四种天然化合物抑制肿瘤血管生成及沙棘总黄酮降血压作用的研究
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摘要
1.四种天然化合物抑制肿瘤血管生成和肿瘤生长的机理研究
肿瘤血管生成(Tumor angiogenesis)在肿瘤生长和转移中发挥关键作用,是目前崭新的、有潜力的抗肿瘤治疗靶点。如何筛选出有效的、安全的、分子基础明确的肿瘤血管生成抑制剂是药物开发面临的巨大挑战,也是肿瘤治疗领域中的重大难题。目前国际临床上使用的血管生成抑制剂多为抗体或可溶性肽,其合成和纯化费用昂贵,应用范围狭窄。因此,寻找新型抗肿瘤血管生成药物,特别是从具有抗癌活性的传统药用植物中寻找,已成为癌症研究的新思路和新热点。
开发肿瘤血管生成抑制剂的首要标准即要明确待测药物的信号分子靶点。由于肿瘤血管生成发生和发展过程中所参与的信号途径错综复杂,且交叉重叠,因而,阐明抗血管生成药物的作用机制是现代药物开发和创新的关键点和难点。本研究第一篇内容根据该领域目前研究所确定的内皮细胞信号通路,筛选出4种抗肿瘤血管生成植物单体化合物,包括藤黄双黄酮(Morelloflavone)、11-羰基-β-乙酰乳香酸(Acetyl-11-keto-β-boswellic acid,AKBA)、雷公藤红素(Celastrol)和1'-乙酰氧基胡椒酚乙酸(1′-acetoxychavicol acetates,ACA)。通过体外细胞、离体组织和体内动物模型三个研究层次,论文首次证实了上述天然化合物抗肿瘤血管生成活性及其分子基础。在体外细胞水平上,利用四甲基偶氮唑蓝(MTT)试验、流式细胞术和细胞凋亡蛋白检测技术,研究了植物单体化合物对人脐静脉内皮细胞(HUVECs)和人前列腺癌细胞(PC-3)增殖和生长的抑制作用;利用愈合迁移试验、跨膜迁移试验和小管状结构形成试验,研究了单体化合物对内皮细胞迁移和分化功能的影响:在离体组织水平,利用大鼠主动脉血管环试验,研究了单体化合物对毛细血管出芽的抑制作用;在体内动物水平,利用基质凝胶植入试验、荷前列腺肿瘤裸鼠模型,研究了单体化合物对肿瘤血管生成和肿瘤生长的抑制作用。在药物分子靶点研究部分,利用蛋白印迹技术(Western blotting)、Pull-down试验和蛋白激酶测定试验,探究了单体化合物对HUVECs和PC-3细胞信号途径的调控作用。下面依次阐述藤黄双黄酮、11-羰基-β-乙酰乳香酸、雷公藤红素和1'-乙酰氧基胡椒酚乙酸这4种天然化合物的抗肿瘤血管生成特性。
藤黄双黄酮提取于传统药物植物藤黄科(Guttiferae)瓜哇凤果(Garciniadulcis),该化合物是否具有抗肿瘤活性未见报道。本研究发现,藤黄双黄酮可剂量依赖性地抑制HUVECs中胞外信号调节激酶(Raf/MEK/ERK)通路的活化,并能调控小G蛋白(Rho GTPases)活力(降低RhoA-GTPase和Rac1-GTPase活力,对Cdc42-GTPase无影响),从而剂量依赖性地降低内皮细胞增殖和迁移。离体大鼠主动脉环试验和基质凝胶植入试验结果显示,藤黄双黄酮可有效抑制毛细血管出芽和功能性、渗透性血管形成。用剂量为8mg/kg·d的藤黄双黄酮治疗荷人前列腺肿瘤(PC-3)裸鼠15d,在不影响荷瘤裸鼠正常体重的情况下,其可显著降低实体肿瘤大小和重量。以上结果揭示藤黄双黄酮具有抗肿瘤生长这一崭新生物学功能。
11-羰基-β-乙酰乳香酸(AKBA)提取于印度传统草药Boswellia serrata。蛋白免疫印迹和体外激酶研究结果显示11-羰基-β-乙酰乳香酸可显著抑制内皮生长因子2型受体(VEGFR2,KDR/Flk-1)激酶活力,IC_(50)为1.68μmol/L。11-羰基-β-乙酰乳香酸通过特异性阻断VEGF/VEGF receptor信号通路介导的血管生成效应,浓度依赖性的抑制内皮细胞中调节存活、迁移和周期的各类蛋白分子,如Src、FAK、AKT、ERK、mTOR和S6K激酶等。在离体大鼠主动脉环试验和基质凝胶植入试验中,AKBA可有效抑制毛细血管分支密度和功能性血管形成。使用剂量为10mg/kg·d的AKBA每天皮下治疗荷PC-3裸鼠模型30d,该化合物可显著降低实体肿瘤体积和重量。血管特异性免疫组化结果证明,11-羰基-β-乙酰乳香酸抑制肿瘤生长的效应与降低肿瘤血管生成紧密相关。以上结果证实11-羰基-β-乙酰乳香酸是一种有效的肿瘤血管生成抑制剂。
