櫸抽出成分延緩老化及阿茲海默症之功效

Extractives from Zelkova serrata Delay the Aging Process and Alzheimer’s Disease

10.6342/NTU201703100

顏佩翎

阿茲海默症 ； 抗發炎活性 ； 抗氧化活性 ； 類澱粉β胜肽 ； 乙醇抽出物 ； 精油 ； 櫸 ； Alzheimer’s disease ； amyloid β-peptide ； antiinflammatory activity ； antioxidant activity ； ethanolic extracts ； essential oils ； Zelkova serrata

國立臺灣大學森林環境暨資源學系學位論文

2017年

博士

張上鎮

繁體中文

櫸 (Zelkova serrata (Thunb.) Makino) 為臺灣闊葉樹五木之一，且為傳統藥用植物。本研究目的為評估櫸心材、邊材及樹皮等3部位精油及乙醇抽出物之抗氧化及抗發炎活性，並利用模式生物－秀麗隱桿線蟲 (Caenorhabditis elegans (Maupas) Dougherty) 評估其延緩老化及減緩阿茲海默症之功效。 體外試驗結果顯示，心材精油具有良好的捕捉自由基活性及含有酚類化合物 (161.4 mg of GAE/g)。樹皮抽出物之總酚類化合物含量高 (288.1 mg of GAE/g) 且具有良好自由基捕捉能力及還原力，卻不具抗發炎活性。心材抽出物的總酚類 (234.8 mg of GAE/g) 及黃酮類化合物含量 (348.5 mg of RE/g) 皆高，不但具有高自由基捕捉能力，且具高抗發炎活性。因此，乃進一步評估心材抽出物各可溶部之抗氧化及抗發炎活性。結果顯示，乙酸乙酯可溶部的收率高且抗氧化活性佳，但不具抗發炎活性；正己烷可溶部的收率次之，兼具抗氧化及抗發炎活性。體內試驗結果顯示，心材精油能顯著降低胡桃醌及高溫誘導野生型C. elegans (N2 strain) 所產生氧化壓力；心材抽出物、其各可溶部及E10次分離部亦能顯著提高野生型C. elegans對胡桃醌及高溫的壓力耐受性。 以生物活性為導向，由櫸心材精油及抽出物共獲得17個成分，包含15個萜類及2個黃酮類化合物，其中，7-Methoxyzelkoserratone (4)、3-Hydroxy-7-methoxy-3(4H)-isocadalen-4-one (5)、4-Methoxymansonone G (6)、6-Hydroxy-5-isopropyl-2,8-dimethyl-2,3-dihydro-[1,4]naphthoquinone (8)、4,7-Dihydroxy-calamenen-3-one (10)、3-Methoxy-7-hydroxy-3(4H)-isocadalen-4-one (11)、1α-Hydroxy-7-methoxy-1(4H)-isocadalen-4-one (12) 為首次在天然物中發現之成分，7-Hydrxycalamenene (1)、7-Hydroxycadalene (2)、7-Hydroxy-calamenen-3-one (9)、3,7-Dihydroxy-3(4H)-isocadalen-4-one (13) 及Mansonone G (15) 則首次由櫸分離而得。 由體外試驗結果得知，7-Hydroxycalamenene (1)、7-Hydroxy-3-methoxycadalene (3) 及Kaempferol-6-C-glucoside (17) 之抗氧化活性較佳；7-Hydroxy-3-methoxycadalene (3)、7-Hydroxy-calamenen-3-one (9) 及3,7-Dihydroxy-3(4H)-isocadalen-4-one (13) 之抗發炎活性較佳。心材精油主成分7-Hydroxycalamenene (1) 為體內抗氧化活性來源，且能減緩基因轉殖C. elegans (CL4176 strain) 因類澱粉β胜肽累積所造成的癱瘓，推論其有潛力成為減緩阿茲海默症之藥劑或保健產品。心材抽出物E10次分離部之主成分－Kaempferol-6-C-glucoside (17) 在正常環境能些微提高野生型C. elegans壽命期，卻無延緩老化之功效；然而，在胡桃醌誘導氧化壓力及高溫環境中，Kaempferol-6-C-glucoside (17) 可顯著提升野生型C. elegans壽命期。進一步研究結果顯示，在胡桃醌氧化壓力下，Kaempferol-6-C-glucoside (17) 可能透過增加轉錄因子DAF-16 (Dauer formation-16) 及SKN-1 (Skinhead-1) 進入細胞核之比例，分別提高下游壓力反應蛋白SOD-3 (Superoxide dismutase-3) 及GST-4 (Glutathione S-transferase-4) 之基因表現量，進而提升C. elegans之壓力耐受性。 本研究結果證實櫸心材精油及抽出物具有體內及體外抗氧化活性，並具有潛力治療阿茲海默症，顯示櫸心材抽出成分極具潛力開發為抗氧化及減緩阿茲海默症之保健食品或藥物。

Taiwan zelkova (Zelkova serrata (Thunb.) Makino) is one of the five most precious hardwood trees in Taiwan, and is also a medical plant based on traditional knowledge. The aim of this study was to evaluate antioxidant and antiinflammatoy activities of essential oils and ethanolic extracts from three plant parts (heartwood, sapwood, and bark) of Z. serrata. In addition, the potential to delay the ageing process and to protect against amyloid-β toxicity of essential oils and ethanolic extracts from Z. serrata were investigated in the model organism Caenorhabditis elegans. Results obtained from in vitro assays demonstrated that the essential oil of Z. serrata heartwood exhibited good radical scavenging activities and high total phenolic content (161.4 mg of GAE/g). The bark extract contained the highest level of total phenolic content (288.1 mg of GAE/g), and possessed excellent free radical scavenging activities and reducing power, but bark extract did not exhibit antiinflammatoy activity. The heartwood extract contained high levels of total phenolic (234.8 mg of GAE/g) and total flavonoid contents (348.5 mg of RE/g), and had both antioxidant and antiinflammatoy activities. The antioxidant and antiinflammatoy activities of 4 soluble fractions from heartwood extract were further examined. Results showed that the ethyl acetate soluble fraction had the highest yield and good antioxidant activities, but no antiinflammatoy potential. The n-hexane soluble fraction had high yield as well as good antioxidant and antiinflammatory activities. In vivo assays showed the essential oil of heartwood significantly inhibited oxidative damage in wild-type C. elegans (N2 strain) under juglone-induced oxidative stress and heat shock. The heartwood extract, its soluble fractions and subfraction E10 also significantly increased stress resistance to juglone and heat stress in wild-type C. elegans. 17 compounds, including 15 sesquiterpenes and 2 flavonoids, were obtained from essential oil and extract of heartwood after a bio-guided fractionation. 7-Methoxyzelkoserratone (4), 3-hydroxy-7-methoxy-3(4H)-isocadalen-4-one (5), 4-methoxymansonone G (6), 6-hydroxy-5-isopropyl-2,8-dimethyl-2,3-dihydro-[1,4] naphthoquinone (8), 4,7-dihydroxy-calamenen-3-one (10), 3-methoxy-7-hydroxy- 3(4H)-isocadalen-4-one (11), and 1α-hydroxy-7-methoxy-1(4H)-isocadalen-4-one (12) were firstly isolated from nature. 7-Hydrxycalamenene (1), 7-hydroxycadalene (2), 7-hydroxy-calamenen-3-one (9), 3,7-dihydroxy-3(4H)-isocadalen-4-one (13), and mansonone G (15) were isolated from Z. serrata for the first time. In vitro assays showed that 7-hydroxycalamenene (1), 7-hydroxy- 3-methoxycadalene (3), and kaempferol-6-C-glucoside (17) exhibited antioxidant activities; 7-hydroxy-3-methoxycadalene (3), 7-hydroxy-calamenen-3-one (9), and 3,7-dihydroxy-3(4H)-isocadalen-4-one (13) had anti-inflammatory activities. Additionally, the major compound in essential oil of heartwood, 7-hydroxycalamenene, may contribute significantly to the observed antioxidant activity. Further evidence showed that 7-hydroxycalamenene (1) significantly delayed the paralysis phenotype in amyloid beta-expressing transgenic C. elegans (CL4176 strain), revealing that the potential for drugs dietary supplements to slow progress of Alzheimer’s disease. The major compound in subfraction E10 of heartwood extract, kaempferol-6-C-glucoside (17), slightly extended the lifespan of wild-type C. elegans but did not affect the aging behaviors under normal condition. However, kaempferol-6-C-glucoside (17) significantly increased the longevity of wild-type C. elegans under juglone-induced oxidative and thermal stresses. Furthermore, results revealed that kaempferol-6-C-glucoside (17) enhanced the translocations of the transcription factors DAF-16 (dauer formation-16) and SKN-1 (skinhead-1), thereby up-regulating the downstream gene expression of stress response proteins SOD-3 (superoxide dismutase-3) and GST-4 (glutathione S-transferase-4), respectively, to enhance the stress resistance in C. elegans. The study demonstrated the essential oils and extracts of Z. serrata exhibited in vitro and in vivo antioxidant activities, and has potential to be used as a source for treatment of Alzheimer’s disease. These findings suggest that the extractives from Z. serrata heartwood has potential to be used as health-care food or drug for antioxidant or Alzheimer’s disease treatment.

