Tomato Seed Extract Containing Lycoperoside H Improves Skin Elasticity in Japanese Female Subjects: A Randomized, Placebo-Controlled, Double-Blind Trial
Background and Objective: Tomato seeds are edible seeds unconsciously ingested with the fruit. However, there are few reports regarding the constituents and biological activities of tomato seed extract (TSE). Recently, we found that saponins are major constituents of TSE including lycoperoside H. Previous reports have described that several plant-derived saponins improve skin diseases such as wounds and microangiopathy. Therefore, to discover the effect of TSE on the skin condition, we conducted a clinical trial of TSE (Tomato Seed Extract-P) standardized with lycoperoside H when orally ingested. Methods: The study was performed as a randomized, double-blind, placebo-controlled study. TSE (200 mg daily) containing 1 mg of lycoperoside H was used as the active sample. We enrolled 44 Japanese women who have concerns about facial elasticity and relatively low facial skin elasticity. All subjects were randomly allocated into either the active group (n = 22) or the placebo group (n = 22) using a computerized random-number generator. Capsules containing either the active sample or a placebo were administered for 8 weeks between October 12, 2020, and January 16, 2021. Facial elasticity, specifically the R7 value, was evaluated as the primary outcome. The remaining facial R parameters, upper arm R parameters, and other skin parameters including epidermal moisture, trans epidermal water loss, dermal parameters, and advanced glycation end products (AGEs) parameters were measured at 0, 4, and 8 weeks of ingestion. Blood, urine, and body parameters were also evaluated for safety. Results: Forty-three subjects completed the trial, and the per protocol set comprised 21 subjects in the TSE group and 22 subjects in the placebo group. After ingesting TSE for 8 weeks, the R7 value was significantly higher in the TSE group compared to the placebo group. Furthermore, the change in R7 values from the baseline at 4 and 8 weeks were also higher in the TSE group. Among the secondary outcomes, facial elasticity parameters including R2, R5, R1, and R4 at 4 weeks and facial R5, R1, and R4 and upper arm R2 at 8 weeks were higher in the TSE group. In addition, plasma pentosidine significantly decreased in the TSE group after 8 weeks of ingestion. There were no significant differences in moisture, DermaLab® parameters and AGEs parameters except plasma pentosidine. Laboratory tests revealed no abnormalities suggesting
References
[1]
Groten, K., Marini, A., Grether-Beck, S., Jaenicke, T., Ibbotson, S.H., Moseley, H., Ferguson, J. and Krutmann, J. (2019) Tomato Phytonutrients Balance UV Response: Results from a Double-Blind, Randomized, Placebo-Controlled Study. Skin Pharmacology and Physiology, 32, 101-108. https://doi.org/10.1159/000497104
[2]
Chaudhary, P., Sharma, A., Singh, B. and Nagpal, A.K. (2018) Bioactivities of Phytochemicals Present in Tomato. Journal of Food Science and Technology, 55, 2833-2849. https://doi.org/10.1007/s13197-018-3221-z
[3]
Agarwal, S. and Rao, A.V. (2000) Tomato Lycopene and Its Role in Human Health and Chronic Diseases. Canadian Medical Association Journal, 163, 739-744.
