番茄红素纳米分散体抗肿瘤瘤功效及机制初探
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摘要
目的:采用纳米技术制备番茄红素纳米分散体并研究其体内外抗肝肿瘤作用及初步探讨作用机制,为开发纳米级别番茄红素抗肿瘤功能性食品提供理论依据。
方法:参照乳化-蒸发工艺,制备番茄红素纳米分散体。采用分光光度法研究番茄红素纳米分散体体外清除活性氧能力。建立小鼠H22肝癌移植瘤模型,结合体内抗氧化实验、病理技术、免疫组化方法研究番茄红素纳米分散体体内抗肿瘤功效及初步探讨机制。体外培养人肝癌HepG2细胞和人肝L-02细胞,结合四甲基偶氮唑盐(MTT)法、生化检测、免疫组化方法等研究番茄红素纳米分散体对人肝癌HepG2细胞细胞增殖的影响及初步探讨机制。
结果:制备的番茄红素纳米分散体Z-均粒径为261nm,水中分散性好。体外抗氧化结果表明番茄红素纳米分散体对活性氧(过氧化氢、羟自由基)具有明显的清除效果,相同浓度下番茄红素纳米分散体的清除率明显高于番茄红素四氢呋喃溶液。荷瘤小鼠抗肿瘤实验结果显示番茄红素纳米分散体对小鼠H22肝癌移植瘤具有显著的体内抗肿瘤作用,1.95、3.9mg·kg-1剂量番茄红素纳米分散体处理后抑瘤率分别为32.37%、54.34%,均比3.9mg·kg-1剂量油溶番茄红素组处理后抑瘤率高;体内抗氧化实验结果表明番茄红素纳米分散体可显著提高荷瘤小鼠血清GSH-Px活性,显著降低血清MDA含量,同时可显著提高小鼠肝组织T-AOC、SOD活性,显著降低肝组织H2O2、MDA含量;病理检测结果表明用药组肿瘤组织周边结缔组织炎细胞浸润;免疫组化结果显示番茄红素纳米分散体处理荷瘤小鼠后,肿瘤细胞PCNA表达水平明显下调。体外细胞培养实验,MTT结果显示番茄红素纳米分散体和空白乳化剂对人肝癌细胞都有相对选择性毒性作用。检测不同制剂作用HepG2细胞24h后细胞上清液LDH活性,结果显示番茄红素纳米分散体和乳化剂通过影响细胞膜通透性,使细胞受损;免疫组化结果显示2μmol/L番茄红素纳米分散体处理细胞24h后PCNA表达明显下降,而乳化剂并不影响PCNA的表达。
结论:番茄红素纳米分散体体内外均具有较强抗肝肿瘤作用,其作用机制可能与提高体内抗氧化能力、降低PCNA表达、直接损伤肿瘤细胞等有关。
Objective: To prepare lycopene nanodispersion and evaluate the anti-hepatoma effect of lycopene nanodispersion in vitro and in vivo and its mechanism.
Methods: Lycopene nanodispersion was prepared by the emulsification-evaporation process. Scavenging effects of lycopene nanodispersion on reactive oxygen species (·OH and H2O2) were investigated by spectrophotometric methods in vitro. Mice transplanted with H22 liver tumor were established and antitumor effect of lycopene naonodispersion in vivo was analyzed. Study of antioxidant activity, pathological technology and immunohistochemical technology were utilized to detect the antitumor mechanism in vivo. The MTT assay was used to examine the proliferation arrest of carcinoma cell line (HepG2) and normal cell line (L-02) in vitro. And cell morphological observation, biochemical test and immunohistochemical technology were used to detect the antitumor mechanism in vitro.
Results: Lycopene nanodispersion was obtained and the particle size was 261nm. The dispersive property was effectively improved. Lycopene nanodispersion had strong scavenging effects in both radical systems and the anti-radical activities. At the same concentration, the scavenging capabilities of lycopene nanodispersion were stronger than the lycopene dissolved in THF. Mice transplanted with H22 liver tumor were treated with 1.95 mg·kg-1and 3.9 mg·kg-1 lycopene nanodispersion for 10 days respectively, the tumor growth inhibition rate were 32.37% and 54.34%, which were higher than the inhibiton rate caused by 3.9 mg·kg-1 unprocessed lycopene. Lycopene nanodispersion could significantly increase the activities of GSH-Px, and decrese the content of MDA of blood serum of mice. It also could significantly increase the activities of T-AOC and SOD activity, and the reduction of the content of MDA and H2O2 of liver of mice. The results of pathological technology demonstrated that inflammatory cells infiltrated in the surrounding connective tissue of tumors. Lycopene nanodispersion could down-regulate the expression of proliferating cell nuclear antigen (PCNA) in Hepatocarcinoma H22. The MTT assay showed that lycopene nanodispersion had the selective toxicity on HepG2 cells. Tween-20, as emulsifier for lycopene nanodispersion, also had the same selective toxicity. The activities of LDH in HepG2 cells culture supernatant significantly increased after 24h exposure to lycopene nanodispersion and emulsifier, which indicated that they may induce some damages on HepG2 cells membrane. Lycopene nanodispersion could down-regulate the expression of PCNA in HepG2 cells and tween-20 didn’t have the same effect.
