Archives of Dermatological Research

, Volume 311, Issue 3, pp 193–201 | Cite as

Activators of SIRT1 in wound repair: an animal model study

  • Ana Cristina Christovam
  • Viviane Theodoro
  • Fernanda Aparecida Sampaio Mendonça
  • Marcelo Augusto Marretto Esquisatto
  • Gláucia Maria Tech dos Santos
  • Maria Esméria Corezola do AmaralEmail author
Original Paper


Caloric restriction (CR) and resveratrol activate SIRT1 and induce anti-inflammatory and antioxidant properties. We perform excisional lesion on the dorsum of four groups anesthetized animals: ad libitum-AL diet, AL diet with topical application of 2% resveratrol-Rv, 30% calorie restricted, and finally 30% calorie restricted with 2% resveratrol and we examine CR and Rv effects in wound repair. Restricted animals remained with CR for 31 days. The lesion was performed on day 18 of CR, and resveratrol application was started on day 19. Lesion samples were then collected on days 3 and 10 of treatment for structural, morphometric, and protein analyses. Our results showed that CR and Rv group as well as R group had enhanced numbers of blood vessels, VEGF, fibroblast, birefringent collagen fiber areas in the lesion. We conclude that effects in wound repair suggests that both CR and resveratrol may modulate angiogenesis, fibroplasia, and collagenesis, which could be ascribed to the action of SIRT1.


Resveratrol Caloric restriction Tissue repair SIRT1 Skin Collagen 



The authors are grateful to the students Amanda Tomazella, Bruna Assunção Bechtold, Leandro de Souza Rodrigues, and Rafaela Bresciani Rossi, who were responsible for the care of the animals and the collection of tissues on the day of euthanasia.


This work was supported by the PROPesq-Uniararas (Pesquisa Institucional Uniararas).

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.

Ethical approval

All the surgical and experimental procedures employed in this study were performed according to the norms established by the Brazilian College of Animal Experimentation (COBEA) and were approved by the Animal Use Ethics Committee (CEUA) of UNIARARAS (protocol number 023/2014) and conducted according with the Guide for the Care and Use of Laboratory Animals [16].


