Silymarin promotes wound healing through regulating epithelial-mesenchymal transition in rat model: Histopathological and immunohistochemical evidences

Esra Aslan; Tuğçe  Aladağ; Hasan Hüseyin Demirel; Mehmet Bilgehan Pektaş

doi:10.26900/hsq.2364

Authors

Esra Aslan Afyonkarahisar Health Sciences University / Türkiye 0000-0002-3191-4978
Tuğçe Aladağ Afyonkarahisar Health Sciences University / Türkiye 0000-0003-3250-6113
Hasan Hüseyin Demirel Afyon Kocatepe University / Türkiye 0000-0002-4795-2266
Mehmet Bilgehan Pektaş Afyonkarahisar Health Sciences University / Türkiye 0000-0003-0055-7688

10.26900/hsq.2364

Abstract

The wound is the disruption of the normal structure, integrity, and function of the skin and subcutaneous tissue. It is known that current wound management strategies applied in the treatment of acute and chronic wounds both cause an increase in health costs and do not achieve the desired level of success. Therefore, more effective and easily applicable treatment methods are needed. SM is an agent known to have hepatoprotective, anticancer, antidiabetic, cardioprotective, neuroprotective, antimicrobial and antioxidant effects. And it is also used in dermatological applications. However, the therapeutic effects of Silymarin (SM) on wound healing are still unknown. In this study, the effects of SM were investigated by comparing it with dexpanthenol (Dxp), whose favorable effects on wound healing are known. Sham, Dxp, and SM groups were formed. 18 animals were used for each group. Two circular full-thickness skin wounds were taken from the nape of the neck (1.5 cm) using a six-mm punch biopsy tool. SM and Dxp was applied once daily for 15 days, in sufficient amounts to cover the entire wound and the effects of the drugs were investigated immunohistochemically on the 5th, 10th, and 15th days in rats. Inflammation, collagenization and epithelialization were evaluated in histochemical H-E and Masson trichrome staining. E-cadherin, N-cadherin, Occludin, Vimentin, FGF-1 and MMP-9 expression levels were examined immunohistochemically. Based on histological and immunohistochemical results, SM and Dxp enhanced epithelialization and reduced inflammation more than the sham group. Furthermore, there was no significant difference in the effects on the epithelialmesenchymal transition between SM and Dxp. Results indicated that SM is a useful therapeutic agent at least as much as Dxp in wound healing. The wound re-epithelization and anti-inflammatory effects of SM may be a new approach to the treatment of wound healing.

Keywords:

Silymarin wound healing epithelial-mesenchymal transition cadherin NfκB

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References

Wilkinson HN, Hardman MJ. Wound healing: cellular mechanisms and pathological outcomes. Open Biol. 2020 Sep;10(9):200223.

Takeo M, Lee W, Ito M. Wound healing and skin regeneration. Cold Spring Harb Perspect Med. 2015 Jan;5(1):a023267–a023267.

Broughton G, Janis JE, Attinger CE. Wound healing: an overview. Plast Reconstr Surg. 2006 Jun;117(7):1e-S-32e-S.

Lucas W, Leavesley D. MicroRNA regulation of epithelial-to-mesenchymal transition during re-epithelialisation: assessing an open wound. Wound Pract Res. 2015;23(3):132–42.

Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014 Mar;15(3):178–96.

Melincovici CS, Boşca AB, Şuşman S, Mărginean M, Mihu C, Istrate M, et al. Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis. Rom J Morphol Embryol. 2018;59(2):455–67.

Boyar V. Association of systemic or intravitreal antivascular endothelial growth factor (anti-VEGF) and impaired wound healing in pediatric patients. J Wound, Ostomy Cont Nurs. 2021 May;48(3):256–61.

Peng WX, He PX, Liu LJ, Zhu T, Zhong YQ, Xiang L, et al. LncRNA GAS5 activates the HIF1A/VEGF pathway by binding to TAF15 to promote wound healing in diabetic foot ulcers. Lab Investig. 2021 Aug;101(8):1071–83.

