Traditional herbal remedies that influence cell adhesion molecule activity

Many traditional medicines have demonstrated immune activity, however, research has largely neglected their effects on cell adhesion molecules (CAMs). This review reports on extracts from 37 medicinal plant species, similar to or replicating traditional preparations, that up- or downregulate either gene or protein activity of CAMs. The majority of the investigations were in vitro, primarily of the immunoglobulin superfamily of CAMs, specifically intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and secondarily on the integrin (CD11b or MAC-1) and selectin (E-selectin and P-selectin) families of CAMs. The following plant species have demonstrated modulation of multiple CAMs: Artemisia asiatica, Boswellia serrata, Canscora decussata, Cinnamomum povectum, Dehaasia incrassate, Ganoderma lucidum, Ginkgo biloba, Hypericum perforatum, Juglans regia, Lycopus lucidus, Panax notoginseng, Rheum undulatum, Salvia miltiorrhiza. Many other species have documented activity on one CAM. Currently there are limited in vivo/ex vivo investigations, including a clinical trial on Mahonia aquifolium. Although further evidence is needed, the data suggest that the reviewed botanical medicines may have the potential to provide therapeutic potential in disease processes involving CAMs. Additionally, the reported success of many of these plant extracts by traditional cultures and modern phytotherapists may involve the modulation of CAMs.     

Chrysanthemum morifolium Ramat. reduces the oxidized LDL-induced expression of intercellular adhesion molecule-1 and E-selectin in human umbilical vein endothelial cells

Ethnopharmacological relevance

The flower of Chrysanthemum morifolium Ramat. (CM) with antioxidant, cardiovascular protective and anti-inflammatory functions, has been widely used in China for hundreds of years as a healthy beverage and medicine.

Aims of the study

The purpose of the present study is to investigate the effects of HCM (a hot water extract of the flower of Chrysanthemum morifolium Ramat. [CM]), ECM (an ethanol extract of CM), and the abundant flavonoids apigenin and luteolin in CM on the oxidized LDL (oxLDL)-induced expression of ICAM-1 and E-selectin in human umbilical vein endothelial cells (HUVECs). The possible mechanism of these effects was also determined.

Materials and methods

MTT assay was for cell viability. Western blot was used for ICAM-1 and E-selection protein expression, and for activation of protein kinase B (PKB) and cAMP responsive element binding protein (CREB) proteins. Fluorescence flow cytometry was for ICAM-1 and E-selectin expression on cell surface. DCF-DA flow cytometric assay was used for reactive oxygen species (ROS) production.

Results

HCM, ECM, apigenin, and luteolin dose-dependently inhibited ICAM-1 and E-selectin expression and adhesion of HL-60 by oxLDL. HCM, ECM, apigenin, and luteolin reversed the inhibition of phosphorylation of Akt and CREB by oxLDL; however, this reversion was abolished by wortmannin. In addition, wortmannin abrogated the inhibitory effects of CM extracts, apigenin and luteolin on adhesion molecule expression. The ROS scavenging capability of HCM, ECM, apigenin, and luteolin proceeded dose-dependently in the presence of oxLDL.

Conclusion

CM is a plant with cardiovascular-protective potential and the inhibitory effects of CM on ICAM-1 and E-selectin expression are, at least partially, attributed to its antioxidant activity and modulation of the PI3K/Akt signaling pathway.     

Anti-atherogenic effects of the aqueous extract of rhubarb in rats fed an atherogenic diet

The present study was designed to investigate whether the aqueous extract of rhubarb (AR) could prevent the development of atherosclerosis through regulating vascular inflammatory processes in rats fed with an atherogenic diet. AR significantly reduced plasma low-density lipoprotein-cholesterol, and increased plasma high-density lipoprotein-cholesterol in rats fed with an atherogenic diet. AR inhibited vascular expressions of endothelin-1 (ET-1) and endothelin-converting enzyme (ECE) induced in rats with an atherogenic diet. On the other hand, AR augmented the vascular expression of endothelial nitric oxide synthase (ecNOS) and restored vascular nitric oxide (NO) production. Furthermore, AR suppressed the elevated expression of vascular nuclear factor-kappaB (NF-kappaB) p65 as well as adhesion molecules, including intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in rats fed with an atherogenic diet. Also, AR decreased endothelial expression of ICAM-1 and ET-1 in aorta. These results suggest that AR suppresses the development of atherosclerosis in the atherogenic-diet rat model through inhibiting vascular expressions of proinflammatory and adhesion molecules via the regulation of nitric oxide and endothelin system.     

