臺灣博碩士論文加值系統

糖尿病(Diabetes mellitus；DM)與胰島素分泌不足或作用缺失相關，其形成的高血糖使體內產生過多活性氧，造成氧化壓力上升及相關併發症發生，所以抗氧化物質對於活性氧所引發疾病之調控中扮演重要角色。而醣解酵素不但參與人體消化作用，也影響如糖尿病的許多代謝疾病產生，醣解酵素中以α-澱粉酶(α-amylase)及α-葡萄醣苷酶(α-glucosidase)最為重要。中藥草馬鞭草(Verbena officinalis L.)又稱鐵馬鞭，已證實其具有抗氧化、抗發炎、保護神經、止痛、抗真菌等生理功能，本研究室曾自鐵馬鞭草之正丁醇萃取物分離出具抗氧化及抑制醣解酵素作用之isoverbascoside (1)、verbascoside (2)、eukovoside (3) 、eukovoside isomer (4) 及β-hydroxyverbascoside (5)等成分，但鐵馬鞭草並非藥食兩用植物，較不利於發展保健食品；本研究主旨是利用鐵馬鞭草(V. officinalis L.)與藥食兩用之檸檬馬鞭草(Aloysia triphylla)為實驗材料，分析比較其抗氧化性及醣解酵素抑制活性成分。二種馬鞭草分別經由熱水萃取(2kg乾草/100L水)及超音波震盪萃取30min重複3次，將得到之粗萃物進行XAD-7、ODS管柱層析，再經由HPLC分析與製備，最後經由LC/MS/MS及1H-NMR等光譜進行抗氧化及醣解酵素抑制活性成分之解析及比較。結果顯示，檸檬馬鞭草粗萃物之抗氧化活性總酚、總類黃酮含量，總抗氧化、DPPH抑制及抗醣解酵素α-glucosidase抑制活性顯著高於鐵馬鞭草，α-amylase抑制活性則沒有顯著差異。在波長280nm之下，XAD-7管柱層析區分物，鐵馬鞭草區分出I~V個區分物，檸檬馬鞭草區分出I~VI個區分物，而在鐵馬鞭草第III區分物與檸檬馬鞭草第IV區分物中，其抗氧化活性及抗醣解酵素皆顯著高於其他區分物；檸檬馬鞭草第IV區分物其抗氧化活性總酚、總類黃酮、總抗氧化能力、DPPH抑制率及α-glucosidase抑制活性皆顯著高於鐵馬鞭草第III區分物，α-amylase抑制活性則沒有顯著差異。上述區分並利用ODS管柱層析進行進一步分離，目前得知活性區分都落在第I及第II區分上；並繼續經由HPLC、LC/MS/MS及1H-NMR等光譜分析，檸檬馬鞭草水萃取物製備出的純化物質，分別分離出具抗氧化及抑制醣解酵素作用之isoverbascoside (1)、verbascoside (2)、eukovoside (3) 、eukovoside isomer (4) 、ferulic acid (5)及caffeic acid(6)；而鐵馬鞭草同樣也分離出上述 1~6。

Diabetes are related to the insufficient insulin secretion or missing role related to the formation of the high blood sugar to the body produces too much and cause oxidation active oxygen pressure rise and related complications to occur, the oxidation material for active oxygen-caused disease-control plays an important role. The currency of the enzyme role not only in the human body digestion, such as diabetes and metabolic diseases many monetary-enzyme in the α-amylase and α-glucosidase enzyme is the most important Charter. Verbena officinalis L., also known as iron horse whip, has been proved to have antioxidant, anti-inflammatory, neuroprotective, analgesic, antifungal and other physiological functions, the laboratory has been from Verbena n-butanol extract as isoverbascoside (1)、verbascoside (2)、 eukovoside (3)、eukovoside isomer (4) and β-hydroxyverbascoside (5), But Verbena officinalis L. is not a kind of edible plant, which is not conducive to the development of health foods. The main purpose of this study is to study the effects of Verbena officinalis L. and Edible homologous Aloysia triphylla , Analysis and comparison of its antioxidant and glycolytic enzyme inhibitory active ingredients. The two species of Verbena were extracted by hot water (2 kg of hay / 100 L of water) and extracted by ultrasonic wave for 30 min, respectively. The crude extract was subjected to XAD-7 and ODS column chromatography, and then analyzed and prepared by HPLC. Finally, the antioxidant and glycoenzymes inhibitory active components were analyzed and compared by LC / MS / MS and 1H-NMR spectra. The results showed that the antioxidative activity of total extract, total flavonoids, total antioxidant, DPPH and anti-glycolysis α-glucosidase inhibitory activity of Aloysia triphylla extract was significantly higher than that of Verbena officinalis, α-amylase inhibitory activity No significant difference. Under the wavelength of 280nm, XAD-7 column chromatography region, Verbena officinalis distinguish I ~ V Division, Aloysia triphylla distinguish I ~ VI Division, and in Verbena officinalis III Division and Aloysia triphylla IV Division, its antioxidant activity and anti-glycolytic enzymes were significantly higher than other divisions; Aloysia triphylla IV of its antioxidant activity of total