Review Article Published on 14 Mar, 2024

Effect of Caffeic Acid Phenethyl Ester on Wound Healing: A Systematic Review

Caffeic Acid and Skin Wound Healing
Vol. 19 No. 1 : 2024 (25-39)

Abdul Jalil NA Abdul Jalil NA
Ahmad F Ahmad F
Sankar D Sankar D
Hasnol MF Hasnol MF
Azahari NA Azahari NA
Syed Shahrin SA Syed Shahrin SA
Wong Z Wong Z

Abstract
Caffeic acid, a naturally occurring organic compound, possesses antioxidant and anti-inflammatory properties, along with its derivatives. This systematic review aimed to evaluate the effect of caffeic acid and its derivatives on oxidative stress and inflammatory response in cutaneous wound healing. This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Searches were performed in PubMed, Scopus, and Ovid MEDLINE. Articles published between 2000 and June 2022, with seven articles meeting the inclusion criteria were retrieved. The articles constituted in-vivo studies that utilised caffeic acid phenethyl ester (CAPE) as the therapeutic agent in three types of cutaneous wound including full-thickness burn injury (n=4), two incisional wounds, and one pressure ulcer. CAPE scavenged reactive oxidative species and reduced lipid peroxidation, superoxide dismutase, nitrotyrosine, malondialdehyde, catalase, xanthine oxidase, and nitric oxide levels. The treated injured area revealed enhanced granulation tissue formation, vascularisation, and collagenisation as well as long-term effects of CAPE as evidenced by reduced myofibroblast amount, CD68-positive macrophages, and increased collagen deposition. The systematic review emphasised how antioxidant and anti-inflammatory effects of CAPE could improve the process of wound healing, suggesting its substantial potential for clinical applications in this domain.
Keywords : Antioxidant, caffeic acid phenethyl ester, thermal injuries,
Abstrak
Asid kafeik, sebatian organik yang wujud secara semulajadi, mempunyai sifat antioksidan dan anti-radang, bersama dengan bahan terbitannya. Kajian sistematik ini bertujuan untuk menilai kesan asid kafeik dan bahan terbitannya terhadap tekanan oksidatif dan tindak balas keradangan dalam penyembuhan luka kulit. Kajian ini dijalankan mengikut panduan Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020. Carian dilakukan di PubMed, Scopus, dan Ovid MEDLINE. Artikel yang diterbitkan antara tahun 2000 dan Jun 2022, dengan tujuh artikel yang memenuhi kriteria inklusi telah dipilih. Artikel-artikel tersebut merupakan kajian in-vivo yang menggunakan asid kafeik fenetil ester (CAPE) sebagai agen terapeutik dalam tiga jenis luka kulit termasuk kecederaan melecur berketebalan penuh (n=4), dua luka insisi dan satu ulser tekanan. CAPE menurunkan kadar spesies oksidatif reaktif dan mengurangkan peroksidasi lipid, superoksida dismutase, nitrotirosin, malondialdehid, katalase, xanthine oksidase, dan paras nitrik oksida. Kawasan luka yang dirawat menunjukkan peningkatan pembentukan tisu granulasi, vaskularisasi, dan kolagenisasi serta kesan jangka panjang CAPE seperti yang dibuktikan oleh pengurangan jumlah miofibroblas, makrofag CD68-positif, dan peningkatan penyerapan kolagen. Kajian sistematik ini menekankan bagaimana kesan antioksidan dan anti-radang CAPE dapat mempercepatkan penyembuhan luka di mana CAPE juga berpotensi besar untuk  diaplikasikan dalam penggunaan klinikal.
Kata Kunci : Antioksidan, asid kafeik fenetil ester, kecederaan haba,

Correspondance Address
Dr Nahdia Afiifah Abdul Jalil. Department of Anatomy, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur, Malaysia. Tel: +603 9145 8605 Email: nahdia.afiifah@ukm.edu.my

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Balaha, M., De Filippis, B., Cataldi, A., Di Giacomo, V. 2021. CAPE and neuroprotection: A review. Biomolecules 11(2): 1-28.