CML-1 inhibits TNF-alpha-induced NF-kappaB activation and adhesion molecule expression in endothelial cells through inhibition of IkBalpha kinase

CML-1 is a purified extract from a mixture of 13 oriental herbs (Achyranthis Radix, Angelicae Gigantis Radix, Cinnamomi Cortex Spissus, Eucommiae Cortex, Glycyrrhizae Radix, Hoelen, Lycii Fructus, Paeoniae Radix, Rehmanniae Radix Preparata and Atractylodis Rhizoma, Zingiberis Rhizoma, Zizyphi Semen, Acori Graminei Rhizoma) that have been widely used for the treatment of inflammatory diseases in Asia. Since our previous study has been shown to have the anti-inflammatory activity of CML-1 in vivo and the upregulation of adhesion molecules in response to numerous inducing factors is associated with inflammation, this study examined the effect of CML-1 on the expression of adhesion molecules induced by TNF-alpha in cultured human umbilical vein endothelial cells (HUVECs). Preincubation of HUVECs for 20h with CML-1 (1-100mug/ml) dose-dependently inhibited TNF-alpha (10ng/ml)-induced adhesion of THP-1 monocytic cells, as well as mRNA and protein expression of E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). CML-1 was also shown to inhibit NK-kB activation induced by TNF-alpha. Furthermore, CML-1 inhibited TNF-alpha-induced IkB kinase activation, subsequent degradation of IkBalpha, and nuclear translocation of NK-kB. Evidence presented in this report demonstrated that CML-1 inhibited the adhesive capacity of HUVEC and the TNF-alpha-mediated induction of E-selectin, ICAM-1 and VCAM-1 in HUVEC by inhibiting the IkB/NF-kB signaling pathway at the level of IkB kinase, which may explain the ability of CML-1 to suppress inflammation and modulate the immune response.     

Extract of gravel root (rhizome of Eupatorium purpureum) inhibits integrin-dependent U937 cell adhesion

The effect of the antirheumatic herbal drug, gravel root (rhizome of Eupatorium purpureum), was investigated on integrin-dependent U937 cell adhesion to endothelial cells and extracellular matrix protein, fibronectin. In the presence of gravel root extract (6.3–200 μg/mL), U937 cells lowered their capacity for phorbol myristate acetate (PMA)-mediated adhesion to tumour necrosis factor-α (TNF)-activated endothelial cells or ICAM-1 coated plates. Similarly, the PMA mediated, LFA-1-dependent, homotypic cell aggregation in U937 cells was potently inhibited by gravel root extract. The α₄β₁ and α₅β₁-mediated adhesion of unstimulated U937 cells to fibronectin coated plates was also inhibited by gravel root extract. Neither the TNF-induced enhancement of expression of ICAM-1 on endothelial cell surface nor the TNF-induced endothelial adhesiveness to U937 cells was, however, inhibited by gravel root extract. Since all concentrations of gravel root extract tested failed to alter the proliferation of U937 cells, the observed activity was unlikely to be due to nonspecific suppression of cells. © 1998 John Wiley & Sons, Ltd.     