雷公藤(Trypterygium wilfordii Hook F.)作为传统中药,具有多种抗癌活性,然而靶向机理并不透彻。本研究发现,雷公藤活性成分雷公藤红素(又称南蛇藤素,Celastrol)在剂量为2mg/kg·d下治疗荷PC-3裸鼠16d,可显著降低实体肿瘤体积和重量,且对荷瘤鼠正常体重无明显影响。离体大鼠主动脉环试验和基质凝胶植入试验结果显示,雷公藤红素可有效抑制毛细血管分支数目和功能性血管形成。进一步的分子机理研究发现,雷公藤红素可一致性地、剂量依赖性地降低HUVECs和PC-3中AKT/mTOR/S6K信号通路的活化。以上结果提示,AKT/mTOR/S6K信号通路是雷公藤红素抑制肿瘤血管生成和肿瘤生长的新靶点。
提取于姜科(Zingiberaceae)山姜属植物红豆蔻(Alpinia galanga Willd.)的根茎中的小分子天然化合物1'-乙酰氧基胡椒酚乙酸(ACA)可浓度依赖性和时间依赖性的降低HUVECs中Src家族激酶/黏着斑激酶(FAK)激酶磷酸化,且可显著降低Cdc42-GTPase和Rac1-GTPase活力,从而有效调控内皮细胞的迁移和增殖。离体大鼠主动脉环试验和基质凝胶植入模型结果证实,ACA可抑制毛细血管分支数目和功能性血管形成。使用剂量为6mg/kg·d的ACA连续皮下给药治疗荷PC-3裸鼠20d,可显著降低实体肿瘤体积和重量,且对荷瘤裸鼠正常体重无明显影响。血管特异性免疫组化结果提示,ACA抑制肿瘤生长的效应与降低血管生成密切相关。上述结果证明,1'-乙酰氧基胡椒酚乙酸通过靶向Src/FAK复合体和小G蛋白信号途径,抑制肿瘤血管生成和肿瘤生长。
2.沙棘籽渣总黄酮的降血压研究
沙棘黄酮是沙棘(Hippophae rhamnoides L.)的有效活性成分,具有广泛的药理学功能。然而,沙棘黄酮对心血管系统的治疗作用及机制探讨颇有局限。沙棘籽渣是初级利用后的工业弃物,为实现资源深度开发和深度利用,明确总黄酮类化合物对血压的保护作用,本文利用两种高血压动物模型:胰岛素抵抗合并高血压大鼠模型(IRH)和自发性高血压大鼠模型(SHR),研究了沙棘籽渣总黄酮(TFH-SR)的降压效用和机理。
本文采用高蔗糖饲料压迫未成年Sprague Dawley(SD)大鼠,通过生化指标检测和电镜观察,比较了大鼠尾部静脉收缩压(SBP)、空腹血清胰岛素(FPI)、血脂代谢(TG、FFA、TC和HDL-C)、肾脏功能以及内皮结构功能变化,成功建立了IRH大鼠模型。应用梯度剂量的沙棘总黄酮(50mg/kg·d、100 mg/kg·d和150mg/kg·d)治疗模型鼠8周后,高蔗糖餐引发的轻度高血压、高胰岛素血症、血脂代谢紊乱以及血管紧张Ⅱ(AngiotensinⅡ)含量增加,均可以被沙棘总黄酮纠正或改善,其有效剂量为150mg/kg·d。该结果提示,沙棘黄酮可能通过调控胰岛素和血管紧张素这两大循环代谢系统,对胰岛素抵抗引发的心血管疾病有良好的预防或治疗功能。
为了进一步证实沙棘总黄酮的降压作用,本研究采用剂量为100mg/kg·d的沙棘总黄酮灌喂自发性高血压模型鼠。通过检测大鼠SBP、循环和组织血管紧张素Ⅱ水平以及利用免疫组化对大鼠心肌和主动脉血管中血管紧张Ⅱ1型受体(AT_1R)蛋白半定量分析,发现沙棘总黄酮能有效降低SHR血压、血管紧张素Ⅱ和AT_1R蛋白表达水平,提示沙棘总黄酮能够抑制组织血管紧张素转换酶活力,有效控制血压以及保护靶器官。
1.Four Natural Compounds Suppress Tumor Angiogenesis and Tumor Growth
Tumor angiogenesis is the hallmark of tumor growth and tumor metastasis,and it has been a novel and potential target for tumor therapy and drug development.How to select angiogenesis inhibitors which are effective,safe,affordable and with clear molecular basis is a great challenge to modern drug discovery,and also it is a key problem in caner therapy.Recently,most of anti-angiogenic reagents used in clinical are antibodies or soluble peptides,which can not successfully inhibit tumor growth. Therefore,identifying novel tumor angiogenesis inhibitors,especially from traditional herb medicine,has become a promising topic and new direction.