Conclusion: Lycopene nanodispersion was able to inhibit potently the gowth of hepatoma in vitro and in vivo. The mechanism may be associated with increase of anti-oxidation activity, down regulation PCNA expression and direct cytotoxicity.
方法:参照乳化-蒸发工艺,制备番茄红素纳米分散体。采用分光光度法研究番茄红素纳米分散体体外清除活性氧能力。建立小鼠H22肝癌移植瘤模型,结合体内抗氧化实验、病理技术、免疫组化方法研究番茄红素纳米分散体体内抗肿瘤功效及初步探讨机制。体外培养人肝癌HepG2细胞和人肝L-02细胞,结合四甲基偶氮唑盐(MTT)法、生化检测、免疫组化方法等研究番茄红素纳米分散体对人肝癌HepG2细胞细胞增殖的影响及初步探讨机制。
结果:制备的番茄红素纳米分散体Z-均粒径为261nm,水中分散性好。体外抗氧化结果表明番茄红素纳米分散体对活性氧(过氧化氢、羟自由基)具有明显的清除效果,相同浓度下番茄红素纳米分散体的清除率明显高于番茄红素四氢呋喃溶液。荷瘤小鼠抗肿瘤实验结果显示番茄红素纳米分散体对小鼠H22肝癌移植瘤具有显著的体内抗肿瘤作用,1.95、3.9mg·kg-1剂量番茄红素纳米分散体处理后抑瘤率分别为32.37%、54.34%,均比3.9mg·kg-1剂量油溶番茄红素组处理后抑瘤率高;体内抗氧化实验结果表明番茄红素纳米分散体可显著提高荷瘤小鼠血清GSH-Px活性,显著降低血清MDA含量,同时可显著提高小鼠肝组织T-AOC、SOD活性,显著降低肝组织H2O2、MDA含量;病理检测结果表明用药组肿瘤组织周边结缔组织炎细胞浸润;免疫组化结果显示番茄红素纳米分散体处理荷瘤小鼠后,肿瘤细胞PCNA表达水平明显下调。体外细胞培养实验,MTT结果显示番茄红素纳米分散体和空白乳化剂对人肝癌细胞都有相对选择性毒性作用。检测不同制剂作用HepG2细胞24h后细胞上清液LDH活性,结果显示番茄红素纳米分散体和乳化剂通过影响细胞膜通透性,使细胞受损;免疫组化结果显示2μmol/L番茄红素纳米分散体处理细胞24h后PCNA表达明显下降,而乳化剂并不影响PCNA的表达。
结论:番茄红素纳米分散体体内外均具有较强抗肝肿瘤作用,其作用机制可能与提高体内抗氧化能力、降低PCNA表达、直接损伤肿瘤细胞等有关。
Objective: To prepare lycopene nanodispersion and evaluate the anti-hepatoma effect of lycopene nanodispersion in vitro and in vivo and its mechanism.
Methods: Lycopene nanodispersion was prepared by the emulsification-evaporation process. Scavenging effects of lycopene nanodispersion on reactive oxygen species (·OH and H2O2) were investigated by spectrophotometric methods in vitro. Mice transplanted with H22 liver tumor were established and antitumor effect of lycopene naonodispersion in vivo was analyzed. Study of antioxidant activity, pathological technology and immunohistochemical technology were utilized to detect the antitumor mechanism in vivo. The MTT assay was used to examine the proliferation arrest of carcinoma cell line (HepG2) and normal cell line (L-02) in vitro. And cell morphological observation, biochemical test and immunohistochemical technology were used to detect the antitumor mechanism in vitro.
Results: Lycopene nanodispersion was obtained and the particle size was 261nm. The dispersive property was effectively improved. Lycopene nanodispersion had strong scavenging effects in both radical systems and the anti-radical activities. At the same concentration, the scavenging capabilities of lycopene nanodispersion were stronger than the lycopene dissolved in THF. Mice transplanted with H22 liver tumor were treated with 1.95 mg·kg-1and 3.9 mg·kg-1 lycopene nanodispersion for 10 days respectively, the tumor growth inhibition rate were 32.37% and 54.34%, which were higher than the inhibiton rate caused by 3.9 mg·kg-1 unprocessed lycopene. Lycopene nanodispersion could significantly increase the activities of GSH-Px, and decrese the content of MDA of blood serum of mice. It also could significantly increase the activities of T-AOC and SOD activity, and the reduction of the content of MDA and H2O2 of liver of mice. The results of pathological technology demonstrated that inflammatory cells infiltrated in the surrounding connective tissue of tumors. Lycopene nanodispersion could down-regulate the expression of proliferating cell nuclear antigen (PCNA) in Hepatocarcinoma H22. The MTT assay showed that lycopene nanodispersion had the selective toxicity on HepG2 cells. Tween-20, as emulsifier for lycopene nanodispersion, also had the same selective toxicity. The activities of LDH in HepG2 cells culture supernatant significantly increased after 24h exposure to lycopene nanodispersion and emulsifier, which indicated that they may induce some damages on HepG2 cells membrane. Lycopene nanodispersion could down-regulate the expression of PCNA in HepG2 cells and tween-20 didn’t have the same effect.
