咖啡酸锗对小鼠子宫颈癌14号的抑制作用

目的:观察咖啡酸锗对小鼠子宫颈癌14号(U14)的作用。方法:以无菌生理盐水按1∶3稀释,调整细胞数约为2.08×109个/L,于每只小鼠右肢皮下接种0.2mLU14,以咖啡酸锗高、中、低3个剂量连续给药10d,以生理盐水组为模型对照组,计算各剂量组对U14的抑制率。结果:咖啡酸锗高、中剂量对U14有较好的抑制率,低剂量也有一定的抑制作用,且给药前后小鼠体重明显增加。结论:咖啡酸锗对小鼠U14有抑制作用,且毒性很小。     

抗肿瘤血管生成联合介入治疗中晚期肝癌的临床观察

目的探讨抗肿瘤血管生成联合介入治疗中晚期肝癌的临床疗效。方法选取2009年5月～2012年5月我院收治139例中晚期肝癌患者的临床资料进行回顾性分析,按照随机数字表法将其分为观察组72例(抗肿瘤血管生成联合介入化疗)和对照组(仅接受介入化疗)67例,对两组患者的临床疗效和Kamofsky评分进行比较分析。结果 (1)观察组的CR+PR率为43.1%明显高于对照组28.4%,两组比较差异有统计学意义(P0.05);(2)两组患者在Kamofsky评分比较,观察组的Kamofsky评分明显高于对照组,差异有统计学意义(P0.05)。结论抗肿瘤血管生成联合介入治疗中晚期肝癌能有效改善患者生活质量,延长患者生存时间,为治疗肝癌非手术的首选方法。     

咖啡酸锗对小鼠S180细胞生长的抑制作用及其机制的研究

本文应用我院合成的新化合物———咖啡酸锗（专利号031186351）的水溶液灌胃,对荷瘤S180小鼠进行体内抗肿瘤实验及病理形态观察,并探讨其抑瘤机制。1材料1.1瘤株和动物小鼠S180瘤株,杭州医科院肿瘤研究所;昆明种小鼠,中国科学院上海实验动物中心。1.2药品及试剂咖啡酸锗由江西中医学院化学实验中心合成,并经结构检测。免疫组化各种抗体（p53、VEGF、bcl-2）和试剂盒,迈新公司。注射用环磷酰胺,江苏恒瑞医药。苏木精、甲基绿、吡啰红、品红等,上化试剂公司。     

抗肿瘤血管生成类药物致蛋白尿的机制及临床诊治

血管内皮生长因子(vascular endothelial growth factor,VEGF)及其受体(vascular endothelial growth factor receptor,VEGFR)在生理和病理性血管生成中发挥关键作用。由于恶性肿瘤生长离不开新生血管支持,因此抑制VEGF/VEGFR系统的抗肿瘤血管生成药物已成为肿瘤药物治疗重要手段之一。随着药物在临床上被广泛应用,部分患者在用药过程中发生以蛋白尿为表现的肾毒性,其发病机制尚不明确。现就抗肿瘤血管生成药物临床使用致蛋白尿的发生率、机制及临床诊治作一综述,旨在为临床用药提供参考。     

肝癌中血管生成素2和血管内皮生长因子的表达及其临床意义

目的观察血管生成素2（Ang-2）和血管内皮生长因子（VEGF）在肝癌组织中的表达,探讨它们与肿瘤的血管发生、入侵／转移能力和肝细胞性肝癌（HCC）预后之间的关系。方法采用免疫组织化学的方法检测肝癌组织中Ang-2和VEGF的表达,并通过对CD34的免疫组化染色检测肿瘤的微血管密度（MVD）。结果肝癌组织Ang-2表达和病理学分期、门静脉侵犯明显相关（P〈0．05）。VEGF和Ang-2均表达阳性时肝癌组织中MVD显著上调,且预后较差（P〈0.05）。结论肝癌Ang-2和VEGF的共同表达能诱导肿瘤血管发生,并和肝癌的入侵与恶性程度以及预后有关。     