Bankova, V., Dyulgerov, A., S.Popov, Marekov, N. 1986. A GC/MS Study of the propolis phenolic constituents. Z Naturforsch 42c(1987): 147-51.

Barnard, R., Gurevich, K.G. 2005. In vitro bioassay as a predictor of in vivo response. Theor Biol Med Model 2: 3.

Bhattacharyya, A., Chattopadhyay, R., Mitra, S., Crowe, S.E. 2014. Oxidative stress: An essential factor in the pathogenesis of gastrointestinal mucosal diseases. Physiol Rev 94(2): 329-54.

Chen, H.C., Chen, J.H., Chang, C., Shieh, C.J. 2011. Optimization of ultrasound-accelerated synthesis of enzymatic caffeic acid phenethyl ester by response surface methodology. Ultrason Sonochem 18(1): 455-9.

Chen, H.C., Ju, H.Y., Twu, Y.K., Chen, J.H., Chang, C. ming J., Liu, Y.C., Chang, C., Shieh, C.J. 2010. Optimized enzymatic synthesis of caffeic acid phenethyl ester by RSM. N Biotechnol 27(1): 89-93.

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Fırat, F., Özgül, M., Türköz Uluer, E., Inan, S. 2019. Effects of caffeic acid phenethyl ester (CAPE) on angiogenesis, apoptosis and oxidatıve stress ın various cancer cell lines. Biotechnic Histochem 94(7): 491-7.

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Hooijmans, C.R., Rovers, M.M., Vries, R.B. de, Leenaars, M., Ritskes-Hoitinga, M., Langendam, M.W. 2014. SYRCLE’s risk of bias tool for animal studies. BMC Med Resh Methodol 14: 43.

Hoşnuter, M., Gürel, A., Babucçu, O., Armutcu, F., Kargi, E., Işikdemir, A. 2004. The effect of CAPE on lipid peroxidation and nitric oxide levels in the plasma of rats following thermal injury. Burns 30(2): 121-5.

Hu, M.S., Cheng, J., Borrelli, M.R., Leavitt, T., Walmsley, G.G., Zielins, E.R., Hong, W.X., Cheung, A.T.M., Duscher, D., Maan, Z.N., Irizarry, D.M., Stephan, B., Parsa, F.D., Wan, D. C., Gurtner, G.C., Lorenz, H.P., Longaker, M.T. 2018. An improved humanized mouse model for excisional wound healing using double transgenic mice. Adv Wound Care (New Rochelle) 7(1): 11-7.

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Kontas-Askar, T., Altug, M.E., Karapehlivan, M., Atakisi, E., Hismiogullari, A.A. 2009. Is CAPE a therapeutic agent for wound healing? J Anim Vet Adv 8(1): 129-33.

Li, D., Wang, X., Huang, Q., Li, S., Zhou, Y., Li, Z. 2018. Cardioprotection of CAPE-oNO2 against myocardial ischemia/reperfusion induced ROS generation via regulating the SIRT1/eNOS/NF-κB pathway in vivo and in vitro. Redox Biol 15: 62-73.

Monika, P., Rangarajan, M.N.C.A., Waiker, P.V., Murthy, K.N.C. 2022. Challenges in healing wound: Role of complementary and alternative medicine. Front Nutr 2022(8): 791899

Muhammad Abdul Kadar, N.N., Ahmad, F., Teoh, S.L., Yahaya, M.F. 2021. Caffeic acid on metabolic syndrome: A review. Molecules 26(18): 5490

Nair, A.B., Jacob, S. 2016. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharmacy 7(2): 27-31.