Nuclear factor kappaB-mediated down-regulation of adhesion molecules: Possible mechanism for inhibitory activity of bigelovin against inflammatory monocytes adhesion to endothelial cells

The flowers of Inula britannica L. var. chinensis (Rupr.) Reg. (Compositae) are used in traditional medicine to treat asthma, chronic bronchitis, and acute pleurisy in China and Korea. However, the pharmacological actions of Inula britannica L. var. chinensis on endothelial cells and inflammatory monocytes are not clear. In this study, we investigated whether bigelovin, a sesquiterpene lactone isolated from the flowers of Inula britannica L. var. chinensis, inhibits monocyte adhesion and adhesion molecule expression in brain endothelial cells. We measured tumor necrosis factor-α (TNF-α)-enhanced Raw264.7 monocyte binding to brain endothelial cells and the levels of cell adhesion molecules, including vascular adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), and endothelial-selectin (E-selectin) on the surface of brain endothelial cells. Bigelovin significantly inhibited these in a dose-dependent manner without affecting cell viability. Furthermore, bigelovin suppressed the nuclear factor kappaB (NF-κB) promoter-driven luciferase activity, NF-κB activation, and degradation of NF-κB inhibitor protein alpha (IκBα). These results indicate that bigelovin inhibits inflammatory monocyte adhesion to endothelial cells and the expression of VCAM-1, ICAM-1, and E-selectin by blocking IκBα degradation and NF-κB activation.     

左旋四氢巴马汀对脂多糖诱导人脐静脉内皮细胞黏附分子表达的影响

目的:观察左旋四氢巴马汀(l-THP)对脂多糖(lipopolysaccharides, LPS)诱导人脐静脉内皮细胞(HUVEC)细胞间黏附分子-1(ICAM-1)和E选择素(E-selectin)表达的影响,探讨l-THP的抗炎作用.方法:分离纯化人脐静脉内皮细胞,与LPS或LPS加不同浓度l-THP共育,用流式细胞仪检测细胞表面黏附分子表达的变化. 结果: l-THP (250 mg·L-1)显著降低LPS诱导的ICAM-1和E-selectin表达(P<0. 05).l-THP(50 mg·L-1)抑制E-selectin表达(P<0. 05), 然而对ICAM-1的表达无明显影响(P>0. 05).l-THP (10 mg·L-1)对2种黏附分子表达均无明显影响(P>0. 05).50 mg·L-1地塞米松(DXM)完全抑制LPS诱导上述2种黏附分子的表达(P<0. 05).结论:左旋四氢巴马汀能减少LPS诱导的ICAM-1和E-selectin表达,提示l-THP可开发成炎症治疗药物.     

补阳还五汤对血瘀证大鼠血管内皮细胞黏附分子表达的影响

目的研究补阳还五汤对血瘀证大鼠血管内皮细胞黏附分子表达的影响。方法采用免疫组织化学和RT-PCR方法观察补阳还五汤不同剂量对血瘀证大鼠血管内皮细胞细胞间黏附分子-1(ICAM-1)、血管细胞黏附分子-1(VCAM-1)、血小板-内皮细胞黏附分子-1(PECAM-1)和诱生型-氧化氮合酶(iNOS)表达的影响。结果模型组ICAM-1、VCAM-1、PECAM-1、iNOS高表达，补阳还五汤能减少造模动物ICAM-1、VCAM-1、PECAM-1、iNOs的表达，而且随着药物剂量的减少，各分子表达呈递增趋势，具有明显的量效关系。结论补阳还五汤能显著降低血瘀证大鼠血管内皮细胞黏附分子高表达，且量效关系明显。     

