臺灣博碩士論文加值系統

自人類微生物組計畫開展後，越來越多研究發現皮膚共生微生物對於維持皮膚的健康狀態扮演著相當重要的角色。頭皮作為一個毛囊密度最高的皮膚區域，其獨特的生理狀態使得定殖在頭皮上的微生物與其他皮膚部位有相當的差異，目前對於頭皮與微生物的相關研究相對較少，而與特定疾病的關聯性，如雄性禿，更是鮮少被討論。然而皮膚微生物研究時常受限於其低微生物量，取得穩定且具再現性的微生物樣本是研究皮膚微生物最基礎也最重要的步驟，佈滿毛髮的頭皮更是增加取樣的困難度，如何取得足量微生物檢體的採樣方法也是研究微生物相當重要的一環。
大豆為營養價值豐富的食物，根據不同的發酵方式可以增加大豆內機能性成分，強化其抗氧化及抗發炎等生物活性，有調查發現經常飲用大豆飲料可以防止中度到重度的落髮問題，現今市面上亦有許多大豆發酵成分的保養品，也有含大豆機能性成分的髮類養護產品。
本研究欲探討大豆發酵液是否能夠改善雄性禿，以及其頭皮中微生物的變化。首先對於大豆發酵液進行抗氧化活性實驗，發現樣品對於DPPH自由基清除能力約在60%左右。接著開發一個適用於頭皮微生物檢體的採樣流程，將其應用在雄性禿的受試者上，並使用real-time PCR定量常見的頭皮微生物。結果發現在受試者患部區域中的Malassezia globosa數量要明顯低於健康區域(p < 0.01)，而在使用大豆發酵液樣品兩個月後，受試者頭皮的健康區域中Propionibacterium acnes數量有增加的現象(p < 0.05)，並觀察到在患部區域毛髮密度、髮幹直徑都有改善的情形。除此之外亦發現頭皮中Staphylococcus epidermidis及Malassezia restricta與頭髮密度和頭皮敏感度具有關聯性。綜合以上所述，我們推論雄性禿以及頭皮的一些不適反應很可能與其頭皮中的共生微生物失衡有關，而本實驗大豆發酵液樣品作為改善雄性禿的頭皮養護品具有一定的潛力。

Since the Human microbiome project (HMP) was established, more and more studies have found that skin flora play a very important role in maintaining skin health. The scalp, as a part of skin, contains densely hair follicles, with unique physiological state that makes the microbial communities colonizing vary from other regions of body. Only few studies have recently focused on scalp and it’s commensal microflora while the connection with specific diseases, such as androgenetic alopecia(AGA), is even more rarely mentioned. Challenges with studing skin microbiome result in low biomass from human skin samples, and it makes sample collection even more difficult when it comes to hairy scalp. In consideration of the premises, obtaining stable and high amount of biomass is integral to skin microbiome research and the downstream steps.
Soybeans contain several nutrients. The functional activities in soybeans, such as anti-oxidation and anti-inflammation could be improved depending on different fermentation methods. A survey has found that frequent soy bean drink consumption is protective against moderate to severe AGA. There are many skin-care products made with fermented soybean extract nowadays, as well as hair-care products which contain soybean functional compounds.
The Purpose of this study is to investigate whether fermented soybean broth can improve AGA as well as influence common microbes on the scalp. Firstly, the in vitro antioxidant activity assay indicates that the fermented soybean broth presented above 60% of the DPPH free radical scavenging ability. Then we developed a microbiological sampling method which is suitable for scalp, and apply the method to AGA subjects. The amount of common microbes on the scalp of subjects was quantified by real-time PCR.
Significantly lower amount of Malassezia globosa were detected from AGA region of subjects compare to healthy region (p < 0.01). And Propionibacterium acnes from heathy region increased (p < 0.05) after two months of sample intervention. We also observed significant improvement of hair density (p < 0.01) and hair diameter (p < 0.001) in AGA region. Apart from these, our results showed hair density was correlated with a higher amount of Staphylococcus epidermidis and Malassezia restricta. On the contrary, the opposite trend can be observed in scalp sensitivity score. In summary, we suggest that AGA and several uncomfortable sensations might be attributed to microbial dysbiosis on the scalp. And the result of human study suggests the potential of soybean fermentation extract as a promising hair care ingredient for AGA.

口試委員會審定書 #
誌謝 i
摘要 ii
Abstract iii
縮寫表 v
目錄 vi
圖目錄 ix
表目錄 x
壹、 前言 1
貳、 文獻回顧 2
一、 頭皮與落髮疾病 2
(一) 頭皮 2
(二) 頭髮的生長週期 2
(三) 落髮 4
(四) 雄性禿 5
二、 人體的菌相 7
(一) 腸道菌相 7
(二) 皮膚菌相 8
(三) 頭皮菌相 9
三、 大豆與大豆發酵液 11
(一) 簡介 11
(二) 營養成分 11
(三) 機能性成分 13
(四) 大豆發酵液 14
四、 微生物採樣與基因特性 15
(一) 常見皮膚微生物取樣方法 15
(二) 影響皮膚微生物採樣的變因 16
(三) 16s rRNA 17
(四) 內轉錄間隔區 18
參、 研究目的與實驗架構 20
一、 研究目的 20
二、 實驗架構 21
肆、 材料與方法 23
一、實驗材料 23
(一) 大豆發酵液 23
(二) 實驗細胞株 24
(三) 實驗菌株 24
(四) 細胞培養 24
(五) 微生物培養 24
(六) 實驗試劑與套組 25
(七) 其他藥品 26
(八) 實驗耗材 26
(九) 儀器與設備 28
二、實驗方法 29
(一) 細胞培養及相關實驗 29
(二) 體外實驗 31
(三) 採樣方法學之人體試驗 32
(四) 微生物培養及相關實驗 36
(五) 大豆發酵液應用於雄性禿與微生物關聯性之人體試驗 47
(六) 統計分析 52
伍、 實驗結果 53
一、 細胞實驗與體外實驗 53
(一) HaCaT細胞存活率試驗 53
(二) DPPH自由基清除能力之測定 55
(三) 總酚類化合物及總類黃酮含量 57
二、 採樣方法學之人體試驗 59
(一) 受試者招募狀況及基本資料 59
(二) 採檢棒的材質對於頭皮微生物採集量的影響 60
(三) 頭皮清潔至採樣的時間間隔對於頭皮微生物採集量的影響 62
(四) 採樣緩衝液對於頭皮微生物採集量的影響 64
(五) 保存條件對於檢體中微生物數量的影響 66
三、 大豆發酵液應用於雄性禿與微生物關聯性之人體試驗 68
(一) 受試者招募狀況及基本資料 68
(二) 頭皮毛髮檢診儀分析結果 69
(三) 頭皮毛髮檢診儀分析結果的相關性分析 71
(四) 常見頭皮微生物分析結果 73
(五) 頭皮毛髮檢診儀分析結果與頭皮常見微生物數量的相關性分析 78
(六) 樣品感受性問卷結果 80
陸、 討論 83
一、 採樣方法學之人體試驗 83
二、 大豆發酵液應用於雄性禿與微生物關聯性之人體試驗 86
(一) 細胞實驗與體外實驗 86
(二) 頭皮毛髮檢診儀分析結果 86
(三) 頭皮毛髮檢診儀分析結果的相關性分析 87
(四) 常見頭皮微生物分析結果 88
(五) 頭皮毛髮檢診儀分析結果與頭皮常見微生物數量的相關性分析 89
(六) 樣品感受性問卷結果 90
(七) 飲食習慣對於頭皮狀況的影響 90
柒、 結論 92
捌、 參考資料 93
玖、 附錄 111

1.Otberg, N.; Richter, H.; Schaefer, H.; Blume-Peytavi, U.; Sterry, W.; Lademann, J., Variations of Hair Follicle Size and Distribution in Different Body Sites. Journal of Investigative Dermatology 2004, 122 (1), 14-19.

2.Trüeb, R. M., Oxidative stress in ageing of hair. International journal of trichology 2009, 1 (1), 6-14.

3.Cranwell, W.; Sinclair, R., Male Androgenetic Alopecia. In Endotext, Feingold, K. R.; Anawalt, B.; Boyce, A.; Chrousos, G.; Dungan, K.; Grossman, A.; Hershman, J. M.; Kaltsas, G.; Koch, C.; Kopp, P.; Korbonits, M.; McLachlan, R.; Morley, J. E.; New, M.; Perreault, L.; Purnell, J.; Rebar, R.; Singer, F.; Trence, D. L.; Vinik, A.; Wilson, D. P., Eds. South Dartmouth (MA), 2000.