Page, M.J., McKenzie, J.E., Bossuyt, P.M., Boutron, I., Hoffmann, T.C., Mulrow, C.D., Shamseer, L., Tetzlaff, J.M., Akl, E.A., Brennan, S.E., Chou, R., Glanville, J., Grimshaw, J.M., Hróbjartsson, A., Lalu, M.M., Li, T., Loder, E. W., Mayo-Wilson, E., McDonald, S., McGuinness, L.A., Stewart L.A., Thomas J., Tricco A.C., Welch V.A., Whiting P., Moher, D. 2021. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021(372): n71.

Parihar, A., Parihar, M. S., Milner, S., Bhat, S. 2008. Oxidative stress and anti-oxidative mobilization in burn injury. Burns 34(1): 6-17.

Reid, R.R., Sull, A.C., Mogford, J.E., Roy, N., Mustoe, T.A. 2004. A novel murine model of cyclical cutaneous ischemia-reperfusion injury. J Sur Res 116(1): 172-80.

Romana-Souza, B., dos Santos, J.S., Monte-Alto-Costa, A. 2018. Caffeic acid phenethyl ester promotes wound healing of mice pressure ulcers affecting NF-κB, NOS2 and NRF2 expression. Life Sci 207: 158-65.

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Serarslan, G., Altuǧ, E., Kontas, T., Atik, E., Avci, G. 2007. Caffeic acid phenetyl ester accelerates cutaneous wound healing in a rat model and decreases oxidative stress. Clin Exp Dermatol 32(6): 709-15.

Sharma, V., McNeill, J.H. 2009. To scale or not to scale: The principles of dose extrapolation. Br J Pharmacol 157(6): 907-21

Siti, H.N., Kamisah, Y., Kamsiah, J. 2015. The role of oxidative stress, antioxidants and vascular inflammation in cardiovascular disease (a review). Vascul Pharmacol 71: 40-56.

Song, Y.S., Park, E.H., Hur, G.M., Ryu, Y.S., Lee, Y.S., Lee, J.Y., Kim, Y.M., Jin, C. 2002. Caffeic acid phenethyl ester inhibits nitric oxide synthase gene expression and enzyme activity. Cancer Lett 175(1): 53-61.

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Stan, D., Tanase, C., Avram, M., Apetrei, R., Mincu, N.B., Mateescu, A.L., Stan, D. 2021. Wound healing applications of creams and “smart” hydrogels. Exp Dermatol 30(9): 1218-32.

Teke, Z., Bostanci, E.B., Yenisey, C., Kelten, E.C., Sacar, M., Simsek, N.G., Duzcan, S.E., Akoglu, M. 2013. Caffeic acid phenethyl ester prevents detrimental effects of remote ischemia-reperfusion injury on healing of colonic anastomoses. J Invest Surg 26(1): 16-29.

Teke, Z., Bostanci, E.B., Yenisey, C., Kelten, E.C., Sacar, S., Simsek, N.G., Duzcan, S.E., Akoglu, M. 2012. Effects of caffeic acid phenethyl ester on anastomotic healing in secondary peritonitis. J Invest Surg 25(5): 301-10.

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Correspondance Address

Al Shoyaib, A., Archie, S.R., Karamyan, V.T. 2019. Intraperitoneal route of drug administration: Should it be used in experimental animal studies? Pharm Res 37(1): 1-17.

Agrawal, N., Dasaradhi, P.V.N., Mohmmed, A., Malhotra, P., Bhatnagar, R.K., Mukherjee, S.K. 2003. RNA interference: Biology, mechanism, and applications. Microbiol Mol Biol Rev 67(4): 657-85.

Armutcu, F., Gürel, A., Hoşnuter, M., Pabuçcu, O., Altinyazar, C. 2004. Caffeic acid phenethyl ester improves oxidative erythrocyte damage in a rat model of thermal injury. J Burn Care Rehabil 25(2): 171-8.

