues. In this review, we present the different molecular mechanisms of adhesion utilized by group A streptococci and how these interactions lead to colonization and invasion.     

贝前列素钠对早期糖尿病肾病患者血清可溶性细胞间黏附分子1、C反应蛋白及尿微量白蛋白排泄率影响的临床观察

目的 观察贝前列素钠对早期糖尿病肾病(DN)患者的临床疗效.方法 测定27例糖尿病无肾病患者(糖尿病无肾病组)、48例早期DN(DN组)患者血清可溶性细胞间黏附分子1(sICAM-1)浓度,并将48例早期DN患者随机分为两组,常规治疗组和贝前列素钠治疗组,各24例,测定两组治疗前后sICAM-1、C反应蛋白(CRP)及尿微量白蛋白排泄率(UAER)的变化.结果 早期DN患者血清sICAM-1浓度[(1385±171) g/L与(943±167) g/L;t=1.034,P=0.002]明显高于糖尿病无肾病组.贝前列素钠治疗组与常规治疗组治疗前血浆sICAM-1、CRP及UAER浓度比较差异均无统计学意义(P均＞0.05),治疗后均较治疗前改善,差异均有统计学意义(P＜0.05或P＜0.01),且贝前列素钠治疗组较常规治疗组改善明显,差异均有统计学意义(P＜0.05或P＜0.01).结论 早期DN患者即存在血清sICAM-1浓度升高,贝前列素钠治疗显著降低早期DN患者血清sICAM-1、CRP及UAER浓度,对早期DN有保护作用.     

小鼠视神经发育损伤相关基因的凝聚性分层聚类分析

目的对前期工作中采用高密度基因芯片技术筛选到的视神经发育、损伤相关基因进行聚类分析,以了解这些基因之间的相互联系,并根据已知功能和CNS轴突生长、导向相关的基因对部分未知功能基因进行功能预测.方法用Gene Cluster软件对筛选到的视神经发育、损伤相关基因进行凝聚性分层聚类,并对已知功能和CNS轴突生长、导向相关的Ptn、Efnb3所在的小组进行进一步的分析.结果 1 033个符合聚类条件的基因根据聚类的树型图分成6类,其中B类基因的表达模式和小鼠外侧膝状体的发育过程非常类似,它们可能是视神经发育的关键基因;5个功能完全未知的基因Mm.28443、Mm.9671、Mm.25504、Mm.160640、Mm.182895和Ptn基因聚类在同一个小组中,它们和Ptn基因的相关性非常高,Pearson相关系数为0.979～0.996,这些基因我们暂时作为神经轴突生长、导向相关的候选基因;Lamr1基因和Efnb3基因的相似性很高,结合文献,推测Lamr1及其配体是视神经发育的重要轴突导向分子.结论新的轴突导向因子的发现能为基因工程治疗CNS损伤提供潜在的靶基因.     

Blood serum levels of vascular cell adhesion molecule (sVCAM-1), intercellular adhesion molecule (sICAM-1) and endothelial leucocyte adhesion molecule-1 (ELAM-1) in diabetic retinopathy

BACKGROUND: Interaction between cells via intimate cell-cell contact is facilitated by a cell surface molecules, termed adhesion molecules. The aim of the study was to evaluate the blood serum concentration of soluble forms of vascular cell adhesion molecule (VCAM-1), intercellular adhesion molecule (ICAM-1) and endothelial leukocyte adhesion molecule-1 (ELAM-1) in patients with type 1 diabetes mellitus without and with diabetic retinopathy. MATERIALS AND METHODS: The study was performed in 75 patients with type 1 diabetes mellitus, 35 without retinopathy (group 1) and 40 with retinopathy (group 2). Soluble forms of VCAM-1, ICAM-1 and ELAM-1 were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: The serum concentration of sICAM-1 and sELAM-1 were significantly elevated and the concentration sVCAM-1 was elevated but not significantly in diabetic patients when compared with control subjects. There was a significant difference in VCAM-1 concentrations between the control group and group 2 (965.9 +/- 229.0 vs. 1283.7 +/- 387.6 ng/ml, p < 0.05) and between group 1 and group 2 (1115.0 +/- 285.5 vs. 1283.7 +/- 387.6 ng/ml, p < 0.05). There were significant differences in sICAM-1 concentrations between the control group and group 1 (p < 0.05) and between the control group and group 2 (p < 0.05). Where was no significant difference in sICAM-1 concentration between group 1 and 2 (405.2 +/- 135.9 vs. 443.1 +/- 112.7 ng/ml, p = 0.08). ELAM-1 concentration was significantly elevated in group 2 (120.5 +/- 49.3 ng/ml) when compared with the control group (51.7 +/- 18.1 ng/ml, p < 0.005) and with group 1 (81.2 +/- 27.7 ng/ml, p < 0.05). CONCLUSIONS: The correlations found between sVCAM-1, sICAM-1 and sELAM-1 and the presence of retinopathy suggest that cellular adhesion and neovascularization may be linked processes.     

不同类型维生素E对人脐静脉内皮细胞细胞间黏附分子-1表达的影响

目的:观察不同类型维生素E(α、γ、mixed-tocopherols)对氧化型低密度脂蛋白 (oxLDL)及重组人C反应蛋白 (rhCRP)诱导的人脐静脉内皮细胞 (HUVECs)细胞间黏附分子-1 (ICAM-1)表达的影响,以探讨不同类型维生素E的抗炎、抗动脉粥样硬化机制及不同效果. 方法: 体外培养HUVECs,分别加oxLDL、oxLDL α-tocopherol、oxLDL γ-tocopherol、oxLDL mixed-tocopherols、rhCRP、rhCRP α-tocopherol、rhCRP γ-tocopherol、rhCRP mixed-tocopherols孵育 24 h,采用细胞酶联免疫吸附(ELISA)、流式细胞、RT-PCR技术分别测定ICAM-1蛋白和mRNA表达水平. 结果: oxLDL和rhCRP均可诱导HUVECs的ICAM-1蛋白和mRNA表达增加,不同类型维生素E均可抑制oxLDL诱导的HUVECs的ICAM-1蛋白和mRNA表达,并呈浓度依赖性(50～200 μmol/L).与相同浓度的α、γ-tocopherol相比, mixed-tocopherols抑制作用最强.不同类型维生素E均不能抑制 rhCRP诱导的HUVECs的ICAM-1蛋白和mRNA表达.结论: 不同类型维生素E均可抑制oxLDL诱导的HUVECs的ICAM-1蛋白和mRNA表达,与α、γ-tocopherol相比,mixed-tocopherols对oxLDL诱导HUVECs表达ICAM-1的抑制作用最强.