4.Kligman, A. M., The Human Hair Cycle11From the Department of Dermatology of the University of Pennsylvania, Philadelphia, Pa. This research was supported by U.S. Army Research Contract DA 49-007-MD-154. Journal of Investigative Dermatology 1959, 33 (6), 307-316.

5.Price, V. H., Treatment of hair loss. N Engl J Med 1999, 341 (13), 964-73.

6.Phillips, T. G.; Slomiany, W. P.; Allison, R., Hair Loss: Common Causes and Treatment. American family physician 2017, 96 (6), 371-378.

7.Hamilton, J. B., Patterned loss of hair in man; types and incidence. Ann N Y Acad Sci 1951, 53 (3), 708-28.

8.Xu, F.; Sheng, Y.-Y.; Mu, Z.-L.; Lou, W.; Zhou, J.; Ren, Y.-T.; Qi, S.-S.; Wang, X.-S.; Fu, Z.-W.; Yang, Q.-P., Prevalence and types of androgenetic alopecia in Shanghai, China: a community-based study. British Journal of Dermatology 2009, 160 (3), 629-632.

9.Hamilton, J. B., PATTERNED LOSS OF HAIR IN MAN: TYPES AND INCIDENCE. Annals of the New York Academy of Sciences 1951, 53 (3), 708-728.

10.Severi, G.; Sinclair, R.; Hopper, J. L.; English, D. R.; McCredie, M. R.; Boyle, P.; Giles, G. G., Androgenetic alopecia in men aged 40-69 years: prevalence and risk factors. Br J Dermatol 2003, 149 (6), 1207-13.

11.Norwood, O. T., Incidence of female androgenetic alopecia (female pattern alopecia). Dermatol Surg 2001, 27 (1), 53-4.

12.Lee, W.-S.; Lee, H.-J., Characteristics of androgenetic alopecia in asian. Annals of dermatology 2012, 24 (3), 243-252.

13.Lee, W. S.; Lee, H. J.; Choi, G. S.; Cheong, W. K.; Chow, S. K.; Gabriel, M. T.; Hau, K. L.; Kang, H.; Mallari, M. R.; Tsai, R. Y.; Zhang, J.; Zheng, M., Guidelines for management of androgenetic alopecia based on BASP classification--the Asian Consensus Committee guideline. Journal of the European Academy of Dermatology and Venereology : JEADV 2013, 27 (8), 1026-34.

14.Su, L. H.; Hsiu-Hsi, T., Association of androgenetic alopecia with smoking and its prevalence among Asian men - A community-based survey. Arch Dermatol 2007, 143 (11), 1401-1406.

15.Su, L.-H.; Chen, L.-S.; Chen, H.-H., Factors associated with female pattern hair loss and its prevalence in Taiwanese women: A community-based survey. Journal of the American Academy of Dermatology 2013, 69 (2), e69-e77.

16.Kranz, D., Young men's coping with androgenetic alopecia: acceptance counts when hair gets thinner. Body Image 2011, 8 (4), 343-8.

17.Patient-Perceived Importance of Negative Effects of Androgenetic Alopecia in Women. Journal of Women's Health & Gender-Based Medicine 1999, 8 (8), 1091-1095.

18.Lolli, F.; Pallotti, F.; Rossi, A.; Fortuna, M. C.; Caro, G.; Lenzi, A.; Sansone, A.; Lombardo, F., Androgenetic alopecia: a review. Endocrine 2017, 57 (1), 9-17.

19.Prodi, D. A.; Pirastu, N.; Maninchedda, G.; Sassu, A.; Picciau, A.; Palmas, M. A.; Mossa, A.; Persico, I.; Adamo, M.; Angius, A.; Pirastu, M., EDA2R is associated with androgenetic alopecia. The Journal of investigative dermatology 2008, 128 (9), 2268-70.

20.Richards, J. B.; Yuan, X.; Geller, F.; Waterworth, D.; Bataille, V.; Glass, D.; Song, K.; Waeber, G.; Vollenweider, P.; Aben, K. K. H.; Kiemeney, L. A.; Walters, B.; Soranzo, N.; Thorsteinsdottir, U.; Kong, A.; Rafnar, T.; Deloukas, P.; Sulem, P.; Stefansson, H.; Stefansson, K.; Spector, T. D.; Mooser, V., Male-pattern baldness susceptibility locus at 20p11. Nat Genet 2008, 40 (11), 1282-1284.

21.Hillmer, A. M.; Hanneken, S.; Ritzmann, S.; Becker, T.; Freudenberg, J.; Brockschmidt, F. F.; Flaquer, A.; Freudenberg-Hua, Y.; Jamra, R. A.; Metzen, C.; Heyn, U.; Schweiger, N.; Betz, R. C.; Blaumeiser, B.; Hampe, J.; Schreiber, S.; Schulze, T. G.; Hennies, H. C.; Schumacher, J.; Propping, P.; Ruzicka, T.; Cichon, S.; Wienker, T. F.; Kruse, R.; Nothen, M. M., Genetic variation in the human androgen receptor gene is the major determinant of common early-onset androgenetic alopecia. Am J Hum Genet 2005, 77 (1), 140-8.

22.Torkamani, N.; Rufaut, N. W.; Jones, L.; Sinclair, R., Destruction of the arrector pili muscle and fat infiltration in androgenic alopecia. Br J Dermatol 2014, 170 (6), 1291-8.

23.Kibar, M.; Aktan, S.; Bilgin, M., Scalp dermatoscopic findings in androgenetic alopecia and their relations with disease severity. Ann Dermatol 2014, 26 (4), 478-84.

24.Lattanand, A.; Johnson, W. C., Male pattern alopecia a histopathologic and histochemical study. J Cutan Pathol 1975, 2 (2), 58-70.

25.Jaworsky, C.; Kligman, A. M.; Murphy, G. F., Characterization of inflammatory infiltrates in male pattern alopecia: implications for pathogenesis. Br J Dermatol 1992, 127 (3), 239-46.

26.PHILPOTT, M. P.; SANDERS, D. A.; BOWEN, J.; KEALEY, T., Effects of interleukins, colony-stimulating factor and tumour necrosis factor on human hair follicle growth in vitro: a possible role for interleukin-1 and tumour necrosis factor-α in alopecia areata. British Journal of Dermatology 1996, 135 (6), 942-948.

27.Mahé, Y. F.; Michelet, J.-F.; Billoni, N.; Jarrousse, F.; BTS; Buan, B.; BTS; Commo, S.; BTS; Saint-Léger, D.; Bernard, B. A., Androgenetic alopecia and microinflammation. International Journal of Dermatology 2000, 39 (8), 576-584.

28.Huang, J.; Ran, Y.; Pradhan, S.; Yan, W.; Dai, Y., Investigation on Microecology of Hair Root Fungi in Androgenetic Alopecia Patients. Mycopathologia 2019, 184 (4), 505-515.

29.Guarner, F.; Malagelada, J. R., Gut flora in health and disease. Lancet 2003, 361 (9356), 512-9.

30.Joyce, S. A.; Gahan, C. G., The gut microbiota and the metabolic health of the host. Current opinion in gastroenterology 2014, 30 (2), 120-7.

31.Musso, G.; Gambino, R.; Cassader, M., Obesity, diabetes, and gut microbiota: the hygiene hypothesis expanded? Diabetes care 2010, 33 (10), 2277-84.

32.Szablewski, L., Human Gut Microbiota in Health and Alzheimer's Disease. Journal of Alzheimer's disease : JAD 2018, 62 (2), 549-560.

33.Schommer, N. N.; Gallo, R. L., Structure and function of the human skin microbiome. Trends in microbiology 2013, 21 (12), 660-668.

34.Grice, E. A.; Kong, H. H.; Conlan, S.; Deming, C. B.; Davis, J.; Young, A. C.; Program, N. C. S.; Bouffard, G. G.; Blakesley, R. W.; Murray, P. R.; Green, E. D.; Turner, M. L.; Segre, J. A., Topographical and temporal diversity of the human skin microbiome. Science (New York, N.Y.) 2009, 324 (5931), 1190-1192.

35.Structure, function and diversity of the healthy human microbiome. Nature 2012, 486 (7402), 207-14.

36.Costello, E. K.; Lauber, C. L.; Hamady, M.; Fierer, N.; Gordon, J. I.; Knight, R., Bacterial community variation in human body habitats across space and time. Science (New York, N.Y.) 2009, 326 (5960), 1694-1697.

37.Zhai, W.; Huang, Y.; Zhang, X.; Fei, W.; Chang, Y.; Cheng, S.; Zhou, Y.; Gao, J.; Tang, X.; Zhang, X.; Yang, S., Profile of the skin microbiota in a healthy Chinese population. The Journal of dermatology 2018, 45 (11), 1289-1300.