Balaha, M., De Filippis, B., Cataldi, A., Di Giacomo, V. 2021. CAPE and neuroprotection: A review. Biomolecules 11(2): 1-28.

Bankova, V., Dyulgerov, A., S.Popov, Marekov, N. 1986. A GC/MS Study of the propolis phenolic constituents. Z Naturforsch 42c(1987): 147-51.

Barnard, R., Gurevich, K.G. 2005. In vitro bioassay as a predictor of in vivo response. Theor Biol Med Model 2: 3.

Bhattacharyya, A., Chattopadhyay, R., Mitra, S., Crowe, S.E. 2014. Oxidative stress: An essential factor in the pathogenesis of gastrointestinal mucosal diseases. Physiol Rev 94(2): 329-54.

Chen, H.C., Chen, J.H., Chang, C., Shieh, C.J. 2011. Optimization of ultrasound-accelerated synthesis of enzymatic caffeic acid phenethyl ester by response surface methodology. Ultrason Sonochem 18(1): 455-9.

Chen, H.C., Ju, H.Y., Twu, Y.K., Chen, J.H., Chang, C. ming J., Liu, Y.C., Chang, C., Shieh, C.J. 2010. Optimized enzymatic synthesis of caffeic acid phenethyl ester by RSM. N Biotechnol 27(1): 89-93.

Choudhary, P., Tushir, S., Bala, M., Sharma, S., Sangha, M.K., Rani, H., Yewle, N.R., Kumar, P., Singla, D., Chandran, D., Kumar, M., Mekhemar, M. 2023. Exploring the potential of bee-derived antioxidants for maintaining oral hygiene and dental health: A comprehensive review. Antioxidants (Basel) 12(7): 1452

Cordiano, R., Di Gioacchino, M., Mangifesta, R., Panzera, C., Gangemi, S., Minciullo, P. L. 2023. Malondialdehyde as a potential oxidative stress marker for allergy-oriented diseases: An update. Molecules 28(16): 5979.

Deng, L., Du, C., Song, P., Chen, T., Rui, S., Armstrong, D.G., Deng, W. 2021. The role of oxidative stress and antioxidants in diabetic wound healing. Oxid Med Cell Longev 2021(8852759).

Desco, M.C., Asensi, M., Márquez, R., Martínez-Valls, J., Vento, M., Pallardó, F.V., Sastre, J., Viña, J. 2002. Xanthine oxidase is involved in free radical production in type 1 diabetes: Protection by allopurinol. Diabetes 51(4): 1118-24.

Dos Santos, J.S., 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(6): 682-8.

Dunnill, C., Patton, T., Brennan, J., Barrett, J., Dryden, M., Cooke, J., Leaper, D., Georgopoulos, N. T. 2017. Reactive oxygen species (ROS) and wound healing: the functional role of ROS and emerging ROS-modulating technologies for augmentation of the healing process. Int Wound J 14(1): 89-96.

Fang, R.C., Mustoe, T.A. 2008. Animal models of wound healing: Utility in transgenic mice. J Biomater Sci Polym Ed 19(8): 989-1005.

Fırat, F., Özgül, M., Türköz Uluer, E., Inan, S. 2019. Effects of caffeic acid phenethyl ester (CAPE) on angiogenesis, apoptosis and oxidatıve stress ın various cancer cell lines. Biotechnic Histochem 94(7): 491-7.

Förstermann, U., Xia, N., Li, H. 2017. Roles of vascular oxidative stress and nitric oxide in the pathogenesis of atherosclerosis. Circ Res 120(4): 713-5.

Fukai, T., Ushio-Fukai, M. 2011. Superoxide dismutases: Role in redox signaling, vascular function, and diseases. Antioxid Redox Signal 5(6): 1583-606.

Francesko, A., Petkova, P., Tzanov, T. 2018. Hydrogel dressings for advanced wound management. Curr Med Chem 25(41): 5782-97.

