Cornus sanguinea Fruits: a Source of Antioxidant and Antisenescence Compounds Acting on Aged Human Dermal and Gingival Fibroblasts^{[ * ]}

Abstract

Five new compounds, a flavonol glycoside (

1), a megastigmane (

2), 2 cyclohexylethanoids (

3, 4), and a phenylethanoid derivative (

5), together with 15 known compounds (

6–

20) including flavonoid glycosides, cyclohexylethanoids, and phenolic compounds, have been isolated from Cornus sanguinea drupes. All the structures have been determined by 1D and 2D NMR spectroscopic analysis and mass spectrometry data. The antioxidant capability of the most representative isolated compounds was evaluated in the hydrogen peroxide (H₂O₂)-induced premature cellular senescence model of human dermal and gingival fibroblasts. Several derivatives counteracted the increase of reactive oxigen species (ROS) production in both cellular models. Among the most promising, compounds

8, 14, and

20 were able to counteract cell senescence, decreasing the expression of p21 and p53. Furthermore, compound

14 decreased the expression of inflammatory cytokines (IL-6) in both cell models and counteracted the decrease of collagen expression induced by the H₂O₂ in dermal human fibroblasts. These data highlight the anti-aging properties of several isolated compounds from C. sanguinea drupes, supporting its possible use in the cure of skin or periodontitis lesions.

Key words

Cornus sanguinea - Cornaceae - cyclohexylethanoids - flavonol glycosides - antioxidant - human fibroblasts

^* Dedicated to Professor Dr. Arnold Vlietinck on the occasion of his 80th birthday.