银杏叶提取物抑制轻度修饰低密度脂蛋白诱导的血管内皮细胞与单核细胞粘附的

目的：观察银杏叶提取物（EGb）对轻度修饰低密度脂蛋白（MM-LDL）诱导的人脐静脉内皮细胞（HUVEC）与人类单核细胞系U937粘附功能的影响。方法：利用计数法观察HUVEC与U937细胞的粘附率;用ELISA方法检测MM-LDL作用后HUVEC膜表面粘附分子血管细胞附分子-1（VCAM-1）、细胞间粘附分子-1（ICAM-1）及P选择素（P-selectin）的表达。结果：MM-LDL（75ug/ml）作用HUVEC 4h后,其对U937细胞粘附明显增加（P<0.01）,HUVEC膜表面未见VCAM-1、ICAM-1、及P-selectin表达上调,作为阳性对照重组肿瘤坏因子a(rTNFa）5.0ng/ml可显著诱导以上3种粘附分子表达。中药EGb剂量依赖性地抑制MM-LDL诱导HUVEC与U937细胞粘附。结论：EGb能保护HUVEC,减少 MM-LDL对其活化,可能有利于延缓动脉粥样硬化（AS）早期进展。MM-LDL诱导的HUVEC与U937粘附不是通过ICAM-1,VCAM-1及P-selectin介导的。     

黄芪多糖对缺氧再复氧后人心脏微血管内皮细胞ICAM-1 VCAM-1表达的影响

目的:观察黄芪多糖对缺氧再复氧损伤的人心脏微血管内皮细胞细胞间黏附分子-1(ICAM-1)和血管细胞黏附分子-1(VCAM-1)蛋白表达的影响。方法:以体外缺氧缺糖模拟体内缺血,复氧复糖模拟再灌注复制缺血再灌注损伤模型;采用免疫细胞化学法和图象定量分析系统观察ICAM-1、VCAM-1蛋白表达的变化。结果:人心脏微血管内皮细胞复苏48~72h后呈铺路石样生长,在15个细胞倍增周期内,其形态、生物、生理学特性稳定。与正常对照组比较,缺氧再复氧可明显增加ICAM-1、VCAM-1蛋白在人心脏微血管内皮细胞的表达(P<0.01)。黄芪多糖能降低两者的表达,其中100μg/mL抑制ICAM-1表达的作用显著(P<0.05),100、50μg/mL减少VCAM-1表达的作用明显(P<0.01)。结论:黄芪多糖通过减少缺血再灌注损伤的人心脏微血管内皮细胞ICAM-1和VCAM-1的表达,抑制白细胞的浸润,从而减轻心肌缺血再灌注损伤。     

芪黄明目胶囊对糖尿病小鼠视网膜黏附分子的作用及其机制

目的 观察芪黄明目胶囊对糖尿病小鼠视网膜黏附分子的作用并探讨其机制.方法 KK/Upj-Ay小鼠随机分为模型组,芪黄明目高、中、低剂量组,另设C57B L/6小鼠对照组.灌胃给药3个月,观察一般情况,测定空腹血糖(FBG);光镜及电镜观察视网膜形态学变化;Real Time PCR (qPCR)和Western blot法测定视网膜细胞间黏附分子-1(ICAM-1)、血管细胞黏附分子-1(VCAM-1)、E-选择素(E-selectin)和核因子-κB(NF-κB)表达.结果 芪黄明目能不同程度改善模型小鼠症状,降低FBG;改善视网膜病理损伤;降低视网膜ICAM-l、VCAM-1、E-selectin和NF-κB mRNA和蛋白的表达.结论 芪黄明目降低糖尿病小鼠视网膜黏附分子ICAM-1、VCAM-1、E-selectin的表达与下调NF-κB有关.     