苦参碱对小鼠H22 细胞抗肿瘤作用及其机制研究

目的观察苦参碱在体内和体外的抗肿瘤作用,探讨其可能的作用机制。方法 MTT法检测苦参碱对小鼠腹水瘤细胞H22的体外杀伤作用;通过建立动物肿瘤模型,免疫组化法检测其抑瘤率和肿瘤内血管密度,以及瘤体血管内皮生长因子。结果①体外实验显示,1.0、2.0、4.0mg·mL^-1苦参碱对H22肿瘤细胞的生长均有明显的抑制作用,并呈剂量依赖性,与对照组相比有显著性差异（P〈0.05）。②体内实验显示,苦参碱高、中、低剂量组对小鼠H22实体瘤均有抑制作用,并呈现一定的剂量效应关系,其中苦参碱高剂量组瘤重明显小于空白对照组,高剂量组的抑制作用明显强于中、低剂量组,P〈0.01;③免疫组化结果显示,苦参碱组和环磷酰胺组瘤组织内的VEGF蛋白表达阳性率和平均染色强度均低予对照组,组间有显著差异（P〈0.05）。苦参碱高剂量组MVD明显低于对照组,组间差异性非常显著（P〈0.01）,较环磷酰胺组无显著性差异（P〉0.05）。结论苦参碱能够提高H22肉瘤小鼠生存质量,具有抑制肿瘤新生血管生成的作用,可能是通过降低VEGF蛋白表达来实现的。     

靶向血管内皮生长因子/血管内皮生长因子受体-2的血管生成抑制剂

血管内皮生长因子(VEGF)及血管内皮生长因子受体-2(VEGFR-2)是调节血管生成、内皮细胞增殖和迁移等的关键调控因子。通过阻断VEGF与VEGFR-2的结合可抑制新生血管形成,而新生血管的形成是肿瘤生长和转移的基础。介绍VEGF/VEGFR-2在血管形成中的作用,以及具有抗肿瘤作用的靶向VEGF/VEGFR-2的血管生成抑制剂的研究近况。     

七叶皂苷钠对小鼠肝癌H22移植瘤的抗肿瘤作用机制

目的:通过体内模型研探讨七叶皂苷钠对H22小鼠肝癌移植瘤的抗肿瘤作用机制。方法:采用ICR小鼠H22荷瘤肝癌模型观察七叶皂苷钠抗肿瘤作用,采用Western Blot分析肿瘤组织中相关蛋白的表达变化,通过免疫组化分析肿瘤组织中CD31变化,评价微血管密度。结果:1.4和2.8 mg.kg-1七叶皂苷钠对H22的抑瘤率分别为19.2%,40.7%。免疫组化结果显示,七叶皂苷钠能够显著降低肿瘤内部微血管密度,低高剂量组可分别达到44.1%和48.5%。Western Blot证实,七叶皂苷钠能不同程度下调cyclinD1、cdk2、cyclinE、VEGF、p-Akt等蛋白的表达,抑制p65的核转位。结论:七叶皂苷钠有一定的抗肿瘤作用,其机制可能与阻滞细胞周期,抑制血管新生以及干扰信号转导有关。     

血管生成抑制剂SU6668抗肿瘤作用的研究进展

血管生成是实体瘤生长和转移的必要条件，通过抑制血管生成来阻止肿瘤生长的抗血管生成疗法是目前肿瘤治疗的新策略。SU6668作用于广泛的酪氨酸受体，疗效优于选择性酪氨酸激酶受体抑制剂，Ⅰ期临床试验表明，SU6668是一种安全有效的抗癌药。     

VEGF融合蛋白疫苗联合环磷酰胺抗小鼠H22肝癌实验研究

目的探讨分子佐剂修饰的VEGF融合蛋白疫苗与低剂量环磷酰胺(CTX)能否产生协同抗肝癌作用。方法建立小鼠H22肝癌模型,将BALB/c小鼠随机分为4组:生理盐水对照组、CTX单药组、VEGF蛋白疫苗单药组(V2组)、V2与CTX联合治疗组(V2+CTX)。分别在H22肝癌皮下移植瘤及皮内肿瘤模型中评价联合治疗方案抗肿瘤生长及抗血管生成的能力,并通过Western blot及ELISA方法检测抗-VEGF抗体水平。结果皮下移植瘤模型结果显示V2+CTX联合治疗组的肿瘤体积、平均瘤重低于各单药治疗组(P<0.05 vs V2,P<0.01 vs CTX);在皮内肿瘤血管模型中,联合治疗对肿瘤新生血管的抑制作用最为明显,与单独的V2及CTX组相比,差异均有统计学意义(P<0.05 vs V2,P<0.01 vs CTX);Western blot及ELISA的结果显示,V2+CTX联合治疗诱导小鼠产生了高水平的特异性抗-VEGF抗体。结论低剂量CTX与重组VEGF融合蛋白疫苗联合治疗有协同抗肝癌作用。     