Conclusion: Lycopene nanodispersion was able to inhibit potently the gowth of hepatoma in vitro and in vivo. The mechanism may be associated with increase of anti-oxidation activity, down regulation PCNA expression and direct cytotoxicity.
引文
1.彭涛,刘丽波,马建军.抗肿瘤食品的研究[J].食品研究与开发,2004,25(1):61-64
2.杨玲.功能性食品的研究新进展[J].科技资讯,2007,(10):167
3.魏清,周政涛,王燕燕等.功能食品和天然药物在对抗与衰老相关的慢性疾病中的作用和机制[J].时珍国医国药,2007,18(4):957-960
4.符昌雨.抗肿瘤食品的生理功能[J].食品研究与开发,2007,28(3):180-182
5. Singh P, Goyal GK. Dietary lycopene: its properties and anticarcinogenic effects. Food Science and Technology, 2008, 7(3):255-270
6.熊维全,万群.番茄红素研究进展[J].热带农业科技,2007,30(2):48-52
7.隋海霞,徐海滨,严卫星.番茄红素的抗氧化及抗肿瘤作用[J].中国食品卫生杂志,2003,15(6):544-547
8.李春生.番茄红素的研究概况[J].农产品加工(学刊),2009,160(1):71-74
9. Shahrzad S, Cadenas E, Sevanian A, et al. Impact of water-dispersible beadlets as a vehicle for the delivery of carotenoids to cultured cells. Biofactors, 2002, 16(3-4):83-91
10.李京东,傅善江.番茄红素的保健作用及发展前景[J].中国食物与营养,2005(4):49-51
11.吴翠栓,艾秀丽,邱彤等.番茄红素及其保健功能的研究进展[J].中国新药杂志,2007,16(22):1849
12. Lu QY, Hung JC, Heber D, et al. Inverse associations between plasma lycopene and other carotenoids and prostate cancer. Cancer Epide Bio & Pre, 2001, 10 (7): 749-756
13. Weisburger JH. Lycopene and tomato products in heath promotion. Exp Biol Med, 2002,
227(10): 924-927
14. Gann PH. Intermediate biomarkers of lycopene/tomato effects in high-risk prostatic tissue. J Nutr, 2005, 135 (8): 2065 -2067
15. Maserejian NN, Giovannucci E, Rosner B, et al. Prospective study of vitamins C, E, and A and carotenoids and risk of oral premalignant lesions in men. Int J Cancer, 2006,120 (5):
970–977
16. Tang L, Jin T, Zeng X, et al. Lycopene inhibits the growth of human androgen-independent prostate cancer cells in vitro and in BALB/c nude mice, J Nutr, 2005,135(2):287–290
17.潘洪志,姜秀梅,万丽葵等.番茄红素对小鼠S180肿瘤生长及免疫功能的影响[J].营养学报,2004,26(5):406-407
18.张庆英.番茄红素对食管癌预防效果的实验研究[D]:[硕士学位论文].广州:中山医科大学,2001
19.邱伟芬,江汉湖,汪海峰.番茄红素高压处理后抗乳腺癌细胞增殖的研究[J].营养学报,2005,27(6):506-509
20.彭光华,李忠等.类胡萝卜素对乳腺癌细胞株MDA-MBS-435S中DNA损伤作用的影响[J].食品科学,2003,24(9):125-127
21.李垚,付晶,潘宏志.番茄红素对人胃癌细胞生长的抑制作用[J].中国公共卫生,2006,22(10):1223-1225
22.陈晓,张亚楼,张月明等.番茄红素干预食管细胞系(Eca9706)及表皮生长因子表达的研究[J].安徽医药,2005,9(1):19-20
23.王伟华,韩占江.番茄红素的抗氧化性质及对肝癌小鼠H22的抑制作用的研究[J].安徽农业科学,2006,34(14):3378-3380
24. Amir H, Karas M, Giat J, et al. Lycopene and 1, 25-dihydroxyvitamin-D3 cooperate in the inhibition of cell cycle progression and induction of differentiation in HL-60 leukemic cell. Nutrition and Cancer, 1999, 33(1): 105-112
25. Pastori M, Pfander H, Boscoboinik D, et al. Lycopene in association withα-tocopherol inhibits at physiological concentrations proliferation of prostate carcinoma cells. Biochem Biophys Res Commun, 1998, 250(3): 582-585
26. Boileau TWM, Liao Z, Kim S, et al. Prostate carcinogenesis in N-methyl-N-nitrosourea(NMU)-testosterone-treated rats fed tomato powder, lycopene, or energy-restricted diets. J Natl Cancer Inst, 2003, 95(21): 1578-1586
27.谭新平,王银娜,刘昕.番茄红素与癌[J].天然产物研究与开发,2001,13(4):71-75
28. Saada H N, Azab KS. Role of lycopene in recovery of radiation induced injury to mammalian cellular organelles. Pharmazie, 2001, 56 (3): 239-241
29. Matos HR, Mascio DP, Medeiros MHG.Protective effect of lycopene on lipid peroxidation and oxidative DNA damage in cell culture. Arch Biochem Biophys, 2000, 383(1):56-59
