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• W2396749350 abstract "Systemic sclerosis is a chronic autoimmune disease characterized by fibroblast activation and myofibroblast differentiation, leading to excessive accumulation of collagen and fibrosis of skin and internal organs (Ho et al., 2014Ho Y.Y. Lagares D. Tager A.M. Kapoor M. Fibrosis—a lethal component of systemic sclerosis.Nat Rev Rheumatol. 2014; 10: 390-402Crossref PubMed Scopus (213) Google Scholar). Metformin is a widely used antidiabetic medication whose mechanism of action is mainly attributed to a transient inhibition of the mitochondrial respiratory-chain complex 1. Recently, novel pleiotropic effects of this molecule have been disclosed, in particular its antiproliferative (Evans et al., 2005Evans J.M. Donnelly L.A. Emslie-Smith A.M. Alessi D.R. Morris A.D. Metformin and reduced risk of cancer in diabetic patients.BMJ. 2005; 330: 1304-1305Crossref PubMed Scopus (1860) Google Scholar), immunomodulating (Lee et al., 2015Lee S.Y. Lee S.H. Yang E.J. Kim E.K. Kim J.K. Shin D.Y. et al.Metformin ameliorates inflammatory bowel disease by suppression of the STAT3 signaling pathway and regulation of the between Th17/Treg balance.PLoS One. 2015; 10: e0135858PubMed Google Scholar, Son et al., 2014Son H.J. Lee J. Lee S.Y. Kim E.K. Park M.J. Kim K.W. et al.Metformin attenuates experimental autoimmune arthritis through reciprocal regulation of Th17/Treg balance and osteoclastogenesis.Mediators Inflamm. 2014; 2014: 973986Crossref PubMed Scopus (153) Google Scholar), and antifibrotic (Cavaglieri et al., 2015Cavaglieri R.C. Day R.T. Feliers D. Abboud H.E. Metformin prevents renal interstitial fibrosis in mice with unilateral ureteral obstruction.Mol Cell Endocrinol. 2015; 412: 116-122Crossref PubMed Scopus (54) Google Scholar, Tripathi et al., 2015Tripathi D.M. Erice E. Lafoz E. Garcia-Caldero H. Sarin S.K. Bosch J. et al.Metformin reduces hepatic resistance and portal pressure in cirrhotic rats.Am J Physiol Gastrointest Liver Physiol. 2015; 309: G301-G309Crossref PubMed Scopus (32) Google Scholar) activity. In this preliminary study, we aimed to evaluate the effect of metformin in a mouse model of skin fibrosis. For this purpose, 6-week-old C3H mice (The Jackson Laboratory, USA) were bred and maintained at the animal care facility, University of Catanzaro (Italy). All experimental procedures were approved by local animal care committee and conducted according to the Italian guidelines for care and use of laboratory animals. The bleomycin-induced fibrosis model described by Yamamoto et al., 1999Yamamoto T. Takagawa S. Katayama I. Yamazaki K. Hamazaki Y. Shinkai H. et al.Animal model of sclerotic skin: I. Local injections of bleomycin induce sclerotic skin mimicking scleroderma.J Invest Dermatol. 1999; 112: 456-462Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar was used. Briefly, 100 μl of bleomycin dissolved in 0.9% NaCl at a concentration of 0.5 mg/ml was administered every day subcutaneously on the upper back for 21 days. Injection of 100 μl 0.9% NaCl was used as control. Metformin was administered orally dissolved in drinking water at a dose of 250 mg/kg/day, equivalent to a human dose of 20.3 mg/kg or 1,216 mg/day for an average adult human, within the safe therapeutic range commonly used. Female C3H mice were divided into five groups, each composed of 10 mice: (i) treated with NaCl (group A; control); (ii) bleomycin plus tap water (group B); (iii) bleomycin plus metformin for 21 days starting contemporarily (group C). Mice in these three groups were killed after 21 days. The last two groups (post-bleomycin) were designed to study the possibility that metformin would reverse bleomycin effects. Therefore, bleomycin was administered per protocol for 21 days and then mice were started on oral metformin for further 21 days (group E) or remained on tap water (negative control, group D) without any further bleomycin administration. After treatment, lesional skin sections were stained with hematoxylin and eosin and dermal thickness was measured at ×100 magnification at five different sites from each mouse. Total collagen content was evaluated with a commercially available assay based on hydroxyproline detection (QuickZyme Biosciences, Leiden, The Netherlands). Collagen content of skin sections was also evaluated with Masson’s trichrome stain (TCS) with aniline blue (Bio-Optica, Milan, Italy). The percentage (%) of blue stained area was calculated with the software ImageJ v1.50e after color deconvolution and automated thresholding. Myofibroblasts in skin sections were identified by staining for α-smooth muscle actin. Antigen retrieval was performed at 96 °C (10 mM/l citrate buffer, pH 6) for 30 minutes. Sections were incubated with the primary antibody smooth muscle actin (B4) 1:300 (Santa Cruz, Dallas, TX) for 50 minutes at room temperature. Immunoreactions were revealed by a Bond Polymer Refine Detection Kit according to the manufacturer's procedure (Leica Microsystems, Milan, Italy). Diaminobenzidine (Leica Microsystems) was used as a chromogenic substrate. The number of α-smooth muscle actin positive cells for microscopic field was determined at ×400 magnification in five different sections from each mouse by two blinded examiners. Bleomycin administration effectively induced skin thickening in