phenols, total flavonoids, total antioxidant capacity, DPPH Inhibition rate and α-glucosidase inhibitory activity were significantly higher than Verbena officinalis Division III, α-amylase inhibitory activity was not significantly different. The above distinction and the use of ODS column chromatography for further separation, the current known activity fell on the distinction between the first and II Division; and continue by HPLC, LC / MS / MS and 1H-NMR spectral analysis, The main purified substances of Aloysia triphylla with antioxidant and inhibit the role of enzymes saccharifying enzyme were identified as isoverbascoside (1)verbascoside (2)、eukovoside (3)、eukovoside isomer (4) and ferulic acid (5), caffeic acid (6) ; and Verbena also separated the above 1 ~ 6.

目錄------------------------------------------------------------------------Ⅰ
圖目錄---------------------------------------------------------------------V
表目錄---------------------------------------------------------------------X
附目錄-------------------------------------------------------------------XII
中文摘要-----------------------------------------------------------------XIII
英文摘要-------------------------------------------------------------------XV
壹、前言--------------------------------------------------------------------1
貳、文獻回顧----------------------------------------------------------------3
一、鐵馬鞭草----------------------------------------------------------------3
(一)鐵馬鞭草之介紹----------------------------------------------------------3
(二)鐵馬鞭草之傳統功效-------------------------------------------------------4
(三)鐵馬鞭草之生理活性-------------------------------------------------------4
二、檸檬馬鞭草-------------------------------------------------------------10
(一)檸檬馬鞭草之介紹--------------------------------------------------------10
(二)檸檬馬鞭草之傳統功效----------------------------------------------------11
(三)檸檬馬鞭草之生理活性----------------------------------------------------11
三、糖尿病-----------------------------------------------------------------16
(一)胰島素(Insulin) ------------------------------------------------------18
(二)糖尿病之類型-----------------------------------------------------------23
(三)糖尿病症狀及所引起之併發症----------------------------------------------26
(四)糖尿病之治療-----------------------------------------------------------31
(五)糖尿病與醣解酵素--------------------------------------------------------37
四、高血糖與活性氧之關聯----------------------------------------------------39
(一)自由基與活性氧---------------------------------------------------------39
(二)自由基種類及介紹-------------------------------------------------------40
(三)自由基導致糖尿病併發症機轉----------------------------------------------41
五、抗氧化作用-------------------------------------------------------------46
(一)抗氧化劑之種類---------------------------------------------------------47
(二)抗氧化劑作用機制-------------------------------------------------------56
(三)抗氧化與脂質氧化之關係--------------------------------------------------59
(四)人體酵素抗氧化防禦系統--------------------------------------------------61
參、研究目的與實驗流程------------------------------------------------------63
一、研究目的---------------------------------------------------------------63
二、實驗架構---------------------------------------------------------------64
肆、材料與方法------------------------------------------------------------65
一、實驗材料--------------------------------------------------------------65
(一)樣品來源---------------------------------------------------------------65
(二)實驗試藥與溶劑---------------------------------------------------------65