1. Abbas, S. and M. Wink (2009) Epigallocatechin gallate from green tea (Camellia sinensis) increases lifespan and stress resistance in Caenorhabditis elegans. Planta Medica 75(3): 216-221.
   連結：
2. Abbas, S. and M. Wink (2010) Epigallocatechin gallate inhibits beta amyloid oligomerization in Caenorhabditis elegans and affects the daf-2/insulin-like signaling pathway. Phytomedicine 17(11): 902-909.
   連結：
3. Aisen, P. S. (2002) The potential of anti-inflammatory drugs for the treatment of Alzheimer's disease. The Lancet Neurology 1(5): 279-284.
   連結：
4. Alexander, A. G., V. Marfil and C. Li (2014) Use of Caenorhabditis elegans as a model to study Alzheimer’s disease and other neurodegenerative diseases. Frontiers in Genetics 5: 279.
   連結：
5. Alvarez, X. A., A. Franco, L. Fernandez-Novoa and R. Cacabelos (1996) Blood levels of histamine, IL-1 beta, and TNF-alpha in patients with mild to moderate Alzheimer disease. Molecular and Chemical Neuropathology 29(2-3): 237-252.
   連結：
6. Alzheimer's Association (2015) Alzheimer's Association report 2015: Alzheimer's disease facts and figures. Alzheimer's and Dementia 11(3): 332-384.
   連結：
7. Amorati, R., M. C. Foti and L. Valgimigli (2013) Antioxidant activity of essential oils. Journal of Agricultural and Food Chemistry 61(46): 10835-10847.
   連結：
8. An, J. H. and T. K. Blackwell (2003) SKN-1 links C. elegans mesendodermal specification to a conserved oxidative stress response. Genes and Development 17(15): 1882-1893.
   連結：
9. Apak, R., M. Ozyurek, K. Guclu and E. Capanoglu (2016a) Antioxidant activity/capacity measurement. 2. Hydrogen atom transfer (HAT)-based, mixed-mode (electron transfer (ET)/HAT), and lipid peroxidation assays. Journal of Agricultural and Food Chemistry 64(5): 1028-1045.
   連結：
10. Apak, R., M. Ozyurek, K. Guclu and E. Capanoglu (2016b) Antioxidant activity/capacity measurement. 1. Classification, physicochemical principles, mechanisms, and electron transfer (ET)-based assays. Journal of Agricultural and Food Chemistry 64(5): 997-1027.
    連結：
11. Azevedo, M., F. Chaves, C. Almeida, H. Bizzo, R. Duarte, G. Campos-Takaki, C. Alviano and D. Alviano (2013) Antioxidant and antimicrobial activities of 7-hydroxy-calamenene-rich essential oils from Croton cajucara Benth. Molecules 18(1): 1128-1137.
    連結：
12. Azevedo, M. M. B., C. A. Almeida, F. C. M. Chaves, G. M. Campos-Takaki, S. Rozental, H. R. Bizzo, C. S. Alviano and D. S. Alviano (2014) Effects of 7-hydroxycalamenene isolated from Croton cajucara essential oil on growth, lipid content and ultrastructural aspects of Rhizopus oryzae. Planta Medica 80(7): 550-556.
    連結：
13. Balaban, R. S., S. Nemoto and T. Finkel (2005) Mitochondria, oxidants, and aging. Cell 120(4): 483-495.
    連結：
14. Bartosz, G. (2006) Use of spectroscopic probes for detection of reactive oxygen species. Clinica Chimica Acta 368(1-2): 53-76.
    連結：
15. Bauer, J. H., S. Goupil, G. B. Garber and S. L. Helfand (2004) An accelerated assay for the identification of lifespan-extending interventions in Drosophila melanogaster. Proceedings of the National Academy of Sciences of the United States of America 101(35): 12980-12985.
    連結：
16. Baur, J. A. and D. A. Sinclair (2006) Therapeutic potential of resveratrol: The in vivo evidence. Nature Reviews Drug Discovery 5(6): 493-506.
    連結：
17. Bavaresco, L., L. Lucini, M. Busconi, R. Flamini and M. De Rosso (2016) Wine resveratrol: From the ground up. Nutrients 8(4): 8.
    連結：
18. Billack, B. (2006) Macrophage activation: Role of toll-like receptors, nitric oxide, and nuclear factor kappa B. American Journal of Pharmaceutical Education 70(5): 102.
    連結：
19. Birrell, M. A., K. McCluskie, S. Wong, L. E. Donnelly, P. J. Barnes and M. G. Belvisi (2005) Resveratrol, an extract of red wine, inhibits lipopolysaccharide induced airway neutrophilia and inflammatory mediators through an NF-kappaB-independent mechanism. FASEB Journal 19(7): 840-841.
    連結：
20. Bohlmann, F., M. Wallmeyer, J. Jakupovic and J. Ziesche (1983) Diterpenes and sesquiterpenes from Osteospermum species. Phytochemistry 22(7): 1645-1651.
    連結：
21. Boumerfeg, S., A. Baghiani, M. Djarmouni, D. Ameni, M. Adjadj, F. Belkhiri, N. Charef, S. Khennouf and L. Arrar (2012) Inhibitory activity on xanthine oxidase and antioxidant properties of Teucrium polium. Chinese Medicine 3(1): 30-41.
    連結：
22. Bowden, B., J. Coll, L. Engelhardt, D. Tapiolas and A. White (1986) Studies of Australian soft corals. XXXVI. The isolation and structure determination of 11 calamenene-based sesquiterpenes from Lemnalia cervicornis (Coelenterata, Octocorallia, Alcyonacea). Australian Journal of Chemistry 39(1): 103-121.
    連結：
23. Braak, H. and E. Braak (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathologica 82(4): 239-259.
    連結：
24. Braak, H. and E. Braak (1994) Morphological criteria for the recognition of Alzheimer's disease and the distribution pattern of cortical changes related to this disorder. Neurobiology of Aging 15(3): 355-356.
    連結：
25. Brenner, S. (1974) The genetics of Caenorhabditis elegans. Genetics 77(1): 71-94.
    連結：
26. Brown, M. K., J. L. Evans and Y. Luo (2006) Beneficial effects of natural antioxidants EGCG and alpha-lipoic acid on life span and age-dependent behavioral declines in Caenorhabditis elegans. Pharmacology Biochemistry and Behavior 85(3): 620-628.
    連結：
27. Budovskaya, Y. V., K. Wu, L. K. Southworth, M. Jiang, P. Tedesco, T. E. Johnson, S. K. Kim (2008) An elt-3/elt-5/elt-6 GATA transcription circuit guides aging in C. elegans. Cell 134(2): 291-303.
    連結：
28. Burden, R. S. and M. S. Kemp (1983) (−)-7-hydroxycalamenene, a phytoalexin from Tilia europea. Phytochemistry 22(4): 1039-1040.
    連結：
29. Burden, R. S. and M. S. Kemp (1984) Sesquiterpene phytoalexins from Ulmus glabra. Phytochemistry 23(2): 383-385.
    連結：
30. Burits, M. and F. Bucar (2000) Antioxidant activity of Nigella sativa essential oil. Phytotherapy Research 14(5): 323-328.
    連結：
31. Burton, G. W., T. Doba, E. J. Gabe, L. Hughes, F. L. Lee, L. Prasad and K. U. Ingold (1985) Autoxidation of biological molecules. 4. Maximizing the antioxidant activity of phenols. Journal of the American Chemical Society 107(24): 7053-7065.
    連結：
32. Butterfield, D. A. and D. Boyd-Kimball (2005) The critical role of methionine 35 in Alzheimer's amyloid-beta-peptide (1-42)-induced oxidative stress and neurotoxicity. BBA-Proteins Proteomics 1703(2): 149-156.
    連結：
33. Cadenas, E. and K. J. A. Davies (2000) Mitochondrial free radical generation, oxidative stress, and aging. Free Radical Biology and Medicine 29(3-4): 222-230.
    連結：
34. Cambie, R. C., A. R. Lal and F. Ahmad (1990) Sesquiterpenes from Heritiera ornithocephala. Phytochemistry 29(7): 2329-2331.
    連結：
35. Cai, W. J., J. H. Huang, S. Q. Zhang, B. Wu, P. Kapahi, X. M. Zhang and Z. Y. Shen (2011) Icariin and its derivative icariside ii extend healthspan via Insulin/IGF-1 pathway in C. elegans. PLoS One 6(12): e28835.
