香叶木苷的生物合成及其抗肿瘤活性
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摘要
柑橘、薄荷、蓬子菜等植物中含有丰富的香叶木苷,体外模型、活体动物、人体志愿者证实了香叶木苷的抗肺癌、乳腺癌、黑色素瘤、结肠癌等恶性肿瘤活性,被广泛用于出血性痔疮、改善肿瘤患者术后水肿并发症的治疗。目前,对香叶木苷生物合成途径的认识主要局限于其主通路上,对糖基化、酰基化以及甲基化等相关的基因和酶类研究较少,随着代谢研究的深入,揭示香叶木苷的积累和分布遗传机理,将会为香叶木苷的生产调控及应用提供理论依据。
Plants,such as Citrus, Mentha haplocalyx and Galium verum are rich in diosmin. In various in vitro and animal models as well as in human volunteers diosmin has been demonstrated to possess antitumor activity against lung cancer, breast cancer, melanoma, colon cancer and other malignant tumors. It is widely used in the treatment of hemorrhagic hemorrhoids and postoperative edema complications in tumor patients. At present, the understanding of the biosynthesis pathway of diosmin is mainly limited to its main pathway, and there are few studies on genes and enzymes related to glycosylation, acylation, and methylation. Further studies on of the metabolism, and molecular mechanisms of accumulation and distribution of diosmin will provide a theoretical basis for the production and application of diosmin.
Plants,such as Citrus, Mentha haplocalyx and Galium verum are rich in diosmin. In various in vitro and animal models as well as in human volunteers diosmin has been demonstrated to possess antitumor activity against lung cancer, breast cancer, melanoma, colon cancer and other malignant tumors. It is widely used in the treatment of hemorrhagic hemorrhoids and postoperative edema complications in tumor patients. At present, the understanding of the biosynthesis pathway of diosmin is mainly limited to its main pathway, and there are few studies on genes and enzymes related to glycosylation, acylation, and methylation. Further studies on of the metabolism, and molecular mechanisms of accumulation and distribution of diosmin will provide a theoretical basis for the production and application of diosmin.
引文
[1] 陈嘉景,彭昭欣,石梅艳,等.柑橘中类黄酮的组成与代谢研究进展[J].园艺学报,2016,43(2):384-400.
[2] ZHOU WJ, LUO JY, ZHAO LH,et al.Influences of different storage environments and packaging materials on the quality of the traditional Chinese health food Herba Menthae Haplocalycis[J]. Food Packaging and Shelf Life,2018(15):56-61.
[3] ZHANG XM, AN DQ, GUO LL,et al.Identification and screening of active components from Ziziphora clinopodioides Lam.in regulating autophagy[J]. Natural Product Research, 2018(16):1-5.
[4] LIU WY, LIOU SS, HONG TY,et al.The Benefits of the Citrus Flavonoid Diosmin on Human Retinal Pigment Epithelial Cells under High-Glucose Conditions[J]. Molecules, 2017, 22(12):1-12.
[5] Adamante G, de Almeida AS, Rigo FK,et al.Diosmetin as a novel transient receptor potential vanilloid 1 antagonist with antinociceptive activity in mice[J]. Life Science, 2019(216): 215-226.
[6] Ballester AR, Lafuente MT. LED Blue Light-induced changes in phenolics and ethylene in citrus fruit: Implication in elicited resistance against Penicillium digitatum infection[J].Food Chemistry, 2017(218):575-583.
[7] Hsu CC,LIN MH,CHENG JT,et al. Antihyperglycaemic action of diosmin,a citrus flavonoid,is induced through endogenous β-endorphin in type I-like diabetic rats[J].Clinical and Experimental Pharmacology and Physiology,2017,44(5):549-555.
[8] Srinivasan S,Pari L.Anti-hyperlipidemic effect of diosmin:A citrus flavonoid on lipid metabolism in experimental diabetic rats[J].Journal of Functional Foods,2013,5(1):484-492.
[9] Prabhu VV,Sathyamurthy D,Ramasamy A,et al. Evaluation of protective effects of diosmin(a citrus flavonoid) in chemical-induced urolithiasis in experimental rats[J].Pharmaceutical Biology,2016,54(9):1513-1525.
[10] Mastantuono T,Battiloro L,Sabatino L,et al.Effects of citrus flavonoids against microvascular damageinduced by hypoperfusion and reperfusion in rat pial Circulation[J].Micro circulation,2015,22(5):378-390.