38.Lai, Y.; Di Nardo, A.; Nakatsuji, T.; Leichtle, A.; Yang, Y.; Cogen, A. L.; Wu, Z. R.; Hooper, L. V.; Schmidt, R. R.; von Aulock, S.; Radek, K. A.; Huang, C. M.; Ryan, A. F.; Gallo, R. L., Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury. Nature medicine 2009, 15 (12), 1377-82.

39.McDonald, D.; Ackermann, G.; Khailova, L.; Baird, C.; Heyland, D.; Kozar, R.; Lemieux, M.; Derenski, K.; King, J.; Vis-Kampen, C.; Knight, R.; Wischmeyer, P. E., Extreme Dysbiosis of the Microbiome in Critical Illness. mSphere 2016, 1 (4).

40.Kim, J., Review of the innate immune response in acne vulgaris: activation of Toll-like receptor 2 in acne triggers inflammatory cytokine responses. Dermatology (Basel, Switzerland) 2005, 211 (3), 193-8.

41.Hauser, C.; Wuethrich, B.; Matter, L.; Wilhelm, J. A.; Sonnabend, W.; Schopfer, K., Staphylococcus aureus skin colonization in atopic dermatitis patients. Dermatologica 1985, 170 (1), 35-9.

42.Perez Perez, G. I.; Gao, Z.; Jourdain, R.; Ramirez, J.; Gany, F.; Clavaud, C.; Demaude, J.; Breton, L.; Blaser, M. J., Body Site Is a More Determinant Factor than Human Population Diversity in the Healthy Skin Microbiome. PloS one 2016, 11 (4), e0151990.

43.Xu, Z.; Wang, Z.; Yuan, C.; Liu, X.; Yang, F.; Wang, T.; Wang, J.; Manabe, K.; Qin, O.; Wang, X.; Zhang, Y.; Zhang, M., Dandruff is associated with the conjoined interactions between host and microorganisms. Scientific Reports 2016, 6, 24877.

44.Gaitanis, G.; Magiatis, P.; Hantschke, M.; Bassukas, I. D.; Velegraki, A., The Malassezia genus in skin and systemic diseases. Clinical microbiology reviews 2012, 25 (1), 106-41.

45.Tanaka, A.; Cho, O.; Saito, C.; Saito, M.; Tsuboi, R.; Sugita, T., Comprehensive pyrosequencing analysis of the bacterial microbiota of the skin of patients with seborrheic dermatitis. Microbiology and immunology 2016, 60 (8), 521-6.

46.Pinto, D.; Rinaldi, F.; Sorbellini, E.; Marzani, B.; Giuliani, G., Human microbiome: What's new in scalp diseases. 2018; Vol. 4, p 1-4.

47.Montgomery, K. S., Soy protein. The Journal of perinatal education 2003, 12 (3), 42-45.

48.Adlercreutz, H.; Markkanen, H.; Watanabe, S., Plasma-Concentrations of Phyto-Estrogens in Japanese Men. Lancet 1993, 342 (8881), 1209-1210.

49.Zhang, X.; Shu, X. O.; Gao, Y. T.; Yang, G.; Li, Q.; Li, H.; Jin, F.; Zheng, W., Soy food consumption is associated with lower risk of coronary heart disease in Chinese women. J Nutr 2003, 133 (9), 2874-2878.

50.Pisani, P.; Parkin, D. M.; Bray, F.; Ferlay, J., Estimates of the worldwide mortality from 25 cancers in 1990. International Journal of Cancer 1999, 83 (1), 18-29.

51.Messina, M., Soy and health update: evaluation of the clinical and epidemiologic literature. Nutrients 2016, 8 (12), 754.

52.Chen, S. T.; Ferng, S. H.; Yang, C. S.; Peng, S. J.; Lee, H. R.; Chen, J. R., Variable effects of soy protein on plasma lipids in hyperlipidemic and normolipidemic hemodialysis patients. Am J Kidney Dis 2005, 46 (6), 1099-106.

53.Krauss, R. M.; Eckel, R. H.; Howard, B.; Appel, L. J.; Daniels, S. R.; Deckelbaum, R. J.; Erdman, J. W.; Kris-Etherton, P.; Goldberg, I. J.; Kotchen, T. A.; Lichtenstein, A. H.; Mitch, W. E.; Mullis, R.; Robinson, K.; Wylie-Rosett, J.; Jeor, S. S.; Suttie, J.; Tribble, D. L.; Bazzarre, T. L., AHA dietary guidelines - Revision 2000: A statement for healthcare professionals from the nutrition committee of the American Heart Association. Circulation 2000, 102 (18), 2284-2299.

54.Bednar, G. E.; Patil, A. R.; Murray, S. M.; Grieshop, C. M.; Merchen, N. R.; Fahey, G. C., Starch and fiber fractions in selected food and feed ingredients affect their small intestinal digestibility and fermentability and their large bowel fermentability in vitro in a canine model. J Nutr 2001, 131 (2), 276-286.

55.Roberfroid, M., Prebiotics: The concept revisited. J Nutr 2007, 137 (3), 830s-837s.

56.Mital, B. K.; Steinkraus, K. H., Utilization of Oligosaccharides by Lactic-Acid Bacteria during Fermentation of Soy Milk. J Food Sci 1975, 40 (1), 114-118.

57.Murphy, P. A.; Barua, K.; Hauck, C. C., Solvent extraction selection in the determination of isoflavones in soy foods. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 2002, 777 (1-2), 129-38.

58.Foti, P.; Erba, D.; Riso, P.; Spadafranca, A.; Criscuoli, F.; Testolin, G., Comparison between daidzein and genistein antioxidant activity in primary and cancer lymphocytes. Archives of biochemistry and biophysics 2005, 433 (2), 421-7.

59.Chin, Y. P.; Tsui, K. C.; Chen, M. C.; Wang, C. Y.; Yang, C. Y.; Lin, Y. L., Bactericidal activity of soymilk fermentation broth by in vitro and animal models. Journal of medicinal food 2012, 15 (6), 520-6.

60.Lengyel, J.; Rimarčík, J.; Vagánek, A.; Klein, E., On the radical scavenging activity of isoflavones: Thermodynamics of O-H bond cleavage. 2013; Vol. 15.

61.Iovine, B.; Iannella, M. L.; Gasparri, F.; Monfrecola, G.; Bevilacqua, M. A., Synergic Effect of Genistein and Daidzein on UVB-Induced DNA Damage: An Effective Photoprotective Combination. J Biomed Biotechnol 2011, 2011, 692846.

62.Dong, J. Y.; Qin, L. Q., Soy isoflavones consumption and risk of breast cancer incidence or recurrence: a meta-analysis of prospective studies. Breast Cancer Res. Treat. 2011, 125 (2), 315-323.

63.Yu, J.; Bi, X. J.; Yu, B.; Chen, D. W., Isoflavones: Anti-Inflammatory Benefit and Possible Caveats. Nutrients 2016, 8 (6), 16.

64.Xiao, J. X.; Peng, G. H.; Zhang, S. H., Prevention effects of soyasaponins on hyperlipidemia mice and its molecular mechanism. 2005; Vol. 27, p 147-150.

65.Koratkar, R.; Rao, A. V., Effect of soya bean saponins on azoxymethane-induced preneoplastic lesions in the colon of mice. Nutrition and cancer 1997, 27 (2), 206-9.

66.Sung, M. K.; Kendall, C. W.; Koo, M. M.; Rao, A. V., Effect of soybean saponins and gypsophilla saponin on growth and viability of colon carcinoma cells in culture. Nutrition and cancer 1995, 23 (3), 259-70.

67.Fox, C. H.; Eberl, M., Phytic acid (IP6), novel broad spectrum anti-neoplastic agent: a systematic review. Complementary therapies in medicine 2002, 10 (4), 229-34.

68.Bradford, P. G.; Awad, A. B., Phytosterols as anticancer compounds. Molecular nutrition & food research 2007, 51 (2), 161-70.

69.Woyengo, T. A.; Ramprasath, V. R.; Jones, P. J., Anticancer effects of phytosterols. European journal of clinical nutrition 2009, 63 (7), 813-20.

70.Bouic, P. J., The role of phytosterols and phytosterolins in immune modulation: a review of the past 10 years. Current opinion in clinical nutrition and metabolic care 2001, 4 (6), 471-5.

71.Bouic, P. J.; Lamprecht, J. H., Plant sterols and sterolins: a review of their immune-modulating properties. Alternative medicine review : a journal of clinical therapeutic 1999, 4 (3), 170-7.

72.Hill, G. D., PLANT ANTINUTRITIONAL FACTORS | Characteristics. In Encyclopedia of Food Sciences and Nutrition (Second Edition), Caballero, B., Ed. Academic Press: Oxford, 2003; pp 4578-4587.