  1. 1.
    Aksenov MY, Markesbery WR (2001) Changes in thiol content and expression of glutathione redox system genes in the hippocampus and cerebellum in Alzheimer’s disease. Neurosci Lett 302:141–145CrossRefGoogle Scholar
  2. 2.
    Bai XZ, Liu JQ, Yang LL et al (2016) Identification of sirtuin 1 as a promising therapeutic target for hypertrophic scars. Br J Pharmacol 173:1589–1601CrossRefGoogle Scholar
  3. 3.
    Barger JL, Kayo T, Vann JM et al (2008) A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One 3(6):e2264CrossRefGoogle Scholar
  4. 4.
    Bashmakov YK, Assaad-Khalil S, Petyaev IM (2011) Resveratrol may be beneficial in treatment of diabetic foot syndrome. Med Hypotheses 77:364–367CrossRefGoogle Scholar
  5. 5.
    Baxter RA (2008) Anti-aging properties of resveratrol: review and report of a potent new antioxidant skin care formulation. J Cosmet Dermatol 7:2–7CrossRefGoogle Scholar
  6. 6.
    Casarin RC, Casati MZ, Pimentel SP (2014) Resveratrol improves bone repair by modulation of bone morphogenetic proteins and osteopontin gene expression in rats. Int J Oral Maxillofac Surg 43:900–906CrossRefGoogle Scholar
  7. 7.
    Chang HC, Guarente L (2014) SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab 25:138–145CrossRefGoogle Scholar
  8. 8.
    Chen Y, Tseng S-H (2007) Pro- and anti-angiogenesis effects of resveratrol. Vivo 21:365–370Google Scholar
  9. 9.
    Chung JH, Manganiello V, Dyck JR (2012) Resveratrol as a calorie restriction mimetic: therapeutic implications. Trends Cell Biol 22:546–554CrossRefGoogle Scholar
  10. 10.
    Feito MJ, Lozano RM, Alcaide M (2011) Immobilization and bioactivity evaluation of FGF-1 and FGF-2 on powdered silicon-doped hydroxyapatite and their scaffolds for bone tissue engineering. J Mater Sci Mater Med 22:405–416CrossRefGoogle Scholar
  11. 11.
    Gurtner GC, Werner S, Barrandon Y et al (2008) Wound repair and regeneration. Nature 15:314–321CrossRefGoogle Scholar
  12. 12.
    Harrison DE, Archer JR (1987) Genetic differences in effects of food restriction on aging in mice. J Nutr 117:376–382CrossRefGoogle Scholar
  13. 13.
    Hubbard BP, Sinclair DA et al (2014) Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol Sci 35:146–154CrossRefGoogle Scholar
  14. 14.
    Hunt ND, Li GD, Zhu M et al (2012) Effect of calorie restriction and refeeding on skin wound healing in the rat. Age (Dordr) 34:1453–1458CrossRefGoogle Scholar
  15. 15.
    Ikeda K, Torigoe T, Matsumoto Y et al (2013) Resveratrol inhibits fibrogenesis and induces apoptosis in keloid fibroblasts. Wound Repair Regen 21:616–623CrossRefGoogle Scholar
  16. 16.
    Institute for Laboratory Animal Research (2011) Guide for the care, and use of laboratory animals. National Academies Press, Washington, DCGoogle Scholar
  17. 17.
    Jung SB, Kim CS, Kim YR et al (2013) Redox factor-1 activates endothelial SIRTUIN1 through reduction of conserved cysteine sulfhydryls in its deacetylase domain. PLoS One 8:e65415CrossRefGoogle Scholar
  18. 18.
    Kasanen IH, Inhilä KJ, Vainio OM et al (2009) The diet board: welfare impacts of a novel method of dietary restriction in laboratory rats. Lab Anim 43:215–223CrossRefGoogle Scholar
  19. 19.
    Kavalukas SL, Barbul A (2011) Nutrition and wound healing: an update. Plast Reconstr Surg 127:38S–43SCrossRefGoogle Scholar
  20. 20.
    Klingberg F, Hinz B, White ES (2013) The myofibroblast matrix: implications for tissue repair and fibrosis. J Pathol 229:298–309CrossRefGoogle Scholar
  21. 21.
    Kohen R, Nyska A (2002) Oxidation of biological systems: oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification. Toxicol Pathol 30:620–650CrossRefGoogle Scholar
  22. 22.
    Maepa M, Razwinani M, Motaung S (2016) Effects of resveratrol on collagen type II protein in the superficial and middle zone chondrocytes of porcine articular cartilage. J Ethnopharmacol 3:25–33CrossRefGoogle Scholar
  23. 23.
    Malfatti CR, Dos Santos FS, Wouk J et al (2017) Intracerebro ventricular administration of the (1 → 6)-β-d-glucan (lasiodiplodan) in male rats prevents d-penicillamine-induced behavioral alterations and lipoperoxidation in the cortex. Pharm Biol 55:1289–1294CrossRefGoogle Scholar
  24. 24.
    Ndiaye M, Philippe C, Mukhtar H et al (2011) The grape antioxidant resveratrol for skin disorders: promise, prospects, and challenges. Arch Biochem Biophys 15:164–170CrossRefGoogle Scholar
  25. 25.
    Ni D, Xu P, Gallagher S (2016) Immunoblotting and immunodetection. Curr Protoc Immunol 114:8.10.1–8.10.36CrossRefGoogle Scholar
  26. 26.
    Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358CrossRefGoogle Scholar
  27. 27.
    Ozaki M, Nakamura M, Teraoka S et al (1997) Ebselen, a novel anti-oxidant compound, protects the rat liver from ischemia–reperfusion injury. Transplant Int 10:96–102CrossRefGoogle Scholar