Protective effect of caffeic acid phenethyl ester against cadmium-induced renal damage in mice

Cadmium (Cd) is classified as an environmental pollutant and human carcinogen. Caffeic acid phenethyl ester (CAPE), a biological active component of honeybee propolis extracts, has been used as a folk medicine with no harmful effects on normal cells. Here we investigated the beneficial effect of CAPE on Cd-induced renal damage in mice. Since renal damage induced by Cd (II) is related to oxidative stress, lipid peroxidation (LPO), protein carbonyl (PCO), superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) were evaluated. Moreover, the concentrations of Cd and zinc (Zn) in the kidney were analyzed. The intoxication of Cd (II) leads to the enhanced production of LPO and PCO, and the decrease of SOD activity and GSH level, probably due to the serious oxidative stress. However, the activities of CAT in the Cd (II)-induced group showed an elevated tendency, probably relating to an adaptive-response to the oxidative damage. The co-administration of CAPE can attenuate the oxidative stress caused by the intoxication of Cd and restore the altered antioxidant defense system. Based on our data, it is proposed that CAPE may involve in the protection of renal damage induced by Cd (II) owing to its antioxidant capacity and anti-inflammatory effect.     

Protective effect of caffeic acid phenethyl ester against carbon tetrachloride-induced hepatotoxicity in mice

This study was designed to investigate the protective effects of the phenethyl ester of caffeic acid (CAPE) against carbon tetrachoride (CCl₄)-induced hepatotoxicities in mice. Pretreatment with CAPE prior to administration of CCl₄ significantly prevented the increases in serum alanine, aspartate aminotransferase and alkaline phosphatase activities, hepatic lipid peroxidation formation, and depletion of glutathione content. In addition, CAPE prevented CCl₄-induced apoptosis and necrosis, as indicated by liver histopathology and DNA laddering studies. To determine whether the Fas/Fas ligand (FasL) pathway is involved in CCl₄-induced acute liver injury, Fas and FasL proteins and caspase-3 and -8 activities were tested by western blotting and ELISA. CAPE markedly decreased CCl₄-induced Fas/FasL protein expression levels and, in turn, attenuated CCl₄-induced caspase-3 and -8 activities in mouse liver. Moreover, the effect of CAPE on CYP2E1, the major isozyme involved in CCl₄ bioactivation, was investigated. Treatment with CAPE significantly decreased the CYP2E1-dependent hydroxylation of aniline. In addition, CAPE attenuated the CCl₄-mediated depletion of antioxidant enzyme (catalase, superoxide dismutase and glutathione-S-transferase) activities. These findings suggest that the protective effects of CAPE against CCl₄-induced acute liver injury may involve its ability to block CYP2El-mediated CCl₄ bioactivation and to protect against Fas/FasL-mediated apoptosis.     

参芪扶正注射液对肝癌细胞株H22的抑制作用及机制研究

目的研究参芪扶正注射液体内外对肝癌H22细胞的抑制作用及其机制。方法 MTT法检测参芪扶正注射液体外对H22细胞增殖的影响;利用H22小鼠模型进行体内抗肿瘤作用试验,计算抑瘤率;酶联免疫ELISA法测荷瘤小鼠血清IFN-γ含量;双抗体夹心ABC-ELSA法测荷瘤小鼠血清TNF-α的含量。结果参芪扶正注射液体内外均能抑制H22细胞的生长,具有浓度和时间依赖性;促进荷瘤小鼠血清中IFN-γ和TNF-α的表达。结论参芪扶正注射液体内外均能抑制肝癌H22的生长,其抗肿瘤作用与调节荷瘤小鼠的免疫功能有关。     