73.劉千瑈; 陳勁初; 張莉妮; 葉淑幸; 李金木, 大豆發酵液之免疫調節功效. 檢驗及品保雜誌 2014, 3 (4), 175-184.

74.Lee, S.; Kim, J. E.; Suk, S.; Kwon, O. W.; Park, G.; Lim, T. G.; Seo, S. G.; Kim, J. R.; Kim, D. E.; Lee, M.; Chung, D. K.; Jeon, J. E.; Cho, D. W.; Hurh, B. S.; Kim, S. Y.; Lee, K. W., A fermented barley and soybean formula enhances skin hydration. Journal of clinical biochemistry and nutrition 2015, 57 (2), 156-63.

75.Miyazaki, K.; Hanamizu, T.; Iizuka, R.; Chiba, K., Bifidobacterium-fermented soy milk extract stimulates hyaluronic acid production in human skin cells and hairless mouse skin. Skin pharmacology and applied skin physiology 2003, 16 (2), 108-16.

76.Aagaard, K.; Petrosino, J.; Keitel, W.; Watson, M.; Katancik, J.; Garcia, N.; Patel, S.; Cutting, M.; Madden, T.; Hamilton, H.; Harris, E.; Gevers, D.; Simone, G.; McInnes, P.; Versalovic, J., The Human Microbiome Project strategy for comprehensive sampling of the human microbiome and why it matters. The FASEB Journal 2013, 27 (3), 1012-1022.

77.Methé, B. A.; Nelson, K. E.; Pop, M.; Creasy, H. H.; Giglio, M. G.; Huttenhower, C.; Gevers, D.; Petrosino, J. F.; Abubucker, S.; Badger, J. H.; Chinwalla, A. T.; Earl, A. M.; FitzGerald, M. G.; Fulton, R. S.; Hallsworth-Pepin, K.; Lobos, E. A.; Madupu, R.; Magrini, V.; Martin, J. C.; Mitreva, M.; Muzny, D. M.; Sodergren, E. J.; Versalovic, J.; Wollam, A. M.; Worley, K. C.; Wortman, J. R.; Young, S. K.; Zeng, Q.; Aagaard, K. M.; Abolude, O. O.; Allen-Vercoe, E.; Alm, E. J.; Alvarado, L.; Andersen, G. L.; Anderson, S.; Appelbaum, E.; Arachchi, H. M.; Armitage, G.; Arze, C. A.; Ayvaz, T.; Baker, C. C.; Begg, L.; Belachew, T.; Bhonagiri, V.; Bihan, M.; Blaser, M. J.; Bloom, T.; Bonazzi, V. R.; Brooks, P.; Buck, G. A.; Buhay, C. J.; Busam, D. A.; Campbell, J. L.; Canon, S. R.; Cantarel, B. L.; Chain, P. S.; Chen, I. M. A.; Chen, L.; Chhibba, S.; Chu, K.; Ciulla, D. M.; Clemente, J. C.; Clifton, S. W.; Conlan, S.; Crabtree, J.; Cutting, M. A.; Davidovics, N. J.; Davis, C. C.; DeSantis, T. Z.; Deal, C.; Delehaunty, K. D.; Dewhirst, F. E.; Deych, E.; Ding, Y.; Dooling, D. J.; Dugan, S. P.; Michael Dunne, W.; Scott Durkin, A.; Edgar, R. C.; Erlich, R. L.; Farmer, C. N.; Farrell, R. M.; Faust, K.; Feldgarden, M.; Felix, V. M.; Fisher, S.; Fodor, A. A.; Forney, L.; Foster, L.; Di Francesco, V.; Friedman, J.; Friedrich, D. C.; Fronick, C. C.; Fulton, L. L.; Gao, H.; Garcia, N.; Giannoukos, G.; Giblin, C.; Giovanni, M. Y.; Goldberg, J. M.; Goll, J.; Gonzalez, A.; Griggs, A.; Gujja, S.; Haas, B. J.; Hamilton, H. A.; Harris, E. L.; Hepburn, T. A.; Herter, B.; Hoffmann, D. E.; Holder, M. E.; Howarth, C.; Huang, K. H.; Huse, S. M.; Izard, J.; Jansson, J. K.; Jiang, H.; Jordan, C.; Joshi, V.; Katancik, J. A.; Keitel, W. A.; Kelley, S. T.; Kells, C.; Kinder-Haake, S.; King, N. B.; Knight, R.; Knights, D.; Kong, H. H.; Koren, O.; Koren, S.; Kota, K. C.; Kovar, C. L.; Kyrpides, N. C.; La Rosa, P. S.; Lee, S. L.; Lemon, K. P.; Lennon, N.; Lewis, C. M.; Lewis, L.; Ley, R. E.; Li, K.; Liolios, K.; Liu, B.; Liu, Y.; Lo, C.-C.; Lozupone, C. A.; Dwayne Lunsford, R.; Madden, T.; Mahurkar, A. A.; Mannon, P. J.; Mardis, E. R.; Markowitz, V. M.; Mavrommatis, K.; McCorrison, J. M.; McDonald, D.; McEwen, J.; McGuire, A. L.; McInnes, P.; Mehta, T.; Mihindukulasuriya, K. A.; Miller, J. R.; Minx, P. J.; Newsham, I.; Nusbaum, C.; O’Laughlin, M.; Orvis, J.; Pagani, I.; Palaniappan, K.; Patel, S. M.; Pearson, M.; Peterson, J.; Podar, M.; Pohl, C.; Pollard, K. S.; Priest, M. E.; Proctor, L. M.; Qin, X.; Raes, J.; Ravel, J.; Reid, J. G.; Rho, M.; Rhodes, R.; Riehle, K. P.; Rivera, M. C.; Rodriguez-Mueller, B.; Rogers, Y.-H.; Ross, M. C.; Russ, C.; Sanka, R. K.; Sankar, P.; Fah Sathirapongsasuti, J.; Schloss, J. A.; Schloss, P. D.; Schmidt, T. M.; Scholz, M.; Schriml, L.; Schubert, A. M.; Segata, N.; Segre, J. A.; Shannon, W. D.; Sharp, R. R.; Sharpton, T. J.; Shenoy, N.; Sheth, N. U.; Simone, G. A.; Singh, I.; Smillie, C. S.; Sobel, J. D.; Sommer, D. D.; Spicer, P.; Sutton, G. G.; Sykes, S. M.; Tabbaa, D. G.; Thiagarajan, M.; Tomlinson, C. M.; Torralba, M.; Treangen, T. J.; Truty, R. M.; Vishnivetskaya, T. A.; Walker, J.; Wang, L.; Wang, Z.; Ward, D. V.; Warren, W.; Watson, M. A.; Wellington, C.; Wetterstrand, K. A.; White, J. R.; Wilczek-Boney, K.; Qing Wu, Y.; Wylie, K. M.; Wylie, T.; Yandava, C.; Ye, L.; Ye, Y.; Yooseph, S.; Youmans, B. P.; Zhang, L.; Zhou, Y.; Zhu, Y.; Zoloth, L.; Zucker, J. D.; Birren, B. W.; Gibbs, R. A.; Highlander, S. K.; Weinstock, G. M.; Wilson, R. K.; White, O.; The Human Microbiome Project, C., A framework for human microbiome research. Nature 2012, 486 (7402), 215-221.

