Metformin reverses the effects of high glucose on human dermal fibroblasts of aged skin via downregulating RELA/p65 expression


Soydas T., Sayitoglu M., Sarac E. Y., Cinar S., Solakoglu S., Tiryaki T., ...More

JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY, vol.77, no.3, pp.443-450, 2021 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 77 Issue: 3
  • Publication Date: 2021
  • Doi Number: 10.1007/s13105-021-00823-y
  • Journal Name: JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CAB Abstracts, EMBASE, Food Science & Technology Abstracts, MEDLINE, Veterinary Science Database, DIALNET
  • Page Numbers: pp.443-450
  • Keywords: Aging, Apoptosis, Collagen, Human primary dermal fibroblasts, Metformin, NF-kB, NF-KAPPA-B, TRANSCRIPTION, MECHANISMS, SENESCENCE, STRESS
  • Istanbul University Affiliated: Yes

Abstract

Metformin has been successfully used as an anti-aging agent but exact molecular mechanisms of metformin in anti-aging remain unknown. Hyperglycemia during skin aging not only causes oxidative damage to cellular macromolecules, like dermal collagen, but also modulates the activation of transcription factor nuclear factor kappa B (NF-kB). We aimed to investigate in vitro effects of high glucose (HG) and metformin treatment on proliferation and apoptosis of human primary dermal fibroblasts (HDFs), and the expression of COL1A1, COL3A1, and RELA/p65 genes. Effects of normal glucose (5.5 mM) and HG concentration (50 mM HG) on HDFs, with two doses of metformin (50 mu M and 500 mu M), were investigated by immunostaining. Apoptotic levels were analyzed by flow cytometry. Expression of COL1A1, COL3A1, and RELA/p65 genes was measured by quantitative real-time PCR. The proliferation of HDFs was decreased significantly (P < 0.01) and expression of COL1A1 was downregulated by HG without metformin, whereas proliferation was elevated and expression was upregulated with 500 mu M metformin + HG compared to 5.5 mM glucose (P < 0.05). The expression of COL3A1 and RELA/p65 were upregulated (P < 0.01 for COL3A1), and percentage of late apoptotic cells increased significantly by HG without metformin (P < 0.001) while it decreased in two concentrations of metformin dramatically compared with 5.5 mM glucose (P < 0.01 for expressions and < 0.001 for apoptosis). Metformin not only significantly downregulated RELA/p65 expression, but also inhibited the apoptosis of HDFs from aged human skin at toxic glucose concentrations which could be inversely mediated via COL1A1 and COL3A1 expression.