Immunomodulatory effect of caffeic acid phenethyl ester in Balb/c mice

Caffeic acid phenethyl ester (CAPE), an the active component of propolis, is known to have anticarcinogenic, antiviral and various biological activities; however, the effect of CAPE on the immunomodulatory activity in vivo remains unknown. We have investigated the effect of CAPE on the immune system in female Balb/c mice. CAPE (0, 5, 10, 20 mg/kg) was given to mice orally for 14 days. Immunomodulatory activity was evaluated by assessment of body and organ weight, lymphocyte blastogenesis, plaque-forming cell (PFC) assay, lymphocyte subpopulation by flow cytometry and cytokine production. Even though the change of body weight was not observed in CAPE-administered group, thymus weight and/or cellularity of thymus and spleen are decreased at the all dose groups of CAPE (5, 10, 20 mg/kg). On the other hand, CAPE had no effect on B lymphocyte proliferation induced by lipopolysaccharide (LPS) but increased T lymphocyte blastogenesis induced by concanavalin A (Con A) at the dose of 20 mg/kg. In the case of lymphocyte subpopulation, the population of T and B cells was not changed but CD4(+) T cell subsets are significantly increased in exposure to CAPE. The antibody responses to T lymphocyte dependent antigen, sheep red blood cell and keyhole limpet hemocyanin (KLH) were increased more than 10 mg/kg in CAPE-treated group. Likewise, the cytokine, IL-2, IL-4 and IFN-gamma were significantly increased at the dose of 20 mg/kg CAPE group. These results suggest that CAPE could have immunomodulatory effects in vivo.     

Rosmarinic acid and caffeic acid produce antidepressive-like effect in the forced swimming test in mice

We previously showed that rosmarinic acid from the leaves of Perilla frutescens Britton var. acuta Kudo (Perillae Herba) has antidepressive-like activity. The aim of the present study was to examine (i) whether caffeic acid, a major metabolite of rosmarinic acid, also has antidepressive-like activity, and (ii) whether these substances inhibit either the uptake of monoamines to synaptosomes or mitochondrial monoamine oxidase activity. Rosmarinic acid (2 mg/kg, i.p.) and caffeic acid (4 mg/kg, i.p.) each significantly reduced the duration of immobility in the forced swimming test in mice. In contrast, neither substance, at doses that produced a significant reduction in the immobile response in the forced swimming test, affected spontaneous motor activity. These results indicate that, like rosmarinic acid, caffeic acid also possesses antidepressive-like activity. In neuropharmacological studies, neither rosmarinic acid (10 x (-9)-10 x (-3) M) nor caffeic acid (10 x (-9)-10 x (-3) M) affected either the uptake of monoamines to synaptosomes or mitochondrial monoamine oxidase activity in the mouse brain. These results suggest that both caffeic acid and rosmarinic acid may produce antidepressive-like activity via some mechanism(s) other than the inhibition of monoamine transporters and monoamine oxidase.     

Preventive and therapeutic effects of caffeic acid against inflammatory injury in striatum of MPTP-treated mice

Preventive or therapeutic effects of caffeic acid in brain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated mice against inflammatory injury were examined. Caffeic acid at 0.5, 1 or 2% was supplied either pre-intake or post-intake for 4 weeks. Brain caffeic acid content was increased by caffeic acid pre-intake at 1 and 2%, and post-intake at 2% (P < 0.05). MPTP treatment enhanced the release of interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, IL-4 and IL-10 (P < 0.05). Pre-intake of caffeic acid decreased the production of test cytokines (P < 0.05); however, post-intake only at 2% reduced the level of IL-1beta, IL-6 and TNF-alpha (P < 0.05). MPTP treatment up-regulated mRNA expression of inducible nitric oxide synthase (iNOS), neuronal NOS, cyclooxygenase (COX)-2, glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1, and increased production of nitric oxide (NO) and prostaglandin E? (PGE?) (P < 0.05). Caffeic acid pre-intake at test doses and post-intake at 2% declined the expression of iNOS, COX-2 and GFAP; and lowered the production of NO and PGE? (P < 0.05). MPTP treatment suppressed mRNA expression of brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor and tyrosine hydroxylase (TH), and lowered dopamine level (P < 0.05). Caffeic acid pre-intake retained the expression of these factors, maintained TH activity and protein production, and dopamine synthesis (P < 0.05). These results suggest that caffeic acid is a potent neuroprotective agent against the development of Parkinson's disease.     