30. Velmurugan B, Bhuvaneswari V, Burra UK, et al. Prevention of N-methyl-N′-nitro-N-nitrosoguanidine and saturated sodium chloride induced gastric carcinogenesis in Wistar rats by lycopene. Eur J Cancer Prev, 2002, 11(1):19-26
31. Cheng H, Chien H, Liao C, et al. Carotenoids suppress proliferating cell nuclear antigen and cyclin D1 expression in oral carcinogenic models. J Nutr Biochem, 2007, 18(10): 667–675
32. Nahum A, Hirsch K, Danillenko M, et al. Lycopene inhibition of cell cycle progression inbreast and endometrial cancer cells is associated with reduction in cyclin D levels and retention of p27Kip1 in the cyclin E-cdk2 complexes. Oncogene, 2001, 20(26): 3428-3436
33. Liu C, Lian F, Smith DE, et al. Lycopene supplementation inhibits lung squamous metaplasia and induces apoptosis via up-regulating insulin-like growth factor-bind-ing protein 3 in cigarette smoke-exposed ferrets. Cancer Res, 2003, 63: 3138-3144
34. Hsin-Chung Chenga, Hsin Chienb, Chia-Hui Liaoc. Carotenoids suppress proliferating cell nuclear antigen and cyclin D1 expression in oral carcinogenic models. J Nutr Bio, 2007, 18: 667–675
35. Huang CS, Liao JW, Hu ML. Lycopene Inhibits Experimental Metastasis of Human Hepatoma SK-Hep-1 Cells in Athymic Nude Mice. Nutr Immuno. 2008, 138(3):538-543
36. Karas M, Amir H, Fishman D, et al. Lycopene interferes with cell cycle progression and insulin-like growth factor I signaling mammary cancer cells. Nutr Cancer, 2000, 36(1): 101-111
37. Mucci L A, Tamimi R, Lagiou P, et al. Are dietary influences on the risk of prostate cancermediated through the insulin-like growth factor system?. BJU Int, 2001, 87(9): 814-820
38. Krutovskikh V, Asamoto M, Takasuka N, et al. Differential dose dependent effects ofα-,β-carotenes and lycopene on gap-junctional intercellular communication in rat liver in vivo. Japan J Cancer Res, 1997, 88(12):1121-1124.
39. Bertram JS, Bortkiewicz H. Dietary carotenoids inhibit neoplastic transformation and modulate gene expression in mouse and human cells. Am J Clin Nutr, 1995, 62(6 Suppl): 1327S-1336S
40. Aust O, Ale-Agha N, Zhang L, et al. Lycopene oxidation product enhances gap junctional communication. Food Chem Toxico, 2003, 41(10): 1399-1407.
41. Huang CS, Fan YE, Lin CY, et al. Lycopene inhibits matrix metalloproteinase-9 expression and down-regulates the binding activity of nuclear factor-kappa B and stimulatory protein-1, J Nutr Biochem, 2007, 18(7): 449–456
42. Huang CS, Shih MK, Chuang CH, et al. Lycopene inhibits cell migration and invasion and upregulates Nm23-H1 in a highly invasive hepatocarcinoma, SK-Hep-1 cells. J Nutr. 2005, 135(9): 2119–2123
43. Chiang HS, Wu WB, Fang JY, et al. Lycopene inhibits PDGF-BB-induced signaling and migration in human dermal fibroblasts through interaction with PDF-BB. Life Sci, 2007, 81(21-22): 1509–1517
44. Hantz HL, Young LF, Martin KR. Physiologically attainable concentrations of lycopene induce mitochondrial apoptosis in LNCaP human prostate cancer cells. Exp Biol Med, 2005, 230(3): 171–179
45. Ivanov N , Cowell S , Brown P, et al. Lycopene differentially induces quiescence and apoptosis in androgen-responsive and -independent prostate cancer cell lines. Clin Nutr, 2007, 26(2): 252–263
46. Salman H, Bergman M, Djaldetti M, et al. Lycopene affects proliferation and apoptosis of four malignant cell lines. Biomed Pharmacother, 2007, 61(6): 366–369