    連結：
36. Chan, E. D. and D. W. H. Riches (2001) IFN-γ+LPS induction of iNOS is modulated by ERK, JNK/SAPK, and p38 MAPK in a mouse macrophage cell line. American Journal of Physiology - Cell Physiology 280(3): C441-C450.
    連結：
37. Chang, C. H., C. T. Ho and V. H. Liao (2017) N-gamma-(L-glutamyl)-L-selenomethionine enhances stress resistance and ameliorates aging indicators via the selenoprotein TRXR-1 in Caenorhabditis elegans. Molecular Nutrition and Food Research doi: 10.1002/mnfr.201600954.
    連結：
38. Chao, L. K. P., K. F. Hua, H. Y. Hsu, Y. C. Su and S. T. Chang (2006) Bioactivity assay of extracts from Calocedrus macrolepis var. formosana bark. Bioresource Technology 97(18): 2462-2465.
    連結：
39. Chen, G., W. Shan, Y. Wu, L. Ren, J. Dong and Z. Ji (2005) Synthesis and anti-inflammatory activity of resveratrol analogs. Chemical and Pharmaceutical Bulletin 53(12): 1587-1590.
    連結：
40. Chen, W., I. R. Sudji, E. Wang, E. Joubert, B. E. van Wyk and M. Wink (2013) Ameliorative effect of aspalathin from rooibos (Aspalathus linearis) on acute oxidative stress in Caenorhabditis elegans. Phytomedicine 20(3-4): 380-386.
    連結：
41. Cheng, S. C., W. H. Li, Y. C. Shi, P. L. Yen, H. Y. Lin, V. H. C. Liao and S. T. Chang (2014) Antioxidant activity and delayed aging effects of hot water extract from Chamaecyparis obtusa var. formosana leaves. Journal of Agricultural and Food Chemistry 62(18): 4159-4165.
    連結：
42. Cheng, S. S., P. L. Yen and S. T. Chang (2015) Phytochemicals from wood extract of Cunninghamia konishii Hayata as antioxidant agents. Industrial Crops and Products 64: 39-44.
    連結：
43. Choi, Y. T., C. H. Jung, S. R. Lee, J. H. Bae, W. K. Baek, M. H. Suh, J. Park, C. W. Park and S. I. Suh (2001) The green tea polyphenol (−)-epigallocatechin gallate attenuates β-amyloid-induced neurotoxicity in cultured hippocampal neurons. Life Sciences 70(5): 603-614.
    連結：
44. Choi, S. Y., S. Lee, W. H. Choi, Y. Lee, Y. O. Jo and T. Y. Ha (2010) Isolation and anti-Inflammatory activity of bakuchiol from Ulmus davidiana var. japonica. Journal of Medicinal Food 13(4): 1019-1023.
    連結：
45. Chung, H. Y., B. Sung, K. J. Jung, Y. Zou and B. P. Yu (2006) The molecular inflammatory process in aging. Antioxidants and Redox Signaling 8(3-4): 572-581.
    連結：
46. Cohen, M. C. and S. Cohen (1996) Cytokine function - A study in biologic diversity. American Journal of Clinical Pathology 105(5): 589-598.
    連結：
47. Collins, J. S., R. T. Perry, B. Watson, L. E. Harrell, R. T. Acton, D. Blacker, M. S. Albert, R. E. Tanzi, S. S. Bassett, M. G. McInnis, R. D. Campbell and R. C. P. Go (2000) Association of a haplotype for tumor necrosis factor in siblings with late-onset Alzheimer disease: The NIMH Alzheimer disease genetics initiative. American Journal of Medical Genetics 96(6): 823-830.
    連結：
48. Collins, J. J., C. Huang, S. Hughes and K. Kornfeld (2008) The measurement and analysis of age-related changes in Caenorhabditis elegans. WormBook 24: 1-21.
    連結：
49. Conaghan, P. G. (2012) A turbulent decade for NSAIDs: Update on current concepts of classification, epidemiology, comparative efficacy, and toxicity. Rheumatology International 32(6): 1491-1502.
    連結：
50. Coombes, A. J. (2012) The A to Z of Plant Names: A Quick Reference Guide to 4000 Garden Plants, Timber Press, Oregon. 312 pp.
    連結：
51. Coutinho, A. E. and K. E. Chapman (2011) The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Molecular and Cellular Endocrinology 335(1): 2-13.
    連結：
52. Croll, N. A., J. M. Smith and B. M. Zuckerman (1977) The aging process of the nematode Caenorhabditis elegans in bacterial and axenic culture. Experimental Aging Research 3(3): 175-189.
    連結：
53. Da Costa, J. P., R. Vitorino, G. M. Silva, C. Vogel, A. C. Duarte and T. Rocha-Santos (2016) A synopsis on aging—Theories, mechanisms and future prospects. Ageing Research Reviews 29: 90-112.
    連結：
54. Da Silva, J. K. R., P. J. C. Sousa, E. H. A. Andrade and J. G. S. Maia (2007) Antioxidant capacity and cytotoxicity of essential oil and methanol extract of Aniba canelilla (H.B.K.) Mez. Journal of Agricultural and Food Chemistry 55(23): 9422-9426.
    連結：
55. Das, N. P. and T. A. Pereira (1990) Effects of flavonoids on thermal autoxidation of palm oil: Structure-activity relationships. Journal of the American Oil Chemists Society 67(4): 255-258.
    連結：
56. Davila-Huerta, G., H. Hamada, G. D. Davis, R. D. Stipanovic, C. M. Adams and M. Essenberg (1995) Cadinane-type sesquiterpenes induced in Gossypium cotyledons by bacterial inoculation. Phytochemistry 39(3): 531-536.
    連結：
57. Di Meo, S., T. T. Reed, P. Venditti and V. M. Victor (2016) Role of ROS and RNS sources in physiological and pathological conditions. Oxidative Medicine and Cellular Longevity 2016: 1245049.
    連結：
58. Diomede, L., G. Cassata, F. Fiordaliso, M. Salio, D. Ami, A. Natalello, S. M. Doglia, A. De Luigi and M. Salmona (2010) Tetracycline and its analogues protect Caenorhabditis elegans from beta amyloid-induced toxicity by targeting oligomers. Neurobiology of Disease 40(2): 424-431.
    連結：
59. Djouahri, A., S. Boualem, L. Boudarene and A. Baaliouamer (2015) Geographic's variation impact on chemical composition, antioxidant and anti-inflammatory activities of essential oils from wood and leaves of Tetraclinis articulata (Vahl) Masters. Industrial Crops and Products 63: 138-146.
    連結：
60. Doonan, R. J. J. McElwee, F. Matthijssens, G. A. Walker, K. Houthoofd, P. Back, A. Matscheski, J. R. Vanfleteren and D. Gems (2008) Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans. Genes and Development 22(23): 3236–3241.
    連結：
61. Drake, J., C. D. Link and D. A. Butterfield (2003) Oxidative stress precedes fibrillar deposition of Alzheimer's disease amyloid beta-peptide (1-42) in a transgenic Caenorhabditis elegans model. Neurobiology of Aging 24(3): 415-420.
    連結：
62. Dubois, R. N., S. B. Abramson, L. Crofford, R. A. Gupta, L. S. Simon, L. B. A. van De Putte and P. E. Lipsky (1998) Cyclooxygenase in biology and disease. FASEB Journal 12(12): 1063-1073.
    連結：
63. Fauconneau, B., P. Waffo-Teguo, F. Huguet, L. Barrier, A. Decendit and J. M. Merillon (1997) Comparative study of radical scavenger and antioxidant properties of phenolic compounds from Vitis vinifera cell cultures using in vitro tests. Life Sciences 61(21): 2103-2110.
    連結：
64. Fenton, H. J. H. (1894) LXXIII.-Oxidation of tartaric acid in presence of iron. Journal of the Chemical Society, Transactions 65: 899-910.
    連結：
65. Fillit, H., W. Ding, L. Buee, J. Kalman, L. Altstiel, B. Lawlor and G. Wolfklein (1991) Elevated circulating tumor-necrosis-factor levels in Alzheimers-disease. Neuroscience Letters 129(2): 318-320.
    連結：
66. Firuzi, O., M. Asadollahi, M. Gholami and K. Javidnia (2010) Composition and biological activities of essential oils from four Heracleum species. Food Chemistry 122(1): 117-122.
    連結：
67. Frankel, E. N. and J. W. Finley (2008) How to standardize the multiplicity of methods to evaluate natural antioxidants. Journal of Agricultural and Food Chemistry 56(13): 4901-4908.
    連結：
68. Gerstbrein, B., G. Stamatas, N. Kollias and M. Driscoll (2005) In vivo spectrofluorimetry reveals endogenous biomarkers that report healthspan and dietary restriction in Caenorhabditis elegans. Aging Cell 4(3): 127-137.
    連結：
69. Gillespie, Z. E., J. Pickering and C. H. Eskiw (2016) Better living through chemistry: Caloric restriction (CR) and CR mimetics alter genome function to promote increased health and lifespan. Frontiers in Genetics 18(7): 142.
