Potential Benefit of Flavonoid in Papaya Leave Gel in Neutrophil, Angiogenesis, and Wound size in Rattus Norvegicus

Authors

  • Siti Nurhidayah Magister Program of Midwifery, Faculty of Medicine, Brawijaya University, Malang, Indonesia, 65145
  • Iin Tri Marlinawati Magister Program of Midwifery, Faculty of Medicine, Brawijaya University, Malang, Indonesia, 65145
  • Sri Winarsih Department of Microbiology, Faculty of Medicine, Brawijaya University, Malang, Indonesia, 65145, Department of Pharmacy, Faculty of Medicine, Brawijaya University, Malang, Indonesia, 65145
  • Tatit Nurseta Oncology Division, Department of Obstetrics and Gynecology, Faculty of Medicine, Brawijaya University, Malang, Indonesia, 65614, Department of Obstetrics and Gynecology, Saiful Anwar Hospital, Malang, Indonesia, 65122

DOI:

https://doi.org/10.31964/mltj.v8i1.464

Abstract

An incision wound is the destruction of several cells in the skin area that has experienced an incision. Several factors influencing wound healing are neutrophils as causative agents of inflammation, angiogenesis, and wound closure. These three factors should undergo physiologically to obtain the optimal healing process. Currently, herbal products are preferred because they have lower side effects than synthetic ones. Papaya leaves contain flavonoids with various functions, including wound closure and anti-inflammatory and antioxidant effects. Topical intervention, especially gel, is good for healing because it can keep the wound moist. This research aimed to determine the effect of the administration of papaya leaf gel on wound closure, neutrophil, and angiogenesis. Thirty white rats were used as the model animals in a randomized experimental study divided into five groups comprising negative control (0,9% NaCl), positive control (10% Povidone-iodine), and three intervention groups treated with gel of Carica papaya leaves at a dosage 10%, 20%, and 30%. All groups were topically administered treatment once a day on the dorsal surface for seven days. Carica papaya leaves contain flavonoids, saponin, tannin, and alkaloids qualitatively and 7,734 mg/kg of the flavonoid quantitatively. There were no significant differences in wound size in all three groups on three days, but Carica papaya leave gel had a superior effect compared to 10% PI and 0,9% NaCl in the wound closure process. There were significant differences in all groups in neutrophil and angiogenesis. Nevertheless, 20% papaya leave gel showed the lowest number of neutrophils and had a superior effect on improving the new blood vessels significantly compared to negative and positive groups.

References

Ajiboye, A.E. and Olawoyin, R.A. (2020). Antibacterial activities and phytochemical screening of crude extract of Carica papaya leaf against selected pathogens. Global Journal of Pure and Applied Sciences, 26(2), 165–170. Available at: https://doi.org/10.4314/gjpas.v26i2.8.

Ancy, J. (2018) ‘Surgical wound healing after wound care with normal saline over wound care with povidone iodine among the clients who have undergone laparotomy. The Journal of Nursing Trendz, 9(3), 18. Available at: https://doi.org/10.5958/2249-3190.2018.00038.x.

Anjum, V., Arora, P., Ansari, S.H., Najmi, A.K. and Ahmad, S. (2017). Antithrombocytopenic and immunomodulatory potential of metabolically characterized aqueous extract of Carica papaya leaves. Pharmaceutical Biology, 55(1), 2043–2056. Available at: https://doi.org/10.1080/13880209.2017. 1346690.

Antunes-Ricardo, M., Gutierrez-Uribe, J. and Serna-Saldivar, S.O. (2015). Anti-inflammatory Glycosylated Flavonoids as Therapeutic Agents for Treatment of Diabetes-Impaired Wounds. Curr Top Med Chem, 15(23), 2456–63. Available at: https://doi.org/10.2174/1568026615666150619141702.

Aruljothi, S., Uma, C., Sivagurunathan, P. and Bhuvaneswari, M. (2014). Investigation on Antibacterial Activity of Carica Papaya Leaf Extracts against Wound Infection-Causing Bacteria. International Journal of Research Studies in Biosciences, 2(11), 8–12. Available at: www.arcjournals.org.

