Abstract
Chlorogenic acid (CGA) is a well-known natural antioxidant in human diet. To understand the effects of CGA on wound healing by enhancing antioxidant defense in the body, the present study sought to investigate the potential role of systemic CGA therapy on wound healing and oxidative stress markers of the skin. We also aimed to understand whether chronic CGA treatment has side effects on pivotal organs or rat bone marrow during therapy. Full-thickness experimental wounds were created on the backs of rats. CGA (25, 50, 100, 200 mg/kg) or vehicle was administered intraperitoneally for 15 days. All rats were sacrificed on the 16th day. Biochemical, histopathological, and immunohistochemical examinations were performed. Possible side effects were also investigated. The results suggested that CGA accelerated wound healing in a dose-dependent manner. CGA enhanced hydroxyproline content, decreased malondialdehyde and nitric oxide levels. and elevated reduced glutathione, superoxide dismutase, and catalase levels in wound tissues. Epithelialization, angiogenesis, fibroblast proliferation, and collagen formation increased by CGA while polymorph nuclear leukocytes infiltration decreased. CGA modulated matrix metalloproteinase-9 and tissue inhibitor-2 expression in biopsies. Otherwise, high dose of CGA increased lipid peroxidation of liver and kidney without affecting the heart and muscle samples. Chronic CGA increased micronuclei formation and induced cytotoxicity in the bone marrow. In conclusion, systemic CGA has beneficial effects in improving wound repair. Antioxidant, free radical scavenger, angiogenesis, and anti-inflammatory effects of CGA may ameliorate wound healing. High dose of CGA may induce side effects. In light of these observations, CGA supplementation or dietary CGA may have benefit on wound healing.
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Abbreviations
- CAT:
-
Catalase
- CGA:
-
Chlorogenic acid
- GSH:
-
Reduced glutathione
- MDA:
-
Malondialdehyde
- MMP-9:
-
Matrix metalloproteinase-9
- MNPCE:
-
Micronucleated polychromatic erythrocytes
- NCE:
-
Normochromatic erythrocytes
- NO:
-
Nitric oxide
- PBS:
-
Phosphate buffered saline
- PCE:
-
Polychromatic erythrocytes
- PMNL:
-
Polymorphonuclear leukocytes
- ROS:
-
Reactive oxygen species
- SOD:
-
Superoxide dismutase
- TIMP-2:
-
Tissue inhibitor-2
References
Abraham SK, Khandelwal N (2013) Ascorbic acid and dietary polyphenol combinations protect against genotoxic damage induced in mice by endogenous nitrosation. Mutat Res 757:167–72. doi:10.1016/j.mrgentox.2013.08.004
Abraham SK, Schupp N, Schmid U, Stopper H (2007) Antigenotoxic effects of the phytoestrogen pelargonidin chloride and the polyphenol chlorogenic acid. Mol Nutr Food Res 51:880–887. doi:10.1002/mnfr.200600214
Albina JE, Mills CD, Henry WL Jr, Caldwell MD (1990) Temporal expression of different pathways of l-arginine metabolism in healing wound. J Immunol 144:3877-3880. http://www.jimmunol.org/content/144/10/3877.long
Ashoori F, Suzuki S, Zhou JH, Isshiki N, Miyachi Y (1994) Involvement of lipid peroxidation in necrosis of skin flaps and its suppression by ellagic acid. Plast Reconstr Surg 7:1027–1037. http://journals.lww.com/plasreconsurg/Abstract/1994/12000/Involvement_of_Lipid_Peroxidation_in_Necrosis_of.18.aspx
Azam S, Hadi N, Khan NU, Hadi SM (2004) Prooxidant property of green tea polyphenols epicatechin and epigallocatechin-3-gallate: implications for anticancer properties. Toxicol In Vitro 18:555–561. doi:10.1016/j.tiv.2003.12.012
Azuma K, Ippoushi K, Nakayama M, Ito H, Higashio H, Terao J (2000) Absorption of chlorogenic acid and caffeic acid in rats after oral administration. J Agric Food Chem 48:5496–5500. doi:10.1021/jf000483q