(三)實驗儀器設備-----------------------------------------------------------67
二、實驗方法---------------------------------------------------------------69
(一)萃取樣品---------------------------------------------------------------69
(二)總酚含量測定(total phenolic compounds determination) ------------------70
(三)總類黃酮含量測定(Flavonoid determination) ------------------------------70
(四)DPPH自由基清除能力試驗 -----------------------------------------------71
(五)總抗氧化能力測定(Trolox equivalent antioxidant capacity,TEAC)-----------72
(六)α-amylase 抑制作用測定-------------------------------------------------73
(七)α-glucosidase抑制作用測定 ---------------------------------------------74
(八)檸檬馬鞭草、鐵馬鞭草草抗氧化及醣解酵素抑制成分之萃 取、分離與純化 ----------75
(九)高效液相層析分析法(high performance liquid chromatography,HPLC) --------78
(十)液相層析串聯質譜法(Liquid chromatography tandem-mass spectrometry, LC-
MS/MS) ---------------------------------------------------------------79
(十一)純化物質之結構鑑定----------------------------------------------------81
(十二)統計分析-------------------------------------------------------------81
伍、結果與討論-------------------------------------------------------------82
一、檸檬馬鞭草及鐵馬鞭草水萃物之產率-----------------------------------------82
二、檸檬馬鞭草及鐵馬鞭草水萃物總酚含量---------------------------------------82
三、檸檬馬鞭草及鐵馬鞭草水萃物之總類黃酮含量----------------------------------83
四、檸檬馬鞭草與鐵馬鞭草 DPPH 自由基清除能力 --------------------------------84
五、檸檬馬鞭草與鐵馬鞭草之總抗氧化能力測定------------------------------------85
六、檸檬馬鞭草與鐵馬鞭草對醣解酵素之抑制活性----------------------------------86
七、檸檬馬鞭草抗氧化及抑制醣解酵素活性成分之分離純化---------------------------87
(一)檸檬馬鞭草之 XAD-7 液相管柱層析-----------------------------------------87
(二)檸檬馬鞭草區分(IV)之Cosmosil 75 C18-OPN 液相管柱層析---------------------92
(三)經由 Cosmosil 75 C18-OPN 液相管柱層析之檸檬馬鞭區分物I、II之 HPLC 分析及製
備--97
(四)檸檬馬鞭草 1-1~1-5 、 2-1~2-4 區分物之 HPLC 分析及製備-------------------99
(五)檸檬馬鞭草純化物質 1~6 之HPLC分析及製備---------------------------------105
八、鐵馬鞭草抗氧化及抑制醣解酵素活性成分之分離純化---------------------------109
(一)鐵馬鞭草之 XAD-7 液相管柱層析------------------------------------------109
(二)鐵馬鞭草區分(III)之第一次Cosmosil 75 C18-OPN 液相管柱層析---------------114
(三)經由 Cosmosil 75 C18-OPN 液相管柱層析之鐵馬鞭區分物I、II 之 HPLC 分析及製備 --119
(四)鐵馬鞭草 1-1~1-5、2-1~2-3 區分物之 HPLC 分析及製備---------------------121
(五)鐵馬鞭草純物質 1~9 之HPLC分析及製備-----------------------------------126
九、檸檬馬鞭草之LC/MS/MS分析及結構鑑定 -----------------------------------130
十、檸檬馬鞭草水萃取物純化物質之結構鑑定 -----------------------------------132
(一) 純化物質1(isoverbascoside)之結構鑑定 --------------------------------132
(二) 純化物質2(verbascoside)之結構鑑定 ---------------------------------137
(三) 純化物質3(eukovoside)之結構鑑定 ------------------------------------140
(四) 純化物質4(eukovoside isomer)之結構鑑定 -----------------------------143
(五) 純化物質5(ferulic acid)之結構鑑定 -----------------------------------146
(六) 純化物質6(caffeic acid)之結構鑑定 -----------------------------------149
十一、鐵馬鞭草水萃取物純化物質之結構鑑定 -----------------------------------152
(一) 純化物質1(isoverbascoside)之結構鑑定 -------------------------------152
(二) 純化物質2(verbascoside)之結構鑑定 ---------------------------------155
(三) 純化物質3(eukovoside)之結構鑑定 ------------------------------------157
(四) 純化物質4(eukovoside isomer)之結構鑑定 -----------------------------159
(五) 純化物質5(ferulic acid)之結構鑑定 ----------------------------------161
(六) 純化物質6(caffeic acid)之結構鑑定 -----------------------------------163
十二、檸檬馬鞭草、鐵馬鞭草水萃取物及鐵馬鞭草正丁醇萃取物之產率比較-------------165
陸、結論------------------------------------------------------------------168
柒、參考文獻--------------------------------------------------------------170
捌、附錄------------------------------------------------------------------179

行政院衛生福利部統計處. (2016). 105年國人十大死因統計.