Bikle DD. Role of vitamin D and calcium signaling in epidermal wound healing. J Endocrinol Invest. 2022 Aug;46(2):205–12.

Cao J, Schnittler H. Putting VE-cadherin into JAIL for junction remodeling. J Cell Sci. 2019 Jan;132(1):jcs222893.

Rousselle P, Braye F, Dayan G. Re-epithelialization of adult skin wounds: cellular mechanisms and therapeutic strategies. Adv Drug Deliv Rev. 2019 Jun;146:344–65.

Ostrowska‐Podhorodecka Z, McCulloch CA. Vimentin regulates the assembly and function of matrix adhesions. Wound Repair Regen. 2021 Jul;29(4):602–12.

Qu BL, Yu W, Huang YR, Cai BN, Du LH, Liu F. 6-OH-BDE-47 promotes human lung cancer cells epithelial mesenchymal transition via the AKT/Snail signal pathway. Environ Toxicol Pharmacol. 2015 Jan;39(1):271–9.

Ramos C, Becerril C, Montaño M, García-De-Alba C, Ramírez R, Checa M, et al. FGF-1 reverts epithelial-mesenchymal transition induced by TGF-β1 through MAPK/ERK kinase pathway. Am J Physiol Cell Mol Physiol. 2010 Aug;299(2):L222–31.

Gorski J, Proksch E, Baron JM, Schmid D, Zhang L. Dexpanthenol in wound healing after medical and cosmetic interventions. Pharmaceuticals. 2020 Jun;13(7):138.

Gill S, Parks W. Metalloproteinases and their inhibitors: regulators of wound healing. Int J Biochem Cell Biol. 2008 Jun;40(6–7):1334–47.

Heise R, Schmitt L, Huth L, Krings L, Kluwig D, Katsoulari KV, et al. Accelerated wound healing with a dexpanthenol-containing ointment after fractional ablative CO 2 laser resurfacing of photo-damaged skin in a randomized prospective clinical trial. Cutan Ocul Toxicol. 2019 Jul;38(3):274–8.

Wang X, Zhang Z, Wu SC. Health Benefits of Silybum marianum: Phytochemistry, Pharmacology, and Applications. J Agric Food Chem. 2020;68(42).

Kren V, Walterová D. Silybin and silymarin--new effects and applications. Vol. 149, Biomedical papers of the Medical Faculty of the University Palacký, Olomouc, Czechoslovakia. 2005.

Soleimani V, Delghandi PS, Moallem SA, Karimi G. Safety and toxicity of silymarin, the major constituent of milk thistle extract: An updated review. Phyther Res. 2019 Jun;33(6):1627–38.

Camini FC, Costa DC. Silymarin: not just another antioxidant. J Basic Clin Physiol Pharmacol. 2020 May;31(4):20190206.

Devi KP, Malar DS, Braidy N, Nabavi SM, Nabavi SF. A mini review on the chemistry and neuroprotective effects of silymarin. Curr Drug Targets. 2017 Sep;18(13):1529–36.

MacDonald-Ramos K, Michán L, Martínez-Ibarra A, Cerbón M. Silymarin is an ally against insulin resistance: A review. Ann Hepatol. 2021 Jul;23:100255.

Madrigal-Santillán E, Madrigal-Bujaidar E, Álvarez-González I, Sumaya-Martínez MT, Gutiérrez-Salinas J, Bautista M, Morales-González Á, García-Luna y González-Rubio M, Aguilar-Faisal JL MGJ. Review of natural products with hepatoprotective effects. World J Gastroenterol. 2014;20(40):14787–804.

Stolf AM, Cardoso CC, Acco A. Effects of Silymarin on Diabetes Mellitus Complications: A Review. Vol. 31, Phytotherapy Research. 2017.