Ayoola, P.B., Adeyeye, A. and State, O. (2010). Phytochemical and Nutrient Evaluation of Carica Papaya ( Pawpaw ) Leaves . 5(December), 325–328.

Beyer, S., Koch, M., Lee, Y.H., Jung, F. and Blocki, A. (2018). An in vitro model of angiogenesis during wound healing provides insights into the complex role of cells and factors in the inflammatory and proliferation phase. International Journal of Molecular Sciences, 19(10). Available at: https://doi.org/10.3390/ijms19102913.

Bhar, K., Mondal, S., Udayabhanu, B. and Priya, A.S.S. (2013). Healing Potential of Carica Papaya Leaf. American Journal of PharmTech Research, 3(6), 715–722.

Bigliardi, P., Langer, S., Cruz, J.J., Kim, S.W., Nair, H. and Srisawasdi, G. (2017). An Asian Perspective on Povidone Iodine in Wound Healing. Dermatology, 233(2–3), 223–233. Available at: https://doi.org/10.1159/000479150.

Cañedo-Dorantes, L. and Cañedo-Ayala, M. (2019). Skin acute wound healing: A comprehensive review. International Journal of Inflammation, 2019. Available at: https://doi.org/10.1155/2019/3706315.

Carvalho, M.T.B., Araújo-Filho, H.G., Barreto, A.S., Quintans-Júnior, L.J., Quintans, J.S.S. and Barreto, R.S.S. (2021). Wound healing properties of flavonoids: A systematic review highlighting the mechanisms of action. Phytomedicine, 90(May). Available at: https://doi.org/10.1016/j.phymed.2021.153636.

Dev, S.K., Choudhury, P.K., Srivastava, R. and Sharma, M. (2019). Antimicrobial, anti-inflammatory and wound healing activity of polyherbal formulation. Biomedicine and Pharmacotherapy, 111(December 2018), 555–567. Available at: https://doi.org/10.1016/j.biopha.2018.12.075.

Dios, R.-I., Kaluwanchikudy, J. and Gopalasingam, A. (2017). A comparative study between topical povidone iodine and normal saline solutions as wet-to-dry dressing for wound lacerations or abrasions among Adult Patients. Journal for Research, 02(11), 20–24.

Ellis, S., Lin, E.J. and Tartar, D. (2018). Immunology of Wound Healing. Current Dermatology Reports, 7(4), 350–358. Available at: https://doi.org/10.1007/s13671-018-0234-9.

Femilian, A., Agustina, D. and Subagyo, G. (2019). The effect of papaya leaf extract (Carica papaya L) on healing process of buccal traumatic ulcer in wistar rats. Majalah Kedokteran Gigi Indonesia, 1(1), 15. Available at: https://doi.org/10.22146/majkedgiind.37026.

Freitas, M., Ribeiro, D., Tomé, S.M., Silva, A.M.S. and Fernandes, E. (2014). Synthesis of chlorinated flavonoids with anti-inflammatory and pro-apoptotic activities in human neutrophils. European Journal of Medicinal Chemistry, 86, 153–164. Available at: https://doi.org/10.1016/j.ejmech.2014.08.035.

Giri, P., Krishnaraj, B., Chandra Sistla, S., Sistla, S., Basu, D., Shankar, G., Akkilagunta, S. and Ruparelia, J. (2021). Does negative pressure wound therapy with saline instillation improve wound healing compared to conventional negative pressure wound therapy? - A randomized controlled trial in patients with extremity ulcers. Annals of Medicine and Surgery, 61(November 2020), 73–80. Available at: https://doi.org/10.1016/j.amsu.2020.12.015.

Gopi, E.V., Basava, A.H. and Matad, S. (2017). A prospective study to compare the effectiveness of saline dressing versus povidone iodine dressing in chronic diabetic wound healing: study from a tertiary hospital in south India. International Surgery Journal, 4(4), 1371. Available at: https://doi.org/10.18203/2349-2902.isj20171144.