李先佳, 任麗平, & 金少舉. (2017). 馬鞭草總黃酮對肝癌 HepG-2 細胞凋亡的影響機制研究. 現代預防醫學.
林雁中, & 吳芳禎. (2010). 檸檬馬鞭草水萃取液對大腸直腸癌細胞株 (Caco-2) 之效應. 大葉大學生物產業科技學系碩士班.
張立平, 羅莉, 王家俊, & 徐昌芬. (2004). 馬鞭草提取液 C 部位對人絨毛膜癌 JAR 細胞增殖的影響. 南京醫科大學學報 (自然科學版), 24 (5), 470-472。
陳金滄. (2009). 馬鞭草水淬取物對四氯化碳誘導大鼠肝損傷之護肝及抗氧化功效評估 (仁研 98081)。
衛生福利部食品藥物管理署. (2017). 可供食品使用原料彙整一覽表.
Abuhamdah, R., & Mohammed, A. (2014). Chemical, molecular pharmacology and neuroprotective properties of the essential oil derived from Aloysia citrodora Palau. durham university.
Aruoma, O. I. (1998). Free radicals, oxidative stress, and antioxidants in human health and disease. Journal of the American oil chemists' society, 75 (2), 199-212.
Association, A. D. (2014). Diagnosis and classification of diabetes mellitus. Diabetes care, 37 (Supplement 1), S81-S90.
Association, A. D. (2017). Diagnosing Diabetes and Learning About Prediabetes. In.
Becker, A. G., Luz, R. K., Mattioli, C. C., Nakayama, C. L., de Souza e Silva, W., de Oliveira Paes Leme, F., de Mendonça Mendes, H. C. P., Heinzmann, B. M., & Baldisserotto, B. (2015). Can the essential oil of Aloysia triphylla have anesthetic effect and improve the physiological parameters of the carnivorous freshwater catfish Lophiosilurus alexandri after transport? Aquaculture, 481 (Supplement C), 184-190.
Beyer, R. E. (1994). The role of ascorbate in antioxidant protection of biomembranes: interaction with vitamin E and coenzyme Q. Journal of bioenergetics and biomembranes, 26 (4), 349-358.
BIAN, J.-s., FENG, J.-n., TAN, Q.-y., & DENG, B. (2013). Study on the ultrasonic-assisted extraction and antioxidant activity of total flavonoids from Verbena officinalis L.[J]. journal of baoji university of arts and sciences (Natural Science Edition), 1, 007.
Bierhaus, A., Hofmann, M. A., Ziegler, R., & Nawroth, P. P. (1998). AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept. cardiovascular research, 37 (3), 586-600.
Bilia, A. R., Giomi, M., Innocenti, M., Gallori, S., & Vincieri, F. F. (2008). HPLC- DAD–ESI–MS analysis of the constituents of aqueous preparations of verbena and lemon verbena and evaluation of the antioxidant activity. Journal of Pharmaceutical and Biomedical Analysis, 46 (3), 463-470.
Boix-Castejón, M., Herranz-López, M., Caturla, N., Roche, E., Barrajón-Catalán, E., & Micol, V. (2016). P 226 - Hibiscus and lemon verbena polyphenols: Assessment for weight management in overweight volunteers. Appetite control and satiety. free radical biology and medicine, 108 (Supplement 1), S96.
Buse, M. G. (2006). Hexosamines, insulin resistance, and the complications of diabetes: current status. American Journal of Physiology-Endocrinology And Metabolism, 290 (1), E1-E8.
Calvo, M. I. (2006). Anti-inflammatory and analgesic activity of the topical preparation of Verbena officinalis L. Journal of Ethnopharmacology, 107 (3), 380-382.
Calvo, M. I., Vilalta, N., San Julián, A., & Fernández, M. (1998). Anti-inflammatory activity of leaf extract of Verbena officinalis L. Phytomedicine, 5 (6), 465-467.