[4]
Imran, M., Ghorat, F., Ul-Haq, I., Ur-Rehman, H., Aslam, F., Heydari, M., Shariati, M.A., Okuskhanova, E., Yessimbekov, Z., Thiruvengadam, M., Hashempur, M.H. and Rebezov, M. (2020) Lycopene as a Natural Antioxidant Used to Prevent Human Health Disorders. Antioxidants, 9, Article No. 706. https://doi.org/10.3390/antiox9080706
[5]
Stahl, W., Heinrich, U., Aust, O., Tronnier, H. and Sies, H. (2006) Lycopene-Rich Products and Dietary Photoprotection. Photochemical and Photobiological Sciences, 5, 238-242. https://doi.org/10.1039/B505312A
[6]
Rizwan, M., Rodriguez-Blanco, I., Harbottle, A., Birch-Machin, M.A., Watson, R.E. and Rhodes, L.E. (2010) Tomato Paste Rich in Lycopene Protects against Cutaneous Photodamage in Humans in Vivo: A Randomized Controlled Trial. British Journal of Dermatology, 164, 154-162. https://doi.org/10.1111/j.1365-2133.2010.10057.x
[7]
Stahl, W., Heinrich, U., Wiseman, S., Eichler, O., Sies, H. and Tronnier, H. (2001) Dietary Tomato Paste Protects Against Ultraviolet Light-Induced Erythema in Humans. The Journal of Nutrition, 131, 1449-1451. https://doi.org/10.1093/jn/131.5.1449
[8]
Martínez-Huélamo, M., Vallverdú-Queralt, A., Di Lecce, G., Valderas-Martínez, P., Tulipani, S., Jáuregui, O., Escribano-Ferrer, E., Estruch, R., Illan, M. and Lamuela-Raventós, R.M. (2016) Bioavailability of Tomato Polyphenols Is Enhanced by Processing and Fat Addition: Evidence from a Randomized Feeding Trial. Molecular Nutrition & Food Research, 60, 1578-1589. https://doi.org/10.1002/mnfr.201500820
[9]
Yamamoto, T., Yoshimura, M., Yamaguchi, F., Kouchi, T., Tsuji, R., Saito, M., Obata, A. and Kikuchi, M. (2004) Anti-Allergic Activity of Naringenin Chalcone from a Tomato Skin Extract. Bioscience, Biotechnology, and Biochemistry, 68, 1706-1711. https://doi.org/10.1271/bbb.68.1706
[10]
Nagula, R.L. and Wairkar, S. (2020) Cellulose Microsponges Based Gel of Naringenin for Atopic Dermatitis: Design, Optimization, in Vitro and in Vivo Investigation. International Journal of Biological Macromolecules. 164, 717-725. https://doi.org/10.1016/j.ijbiomac.2020.07.168
[11]
Tsai, M.J., Huang, Y.B., Fang, J.W., Fu, Y.S. and Wu, P.C. (2015) Preparation and Characterization of Naringenin-Loaded Elastic Liposomes for Topical Application. PLoS ONE, 10, e0131026. https://doi.org/10.1371/journal.pone.0131026
[12]
Bhia, M., Motallebi, M., Abadi, B., Zarepour, A., Pereira-Silva, M., Saremnejad, F., Santos, A.C., Zarrabi, A., Melero, A., Jafari, S.M. and Shakibaei, M. (2021) Naringenin Nano-Delivery Systems and Their Therapeutic Applications. Pharmaceutics, 13, Article No. 291. https://doi.org/10.3390/pharmaceutics13020291
[13]
Akrawi, S.H., Gorain, B., Nair, A.B., Choudhury, H., Pandey, M., Shah, J.N. and Venugopala, K.N. (2020) Development and Optimization of Naringenin-Loaded Chitosan-Coated Nanoemulsion for Topical Therapy in Wound Healing. Pharmaceutics, 12, Artilce No. 893. https://doi.org/10.3390/pharmaceutics12090893
[14]
Al-Roujayee, A.S. (2017) Naringenin Improves the Healing Process of Thermally-induced Skin Damage in Rats. The Journal of Medical Internet Research, 45, 570-582. https://doi.org/10.1177%2F0300060517692483