Gudimella, K. kanthi, Gedda, G., Kumar, P.S., Babu, B.K., Yamajala, B., Rao, B.V., Singh, P.P., Kumar, D. and Sharma, A. (2022). Novel synthesis of fluorescent carbon dots from bio-based Carica Papaya Leaves: Optical and structural properties with antioxidant and anti-inflammatory activities. Environmental Research, 204(PA), 111854. Available at: https://doi.org/10.1016/j.envres.2021.111854.

Gumay, A.R., Bakri, S., Oktavia, D., Saritsya, K.V., Retnoningrum, D., Indraswari, D.A., Saraswati, I., Istiadi, H., Purwoko, Y., Muniroh, M. and Hardian (2020). Chemopreventive effect of carica pubescens leaf extract on neutrophil-lymphocyte ratio, erythrocyte count, and colon histopathological appearance of dimethylhydrazine-induced colon cancer rats. Malaysian Journal of Medicine and Health Sciences, 16, 50–56.

Guo, B., Dong, R., Liang, Y. and Li, M. (2021). Haemostatic materials for wound healing applications. Nature Reviews Chemistry, 5, 773–791. Available at: https://doi.org/https://doi.org/10.1038/s41570-021-00323-z.

HG, V., Kirankumar, G, R., P, A. and B, U. (2018). Comparison of the Efficacy of Povidone-Iodine and Normal Saline Wash in Preventing Surgical Site Infections in Laparotomy Wounds-Randomized Controlled Trial. Surgery: Current Research, 08(02), 2018–2020. Available at: https://doi.org/10.4172/2161-1076.1000319.

Hurlow, J. and Bowler, P.G. (2022). Acute and chronic wound infections: microbiological, immunological, clinical and therapeutic distinctions. Journal of wound care, 31(5), 436–445. Available at: https://doi.org/10.12968/jowc.2022.31.5.436.

Husin, F., Ya’akob, H., Rashid, S.N.A., Shahar, S. and Soib, H.H. (2019). Cytotoxicity study and antioxidant activity of crude extracts and SPE fractions from Carica papaya leaves. Biocatalysis and Agricultural Biotechnology, 19(November 2018), 101130. Available at: https://doi.org/10.1016/j.bcab.2019.101130.

Jamadar, M.J. and Shaikh, R.H. (2017). Preparatıon and evaluatıon of herbal gel formulatıon. Journal of Pharmaceutical Research & Education, 1(2), 201–224.

Karak, P. (2019). Biological Activities of Flavonoids: an Overview. International Journal of Pharmaceutical Sciences and Research, 10(4), 1567–1574. Available at: https://doi.org/10.13040/IJPSR.0975-8232.10(4).1567-74.

Karppinen, S.-M., Heljasvaara, R., Gullberg, D., Tasanen, K. and Pihlajaniemi, T. (2019). Toward understanding scarless skin wound healing and pathological scarring. F1000Research, 8, 787. Available at: https://doi.org/10.12688/f1000research.18293.1.

Kim, P.J., Attinger, C.E., Oliver, N., Garwood, C., Evans, K.K., Steinberg, J.S. and Lavery, L.A. (2015). Comparison of outcomes for normal saline and an antiseptic solution for negative-pressure wound therapy with instillation. Plastic and Reconstructive Surgery, 136(5), 657e-664e. Available at: https://doi.org/10.1097/PRS.0000000000001709.

Kumar, P., Kumar, S., Udupa, E.P., Kumar, U., Rao, P. and Honnegowda, T. (2015). Role of angiogenesis and angiogenic factors in acute and chronic wound healing. Plastic and Aesthetic Research, 2(5), 243. Available at: https://doi.org/10.4103/2347-9264.165438.

Kurniati, N. (2021). Inhibitory power of papaya leaves to the adhesion of streptococcus mutans bacteria to neutrophils. Biomedical and Pharmacology Journal, 14(3), 1381–1387. Available at: https://doi.org/10.13005/bpj/2240.