[11] Arab HH,Salama SA,Omar HA,et al. Diosmin protects against ethanol-induced gastric injury in rats:Novel anti-ulcer actions[J].Public Library of Science,2015,10(3):1-21.
[12] 张红.香叶木苷诱导肝癌细胞HepG2坏死作用研究[D].哈尔滨:哈尔滨工业大学,2017.
[13] JIANG Z,CAO J.The impact of micronized purified flavonoid fraction on the treatment of acute haemorrhoidal episodes[J].Current Medical Research and Opinion,2006,22(6):1141-1147.
[14] Dada A,Elnour S,Pawa A,et al. Litigation relating to central and peripheral venous access by anaesthetists[J].Anaesthesia,2011,66(7):627-628.
[15] Mcquaid D,Bortfeld T.4D planning over the full course of fractionation:assessment of the benefit of tumor trailing[J].Physics in Medicine and Biology,2011,56(21):6935-6949.
[16] 崔功廷.地奥司明治疗慢性非细菌性前列腺炎的动物实验研究[D].张家口:河北北方学院,2014.
[17] 马超.蓬子菜活性指标成分—香叶木苷的药物动力学研究[D].哈尔滨:黑龙江中医药大学,2007.
[18] Hajimahmoodi M,Moghaddam G,Mousavi S,et al. Total Antioxidant Activity,and Hesperidin,Diosmin,Eriocitrin and Quercetin Contents of Various Lemon Juices[J].Tropical Journal of Pharmaceutical Research,2014,13(6):951-956.
[19] 冯涵,李娜,王华林,等.藤茶中黄酮类成分的功效研究进展[J].公共卫生与预防医学,2018,29(1):82-86.
[20] 唐晓荞,樊柏林,李新兰.常用降糖天然植物有效成分及其作用机制研究进展[J].公共卫生与预防医学,2006,17(2):45-47.
[21] FANG HI,LI WI,LIANG CY,et al. Chemical constituents from above-ground part of Mentha haplocalyx after extracting volatile oil[J].Journal of Plant Resources and Environment,2007,16(2):73-74.
[22] LEI Z,SHOU Z.Chemical Constituents from Lygodium japonicum[J].Chinese Journal of Natural Medicines,2006,4(2):154-155.
[23] Eldomiaty M,Wink M,Aal MM,et al. Antihepatotoxic activity and chemical constituents of Buddleja asiatica Lour[J].Zeitschrift für Naturforschung C,2009,64(1):11-19.
[24] Park NI,Li X,Thwe AA,et al. Enhancement of rutin in Fagopyrum esculentum hairy root cultures by the Arabidopsis transcriptionfactor AtMYB12[J].Biotechnology Letters,2012,34(3):577-583.
[25] Strack S,Detzel T,Wahl M,et al. Cytotoxicity of TBBPA and effects on proliferation,cell cycle and MAPK pathways in mammalian cells[J].Chemosphere,2007,67(9):405-S411.
[26] 于龙江,赵春芳.次生代谢产物生物合成[M].北京:化学工业出版社,2016.
[27] 张强.黄酮及黄酮醇的抗癌作用[M].北京:化学工业出版社,2017.
[28] 李明.类黄酮调控基因AtMYB12的异源表达及其对植物抗病性的贡献[D].泰安:山东农业大学,2012.
[29] Ortuno A,Diaz L,Alvarez N,et al. Comparative study of flavonoid and scoparone accumulation in different Citrus species and their susceptibility to Penicillium digitatum[J].Food Chemistry,2011,125(1):232-239.
[30] Williams GJ,Breazeale SD,Raetz CR,et al. Structure and Function of Both Domains of ArnA,a Dual Function Decarboxylase and a Formyltransferase,Involved in 4-Amino-4-deoxy-L-arabinose Biosynthesis[J].Journal of Biological Chemistry,2005,280(24):23000-23008.
[31] Williams GJ,Breazeale SD,Raetz CR,et al. Structure and function of both domains of ArnA,a dual function decarboxylase and a formyltransferase,involved in 4-amino-4-deoxy-L-arabinose biosynthesis[J].Journal of Biological Chemistry,2005,280(24):23000-23008.
[32] El-Fawal REl, Fayoumi HM,Mahmoud MF. Diosmin and crocin alleviate nephropathy in metabolic syndrome rat model: Effect on oxidative stress and low grade inflammation[J].Biomedicine & Pharmacotherapy, 2018(102):930-937.
