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

• Published in: Journal of physiology and biochemistry Vol. 77; no. 3; pp. 443 - 450
• Main Authors: Soydas, Tugba, Sayitoglu, Muge, Sarac, Elif Yaprak, Cınar, Suzan, Solakoglu, Seyhun, Tiryaki, Tunc, Sultuybek, Gonul Kanıgur
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.08.2021; Springer Nature B.V
• Subjects: Aging; Animal Physiology; Apoptosis; Biomedical and Life Sciences; Biomedicine; Collagen; Collagen (type I); Fibroblasts; Flow cytometry; Genes; Glucose; Human Physiology; Hyperglycemia; Macromolecules; Metformin; Molecular modelling; NF-κB protein; Original Article; RelA protein; Skin; Transcription activation; Aging; Metformin; Human primary dermal fibroblasts; Collagen; NF-kB; Apoptosis
• ISSN: 1138-7548; 1877-8755
• DOI: 10.1007/s13105-021-00823-y

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 μM and 500 μM), 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 μM 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.