Liu, Y.Q., Maloni, J.A. and Petrini, M.A. (2014). Effect of Postpartum Practices of Doing the Month on Chinese Women’s Physical and Psychological Health. Biological Research for Nursing, 16(1), 55–63. Available at: https://doi.org/10.1177/1099800412465107.

López-Cano, M., Kraft, M., Curell, A., Puig-Asensio, M., Balibrea, J., Armengol-Carrasco, M. and García-Alamino, J.M. (2019). A Meta-analysis of Prophylaxis of Surgical Site Infections with Topical Application of Povidone Iodine Before Primary Closure. World Journal of Surgery, 43(2), 374–384. Available at: https://doi.org/10.1007/s00268-018-4798-0.

Maisarah, A.M., Nurul Amira, B., Asmah, R. and Fauziah, O. (2013). Antioxidant analysis of different parts of Carica papaya. International Food Research Journal, 20(3), 1043–1048.

Maksym K. Gmur, T.M.K. (2020). Povidone-iodine in wound healing and prevention of wound infections. European Journal of Biological Research, 10(3), 232–239.

Maleki, S.J., Crespo, J.F. and Cabanillas, B. (2019). Anti-inflammatory effects of flavonoids. Food Chemistry, 299(July). Available at: https://doi.org/10.1016/j.foodchem.2019.125124.

Marlinawati, I.T., Nurhidayah, S., Santoso, S. and Irwanto, Y. (2022). Effect of Papaya Leaf Extract Gel (Carica papaya) on Incision Wound Healing in Rattus norvegicus. Medical Laboratory Technology Journal [Preprint]. Available at: https://doi.org/10.31964/mltj.v0i0.455.

Marpaung, O.P.., Bangun, D. and Ilyas, S. (2019). Effects of Methanol Extract and N-Hexane Extract of Papaya Leaves (Carica Papaya L) on Total and Differential White Blood Cell Counts in Male Wistar Rats After Carrageenan Induction. Buletin Farmatera, 4(2). Available at: https://doi.org/10.30596/bf.v4i2.3016.

Misal, G., Dixit, G. and Gulkari, V. (2012). Formulation and evaluation of herbal gel. Indian Journal of Natural Products and Resources, 3(4), 501–505.

Nishimura, F.D.C.Y., De Almeida, A.C., Ratti, B.A., Ueda-Nakamura, T., Nakamura, C.V., Ximenes, V.F. and De Oliveira Silva, S. (2013). Antioxidant effects of quercetin and naringenin are associated with impaired neutrophil microbicidal activity. Evidence-based Complementary and Alternative Medicine, 2013. Available at: https://doi.org/10.1155/2013/795916.

Nugroho, A., Heryani, H., Choi, J.S. and Park, H.J. (2017). Identification and quantification of flavonoids in Carica papaya leaf and peroxynitrite-scavenging activity. Asian Pacific Journal of Tropical Biomedicine, 7(3), 208–213. Available at: https://doi.org/10.1016/j.apjtb.2016.12.009.

Oladunmoye, M.K. and Osho, I.B. (2007). Antiinflammatory activity of ethanolic leaf extract from Carica papaya in rats orogastrically dosed with Salmonella typhi and Staphylococcus aureus. Journal of Plant Sciences, 447–452. Available at: https://doi.org/10.3923/jps.2007.447.452.

Pang, Y., Zhang, Yan, Huang, L., Xu, L., Wang, K., Wang, D., Guan, L., Zhang, Yingbo, Yu, F., Chen, Z. and Xie, X. (2017). Effects and mechanisms of total flavonoids from Blumea balsamifera (L.) DC. on skin wound in rats. International Journal of Molecular Sciences, 18(12), 1–12. Available at: https://doi.org/10.3390/ijms18122766.

Pertiwi, D., Hafiz, I. and Salma, R. (2019). Antibacterial Activity of Ethanol Extract of Papaya leaves (Carica papaya L.) Gel against P.acnes. Indonesian Journal of Pharmaceutical and Clinical Research (IDJPCR), 2(1), 1–6.