Publikationsverlauf

Eingereicht: 07. Januar 2021

Angenommen nach Revision: 24. März 2021

Artikel online veröffentlicht:
15. April 2021

• References

• 1 Grossoni P, Bruschi P, Bussotti F, Pollastrini M, Selvi F. Trattato di Botanica Forestale. 2 Angiosperme. Milano: Cedam; 2020: 475-478
• 2 Murrell ZE. Phylogenetic relationships in Cornus (Cornaceae). Syst Bot 1993; 18: 469-495
• 3 Pawlowska AM, Camangi F, Braca A. Quali-quantitative analysis of flavonoids of Cornus mas L. (Cornaceae) fruits. Food Chem 2010; 119: 1257-1261
• 4 Seeram NP, Schutzki R, Chandra A, Nair MG. Characterization, quantification, and bioactivities of anthocyanins in Cornus species. J Agric Food Chem 2002; 50: 2519-2523
• 5 Popescu I, Caudullo G, de Rigo D. Cornus sanguinea in Europe: distribution, habitat, usage and threats. In: European Atlas of Forest Tree Species. Luxembourg: Publication Office of the European Union; 2016: 84
• 6 Taylor T, Vovk I, Jug U. The use of Cornus sanguinea L. (dogwood) fruits in the Late Neolithic. Veg Hist Archaeobot 2020;
• 7 Di Novella R, Di Novella N, De Martino L, Mancini E, De Feo V. Traditional plant use in the National Park of Cilento and Vallo di Diano, Campania, Southern, Italy. J Ethnopharmacol 2013; 1451: 328-342
• 8 Caneva G, Pieroni A, Guarrera PM. Etnobotanica. Conservazione di un patrimonio culturale come risorsa per uno sviluppo sostenibile. In: Caneva G, Pieroni A, Guarrera PM Centro Universitario Europeo per i Beni Culturali di Ravello. Bari: Edipuglia; 2013. 3. 71-112 and 5: 143–166
• 9 Popović Z, Bajić-Ljubičić J, Matić R, Bojović S. First evidence and quantification of quercetin derivatives in dogberries (Cornus sanguinea L.). Turk J Biochem 2017; 42: 513-518
• 10 Truba J, Stanisławska I, Walasek M, Wieczorkowska W, Wolinski K, Buchholz T, Melzig MF, Czerwinska ME. Inhibition of digestive enzymes and antioxidant activity of extracts from fruits of Cornus alba, Cornus sanguinea subsp. hungarica and Cornus florida. A comparative study. Plants 2020; 9: 122
• 11 Stanković MS, Topuzović MD. In vitro antioxidant activity of extracts from leaves and fruits of common dogwood (Cornus sanguinea L.). Acta Bot Gall 2012; 159: 79-83
• 12 David L, Moldovan B, Baldea I, Olteanu D, Bolfa P, Clichici S, Filip GA. Modulatory effects of Cornus sanguinea L. mediated green synthesized silver nanoparticles on oxidative stress, COX-2/NOS2 and NFkB/pNFkB expressions in experimental inflammation in Wistar rats. Mater Sci Eng C Mater Biol Appl 2020; 110: 110709
• 13 Iannuzzi AM, Giacomelli C, De Leo M, Pietrobono D, Camangi F, De Tommasi N, Martini C, Trincavelli ML, Braca A. Antioxidant activity of compounds isolated from Elaeagnus umbellata promotes human gingival fibroblast well-being. J Nat Prod 2020; 83: 626-637
• 14 Wang J, Fang X, Ge L, Cao F, Zhao L, Wang Z, Xiao W. Antitumor, antioxidant and anti-inflammatory activities of kaempferol and its corresponding glycosides and the enzymatic preparation of kaempferol. PLoS One 2018; 13: e0197563
• 15 Childs BG, Durik M, Baker DJ, van Deursen JM. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med 2015; 21: 1424-1435
• 16 Cáceres M, Oyarzún A, Smith PC. Defective wound healing in the aging gingival tissue. J Dent Res 2014; 93: 691-697
• 17 Lämmermann I, Terlecki-Zaniewicz L, Weinmüllner R, Schosserer M, Dellago H, de Matos Branco AD, Autheried D, Sevcnikar B, Kleissl L, Berlin I, Morizot F, Lejeune F, Fuzzati N, Forestier S, Toribio A, Tromeur A, Weinberg L, Higareda Almaraz JC, Scheideler M, Rietveld M, El Ghalbzouri A, Tschachler E, Gruber F, Grillari J. Blocking negative effects of senescence in human skin fibroblasts with a plant extract. NPJ Aging Mech Dis 2018; 4: 4
• 18 Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, Laberge RM, Vijg J, Van Steeg H, Dollé ME, Hoeijmakers JH, de Bruin A, Hara E, Campisi J. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell 2014; 31: 722-733
• 19 Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton JP, Athineos D, Kang TW, Lasitschka F, Andrulis M, Pascual G, Morris KJ, Khan S, Jin H, Dharmalingam G, Snijders AP, Carroll T, Capper D, Pritchard C, Inman GJ, Longerich T, Sansom OJ, Benitah SA, Zender L, Gil J. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol 2013; 15: 978-990
• 20 Ramesh A, Varghese SS, Doraiswamy JN, Malaiappan S. Herbs as an antioxidant arsenal for periodontal diseases. J Intercult Ethnopharmacol 2016; 5: 92-96
• 21 Giacomelli C, Natali L, Nisi M, De Leo M, Daniele S, Costa B, Graziani F, Gabriele M, Braca A, Trincavelli ML, Martini C. Negative effects of a high tumour necrosis factor-α concentration on human gingival mesenchymal stem cell trophism: the use of natural compounds as modulatory agents. Stem Cell Res Ther 2018; 9: 135
• 22 Braca A, Bilia AR, Mendez J, Morelli I. Three flavonoids from Licania densiflora . Phytochemistry 1999; 51: 1125-1128
• 23 De Leo M, Peruzzi L, Granchi C, Tuccinardi T, Minutolo F, De Tommasi N, Braca A. Constituents of Polygala flavescens ssp. flavescens and their activity as inhibitors of human lactate dehydrogenase. J Nat Prod 2017; 80: 2077-2087