Making clear of underlying molecular targets of certain drugs is the primary criterion to exploit angiogenesis inhibitors.Because the signaling pathways involved in tumor angiogenesis are complex and interactional,it is difficult to identify their detailed mechanism.Based on the well-known endothelial cell signaling pathways, we selected four angiogenesis inhibitors(Morelloflavone,acetyl-11-keto-β-boswellic acid,Celastrol and l'-acetoxychavicol acetates) from natural compounds and reported their underlying mechanisms for the first time.Through working on different platforms that are in vitro,ex vivo and in vivo models,we systematically investigated the biological activities of compounds on tumor angiogenesis.In in vitro models,we evaluated the anti-proliferative effect of compounds on primarily cultured human umbilical vascular endothelial cells(HUVECs) and human prostate cancer cells(PC-3) through MTT assay,flow cytometry and apoptosis protein detection.And also,we evaluated the inhibitory effects of compounds on biological functions of endothelial cells using wound-healing migration assay,invasion assay and capillary-structure formation assay.In ex vivo model,we carried out rat aortic ring assay to investigate the inhibitory function of indicated compounds on microvessel sprouting.And,further in in vivo mouse models,we used Matrigel plug assay and xenograft human prostate tumor mice to evaluate the inhibitory actions of compounds on infiltrating blood vessel formation and tumor growth.Finally,in molecular and biochemistry study,we used western blotting,pull-down assay and in vitro kinase assay to reveal the underlying mechanism.
Morelloflavone,a biflavonoid extracted from Garcinia dulcis.However,the function and the mechanism of this compound in cancer treatment and tumor angiogenesis have not been elucidated to date.We demonstrated that morelloflavone could inhibit the activation of both RhoA-GTPases and Racl-GTPases,but have little effect on the activation of Cdc42-GTPase.Additionally,morelloflavone inhibited the phosphorylation and activation of Raf/MEK/ERK pathway kinases without affecting VEGFR2 activity,by which morelloflavone inhibits cell proliferation,migration, invasion,and capillary-like tube formation of HUVECs in a dose-dependent manner. Morelloflavone effectively inhibited microvessel sprouting of endothelial cells in the aortic ring assay and the formation of new blood microvessels induced by VEGF in the mouse Matrigel plug assay.Furthermore,Morelloflavone(8mg/kg·d,15d,n=5) could inhibit tumor growth and tumor angiogenesis by PC-3 in xenograft mouse tumor model in vivo,without toxic effect on mice body weight.These findings are the first to reveal the novel functions of Morelloflavone in tumor angiogenesis and its molecular basis for the anticancer action.
VEGF/VEGF receptor signaling plays critical role in angiogenesis.In this study, we also demonstrated that Acetyl-11-keto-β-boswellic acid(AKBA),an active component from an Ayurvedic medicinal plant(Boswellia serrata),could strongly inhibit tumor angiogenesis.Western blot analysis and in vitro kinase assay revealed that AKBA suppressed VEGF-induced phosphorylation of VEGF receptor 2 kinase (KDR/Flk-1) with IC50 of 1.68μmol/L.Specifically,AKBA suppressed the downstream protein kinases of VEGFR2,including Src family kinase,focal adhesion kinase,extracellular signal-related kinase,AKT,mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase(S6K).AKBA significantly inhibited blood vessel formation in the Matrigel plug assay in mice and effectively suppressed microvessel sprouting in rat aortic ring assay ex vivo.Importantly,AKBA inhibited tumor growth in the human prostate tumor xenograft mice treated daily(10 mg/kg, n=5) and the inhibitory effect of AKBA on tumor growth was well-correlated with suppression of angiogenesis.