Phillipson, M. and Kubes, P. (2019). The Healing Power of Neutrophils. Trends in Immunology, 40(7), 635–647. Available at: https://doi.org/10.1016/j.it.2019.05.001.

Razak, M.R.M.A., Norahmad, N.A., Jelas, N.H.M., Afzan, A., Misnan, N.M., Ripen, A.M., Thayan, R., Zainol, M. and Mohamed, A.F.S. (2021). Immunomodulatory activities of Carica papaya L. Leaf juice in a non-lethal, symptomatic dengue mouse model. Pathogens, 10(5). Available at: https://doi.org/10.3390/pathogens10050501.

Rüther, L. and Voss, W. (2021). Hydrogel or ointment? Comparison of five different galenics regarding tissue breathability and transepidermal water loss. Heliyon, 7(1), e06071. Available at: https://doi.org/10.1016/j.heliyon.2021.e06071.

Setyawaty, R., Aptuning B, R. and Dewanto, D. (2020). Preliminary Studies on the Content of Phytochemical Compounds On Skin of Salak Fruit (Salacca zalacca). Pharmaceutical Journal of Indonesia, 6(1), 1–6. Available at: https://doi.org/10.21776/ub.pji.2020.006.01.1.

Shubham, S., Mishra, R., Gautam, N., Nepal, M., Kashyap, N. and Dutta, K. (2019). Phytochemical Analysis of Papaya Leaf Extract: Screening Test. EC Dental Science, 3, 485–490.

Singh, S.P., Kumar, Sanjay, Mathan, S. V., Tomar, M.S., Singh, R.K., Verma, P.K., Kumar, A., Kumar, Sandeep, Singh, R.P. and Acharya, A. (2020). Therapeutic application of Carica papaya leaf extract in the management of human diseases. DARU, Journal of Pharmaceutical Sciences, 28(2), 735–744. Available at: https://doi.org/10.1007/s40199-020-00348-7.

Soib, H.H., Ismail, H.F., Bakar, M.H.A., Yaakob, H. and Sarmidi, M.R. (2020). NoBioassay-Guided Different Extraction Techniques of Carica papaya (Linn.) Leaves on In Vitro Wound-Healing Activities. Molecules [Preprint], (25,517). Available at: https://doi.org/10.3390/molecules25030517.

Thibodeau, A. (2017). Naturally emulsifying with biomimetic clinical benefits. (September), 30–34.

Tridge. (2019). Fresh Papaya. Available at: https://www.tridge.com/intelligences/papaya/production.

Ukoba, O., Adefisan, I.E. and Aguwa, U.S. (2016). The Wound Healing Effect of Powdered Carica Papaya Leave. IMPACT: International Journal of Research in Applied, Natural and Social Sciences, 4(3), 1–10.

Wang, J. (2018). Neutrophils in tissue injury and repair. Cell and Tissue Research, 371(3), 531–539. Available at: https://doi.org/10.1007/s00441-017-2785-7.

Wang, L., Qin, W., Zhou, Y., Chen, B., Zhao, X., Zhao, H., Mi, Emma, Mi, Ella, Wang, Q. and Ning, J. (2017). Transforming growth factor β plays an important role in enhancing wound healing by topical application of Povidone-iodine. Scientific Reports, 7(1), 1–8. Available at: https://doi.org/10.1038/s41598-017-01116-5.

Wilgus, T.A., Roy, S. and McDaniel, J.C. (2013). Neutrophils and Wound Repair: Positive Actions and Negative Reactions. Advances in Wound Care, 2(7), 379–388. Available at: https://doi.org/10.1089/wound.2012.0383.

Downloads

Published

2022-09-28

How to Cite

Nurhidayah, S., Marlinawati, I. T., Winarsih, S., & Nurseta, T. (2022). Potential Benefit of Flavonoid in Papaya Leave Gel in Neutrophil, Angiogenesis, and Wound size in Rattus Norvegicus. Medical Laboratory Technology Journal. https://doi.org/10.31964/mltj.v8i1.464

Issue

Section

Articles

Most read articles by the same author(s)