• 24 DʼAbrosca B, DellaGreca M, Fiorentino A, Monaco P, Oriano P, Temussi F. Structure elucidation and phytotoxicity of C₁₃ nor-isoprenoids from Cestrum parqui . Phytochemistry 2004; 65: 497-505
• 25 Huang ZS, Pei YH, Shen YH, Lin S, Liu CM, Lu M, Zhang WD. Cyclohexyl-ethanol derivatives from the roots of Incarvillea mairei . J Asian Nat Prod Res 2009; 11: 523-528
• 26 Tian J, Zhao QS, Zhang HJ, Lin ZW, Sun HD. New cleroindicins from Clerodendrum indicum . J Nat Prod 1997; 60: 766-769
• 27 Valente L, Olesrer A, Barat LES, Rabanal R, Lukacs G, Thang TT. A stereospecific synthesis of evalose, a constituent of orthosomycin antibiotics. Carbohydr Res 1981; 90: 329-333
• 28 Luboradzki R, Pakulski Z, Sartowska B. Glucofuranose derivatives as a library for designing and investigating low molecular mass organogelators. Tetrahedron 2005; 61: 10122-10128
• 29 Zhang Z, Xiao B, Chen Q, Lian XY. Synthesis and biological evaluation of caffeic acid 3,4-dihydroxyphenethyl ester. J Nat Prod 2010; 73: 252-254
• 30 Jaramillo K, Dawid C, Hofmann T, Fujimoto Y, Osorio C. Identification and antioxidative flavonols and anthocyanins in Sicania odorifera fruit peel. J Agric Food Chem 2011; 59: 975-983
• 31 Agrawal PK. Carbon-13 NMR of Flavonoid. Amsterdam: Elsevier; 1989: 336-337 341–342
• 32 Parejo I, Viladomat F, Bastida J, Schmeda-Hirshmann G, Burillo J, Codina C. Bioguided isolation and identification of the nonvolatile antioxidant compounds from fennel (Foeniculum vulgare Mill.) waste. J Agric Food Chem 2004; 52: 1890-1897
• 33 Dong M, He X, Liu RH. Phytochemicals of black bean seed coats: isolation, structure elucidation, and their antiproliferative and antioxidative activities. J Agric Food Chem 2007; 55: 6044-6051
• 34 Merfort I, Wendisch D. Flavonoids glucuronides from the flowers of Arnica montana . Planta Med 1988; 54: 247-250
• 35 Messana I, Sperandei M, Multari J, Galeffi C, Marini Bettolo GB. A cyclohexadienone and a cyclohexenone from Halleria lucida . Phytochemistry 1984; 23: 2617-2619
• 36 Navarro E, Trujillo J, Breton JL, Boada J. Cyclohexyl-ethanol derivatives from Isoplexis chalcantha . Phytochemistry 1986; 25: 1990-1991
• 37 Hase T, Kawamoto Y, Ohtani K, Kasai R, Yamasaki K, Picheansoonthon C. Cycloxexylethanoids and related glucosides from Millingtonia hortensis . Phytochemistry 1995; 39: 235-241
• 38 Guiso M, Marra C, Piccioni F, Nicoletti M. Iridoid and phenylpropanoid glucosides from Tecoma capensis . Phytochemistry 1997; 45: 193-194
• 39 Shimomura H, Sashida Y, Adachi T. Phenolic glycosides from Prunus grayana . Phytochemistry 1987; 26: 249-251
• 40 Choi SJ, Lee SN, Kim K, Joo da H, Shin S, Lee J, Lee HK, Kim J, Kwon SB, Kim MJ, Ahn KJ, An IS, An S, Cha HJ. Biological effects of rutin on skin aging. Int J Mol Med 2016; 38: 357-363
• 41 Ustuner O, Anlas C, Bakirel T, Ustun-Alkan F, Diren Sigirci B, Ak S, Akpulat HA, Donmez C, Koca-Caliskan U. In vitro evaluation of antioxidant, anti-inflammatory, antimicrobial and wound healing potential of Thymus sipyleus Boiss. subsp. rosulans (Borbas) Jalas. Molecules 2019; 24: 3353
• 42 Seo JY, Pyo E, Park J, Kim JS, Sung SH, Oh WK. Nrf2-mediated HO-1 induction and antineuroinflammatory activities of halleridone. J Med Food 2017; 20: 1091-1099
• 43 Soto-Gamez A, Quax WJ, Demaria M. Regulation of survival networks in senescent cells: from mechanisms to interventions. J Mol Biol 2019; 431: 2629-2643
• 44 Ortiz-Espín A, Morel E, Juarranz Á, Guerrero A, González S, Jiménez A, Sevilla F. An extract from the plant Deschampsia antarctica protects fibroblasts from senescence induced by hydrogen peroxide. Oxid Med Cell Longev 2017; 2017: 2694945
• 45 Kiyoshima T, Enoki N, Kobayashi I, Sakai T, Nagata K, Wada H, Fujiwara H, Ookuma Y, Sakai H. Oxidative stress caused by a low concentration of hydrogen peroxide induces senescence-like changes in mouse gingival fibroblasts. Int J Mol Med 2012; 30: 1007-1112
• 46 Zaw KK, Yokoyama Y, Abe M, Ishikawa O. Catalase restores the altered mRNA expression of collagen and matrix metalloproteinases by dermal fibroblasts exposed to reactive oxygen species. Eur J Dermatol 2006; 16: 375-379
• 47 Galicka A, Krętowski R, Nazaruk J, Cechowska-Pasko M. Anethole prevents hydrogen peroxide-induced apoptosis and collagen metabolism alterations in human skin fibroblasts. Mol Cell Biochem 2014; 394: 217-224
• 48 Zhang Q, Liu C, Hong S, Min J, Yang Q, Hu M, Zhao Y, Hong L. Excess mechanical stress and hydrogen peroxide remodel extracellular matrix of cultured human uterosacral ligament fibroblasts by disturbing the balance of MMPs/TIMPs via the regulation of TGF β1 signalling pathway. Mol Med Rep 2017; 15: 423-430
• 49 Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O, Peacocke M, Campisi J. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 1995; 92: 9363-9367
• 50 Giacomelli C, Natali L, Trincavelli ML, Daniele S, Bertoli A, Flamini G, Braca A, Martini C. New insights into the anticancer activity of carnosol: p53 reactivation in the U87MG human glioblastoma cell line. Int J Biochem Cell Biol 2016; 74: 95-108