47. Chen L, Stacewicz-Sapuntzakis M, Duncan C, et al. Oxidative DNA damage in prostate cancer patients consuming tomato sauce-based entrees as a whole-food intervention. J Natl Cancer Inst, 2001, 93(24): 1872–1879
48. Nara E, Hayashi H, Kotake M, et al. Acyclic carotenoids and their oxidation mixtures inhibit the growth of HL-60 human promyelocytic leukemia cells. Nutr Cancer, 2001, 39(2): 273-283
49. Ben-Dor A, Steiner M, Gheber L, et al. Carotenoids activate the antioxidant response element transcription system. Mol Cancer Ther, 2005, 4(1): 177–186
50. Goo YA, Li Z, Pajkovic N, et al. Systematic investigation of lycopene effects in LNCaP cells by use of novel large-scale proteomic analysis software. Proteomics Clin Appl, 2007, 1(5): 513–523
51. Tibaduiza EC, Fleet JC, Russell RM, et al. Excentric cleavange products of beta-carotene inhibit estrogen receptor positive and negative breast tumor cell growth in vitro and inhibit activator protein-1-mediated transcriptional activation. J Nutr, 2002, 132(6): 1368~1375
52.龚非力.医学免疫学[M].北京:科学出版社,2004,374
53. Briviba K, Kulling S E, Moseneder J, et al. Effects of supplementing a low-carotenoid diet with a tomato extract for 2 weeks on endogenous levels of DNA single strand breaks and immune functions in healthy nonsmokers and smokers. Carcinogenesis, 2004, 25(12):2373-2378
54. Watzl B, Bub A, Briviba K, et al. Supplementation of a low-carotenoid diet with tomato or carrot juice modulates immune functions in healthy men. Ann Nutr Metab, 2003, 47(6):255-261
55.潘喜华,仲伟鉴,肖萍等.番茄红素调节免疫作用及机制研究[J].上海预防医学杂志,2006,18(6):261-263
55.任亮,李新伟,林海红.番茄红素对氟尿嘧啶治疗小鼠肉瘤S180的影响[J].中华中医药学刊,2007,25(8):1706-1708
56.康红钰,任亮,刘春杰等.番茄红素对环磷酰胺治疗小鼠肉瘤H22的影响[J].郑州大学学报(医学版),2008,43(4):751-753
57.李华佳,辛志红,胡秋辉.食品纳米技术与纳米食品研究进展[J].食品科学,2006,27(9):271-274
58.于霞飞,高学云.纳米超微粉在保健食品中的应用[J].纳米技术产业,2000,(6):35
59.赵秋艳,李汴生.新型铁营养强化剂——超微细元素铁粉[J].食品与发酵工业,2001,27(6):67-69
60.王建辉,吕武兴.纳米氧化锌在动物营养中的应用前景[J].饲料广角,2003,(18):21-23
61.赵成萍,田野.纳米级维生素的研究[J].饲料工业,2006,27(6):62-64.
62.张劲松,高学云,张立德,等.纳米红色元素硒的护肝、抑瘤和免疫调节作用[J].营养学报,2001,23(1):32-35.
63. Huang B, Zhang J, Hou J, et al. Free radicals scavenging efficiency of Nano-Se in vitro. Free Radical Biology and Medicine, 2003, 35(7): 805-813
64. Pison U, Welte T, Giersig M, et al. Nanomedicine for respiratory diseases. European Journal of Pharmacology, 2006, 533(1-3):341-350.
65. Shibata T. Method for producing green tea in microfine powder: The United States of America, US6416803B1 [P]. 2002
66.夏书芹.辅酶Ql0纳米脂质体的研制[D]:[硕士学位论文].无锡:江南大学,2006
67.侯振建,付子林,陈俊生等.蜂胶纳米化技术研究[J].食品科学,2008,29(5):199-200
68.孙勇,李华佳,辛志红等.纳米食品的活性与安全[J].食品科学,2006,27(12):936-939
69.孙莹.番茄红素纳米分散体的制备及稳定性研究[D]:[硕士学位论文].无锡:江南大学,2008
70.王静,刘大川.紫(白)苏叶黄酮类化合物抗氧化性能的研究[J].中国油脂, 2004,29(3):33-36
71.范冠宇,谢虹,吴志刚.水溶性几丁聚糖对羟自由基的清除作用[J].中国公共卫生,2006,22(6):676-677
72.王朝杰.槲皮素对QGY、HepG2细胞系细胞周期影响的实验研究[D]:[硕士学位论文].重庆:重庆医科大学,2002
73.徐辉碧.纳米医药[M].北京:清华大学出版社, 2004,9
74.张连琴.自由基与疾病[J].天津医科大学学报,1997,3(2):85-88
75.方允中,杨胜,伍国耀.自由基、抗氧化剂、营养素与健康的关系[J].营养学报,2003,25(4):337-342
76.李艳红.鹰嘴豆蛋白酶解物的制备及其抗氧化肽的研究[D]:[博士学位论文].无锡:江南大学,2008
77.孙晓萍.天然产物的提取及其抗自由基活性的研究[D]:[硕士学位论文].郑州:郑州大学,2004
78.谷梅,柏志全,肖瑞等.过氧化氢对黑素细胞增殖活性的影响[J].岭南皮肤性病科杂志,2006,13(2):82-83
79. Burdon RH, Gill V. Cellularly generated active oxygen species and Hela cell proliferation. Free Radical Research, 1993, 19(3): 203-213
80.方允中.茶叶抗氧化作用的抗癌机制[J].中国肿瘤,2000,9(1):21-22
81.尹美珍,李世普,韩颖超.羟基磷灰石纳米粒子对肝癌细胞PCNA表达的影响[J].武汉理工大学学报,2007,29(8):58-61
82.任秀华.药用辅料抑制细胞色素P450 3A作用研究[D]:[博士学位论文].武汉:华中科技大学,2008
