Naphthoquinones from Handroanthus impetiginosus promote skin wound healing through Sirt3 regulation

Document Type : Original Article

Authors

1 Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, 45320 Islamabad, Pakistan

2 College of Pharmacy, Gachon University, 191 Hambakmaero, Incheon, South Korea

3 Department of Biological Sciences, National University of Medical Sciences, C/O Military Hospital, Mall Road Rawalpindi, Pakistan

Abstract

Objective(s): Lapachone is a natural naphthoquinone-derived compound found in Tabebuia avellanedae. It is well-known for its analgesic, anti-inflammatory, anti-microbial, diuretic, and anti-cancerous effects. However, the wound-healing effects of this compound are not known yet. The aim of this study was to investigate the wound healing activity of naphthoquinones (α-lapachone and β-lapachone) from Handroanthus impetiginosus.
Materials and Methods: Expression of Sirt3, migration-related proteins (Rac1, Cdc42, α-Pak) and angiogenesis-related protein of vascular endothelial growth factor (VEGF) was monitored using western blot analysis. Blood vessel formation and tissue development were monitored by angiogenesis assay and hematoxylin & eosin (H & E) staining, respectively on mouse skin tissue samples. Both α-lapachone and β-lapachone increased Sirt3 expression in vivo, but only β-lapachone increased Sirt3 expression in vitro.
Results: Both the compounds accelerated wound healing in cultured skin cells as well as mouse skin; however, β-lapachone was more effective at lower concentrations. Both of the compounds increased the expression of migration-related proteins both in vitro and in vivo. Similarly, α-lapachone and β-lapachone increased VEGF expression, tissue development and blood vessel formation in mouse skin.
Conclusion: These findings indicated that α-lapachone and β-lapachone are novel Sirt3 activators, and Sirt3 has a role in wound healing. Thus, Sirt3 and its regulators come out as a novel target and potential drug candidates, respectively in the important field of cutaneous wound healing.

Keywords

References

1. Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M. Growth factors and cytokines in wound healing. Wound Repair Regen 2008;16:585-601.
2. Versteeg HH, Heemskerk JW, Levi M, Reitsma PH. New fundamentals in hemostasis. Physiol Rev 2013;93:327-358.
3. Eming SA, Martin P, Tomic-Canic M. Wound repair and regeneration: Mechanisms, signaling, and translation. Sci Transl Med 2014;6:265sr6.
4.    Mofazzal Jahromi MA, Sahandi Zangabad P, Moosavi Basri SM, Sahandi Zangabad K, Ghamarypour A, Aref AR, et al. Nanomedicine and advanced technologies for burns: Preventing infection and facilitating wound healing. Adv Drug Deliv Rev 2018;123:33-64.
5.    Shedoeva A, Leavesley D. Wound Healing and the Use of Medicinal Plants. Evid Based Complement Alternat Med 2019;2019:2684108-2684137.
6. Olczyk P, Mencner L, Komosinska-Vassev K. The role of the extracellular matrix components in cutaneous wound healing. Biomed Res Int 2014;2014:747584-747591.
7. Braun A, Dang K, Buslig F, Baird MA, Davidson MW, Waterman CM, et al. Rac1 and Aurora A regulate MCAK to polarize microtubule growth in migrating endothelial cells. J Cell Biol 2014;206:97-112.
8. Abreu-Blanco MT, Verboon JM, Parkhurst SM. Coordination of Rho family GTPase activities to orchestrate cytoskeleton responses during cell wound repair. Curr Biol 2014;24:144-155.
9. Shukla SK, Sharma AK, Gupta V, Yashavarddhan MH. Pharmacological control of inflammation in wound healing.  J tissue viability 2019;28:218-222.
10.    Kung HN, Yang MJ, Chang CF, Chau YP, Lu KS. In vitro and in vivo wound healing-promoting activities of beta-lapachone. Am J Physiol Cell Physiol 2008;295:C931-943.
11.    Salameh A, Galvagni F, Bardelli M, Bussolino F, Oliviero S. Direct recruitment of CRK and GRB2 to VEGFR-3 induces proliferation, migration, and survival of endothelial cells through the activation of ERK, AKT, and JNK pathways. Blood 2005;106:3423-3431.
12.    Xu HL, Yu XF, Qu SC, Zhang R, Qu XR, Chen YP, et al. Anti-proliferative effect of Juglone from Juglans mandshurica Maxim on human leukemia cell HL-60 by inducing apoptosis through the mitochondria-dependent pathway. Eur J pharmacol 2010;645:14-22.
13.    Zhang W, Liu A, Li Y, Zhao X, Lv S, Zhu W, et al. Anticancer activity and mechanism of juglone on human cervical carcinoma HeLa cells. Can J Physiol Pharmacol 2012;90:1553-1558.
14.    Asthana J, Yadav AK, Pant A, Pandey S, Gupta MM, Pandey R. Specioside ameliorates oxidative stress and promotes longevity in Caenorhabditis elegans. Com Biochem Physiol Toxicol Pharmacol 2015;169:25-34.
15.    Cho YA, Jue SS, Bae WJ, Heo SH, Shin SI, Kwon IK, et al. PIN1 inhibition suppresses osteoclast differentiation and inflammatory responses. J Dent Res 2015;94:371-380.
16.    Zhang W, Li Y, Luo J, Lu X, Chen M, Zhu W, et al. [Juglone inhibits proliferation and induces apoptosis of human cervical squamous cancer SiHa cells]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2015;31:186-189.
17.    Wahedi HM, Lee TH, Moon EY, Kim SY. Juglone up-regulates sirt1 in skin cells under normal and UVB irradiated conditions. J Dermatol Sci 2016;81:210-212.
18.    Lu J, Zhang M, Huang Z, Sun S, Zhang Y, Zhang L, et al. SIRT1 in B[a]P-induced lung tumorigenesis. Oncotarget 2015;6:27113-27129.
19.    Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol 2012;13:225-238.
20.    Bause AS, Matsui MS, Haigis MC. The protein deacetylase SIRT3 prevents oxidative stress-induced keratinocyte differentiation. J Biol Chem 2013;288:36484-36491.
21.    Spallotta F, Cencioni C, Straino S, Nanni S, Rosati J, Artuso S, et al. A nitric oxide-dependent cross-talk between class I and III histone deacetylases accelerates skin repair. J Biol Chem 2013;288:11004-11012.
22.    Wahedi HM, Park YU, Moon EY, Kim SY. Juglone ameliorates skin wound healing by promoting skin cell migration through Rac1/Cdc42/PAK pathway. Wound Repair Regen 2016;24:786-794.
23.    Funasaka K, Ito S, Hasegawa H, Goldberg GS, Hirooka Y, Goto H, et al. Cas utilizes Nck2 to activate Cdc42 and regulate cell polarization during cell migration in response to wound healing. FEBS J 2010;277:3502-3513.
Iranian Journal of Basic Medical Sciences
Volume 23, Issue 9
September 2020
Pages 1139-1145

Files

Share

How to cite

Statistics