Understanding molecular basis and target of traditional medicine is critical for modern drug development.Although Celastrol,derived from Trypterygium wilfordii Hook F.("Thunder of God Vine") of traditional Chinese medicine,could potentiate apoptosis in many kinds of tumor,its mechanism is still unclear.In this study,when administration with Celastrol(2 mg/kg) in xenograft human prostate cancer mice (n=5),we found Celastrol effectively suppressed the volume and the weight of solid tumors.In angiogenesis study,we found Celastrol significantly inhibited VEGF-triggered inflating neovessels in the Matrigel plug assay in vivo and microvessel sprouts in a rat aortic ring assay ex vivo.Our western blotting results showed that Celastrol could consistently suppress the phosphorylation of AKT,mTOR and S6K in treated HUVECs and PC-3 cells with a dose-dependent manner.Taken together,these findings suggest that Celastrol targets AKT/mTOR/S6K pathway, leading to effective suppression of tumor angiogenesis and tumor growth.
The complex of Src family kinase and focal adhesion kinaes and small Rho GTPase are key components to regulate cell cytoskeleton,cell migration and vascular permeability.In this study,we found small molecular compound l'-acetoxychavicol acetates(ACA),extracted from Alpinia galangal,could effectively inhibit the activation of Src and FAK in a concentration-dependent and a time-dependent in HUVECs.Additionally,the activities of small Rho GTPase,especially Cdc42-GTPase and Racl-GTPase,were suppressed by ACA.Through the above molecular mechanisms,ACA could regulate endothelial cell migration,proliferation and survival. Furthermore,microvessel sprouting of endothelial cells in the aortic ring assay and the formation of new blood microvessels induced by VEGF in the mouse Matrigel plug assay could all be suppressed by ACA's treatment,l'-acetoxychavicol acetates could also inhibit tumor growth in human prostate tumor xenograft mice treated daily (6 mg/kg,n=5) and the immunochemistry analysis reveled that the inhibitory effect on tumor growth was accompanied with suppression of angiogenesis.These findings suggest that l'-acetoxychavicol acetates inhibits tumor angiogenesis through targeting Src/focal adhesion kinaes and small Rho GTPases.
2.Antihypertensive Effect of Total Flavones Extracted from Hippophae rhamnoides L.
The total flavones are active ingredient of Hippophae rhamnoides L.(TFH) and have diverse pharmacological functions.However,its protection on the cardiovascular system is still limited.Seed residues of Hippophae rhamnoides L.are rubbishes of primary manufacture in the industry.In order to deeply explore the resource of Hippophae rhamnoides L.and understand the biological function of TFH on hypertension,we used two kinds of hypertensive rat model to evaluate the cardio-protection of the total flavones extracted from Seed residues of Hippophae rhamnoides L.(TFH-SR).One model is insulin resistant and mild hypertensive rat model(IRH),and the other is spontaneously hypertensive rat model(SHR).
We successfully set up IRH rat model through high-sucrose diet feeding by observation and comparison of systolic blood presser(SBP),serum insulin,lipid metabolism,and kidney and endothelial function.Further,we treated those IRH rats with different doses of TFH-SR(50mg/kg·d,100 mg/kg·d and 150mg/kg·d) for 8 weeks.The results showed that hypertension,hyperinsulinemia,dyslipidemia,and activated angiotensinⅡprovoked by the high sucrose diet all could be ameliorated or modulated by TFH-SR,and the effective dose is 150mg/kg·d.These data suggests that the total flavones might prove useful in the treatment and/or prevention of insulin resistance in non-diabetic state with cardiovascular disease by decreasing insulin resistance and blocking angiotensinⅡpathway.
To further examine and confirm the antihypertensive action of TFH-SR,we treated SHR with TFH-SR at a dose of 100mg/kg·d.Though detection of SBP, circulatory and local angiotensinⅡlevel,and semi-analysis of the expression level of angiotensinⅡtype 1 receptor(AT_1R) using immunochemistry,we found TFH-SR could effectively decrease SBP,the formation of angiotensinⅡand the expression of AT_1R.These results indicate that TFH-SR could decrease blood pressure and protects target organs through inhibiting angiotensin converting enzyme activity and down-regulating the expression of AT_1R in SHR.