Plausible anti-inflammatory mechanism of resveratrol and caffeic acid against chronic stress-induced insulin resistance in mice

Stress is associated with many diseases and dysfunctions, such as depression, cardiovascular alterations, immunological function disorder, inflammation, obesity, and insulin resistance. Stress-induced inflammation is associated with the genesis of insulin resistance. Stress activates hypothalamic pituitary adrenal axis, Renin Angiotensin System pathway, and sympatho-adrenal system, all of which are involved in the production of cytokines, causing the negative downregulation of insulin signaling either by phosphorylating serine residues of IRS or by inhibiting the activity of Akt leading to insulin resistance. In this study, male LACA mice (20–30 g) were subjected to 2 h of chronic restraint stress daily for 30 days at variable time. Resveratrol, caffeic acid, glibenclamide, and their combinations were administered 45 min prior to restraint stress daily for 30 days and their anti-inflammatory effect was examined on CRS-induced behavioral, biochemical, and metabolic alterations. Induction of stress in mice was evident by increased corticosterone and decreased bodyweight. Chronic restraint stress for 30 days developed insulin resistance characterized by hyperglycemia, hyperinsulinemia, increased glycosylated haemoglobin (HbA1c), and homeostasis model assessment of insulin resistance index, hyperlipidemia, increased inflammatory cytokines, and TNF-α. Treatment with resveratrol, caffeic acid, and their combinations has attenuated stress-induced insulin resistance by reducing inflammation.     

Preventive effect of Metformin against N-nitrosodiethylamine-initiated hepatocellular carcinoma in rats

Effect of Metformin in chemically induced hepatocarcinogenesis was assessed in Wistar rats. Intraperitoneal administration of chemical carcinogen diethyl nitrosamine (DENA) (200 mg/kg) in single dose elevated the levels of serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), total cholesterol (TC), triglycerides (TG) and reduced high density lipoproteins (HDL), total proteins (TPR) and blood glucose level in tested animals. Histopathological examinations of the liver tissue showed marked carcinogenicity of the chemical carcinogen. Food and water intake, animal weights and serum albumin (ALB) were also assessed. The animals exposed to DENA showed a significant decrease in the body weights and, there were no significant alterations found in the total bilirubin (TBR) levels and gamma-glutamyltranspeptidase (GGTP), whereas the decreased levels of serum ALB were maintained by Metformin treatment. The elevated levels of serum SGOT, SGPT, ALP, AFP, TC and TG were restored by administration of Metformin in reduced dose (125 mg/kg) daily for 16 weeks p.o. Physiological and biochemical analysis showed the beneficial effects of Metformin in the animals exposed to DENA.     

The protective effect of caffeic acid phenethyl ester against cyclosporine A-induced cardiotoxicity in rats

Cyclosporine A (CsA) is the immunosuppressor, which is most frequently used in transplant surgery and in the treatment of autoimmune diseases. Oxidative stress has been considered as one of the possible mechanisms of CsA-induced cardiotoxicity. The present investigation examines the ability of caffeic acid phenethyl ester (CAPE), which is an active component of propolis extracts, as a natural antioxidant to protect against CsA-induced oxidative stress and cardiotoxicity. CsA cardiotoxicity was induced by subcutaneous injection of CsA at a dose of 15 mg/kg/body weight daily for 21 days in rats. Cardiotoxicity was evaluated by morphological and biochemical studies. CsA treated rats showed degenerative changes with cardiac fibrosis localized around the fibers. These latters were disorganised and the network was disappeared. The ROS production was increased whereas cytochrome-c-oxidase decreased. The expression and levels of matrix metalloproteinase 2 (MMP2) were increased whereas those of its inhibitor were downregulated. CAPE subcutaneous administration (15 micromol/kg/day) improved cardiac cytoarchitecture, decreased the levels and the expression of MMP2, and increased those of TIMP2 proteins. Moreover, it increased cytochrome-c-oxidase activity and decreased ROS production. These results suggest that CAPE could have protective effect against CsA-induced cardiotoxicity.