78.Huttenhower, C.; Gevers, D.; Knight, R.; Abubucker, S.; Badger, J. H.; Chinwalla, A. T.; Creasy, H. H.; Earl, A. M.; FitzGerald, M. G.; Fulton, R. S.; Giglio, M. G.; Hallsworth-Pepin, K.; Lobos, E. A.; Madupu, R.; Magrini, V.; Martin, J. C.; Mitreva, M.; Muzny, D. M.; Sodergren, E. J.; Versalovic, J.; Wollam, A. M.; Worley, K. C.; Wortman, J. R.; Young, S. K.; Zeng, Q.; Aagaard, K. M.; Abolude, O. O.; Allen-Vercoe, E.; Alm, E. J.; Alvarado, L.; Andersen, G. L.; Anderson, S.; Appelbaum, E.; Arachchi, H. M.; Armitage, G.; Arze, C. A.; Ayvaz, T.; Baker, C. C.; Begg, L.; Belachew, T.; Bhonagiri, V.; Bihan, M.; Blaser, M. J.; Bloom, T.; Bonazzi, V.; Paul Brooks, J.; Buck, G. A.; Buhay, C. J.; Busam, D. A.; Campbell, J. L.; Canon, S. R.; Cantarel, B. L.; Chain, P. S. G.; Chen, I. M. A.; Chen, L.; Chhibba, S.; Chu, K.; Ciulla, D. M.; Clemente, J. C.; Clifton, S. W.; Conlan, S.; Crabtree, J.; Cutting, M. A.; Davidovics, N. J.; Davis, C. C.; DeSantis, T. Z.; Deal, C.; Delehaunty, K. D.; Dewhirst, F. E.; Deych, E.; Ding, Y.; Dooling, D. J.; Dugan, S. P.; Michael Dunne, W.; Scott Durkin, A.; Edgar, R. C.; Erlich, R. L.; Farmer, C. N.; Farrell, R. M.; Faust, K.; Feldgarden, M.; Felix, V. M.; Fisher, S.; Fodor, A. A.; Forney, L. J.; Foster, L.; Di Francesco, V.; Friedman, J.; Friedrich, D. C.; Fronick, C. C.; Fulton, L. L.; Gao, H.; Garcia, N.; Giannoukos, G.; Giblin, C.; Giovanni, M. Y.; Goldberg, J. M.; Goll, J.; Gonzalez, A.; Griggs, A.; Gujja, S.; Kinder Haake, S.; Haas, B. J.; Hamilton, H. A.; Harris, E. L.; Hepburn, T. A.; Herter, B.; Hoffmann, D. E.; Holder, M. E.; Howarth, C.; Huang, K. H.; Huse, S. M.; Izard, J.; Jansson, J. K.; Jiang, H.; Jordan, C.; Joshi, V.; Katancik, J. A.; Keitel, W. A.; Kelley, S. T.; Kells, C.; King, N. B.; Knights, D.; Kong, H. H.; Koren, O.; Koren, S.; Kota, K. C.; Kovar, C. L.; Kyrpides, N. C.; La Rosa, P. S.; Lee, S. L.; Lemon, K. P.; Lennon, N.; Lewis, C. M.; Lewis, L.; Ley, R. E.; Li, K.; Liolios, K.; Liu, B.; Liu, Y.; Lo, C.-C.; Lozupone, C. A.; Dwayne Lunsford, R.; Madden, T.; Mahurkar, A. A.; Mannon, P. J.; Mardis, E. R.; Markowitz, V. M.; Mavromatis, K.; McCorrison, J. M.; McDonald, D.; McEwen, J.; McGuire, A. L.; McInnes, P.; Mehta, T.; Mihindukulasuriya, K. A.; Miller, J. R.; Minx, P. J.; Newsham, I.; Nusbaum, C.; O’Laughlin, M.; Orvis, J.; Pagani, I.; Palaniappan, K.; Patel, S. M.; Pearson, M.; Peterson, J.; Podar, M.; Pohl, C.; Pollard, K. S.; Pop, M.; Priest, M. E.; Proctor, L. M.; Qin, X.; Raes, J.; Ravel, J.; Reid, J. G.; Rho, M.; Rhodes, R.; Riehle, K. P.; Rivera, M. C.; Rodriguez-Mueller, B.; Rogers, Y.-H.; Ross, M. C.; Russ, C.; Sanka, R. K.; Sankar, P.; Fah Sathirapongsasuti, J.; Schloss, J. A.; Schloss, P. D.; Schmidt, T. M.; Scholz, M.; Schriml, L.; Schubert, A. M.; Segata, N.; Segre, J. A.; Shannon, W. D.; Sharp, R. R.; Sharpton, T. J.; Shenoy, N.; Sheth, N. U.; Simone, G. A.; Singh, I.; Smillie, C. S.; Sobel, J. D.; Sommer, D. D.; Spicer, P.; Sutton, G. G.; Sykes, S. M.; Tabbaa, D. G.; Thiagarajan, M.; Tomlinson, C. M.; Torralba, M.; Treangen, T. J.; Truty, R. M.; Vishnivetskaya, T. A.; Walker, J.; Wang, L.; Wang, Z.; Ward, D. V.; Warren, W.; Watson, M. A.; Wellington, C.; Wetterstrand, K. A.; White, J. R.; Wilczek-Boney, K.; Wu, Y.; Wylie, K. M.; Wylie, T.; Yandava, C.; Ye, L.; Ye, Y.; Yooseph, S.; Youmans, B. P.; Zhang, L.; Zhou, Y.; Zhu, Y.; Zoloth, L.; Zucker, J. D.; Birren, B. W.; Gibbs, R. A.; Highlander, S. K.; Methé, B. A.; Nelson, K. E.; Petrosino, J. F.; Weinstock, G. M.; Wilson, R. K.; White, O.; The Human Microbiome Project, C., Structure, function and diversity of the healthy human microbiome. Nature 2012, 486 (7402), 207-214.

79.Paulino, L. C.; Tseng, C. H.; Strober, B. E.; Blaser, M. J., Molecular analysis of fungal microbiota in samples from healthy human skin and psoriatic lesions. Journal of Clinical Microbiology 2006, 44 (8), 2933-2941.

80.Schowalter, R. M.; Pastrana, D. V.; Pumphrey, K. A.; Moyer, A. L.; Buck, C. B., Merkel Cell Polyomavirus and Two Previously Unknown Polyomaviruses Are Chronically Shed from Human Skin. Cell Host & Microbe 2010, 7 (6), 509-515.

81.Gao, Z.; Tseng, C.-h.; Pei, Z.; Blaser, M. J., Molecular analysis of human forearm superficial skin bacterial biota. Proceedings of the National Academy of Sciences 2007, 104 (8), 2927.

82.Grice, E. A.; Kong, H. H.; Renaud, G.; Young, A. C.; Bouffard, G. G.; Blakesley, R. W.; Wolfsberg, T. G.; Turner, M. L.; Segre, J. A., A diversity profile of the human skin microbiota. Genome research 2008, 18 (7), 1043-1050.

83.Van Horn, K. G.; Audette, C. D.; Tucker, K. A.; Sebeck, D., Comparison of 3 swab transport systems for direct release and recovery of aerobic and anaerobic bacteria. Diagnostic microbiology and infectious disease 2008, 62 (4), 471-473.

84.Capone, K. A.; Dowd, S. E.; Stamatas, G. N.; Nikolovski, J., Diversity of the human skin microbiome early in life. Journal of Investigative Dermatology 2011, 131 (10), 2026-2032.

85.Huttenhower, C.; Gevers, D.; Knight, R.; Abubucker, S.; Badger, J. H.; Chinwalla, A. T.; Creasy, H. H.; Earl, A. M.; FitzGerald, M. G.; Fulton, R. S., Structure, function and diversity of the healthy human microbiome. Nature 2012, 486 (7402), 207.

86.Lagier, J.-C.; Edouard, S.; Pagnier, I.; Mediannikov, O.; Drancourt, M.; Raoult, D., Current and past strategies for bacterial culture in clinical microbiology. Clinical microbiology reviews 2015, 28 (1), 208-236.

87.Whyte, W.; Carson, W.; Hambraeus, A., Methods for calculating the efficiency of bacterial surface sampling techniques. Journal of Hospital Infection 1989, 13 (1), 33-41.

88.Hambraeus, A.; Hoborn, J.; Whyte, W., Skin sampling—validation of a pad method and comparison with commonly used methods. Journal of Hospital Infection 1990, 16 (1), 19-27.

89.Grice, E. A.; Segre, J. A., The skin microbiome. Nat Rev Microbiol 2011, 9 (4), 244-53.

90.Updegraff, D. M., Methods for determining the distribution of bacteria in the skin. Journal of the American Oil Chemists’ Society 1967, 44 (8), 481-483.

91.Findley, K.; Oh, J.; Yang, J.; Conlan, S.; Deming, C.; Meyer, J. A.; Schoenfeld, D.; Nomicos, E.; Park, M.; Sequencing, N. I. S. C. C., Topographic diversity of fungal and bacterial communities in human skin. Nature 2013, 498 (7454), 367-370.

92.Grice, E. A.; Segre, J. A., The skin microbiome. Nature Reviews Microbiology 2011, 9 (4), 244-253.

93.Zuber, T. J., Punch biopsy of the skin. American family physician 2002, 65 (6), 1155-8, 1161-2, 1164.

94.Kong, H. H.; Andersson, B.; Clavel, T.; Common, J. E.; Jackson, S. A.; Olson, N. D.; Segre, J. A.; Traidl-Hoffmann, C., Performing Skin Microbiome Research: A Method to the Madness. The Journal of investigative dermatology 2017, 137 (3), 561-568.

95.Daley, P.; Castriciano, S.; Chernesky, M.; Smieja, M., Comparison of flocked and rayon swabs for collection of respiratory epithelial cells from uninfected volunteers and symptomatic patients. J Clin Microbiol 2006, 44 (6), 2265-7.

