Levels of total, apoptotic and necrotic cells death markers for diagnosis of advanced fibrosis (F≥3) in 143 alcoholic patients.

<p>The area under the ROC curves are shown for the performance of the total (CK18 total), apoptotic (CK18 fragment) and necrotic (CK18 total-fragment) cell death markers for predicting advanced fibrosis (F≥3).</p

Correlation between hepatic TGFβ, TNFα and Fas-L gene expression and circulating levels of total, apoptotic and necrotic cell death markers in 24 alcoholic patients.

<p>The correlation between the expression levels of TGFβ, TNFα and Fas-L mRNA (ΔCt) and circulating levels of biomarkers was analyzed using the Spearman's rank correlation test.</p

Characteristics of Serum and Gene groups.

<p>Data are expressed as Median (25th, 75th percentile) or %. AST: aspartate amino-tranferase; ALT: alanine amino-transferase; γGT: Gamma Glutamyl Transpeptidase.</p

Correlation between circulating levels of total, apoptotic and necrotic cell death markers and hepatic inflammation, Mallory-Denk bodies, ballooning and fibrosis in 143 alcoholic patients.

<p>Spearman's rank correlation test.</p

Total, apoptotic and necrotic cell death marker levels for prediction of severe fibrosis (F≥3) (n = 143).

<p>PPV: Positive Predictive value, NPV: Negative Predictive value; Prev: Prevalence.</p

Univariate analysis of the 143 alcoholic patients according to the severity of liver disease.

<p>Patients were classified as Fibrosis (F) <3 or ≥3. Quantitative results are expressed as means ± standard deviations. AST: aspartate amino-tranferase; ALT: alanine amino-transferase; γGT: Gamma Glutamyl Transpeptidase.</p

Elevated serum levels of total, apoptotic and necrotic cell death markers in patients with hepatic inflammation and advanced fibrosis.

<p>The serum of 143 alcoholic patients were used to evaluate the circulating levels of total CK18 (M65® ELISA) and the caspases-generated CK18 fragment (M30 Apoptosense® ELISA). Results were expressed as median (25^th, 75^th percentile) in function to: (A) hepatic inflammation (A1) and (B) advanced fibrosis (F3/4).</p

Glucose metabolism is altered in transgenic <i>Fgfr3</i>^<i>ach/+</i> mice and restored with sFGFR3 treatment.

<p>Fasting glycemia and insulinemia of mice following 10 weeks of (<b>A</b>) ND or (<b>B</b>) HFD. (<b>C</b>) glucose tolerance test; glucose levels were normalized to the value of time -15 min and area under the curve corresponding to each group of mice. (<b>D</b>) Mice pancreas insulin content (immunohistochemistry of paraffin-embedded sections, red: insulin; green: glucose; blue: DAPI staining), mean of pancreas islets normalized to total surface and mean of islets number in each group under HFD condition. (<b>E</b>) Liver H&E and PAS staining under HFD condition. (<b>F</b>) H&E staining of hepatic nodules. Data are represented as mean ± SD (n = 8–10 mice to each group). Data followed normal distribution. **<i>p</i><0.01, ***<i>p</i><0.001 versus vehicle-treated WT, ^#<i>p</i><0.05, ^##<i>p</i><0.01 versus vehicle-treated <i>Fgfr3</i>^<i>ach/+</i>; Student’s <i>t</i> test.</p

MSCs isolated from untreated or sFGFR3-treated <i>Fgfr3</i>^<i>ach/+</i> mice show pre-engagement towards adipogenesis with no alteration of the insulin response compared to WT mice.

<p><b>(A)</b> Expression of genes involved in different steps of adipogenesis differentiation (Genes are listed in <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0195876#pone.0195876.s005" target="_blank">S2 Table</a></b>). Expression was normalized to HPRT, RPL6 and RPL13a expression and expressed as percent of change compared to WT. (<b>B</b>) Cells were stimulated with 50nM of insulin for 0, 5, 15 or 30 min or with 0, 1, 10, 50 or 100nM of insulin during 5 min. P-Erk1/2 expression, normalized to Erk1/2 total expression, was expressed as normalized value to WT. Data are represented as mean ± SD. Data followed normal distribution. *<i>p</i><0.05, **<i>p</i><0.01, ***<i>p</i><0.001 versus vehicle-treated WT, ^#<i>p</i><0.05, ^##<i>p</i><0.01 versus vehicle-treated <i>Fgfr3</i>^<i>ach/+</i>; Two-way ANOVA with Tukey’s multiple test.</p

Transgenic <i>Fgfr3</i>^<i>ach/+</i> mice preferentially develop visceral obesity that is prevented upon sFGFR3 treatment.

<p>(<b>A</b>), body weight of vehicle-treated WT and <i>Fgfr3</i>^<i>ach/+</i> mice and sFGFR3 treated <i>Fgfr3</i>^<i>ach/+</i> mice after 10 weeks of ND or HFD challenge. (<b>B</b>), abdominal lean:fat ratio. (<b>C</b>) epididymal adipose tissue (eAT) weight and (<b>D</b>) subcutaneous adipose tissue (scAT) weight per g of body weight. (<b>E</b>) scAT and (<b>F</b>) eAT adipocyte area (μm²). (<b>G</b>) scAT and (<b>H</b>) eAT scattering of adipocytes according to their diameter. Data are represented as mean ± SD (n = 8–10 mice to each group). Data followed normal distribution. *<i>p</i><0.05, **<i>p</i><0.01, ***<i>p</i><0.001 versus vehicle-treated WT, ^#<i>p</i><0.05, ^##<i>p</i><0.01 versus vehicle-treated <i>Fgfr3</i>^<i>ach/+</i>; Student’s <i>t</i> test.</p