[15]
Karuppagounder, V., Arumugam, S., Thandavarayan, R.A., Sreedhar, R., Giridharan, V.V., Pitchaimani, V., Afrin, R., Harima, M., Krishnamurthy, P., Suzuki, K., Nakamura, M., Ueno, K. and Watanabe, K. (2016) Naringenin Ameliorates Skin Inflammation and Accelerates Phenotypic Reprogramming from M1 to M2 Macrophage Polarization in Atopic Dermatitis NC/Nga Mouse Model. Experimental Dermatology, 25, 404-407. https://doi.org/10.1111/exd.12962
[16]
Kim, T.H., Kim, G.D., Ahn, H.J., Cho, J.J., Park, Y.S. and Park, C.S. (2013) The Inhibitory Effect of Naringenin on Atopic Dermatitis Induced by DNFB in NC/Nga Mice. Life Sciences, 93, 516-524. https://doi.org/10.1016/j.lfs.2013.07.027
[17]
Martinez, R.M., Pinho-Ribeiro, F.A., Steffen, V.S., Caviglione, C.V., Vignoli, J.A., Barbosa, D.S., Baracat, M.M., Georgetti, S.R., Verri Jr., W.A. and Casagrande, R. (2015) Naringenin Inhibits UVB Irradiation-Induced Inflammation and Oxidative Stress in the Skin of Hairless Mice. Journal of Natural Products, 78, 1647-1655. https://doi.org/10.1021/acs.jnatprod.5b00198
[18]
El-Mahdy, M.A., Zhu, Q., Wang, Q.E., Wani, G., Patnaik, S., Zhao, Q., Arafa, El.-S., Barakat, B., Mir, S.N. and Wani, A.A. (2008) Naringenin Protects HaCaT Human Keratinocytes Against UVB-Induced Apoptosis and Enhances the Removal of Cyclobutane Pyrimidine Dimers from the Genome. Photochemistry and Photobiology, 84, 307-316. https://doi.org/10.1111/j.1751-1097.2007.00255.x
[19]
Martinez, R.M., Pinho-Ribeiro, F.A., Steffen, V.S., Silva, T.C., Caviglione, C.V., Bottura, C., Fonseca, M.J., Vicentini, F.T., Vignoli, J.A., Baracat, M.M., Georgetti, S.R., Verri Jr., W.A. and Casagrande, R. (2016) Topical Formulation Containing Naringenin: Efficacy Against Ultraviolet B Irradiation-Induced Skin Inflammation and Oxidative Stress in Mice. PLoS ONE, 11, e0146296. https://doi.org/10.1371/journal.pone.0146296
[20]
Jung, S.K., Ha, S.J., Jung, C.H., Kim, Y.T., Lee, H.K., Kim, M.O., Lee, M.H., Mottamal, M., Bode, A.M., Lee, K.W. and Dong, Z. (2016) Naringenin Targets ERK2 and Suppresses UVB-Induced Photoaging. Jounal of Cellular and Molecular Medicine, 20, 909-919. https://doi.org/10.1111/jcmm.12780
[21]
Nasr Bouzaiene, N., Chaabane, F., Sassi, A., Chekir-Ghedira, L. and Ghedira, K. (2016) Effect of Apigenin-7-Glucoside, Genkwanin and Naringenin on Tyrosinase Activity and Melanin Synthesis in B16F10 Melanoma Cells. Life Sciences. 144, 80-85. https://doi.org/10.1016/j.lfs.2015.11.030
[22]
Nohara, T., Ono, M., Ikeda, T., Fujiwara, Y. and El-Aasr, M. (2010) The Tomato Saponin, Esculeoside A. Journal of Natural Products, 73, 1734-1741. https://doi.org/10.1021/np100311t
[23]
Nielen, M.W.F. and Van Beek, T.A. (2014) Macroscopic and Microscopic Spatially-Resolved Analysis of Food Contaminants and Constituents Using Laser-Ablation Electrospray Ionization Mass Spectrometry Imaging. Analytical and Bioanalytical Chemistry, 406, 6805-6815. https://doi.org/10.1007/s00216-014-7948-8
[24]
Yahara, S., Uda, N. and Nohara, T. (1996) Lycoperosides A-C, Three Stereoisomeric 23-Acetoxyspirosolan-3β-ol β-Lycotetraosides from Lycopersicon esculentum. Phytochemistry, 42, 169-172. https://doi.org/10.1016/0031-9422(95)00854-3