肿瘤血管生成(Tumor angiogenesis)在肿瘤生长和转移中发挥关键作用,是目前崭新的、有潜力的抗肿瘤治疗靶点。如何筛选出有效的、安全的、分子基础明确的肿瘤血管生成抑制剂是药物开发面临的巨大挑战,也是肿瘤治疗领域中的重大难题。目前国际临床上使用的血管生成抑制剂多为抗体或可溶性肽,其合成和纯化费用昂贵,应用范围狭窄。因此,寻找新型抗肿瘤血管生成药物,特别是从具有抗癌活性的传统药用植物中寻找,已成为癌症研究的新思路和新热点。
开发肿瘤血管生成抑制剂的首要标准即要明确待测药物的信号分子靶点。由于肿瘤血管生成发生和发展过程中所参与的信号途径错综复杂,且交叉重叠,因而,阐明抗血管生成药物的作用机制是现代药物开发和创新的关键点和难点。本研究第一篇内容根据该领域目前研究所确定的内皮细胞信号通路,筛选出4种抗肿瘤血管生成植物单体化合物,包括藤黄双黄酮(Morelloflavone)、11-羰基-β-乙酰乳香酸(Acetyl-11-keto-β-boswellic acid,AKBA)、雷公藤红素(Celastrol)和1'-乙酰氧基胡椒酚乙酸(1′-acetoxychavicol acetates,ACA)。通过体外细胞、离体组织和体内动物模型三个研究层次,论文首次证实了上述天然化合物抗肿瘤血管生成活性及其分子基础。在体外细胞水平上,利用四甲基偶氮唑蓝(MTT)试验、流式细胞术和细胞凋亡蛋白检测技术,研究了植物单体化合物对人脐静脉内皮细胞(HUVECs)和人前列腺癌细胞(PC-3)增殖和生长的抑制作用;利用愈合迁移试验、跨膜迁移试验和小管状结构形成试验,研究了单体化合物对内皮细胞迁移和分化功能的影响:在离体组织水平,利用大鼠主动脉血管环试验,研究了单体化合物对毛细血管出芽的抑制作用;在体内动物水平,利用基质凝胶植入试验、荷前列腺肿瘤裸鼠模型,研究了单体化合物对肿瘤血管生成和肿瘤生长的抑制作用。在药物分子靶点研究部分,利用蛋白印迹技术(Western blotting)、Pull-down试验和蛋白激酶测定试验,探究了单体化合物对HUVECs和PC-3细胞信号途径的调控作用。下面依次阐述藤黄双黄酮、11-羰基-β-乙酰乳香酸、雷公藤红素和1'-乙酰氧基胡椒酚乙酸这4种天然化合物的抗肿瘤血管生成特性。
藤黄双黄酮提取于传统药物植物藤黄科(Guttiferae)瓜哇凤果(Garciniadulcis),该化合物是否具有抗肿瘤活性未见报道。本研究发现,藤黄双黄酮可剂量依赖性地抑制HUVECs中胞外信号调节激酶(Raf/MEK/ERK)通路的活化,并能调控小G蛋白(Rho GTPases)活力(降低RhoA-GTPase和Rac1-GTPase活力,对Cdc42-GTPase无影响),从而剂量依赖性地降低内皮细胞增殖和迁移。离体大鼠主动脉环试验和基质凝胶植入试验结果显示,藤黄双黄酮可有效抑制毛细血管出芽和功能性、渗透性血管形成。用剂量为8mg/kg·d的藤黄双黄酮治疗荷人前列腺肿瘤(PC-3)裸鼠15d,在不影响荷瘤裸鼠正常体重的情况下,其可显著降低实体肿瘤大小和重量。以上结果揭示藤黄双黄酮具有抗肿瘤生长这一崭新生物学功能。
11-羰基-β-乙酰乳香酸(AKBA)提取于印度传统草药Boswellia serrata。蛋白免疫印迹和体外激酶研究结果显示11-羰基-β-乙酰乳香酸可显著抑制内皮生长因子2型受体(VEGFR2,KDR/Flk-1)激酶活力,IC_(50)为1.68μmol/L。11-羰基-β-乙酰乳香酸通过特异性阻断VEGF/VEGF receptor信号通路介导的血管生成效应,浓度依赖性的抑制内皮细胞中调节存活、迁移和周期的各类蛋白分子,如Src、FAK、AKT、ERK、mTOR和S6K激酶等。在离体大鼠主动脉环试验和基质凝胶植入试验中,AKBA可有效抑制毛细血管分支密度和功能性血管形成。使用剂量为10mg/kg·d的AKBA每天皮下治疗荷PC-3裸鼠模型30d,该化合物可显著降低实体肿瘤体积和重量。血管特异性免疫组化结果证明,11-羰基-β-乙酰乳香酸抑制肿瘤生长的效应与降低肿瘤血管生成紧密相关。以上结果证实11-羰基-β-乙酰乳香酸是一种有效的肿瘤血管生成抑制剂。
雷公藤(Trypterygium wilfordii Hook F.)作为传统中药,具有多种抗癌活性,然而靶向机理并不透彻。本研究发现,雷公藤活性成分雷公藤红素(又称南蛇藤素,Celastrol)在剂量为2mg/kg·d下治疗荷PC-3裸鼠16d,可显著降低实体肿瘤体积和重量,且对荷瘤鼠正常体重无明显影响。离体大鼠主动脉环试验和基质凝胶植入试验结果显示,雷公藤红素可有效抑制毛细血管分支数目和功能性血管形成。进一步的分子机理研究发现,雷公藤红素可一致性地、剂量依赖性地降低HUVECs和PC-3中AKT/mTOR/S6K信号通路的活化。以上结果提示,AKT/mTOR/S6K信号通路是雷公藤红素抑制肿瘤血管生成和肿瘤生长的新靶点。