treated mice versus NaCl controls (302 ± 58 μm [group B] vs. 191 ± 41.5 μm [group A], P < 0.0001). Notwithstanding, in comparison with bleomycin controls, treatment with metformin attenuated bleomycin-induced skin thickening after both concurrent administration (−59% skin thickening in group C vs. group B, P < 0.0001) and post-bleomycin administration (−64% skin thickening in group E vs. group D, P < 0.0001) (Figure 1a and b). Similarly, bleomycin administration increased collagen content as expressed by hydroxyproline assay (+376% of control thickness) and TCS blue-stained area (30.1 ± 4.2% [group B] vs. 14.2 ± 1.1% [group A], P = 0.008) in treated mice versus NaCl controls. Metformin treatment significantly attenuated collagen accumulation in bleomycin-treated skin samples, as demonstrated by a significant reduction in hydroxyproline content (61% mean reduction, P = 0.02, Figure 2c) and the percentage of blue-stained area after MTS (13.6 ± 1.0% [group C] vs. 30.1 ± 4.2% [group B], P = 0.003, Figure 2a and b). Similar findings were observed using the post-bleomycin approach for both hydroxyproline content (58% mean reduction, P = 0.05, Figure 2c) and MTS (16.0 ± 1.0% [group E] vs. 19.7 ± 1.1% [group D], P = 0.03, Figure 2a and b). The reduction in skin thickness and collagen content was accompanied by a significant reduction in the number of lesional myofibroblasts, as detected by α-smooth muscle actin staining, when metformin was administered concurrently (2.3 ± 0.2 [group C] vs. 8.2 ± 1.2 [group B], P < 0.0001, Figure 2d) or post-bleomycin (2.2 ± 0.6 [group E] vs. 8.3 ± 0.6 [group D], P < 0.0001, Figure 2d). The bleomycin-induced fibrosis is a widely used model of scleroderma and other fibrosing skin diseases, specially suitable to explore collagen accumulation and inflammatory changes occurring early during the course of the disease (Beyer et al., 2010Beyer C. Schett G. Distler O. Distler J.H. Animal models of systemic sclerosis: prospects and limitations.Arthritis Rheum. 2010; 62: 2831-2844Crossref PubMed Scopus (126) Google Scholar). Our preliminary data support the hypothesis that metformin could ameliorate skin involvement in bleomycin-induced fibrosis as demonstrated by a significant reduction in skin thickening and collagen accumulation in both disease models. This phenomenon was accompanied by a significant reduction in infiltrating myofibroblasts, which, under the influence of transforming growth factor-β, play a pivotal role in the pathogenesis of skin fibrosis (Kawakami et al., 1998Kawakami T. Ihn H. Xu W. Smith E. LeRoy C. Trojanowska M. Increased expression of TGF-beta receptors by scleroderma fibroblasts: evidence for contribution of autocrine TGF-beta signaling to scleroderma phenotype.J Invest Dermatol. 1998; 110: 47-51Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). This finding is consistent with the recent literature, in which oral metformin has been shown to inhibit transforming growth factor-β-induced fibrosis (Li et al., 2015Li L. Huang W. Li K. Zhang K. Lin C. Han R. et al.Metformin attenuates gefitinib-induced exacerbation of pulmonary fibrosis by inhibition of TGF-beta signaling pathway.Oncotarget. 2015; 6: 43605-43619Crossref PubMed Scopus (71) Google Scholar, Lu et al., 2015Lu J. Shi J. Li M. Gui B. Fu R. Yao G. et al.Activation of AMPK by metformin inhibits TGF-beta-induced collagen production in mouse renal fibroblasts.Life Sci. 2015; 127: 59-65Crossref PubMed Scopus (80) Google Scholar, Park et al., 2014Park I.H. Um J.Y. Hong S.M. Cho J.S. Lee S.H. Lee H.M. et al.Metformin reduces TGF-beta1-induced extracellular matrix production in nasal polyp-derived fibroblasts.Otolaryngol Head Neck Surg. 2014; 150: 148-153Crossref PubMed Scopus (26) Google Scholar, Soraya et al., 2015Soraya H. Rameshrad M. Mokarizadeh A. Garjani A. Metformin attenuates myocardial remodeling and neutrophil recruitment after myocardial infarction in rat.Bioimpacts. 2015; 5: 3-8Crossref PubMed Scopus (28) Google Scholar, Xiao et al., 2010Xiao H. Ma X. Feng W. Fu Y. Lu Z. Xu M. et al.Metformin attenuates cardiac fibrosis by inhibiting the TGFbeta1-Smad3 signalling pathway.Cardiovasc Res. 2010; 87: 504-513Crossref PubMed Scopus (174) Google Scholar) and myofibroblast differentiation (Bai et al., 2013Bai J. Zhang N. Hua Y. Wang B. Ling L. Ferro A. et al.Metformin inhibits angiotensin II-induced differentiation of cardiac fibroblasts into myofibroblasts.PLoS One. 2013; 8: e72120Crossref PubMed Scopus (53) Google Scholar) in different disease models and cell lines. In conclusion, our data, although preliminary, support a potential role of metformin as a fibrosis-alleviating agent in skin diseases such as scleroderma. Further studies are needed to investigate the exact mechanisms and to evaluate the possibility of performing clinical trials on patients with scleroderma, considering the favorable adverse event profile of this molecule. The authors state no conflict of interest. This study was conducted with funding from Italian Ministry of Health (PRIN 2010JCWWKM_002)." @default.
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• W2396749350 date "2016-09-01" @default.
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• W2396749350 title "Oral Metformin Ameliorates Bleomycin-Induced Skin Fibrosis" @default.
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