密蒙花方对链脲佐菌素性糖尿病大鼠视网膜病理形态的影响

目的探讨密蒙花方对链脲佐菌素性糖尿病大鼠视网膜病理形态的影响。方法选用链脲佐菌素(streptozocin,STZ)诱导的糖尿病大鼠作为动物模型,以羟苯磺酸钙胶囊(昊畅)作为阳性对照药。密蒙花方煎剂分为低、中、高3种不同浓度。糖尿病大鼠成模后分别以前述不同药物灌胃4个月。进行以下几方面的研究:①STZ性DM大鼠一般状况观察:饮食、尿量、体质量变化等。②HE染色观察STZ性DM大鼠视网膜病理形态学变化。③免疫组织化学法检测STZ性DM大鼠视网膜ICAM-1、E-selectin蛋白表达情况。结果①一般状况:STZ诱导的DM大鼠高血糖状态持久稳定,表现为明显的"三多一少"典型症状。密蒙花方中剂量组体质量高于DM模型组,具有统计学意义(P<0.05)。②DM模型组视网膜各层出现典型的病理学改变,密蒙花方中剂量组视网膜病理学改变较DM模型组减轻。③DM模型组大鼠视网膜ICAM-1、E-selectin表达较正常组明显增多(P<0.01);昊畅组及各密蒙花方组ICAM-1、E-selectin表达均较模型组有不同程度的减少,差异具有统计学意义(P<0.01)。与昊畅组比较,密蒙花方中剂量组ICAM-1、E-selectin表达降低,差异具有统计学意义。结论 STZ诱导的DM大鼠是一种相对简单易行、可靠的模型制备方法。密蒙花方中剂量能在一定程度上减轻STZ性DM大鼠视网膜及视网膜毛细血管的病理改变。密蒙花方改善大鼠视网膜及视网膜毛细血管病理改变的作用与减少视网膜ICAM-1、E-selectin表达有关。     

Potential immunosuppressive and antiinflammatory activities of Malaysian medicinal plants characterized by reduced cell surface expression of cell adhesion molecules.

In the search for agents effective against immune-mediated disorders and inflammation, we have screened Malaysian medicinal plants for the ability to inhibit the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on the surface of murine endothelial cells (F-2), and mouse myeloid leukaemia cells (M1), respectively. Of 41 kinds (29 species, 24 genera, 16 families) of Malaysian plants tested, 10 and 19 plant samples significantly downregulated the expression of ICAM-1 and VCAM-1, respectively. Bioassay-directed fractionation of an extract prepared from the bark of Goniothalamus andersonii showed that its ingredients, goniothalamin (1) and goniodiol (2) inhibited the cell surface expression of both ICAM-1 and VCAM-1. The present results suggest that Malaysian medicinal plants may be abundant natural resources for immunosuppressive and antiinflammatory substances.     

灯盏细辛总咖啡酸酯对TNF-α诱导脑微血管内皮细胞ICAM-1表达的影响

目的:研究灯盏细辛中总咖啡酸酯(total Caffeoyl quinic acid ester,Caf)对离体培养的大鼠脑微血管内皮细胞(brain microvascular endothelial cell,BMEC)细胞间黏附分子-1(intercellular adhesion molecule-1,ICAM-1)基因与蛋白表达的影响,初步探讨Caf抗脑缺血炎症损伤的机制。方法:采用肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)建立离体培养的大鼠BMEC炎症损伤模型,选用25μg/mL Caf处理内皮细胞,利用Real time RT-PCR方法检测实验各组ICAM-1mRNA表达,流式细胞仪测定实验各组ICAM-1蛋白荧光强度。结果:Caf可以下调TNF-α诱导的内皮细胞ICAM-1mRNA高表达,并抑制TNF-α诱导的内皮细胞膜ICAM-1蛋白高表达。结论:Caf可以降低由TNF-α诱导的内皮细胞过度表达ICAM-1,可能是其发挥抗脑缺血炎症损伤的部分机制。     

活血注射液对ox-LDL诱导人脐静脉内皮细胞活化的影响

目的：观察活血注射液对氧化型低密度脂蛋白(ox-LDL)诱导的人脐静脉内皮细胞(HUVEC) 的细胞间黏附分子-1(ICAM-1)、血管细胞黏附分子-1(VCAM-1)的表达及与人单核细胞黏附作用的影响，并探讨核转录因子kappa B(NF-κB) 在其中的调控作用。方法：HUVEC与单核细胞的黏附率用蛋白定量法检测；ICAM-1，VCAM-1 mRNA和蛋白表达分别用RT-PCR技术和流式细胞仪检测；NF-κB p65的阳性细胞百分率和细胞核/浆染色的灰度比值用免疫细胞化学法测定。结果：ox-LDL作用HUVEC后12,24 h时，人单核细胞与HUVEC的黏附率显著升高, HUVEC中ICAM-1和VCAM-1的mRNA和蛋白表达水平也均明显升高, HUVEC的NF-κB p65的阳性细胞百分率和细胞核/浆染色的灰度比值明显增高，明显高于正常组(P<0.05，P<0.01)，而活血注射液可明显降低人单核细胞与HUVEC的黏附率和HUVEC ICAM-1，VCAM-1 mRNA和蛋白表达水平，以及显著降低HUVEC中NF-κB p65的阳性细胞百分率和细胞核/浆染色的灰度比值，与ox-LDL组相比均有显著性差异(P<0.05，P<0.01)，这种作用随着剂量的增加而增强。结论：活血注射液能通过下调内皮细胞表面ICAM-1，VCAM-1 mRNA和蛋白表达抑制单核-血管内皮细胞黏附,其可能机制是其通过抑制内皮细胞NF-κB p65的活性，从而发挥对血管内皮细胞的保护作用。     