96.Fierer, N.; Hamady, M.; Lauber, C. L.; Knight, R., The influence of sex, handedness, and washing on the diversity of hand surface bacteria. Proc Natl Acad Sci U S A 2008, 105 (46), 17994-9.

97.Oh, J.; Byrd, A. L.; Park, M.; Program, N. C. S.; Kong, H. H.; Segre, J. A., Temporal Stability of the Human Skin Microbiome. Cell 2016, 165 (4), 854-66.

98.Pinto, D.; Sorbellini, E.; Marzani, B.; Rucco, M.; Giuliani, G.; Rinaldi, F., Scalp bacterial shift in Alopecia areata. PloS one 2019, 14 (4), e0215206.

99.Ho, B. S.; Ho, E. X. P.; Chu, C. W.; Ramasamy, S.; Bigliardi-Qi, M.; de Sessions, P. F.; Bigliardi, P. L., Microbiome in the hair follicle of androgenetic alopecia patients. PloS one 2019, 14 (5), e0216330.

100.Nakatsuji, T.; Chiang, H. I.; Jiang, S. B.; Nagarajan, H.; Zengler, K.; Gallo, R. L., The microbiome extends to subepidermal compartments of normal skin. Nat Commun 2013, 4, 1431.

101.Flores, G. E.; Seite, S.; Henley, J. B.; Martin, R.; Zelenkova, H.; Aguilar, L.; Fierer, N., Microbiome of Affected and Unaffected Skin of Patients With Atopic Dermatitis Before and After Emollient Treatment. J Drugs Dermatol 2014, 13 (11), 1365-1372.

102.Kong, H. H.; Oh, J.; Deming, C.; Conlan, S.; Grice, E. A.; Beatson, M. A.; Nomicos, E.; Polley, E. C.; Komarow, H. D.; Program, N. C. S.; Murray, P. R.; Turner, M. L.; Segre, J. A., Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res 2012, 22 (5), 850-9.

103.Li, M.; Budding, A. E.; van der Lugt-Degen, M.; Du-Thumm, L.; Vandeven, M.; Fan, A., The influence of age, gender and race/ethnicity on the composition of the human axillary microbiome. International journal of cosmetic science 2019, 41 (4), 371-377.

104.Ying, S.; Zeng, D. N.; Chi, L.; Tan, Y.; Galzote, C.; Cardona, C.; Lax, S.; Gilbert, J.; Quan, Z. X., The Influence of Age and Gender on Skin-Associated Microbial Communities in Urban and Rural Human Populations. PloS one 2015, 10 (10), e0141842.

105.Kim, H. J.; Kim, J. J.; Myeong, N. R.; Kim, T.; Kim, D.; An, S.; Kim, H.; Park, T.; Jang, S. I.; Yeon, J. H.; Kwack, I.; Sul, W. J., Segregation of age-related skin microbiome characteristics by functionality. Sci Rep 2019, 9 (1), 16748.

106.Shibagaki, N.; Suda, W.; Clavaud, C.; Bastien, P.; Takayasu, L.; Iioka, E.; Kurokawa, R.; Yamashita, N.; Hattori, Y.; Shindo, C.; Breton, L.; Hattori, M., Aging-related changes in the diversity of women's skin microbiomes associated with oral bacteria. Sci Rep 2017, 7 (1), 10567.

107.Huang, S.; Haiminen, N.; Carrieri, A. P.; Hu, R.; Jiang, L.; Parida, L.; Russell, B.; Allaband, C.; Zarrinpar, A.; Vazquez-Baeza, Y.; Belda-Ferre, P.; Zhou, H.; Kim, H. C.; Swafford, A. D.; Knight, R.; Xu, Z. Z., Human Skin, Oral, and Gut Microbiomes Predict Chronological Age. mSystems 2020, 5 (1).

108.Bjerre, R. D.; Hugerth, L. W.; Boulund, F.; Seifert, M.; Johansen, J. D.; Engstrand, L., Effects of sampling strategy and DNA extraction on human skin microbiome investigations. Sci Rep 2019, 9 (1), 17287.

109.Srinivasan, R.; Karaoz, U.; Volegova, M.; MacKichan, J.; Kato-Maeda, M.; Miller, S.; Nadarajan, R.; Brodie, E. L.; Lynch, S. V., Use of 16S rRNA Gene for Identification of a Broad Range of Clinically Relevant Bacterial Pathogens. PloS one 2015, 10 (2).

110.Chakravorty, S.; Helb, D.; Burday, M.; Connell, N.; Alland, D., A detailed analysis of 16S ribosomal RNA gene segments for the diagnosis of pathogenic bacteria. J Microbiol Meth 2007, 69 (2), 330-339.

111.Ghyselinck, J.; Pfeiffer, S.; Heylen, K.; Sessitsch, A.; De Vos, P., The Effect of Primer Choice and Short Read Sequences on the Outcome of 16S rRNA Gene Based Diversity Studies. PloS one 2013, 8 (8).

112.Mizrahi-Man, O.; Davenport, E. R.; Gilad, Y., Taxonomic Classification of Bacterial 16S rRNA Genes Using Short Sequencing Reads: Evaluation of Effective Study Designs. PloS one 2013, 8 (1).

113.Zheng, W.; Tsompana, M.; Ruscitto, A.; Sharma, A.; Genco, R.; Sun, Y. J.; Buck, M. J., An accurate and efficient experimental approach for characterization of the complex oral microbiota. Microbiome 2015, 3.

114.Castelino, M.; Eyre, S.; Moat, J.; Fox, G.; Martin, P.; Ho, P.; Upton, M.; Barton, A., Optimisation of methods for bacterial skin microbiome investigation: primer selection and comparison of the 454 versus MiSeq platform. Bmc Microbiol 2017, 17.

115.Stehlikova, Z.; Kostovcik, M.; Kostovcikova, K.; Kverka, M.; Juzlova, K.; Rob, F.; Hercogova, J.; Bohac, P.; Pinto, Y.; Uzan, A.; Koren, O.; Tlaskalova-Hogenova, H.; Zakostelska, Z. J., Dysbiosis of Skin Microbiota in Psoriatic Patients: Co-occurrence of Fungal and Bacterial Communities. Front Microbiol 2019, 10.

116.Barb, J. J.; Oler, A. J.; Kim, H. S.; Chalmers, N.; Wallen, G. R.; Cashion, A.; Munson, P. J.; Ames, N. J., Development of an Analysis Pipeline Characterizing Multiple Hypervariable Regions of 16S rRNA Using Mock Samples. PloS one 2016, 11 (2).

117.Baldwin, B. G.; Sanderson, M. J.; Porter, J. M.; Wojciechowski, M. F.; Campbell, C. S.; Donoghue, M. J., The its Region of Nuclear Ribosomal DNA: A Valuable Source of Evidence on Angiosperm Phylogeny. Annals of the Missouri Botanical Garden 1995, 82 (2), 247-277.

118.Vilgalys, R.; Gonzalez, D., Organization of ribosomal DNA in the basidiomycete Thanatephorus praticola. Current genetics 1990, 18 (3), 277-280.

119.Song, J.; Shi, L.; Li, D.; Sun, Y.; Niu, Y.; Chen, Z.; Luo, H.; Pang, X.; Sun, Z.; Liu, C.; Lv, A.; Deng, Y.; Larson-Rabin, Z.; Wilkinson, M.; Chen, S., Extensive pyrosequencing reveals frequent intra-genomic variations of internal transcribed spacer regions of nuclear ribosomal DNA. PloS one 2012, 7 (8), e43971-e43971.

120.Buée, M.; Reich, M.; Murat, C.; Morin, E.; Nilsson, R.; Uroz, S.; Martin, F., 454 Pyrosequencing analyses of forest soils reveal an unexpectedly high fungal diversity. New phytologist 2009, 184 (2), 449-456.

121.Lv, X.-C.; Jiang, Y.-J.; Liu, J.; Guo, W.-L.; Liu, Z.-B.; Zhang, W.; Rao, P.-F.; Ni, L., Evaluation of different PCR primers for denaturing gradient gel electrophoresis (DGGE) analysis of fungal community structure in traditional fermentation starters used for Hong Qu glutinous rice wine. International journal of food microbiology 2017, 255, 58-65.

122.Nilsson, R. H.; Ryberg, M.; Abarenkov, K.; Sjökvist, E.; Kristiansson, E., The ITS region as a target for characterization of fungal communities using emerging sequencing technologies. FEMS Microbiology Letters 2009, 296 (1), 97-101.

123.Schoch, C. L.; Seifert, K. A.; Huhndorf, S.; Robert, V.; Spouge, J. L.; Levesque, C. A.; Chen, W.; Consortium, F. B., Nuclear ribosomal internal transcribed spacer (ITS) region as a universal DNA barcode marker for Fungi. Proceedings of the National Academy of Sciences 2012, 109 (16), 6241-6246.