Gurel, A., Armutcu, F., Hosnuter, M., Unalacak, M., Kargi, E., Altinyazar, C. 2004. Caffeic acid phenethyl ester improves oxidative organ damage in rat model of thermal trauma. Physiol Res 53: 675-82.

Hooijmans, C.R., Rovers, M.M., Vries, R.B. de, Leenaars, M., Ritskes-Hoitinga, M., Langendam, M.W. 2014. SYRCLE’s risk of bias tool for animal studies. BMC Med Resh Methodol 14: 43.

Hoşnuter, M., Gürel, A., Babucçu, O., Armutcu, F., Kargi, E., Işikdemir, A. 2004. The effect of CAPE on lipid peroxidation and nitric oxide levels in the plasma of rats following thermal injury. Burns 30(2): 121-5.

Hu, M.S., Cheng, J., Borrelli, M.R., Leavitt, T., Walmsley, G.G., Zielins, E.R., Hong, W.X., Cheung, A.T.M., Duscher, D., Maan, Z.N., Irizarry, D.M., Stephan, B., Parsa, F.D., Wan, D. C., Gurtner, G.C., Lorenz, H.P., Longaker, M.T. 2018. An improved humanized mouse model for excisional wound healing using double transgenic mice. Adv Wound Care (New Rochelle) 7(1): 11-7.

Kim, I., Mogford, J.E., Chao, J.D., Mustoe, T.A. 2001. Wound epithelialization deficits in the transforming growth factor-α knockout mouse. Wound Repair Regen 9(5): 386-90.

Kitano, T., Yamada, H., Kida, M., Okada, Y., Saika, S., Yoshida, M. 2017. Impaired healing of a cutaneous wound in an inducible nitric oxide synthase-knockout mouse. Dermatol Res Pract 2017(2184040): 1-11.

Kontas-Askar, T., Altug, M.E., Karapehlivan, M., Atakisi, E., Hismiogullari, A.A. 2009. Is CAPE a therapeutic agent for wound healing? J Anim Vet Adv 8(1): 129-33.

Li, D., Wang, X., Huang, Q., Li, S., Zhou, Y., Li, Z. 2018. Cardioprotection of CAPE-oNO2 against myocardial ischemia/reperfusion induced ROS generation via regulating the SIRT1/eNOS/NF-κB pathway in vivo and in vitro. Redox Biol 15: 62-73.

Monika, P., Rangarajan, M.N.C.A., Waiker, P.V., Murthy, K.N.C. 2022. Challenges in healing wound: Role of complementary and alternative medicine. Front Nutr 2022(8): 791899

Muhammad Abdul Kadar, N.N., Ahmad, F., Teoh, S.L., Yahaya, M.F. 2021. Caffeic acid on metabolic syndrome: A review. Molecules 26(18): 5490

Nair, A.B., Jacob, S. 2016. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharmacy 7(2): 27-31.

Page, M.J., McKenzie, J.E., Bossuyt, P.M., Boutron, I., Hoffmann, T.C., Mulrow, C.D., Shamseer, L., Tetzlaff, J.M., Akl, E.A., Brennan, S.E., Chou, R., Glanville, J., Grimshaw, J.M., Hróbjartsson, A., Lalu, M.M., Li, T., Loder, E. W., Mayo-Wilson, E., McDonald, S., McGuinness, L.A., Stewart L.A., Thomas J., Tricco A.C., Welch V.A., Whiting P., Moher, D. 2021. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021(372): n71.

Parihar, A., Parihar, M. S., Milner, S., Bhat, S. 2008. Oxidative stress and anti-oxidative mobilization in burn injury. Burns 34(1): 6-17.

Reid, R.R., Sull, A.C., Mogford, J.E., Roy, N., Mustoe, T.A. 2004. A novel murine model of cyclical cutaneous ischemia-reperfusion injury. J Sur Res 116(1): 172-80.