三七总皂苷对以尿酸钠诱导血管内皮细胞凋亡的影响

目的:观察三七总皂苷片剂对以尿酸钠(MSU)100μg.mL-1诱导血管内皮细胞凋亡的影响。方法:体外培养的血管内皮细胞,以尿酸钠(MSU)100μg.mL-1为凋亡诱导因子,建立血管内皮细胞凋亡诱导模型,继而采用2.5、5、10μg.mL-1浓度的三七总皂苷进行干预,用流式细胞仪测定细胞凋亡率,采用实时定量PCR检测ICAM-1基因的表达。结果:三七总皂苷组2.5μg.mL-1明显抑制细胞凋亡(6.9±1.07)%,与模型组比较P0.01;能显著抑制ICAM-1基因的表达。结论:三七总皂苷能明显抑制以尿酸钠(MSU)100μg.mL-1诱导的血管内皮细胞凋亡。     

导痰汤通过NF-κB信号通路抑制人脐静脉内皮细胞ICAM-1表达的研究

目的:研究导痰汤能否通过对核因子-κB(NF-κB)信号通路的调节而干预ICAM-1的表达,以揭示导痰汤治疗动脉粥样硬化的机制。方法:通过PCR和Western blot等方法,观察导痰汤对肿瘤坏因子-α(TNF-α)刺激脐静脉内皮细胞(HUVEC)培养内皮细胞细胞间黏附分子-1(ICAM-1)和NF-κB表达的影响。结果:TNF-α诱导组ICAM-1和NF-κB显著高于空白对照组和导痰汤对照组(P<0.01);使用导痰汤含药血清或吡咯烷二硫氧基甲酸(PDTC)处理后,ICAM-1和NF-κB p65表达显著下降(P<0.05,P<0.01);NF-κB活性与ICAM-1 mRNA水平呈显著正相关(r=0.716,P<0.01)。结论:导痰汤可以调节NF-κB信号通路,从而有效抑制TNF-α刺激所致的脐静脉内皮细胞ICAM-1的表达。     

三七总皂苷对大鼠脑梗死区ICAM-1表达和中性粒细胞浸润的影响

目的:研究三七总皂苷对大鼠脑梗死区细胞间粘附分子-1(ICAM-1)表达和中性粒细胞浸润的影响.方法:大鼠大脑中动脉短暂阻塞制成局灶性脑缺血2 h再灌注24 h模型.再灌注后2 h腹腔注射三七总皂苷25或50 mg/kg.再灌注24 h后分光光度法测定缺血区大脑皮层和尾壳核髓过氧化物酶(MPO)活性,免疫组织化学染色测定大脑皮层和尾壳核细胞间粘附分子-1(ICAM-1)的表达.结果:大鼠局灶性脑缺血再灌注后,缺血区大脑皮层和尾壳核MPO活性和ICAM-1表达明显增加,三七总皂苷50 mg/kg治疗用药能降低MPO活性和抑制ICAM-1表达.结论:三七总皂苷可抑制大鼠局灶性脑缺血再灌注后ICAM-1表达和中性粒细胞浸润,减轻脑梗死区炎症反应.