    連結：
70. Govindarajan, V. S. and W. H. Stahl (1980) Turmeric—chemistry, technology, and quality. C R C Critical Reviews in Food Science and Nutrition 12(3): 199-301.
    連結：
71. Grünz, G., K. Haas, S. Soukup, M. Klingenspor, S. E. Kulling, H. Daniel and B. Spanier (2012) Structural features and bioavailability of four flavonoids and their implications for lifespan-extending and antioxidant actions in C. elegans. Mechanisms of Ageing and Development 133(1): 1-10.
    連結：
72. Guarente, L. and C. Kenyon (2000) Genetic pathways that regulate ageing in model organisms. Nature 408(6809): 255-262.
    連結：
73. Guha, S., M. Cao, R. M. Kane, A. M. Savino, S. Zou and Y. Dong (2013) The longevity effect of cranberry extract in Caenorhabditis elegans is modulated by daf-16 and osr-1. Age 35(5): 1559-1574.
    連結：
74. Gutierrez-Zepeda, A., R. Santell, Z. X. Wu, M. Brown, Y. J. Wu, I. Khan, C. D. Link, B. L. Zhao and Y. Luo (2005) Soy isoflavone glycitein protects against beta amyloid-induced toxicity and oxidative stress in transgenic Caenorhabditis elegans. BMC Neuroscience 6: 54.
    連結：
75. Halliwell, B. and J. M. C. Gutteridge (1999) Free Radicals in Biology and Medicine. Oxford University Press, New York. 704 pp.
    連結：
76. Haque, A. M., M. Hashimoto, M. Katakura, Y. Hara and O. Shido (2008) Green tea catechins prevent cognitive deficits caused by Abeta1-40 in rats. Journal of Nutritional Biochemistry 19(9): 619-626.
    連結：
77. Heilbronn, L. K. and E. Ravussin (2003) Calorie restriction and aging: Review of the literature and implications for studies in humans. American Journal of Clinical Nutrition 78(3): 361-369.
    連結：
78. Higdon, J. V. and B. Frei (2003) Tea catechins and polyphenols: Health effects, metabolism, and antioxidant functions. Critical Reviews in Food Science and Nutrition 43(1): 89-143.
    連結：
79. Holtzman, D. M., J. C. Morris and A. M. Goate (2011) Alzheimer's disease: The challenge of the second century. Science Translational Medicine 3(77): 77sr1.
    連結：
80. Honda, Y. and S.Honda (1999) The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. FASEB Journal 13(11): 1385–1393.
    連結：
81. Hopkins, C. Y. and M. J. Chisholm (1959) Composition of Zelkova seed oil. Journal of the American Oil Chemists Society 36(5): 210-212.
    連結：
82. Hosono, R., S. Nishimoto and S. Kuno (1989) Alterations of life-span in the nematode Caenorhabditis elegans under monoxenic culture conditions. Experimental Gerontology 24(3): 251-264.
    連結：
83. Howitz, K. T., K. J. Bitterman, H. Y. Cohen, D. W. Lamming, S. Lavu, J. G. Wood, R. E. Zipkin, P. Chung, A. Kisielewski, L. L. Zhang, B. Scherer and D. A. Sinclair (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425(6954): 191-196.
    連結：
84. Hsieh, C. Y. and S. T. Chang (2010) Antioxidant activities and xanthine oxidase inhibitory effects of phenolic phytochemicals from Acacia confusa twigs and branches. Journal of Agricultural and Food Chemistry 58(3): 1578-1583.
    連結：
85. Huberman, M., B. Sredni, L. Stern, E. Kott and F. Shalit (1995) IL-2 and IL-6 secretion in dementia - Correlation with type and severity of disease. Journal of the Neurological Sciences 130(2): 161-164.
    連結：
86. Hulbert, A. J. (2005) On the importance of fatty acid composition of membranes for aging. Journal of Theoretical Biology 234(2): 277-288.
    連結：
87. Hulbert, A. J. (2010) Metabolism and longevity: Is there a role for membrane fatty acids? Integrative and Comparative Biology 50(5): 808-817.
    連結：
88. Hulbert, A. J., S. C. Faulks and R. Buffenstein (2006) Oxidation-resistant membrane phospholipids can explain longevity differences among the longest-living rodents and similarly-sized mice. Journals of Gerontology Series A-Biological Sciences and Medical Sciences 61(10): 1009-1018.
    連結：
89. Hulbert, A. J., R. Pamplona, R. Buffenstein and W. A. Buttemer (2007) Life and death: Metabolic rate, membrane composition, and life span of animals. Physiological Reviews 87(4): 1175-1213.
    連結：
90. Hull, M., K. Lieb and B. L. Fiebich (2002) Pathways of inflammatory activation in Alzheimer's disease: Potential targets for disease modifying drugs. Current Medicinal Chemistry 9(1): 83-88.
    連結：
91. Ihara, S. and T. Tanaka (1978) Fatty acid compositions of oils of Celtis sinensis var. japonica and Zelkova serrata. Journal of the American Oil Chemists Society 55(5): 471-472.
    連結：
92. Inbaraj, J. J. and C. F. Chignell (2004) Cytotoxic action of juglone and plumbagin: A mechanistic study using HaCaT keratinocytes. Chemical Research in Toxicology 17(1): 55-62.
    連結：
93. Jack, C. R. and D. M. Holtzman (2013) Biomarker modeling of Alzheimer's disease. Neuron 80(6): 1347-1358.
    連結：
94. Jin, K. (2010) Modern biological theories of aging. Aging and Disease 1(2): 72-74.
    連結：
95. Joo, T., K. Sowndhararajan, S. Hong, J. Lee, S. Y. Park, S. Kim and J. W. Jhoo (2014) Inhibition of nitric oxide production in LPS-stimulated RAW 264.7 cells by stem bark of Ulmus pumila L. Saudi Journal of Biological Sciences 21(5): 427-435.
    連結：
96. Jung, H. J., H. J. Kang, Y. S. Song, C. J. Lim and E. H. Park (2008) Antioxidant and anti-nociceptive activities of Ulmus davidiana var. japonica. Biomolecules and Therapeutics 16(1): 9-13.
    連結：
97. Kaletta, T. and M. O. Hengartner (2006) Finding function in novel targets: C. elegans as a model organism. Nature Reviews Drug Discovery 5(5): 387-398.
    連結：
98. Kampkötter, A., C. G. Nkwonkam, R. F. Zurawski, C. Timpel, Y. Chovolou, W. Wätjen and R. Kahl (2007) Effects of the flavonoids kaempferol and fisetin on thermotolerance, oxidative stress and FoxO transcription factor DAF-16 in the model organism Caenorhabditis elegans. Archives of Toxicology 81(12): 849-58.
    連結：
99. Kang, G., P. J. Kong, Y. J. Yuh, S. Y. Lim, S. V. Yim, W. Chun and S. S. Kim (2004) Curcumin suppresses lipopolysaccharide-induced cyclooxygenase-2 expression by inhibiting activator protein 1 and nuclear factor kappab bindings in BV2 microglial cells. Journal of Pharmacological Sciences 94(3): 325-328.
    連結：
100. Kang, K. W., S. J. Oh, S. Y. Ryu, G. Y. Song, B. H. Kim, J. S. Kang and S. K. Kim (2010) Evaluation of the total oxy-radical scavenging capacity of catechins isolated from green tea. Food Chemistry 121(4): 1089-1094.
     連結：
101. Kang, H. J. and Y. J. Jang (2012) Selective apoptotic effect of Zelkova serrata twig extract on mouth epidermoid carcinoma through p53 activation. International Journal of Oral Science 4(2): 78-84.
     連結：
102. Karuppagounder, S. S., J. T. Pinto, H. Xu, H. L. Chen, M. F. Beal and G. E. Gibson (2009) Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer's disease. Neurochemistry International 54(2): 111-118.
     連結：
103. Kaur, G. and I. M. Dufour (2012) Cell lines: Valuable tools or useless artifacts. Spermatogenesis 2(1): 1-5.
     連結：
104. Kenyon, C. J. (2010) The genetics of ageing. Nature 464(7288): 504-512.
     連結：
105. Keowkase, R., M. Aboukhatwa and Y. Luo (2010) Fluoxetine protects against amyloid-beta toxicity, in part via daf-16 mediated cell signaling pathway, in Caenorhabditis elegans. Neuropharmacology 59(4-5): 358-65.
     連結：
106. Kim, H. P., K. H. Son, H. W. Chang and S. S. Kang (2004a) Anti-inflammatory plant flavonoids and cellular action mechanisms. Journal of Pharmacological Sciences 96(3): 229-245.
     連結：
107. Kim, J. H., H. J. Lee, S. C. Yeon, D. H. Choi, S. S. Lee, J. K. Kang, C. H. Chae, N. W. Paik, K. H. Lee and M. H. Cho (2004c) Antioxidative effects of 7-hydroxy-3-methoxy-cadalene extracted from Zelkova serrata on 4-(methylinitros amino)-1-(3-pyridyl)-1-butanone-induced oxidative stress in A/J mice. Phytotherapy Research 18(5): 425-427.