[33] Shalkami AS, Hassan M, Bakr AG. Anti-inflammatory, antioxidant and anti-apoptotic activity of diosmin in acetic acid-induced ulcerative colitis[J].Human & Experimental Toxicology, 2018, 37(2):78-86.
[34] Mirshekar MA,Fanaei H,Keikhaei F,et al. Diosmin improved cognitive deficit and amplified brain electrical activity in the rat model of traumatic brain injury[J].Biomedicine & pharmacotherapy, 2017, 93(17):1220.
[35] Lewinska A,Adamczykgrochala J,Kwasniewicz E,et al.Diosmin-induced senescence, apoptosis and autophagy in breast cancer cells of different p53 status and ERK activity[J].Toxicology Letters, 2016(265):117-130.
[36] Buddhan R,Manoharan S. Diosmin reduces cell viability of A431 skin cancer cells through apoptotic induction[J].Journal of Cancer Research & Therapeutics, 2017,13(3):471-476.
[37] 吴炳义,董惠玲,王在翔,等.恶性肿瘤对平均预期寿命影响的生命表分析[J].现代预防医学,2015(23):4328-4331.
[38] Mandal P,Kumar BS,Mandal G,et al. CCL2conditionally determines CCL22-dependent Th2-accumulation during TGF-β-induced breast cancer progression[J].Elsevier GmbH,2018,223(2):151-161.
[39] Lewinska A,Adamczykgrochala J,Kwasniewicz E,et al. Diosmin-induced senescence,apoptosis and autophagy in breast cancer cells of different p53 status and ERK activity[J].Toxicology Letters,2017,265(4):117-130.
[40] 刘宁宁.地奥司明(DOSM)对Hep G2肝癌细胞诱导分化作用的研究[D].北京:首都师范大学,2009.
[41] HUANG JZ, Ma HT. Comparative Phosphoproteomic Analysis of the Effects and Regulation of DHEA on Hepaticin Lipids Metabolism in Broiler Chickens[C].全国动物生理生化第十一次学术交流会论文摘要汇编,2010.
[42] XIE Y,YUAN D,YANG J,et al. Cytotoxic activity of flavonoids from the flowers of chrysanthemum morifolium on human colon cancer colon205 cells.[J].Journal of Asian Natural Products Research,2009,11(9):771-778.
[43] Rajasekar M,Suresh K,Sivakumar K,et al. Diosmin induce apoptosis through modulation of STAT-3 signaling in 7,12 dimethylbenz(a)anthracene induced harmster buccal pouch carcinogenesis[J].Biomedicine & Pharmacotherapy,2016(83):1064-1070.
[44] Dholakiya SL,Benzeroual KE.Protective effect of diosmin on LPS-induced apoptosis in PC12 cells and inhibition of TNF-α expression[J].Toxicology In Vitro,2011,25(5):1039-1044.
[45] Kahali B,Marquez SB,Thompson KW,et al. Flavonoids from each of the six structural groups reactivate BRM,a possible cofactor for the anticancer effects of flavonoids[J].Carcinogenesis,2014,35(10):2183-2193.
[46] Lewinska A,Siwak J,Rzeszutek I,et al. Diosmin induces genotoxicity and apoptosis in DU145 prostate cancer cell line[J].Toxicology In Vitro,2015,29(3):417-425.
[47] YANG J,Tanaka T,Hirose Y,et al. Chemopreventive effects of diosmin and hesperidin on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary-bladder carcinogenesis in male ICR mice[J].International Journal of Cancer,1997,73(5):719-724.
[48] Tanaka T,Makita H,Kawabata K,et al. Modulation of N-methyl-N-amylnitrosamine-induced rat oesophageal tumourigenesis by dietary feeding of diosmin and hesperidin,both alone and in combination[J].Carcinogenesis,1997,18(4):761-769.
[49] Conesa CM,Ortega VV,Gascon MJ, et al. Treatment of metastatic melanoma B16F10 by the flavonoids tangeretin,rutin,and diosmin[J].Journalof Agricultural and Food Chemistry,2005,53(17):6791-6797.
[50] Tahir M,Rehman MU,Lateef A,et al. Diosmin protects against ethanol-induced hepatic injury via alleviation of inflammation and regulation of TNF-α and NF-κB activation[J].Alcohol,2013,47(2):131-139.
