Weanling pigs, with an underdeveloped intestine and immature immune system, are usually subjected to depressed feed intake, <em>growth</em> retardation, and postweaning diarrhea. The aim of this study was to determine 1) the <em>growth</em> response of weaned pigs to supplemental tributyrin (TB) and 2) the potential effects and mechanisms of TB in modulating immune responses of lipopolysaccharide (LPS)-challenged piglets. A total of 240 piglets (Duroc × Large White × Landrace) were weaned at 21 d of age to a control (basal diet), supplemented with antibiotics (AB; +AB), supplemented with TB (+TB), or with supplemental AB and TB (+AB+TB) diets, with 10 replicate pens (6 piglets/pen) per diet. At 49 d of age, male pigs from the control and +TB groups were intraperitoneally injected with LPS (25 μg/kg BW) or saline ( = 6) and sacrificed at 4 h after injection to collect blood, intestine, and digesta samples for biochemical analysis. There were higher ( < 0.05) feed intake and lower ( < 0.05) percentage of negative <em>growth</em> piglets in the +TB groups than in the control group during the first week after weaning. For piglets without LPS challenge, there were higher ( < 0.05) ileal <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> () mRNA abundance and total bile acid concentrations in the +TB groups than in the control group, whereas downregulated ( < 0.05) expression was observed in the +TB groups after LPS challenge. Lipopolysaccharide challenge in the control group increased ( < 0.05) plasma tumor necrosis <em>factor</em> α and IL-6 concentrations and colonic amount and decreased ( < 0.05) colonic goblet cells and colonic and cecal acetate concentrations, with no differences (>> 0.05) observed between +TB groups following LPS challenge. Taken together, dietary supplementation with TB prevented <em>growth</em> retardation through stimulating the appetite of weaned pigs and protected piglets against lethal infection via modulation of inflammatory cytokines production, ileal expression, and intestinal acetate fermentation.

<em>Fibroblast</em> <em>growth</em> <em>factor</em> (FGF) <em>19</em> is a member of the FGF15/<em>19</em> subfamily of FGFs that includes FGF15/<em>19</em>, FGF21, and FGF23. FGF<em>19</em> has been shown to have profound effects on liver metabolism and regeneration. FGF<em>19</em> binds to FGFR4 and its coreceptor β-Klotho to activate intracellular kinases, including Erk1/2. Studies have shown that proinflammatory cytokines such as TNFα impair FGF21 signaling in adipose cells by repressing β-Klotho expression. However, little is known about the effects of inflammation on the FGF<em>19</em> pathway in the liver. In the present study, we found that lipopolysaccharide (LPS) inhibited β-Klotho and Fgfr4 expression in livers in mice, whereas LPS had no effects on the two FGF<em>19</em> receptors in Huh-7 and HepG2 cells. Of the three inflammatory cytokines TNFα, IL-1β, and IL-6, IL-1β drastically inhibited β-Klotho expression, whereas TNFα and IL-6 had no or minor effects. None of the three cytokines had any effects on FGFR4 expression. IL-1β directly inhibited β-Klotho transcription, and this inhibition required both the JNK and NF-κB pathways. In addition, IL-1β inhibited FGF<em>19</em>-induced Erk1/2 activation and cell proliferation. These results suggest that inflammation and IL-1β play an important role in regulating FGF<em>19</em> signaling and function in the liver.

Bile acid synthesis plays a key role in regulating whole body cholesterol homeostasis. Transcriptional <em>factor</em> EB (TFEB) is a nutrient and stress-sensing transcriptional <em>factor</em> that promotes lysosomal biogenesis. Here we report a role of TFEB in regulating hepatic bile acid synthesis. We show that TFEB induces cholesterol 7α-hydroxylase (CYP7A1) in human hepatocytes and mouse livers and prevents hepatic cholesterol accumulation and hypercholesterolemia in Western diet-fed mice. Furthermore, we find that cholesterol-induced lysosomal stress feed-forward activates TFEB via promoting TFEB nuclear translocation, while bile acid-induced <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>), acting via mTOR/ERK signaling and TFEB phosphorylation, feedback inhibits TFEB nuclear translocation in hepatocytes. Consistently, blocking intestinal bile acid uptake by an apical sodium-bile acid transporter (ASBT) inhibitor decreases ileal FGF15, enhances hepatic TFEB nuclear localization and improves cholesterol homeostasis in Western diet-fed mice. This study has identified a TFEB-mediated gut-liver signaling axis that regulates hepatic cholesterol and bile acid homeostasis.