     連結：
108. Kubo, I., H. Muroi, A. Kubo, S. K. Chaudhuri, Y. Sanchez and T. Ogura (1994) Antimicrobial agents from Heterotheca inuloides. Planta Medica 60(3): 218-221.
     連結：
109. Kunchandy, E. and M. N. A. Rao (1989) Effect of curcumin on hydroxyl radical generation through Fenton reaction. International Journal of Pharmaceutics 57(2): 173-176.
     連結：
110. Kunchandy, E. and M. N. A. Rao (1990) Oxygen radical scavenging activity of curcumin. International Journal of Pharmaceutics 58(3): 237-240.
     連結：
111. Kuo, Y. H. and M. T. Yu (1996) Two new sesquiterpenes, (-)-15-hydroxycalamenene and (-)-1-hydroxy-1,3,5-bisabolatrien-10-one, from the heartwood of Juniperus formosana Hay. var. concolor Hay. Chemical and Pharmaceutical Bulletin 44(11): 2150-2152.
     連結：
112. Kwon, J. H., S. B. Kim, K. H. Park and M. W. Lee (2011) Antioxidative and anti-inflammatory effects of phenolic compounds from the roots of Ulmus macrocarpa. Archives of Pharmacal Research 34(9): 1459-1466.
     連結：
113. Laganiere, S. and B. P. Yu (1987) Anti-lipoperoxidation action of food restriction. Biochemical and Biophysical Research Communications 145(3): 1185-1191.
     連結：
114. Laine, L. (2001) Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient. Gastroenterology 120(3): 594-606.
     連結：
115. Lamming, D. W., J. G. Wood and D. A. Sinclair (2004) Small molecules that regulate lifespan: Evidence for xenohormesis. Molecular Microbiology 53(4): 1003-1009.
     連結：
116. Lee, H. Y., J. T. Kwon, M. Koh, M. H. Cho and S. B. Park (2007) Enhanced efficacy of 7-hydroxy-3-methoxycadalene via glycosylation in in vivo xenograft study. Bioorganic and Medicinal Chemistry Letters 17(22): 6335-6339.
     連結：
117. Lee, K. S., B. S. Lee, S. Semnani, A. Avanesian, C. Y. Um, H. J. Jeon, K. M. Seong, K. Yu, K. J. Min and M. Jafari (2010) Curcumin extends life span, improves health span, and modulates the expression of age-associated aging genes in Drosophila melanogaster. Rejuvenation Research 13(5): 561-570.
     連結：
118. Lee, E. B., J. H. Kim, Y. S. Cha, M. Kim, S. B. Song, D. S. Cha, H. Jeon, J. S. Eun, S. Han and D. K. Kim (2015) Lifespan extending and stress resistant properties of vitexin from Vigna angularis in Caenorhabditis elegans. Biomolecules and Therapeutics 23(6): 582-589.
     連結：
119. Leiers, B., A. Kampkötter, C. G. Grevelding, C. D. Link, T. E. Johnson and K Henkle-Dührsen (2003) A stress-responsive glutathione S-transferase confers resistance to oxidative stress in Caenorhabditis elegans. Free Radical Biology and Medicine 34(11): 1405-1415.
     連結：
120. Leroux, M. R., R. Melki, B. Gordon, G. Batelier and E. P. M. Candido (1997) Structure-function studies on small heat shock protein oligomeric assembly and interaction with unfolded polypeptides. Journal of Biological Chemistry 272(39): 24646-24656.
     連結：
121. Li, W. H., Y. C. Shi, C. H. Chang, C. W. Huang and V. H. C. Liao (2014) Selenite protects Caenorhabditis elegans from oxidative stress via DAF-16 and TRXR-1. Molecular Nutrition and Food Research 58(4): 863-874.
     連結：
122. Liao, V. H. C., C. W. Yu, Y. J. Chu, W. H. Li, Y. C. Hsieh and T. T. Wang (2011) Curcumin-mediated lifespan extension in Caenorhabditis elegans. Mechanisms of Ageing and Development 132(10): 480-487.
     連結：
123. Licastro, F., S. Pedrini, L. Caputo, G. Annoni, L. J. Davis, C. Ferri, V. Casadei and L. M. E. Grimaldi (2000) Increased plasma levels of interleukin-1, interleukin-6 and alpha-1-antichymotrypsin in patients with Alzheimer's disease: Peripheral inflammation or signals from the brain? Journal of Neuroimmunology 103(1): 97-102.
     連結：
124. Lin, Y. L. and J. K. Lin (1997) (-)-Epigallocatechin-3-gallate blocks the induction of nitric oxide synthase by down-regulating lipopolysaccharide-induced activity of transcription factor nuclear factor-kappa B. Molecular Pharmacology 52(3): 465-472.
     連結：
125. Lin, S. J., P. A. Defossez and L. Guarente (2000) Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289(5487): 2126-2128.
     連結：
126. Lindsay, J., D. Laurin, R. Verreault, R. Hebert, B. Helliwell, G. B. Hill and I. McDowell (2002) Risk factors for Alzheimer's disease: A prospective analysis from the Canadian study of health and aging. American Journal of Epidemiology 156(5): 445-453.
     連結：
127. Link, C. D. (2006) C. elegans models of age-associated neurodegenerative diseases: Lessons from transgenic worm models of Alzheimer’s disease. Experimental Gerontology 41(10): 1007-1013.
     連結：
128. Link, C. D., A. Taft, V. Kapulkin, K. Duke, S. Kim, Q. Fei, D. E. Wood and B. G. Sahagan (2003) Gene expression analysis in a transgenic Caenorhabditis elegans Alzheimer's disease model. Neurobiol Aging 24(3): 397-413.
     連結：
129. Lithgow, G. J. and G. A. Walker (2002) Stress resistance as a determinate of C. elegans lifespan. Mechanisms of Ageing and Development 123(7): 765-771.
     連結：
130. Luchsinger, J. A., M. X. Tang, M. Siddiqui, S. Shea and R. Mayeux (2004) Alcohol intake and risk of dementia. Journal of the American Geriatrics Society 52(4): 540-546.
     連結：
131. Mackenzie, I. R. (2001) Postmortem studies of the effect of anti-inflammatory drugs on Alzheimer-type pathology and associated inflammation. Neurobiology of Aging 22(6): 819-822.
     連結：
132. Marambaud, P., H. Zhao and P. Davies (2005) Resveratrol promotes clearance of Alzheimer's disease amyloid-beta peptides. Journal of Biological Chemistry 280(45): 37377-37382.
     連結：
133. Marimuthu, P., C. L. Wu, H. T. Chang and S. T. Chang (2008) Antioxidant activity of the ethanolic extract from the bark of Chamaecyparis obtusa var. formosana. Journal of the Science of Food and Agriculture 88(8): 1400-1405.
     連結：
134. Markaki, M. and N. Tavernarakis (2010) Modeling human diseases in Caenorhabditis elegans. Biotechnology Journal 5(12): 1261-1276.
     連結：
135. Masoro, E. J. (1998) Hormesis and the antiaging action of dietary restriction. Experimental Gerontology 33(1-2): 61-66.
     連結：
136. Matthews, S., I. Mila, A. Scalbert and D. M. X. Donnelly (1997) Extractable and non-extractable proanthocyanidins in barks. Phytochemistry 45(2): 405-410.
     連結：
137. Mbafor, J. T., Z. T. Fomum, R. Promsattha, D. R. Sanson and M. S. Tempesta (1989) Isolation and characterization of taxifolin 6-C-glucoside from Garcinia epunctata. Jod of Natural Products 52(2): 417-419.
     連結：
138. McCallum, K.C., B. Liu, J. C. Fierro-Gonzalez, P. Swoboda, S. Arur, A. Miranda-Vizuete and D. A. Garsin (2016) TRX-1 regulates SKN-1 nuclear localization cell non-autonomously in Caenorhabditis elegans. Genetics 203: 387-402.
     連結：
139. McCay, C. M., M. F. Crowell and L. A. Maynard (1935) The effect of retarded growth upon the length of life span and upon the ultimate body size. Journal of Nutrition 10(1): 63-79.
     連結：
140. Merly, L. and S. L. Smith (2017) Murine RAW 264.7 cell line as an immune target: Are we missing something? Immunopharmacology and Immunotoxicology 39(2): 55-58.
     連結：
141. Miller, R. A. (1996) The aging immune system: Primer and prospectus. Science 273(5271): 70-74.
     連結：
142. Miura, D., Y. Miura and K. Yagasaki (2003) Hypolipidemic action of dietary resveratrol, a phytoalexin in grapes and red wine, in hepatoma-bearing rats. Life Sciences 73(11): 1393-1400.