[51] Mohamed MA,Hesham AK,Abushouk AI,et al. Diosmin Attenuates Methotrexate-Induced Hepatic,Renal,and Cardiac Injury:A Biochemical and Histopathological Study in Mice[J].Oxidative Medicine and Cellular Longevity,2017(30):1-10.
[52] 李宁华.地奥司明治疗乳腺癌术后上肢淋巴水肿临床观察[J].中国医学创新,2012,233(23):37-38.
[53] 费阳,王世斌.地奥司明预防乳腺癌手术后并发症43例[J].医药导报,2010(10):1310-1311.
[54] 梁宛伶,肖天保.地奥司明片治疗直肠癌术后并发下肢深静脉血栓1例的临床疗效分析[C].贵州省中西医结合学会,2010.
[55] Burkina V,Zlabek V,Halsne R,et al. In vitro effects of the citrus flavonoids diosmin,naringenin and naringin on the hepatic drug-metabolizing CYP3A enzyme in human,pig,mouse and fish[J].Biochemical Pharmacology,2016(110-111):109-116.
[56] 王福生.柑橘类柠檬苦素生物合成相关基因的鉴定与功能验证[D].重庆:西南大学,2016.
[2] ZHOU WJ, LUO JY, ZHAO LH,et al.Influences of different storage environments and packaging materials on the quality of the traditional Chinese health food Herba Menthae Haplocalycis[J]. Food Packaging and Shelf Life,2018(15):56-61.
[3] ZHANG XM, AN DQ, GUO LL,et al.Identification and screening of active components from Ziziphora clinopodioides Lam.in regulating autophagy[J]. Natural Product Research, 2018(16):1-5.
[4] LIU WY, LIOU SS, HONG TY,et al.The Benefits of the Citrus Flavonoid Diosmin on Human Retinal Pigment Epithelial Cells under High-Glucose Conditions[J]. Molecules, 2017, 22(12):1-12.
[5] Adamante G, de Almeida AS, Rigo FK,et al.Diosmetin as a novel transient receptor potential vanilloid 1 antagonist with antinociceptive activity in mice[J]. Life Science, 2019(216): 215-226.
[6] Ballester AR, Lafuente MT. LED Blue Light-induced changes in phenolics and ethylene in citrus fruit: Implication in elicited resistance against Penicillium digitatum infection[J].Food Chemistry, 2017(218):575-583.
[7] Hsu CC,LIN MH,CHENG JT,et al. Antihyperglycaemic action of diosmin,a citrus flavonoid,is induced through endogenous β-endorphin in type I-like diabetic rats[J].Clinical and Experimental Pharmacology and Physiology,2017,44(5):549-555.
[8] Srinivasan S,Pari L.Anti-hyperlipidemic effect of diosmin:A citrus flavonoid on lipid metabolism in experimental diabetic rats[J].Journal of Functional Foods,2013,5(1):484-492.
[9] Prabhu VV,Sathyamurthy D,Ramasamy A,et al. Evaluation of protective effects of diosmin(a citrus flavonoid) in chemical-induced urolithiasis in experimental rats[J].Pharmaceutical Biology,2016,54(9):1513-1525.
[10] Mastantuono T,Battiloro L,Sabatino L,et al.Effects of citrus flavonoids against microvascular damageinduced by hypoperfusion and reperfusion in rat pial Circulation[J].Micro circulation,2015,22(5):378-390.
[11] Arab HH,Salama SA,Omar HA,et al. Diosmin protects against ethanol-induced gastric injury in rats:Novel anti-ulcer actions[J].Public Library of Science,2015,10(3):1-21.
[12] 张红.香叶木苷诱导肝癌细胞HepG2坏死作用研究[D].哈尔滨:哈尔滨工业大学,2017.
[13] JIANG Z,CAO J.The impact of micronized purified flavonoid fraction on the treatment of acute haemorrhoidal episodes[J].Current Medical Research and Opinion,2006,22(6):1141-1147.
[14] Dada A,Elnour S,Pawa A,et al. Litigation relating to central and peripheral venous access by anaesthetists[J].Anaesthesia,2011,66(7):627-628.
[15] Mcquaid D,Bortfeld T.4D planning over the full course of fractionation:assessment of the benefit of tumor trailing[J].Physics in Medicine and Biology,2011,56(21):6935-6949.
[16] 崔功廷.地奥司明治疗慢性非细菌性前列腺炎的动物实验研究[D].张家口:河北北方学院,2014.