Carocho, M., & Ferreira, I. C. (2013). A review on antioxidants, prooxidants and related controversy: natural and synthetic compounds, screening and analysis methodologies and future perspectives. Food and chemical toxicology, 51, 15-25.
Carrera‐Quintanar, L., Funes, L., Viudes, E., Tur, J., Micol, V., Roche, E., & Pons, A. (2012). Antioxidant effect of lemon verbena extracts in lymphocytes of university students performing aerobic training program. Scandinavian journal of medicine & science in sports, 22 (4), 454-461.
Casanova, E., García-Mina, J., & Calvo, M. (2008). Antioxidant and antifungal activity of Verbena officinalis L. leaves. Plant Foods for Human Nutrition, 63 (3), 93-97.
Chang-Chen, K., Mullur, R., & Bernal-Mizrachi, E. (2008). β-cell failure as a complication of diabetes. Reviews in Endocrine and Metabolic Disorders, 9 (4), 329.
Choupani, M., Arabshahi Delouee, S., & Alami, M. (2014). Antioxidant properties of various solvent extracts of Lemon Verbena (Lippia citriodora) leaves. International Journal of Advanced Biological and Biomedical Research, 2 (4), 1340-1346.
Chung, S. S., Ho, E. C., Lam, K. S., & Chung, S. K. (2003). Contribution of polyol pathway to diabetes-induced oxidative stress. Journal of the American Society of Nephrology, 14 (suppl 3), S233-S236.
de Bodo, R. C., & Altzuler, N. (1956). Hormonal Regulation of Carbohydrate Metabolism. In Medical Society in the City of New York, Vol. 14 (pp. 51-53): Karger Publishers.
De Martino, L., De Feo, V., Fratianni, F., & Nazzaro, F. (2009). Chemistry, antioxidant, antibacterial and antifungal activities of volatile oils and their components. Natural product communications, 4 (12), 1741-1750.
Deepak, M., & Handa, S. S. (2000). Antiinflammatory activity and chemical composition of extracts of Verbena officinalis. Phytotherapy Research, 14 (6), 463-465.
Di Mascio, P., Kaiser, S., & Sies, H. (1989). Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Archives of biochemistry and biophysics, 274 (2), 532-538.
Diano, S., & Horvath, T. L. (2010). A Sympathetic View on Free Radicals in Diabetes. Neuron, 66 (6), 809-811.
Djordjevic, A., Spasic, S., Jovanovic-Galovic, A., Djordjevic, R., & Grubor-Lajsic, G. (2004). Oxidative stress in diabetic pregnancy: SOD, CAT and GSH-Px activity and lipid peroxidation products. The Journal of Maternal-Fetal & Neonatal Medicine, 16 (6), 367-372.
Du, X., Matsumura, T., Edelstein, D., Rossetti, L., Zsengellér, Z., Szabó, C., & Brownlee, M. (2003). Inhibition of GAPDH activity by poly (ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. Journal of Clinical Investigation, 112 (7), 1049.
Dudai, N., Weinstein, Y., Krup, M., Rabinski, T., & Ofir, R. (2005). Citral is a new inducer of caspase-3 in tumor cell lines. Planta medica, 71 (05), 484-488.
Edelman, S. V. (1998). Type II diabetes mellitus. Advances in internal medicine, 43, 449-500.
Eisenbarth, G. S. (2005). Type 1 diabetes mellitus. Joslin's diabetes mellitus, 14, 399-424.
Encalada, M. A., Rehecho, S., Ansorena, D., Astiasarán, I., Cavero, R. Y., & Calvo, M. I. (2015). Antiproliferative effect of phenylethanoid glycosides from Verbena officinalis L. on Colon Cancer Cell Lines. LWT - Food Science and Technology, 63 (2), 1016-1022.
Fang, Y.-Z., Yang, S., & Wu, G. (2002). Free radicals, antioxidants, and nutrition. Nutrition, 18 (10), 872-879.
Felgines, C., Fraisse, D., Besson, C., Vasson, M.-P., & Texier, O. (2014). Bioavailability of lemon verbena (Aloysia triphylla) polyphenols in rats: impact of colonic inflammation. British Journal of Nutrition, 111 (10), 1773-1781.