     連結：
143. Murphy, C. T. (2006) The search for DAF-16/FOXO transcriptional targets: Approaches and discoveries. Experimental Gerontology 41(10): 910-921.
     連結：
144. Nabeta, K., K. Katayama, S. Nakagawara and K. Katoh (1992) Sesquiterpenes of cadinane type from cultured cells of the liverwort, Heteroscyphus planus. Phytochemistry 32(1): 117-122.
     連結：
145. Nagasawa, T., H. Hayashi, N. Fujimaki, N. Nishizawa and D. D. Kitts (2000) Induction of oxidatively modified proteins in skeletal muscle by electrical stimulation and its suppression by dietary supplementation of (-)-epigallocatechin gallate. Bioscience, Biotechnology, and Biochemistry 64(5): 1004-1010.
     連結：
146. Nakachi, K., S. Matsuyama, S. Miyake, M. Suganuma and K. Imai (2000) Preventive effects of drinking green tea on cancer and cardiovascular disease: Epidemiological evidence for multiple targeting prevention. Biofactors 13(1-4): 49-54.
     連結：
147. Nathan, C. and A. Ding (2010) Nonresolving inflammation. Cell 140(6): 871-882.
     連結：
148. Nisbet, R. M., J.-C. Polanco, L. M. Ittner and J. Götz (2015) Tau aggregation and its interplay with amyloid-β. Acta Neuropathologica 129(2): 207-220.
     連結：
149. Oliveira, R. P., J. P. Abate, K. Dilks, J. Landis, J. Ashraf, C. T. Murphy and T. K. Blackwell (2009) Condition-adapted stress and longevity gene regulation by Caenorhabditis elegans SKN-1/Nrf. Aging Cell 8(5): 524-541.
     連結：
150. Oyaizu, M. (1986) Studies on products of browning reaction: Antioxidative activities of products of browning reaction prepared from glucosamine. The Japanese Journal of Nutrition and Dietetics 44(6): 307-315.
     連結：
151. Parsons, C. G., W. Danysz, A. Dekundy and I. Pulte (2013) Memantine and cholinesterase inhibitors: Complementary mechanisms in the treatment of Alzheimer's disease. Neurotoxicity Research 24(3): 358-369.
     連結：
152. Partridge, L., M. D. W. Piper and W. Mair (2005) Dietary restriction in Drosophila. Mechanisms of Ageing and Development 126(9): 938-950.
     連結：
153. Porquet, D., G. Casadesus, S. Bayod, A. Vicente, A. M. Canudas, J. Vilaplana, C. Pelegri, C. Sanfeliu, A. Camins, M. Pallas and J. del Valle (2013) Dietary resveratrol prevents Alzheimer's markers and increases life span in SAMP8. Age 35(5): 1851-1865.
     連結：
154. Prince, M., R. Bryce, E. Albanese, A. Wimo, W. Ribeiro and C. P. Ferri (2013) The global prevalence of dementia: A systematic review and metaanalysis. Alzheimer's and Dementia 9(1): 63-75.e62.
     連結：
155. Prior, R. L., X. L. Wu and K. Schaich (2005) Standardized methods for the determination of antioxidant capacity and phenolics in foods and dietary supplements. Journal of Agricultural and Food Chemistry 53(10): 4290-4302.
     連結：
156. Puckhaber, L. S. and R. D. Stipanovic (2004) Thespesenone and dehydrooxoperezinone-6-methyl ether, new sesquiterpene quinones from Thespesia populnea. Journal of Natural Products 67(9): 1571-1573.
     連結：
157. Rattan, S. I. S. (2008) Hormesis in aging. Ageing Research Reviews 7(1): 63-78.
     連結：
158. Rhen, T. and J. A. Cidlowski (2005) Antiinflammatory action of glucocorticoids — New mechanisms for old drugs. New England Journal of Medicine 353(16): 1711-1723.
     連結：
159. Ristow, M. and K. Zarse (2010) How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis). Experimental Gerontology 45(6): 410-418.
     連結：
160. Rodrigues, I., M. M. Azevedo, F. C. Chaves, H. Bizzo, S. Corte-Real, D. Alviano, C. Alviano, M. S. Rosa and A. Vermelho (2013) In vitro cytocidal effects of the essential oil from Croton cajucara (red sacaca) and its major constituent 7-hydroxycalamenene against Leishmania chagasi. BMC Complementary and Alternative Medicine 13(1): 249.
     連結：
161. Rowe, J. W., M. K. Seikel, D. N. Roy and E. Jorgensen (1972) Chemotaxonomy of Ulmus. Phytochemistry 11(8): 2513-2517.
     連結：
162. Rubio-Perez, J. M. and J. M. Morillas-Ruiz (2012) A review: Inflammatory process in Alzheimer's disease, role of cytokines. Scientific World Journal 2012: 756357.
     連結：
163. Ruby, A. J., G. Kuttan, K. D. Babu, K. N. Rajasekharan and R. Kuttan (1995) Anti-tumour and antioxidant activity of natural curcuminoids. Cancer Letters 94(1): 79-83.
     連結：
164. Sabatino, F., E. J. Masoro, C. A. McMahan and R. W. Kuhn (1991) Assessment of the role of the glucocorticoid system in aging processes and in the action of food restriction. Journal of Gerontology 46(5): B171-B179.
     連結：
165. Sankaram, A. V. B., N. S. Reddy and J. N. Shoolery (1981) New sesquiterpenoids of Bombax malabaricum. Phytochemistry 20(8): 1877-1881.
     連結：
166. Sano, M., M. Tabata, M. Suzuki, M. Degawa, T. Miyase and M. Maeda-Yamamoto (2001) Simultaneous determination of twelve tea catechins by high-performance liquid chromatography with electrochemical detection. Analyst 126(6): 816-820.
     連結：
167. Scapagnini, G., C. Colombrita, M. Amadio, V. D'Agata, E. Arcelli, M. Sapienza, A. Quattrone and V. Calabrese (2006) Curcumin activates defensive genes and protects neurons against oxidative stress. Antioxidants and Redox Signaling 8(3-4): 395-403.
     連結：
168. Schneider, L. S., F. Mangialasche, N. Andreasen, H. Feldman, E. Giacobini, R. Jones, V. Mantua, P. Mecocci, L. Pani, B. Winblad and M. Kivipelto (2014) Clinical trials and late-stage drug development for Alzheimer's disease: An appraisal from 1984 to 2014. Journal of Internal Medicine 275(3): 251-283.
     連結：
169. Schram, M. T., S. M. Euser, A. J. de Craen, J. C. Witteman, M. Frolich, A. Hofman, J. Jolles, M. M. Breteler and R. G. Westendorp (2007) Systemic markers of inflammation and cognitive decline in old age. Journal of the American Geriatrics Society 55(5): 708-716.
     連結：
170. Shah, N. A., M. R. Khan, B. Ahmad, F. Noureen, U. Rashid and R. A. Khan (2013) Investigation on flavonoid composition and anti free radical potential of Sida cordata. BMC Complementary and Alternative Medicine 13: 276.
     連結：
171. Shaye, D. D. and I. Greenwald (2011) OrthoList: A compendium of C. elegans genes with human orthologs. PLoS One 6(5): e20085.
     連結：
172. Shen, L. R., F. Xiao, P. Yuan, Y. Chen, Q. K. Gao, L. D. Parnell, M. Meydani, J. M. Ordovas, D. Li and C. Q. Lai (2013) Curcumin-supplemented diets increase superoxide dismutase activity and mean lifespan in Drosophila. Age (Dordr) 35(4): 1133-1142.
     連結：
173. Shi, H., M. V. Kokoeva, K. Inouye, I. Tzameli, H. Yin and J. S. Flier (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. Journal of Clinical Investigation 116(11): 3015-3025.
     連結：
174. Shuai, K. and B. Liu (2003) Regulation of JAK-STAT signalling in the immune system. Nature Reviews Immunology 3: 900-911.
     連結：
175. Slimen, I. B., T. Najar, A. Ghram, H. Dabbebi, M. Ben Mrad and M. Abdrabbah (2014) Reactive oxygen species, heat stress and oxidative-induced mitochondrial damage. A review. International Journal of Hyperthermia 30(7): 513-523.
     連結：
176. Smith, R. S. (1991) The macrophage theory of depression. Medical Hypotheses 35(4): 298-306.
     連結：
177. Socolsky, C., N. Muruaga and A. Bardón (2005) Drimanes and other terpenoids from the fern Thelypteris hispidula (Decne.) Reed. Chemistry and Biodiversity 2(8): 1105-1108.
     連結：
178. Sreejayan and M. N. A. Rao (1996) Free radical scavenging activity of curcuminoids. Arzneimittelforschung 46(2): 169-171.
     連結：
179. Sreejayan and M. N. A. Rao (1997) Nitric oxide scavenging by curcuminoids. Journal of Pharmacy and Pharmacology 49(1): 105-107.