83.董杰明,吴瑞华,袁昌鲁等.γ-亚麻酸的保健作用[J].卫生研究,2003,32(3):299-301
84.王明衡,白剑英,原福胜.食品添加剂亚硫酸钠对HL-7702肝细胞的毒性作用[J].山西医科大学学报,2008,39(1):21-23
2.杨玲.功能性食品的研究新进展[J].科技资讯,2007,(10):167
3.魏清,周政涛,王燕燕等.功能食品和天然药物在对抗与衰老相关的慢性疾病中的作用和机制[J].时珍国医国药,2007,18(4):957-960
4.符昌雨.抗肿瘤食品的生理功能[J].食品研究与开发,2007,28(3):180-182
5. Singh P, Goyal GK. Dietary lycopene: its properties and anticarcinogenic effects. Food Science and Technology, 2008, 7(3):255-270
6.熊维全,万群.番茄红素研究进展[J].热带农业科技,2007,30(2):48-52
7.隋海霞,徐海滨,严卫星.番茄红素的抗氧化及抗肿瘤作用[J].中国食品卫生杂志,2003,15(6):544-547
8.李春生.番茄红素的研究概况[J].农产品加工(学刊),2009,160(1):71-74
9. Shahrzad S, Cadenas E, Sevanian A, et al. Impact of water-dispersible beadlets as a vehicle for the delivery of carotenoids to cultured cells. Biofactors, 2002, 16(3-4):83-91
10.李京东,傅善江.番茄红素的保健作用及发展前景[J].中国食物与营养,2005(4):49-51
11.吴翠栓,艾秀丽,邱彤等.番茄红素及其保健功能的研究进展[J].中国新药杂志,2007,16(22):1849
12. Lu QY, Hung JC, Heber D, et al. Inverse associations between plasma lycopene and other carotenoids and prostate cancer. Cancer Epide Bio & Pre, 2001, 10 (7): 749-756
13. Weisburger JH. Lycopene and tomato products in heath promotion. Exp Biol Med, 2002,
227(10): 924-927
14. Gann PH. Intermediate biomarkers of lycopene/tomato effects in high-risk prostatic tissue. J Nutr, 2005, 135 (8): 2065 -2067
15. Maserejian NN, Giovannucci E, Rosner B, et al. Prospective study of vitamins C, E, and A and carotenoids and risk of oral premalignant lesions in men. Int J Cancer, 2006,120 (5):
970–977
16. Tang L, Jin T, Zeng X, et al. Lycopene inhibits the growth of human androgen-independent prostate cancer cells in vitro and in BALB/c nude mice, J Nutr, 2005,135(2):287–290
17.潘洪志,姜秀梅,万丽葵等.番茄红素对小鼠S180肿瘤生长及免疫功能的影响[J].营养学报,2004,26(5):406-407
18.张庆英.番茄红素对食管癌预防效果的实验研究[D]:[硕士学位论文].广州:中山医科大学,2001
19.邱伟芬,江汉湖,汪海峰.番茄红素高压处理后抗乳腺癌细胞增殖的研究[J].营养学报,2005,27(6):506-509
20.彭光华,李忠等.类胡萝卜素对乳腺癌细胞株MDA-MBS-435S中DNA损伤作用的影响[J].食品科学,2003,24(9):125-127
21.李垚,付晶,潘宏志.番茄红素对人胃癌细胞生长的抑制作用[J].中国公共卫生,2006,22(10):1223-1225
22.陈晓,张亚楼,张月明等.番茄红素干预食管细胞系(Eca9706)及表皮生长因子表达的研究[J].安徽医药,2005,9(1):19-20
23.王伟华,韩占江.番茄红素的抗氧化性质及对肝癌小鼠H22的抑制作用的研究[J].安徽农业科学,2006,34(14):3378-3380
24. Amir H, Karas M, Giat J, et al. Lycopene and 1, 25-dihydroxyvitamin-D3 cooperate in the inhibition of cell cycle progression and induction of differentiation in HL-60 leukemic cell. Nutrition and Cancer, 1999, 33(1): 105-112
25. Pastori M, Pfander H, Boscoboinik D, et al. Lycopene in association withα-tocopherol inhibits at physiological concentrations proliferation of prostate carcinoma cells. Biochem Biophys Res Commun, 1998, 250(3): 582-585
26. Boileau TWM, Liao Z, Kim S, et al. Prostate carcinogenesis in N-methyl-N-nitrosourea(NMU)-testosterone-treated rats fed tomato powder, lycopene, or energy-restricted diets. J Natl Cancer Inst, 2003, 95(21): 1578-1586
27.谭新平,王银娜,刘昕.番茄红素与癌[J].天然产物研究与开发,2001,13(4):71-75
28. Saada H N, Azab KS. Role of lycopene in recovery of radiation induced injury to mammalian cellular organelles. Pharmazie, 2001, 56 (3): 239-241
29. Matos HR, Mascio DP, Medeiros MHG.Protective effect of lycopene on lipid peroxidation and oxidative DNA damage in cell culture. Arch Biochem Biophys, 2000, 383(1):56-59
30. Velmurugan B, Bhuvaneswari V, Burra UK, et al. Prevention of N-methyl-N′-nitro-N-nitrosoguanidine and saturated sodium chloride induced gastric carcinogenesis in Wistar rats by lycopene. Eur J Cancer Prev, 2002, 11(1):19-26