Romana-Souza, B., dos Santos, J.S., Monte-Alto-Costa, A. 2018. Caffeic acid phenethyl ester promotes wound healing of mice pressure ulcers affecting NF-κB, NOS2 and NRF2 expression. Life Sci 207: 158-65.

Saitoh, D., Shirani, K.Z., Cioffi, W.G., Kizaki, T., Ohno, H., Okada, Y., Mason, A.D., Pruitt, B.A. 2001. Changes in the tissue and plasma superoxide dismutase (SOD) levels in a burned rat model. Tohoku J Exp Med 193(1): 27-36.

Semis, H.S., Gur, C., Ileriturk, M., Kaynar, O., Kandemir, F.M. 2021. Investigation of the anti-inflammatory effects of caffeic acid phenethyl ester in a model of λ-Carrageenan-induced paw edema in rats. Hum Exp Toxicol 40(12_suppl): S721-38.

Serarslan, G., Altuǧ, E., Kontas, T., Atik, E., Avci, G. 2007. Caffeic acid phenetyl ester accelerates cutaneous wound healing in a rat model and decreases oxidative stress. Clin Exp Dermatol 32(6): 709-15.

Sharma, V., McNeill, J.H. 2009. To scale or not to scale: The principles of dose extrapolation. Br J Pharmacol 157(6): 907-21

Siti, H.N., Kamisah, Y., Kamsiah, J. 2015. The role of oxidative stress, antioxidants and vascular inflammation in cardiovascular disease (a review). Vascul Pharmacol 71: 40-56.

Song, Y.S., Park, E.H., Hur, G.M., Ryu, Y.S., Lee, Y.S., Lee, J.Y., Kim, Y.M., Jin, C. 2002. Caffeic acid phenethyl ester inhibits nitric oxide synthase gene expression and enzyme activity. Cancer Lett 175(1): 53-61.

Sorkin, B.C., Kuszak, A.J., Bloss, G., Fukagawa, N. K., Hoffman, F.A., Jafari, M., Barrett, B., Brown, P. N., Bushman, F.D., Casper, S.J., Chilton, F.H., Coffey, C.S., Ferruzzi, M.G., Hopp, D.C., Kiely, M., Lakens, D., MacMillan, J.B., Meltzer, D.O., Pahor, M., Pauli, G.F. 2020. Improving natural product research translation: From source to clinical trial. FASEB J 34(1): 41-65

Stan, D., Tanase, C., Avram, M., Apetrei, R., Mincu, N.B., Mateescu, A.L., Stan, D. 2021. Wound healing applications of creams and “smart” hydrogels. Exp Dermatol 30(9): 1218-32.

Teke, Z., Bostanci, E.B., Yenisey, C., Kelten, E.C., Sacar, M., Simsek, N.G., Duzcan, S.E., Akoglu, M. 2013. Caffeic acid phenethyl ester prevents detrimental effects of remote ischemia-reperfusion injury on healing of colonic anastomoses. J Invest Surg 26(1): 16-29.

Teke, Z., Bostanci, E.B., Yenisey, C., Kelten, E.C., Sacar, S., Simsek, N.G., Duzcan, S.E., Akoglu, M. 2012. Effects of caffeic acid phenethyl ester on anastomotic healing in secondary peritonitis. J Invest Surg 25(5): 301-10.

Tolba, M.F., Azab, S.S., Khalifa, A.E., Abdel-Rahman, S.Z., Abdel-Naim, A.B. 2013. Caffeic acid phenethyl ester, a promising component of propolis with a plethora of biological activities: A review on its anti-inflammatory, neuroprotective, hepatoprotective, and cardioprotective effects. IUBMB Life 65(8): 699-709.

Wang, G., Yang, F., Zhou, W., Xiao, N., Luo, M., Tang, Z. 2023. The initiation of oxidative stress and therapeutic strategies in wound healing. Biomed. Pharmacother 157: 114004.

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