Frankel, E. N. (2014). Lipid oxidation: Elsevier.
Freeman, B. A., & Crapo, J. D. (1982). Biology of disease: free radicals and tissue injury. Laboratory investigation; a journal of technical methods and pathology, 47 (5), 412-426.
Frei, B. (1994). Reactive oxygen species and antioxidant vitamins: mechanisms of action. The American journal of medicine, 97 (3), S5-S13.
Fryer, L. G., Parbu-Patel, A., & Carling, D. (2002). The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. Journal of Biological Chemistry, 277 (28), 25226-25232.
Funes, L., Carrera-Quintanar, L., Cerdán-Calero, M., Ferrer, M. D., Drobnic, F., Pons, A., Roche, E., & Micol, V. (2011). Effect of lemon verbena supplementation on muscular damage markers, proinflammatory cytokines release and neutrophils’ oxidative stress in chronic exercise. European journal of applied physiology, 111 (4), 695-705.
Funes, L., Fernández-Arroyo, S., Laporta, O., Pons, A., Roche, E., Segura-Carretero, A., Fernández-Gutiérrez, A., & Micol, V. (2009). Correlation between plasma antioxidant capacity and verbascoside levels in rats after oral administration of lemon verbena extract. Food Chemistry, 117 (4), 589-598.
Georgiev, M., Alipieva, K., Orhan, I., Abrashev, R., Denev, P., & Angelova, M. (2011). Antioxidant and cholinesterases inhibitory activities of Verbascum xanthophoeniceum Griseb. and its phenylethanoid glycosides. Food Chemistry, 128 (1), 100-105.
Ghaemi, E., Khorshidi, D., Moradi, A., Seifi, A., Mazendrani, M., Bazouri, M., & Mansourian, A. R. (2007). The efficacy of Ethanolic extract of Lemon Verbena on the Skin Infection Due to Staphylococcus aureus in an Animal Model. Pakistan Journal of Biological Sciences, 10 (22), 4132-4135.
Goodman, D., McDonnel, J., Nelson, H., Vaughan, T., & Weber, R. (1990). Chronic urticaria exacerbated by the antioxidant food preservatives, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). Journal of allergy and clinical immunology, 86 (4), 570-575.
Halliwell, B. (1995). Antioxidant characterization: methodology and mechanism. Biochemical pharmacology, 49 (10), 1341-1348.
Hernández, N. E., Tereschuk, M. L., & Abdala, L. R. (2000). Antimicrobial activity of flavonoids in medicinal plants from Tafı́ del Valle (Tucumán, Argentina). Journal of Ethnopharmacology, 73 (1), 317-322.
Herranz-López, M., Barrajón-Catalán, E., Segura-Carretero, A., Menéndez, J. A., Joven, J., & Micol, V. (2015). Lemon verbena (Lippia citriodora) polyphenols alleviate obesity-related disturbances in hypertrophic adipocytes through AMPK-dependent mechanisms. Phytomedicine, 22 (6), 605-614.
Jacob, R. A., & Burri, B. J. (1996). Oxidative damage and defense. The American journal of clinical nutrition, 63 (6), 985S-990S.
Jagdale, A. D., Bavkar, L. N., More, T. A., Joglekar, M. M., & Arvindekar, A. U. (2016). Strong inhibition of the polyol pathway diverts glucose flux to protein glycation leading to rapid establishment of secondary complications in diabetes mellitus. Journal of Diabetes and its Complications, 30 (3), 398-405.
Jefferson, J. A., Shankland, S. J., & Pichler, R. H. (2008). Proteinuria in diabetic kidney disease: A mechanistic viewpoint. Kidney International, 74 (1), 22-36.
Junior, G. B., de Abreu, M. S., dos Santos da Rosa, J. G., Pinheiro, C. G., Heinzmann, B. M., Caron, B. O., Baldisserotto, B., & Barcellos, L. J. G. (2015). Lippia alba and Aloysia triphylla essential oils are anxiolytic without inducing aversiveness in fish. Aquaculture.
Kim, K.-H., Tsao, R., Yang, R., & Cui, S. W. (2006). Phenolic acid profiles and antioxidant activities of wheat bran extracts and the effect of hydrolysis conditions. Food Chemistry, 95 (3), 466-473.