  28. 28.
    Pearson KJ, Baur JA, Lewis KN et al (2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 8:157–168CrossRefGoogle Scholar
  29. 29.
    Polonini HC, Soldati PP, de Almeida PA et al (2015) Permeation profiles of resveratrol cream delivered through porcine vaginal mucosa: evaluation of different HPLC stationary phases. J Chromatogr B Anal Technol Biomed Life Sci 1002:8–12CrossRefGoogle Scholar
  30. 30.
    Qiang L, Sample A, Liu H et al (2017) Epidermal SIRT1 regulates inflammation, cell migration, and wound healing. Sci Rep 26:14110CrossRefGoogle Scholar
  31. 31.
    Reed MJ, Penn PE, Li Y et al Vernon RB, Johnson TS, Pendergrass WR, Sage EH, Abrass IB, Wolf NS (1996) Enhanced cell proliferation and biosynthesis mediate improved wound repair in refed, caloric-restricted mice. Mech Ageing Dev 31:21–43CrossRefGoogle Scholar
  32. 32.
    Reiser K, McGee C, Rucker R et al (1995) Effects of aging and caloric restriction on extracellular matrix biosynthesis in a model of injury repair in rats. J Gerontol A Biol Sci Med Sci 50a:B40–B47CrossRefGoogle Scholar
  33. 33.
    Rich L, Whittaker P (2005) Collagen and Picrosirius Red staining: a polarized light assessment of fibrillar hue and spatial distribution. J Morphol Sci 22:97–104Google Scholar
  34. 34.
    Roth GS, Kowatch MA, Hengemihle J et al (1997) Effect of age and caloric restriction on cutaneous wound closure in rats and monkeys. J Gerontol Biol Sci 52:B98–B102CrossRefGoogle Scholar
  35. 35.
    Sell DR, Lane MA, Obrenovich ME et al (2003) The effect of caloric restriction on glycation and glycoxidation in skin collagen of nonhuman primates. J Gerontol A Biol Sci Med Sci 58:508–516CrossRefGoogle Scholar
  36. 36.
    Simic P, Williams EO, Bell EL et al (2013) SIRT1 suppresses the epithelial-to-mesenchymal transition in cancer metastasis and organ fibrosis. Cell Rep 3:1175–1186CrossRefGoogle Scholar
  37. 37.
    Smith JJ, Kenney RD, Gagne DJ (2009) Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo. BMC Syst Biol 3:31CrossRefGoogle Scholar
  38. 38.
    Spanheimer R, Zlatev T, Umpierrez G et al (1991) Collagen production in fasted and food-restricted rats: response to duration and severity of food deprivation. J Nutr 121:518–524CrossRefGoogle Scholar
  39. 39.
    Stankovic M, Mladenovic D, Ninkovic M et al (2013) Effects of caloric restriction on oxidative stress parameters. Gen Physiol Biophys 32:277–283CrossRefGoogle Scholar
  40. 40.
    Sugino H, Hashimoto I, Tanaka Y (2014) Relation between the serum albumin level and nutrition supply in patients with pressure ulcers: retrospective study in an acute care setting. J Med Investig 61:15–21CrossRefGoogle Scholar
  41. 41.
    Sung JS, Demple B (2006) Roles of base excision repair subpathways in correcting oxidized abasic sites in DNA. FEBS J 273:1620–1629CrossRefGoogle Scholar
  42. 42.
    Thakur S, Dhiman M, Tell G (2015) A review on protein–protein interaction network of APE1/Ref-1 and its associated biological functions. Cell Biochem Funct 33:101–112CrossRefGoogle Scholar
  43. 43.
    Todorovic V (2002) Food and wounds: nutritional factors in wound formation and healing. Br J Community Nurs 7:43–44, 46, 48CrossRefGoogle Scholar
  44. 44.
    Vilhena MIM, Correa-Da-Silva MV, Arruda AC et al (2016) Measuring the antioxidant capacity induced by reduced thiols in human erythrocytes using SW-voltammetry. Int J Electrochem Sci 11:6453–6465CrossRefGoogle Scholar
  45. 45.
    Xia J, Wu X, Yang Y et al (2012) SIRT1 deacetylates RFX5 and antagonizes repression of collagen type I (COL1A2) transcription in smooth muscle cells. Biochem Biophys Res Commun 428:264–270CrossRefGoogle Scholar
  46. 46.
    Yaman I, Derici H, Kara C et al (2013) Effects of resveratrol on incisional wound healing in rats. Surg Today 43:1433–1438CrossRefGoogle Scholar
  47. 47.
    Zeng G, Zhong F, Li J et al (2013) Resveratrol-mediated reduction of collagen by inhibiting proliferation and producing apoptosis in human hypertrophic scar fibroblasts. Biosci Biotechnol Biochem 77:2389–2396CrossRefGoogle Scholar
  48. 48.
    Zhao P, Sui BD, Liu N et al (2017) Anti-aging pharmacology in cutaneous wound healing: effects of metformin, resveratrol, and rapamycin by local application. Aging Cell 16:1083–1093CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Ana Cristina Christovam
    • 1
  • Viviane Theodoro
    • 1
  • Fernanda Aparecida Sampaio Mendonça
    • 1
  • Marcelo Augusto Marretto Esquisatto
    • 1
  • Gláucia Maria Tech dos Santos
    • 1
  • Maria Esméria Corezola do Amaral
    • 1
    Email author
  1. 1.Graduate Program in Biomedical SciencesCentro Universitário da Fundação Hermínio Ometto, FHOArarasBrazil

Personalised recommendations