[17] 马超.蓬子菜活性指标成分—香叶木苷的药物动力学研究[D].哈尔滨:黑龙江中医药大学,2007.
[18] Hajimahmoodi M,Moghaddam G,Mousavi S,et al. Total Antioxidant Activity,and Hesperidin,Diosmin,Eriocitrin and Quercetin Contents of Various Lemon Juices[J].Tropical Journal of Pharmaceutical Research,2014,13(6):951-956.
[19] 冯涵,李娜,王华林,等.藤茶中黄酮类成分的功效研究进展[J].公共卫生与预防医学,2018,29(1):82-86.
[20] 唐晓荞,樊柏林,李新兰.常用降糖天然植物有效成分及其作用机制研究进展[J].公共卫生与预防医学,2006,17(2):45-47.
[21] FANG HI,LI WI,LIANG CY,et al. Chemical constituents from above-ground part of Mentha haplocalyx after extracting volatile oil[J].Journal of Plant Resources and Environment,2007,16(2):73-74.
[22] LEI Z,SHOU Z.Chemical Constituents from Lygodium japonicum[J].Chinese Journal of Natural Medicines,2006,4(2):154-155.
[23] Eldomiaty M,Wink M,Aal MM,et al. Antihepatotoxic activity and chemical constituents of Buddleja asiatica Lour[J].Zeitschrift für Naturforschung C,2009,64(1):11-19.
[24] Park NI,Li X,Thwe AA,et al. Enhancement of rutin in Fagopyrum esculentum hairy root cultures by the Arabidopsis transcriptionfactor AtMYB12[J].Biotechnology Letters,2012,34(3):577-583.
[25] Strack S,Detzel T,Wahl M,et al. Cytotoxicity of TBBPA and effects on proliferation,cell cycle and MAPK pathways in mammalian cells[J].Chemosphere,2007,67(9):405-S411.
[26] 于龙江,赵春芳.次生代谢产物生物合成[M].北京:化学工业出版社,2016.
[27] 张强.黄酮及黄酮醇的抗癌作用[M].北京:化学工业出版社,2017.
[28] 李明.类黄酮调控基因AtMYB12的异源表达及其对植物抗病性的贡献[D].泰安:山东农业大学,2012.
[29] Ortuno A,Diaz L,Alvarez N,et al. Comparative study of flavonoid and scoparone accumulation in different Citrus species and their susceptibility to Penicillium digitatum[J].Food Chemistry,2011,125(1):232-239.
[30] Williams GJ,Breazeale SD,Raetz CR,et al. Structure and Function of Both Domains of ArnA,a Dual Function Decarboxylase and a Formyltransferase,Involved in 4-Amino-4-deoxy-L-arabinose Biosynthesis[J].Journal of Biological Chemistry,2005,280(24):23000-23008.
[31] Williams GJ,Breazeale SD,Raetz CR,et al. Structure and function of both domains of ArnA,a dual function decarboxylase and a formyltransferase,involved in 4-amino-4-deoxy-L-arabinose biosynthesis[J].Journal of Biological Chemistry,2005,280(24):23000-23008.
[32] El-Fawal REl, Fayoumi HM,Mahmoud MF. Diosmin and crocin alleviate nephropathy in metabolic syndrome rat model: Effect on oxidative stress and low grade inflammation[J].Biomedicine & Pharmacotherapy, 2018(102):930-937.
[33] Shalkami AS, Hassan M, Bakr AG. Anti-inflammatory, antioxidant and anti-apoptotic activity of diosmin in acetic acid-induced ulcerative colitis[J].Human & Experimental Toxicology, 2018, 37(2):78-86.
[34] Mirshekar MA,Fanaei H,Keikhaei F,et al. Diosmin improved cognitive deficit and amplified brain electrical activity in the rat model of traumatic brain injury[J].Biomedicine & pharmacotherapy, 2017, 93(17):1220.
[35] Lewinska A,Adamczykgrochala J,Kwasniewicz E,et al.Diosmin-induced senescence, apoptosis and autophagy in breast cancer cells of different p53 status and ERK activity[J].Toxicology Letters, 2016(265):117-130.
[36] Buddhan R,Manoharan S. Diosmin reduces cell viability of A431 skin cancer cells through apoptotic induction[J].Journal of Cancer Research & Therapeutics, 2017,13(3):471-476.
[37] 吴炳义,董惠玲,王在翔,等.恶性肿瘤对平均预期寿命影响的生命表分析[J].现代预防医学,2015(23):4328-4331.