Koya, D., & King, G. L. (1998). Protein kinase C activation and the development of diabetic complications. Diabetes, 47 (6), 859-866.
Krauter, T., Ruppersberg, J. P., & Baukrowitz, T. (2001). Phospholipids as modulators of KATP channels: distinct mechanisms for control of sensitivity to sulphonylureas, K+ channel openers, and ATP. Molecular Pharmacology, 59 (5), 1086-1093.
Lai, S.-W., Yu, M.-S., Yuen, W.-H., & Chang, R. C.-C. (2006). Novel neuroprotective effects of the aqueous extracts from Verbena officinalis Linn. Neuropharmacology, 50 (6), 641-650.
Larsen, J., Hylleberg, B., Ng, K., & Damsbo, P. (2001). Glucagon-like peptide-1 infusion must be maintained for 24 h/day to obtain acceptable glycemia in type 2 diabetic patients who are poorly controlled on sulphonylurea treatment. Diabetes care, 24 (8), 1416-1421.
Lin, P.-C., Lee, J. J., & Chang, I. J. (2016). Essential oils from Taiwan: Chemical composition and antibacterial activity against Escherichia coli. Journal of Food and Drug Analysis, 24 (3), 464-470.
Makino, Y., Kondo, S., Nishimura, Y., Tsukamoto, Y., HUANG, Z. L., & Urade, Y. (2009). Hastatoside and verbenalin are sleep‐promoting components in Verbena officinalis. Sleep and Biological Rhythms, 7 (3), 211-217.
Matschinsky, F. M. (1990). Glucokinase as glucose sensor and metabolic signal generator in pancreatic β-cells and hepatocytes. Diabetes, 39 (6), 647-652.
Mayer, J. P., Zhang, F., & DiMarchi, R. D. (2007). Insulin structure and function. Peptide Science, 88 (5), 687-713.
Miller, R. A., Chu, Q., Xie, J., Foretz, M., Viollet, B., & Birnbaum, M. J. (2013). Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature, 494 (7436), 256-260.
Murakami, K., Tobe, K., Ide, T., Mochizuki, T., Ohashi, M., Akanuma, Y., Yazaki, Y., & Kadowaki, T. (1998). A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and PPAR-gamma: effect of PPAR-alpha activation on abnormal lipid metabolism in liver of Zucker fatty rats. Diabetes, 47 (12), 1841-1847.
Nauck, M., Kleine, N., Ørskov, C., Holst, J. J., Willms, B., & Creutzfeldt, W. (1993). Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia, 36 (8), 741-744.
Ohno, T., Kita, M., Yamaoka, Y., Imamura, S., Yamamoto, T., Mitsufuji, S., Kodama, T., Kashima, K., & Imanishi, J. (2003). Antimicrobial activity of essential oils against Helicobacter pylori. Helicobacter, 8 (3), 207-215.
Olefsky, J. M., Saekow, M., Tager, H., & Rubenstein, A. (1980). Characterization of a mutant human insulin species. Journal of Biological Chemistry, 255 (13), 6098-6105.
Phan, C.-W., Lee, G.-S., Hong, S.-L., Wong, Y.-T., Brkljača, R., Urban, S., Malek, S. N. A., & Sabaratnam, V. (2014). Hericium erinaceus (Bull.: Fr) Pers. cultivated under tropical conditions: isolation of hericenones and demonstration of NGF-mediated neurite outgrowth in PC12 cells via MEK/ERK and PI3K-Akt signaling pathways. Food & function, 5 (12), 3160-3169.
Rasmussen, B. B., Fujita, S., Wolfe, R. R., Mittendorfer, B., Roy, M., Rowe, V. L., & Volpi, E. (2006). Insulin resistance of muscle protein metabolism in aging. The FASEB journal, 20 (6), 768-769.
Razavi, M., Zargarani, N., & Hosseinzadeh, H. (2017). Anti-anxiety and hypnotic effects of ethanolic and aqueous extracts of Lippia citriodora leaves and verbascoside in mice. Avicenna Journal of Phytomedicine, 1-11.