Bagdas D, Cinkilic N, Ozboluk HY, Ozyigit MO, Gurun MS (2013) Antihyperalgesic activity of chlorogenic acid in experimental neuropathic pain. J Nat Med 67:698–704. doi:10.1007/s11418-012-0726-z
Bagdas D, Cam Etoz B, Inan Ozturkoglu S, Cinkilic N, Ozyigit MO, Gul Z, Isbil Buyukcoskun N, Ozluk K, Gurun MS (2014) Effects of systemic chlorogenic acid on random-pattern dorsal skin flap survival in diabetic rats. Biol Pharm Bull 37(3):361–370. doi:10.1248/bpb.b13-00635
Bouayed J, Bohn T (2010) Exogenous antioxidants—double-edged swords in cellular redox state: health beneficial effects at physiologic doses versus deleterious effects at high doses. Oxid Med Cell Longev 3:228–237. doi:10.4161/oxim.3.4.12858
Brown LF, Yeo KT, Berse B, Yeo TK, Senger DR, Dvorak HF, Van de Water L (1992) Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing. J Exp Med 176:1375–1379. http://jem.rupress.org/content/176/5/1375.long
Cals-Grierson M, Ormerod A (2004) Nitric oxide function on the skin. Nitric Oxide 10:179–193. http://www.sciencedirect.com/science/article/pii/S1089860304000734
Chen WP, Tang JL, Bao JP, Hu PF, Shi ZL, Wu LD (2011) Anti-arthritic effects of chlorogenic acid in interleukin-1β-induced rabbit chondrocytes and a rabbit osteoarthritis model. Int Immunopharmacol 11:23–28. doi:10.1016/j.intimp.2010.09.021
Chen WC, Liou SS, Tzeng TF, Lee SL, Liu IM (2013) Effect of topical application of chlorogenic acid on excision wound healing in rats. Planta Med 79:616–621. doi:10.1055/s-0032-1328364
Cinkilic N, Cetintas SK, Zorlu T, Vatan O, Yilmaz D, Cavas T, Tunc S, Ozkan L, Bilaloglu R (2013) Radioprotection by two phenolic compounds: chlorogenic and quinic acid, on X-ray induced DNA damage in human blood lymphocytes in vitro. Food Chem Toxicol 53:359–363. doi:10.1016/j.fct.2012.12.008
Clark RA (1985) Cutaneous tissue repair: basic biologic considerations. I J Am Acad Dermatol 13(5 Pt 1):701–725. doi:10.1016/j.intimp.2010.09.021
Clifford MN (1999) Chlorogenic acids and other cinnamates—nature, occurrence and dietary burden. J Sci Food Agric 79:362–372. doi:10.1002/(SICI)1097-0010(19990301)79:3<362::AID-JSFA256>3.0.CO;2-D
Dos Santos JS, Monte-Alto-Costa A (2013) Caffeic acid phenethyl ester improves burn healing in rats through anti-inflammatory and antioxidant effects. J Burn Care Res 34:682–688. doi:10.1097/BCR.0b013e3182839b1c
Dos Santos MD, Almeida MC, Lopes NP, de Souza GE (2006) Evaluation of the anti-inflammatory, analgesic and antipyretic activities of the natural polyphenol chlorogenic acid. Biol Pharm Bull 29:2236–2240. doi:10.1248/bpb.29.2236
Duarte MP, Laires A, Gaspar J, Leão D, Oliveira JS, Rueff J (1999) Genotoxicity of instant coffee: possible involvement of phenolic compounds. Mutat Res 442:43–51. doi:10.1016/S1383-5718(99)00057-1
Duarte MP, Laires A, Gaspar J, Oliveira JS, Rueff J (2000) Genotoxicity of instant coffee and of some phenolic compounds present in coffee upon nitrosation. Teratog Carcinog Mutagen 20:241–249. doi:10.1002/1520-6866(2000)20:4<241::AID-TCM6>3.0.CO;2-4
Edwards CA, O’Brien WD Jr (1980) Modified assay for determination of hydroxyproline in a tissue hydrolyzate. Clin Chim Acta:104-161. http://dx.doi.org/10.1016/0009-8981(80)90192-8
Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77. doi:10.1016/0003-9861(59)90090-6
Fukumoto LR, Mazza G (2000) Assessing antioxidant and prooxidant activities of phenolic compounds. J Agric Food Chem 48:3597–3604. doi:10.1021/jf000220w
Giner E, Andújar I, Recio MC, Ríos JL, Cerdá-Nicolás JM, Giner RMT (2011) Oleuropein ameliorates acute colitis in mice. J Agric Food Chem 59:12882–12892. doi:10.1021/jf203715m
Graham HN (1992) Green tea composition, consumption, and polyphenol chemistry. Prev Med 21:334–350. http://www.ncbi.nlm.nih.gov/pubmed/1614995