     連結：
180. Stark, T. D., T. Matsutomo, S. Lösch, P. A. Boakye, O. B. Balemba, S. P. Pasilis and T. Hofmann (2012) Isolation and structure elucidation of highly antioxidative 3,8-linked biflavanones and flavanone-C-glycosides from Garcinia buchananii Bark. Journal of Agricultural and Food Chemistry 60(8): 2053-2062.
     連結：
181. Strayer, A., Z. Wu, Y. Christen, C. D. Link and Y. Luo (2003) Expression of the small heat-shock protein Hsp16-2 in Caenorhabditis elegans is suppressed by Ginkgo biloba extract EGb 761. FASEB Journal 17(15): 2305-2307.
     連結：
182. Sugizaki, M. M., A. S. Leopoldo, M. P. Okoshi, A. Bruno, S. J. Conde, A. P. Lima-Leopoldo, C. R. Padovani, R. F. Carvalho, A. F. do Nascimento, D. H. S. de Campos, C. R. Nogueira and A. C. Cicogna (2009) Severe food restriction induces myocardial dysfunction related to SERCA2 activity. Canadian Journal of Physiology and Pharmacology 87(9): 666-673.
     連結：
183. Sun, T. and C. T. Ho (2001) Antiradical efficiency of tea components. Journal of Food Lipids 8(3): 231-238.
     連結：
184. Tanaka, T., Z. H. Jiang and I. Kouno (1998) Distribution of ellagic acid derivatives and a diarylheptanoid in wood of Platycarya strobilacea. Phytochemistry 47(5): 851-854.
     連結：
185. Tian, X. and K. M. Schaich (2013) Effects of molecular structure on kinetics and dynamics of the trolox equivalent antioxidant capacity assay with ABTS+·. Journal of Agricultural and Food Chemistry 61(23): 5511-5519.
     連結：
186. Tung, Y. T., P. L. Yen, C. Y. Lin and S. T. Chang (2010) Anti-inflammatory activities of essential oils and their constituents from different provenances of indigenous cinnamon (Cinnamomum osmophloeum) leaves. Pharmaceutical Biology 48(10): 1130-1136.
     連結：
187. Viswanathan, M., S. K. Kim, A. Berdichevsky and L. Guarente (2005) A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span. Developmental Cell 9(5): 605-615.
     連結：
188. Vukics, V. and A. Guttman (2010) Structural characterization of flavonoid glycosides by multi-stage mass spectrometry. Mass Spectrometry Reviews 29(1): 1-16.
     連結：
189. Wei, A. and T. Shibamoto (2007) Antioxidant activities and volatile constituents of various essential oils. Journal of Agricultural and Food Chemistry 55(5): 1737-1742.
     連結：
190. Wei, C. C., C. W. Yu, P. L. Yen, H. Y. Lin, S. T. Chang, F. L. Hsu and V. H. C. Liao (2014) Antioxidant activity, delayed aging, and reduced amyloid-β toxicity of methanol extracts of tea seed pomace from Camellia tenuifolia. Journal of Agricultural and Food Chemistry 62(44): 10701-10707.
     連結：
191. Weitzberg, E., M. Hezel and J. O. Lundberg (2010) Nitrate-nitrite-nitric oxide pathway implications for anesthesiology and intensive care. Anesthesiology 113(6):1460-1475.
     連結：
192. Wenzel, E., T. Soldo, H. Erbersdobler and V. Somoza (2005) Bioactivity and metabolism of trans-resveratrol orally administered to Wistar rats. Molecular Nutrition and Food Research 49(5): 482-494.
     連結：
193. Williams, J. A., R. Hyland, B. C. Jones, D. A. Smith, S. Hurst, T. C. Goosen, V. Peterkin, J. R. Koup and S. E. Ball (2004) Drug-drug interactions for UDP-glucuronosyltransferase substrates: A pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metabolism and Disposition 32(11): 1201-1208.
     連結：
194. Wu, Y. J., Z. X. Wu, P. Butko, Y. Christen, M. P. Lambert, W. L. Klein, C. D. Link and Y. Luo (2006) Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. Journal of Neuroscience 26(50): 13102-13113.
     連結：
195. Yang, F. S., G. P. Lim, A. N. Begum, O. J. Ubeda, M. R. Simmons, S. S. Ambegaokar, P. P. Chen, R. Kayed, C. G. Glabe, S. A. Frautschy and G. M. Cole (2005) Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. Journal of Biological Chemistry 280(7): 5892-5901.
     連結：
196. Yin, D. (1996) Biochemical basis of lipofuscin, ceroid, and age pigment-like fluorophores. Free Radical Biology and Medicine 21(6): 871-888.
     連結：
197. Yu, C. W., C. C. Wei and V. H. C. Liao (2014) Curcumin-mediated oxidative stress resistance in Caenorhabditis elegans is modulated by age-1, akt-1, pdk-1, osr-1, unc-43, sek-1, skn-1, sir-2.1, and mev-1. Free Radical Research 48(3): 371-379.
     連結：
198. Yun, K. J., J. Y. Kim, J. B. Kim, K. W. Lee, S. Y. Jeong, H. J. Park, H. J. Jung, Y. W. Cho, K. Yun and K. T. Lee (2008) Inhibition of LPS-induced NO and PGE2 production by asiatic acid via NF-kappa B inactivation in RAW 264.7 macrophages: Possible involvement of the IKK and MAPK pathways. International Immunopharmacology 8(3): 431-441.
     連結：
199. Zaveri, N. T. (2006) Green tea and its polyphenolic catechins: Medicinal uses in cancer and noncancer applications. Life Sciences 78(18): 2073-2080.
     連結：
200. Zhang, L., G. Jie, J. Zhang and B. Zhao (2009) Significant longevity-extending effects of EGCG on Caenorhabditis elegans under stress. Free Radical Biology and Medicine 46(3): 414-421.
     連結：
201. Zhang, L. Z., G. L. Jie, J. J. Zhang and B. L. Zhao (2009) Significant longevity-extending effects of EGCG on Caenorhabditis elegans under stress. Free Radical Biology and Medicine 46(3): 414-421.
     連結：
202. 呂福原、歐辰雄、呂金誠 (1998) 臺灣樹木解說。國立中興大學森林系。臺中市。第63頁。
203. 邱立文、黃群修、吳俊奇、謝小恬 (2015) 第4次全國森林資源調查成果概要。台灣林業41: 3-13。
204. 徐原田 (2006) 2006藥用保健植物種原保存、開發與利用。行政院農業委員會農業試驗所。臺中縣。第395頁。
205. 劉棠瑞、廖日京 (1980) 樹木學。臺灣商務。臺北市。第222-223頁。
206. 劉業經 (1964) 樹木學。臺灣省立中興大學農學院出版委員會。臺中市。第220-221頁。
207. 應紹舜 (1985) 臺灣高等植物彩色圖誌。著者。臺北縣。第315-316頁。
208. Adams, R. P. (2007) Identification of essential oil components by gas chromatography/mass spectorscopy. Allured Pub. Corp, Illinois. 804 pp.
209. Ames, B. N., M. K. Shigenaga and T. M. Hagen (1993) Oxidants, antioxidants, and the degenerative diseases of aging. Proceedings of the National Academy of Sciences of the United States of America 90(17): 7915-7922.
210. Baum, L., C. W. K. Lam, S. K. K. Cheung, T. Kwok, V. Lui, J. Tsoh, L. Lam, V. Leung, E. Hui, C. Ng, J. Woo, H. F. K. Chiu, W. B. Goggins, B. C. Y. Zee, K. F. Cheng, C. Y. S. Fong, A. Wong, H. Mok, M. S. S. Chow, P. C. Ho, S. P. Ip, C. S. Ho, X. W. Yu, C. Y. L. Lai, M. H. Chan, S. Szeto, I. H. S. Chan and V. Mok (2008) Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. Journal of Clinical Psychopharmacology 28(1): 110-113.
211. Bonomo, L. d. F., D. N. Silva, P. F. Boasquivis, F. A. Paiva, J. F. d. C. Guerra, T. A. F. Martins, Á. G. de Jesus Torres, I. T. B. R. de Paula, W. L. Caneschi, P. Jacolot, N. Grossin, F. J. Tessier, E. Boulanger, M. E. Silva, M. L. Pedrosa and R. de Paula Oliveira (2014) Açaí (Euterpe oleracea Mart.) modulates oxidative stress resistance in Caenorhabditis elegans by direct and indirect mechanisms. PLoS One 9(3): e89933.
212. Boulin, T., J. F. Etchberger and O. Hobert (2006) Reporter gene fusions. 23 pp. In V. Ambros ed. WormBook. The C. elegans Research Community, Pasadena, CA. URL (http://www.wormbook.org ) (2017.08.15).
213. Charlton, A. J., N. J. Baxter, M. L. Khan, A. J. G. Moir, E. Haslam, A. P. Davies and M. P. Williamson (2002) Polyphenol/peptide binding and precipitation. Journal of Agricultural and Food Chemistry 50(6): 1593-1601.