提取于姜科(Zingiberaceae)山姜属植物红豆蔻(Alpinia galanga Willd.)的根茎中的小分子天然化合物1'-乙酰氧基胡椒酚乙酸(ACA)可浓度依赖性和时间依赖性的降低HUVECs中Src家族激酶/黏着斑激酶(FAK)激酶磷酸化,且可显著降低Cdc42-GTPase和Rac1-GTPase活力,从而有效调控内皮细胞的迁移和增殖。离体大鼠主动脉环试验和基质凝胶植入模型结果证实,ACA可抑制毛细血管分支数目和功能性血管形成。使用剂量为6mg/kg·d的ACA连续皮下给药治疗荷PC-3裸鼠20d,可显著降低实体肿瘤体积和重量,且对荷瘤裸鼠正常体重无明显影响。血管特异性免疫组化结果提示,ACA抑制肿瘤生长的效应与降低血管生成密切相关。上述结果证明,1'-乙酰氧基胡椒酚乙酸通过靶向Src/FAK复合体和小G蛋白信号途径,抑制肿瘤血管生成和肿瘤生长。
2.沙棘籽渣总黄酮的降血压研究
沙棘黄酮是沙棘(Hippophae rhamnoides L.)的有效活性成分,具有广泛的药理学功能。然而,沙棘黄酮对心血管系统的治疗作用及机制探讨颇有局限。沙棘籽渣是初级利用后的工业弃物,为实现资源深度开发和深度利用,明确总黄酮类化合物对血压的保护作用,本文利用两种高血压动物模型:胰岛素抵抗合并高血压大鼠模型(IRH)和自发性高血压大鼠模型(SHR),研究了沙棘籽渣总黄酮(TFH-SR)的降压效用和机理。
本文采用高蔗糖饲料压迫未成年Sprague Dawley(SD)大鼠,通过生化指标检测和电镜观察,比较了大鼠尾部静脉收缩压(SBP)、空腹血清胰岛素(FPI)、血脂代谢(TG、FFA、TC和HDL-C)、肾脏功能以及内皮结构功能变化,成功建立了IRH大鼠模型。应用梯度剂量的沙棘总黄酮(50mg/kg·d、100 mg/kg·d和150mg/kg·d)治疗模型鼠8周后,高蔗糖餐引发的轻度高血压、高胰岛素血症、血脂代谢紊乱以及血管紧张Ⅱ(AngiotensinⅡ)含量增加,均可以被沙棘总黄酮纠正或改善,其有效剂量为150mg/kg·d。该结果提示,沙棘黄酮可能通过调控胰岛素和血管紧张素这两大循环代谢系统,对胰岛素抵抗引发的心血管疾病有良好的预防或治疗功能。
为了进一步证实沙棘总黄酮的降压作用,本研究采用剂量为100mg/kg·d的沙棘总黄酮灌喂自发性高血压模型鼠。通过检测大鼠SBP、循环和组织血管紧张素Ⅱ水平以及利用免疫组化对大鼠心肌和主动脉血管中血管紧张Ⅱ1型受体(AT_1R)蛋白半定量分析,发现沙棘总黄酮能有效降低SHR血压、血管紧张素Ⅱ和AT_1R蛋白表达水平,提示沙棘总黄酮能够抑制组织血管紧张素转换酶活力,有效控制血压以及保护靶器官。
1.Four Natural Compounds Suppress Tumor Angiogenesis and Tumor Growth
Tumor angiogenesis is the hallmark of tumor growth and tumor metastasis,and it has been a novel and potential target for tumor therapy and drug development.How to select angiogenesis inhibitors which are effective,safe,affordable and with clear molecular basis is a great challenge to modern drug discovery,and also it is a key problem in caner therapy.Recently,most of anti-angiogenic reagents used in clinical are antibodies or soluble peptides,which can not successfully inhibit tumor growth. Therefore,identifying novel tumor angiogenesis inhibitors,especially from traditional herb medicine,has become a promising topic and new direction.