[38] Mandal P,Kumar BS,Mandal G,et al. CCL2conditionally determines CCL22-dependent Th2-accumulation during TGF-β-induced breast cancer progression[J].Elsevier GmbH,2018,223(2):151-161.
[39] Lewinska A,Adamczykgrochala J,Kwasniewicz E,et al. Diosmin-induced senescence,apoptosis and autophagy in breast cancer cells of different p53 status and ERK activity[J].Toxicology Letters,2017,265(4):117-130.
[40] 刘宁宁.地奥司明(DOSM)对Hep G2肝癌细胞诱导分化作用的研究[D].北京:首都师范大学,2009.
[41] HUANG JZ, Ma HT. Comparative Phosphoproteomic Analysis of the Effects and Regulation of DHEA on Hepaticin Lipids Metabolism in Broiler Chickens[C].全国动物生理生化第十一次学术交流会论文摘要汇编,2010.
[42] XIE Y,YUAN D,YANG J,et al. Cytotoxic activity of flavonoids from the flowers of chrysanthemum morifolium on human colon cancer colon205 cells.[J].Journal of Asian Natural Products Research,2009,11(9):771-778.
[43] Rajasekar M,Suresh K,Sivakumar K,et al. Diosmin induce apoptosis through modulation of STAT-3 signaling in 7,12 dimethylbenz(a)anthracene induced harmster buccal pouch carcinogenesis[J].Biomedicine & Pharmacotherapy,2016(83):1064-1070.
[44] Dholakiya SL,Benzeroual KE.Protective effect of diosmin on LPS-induced apoptosis in PC12 cells and inhibition of TNF-α expression[J].Toxicology In Vitro,2011,25(5):1039-1044.
[45] Kahali B,Marquez SB,Thompson KW,et al. Flavonoids from each of the six structural groups reactivate BRM,a possible cofactor for the anticancer effects of flavonoids[J].Carcinogenesis,2014,35(10):2183-2193.
[46] Lewinska A,Siwak J,Rzeszutek I,et al. Diosmin induces genotoxicity and apoptosis in DU145 prostate cancer cell line[J].Toxicology In Vitro,2015,29(3):417-425.
[47] YANG J,Tanaka T,Hirose Y,et al. Chemopreventive effects of diosmin and hesperidin on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary-bladder carcinogenesis in male ICR mice[J].International Journal of Cancer,1997,73(5):719-724.
[48] Tanaka T,Makita H,Kawabata K,et al. Modulation of N-methyl-N-amylnitrosamine-induced rat oesophageal tumourigenesis by dietary feeding of diosmin and hesperidin,both alone and in combination[J].Carcinogenesis,1997,18(4):761-769.
[49] Conesa CM,Ortega VV,Gascon MJ, et al. Treatment of metastatic melanoma B16F10 by the flavonoids tangeretin,rutin,and diosmin[J].Journalof Agricultural and Food Chemistry,2005,53(17):6791-6797.
[50] Tahir M,Rehman MU,Lateef A,et al. Diosmin protects against ethanol-induced hepatic injury via alleviation of inflammation and regulation of TNF-α and NF-κB activation[J].Alcohol,2013,47(2):131-139.
[51] Mohamed MA,Hesham AK,Abushouk AI,et al. Diosmin Attenuates Methotrexate-Induced Hepatic,Renal,and Cardiac Injury:A Biochemical and Histopathological Study in Mice[J].Oxidative Medicine and Cellular Longevity,2017(30):1-10.
[52] 李宁华.地奥司明治疗乳腺癌术后上肢淋巴水肿临床观察[J].中国医学创新,2012,233(23):37-38.
[53] 费阳,王世斌.地奥司明预防乳腺癌手术后并发症43例[J].医药导报,2010(10):1310-1311.
[54] 梁宛伶,肖天保.地奥司明片治疗直肠癌术后并发下肢深静脉血栓1例的临床疗效分析[C].贵州省中西医结合学会,2010.
[55] Burkina V,Zlabek V,Halsne R,et al. In vitro effects of the citrus flavonoids diosmin,naringenin and naringin on the hepatic drug-metabolizing CYP3A enzyme in human,pig,mouse and fish[J].Biochemical Pharmacology,2016(110-111):109-116.
[56] 王福生.柑橘类柠檬苦素生物合成相关基因的鉴定与功能验证[D].重庆:西南大学,2016.