124.Větrovský, T.; Baldrian, P., Analysis of soil fungal communities by amplicon pyrosequencing: current approaches to data analysis and the introduction of the pipeline SEED. Biology and Fertility of Soils 2013, 49 (8), 1027-1037.

125.Yahr, R.; Schoch, C. L.; Dentinger, B. T., Scaling up discovery of hidden diversity in fungi: impacts of barcoding approaches. Philosophical Transactions of the Royal Society B: Biological Sciences 2016, 371 (1702), 20150336.

126.Abarenkov, K.; Henrik Nilsson, R.; Larsson, K. H.; Alexander, I. J.; Eberhardt, U.; Erland, S.; Høiland, K.; Kjøller, R.; Larsson, E.; Pennanen, T., The UNITE database for molecular identification of fungi–recent updates and future perspectives. New Phytologist 2010, 186 (2), 281-285.

127.Ryberg, M.; Kristiansson, E.; Sjökvist, E.; Nilsson, R. H., An outlook on the fungal internal transcribed spacer sequences in GenBank and the introduction of a web‐based tool for the exploration of fungal diversity. New Phytologist 2009, 181 (2), 471-477.

128.Grice, E. A.; Kong, H. H.; Renaud, G.; Young, A. C.; Program, N. C. S.; Bouffard, G. G.; Blakesley, R. W.; Wolfsberg, T. G.; Turner, M. L.; Segre, J. A., A diversity profile of the human skin microbiota. Genome research 2008, 18 (7), 1043-1050.

129.Wu, Z.; Wang, X. R.; Blomquist, G., Evaluation of PCR primers and PCR conditions for specific detection of common airborne fungi. J Environ Monit 2002, 4 (3), 377-82.

130.Tripathy, S. K.; Maharana, M., Exploring Rapid and Efficient Protocol for Isolation of Fungal DNA. International Journal of Current Microbiology and Applied Sciences 2017, 6, 951-960.

131.Ludwig, W.; Schleifer, K. H., How quantitative is quantitative PCR with respect to cell counts? Syst Appl Microbiol 2000, 23 (4), 556-62.

132.de Morais Cavalcanti, S. M.; de França, E. R.; Magalhães, M.; Lins, A. K.; Brandão, L. C.; Magalhães, V., A quantitative analysis of Propionibacterium acnes in lesional and non-lesional skin of patients with progressive macular hypomelanosis by real-time polymerase chain reaction. Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology] 2011, 42 (2), 423-429.

133.Xie, Z.; Ran, Y.; Zhang, H.; Zhang, M.; Wan, H.; Li, C., An analysis of the Malassezia species distribution in the skin of patients with pityriasis versicolor in Chengdu, China. ScientificWorldJournal 2014, 2014, 182596-182596.

134.Schnuch, A.; Aberer, W.; Agathos, M.; Becker, D.; Brasch, J.; Elsner, P.; Frosch, P.; Fuchs, T.; Geier, J.; Hillen, U.; Löffler, H.; Mahler, V., Patch testing with contact allergens. Journal Der Deutschen Dermatologischen Gesellschaft - J DTSCH DERMATOL GES 2008, 6, 770-775.

135.Qian, F.; Zhang, J.; Hou, K.; Zhang, Y.; Wang, Z.; Luo, P.; Tuo, Y., In vitro study of the antioxidative and antiproliferative capabilities of Lactobacillus casei 16-fermented soymilk. Food Sci Nutr 2020, 8 (1), 48-57.

136.Samruan, W.; Gasaluck, P.; Oonsivilai, R., Total Phenolic and Flavonoid Contents of Soybean Fermentation by Bacillus subtilis SB-MYP-1. Advanced Materials Research 2014, 931-932, 1587-1591.

137.Singleton, V. L.; Orthofer, R.; Lamuela-Raventós, R. M. In Analysis of total phenols and other oxidation substrates and antioxidants by means of folin-ciocalteu reagent, 1999.

138.Chang, C. C.; Yang, M. H.; Wen, H. M.; Chern, J. C., Estimation of total flavonoid content in propolis by two complementary colorimetric methods. J Food Drug Anal 2002, 10 (3), 178-182.

139.Rose, L.; Jensen, B.; Peterson, A.; Banerjee, S. N.; Srduino, M. J., Swab materials and Bacillus anthracis spore recovery from nonporous surfaces. Emerg Infect Dis 2004, 10 (6), 1023-1029.

140.Park, H. K.; Ha, M. H.; Park, S. G.; Kim, M. N.; Kim, B. J.; Kim, W., Characterization of the fungal microbiota (mycobiome) in healthy and dandruff-afflicted human scalps. PloS one 2012, 7 (2), e32847.

141.Saxena, R.; Mittal, P.; Clavaud, C.; Dhakan, D. B.; Hegde, P.; Veeranagaiah, M. M.; Saha, S.; Souverain, L.; Roy, N.; Breton, L.; Misra, N.; Sharma, V. K., Comparison of Healthy and Dandruff Scalp Microbiome Reveals the Role of Commensals in Scalp Health. Front Cell Infect Microbiol 2018, 8, 346.

142.Clavaud, C.; Jourdain, R.; Bar-Hen, A.; Tichit, M.; Bouchier, C.; Pouradier, F.; El Rawadi, C.; Guillot, J.; Menard-Szczebara, F.; Breton, L.; Latge, J. P.; Mouyna, I., Dandruff Is Associated with Disequilibrium in the Proportion of the Major Bacterial and Fungal Populations Colonizing the Scalp. PloS one 2013, 8 (3).

143.Wang, L.; Clavaud, C.; Bar-Hen, A.; Cui, M.; Gao, J.; Liu, Y.; Liu, C.; Shibagaki, N.; Gueniche, A.; Jourdain, R.; Lan, K.; Zhang, C.; Altmeyer, R.; Breton, L., Characterization of the major bacterial-fungal populations colonizing dandruff scalps in Shanghai, China, shows microbial disequilibrium. Exp Dermatol 2015, 24 (5), 398-400.

144.Hall, J. B.; Cong, Z.; Imamura-Kawasawa, Y.; Kidd, B. A.; Dudley, J. T.; Thiboutot, D. M.; Nelson, A. M., Isolation and Identification of the Follicular Microbiome: Implications for Acne Research. The Journal of investigative dermatology 2018, 138 (9), 2033-2040.

145.Ogai, K.; Nagase, S.; Mukai, K.; Iuchi, T.; Mori, Y.; Matsue, M.; Sugitani, K.; Sugama, J.; Okamoto, S., A Comparison of Techniques for Collecting Skin Microbiome Samples: Swabbing Versus Tape-Stripping. Front Microbiol 2018, 9, 2362.

146.Fierer, N.; Hamady, M.; Lauber, C. L.; Knight, R., The influence of sex, handedness, and washing on the diversity of hand surface bacteria. Proceedings of the National Academy of Sciences 2008, 105 (46), 17994-17999.

147.Oh, J.; Conlan, S.; Polley, E. C.; Segre, J. A.; Kong, H. H., Shifts in human skin and nares microbiota of healthy children and adults. Genome Med 2012, 4 (10), 77.

148.Ma, L.; Guichard, A.; Cheng, Y.; Li, J.; Qin, O.; Wang, X.; Liu, W.; Tan, Y., Sensitive scalp is associated with excessive sebum and perturbed microbiome. Journal of cosmetic dermatology 2018.

149.Lauber, C. L.; Zhou, N.; Gordon, J. I.; Knight, R.; Fierer, N., Effect of storage conditions on the assessment of bacterial community structure in soil and human-associated samples. Fems Microbiology Letters 2010, 307 (1), 80-86.

150.Goodrich, J. K.; Di Rienzi, S. C.; Poole, A. C.; Koren, O.; Walters, W. A.; Caporaso, J. G.; Knight, R.; Ley, R. E., Conducting a microbiome study. Cell 2014, 158 (2), 250-262.

151.Harada, N.; Okajima, K., Effects of capsaicin and isoflavone on blood pressure and serum levels of insulin-like growth factor-I in normotensive and hypertensive volunteers with alopecia. Biosci Biotechnol Biochem 2009, 73 (6), 1456-9.

152.Harada, N.; Okajima, K.; Arai, M.; Kurihara, H.; Nakagata, N., Administration of capsaicin and isoflavone promotes hair growth by increasing insulin-like growth factor-I production in mice and in humans with alopecia. Growth Horm IGF Res 2007, 17 (5), 408-15.

153.Trüeb, R. M., Further Clinical Evidence for the Effect of IGF-1 on Hair Growth and Alopecia. Skin Appendage Disord 2018, 4 (2), 90-95.