Griess P (1879) Bemerkungen zu der Abhandlung der HH. Weselsky und Benedikt “Ueber einige Azoverbindungen”. Ber Dtsch Chem Ges 12:426–428. doi:10.1002/cber.187901201117
Hunyadi A, Martins A, Hsieh TJ, Seres A, Zupkó I (2012) Chlorogenic acid and rutin play a major role in the in vivo anti-diabetic activity of Morus alba leaf extract on type II diabetic rats. PLoS One 7:e50619. doi:10.1371/journal.pone.0050619
Jefferies H, Coster J, Khalil A, Bot J, McCauley RD, Hall JC (2003) Glutathione. ANZ J Surg 73:517–522. doi:10.1046/j.1445-1433.2003.02682.x
Jin UH, Chung TW, Kang SK, Suh SJ, Kim JK, Chung KH, Gu YH, Suzuki I, Kim CH (2005a) Caffeic acid phenyl ester in propolis is a strong inhibitor of matrix metalloproteinase-9 and invasion inhibitor: isolation and identification. Clin Chim Acta 362:57–64. doi:10.1016/j.cccn.2005.05.009
Jin UH, Lee JY, Kang SK, Kim JK, Park WH, Kim JG, Moon SK, Kim CH (2005b) A phenolic compound, 5-caffeoylquinic acid (chlorogenic acid), is a new type and strong matrix metalloproteinase-9 inhibitor: isolation and identification from methanol extract of Euonymus alatus. Life Sci 77:2760–2769. doi:10.1016/j.lfs.2005.02.028
Kang S, Cho S, Chung JH, Hammerberg C, Fisher GJ, Voorhees JJ (2005) Inflammation and extracellular matrix degradation mediated by activated transcription factors nuclear factor-kappaB and activator protein-1 in inflammatory acne lesions in vivo. Am J Pathol 166:1691–1699. doi:10.1016/S0002-9440(10)62479-0
Karthikesan K, Pari L, Menon VP (2010a) Antihyperlipidemic effect of chlorogenic acid and tetrahydrocurcumin in rats subjected to diabetogenic agents. Chem Biol Interact 188:643–650. doi:10.1016/j.cbi.2010.07.026
Karthikesan K, Pari L, Menon VP (2010b) Combined treatment of tetrahydrocurcumin and chlorogenic acid exerts potential antihyperglycemic effect on streptozotocin-nicotinamide-induced diabetic rats. Gen Physiol Biophys 29:23–30
Khalil AA, Aziz FA, Hall JC (2006) Reperfusion injury. Plast Reconstr Surg 117:1024–1033. doi:10.1097/01.prs.0000204766.17127.54
Korhonen R, Lahti A, Kankaanranta H, Moilanen E (2005) Nitric oxide production and signaling in inflammation. Curr Drug Targets Inflamm Allergy 4:471–479. doi:10.2174/1568010054526359
Krischel V, Bruch-Gerharz D, Suschek C (1998) Biphasic effect of exogenous nitric oxide on proliferation and differentiation on skin derived keratinocytes but not fibroblasts. J Invest Dermatol 111:286–291. doi:10.1046/j.1523-1747.1998.00268.x
Kupeli Akkol E, Acikara OB, Suntar I, Citoglu GS, Keles H, Ergene B (2011) Enhancement of wound healing by topical application of Scorzonera species: determination of the constituents by HPLC with new validated reverse phase method. J Ethnopharmacol 137:1018–1027. doi:10.1016/j.jep.2011.07.029
Lee K, Lee JS, Jang HJ, Kim SM, Chang MS, Park SH, Kim KS, Bae J, Park JW, Lee B, Choi HY, Jeong CH, Bu Y (2012) Chlorogenic acid ameliorates brain damage and edema by inhibiting matrix metalloproteinase-2 and 9 in a rat model of focal cerebral ischemia. Eur J Pharmacol 689:89–95. doi:10.1016/j.ejphar.2012.05.028
Lee RH, Efron D, Tantry U, Barbul A (2001) Nitric oxide in the healing wound: a time-course study. J Surg Res 101:104–108
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275. http://www.jbc.org/content/193/1/265.short#ref-list-1
MacGregor JT, Heddle JA, Hite M, Margolin BH, Ramel C, Salamone MF, Tice RR, Wild D (1987) Guidelines for the conduct of micronucleus assays in mammalian bone marrow erythrocytes. Mutation Res 189:103–112. doi:10.1016/0165-1218(87)90016-4
McDonald JA (1989) Receptors for extracellular matrix components. Am J Physiol 257:L331–L337. http://ajplung.physiology.org/content/257/6/L331.full-text.pdf+html