[25]
Fujiwara, Y., Yahara, S., Ikeda, T., Ono, M. and Nohara, T. (2003) Cytotoxic Major Saponin from Tomato Fruits. Chemical and Pharmaceutical Bulletin, 51, 234-235. https://doi.org/10.1248/cpb.51.234
[26]
Fujiwara, Y., Takaki, A., Uehara, Y., Ikeda, T., Okawa, M., Yamauchi, K., Ono, M., Yoshimitsu, H. and Nohara, T. (2004) Tomato Steroidal Alkaloid Glycosides, Esculeosides A and B, from Ripe Fruits. Tetrahedron, 60, 4915-4920. https://doi.org/10.1016/j.tet.2004.03.088
[27]
Nohara, T., Fujiwara, Y., Zhou, J.R., Urata, J., Ikeda, T., Murakami, K., El-Aasr, M. and Ono, M. (2015) Saponins, Esculeosides B-1 and B-2, in Tomato Juice and Sapogenol, Esculeogenin B1. Chemical and Pharmaceutical Bulletin, 63, 848-850. https://doi.org/10.1248/cpb.c15-00449
[28]
Ono, M., Takara, Y., Egami, M., Uranaka, K., Yoshimitsu, H., Matsushita, S., Fujiwara, Y., Ikeda, T. and Nohara, T. (2006) Steroidal Alkaloid Glycosides, Esculeosides C and D, from the Ripe Fruit of Cherry Tomato. Chemical and Pharmaceutical Bulletin, 54, 237-239. https://doi.org/10.1248/cpb.54.237
[29]
Yoshizaki, M., Matsushita, S., Fujiwara, Y., Ikeda, T., Ono, M. and Nohara, T. (2005) Tomato New Sapogenols, Isoesculeogenin A and Esculeogenin B. Chemical and Pharmaceutical Bulletin, 53, 839-840. https://doi.org/10.1248/cpb.53.839
[30]
Ito, S., Ihara, T., Tamura, H., Tanaka, S., Ikeda, T., Kajihara, H., Dissanayake, C., Abdel-Motaal, F.F. and El-Sayed, M.A. (2007) α-Tomatine, the Major Saponin in Tomato, Induces Programmed Cell Death Mediated by Reactive Oxygen Species in the Fungal Pathogen Fusarium oxysporum. FEBS Letters. 581, 3217-3222. https://doi.org/10.1016/j.febslet.2007.06.010
[31]
Zhou, J.R., Urata, J., Shiraishi, T., Tanaka, C., Nohara, T. and Yokomizo, K. (2018) Tomato Juice Saponin, Esculeoside B Ameliorates Mice Experimental Dermatitis. Functional Foods in Health and Disease, 8, 228-241. https://doi.org/10.31989/ffhd.v8i4.420
[32]
Zhou, J.R., Kanda, Y., Tanaka, A., Manabe, H., Nohara, T. and Yokomizo, K. (2016) Anti-Hyaluronidase Activity in Vitro and Amelioration of Mouse Experimental Dermatitis by Tomato Saponin, Esculeoside A. Journal of Agricultural and Food Chemistry, 64, 403-408. https://doi.org/10.1021/acs.jafc.5b05320
[33]
Takeda, S., Miyasaka, K. and Shimoda, H. (2021) Lycoperoside H, a Steroidal Alkaloid Saponin in Tomato Seeds, Ameliorates Atopic Dermatitis-like Symptoms in IL-33 Transgenic Mice. Journal of Food Biochemistry, e13877. https://doi.org/10.1111/jfbc.13877
[34]
Damkerngsuntorn, W., Rerknimitr, P., Panchaprateep, R., Tangkijngamvong, N., Kumtornrut, C., Kerr, S.J., Asawanonda, P., Tantisira, M.H. and Khemawoot, P. (2020) The Effects of a Standardized Extract of Centella asiatica on Postlaser Resurfacing Wound Healing on the Face: A Split-Face, Double-Blind, Randomized, Placebo-Controlled Trial. Journal of Alternative and Complementary Medicine, 26, 529-536. https://doi.org/10.1089/acm.2019.0325
[35]
Paocharoen, V. (2010) The Efficacy and Side Effects of Oral Centella asiatica Extract for Wound Healing Promotion in Diabetic Wound Patients. Journal of the Medical Association of Thailand, 93, 166-170.