<AbstractText>Disruption of bile acid (BA) homeostasis plays a key role in intestinal inflammation. The gut-liver axis is the main site for the regulation of BA synthesis and BA pool size via the combined action of the nuclear Farnesoid X Receptor (FXR) and the enterokine <em>Fibroblast</em> <em>Growth</em> <em>Factor</em> <em>19</em> (FGF<em>19</em>). Increasing evidence have linked derangement of BA metabolism with dysbiosis and mucosal inflammation. Thus, here we aimed to investigate the potential action of an FGF<em>19</em> analogue on intestinal microbiota and inflammation.</AbstractText><p><div><b>METHODS</b></div>A novel engineered non-tumorigenic variant of the FGF<em>19</em> protein, M52-WO 2016/01682<em>19</em> was generated. WT and FXR^null mice were injected with AAV-FGF<em>19</em>-M52 or the control AAV-GFP and subjected to Sodium Dextran Sulphate-induced colitis.</p><p><div><b>FINDINGS</b></div>FGF<em>19</em>-M52 reduced BA synthesis and pool size, modulated its composition and protected mice from intestinal inflammation. These events were coupled with preservation of the intestinal epithelial barrier integrity, inhibition of inflammatory immune response and modulation of microbiota composition. Interestingly, FGF<em>19</em>-M52-driven systemic and local anti-inflammatory activity was completely abolished in Farnesoid X Receptor (FXR)^null mice, thus underscoring the need of FXR to guarantee enterocytes' fitness and complement FGF<em>19</em> anti-inflammatory activity. To provide a translational perspective, we also show that circulating FGF<em>19</em> levels are reduced in patients with Crohn's disease.</p><AbstractText>Reactivation of the FXR-FGF<em>19</em> axis in a murine model of intestinal inflammation could bona fide provide positive changes in BA metabolism with consequent reduction of intestinal inflammation and modulation of microbiota. These results point to the therapeutic potential of FGF<em>19</em> in the treatment of intestinal inflammation with concomitant derangement of BA homeostasis.</AbstractText><AbstractText>A. Moschetta is funded by MIUR-PRIN 2017 <- 2017J3E2W2; Italian Association for Cancer Research (AIRC, IG 23239); Interreg V-A Greece-Italy 2014-2020-SILVER WELLBEING, MIS5003627; HDHL-INTIMIC EuJPI-FATMAL; MIUR PON "R&I" 2014-2020-ARS01_01220. No money has been paid by NGM Biopharmaceuticals or any other agency to write this article.</AbstractText>

Tropifexor (LJN452) is a potent, orally available, non-bile acid farnesoid X receptor agonist under clinical development for chronic liver diseases. Here, we present results from a first-in-human study of tropifexor following single- and multiple-ascending doses (SAD/MAD) and food effect substudy in healthy volunteers. The SAD study included 6 fasted cohorts receiving 10- to 3000-µg tropifexor or placebo and 1 cohort receiving 300-µg tropifexor with a high-fat meal. The MAD study included 4 lean cohorts receiving 10 to 100 µg and 1 obese cohort receiving 30-µg once-daily doses or placebo for 14 days. Pharmacodynamic assessment of <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> and fasting plasma lipids was performed after dosing. Overall, 95 volunteers received at least 1 tropifexor or placebo dose. Tropifexor was well tolerated up to 3000 µg and 100 µg in the SAD and MAD studies, respectively; however, 2 subjects discontinued the MAD study due to asymptomatic elevation of liver transaminases. At single doses, tropifexor showed a moderate rate of absorption (median time to maximum concentration, 4 hours), dose-proportional increases in exposure, and elimination half-life of 13.5 to 21.9 hours. When taken with food, tropifexor exposure increased by ∼60%. With multiple dosing, steady state was reached on day 4 with <2-fold accumulation. Single and multiple doses showed dose-dependent increases in <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em>. No changes in serum lipids were observed in tropifexor- vs placebo-treated obese subjects. In conclusion, tropifexor was well tolerated, had a pharmacokinetic profile suitable for once-daily dosing and showed dose-dependent target engagement without altering plasma lipids in healthy volunteers.

Ageing, the progressive functional decline of virtually all tissues, affects numerous living organisms. Main phenotypic alterations of human skin during the ageing process include reduced skin thickness and elasticity which are related to extracellular matrix proteins. Dermal <em>fibroblasts</em>, the main source of extracellular fibrillar proteins, exhibit complex alterations during in vivo ageing and any of these are likely to be accompanied or caused by changes in gene expression. We investigated gene expression of short term cultivated in vivo aged human dermal <em>fibroblasts</em> using RNA-seq. Therefore, <em>fibroblast</em> samples derived from unaffected skin were obtained from 30 human donors. The donors were grouped by gender and age (Young: <em>19</em> to 25 years, Middle: 36 to 45 years, Old: 60 to 66 years). Two samples were taken from each donor, one from a sun-exposed and one from a sun-unexposed site. In our data, no consistently changed gene expression associated with donor age can be asserted. Instead, highly correlated expression of a small number of genes associated with transforming <em>growth</em> <em>factor</em> beta signalling was observed. Also, known gene expression alterations of in vivo aged dermal <em>fibroblasts</em> seem to be non-detectable in cultured <em>fibroblasts</em>.