Mubarak A, Bondonno CP, Liu AH, Considine MJ, Rich L, Mas E, Croft KD, Hodgson JM (2012) Acute effects of chlorogenic acid on nitric oxide status, endothelial function, and blood pressure in healthy volunteers: a randomized trial. J Agric Food Chem 60:9130–9136. doi:10.1021/jf303440j
Oboh G, Agunloye OM, Akinyemi AJ, Ademiluyi AO, Adefegha SA (2013) Comparative study on the inhibitory effect of caffeic and chlorogenic acids on key enzymes linked to Alzheimer’s disease and some pro-oxidant induced oxidative stress in rats’ brain in vitro. Neurochem Res 38:413–419. doi:10.1007/s11064-012-0935-6
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358. doi:10.1016/0003-2697(79)90738-3
Ozyigit MO, Kahraman MM, Sonmez G (2005) The identification of matrix metalloproteinases and their tissue inhibitors in broiler chickens by immunohistochemistry. Avian Pathol 34:509–516. doi:10.1080/03079450500368508
Raza H, John A (2005) Green tea polyphenol epigallocatechin-3-gallate differentially modulates oxidative stress in PC12 cell compartments. Toxicol Appl Pharmacol 207:212–220. doi:10.1016/j.taap.2005.01.004
Robson MC, Steed DL, Franz MG (2001) Wound healing: biologic features and approaches to maximize healing trajectories. Curr Probl Surg 38:72–140. http://www.currprobsurg.com/article/S0011-3840(01)00036-3/abstract
Sakihama Y, Cohen MF, Grace SC, Yamasaki H (2002) Plant phenolic antioxidant and prooxidant activities: phenolics-induced oxidative damage mediated by metals in plants. Toxicology 177:67–80. doi:10.1016/S0300-483X(02)00196-8
Sato Y, Itagaki S, Kurokawa T, Ogura J, Kobayashi M, Hirano T, Sugawara M, Iseki K (2011) In vitro and in vivo antioxidant properties of chlorogenic acid and caffeic acid. Int J Pharm 403:136–138. doi:10.1016/j.ijpharm.2010.09.035
Schwentker A, Vodovotz Y, Weller R, Billiar TR (2002) Nitric oxide and wound repair: role of cytokines? Nitric Oxide 7:1–10. doi:10.1016/S1089-8603(02)00002-2
Serarslan G, Altug E, Kontas T, Atik E, Avci G (2007) Caffeic acid phenethyl ester accelerates cutaneous wound healing in a rat model and decreases oxidative stress. Clin Exp Dermatol 32:709–715. doi:10.1111/j.1365-2230.2007.02470.x
Shimoyama AT, Santin JR, Machado ID, de Oliveira e Silva AM, de Melo IL, Mancini-Filho J, Farsky SH (2013) Antiulcerogenic activity of chlorogenic acid in different models of gastric ulcer. Naunyn Schmiedebergs Arch Pharmacol 386:5–14. doi:10.1007/s00210-012-0807-2
Shukla A, Dubey MP, Srivastava R, Srivastava BS (1998) Differential expression of proteins during healing of cutaneous wounds in experimental normal and chronic models. Biochem Biophys Res Commun 244:434–439. doi:10.1006/bbrc.1998.8286
Sinha AK (1972) Colormetric assay of catalase. Anal Bioche 47:389–394
Song HS, Park TW, Sohn UD, Shin YK, Choi BC, Kim CJ, Sim SS (2008) The effect of caffeic acid on wound healing in skin-incised mice. Korean J Physiol Pharmacol 12:343–347. doi:10.4196/kjpp.2008.12.6.343
Soo C, Shaw WW, Zhang X, Longaker MT, Howard EW, Ting K (2000) Differential expression of matrix metalloproteinases and their tissue-derived inhibitors in cutaneous wound repair. Plast Reconstr Surg 105:638–647. http://journals.lww.com/plasreconsurg/pages/articleviewer.aspx?year=2000&issue=02000&article=00024&type=abstract
Stadelmann WK, Digenis AG, Tobin GR (1998) Physiology and healing dynamics of chronic cutaneous wounds. Am J Surg 176:26–38. http://www.americanjournalofsurgery.com/article/S0002-9610(98)00183-4/abstract
Sun Y, Oberley LW, Li Y (1988) A simple method for clinical assay of superoxide dismutase. Clin Chem 34:497–500.http://www.clinchem.org/content/34/3/497.long