154.Amirnia, M.; Sinafar, S.; Sinafar, H.; Nuri, M.; Sadeghi, A., Assessment of Zinc and Copper Contents in the Hair and Serum and Also Superoxide Dismutase, Glutathion Peroxidase and Malondi Aldehyde in Serum in Androgenetic Alopecia and Alopecia Areata. Life Science Journal 2013, 10, 204-209.

155.Prie, B. E.; Iosif, L.; Tivig, I.; Stoian, I.; Giurcaneanu, C., Oxidative stress in androgenetic alopecia. J Med Life 2016, 9 (1), 79-83.

156.Kaya Erdogan, H.; Bulur, I.; Kocaturk, E.; Yildiz, B.; Saracoglu, Z. N.; Alatas, O., The role of oxidative stress in early-onset androgenetic alopecia. Journal of cosmetic dermatology 2017, 16 (4), 527-530.

157.Upton, J. H.; Hannen, R. F.; Bahta, A. W.; Farjo, N.; Farjo, B.; Philpott, M. P., Oxidative Stress–Associated Senescence in Dermal Papilla Cells of Men with Androgenetic Alopecia. Journal of Investigative Dermatology 2015, 135 (5), 1244-1252.

158.Seo, M.; Kim, M.-A.; Yun, E.-Y.; Hwang, J.-S.; Baek, M. In Antioxidant Activity and Hair Growth Promoting Effect of Mealworm (Tenebrio molitor larvae) Extract, 2017.

159.Fischer, T. W.; Trüeb, R. M.; Hänggi, G.; Innocenti, M.; Elsner, P., Topical melatonin for treatment of androgenetic alopecia. International journal of trichology 2012, 4 (4), 236-245.

160.Fischer, T. W.; Hipler, U. C.; Elsner, P., Effect of caffeine and testosterone on the proliferation of human hair follicles in vitro. International Journal of Dermatology 2007, 46 (1), 27-35.

161.Lim, K. M.; An, S.; Lee, O. K.; Lee, M. J.; Lee, J. P.; Lee, K. S.; Lee, G. T.; Lee, K. K.; Bae, S., Analysis of changes in microRNA expression profiles in response to the troxerutin-mediated antioxidant effect in human dermal papilla cells. Mol Med Rep 2015, 12 (2), 2650-2660.

162.Adenuga, P.; Summers, P.; Bergfeld, W., Hair regrowth in a male patient with extensive androgenetic alopecia on estrogen therapy. J Am Acad Dermatol 2012, 67 (3), e121-3.

163.Georgala, S.; Katoulis, A. C.; Georgala, C.; Moussatou, V.; Bozi, E.; Stavrianeas, N. G., Topical estrogen therapy for androgenetic alopecia in menopausal females. Dermatology (Basel, Switzerland) 2004, 208 (2), 178-9.

164.Endres, H. J., [Therapy of alopecia of different etiologies using an estrogen- and corticoid-containing topical preparation]. Z Hautkr 1980, 55 (1), 14-8.

165.Orfanos, C. E.; Wüstner, H., [Penetration and side effects of local estrogen application in alopecia androgenetica]. Hautarzt 1975, 26 (7), 367-9.

166.Wüstner, H.; Orfanos, C. E., [Alopecia androgenetica and its local treatment with estrogen- and corticosteroid externa]. Z Hautkr 1974, 49 (20), 879-88.

167.McElwee, K. J.; Niiyama, S.; Freyschmidt-Paul, P.; Wenzel, E.; Kissling, S.; Sundberg, J. P.; Hoffmann, R., Dietary soy oil content and soy-derived phytoestrogen genistein increase resistance to alopecia areata onset in C3H/HeJ mice. Exp Dermatol 2003, 12 (1), 30-6.

168.Park, K. H.; Kim, J.; Oh, B.; Lee, E.; Hwang-Bo, J.; Ha, J., Evaluation of factors triggering sensitive scalp in Korean adult women. Skin Research and Technology 2019, 25 (6), 862-866.

169.Marples, R. R.; Downing, D. T.; Kligman, A. M., Control of free fatty acids in human surface lipids by Corynebacterium acnes. The Journal of investigative dermatology 1971, 56 (2), 127-31.

170.Perry, A.; Lambert, P., Propionibacterium acnes: infection beyond the skin. Expert Review of Anti-infective Therapy 2011, 9 (12), 1149-1156.

171.Shaheen, B.; Gonzalez, M., A microbial aetiology of acne: what is the evidence? British Journal of Dermatology 2011, 165 (3), 474-485.

172.Park, T.; Kim, H. J.; Myeong, N. R.; Lee, H. G.; Kwack, I.; Lee, J.; Kim, B. J.; Sul, W. J.; An, S., Collapse of human scalp microbiome network in dandruff and seborrhoeic dermatitis. Exp Dermatol 2017, 26 (9), 835-838.

173.Cabañes, F. J., Malassezia yeasts: how many species infect humans and animals? PLoS Pathog 2014, 10 (2), e1003892.

174.Gupta, A. K.; Batra, R.; Bluhm, R.; Boekhout, T.; Dawson, T. L., Skin diseases associated with Malassezia species. Journal of the American Academy of Dermatology 2004, 51 (5), 785-798.

175.Erchiga, V. C.; Hay, R. J., Pityriasis versicolor and other Malassezia skin diseases. In Malassezia and the Skin, Springer: 2010; pp 175-199.

176.Gaitanis, G.; Velegraki, A.; Mayser, P.; Bassukas, I. D., Skin diseases associated with Malassezia yeasts: Facts and controversies. Clinics in Dermatology 2013, 31 (4), 455-463.

177.O'Neill, C. A.; Monteleone, G.; McLaughlin, J. T.; Paus, R., The gut-skin axis in health and disease: A paradigm with therapeutic implications. Bioessays 2016, 38 (11), 1167-1176.

178.Vaughn, A. R.; Notay, M.; Clark, A. K.; Sivamani, R. K., Skin-gut axis: The relationship between intestinal bacteria and skin health. World J Dermatol 2017, 6 (4), 52-58.

179.Scher, J. U.; Ubeda, C.; Artacho, A.; Attur, M.; Isaac, S.; Reddy, S. M.; Marmon, S.; Neimann, A.; Brusca, S.; Patel, T.; Manasson, J.; Pamer, E. G.; Littman, D. R.; Abramson, S. B., Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis Rheumatol 2015, 67 (1), 128-39.

180.Holmes, A. D., Potential role of microorganisms in the pathogenesis of rosacea. J Am Acad Dermatol 2013, 69 (6), 1025-32.

181.Lai, C.-H.; Chu, N.-F.; Chang, C.-W.; Wang, S.-L.; Yang, H.-C.; Chu, C.-M.; Chang, C.-T.; Lin, M.-H.; Chien, W.-C.; Su, S.-L.; Chou, Y.-C.; Chen, K.-H.; Wang, W.-M.; Liou, S.-H., Androgenic alopecia is associated with less dietary soy, lower [corrected] blood vanadium and rs1160312 1 polymorphism in Taiwanese communities. PloS one 2013, 8 (12), e79789-e79789.

182.Messina, M., Soyfoods and soybean phyto-oestrogens (isoflavones) as possible alternatives to hormone replacement therapy (HRT). Eur J Cancer 2000, 36 Suppl 4, S71-2.

183.Kang, H. J.; Ansbacher, R.; Hammoud, M. M., Use of alternative and complementary medicine in menopause. Int J Gynaecol Obstet 2002, 79 (3), 195-207.

184.Turner, R.; Baron, T.; Wolffram, S.; Minihane, A. M.; Cassidy, A.; Rimbach, G.; Weinberg, P. D., Effect of circulating forms of soy isoflavones on the oxidation of low density lipoprotein. Free Radic Res 2004, 38 (2), 209-16.

185.Wei, H.; Cai, Q.; Rahn, R. O., Inhibition of UV light- and Fenton reaction-induced oxidative DNA damage by the soybean isoflavone genistein. Carcinogenesis 1996, 17 (1), 73-7.

186.Koca, R.; Armutcu, F.; Altinyazar, C.; Gürel, A., Evaluation of lipid peroxidation, oxidant/antioxidant status, and serum nitric oxide levels in alopecia areata. Med Sci Monit 2005, 11 (6), Cr296-299.

187.Pinto, D.; Rinaldi, F.; Sorbellini, E., Microbiome and Diet Impact in Scalp Disorder: The Example of Alopecia Areata. 2019, 2, 001-009.

188.Pinto, D.; Giuliani, G.; Sorbellini, E.; Rinaldi, F., Diet and Microbiome Influence on Alopecia Areata: Experience from Case Reports. 2019, 5.