31. Cheng H, Chien H, Liao C, et al. Carotenoids suppress proliferating cell nuclear antigen and cyclin D1 expression in oral carcinogenic models. J Nutr Biochem, 2007, 18(10): 667–675
32. Nahum A, Hirsch K, Danillenko M, et al. Lycopene inhibition of cell cycle progression inbreast and endometrial cancer cells is associated with reduction in cyclin D levels and retention of p27Kip1 in the cyclin E-cdk2 complexes. Oncogene, 2001, 20(26): 3428-3436
33. Liu C, Lian F, Smith DE, et al. Lycopene supplementation inhibits lung squamous metaplasia and induces apoptosis via up-regulating insulin-like growth factor-bind-ing protein 3 in cigarette smoke-exposed ferrets. Cancer Res, 2003, 63: 3138-3144
34. Hsin-Chung Chenga, Hsin Chienb, Chia-Hui Liaoc. Carotenoids suppress proliferating cell nuclear antigen and cyclin D1 expression in oral carcinogenic models. J Nutr Bio, 2007, 18: 667–675
35. Huang CS, Liao JW, Hu ML. Lycopene Inhibits Experimental Metastasis of Human Hepatoma SK-Hep-1 Cells in Athymic Nude Mice. Nutr Immuno. 2008, 138(3):538-543
36. Karas M, Amir H, Fishman D, et al. Lycopene interferes with cell cycle progression and insulin-like growth factor I signaling mammary cancer cells. Nutr Cancer, 2000, 36(1): 101-111
37. Mucci L A, Tamimi R, Lagiou P, et al. Are dietary influences on the risk of prostate cancermediated through the insulin-like growth factor system?. BJU Int, 2001, 87(9): 814-820
38. Krutovskikh V, Asamoto M, Takasuka N, et al. Differential dose dependent effects ofα-,β-carotenes and lycopene on gap-junctional intercellular communication in rat liver in vivo. Japan J Cancer Res, 1997, 88(12):1121-1124.
39. Bertram JS, Bortkiewicz H. Dietary carotenoids inhibit neoplastic transformation and modulate gene expression in mouse and human cells. Am J Clin Nutr, 1995, 62(6 Suppl): 1327S-1336S
40. Aust O, Ale-Agha N, Zhang L, et al. Lycopene oxidation product enhances gap junctional communication. Food Chem Toxico, 2003, 41(10): 1399-1407.
41. Huang CS, Fan YE, Lin CY, et al. Lycopene inhibits matrix metalloproteinase-9 expression and down-regulates the binding activity of nuclear factor-kappa B and stimulatory protein-1, J Nutr Biochem, 2007, 18(7): 449–456
42. Huang CS, Shih MK, Chuang CH, et al. Lycopene inhibits cell migration and invasion and upregulates Nm23-H1 in a highly invasive hepatocarcinoma, SK-Hep-1 cells. J Nutr. 2005, 135(9): 2119–2123
43. Chiang HS, Wu WB, Fang JY, et al. Lycopene inhibits PDGF-BB-induced signaling and migration in human dermal fibroblasts through interaction with PDF-BB. Life Sci, 2007, 81(21-22): 1509–1517
44. Hantz HL, Young LF, Martin KR. Physiologically attainable concentrations of lycopene induce mitochondrial apoptosis in LNCaP human prostate cancer cells. Exp Biol Med, 2005, 230(3): 171–179
45. Ivanov N , Cowell S , Brown P, et al. Lycopene differentially induces quiescence and apoptosis in androgen-responsive and -independent prostate cancer cell lines. Clin Nutr, 2007, 26(2): 252–263
46. Salman H, Bergman M, Djaldetti M, et al. Lycopene affects proliferation and apoptosis of four malignant cell lines. Biomed Pharmacother, 2007, 61(6): 366–369
47. Chen L, Stacewicz-Sapuntzakis M, Duncan C, et al. Oxidative DNA damage in prostate cancer patients consuming tomato sauce-based entrees as a whole-food intervention. J Natl Cancer Inst, 2001, 93(24): 1872–1879