Tighe SP, Akhtar D, Iqbal U, Ahmed A. Chronic liver disease and silymarin: a biochemical and clinical review. J Clin Transl Hepatol. 2020 Dec;8(4):1–5.

Toklu HZ, Tunali-Akbay T, Erkanli G, Yüksel M, Ercan F, Şener G. Silymarin, the antioxidant component of Silybum marianum, protects against burn-induced oxidative skin injury. Burns. 2007;33(7).

Sharifi R, Rastegar H, Kamalinejad M, Dehpour AR, Tavangar SM, Paknejad M, et al. Effect of topical application of silymarin (silybum marianum) on excision wound healing in albino rats. Acta Med Iran. 2012;50(9).

Fidrus, Ujhelyi, Fehér, Hegedűs, Janka, Paragh, et al. Silymarin: friend or foe of UV exposed keratinocytes? Molecules. 2019 Apr;24(9):1652.

Duman N, Duman R, Tosun M, Akıcı M, Göksel E, Gökçe B, et al. Topical folinic acid enhances wound healing in rat model. Adv Med Sci. 2018;63(2).

Abramov Y, Golden B, Sullivan M, Botros SM, Miller JJR, Alshahrour A, et al. Histologic characterization of vaginal vs. abdominal surgical wound healing in a rabbit model. Wound Repair Regen. 2007;15(1).

Wang H, Chen P, Liu XX, Zhao W, Shi L, Gu XW, et al. Prognostic impact of gastrointestinal bleeding and expression of PTEN and Ki-67 on primary gastrointestinal stromal tumors. World J Surg Oncol. 2014 Dec;12(1):89.

Marconi GD, Fonticoli L, Rajan TS, Pierdomenico SD, Trubiani O, Pizzicannella J, et al. Epithelial-mesenchymal transition (EMT): the type-2 EMT in wound healing, tissue regeneration and organ fibrosis. Cells. 2021 Jun;10(7):1587.

Wang PH, Huang BS, Horng HC, Yeh CC, Chen YJ. Wound healing. J Chinese Med Assoc. 2018 Feb;81(2):94–101.

Mahmoodi-Nesheli M, Alizadeh S, Solhi H, Mohseni J, Mahmoodi-Nesheli M. Adjuvant effect of oral Silymarin on patients’ wound healing process caused by thermal injuries. Casp J Intern Med. 2018;9(4):341–6.

Juráňová J, Aury-Landas J, Boumediene K, Baugé C, Biedermann D, Ulrichová J, et al. Modulation of skin inflammatory response by active components of silymarin. Molecules. 2018 Dec;24(1):123.

Liu Y, Liu Y, Deng J, Li W, Nie X. Fibroblast growth factor in diabetic foot ulcer: progress and therapeutic prospects. Front Endocrinol (Lausanne). 2021 Oct;12:744868.

Widgerow AD. Chronic wound fluid—thinking outside the box. Wound Repair Regen. 2011 May;19(3):287–91.

Zhang C, Lim J, Jeon HH, Xu F, Tian C, Miao F, et al. FOXO1 deletion in keratinocytes improves diabetic wound healing through MMP9 regulation. Sci Rep. 2017;7(1).

Si L, Fu J, Liu W, Hayashi T, Nie Y, Mizuno K, et al. Silibinin inhibits migration and invasion of breast cancer MDA-MB-231 cells through induction of mitochondrial fusion. Mol Cell Biochem. 2020 Jan;463(1–2):189–201.

Nambiar DK, Rajamani P, Singh RP. Silibinin attenuates ionizing radiation-induced pro-angiogenic response and EMT in prostate cancer cells. Biochem Biophys Res Commun. 2015 Jan;456(1):262–8.

Abhilash PA, Harikrishnan R, Indira M. Ascorbic acid suppresses endotoxemia and NF-κB signaling cascade in alcoholic liver fibrosis in guinea pigs: A mechanistic approach. Toxicol Appl Pharmacol. 2014 Jan;274(2):215–24.