Suntar I, Acikara OB, Citoglu GS, Keles H, Ergene B, Akkol EK (2012) In vivo and in vitro evaluation of the therapeutic potential of some Turkish Scorzonera species as wound healing agent. Curr Pharm Des 18:1421–1433. doi:10.2174/138161212799504867
Suzuki S, Miyachi Y, Niwa Y, Isshiki N (1989) Significance of reactive oxygen species in distal flap necrosis and its salvage with liposomal SOD. Br J Plast Surg 42:559–64
Swaim SF, Bradley DM, Spano JS, McGuire JA, Hoffman CE, Trachy RE (1993) Evaluation of multipeptide copper complex medications on open wound healing in dogs. J Am Anim Hosp Assoc 29:519–527
Teke Z, Bostanci EB, Yenisey C, Kelten EC, Sacar S, Simsek NG, Duzcan SE, Akoglu M (2012) Effects of caffeic acid phenethyl ester on anastomotic healing in secondary peritonitis. J Invest Surg 25:301–310. doi:10.3109/08941939.2011.646450
Thomé RG, dos Santos HB, dos Santos FV, da Silva Oliveira RJ, de Camargos LF, Pereira MN, Longatti TR, Souto CM, Franco CS, de Oliveira Aquino Schüffner R, Ribeiro RI (2012) Evaluation of healing wound and genotoxicity potentials from extracts hydroalcoholic of Plantago major and Siparuna guianensis. Exp Biol Med 237:1379–1386. doi:10.1258/ebm.2012.012139
Tie L, Yang HQ, An Y, Liu SQ, Han J, Xu Y, Hu M, Li WD, Chen AF, Lin ZB, Li XJ (2012) Ganoderma lucidum polysaccharide accelerates refractory wound healing by inhibition of mitochondrial oxidative stress in type 1 diabetes. Cell Physiol Biochem 29:583–594. doi:10.1159/000338512
Trengove NJ, Stacey MC, MacAuley S, Bennett N, Gibson J, Burslem F, Murphy G, Schultz G (1999) Analysis of the acute and chronic wound environments: the role of proteases and their inhibitors. Wound Repair Regen 7:442–452. doi:10.1046/j.1524-475X.1999.00442.x
Trugo LC, Macrae R (1984) A study of the effect of roasting on the chlorogenic acid composition of coffee using HPLC. Food Chem 15:219–227
Wätjen W, Michels G, Steffan B, Niering P, Chovolou Y, Kampkötter A, Tran-Thi QH, Proksch P, Kahl R (2005) Low concentrations of flavonoids are protective in rat H4IIE cells whereas high concentrations cause DNA damage and apoptosis. J Nutr 135:525–531. http://jn.nutrition.org/content/135/3/525.long
Witte MB, Barbul A (2002) Role of nitric oxide in wound repair. Am J Surg 183:406–412. http://www.americanjournalofsurgery.com/article/S0002-9610(02)00815-2/fulltext
Wong TT, Sethi C, Daniels JT, Limb GA, Murphy G, Khaw PT (2002) Matrix metalloproteinases in disease and repair processes in the anterior segment. Surv Ophthalmol 47(3):239–56. http://www.surveyophthalmol.com/article/S0039-6257(02)00287-4/fulltext
Yordi EG, Pérez EM, Matos MJ, Villares EU (2012) Antioxidant and pro-oxidant effects of polyphenolic compounds and structure-activity relationship evidence. In: Jaouad Bouayed (Ed.). Nutrition, well-being and health. ISBN: 978-953-51-0125-3. InTech, doi:10.5772/29471
Yun N, Kang JW, Lee SM (2012) Protective effects of chlorogenic acid against ischemia/reperfusion injury in rat liver: molecular evidence of its antioxidant and anti-inflammatory properties. J Nutr Biochem 23:1249–1255. doi:10.1016/j.jnutbio.2011.06.018
Acknowledgments
This work was supported by grants from Research Foundation of Uludag University (grant no. KUAP (T) 2012/37 and HDP (T) 2012/33). The authors special thank Dr. Pretal P. Muldoon for her contribution in English editing of the manuscript.
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Bagdas, D., Gul, N.Y., Topal, A. et al. Pharmacologic overview of systemic chlorogenic acid therapy on experimental wound healing. Naunyn-Schmiedeberg's Arch Pharmacol 387, 1101–1116 (2014). https://doi.org/10.1007/s00210-014-1034-9
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DOI: https://doi.org/10.1007/s00210-014-1034-9