[36]
De Sanctis, M.T., Cesarone, M.R., Incandela, L., Belcaro, G., Ricci, A. and Griffin, M. (2001) Four-Week Treatment with Essaven Gel in Diabetic Microangiopathy—A Placebo-Controlled, Randomized Study. Angiology, 52, 49-55. https://doi.org/10.1177%2F0003319701052003S10
[37]
De Sanctis, M.T., Cesarone, M.R., Incandela, L., Belcaro, G. and Griffin, M. (2001) Treatment of Superficial Vein Thrombosis with Standardized Application of Essaven Gel—A Placebo-Controlled, Randomized Study. Angiology, 3, 57-62. https://doi.org/10.1177/0003319701052003S11
[38]
Incandela, L., Belcaro, G., Nicolaides, A.N., Geroulakos, G., Cesarone, M.R. and De Sanctis, M.T. (2001) Microcirculation after Standardized Application of Essaven Gel on Normal Skin—A Placebo-Controlled, Randomized Study. Angiology, 3, 5-10. https://doi.org/10.1177%2F0003319701052003S03
[39]
Ghosh, R. and Kline, P. (2019) HPLC with Charged Aerosol Detector (CAD) as a Quality Control Platform for Analysis of Carbohydrate Polymers. BMC Research Notes, 12, Article No. 268. https://doi.org/10.1186/s13104-019-4296-y
[40]
Woo, M.S., Moon, K.J., Jung, H.Y., Park, S.R., Moon, T.K., Kim, N.S. and Lee, B.C. (2014) Comparison of Skin Elasticity Test Results from the Ballistometer® and Cutometer®. Skin Research and Technology, 20, 422-428. https://doi.org/10.1111/srt.12134
[41]
Adatto, M., Adatto-Neilson, R., Servant, J.J., Vester, J., Novak, P. and Krotz, A. (2010) Controlled, Randomized Study Evaluating the Effects of Treating Cellulite with AWT/EPAT. Journal of Cosmetic and Laser Therapy, 12, 176-182. https://doi.org/10.3109/14764172.2010.500392
[42]
Flament, F., Abric, A., Amar, D., Ye, C., Caron, J. and Negre, C. (2020) Changes in Facial Signs Due to Age and Their Respective Weights on the Perception of Age, on a Tired-Look or a Healthy Glow among Differently Aged Chinese Men. International Journal of Cosmetic Science, 42, 452-461. https://doi.org/10.1111/ics.12649
[43]
Halper, J. and Kjaer, M. (2014) Basic Components of Connective Tissues and Extracellular Matrix: Elastin, Fibrillin, Fibulins, Fibrinogen, Fibronectin, Laminin, Tenascins and Thrombospondins. In: Halper, J., Eds., Progress in Heritable Soft Connective Tissue Diseases, Vol. 802, Springer, Dordrecht, 31-47. https://doi.org/10.1007/978-94-007-7893-1_3
[44]
Lo, S. and Fauzi, M.B. (2021) Current Update of Collagen Nanomaterials-Fabrication, Characterisation and Its Applications: A Review. Pharmaceutics, 13, Article No. 316. https://doi.org/10.3390/pharmaceutics13030316
[45]
Langton, A.K., Hann, M., Costello, P., Halai, P., Sisto Alessi César, S., Lien-Lun Chien, A., Kang, S., Griffiths, C.E.M., Sherratt, M.J. and Watson, R.E.B. (2020) Heterogeneity of Fibrillin-Rich Microfibrils Extracted from Human Skin of Diverse Ethnicity. Journal of Anatomy, 237, 478-486. https://doi.org/10.1111/joa.13217
[46]
Chowdhury, A., Nosoudi, N., Karamched, S., Parasaram, V. and Vyavahare, N. (2021) Polyphenol Treatments Increase Elastin and Collagen Deposition by Human Dermal Fibroblasts; Implications to Improve Skin Health. Journal of Dermatological Science, 102, 94-100. https://doi.org/10.1016/j.jdermsci.2021.03.002
[47]
Tang, S., Lucius, R., Wenck, H., Gallinat, S. and Weise, J.M. (2013) UV-Mediated Downregulation of the Endocytic Collagen Receptor, Endo180, Contributes to Accumulation of Extracellular Collagen Fragments in Photoaged Skin. Journal of Dermatological Science, 70, 42-48. https://doi.org/10.1016/j.jdermsci.2013.01.008
[48]
Engelholm, L.H., List, K., Netzel-Arnett, S., Cukierman, E., Mitola, D.J., Aaronson, H., Kjøller, L., Larsen, J.K., Yamada, K.M., Strickland, D.K., Holmbeck, K., Danø, K., Birkedal-Hansen, H., Behrendt, N. and Bugge, T.H. (2003) uPARAP/Endo180 is Essential for Cellular Uptake of Collagen and Promotes Fibroblast Collagen Adhesion. Journal of Cell Biology, 160, 1009-1015. https://doi.org/10.1083/jcb.200211091
[49]
Lephart, E.D. and Naftolin, F. (2021) Menopause and the Skin: Old Favorites and New Innovations in Cosmeceuticals for Estrogen-Deficient Skin. Dermatology and Therapy, 11, 53-69. https://doi.org/10.1007/s13555-020-00468-7
[50]
Proksch, E., Segger, D., Degwert, J., Schunck, M., Zague, V. and Oesser, S. (2014) Oral Supplementation of Specific Collagen Peptides Has Beneficial Effects on Human Skin Physiology: A Double-Blind, Placebo-Controlled Study. Skin Pharmacology and Physiology, 27, 47-55. https://doi.org/10.1159/000351376
[51]
Žmitek, K., Pogačnik, T., Mervic, L., Žmitek, J. and Pravst, I. (2017) The Effect of Dietary Intake of Coenzyme Q10 on Skin Parameters and Condition: Results of a Randomized, Placebo-Controlled, Double-Blind Study. Biofactors, 43, 132-140. https://doi.org/10.1002/biof.1316
[52]
Yonei, Y., Takabe, W. and Yagi, M. (2015) Photoaging and Glycation of Elastin: Effect on Skin. Glycative Stress Research, 2, 182-190.