Making clear of underlying molecular targets of certain drugs is the primary criterion to exploit angiogenesis inhibitors.Because the signaling pathways involved in tumor angiogenesis are complex and interactional,it is difficult to identify their detailed mechanism.Based on the well-known endothelial cell signaling pathways, we selected four angiogenesis inhibitors(Morelloflavone,acetyl-11-keto-β-boswellic acid,Celastrol and l'-acetoxychavicol acetates) from natural compounds and reported their underlying mechanisms for the first time.Through working on different platforms that are in vitro,ex vivo and in vivo models,we systematically investigated the biological activities of compounds on tumor angiogenesis.In in vitro models,we evaluated the anti-proliferative effect of compounds on primarily cultured human umbilical vascular endothelial cells(HUVECs) and human prostate cancer cells(PC-3) through MTT assay,flow cytometry and apoptosis protein detection.And also,we evaluated the inhibitory effects of compounds on biological functions of endothelial cells using wound-healing migration assay,invasion assay and capillary-structure formation assay.In ex vivo model,we carried out rat aortic ring assay to investigate the inhibitory function of indicated compounds on microvessel sprouting.And,further in in vivo mouse models,we used Matrigel plug assay and xenograft human prostate tumor mice to evaluate the inhibitory actions of compounds on infiltrating blood vessel formation and tumor growth.Finally,in molecular and biochemistry study,we used western blotting,pull-down assay and in vitro kinase assay to reveal the underlying mechanism.
Morelloflavone,a biflavonoid extracted from Garcinia dulcis.However,the function and the mechanism of this compound in cancer treatment and tumor angiogenesis have not been elucidated to date.We demonstrated that morelloflavone could inhibit the activation of both RhoA-GTPases and Racl-GTPases,but have little effect on the activation of Cdc42-GTPase.Additionally,morelloflavone inhibited the phosphorylation and activation of Raf/MEK/ERK pathway kinases without affecting VEGFR2 activity,by which morelloflavone inhibits cell proliferation,migration, invasion,and capillary-like tube formation of HUVECs in a dose-dependent manner. Morelloflavone effectively inhibited microvessel sprouting of endothelial cells in the aortic ring assay and the formation of new blood microvessels induced by VEGF in the mouse Matrigel plug assay.Furthermore,Morelloflavone(8mg/kg·d,15d,n=5) could inhibit tumor growth and tumor angiogenesis by PC-3 in xenograft mouse tumor model in vivo,without toxic effect on mice body weight.These findings are the first to reveal the novel functions of Morelloflavone in tumor angiogenesis and its molecular basis for the anticancer action.
VEGF/VEGF receptor signaling plays critical role in angiogenesis.In this study, we also demonstrated that Acetyl-11-keto-β-boswellic acid(AKBA),an active component from an Ayurvedic medicinal plant(Boswellia serrata),could strongly inhibit tumor angiogenesis.Western blot analysis and in vitro kinase assay revealed that AKBA suppressed VEGF-induced phosphorylation of VEGF receptor 2 kinase (KDR/Flk-1) with IC50 of 1.68μmol/L.Specifically,AKBA suppressed the downstream protein kinases of VEGFR2,including Src family kinase,focal adhesion kinase,extracellular signal-related kinase,AKT,mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase(S6K).AKBA significantly inhibited blood vessel formation in the Matrigel plug assay in mice and effectively suppressed microvessel sprouting in rat aortic ring assay ex vivo.Importantly,AKBA inhibited tumor growth in the human prostate tumor xenograft mice treated daily(10 mg/kg, n=5) and the inhibitory effect of AKBA on tumor growth was well-correlated with suppression of angiogenesis.