Rehecho, S., Hidalgo, O., García-Iñiguez de Cirano, M., Navarro, I., Astiasarán, I., Ansorena, D., Cavero, R. Y., & Calvo, M. I. (2011). Chemical composition, mineral content and antioxidant activity of Verbena officinalis L. LWT - Food Science and Technology, 44 (4), 875-882.
Riedl, K. M., Carando, S., Alessio, H. M., McCarthy, M., & Hagerman, A. E. (2002). Antioxidant activity of tannins and tannin-protein complexes: assessment in vitro and in vivo. In: ACS Publications.
Sah, S. P., Singh, B., Choudhary, S., & Kumar, A. (2016). Animal models of insulin resistance: A review. Pharmacological Reports, 68 (6), 1165-1177.
Sahlin, E., Savage, G., & Lister, C. (2004). Investigation of the antioxidant properties of tomatoes after processing. Journal of Food composition and Analysis, 17 (5), 635-647.
Saltiel, A. R., & Kahn, C. R. (2001). Insulin signalling and the regulation of glucose and lipid metabolism. Nature, 414 (6865), 799-806.
Sarma, B. K., & Mugesh, G. (2005). Glutathione peroxidase (GPx)-like antioxidant activity of the organoselenium drug ebselen: unexpected complications with thiol exchange reactions. Journal of the American Chemical Society, 127 (32), 11477-11485.
Schmidt, D., Frommer, W., Junge, B., Müller, L., Wingender, W., Truscheit, E., & Schäfer, D. (1977). α-Glucosidase inhibitors. Naturwissenschaften, 64 (10), 535-536.
Shim, H.-K., Kim, S.-Y., Kim, B.-R., Cho, J.-P., Park, Y.-J., Ji, W.-G., Cha, D.-S., & Jeon, H. (2010). Anti-inflammatory and radical scavenging properties of Verbena officinalis. Oriental Pharmacy and Experimental Medicine, 10 (4), 310-318.
Slivka, A., Mytilineou, C., & Cohen, G. (1987). Histochemical evaluation of glutathione in brain. Brain research, 409 (2), 275-284.
Speroni, E., Cervellati, R., Costa, S., Guerra, M., & Utan, A. (2007). Effects of Differential Extraction of Verbena officinalis on Rat Models of Inflammation, Cicatrization and Gastric Damage. Planta Med, 73, 227-235.
Strachan, M. W. (2003). Insulin and cognitive function. The Lancet, 362 (9392), 1253.
Topinka, J., Binkova, B., Sram, R., & Erin, A. (1989). The influence of α-tocopherol and pyritinol on oxidative DNA damage and lipid peroxidation in human lymphocytes. Mutation Research Letters, 225 (3), 131-136.
Vanajothi, R., Sudha, A., Manikandan, R., Rameshthangam, P., & Srinivasan, P. (2012). Luffa acutangula and Lippia nodiflora leaf extract induces growth inhibitory effect through induction of apoptosis on human lung cancer cell line. Biomedicine & Preventive Nutrition, 2 (4), 287-293.
Veisi, M., Shahidi, S., Komaki, A., & Sarihi, A. (2016). Analgesic Effects of the Aqueous Lemon Verbena Extract in Rats. Neurophysiology, 48 (2), 107-110.
Weyer, C., Funahashi, T., Tanaka, S., Hotta, K., Matsuzawa, Y., Pratley, R. E., & Tataranni, P. A. (2001). Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. The Journal of Clinical Endocrinology & Metabolism, 86 (5), 1930-1935.
Wilkinson, J. M., & Cavanagh, H. (2005). Antibacterial activity of essential oils from Australian native plants. Phytotherapy Research, 19 (7), 643-646.
Williamson, J. R., Chang, K., Frangos, M., Hasan, K. S., Ido, Y., Kawamura, T., Nyengaard, J. R., van Den Enden, M., Kilo, C., & Tilton, R. G. (1993). Hyperglycemic pseudohypoxia and diabetic complications. Diabetes, 42 (6), 801-813.
Yapo-Kicho, D., Lagant, P., & Vergoten, G. (2007). The SPASIBA Force Field for Studying Iron-Tannins Interactions: Application to Fe3+/Fe2+ Catechol Complexe. International journal of molecular sciences, 8 (3), 259-272.