214. Choi, J. W., S. H. Mun and D. H. Choi (2009) Study on cadalene compounds purified from Zelkova serrata Wood Ⅱ - Biological activities of 7-hydroxy-3-methoxycadalene and purification of cadalene homologues. Journal of the Korean Wood Science and Technology 37(1): 78-86.
215. Delgado, G., M. D. Olivares, M. I. Chavez, T. Ramirez-Apan, E. Linares, R. Bye and F. J. Espinosa-Garcia (2001) Antiinflammatory constituents from Heterotheca inuloides. Journal of Natural Products 64(7): 861-864.
216. Fukushige,T., H. E. Smith, J. Miwa, M. W. Krause and J. A. Hanover (2017) A genetic analysis of the Caenorhabditis elegans detoxification response. Genetics 206(2): 939-952.
217. Funaoka, K. (1957) Studies on flavonoids of the wood of Zelkova serrata Makino VIII. Mokuzai Gakkaishi 3(6): 218-224.
218. Funaoka, K. and M. Tanaka (1957a) Studies on flavonoids of the wood of Zelkova serrata Makino VI. Mokuzai Gakkaishi 3(4): 144-146.
219. Funaoka, K. and M. Tanaka (1957b) Studies on flavonoids of the wood of Zelkova serrata Makino VII. Mokuzai Gakkaishi 3(5): 173-176.
220. Grigore, A., I. Paraschiv, S. Colceru-Mihul, C. Bubueanu, E. Draghici and M. Ichim (2010) Chemical composition and antioxidant activity of Thymus vulgaris L. volatile oil obtained by two different methods. Romanian Biotechnological Letters 15(4): 5436-5443.
221. Hayashi, Y. and T. Takahashi (1980) Zelkoserratone and homozelkoserratone, new cadalenic sesquiterpenes from the heartwood of Zelkova serrata. Mokuzai Gakkaishi 26(1): 54-55.
222. Hayashi, Y., M. Yasue and T. Takahashi (1972) Two new naphthalene derivatives from the heartwood of Zelkova serrata Makino. Mokuzai Gakkaishi 18(1): 41-42.
223. Hayashi, Y., K. Sakurai and T. Takahashi (1976) Isolation of a dimer of 7-hydroxy-3-methoxycadalene from the heartwood of Zelkova serrata Makino. Mokuzai Gakkaishi 22(3): 202-203.
224. Hayashi, Y., S. Ohara and T. Takahashi (1987) Isolation of new 3-hydroxylated flavonoid C-glucosides from the heartwood of Zelkova serrata Makino and other Zelkova species. Mokuzai Gakkaishi 33(6): 511-520.
225. Joshi, B. N., R. Seshadri, K. K. Chakravarti and S. C. Bhattacharyya (1964) Terpenoids—LVIII: Base catalysed reactions with N-lithioethylenediamine. Tetrahedron 20(12): 2911-2919.
226. Kim, J. H., H. J. Lee, G. S. Kim, D. H. Choi, S. S. Lee, J. K. Kang, C. Chae, N. W. Paik and M. H. Cho (2004b) Inhibitory effects of 7-hydroxy-3-methoxy-cadalene on 4-(methylinitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice. Cancer Letters 213(2): 139-145.
227. Kindt, T. J., R. A. Goldsby, B. A. Osborne and J. Kuby (2007) Kuby Immunology. W.H. Freeman, New York. 574 pp.
228. Kontogianni, V. G., P. Charisiadis, A. Primikyri, C. G. Pappas, V. Exarchou, A. G. Tzakosa and I. P. Gerothanassis (2013) Hydrogen bonding probes of phenol –OH groups. Organic and Biomolecular Chemistry 11(6): 1013-1025.
229. Kozlowski, G. and J. Gratzfeld (2013) Zelkova, An Ancient Tree: Global Status and Conservation Action, Natural History Museum, Fribourg, Switzerland. 60 pp.
230. Lee, S. S., H. J. Lee, H. Y. Kang and D. H. Choi (1999) Studies on biological activity of wood extractives (I): Antimicrobial and antioxidative activity of heartwood extractives. Forest Research Institute Journal of Forest Science 61: 82-89.
231. Lee, S. S., D. H. Choi, H. J. Lee and H. Y. Kang (2000) Studies on biological activity of wood extractives (II)-Antimicrobial and antioxidative compound isolated from heartwood of Zelkova serrata. Journal of the Korean Wood Science and Technology 28(2): 32-41.
232. Levites, Y., M. B. H. Youdim, G. Maor and S. Mandel (2002) Attenuation of 6-hydroxydopamine (6-OHDA)-induced nuclear factor-kappaB (NF-kappa B) activation and cell death by tea extracts in neuronal cultures. Biochemical Pharmacology 63(1): 21-29.
233. López-Otín, C., M. A. Blasco, L. Partridge, M. Serrano and G. Kroemer (2013) The hallmarks of aging. Cell 153(6): 1194-1217.
234. Marston, A. and K. Hostettmann (2005) Separation and quantification of flavonoids. pp. 1-36. In M. Andersen and K. R. Markhamo eds. Flavonoids Chemistry, Biochemistry and Applications. CRC Press, Taylor & Francis Group, Florida. 1256 pp.
235. Michaud, M., L. Balardy, G. Moulis, C. Gaudin, C. Peyrot, B. Vellas, M. Cesari and F. Nourhashemi (2013) Proinflammatory cytokines, aging, and age-related diseases. Journal of the American Medical Directors Association 14(12): 877-882.
236. Murray, P. J., J. E. Allen, S. K. Biswas, E. A. Fisher, D. W. Gilroy, S. Goerdt, S. Gordon, J. A. Hamilton, L. B. Ivashkiv, T. Lawrence, M. Locati, A. Mantovani, F. O. Martinez, J. L. Mege, D. M. Mosser, G. Natoli, J. P. Saeij, J. L. Schultze, K. A. Shirey, A. Sica, J. Suttles, I. Udalova, J. A. van Ginderachter, S. N. Vogel and T. A. Wynn (2014) Macrophage activation and polarization: Nomenclature and experimental guidelines. Immunity 41(1): 14-20.
237. Nieman, L. K., B. M. K. Biller, J. W. Findling, J. Newell-Price, M. O. Savage, P. M. Stewart and V. M. Montori (2008) The diagnosis of Cushing's syndrome: An endocrine society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 93(5): 1526-1540.
238. North, B. J. and E. Verdin (2004) Sirtuins: Sir2-related NAD-dependent protein deacetylases. Genome Biology 5(5): 224.
239. Pearl, R. (1928) The rate of living: Being an account of some experimental studies on the biology of life duration. Alfred A. Knopf, Inc., New York. 185 pp.
240. Pinheiro, P. F. and G. C. Justino (2012) Structural analysis of flavonoids and related compounds - A review of spectroscopic applications. pp. 33-57. In V. Rao ed. Phytochemicals - A Global Perspective of Their Role in Nutrition and Health. InTech, Rijeka, Croatia. 548 pp.
241. Ringman, J. M., S. A. Frautschy, E. Teng, A. N. Begum, J. Bardens, M. Beigi, K. H. Gylys, V. Badmaev, D. D. Heath, L. G. Apostolova, V. Porter, Z. Vanek, G. A. Marshall, G. Hellemann, C. Sugar, D. L. Masterman, T. J. Montine, J. L. Cummings and G. M. Cole (2012) Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study. Alzheimers Research and Therapy 4(5): 8.
242. Salmoun, M., J. C. Braekman, Y. Ranarivelo, R. Rasamoelisendra, D. Ralambomanana, J. Dewelle, F. Darro and R. Kiss (2007) New calamenene sesquiterpenes from Tarenna madagascariensis. Natural Product Research 21(2): 111-120.
243. Shahidi, F., P. K. Janitha and P. D. Wanasundara (1992) Phenolic antioxidants. Critical Reviews in Food Science and Nutrition 32(1): 67-103.
244. Stiernagle, T. (2006) Maintenance of C. elegans. 11 pp. In D. Fay ed. WormBook. The C. elegans Research Community, Pasadena, CA. URL (http://www.wormbook.org ) (2017.08.15).
245. Suckow, B. K. and M. A. Suckow (2006) Lifespan extension by the antioxidant curcumin in Drosophila melanogaster. International Journal of Biomedical Science 2(4): 402-405.
246. Weggen, S., J. L. Eriksen, P. Das, S. A. Sagi, R. Wang, C. U. Pietrzik, K. A. Findlay, T. E. Smith, M. P. Murphy, T. Bulter, D. E. Kang, N. Marquez-Sterling, T. E. Golde and E. H. Koo (2001) A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature 414(6860): 212-216.
247. Yatin, S. M., S. Varadarajan, C. D. Link and D. A. Butterfield (1999) In vitro and in vivo oxidative stress associated with Alzheimer's amyloid beta-peptide (1-42). Neurobiol Aging 20(3): 325-330.