[53]
Zarkovic, K., Larroque-Cardoso, P., Pucelle, M., Salvayre, R., Waeg, G., Nègre-Salvayre, A. and Zarkovic, N. (2015) Elastin Aging and Lipid Oxidation Products in Human Aorta Redox Biology, 4, 109-117. https://doi.org/10.1016/j.redox.2014.12.008
[54]
Matsuyama, A., Kikuchi, M. and Shimoda, H. (2018) Effect on Skin Condition by 8-Week Ingestion of Standardized Cherry Blossom Flower Extract (Sakura Extract-P). International Journal of Biomedical Science, 14, 12-19.
[55]
Takabe, W., Yagi, M., Ogura, M. and Yonei, Y. (2017) Effect of Mangosteen Pericarp Extract-Containing Black Vinegar Drink on Skin Quality through Anti-Glycative Actions. Glycative Stress Research, 4, 158-171. https://doi.org/10.24659/gsr.4.3_158
[56]
Lee, K.C., Dretzke, J., Grover, L., Logan, A. and Moiemen, N. (2016) A Systematic Review of Objective Burn Scar Measurements. Burns & Trauma, 4, Article ID: s41038-016-0036-x. https://doi.org/10.1186/s41038-016-0036-x
[57]
Kawałkiewicz, W., Matthews-Kozanecka, M., Janus-Kubiak, M., Kubisz, L. and Hojan-Jezierska, D. (2021) Instrumental Diagnosis of Facial Skin—A Necessity or a Pretreatment Recommendation in Esthetic Medicine. Journal of Cosmetic Dermatology, 20, 875-883. https://doi.org/10.1111/jocd.13638
[58]
Ohshima, H., Kinoshita, S., Oyobikawa, M., Futagawa, M., Takiwaki, H., Ishiko, A. and Kanto, H. (2012) Use of Cutometer Area Parameters in Evaluating Age-Related Changes in the Skin Elasticity of the Cheek. Skin Research and Technology, 19, e238-e242. https://doi.org/10.1111/j.1600-0846.2012.00634.x
[59]
Ezure, T. and Amano, S. (2010) Influence of Subcutaneous Adipose Tissue Mass on Dermal Elasticity and Sagging Severity in Lower Cheek. Skin Research and Technology, 16, 332-338. https://doi.org/10.1111/j.1600-0846.2010.00438.x
[60]
Morita, Y., Yagi, M., Ishizaki, K., Takabe, W., Komatsu, T., Nakazawa, M., Matsushima, M., Urata, T. and Yonei, Y. (2019) Evaluation of the Glycative Stress by Non-Invansive Skin AGEs Measurement Devices. Glycative Stress Research, 6, 92-102. https://doi.org/10.24659/gsr.6.2_92
[61]
Tan, S.M.Q., Chiew, Y., Ahmad, B. and Kadir, K.A. (2018) Tocotrienol-Rich Vitamin E from Palm Oil (Tocovid) and Its Effects in Diabetes and Diabetic Nephropathy: A Pilot Phase II Clinical Trial. Nutrients, 10, Article No. 1315. https://doi.org/10.3390/nu10091315