48. Nara E, Hayashi H, Kotake M, et al. Acyclic carotenoids and their oxidation mixtures inhibit the growth of HL-60 human promyelocytic leukemia cells. Nutr Cancer, 2001, 39(2): 273-283
49. Ben-Dor A, Steiner M, Gheber L, et al. Carotenoids activate the antioxidant response element transcription system. Mol Cancer Ther, 2005, 4(1): 177–186
50. Goo YA, Li Z, Pajkovic N, et al. Systematic investigation of lycopene effects in LNCaP cells by use of novel large-scale proteomic analysis software. Proteomics Clin Appl, 2007, 1(5): 513–523
51. Tibaduiza EC, Fleet JC, Russell RM, et al. Excentric cleavange products of beta-carotene inhibit estrogen receptor positive and negative breast tumor cell growth in vitro and inhibit activator protein-1-mediated transcriptional activation. J Nutr, 2002, 132(6): 1368~1375
52.龚非力.医学免疫学[M].北京:科学出版社,2004,374
53. Briviba K, Kulling S E, Moseneder J, et al. Effects of supplementing a low-carotenoid diet with a tomato extract for 2 weeks on endogenous levels of DNA single strand breaks and immune functions in healthy nonsmokers and smokers. Carcinogenesis, 2004, 25(12):2373-2378
54. Watzl B, Bub A, Briviba K, et al. Supplementation of a low-carotenoid diet with tomato or carrot juice modulates immune functions in healthy men. Ann Nutr Metab, 2003, 47(6):255-261
55.潘喜华,仲伟鉴,肖萍等.番茄红素调节免疫作用及机制研究[J].上海预防医学杂志,2006,18(6):261-263
55.任亮,李新伟,林海红.番茄红素对氟尿嘧啶治疗小鼠肉瘤S180的影响[J].中华中医药学刊,2007,25(8):1706-1708
56.康红钰,任亮,刘春杰等.番茄红素对环磷酰胺治疗小鼠肉瘤H22的影响[J].郑州大学学报(医学版),2008,43(4):751-753
57.李华佳,辛志红,胡秋辉.食品纳米技术与纳米食品研究进展[J].食品科学,2006,27(9):271-274
58.于霞飞,高学云.纳米超微粉在保健食品中的应用[J].纳米技术产业,2000,(6):35
59.赵秋艳,李汴生.新型铁营养强化剂——超微细元素铁粉[J].食品与发酵工业,2001,27(6):67-69
60.王建辉,吕武兴.纳米氧化锌在动物营养中的应用前景[J].饲料广角,2003,(18):21-23
61.赵成萍,田野.纳米级维生素的研究[J].饲料工业,2006,27(6):62-64.
62.张劲松,高学云,张立德,等.纳米红色元素硒的护肝、抑瘤和免疫调节作用[J].营养学报,2001,23(1):32-35.
63. Huang B, Zhang J, Hou J, et al. Free radicals scavenging efficiency of Nano-Se in vitro. Free Radical Biology and Medicine, 2003, 35(7): 805-813
64. Pison U, Welte T, Giersig M, et al. Nanomedicine for respiratory diseases. European Journal of Pharmacology, 2006, 533(1-3):341-350.
65. Shibata T. Method for producing green tea in microfine powder: The United States of America, US6416803B1 [P]. 2002
66.夏书芹.辅酶Ql0纳米脂质体的研制[D]:[硕士学位论文].无锡:江南大学,2006
67.侯振建,付子林,陈俊生等.蜂胶纳米化技术研究[J].食品科学,2008,29(5):199-200
68.孙勇,李华佳,辛志红等.纳米食品的活性与安全[J].食品科学,2006,27(12):936-939
69.孙莹.番茄红素纳米分散体的制备及稳定性研究[D]:[硕士学位论文].无锡:江南大学,2008
70.王静,刘大川.紫(白)苏叶黄酮类化合物抗氧化性能的研究[J].中国油脂, 2004,29(3):33-36
71.范冠宇,谢虹,吴志刚.水溶性几丁聚糖对羟自由基的清除作用[J].中国公共卫生,2006,22(6):676-677
72.王朝杰.槲皮素对QGY、HepG2细胞系细胞周期影响的实验研究[D]:[硕士学位论文].重庆:重庆医科大学,2002
73.徐辉碧.纳米医药[M].北京:清华大学出版社, 2004,9
74.张连琴.自由基与疾病[J].天津医科大学学报,1997,3(2):85-88
75.方允中,杨胜,伍国耀.自由基、抗氧化剂、营养素与健康的关系[J].营养学报,2003,25(4):337-342
76.李艳红.鹰嘴豆蛋白酶解物的制备及其抗氧化肽的研究[D]:[博士学位论文].无锡:江南大学,2008
77.孙晓萍.天然产物的提取及其抗自由基活性的研究[D]:[硕士学位论文].郑州:郑州大学,2004
78.谷梅,柏志全,肖瑞等.过氧化氢对黑素细胞增殖活性的影响[J].岭南皮肤性病科杂志,2006,13(2):82-83
79. Burdon RH, Gill V. Cellularly generated active oxygen species and Hela cell proliferation. Free Radical Research, 1993, 19(3): 203-213
80.方允中.茶叶抗氧化作用的抗癌机制[J].中国肿瘤,2000,9(1):21-22
81.尹美珍,李世普,韩颖超.羟基磷灰石纳米粒子对肝癌细胞PCNA表达的影响[J].武汉理工大学学报,2007,29(8):58-61
82.任秀华.药用辅料抑制细胞色素P450 3A作用研究[D]:[博士学位论文].武汉:华中科技大学,2008
83.董杰明,吴瑞华,袁昌鲁等.γ-亚麻酸的保健作用[J].卫生研究,2003,32(3):299-301
84.王明衡,白剑英,原福胜.食品添加剂亚硫酸钠对HL-7702肝细胞的毒性作用[J].山西医科大学学报,2008,39(1):21-23