Understanding molecular basis and target of traditional medicine is critical for modern drug development.Although Celastrol,derived from Trypterygium wilfordii Hook F.("Thunder of God Vine") of traditional Chinese medicine,could potentiate apoptosis in many kinds of tumor,its mechanism is still unclear.In this study,when administration with Celastrol(2 mg/kg) in xenograft human prostate cancer mice (n=5),we found Celastrol effectively suppressed the volume and the weight of solid tumors.In angiogenesis study,we found Celastrol significantly inhibited VEGF-triggered inflating neovessels in the Matrigel plug assay in vivo and microvessel sprouts in a rat aortic ring assay ex vivo.Our western blotting results showed that Celastrol could consistently suppress the phosphorylation of AKT,mTOR and S6K in treated HUVECs and PC-3 cells with a dose-dependent manner.Taken together,these findings suggest that Celastrol targets AKT/mTOR/S6K pathway, leading to effective suppression of tumor angiogenesis and tumor growth.
The complex of Src family kinase and focal adhesion kinaes and small Rho GTPase are key components to regulate cell cytoskeleton,cell migration and vascular permeability.In this study,we found small molecular compound l'-acetoxychavicol acetates(ACA),extracted from Alpinia galangal,could effectively inhibit the activation of Src and FAK in a concentration-dependent and a time-dependent in HUVECs.Additionally,the activities of small Rho GTPase,especially Cdc42-GTPase and Racl-GTPase,were suppressed by ACA.Through the above molecular mechanisms,ACA could regulate endothelial cell migration,proliferation and survival. Furthermore,microvessel sprouting of endothelial cells in the aortic ring assay and the formation of new blood microvessels induced by VEGF in the mouse Matrigel plug assay could all be suppressed by ACA's treatment,l'-acetoxychavicol acetates could also inhibit tumor growth in human prostate tumor xenograft mice treated daily (6 mg/kg,n=5) and the immunochemistry analysis reveled that the inhibitory effect on tumor growth was accompanied with suppression of angiogenesis.These findings suggest that l'-acetoxychavicol acetates inhibits tumor angiogenesis through targeting Src/focal adhesion kinaes and small Rho GTPases.
2.Antihypertensive Effect of Total Flavones Extracted from Hippophae rhamnoides L.
The total flavones are active ingredient of Hippophae rhamnoides L.(TFH) and have diverse pharmacological functions.However,its protection on the cardiovascular system is still limited.Seed residues of Hippophae rhamnoides L.are rubbishes of primary manufacture in the industry.In order to deeply explore the resource of Hippophae rhamnoides L.and understand the biological function of TFH on hypertension,we used two kinds of hypertensive rat model to evaluate the cardio-protection of the total flavones extracted from Seed residues of Hippophae rhamnoides L.(TFH-SR).One model is insulin resistant and mild hypertensive rat model(IRH),and the other is spontaneously hypertensive rat model(SHR).
We successfully set up IRH rat model through high-sucrose diet feeding by observation and comparison of systolic blood presser(SBP),serum insulin,lipid metabolism,and kidney and endothelial function.Further,we treated those IRH rats with different doses of TFH-SR(50mg/kg·d,100 mg/kg·d and 150mg/kg·d) for 8 weeks.The results showed that hypertension,hyperinsulinemia,dyslipidemia,and activated angiotensinⅡprovoked by the high sucrose diet all could be ameliorated or modulated by TFH-SR,and the effective dose is 150mg/kg·d.These data suggests that the total flavones might prove useful in the treatment and/or prevention of insulin resistance in non-diabetic state with cardiovascular disease by decreasing insulin resistance and blocking angiotensinⅡpathway.
To further examine and confirm the antihypertensive action of TFH-SR,we treated SHR with TFH-SR at a dose of 100mg/kg·d.Though detection of SBP, circulatory and local angiotensinⅡlevel,and semi-analysis of the expression level of angiotensinⅡtype 1 receptor(AT_1R) using immunochemistry,we found TFH-SR could effectively decrease SBP,the formation of angiotensinⅡand the expression of AT_1R.These results indicate that TFH-SR could decrease blood pressure and protects target organs through inhibiting angiotensin converting enzyme activity and down-regulating the expression of AT_1R in SHR.
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