The bile acid (BA)-sensing nuclear receptor, farnesoid X receptor (FXR), regulates postprandial metabolic responses, including inhibition of BA synthesis, by inducing the intestinal hormone, <em>fibroblast</em> <em>growth</em> <em>factor</em> (FGF)15 (FGF<em>19</em> in human). In this study, we tested a novel hypothesis that FXR not only induces intestinal FGF15 but also primes the liver for effectively responding to the signal by transcriptional induction of the obligate coreceptor for FGF15, β-Klotho (βKL). Activation of FXR by a synthetic agonist, GW4064, in mice increased occupancy of FXR and its DNA-binding partner, retinoid X receptor-α, at FGF15-signaling component genes, particularly βKL, and induced expression of these genes. Interestingly, mRNA levels of Fgfr4, the FGF15 receptor, were not increased by GW4064, but protein levels increased as a result of βKL-dependent increased protein stability. Both FGF receptor 4 and βKL protein levels were substantially decreased in FXR-knockout (KO) mice, and FGF<em>19</em> signaling, monitored by phosphorylated ERK, was blunted in FXR-KO mice, FXR-KO mouse hepatocytes, and FXR-down-regulated human hepatocytes. Overexpression of βKL in FXR-lacking hepatocytes partially restored FGF<em>19</em> signaling and inhibition by FGF<em>19</em> of Cyp7a1, which encodes the rate-limiting BA biosynthetic enzyme. In mice, transient inductions of intestinal Fgf15 and hepatic βKL were temporally correlated after GW4064 treatment, and pretreatment of hepatocytes with GW4064 before FGF<em>19</em> treatment enhanced FGF<em>19</em> signaling, which was abolished by transcriptional inhibition or βKL down-regulation. This study identifies FXR as a gut-liver metabolic coordinator for FGF15/<em>19</em> action that orchestrates transient induction of hepatic βKL and intestinal Fgf15/<em>19</em> in a temporally correlated manner.

FGF<em>19</em> (<em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em>), expressed in the small intestine, acts as an enterohepatic hormone by mediating inhibitory effects on the bile acid synthetic pathway and regulating carbohydrate and lipid metabolism. In an attempt to identify novel agents other than bile acids that induce increased FGF<em>19</em> expression, we found that some ER (endoplasmic reticulum) stress inducers were effective. When intestinal epithelial Caco-2 cells were incubated with thapsigargin, marked increases were observed in the mRNA and secreted protein levels of FGF<em>19</em>. This was not associated with the farnesoid X receptor. Reporter gene analyses using the 5'-promoter region of FGF<em>19</em> revealed that a functional AARE (amino-acid-response element) was localized in this region, and this site was responsible for inducing its transcription through ATF4 (activating transcription <em>factor</em> 4), which is activated in response to ER stress. EMSAs (electrophoretic mobility-shift assays) and ChIP (chromatin immunoprecipitation) assays showed that ATF4 bound to this site and enhanced FGF<em>19</em> expression. Overexpression of ATF4 in Caco-2 cells induced increased FGF<em>19</em> mRNA expression, whereas shRNA (short hairpin RNA)-mediated depletion of ATF4 significantly attenuated a thapsigargin-induced increase in FGF<em>19</em> mRNA.

Sterol regulatory element-binding protein-2 (SREBP-2) is a basic helix-loop-helix-leucine zipper transcription <em>factor</em> that positively regulates transcription of target genes involved in cholesterol metabolism. In the present study, we have investigated a possible involvement of SREBP-2 in human intestinal expression of <em>fibroblast</em> <em>growth</em> <em>factor</em> (FGF)<em>19</em>, which is an endocrine hormone involved in the regulation of lipid and glucose metabolism. Overexpression of constitutively active SREBP-2 decreased FGF<em>19</em> mRNA levels in human colon-derived LS174T cells. In reporter assays, active SREBP-2 overexpression suppressed GW4064/FXR-mediated increase in reporter activities in regions containing the IR-1 motif (+848 to +5200) in the FGF<em>19</em> gene. The suppressive effect disappeared in reporter activities in the region containing the IR-1 motif when the mutation was introduced into the IR-1 motif. In electrophoretic mobility shift assays, binding of the FXR/retinoid X receptor α heterodimer to the IR-1 motif was attenuated by adding active SREBP-2, but SREBP-2 binding to the IR-1 motif was not observed. In chromatin immunoprecipitation assays, specific binding of FXR to the IR-1-containing region of the FGF<em>19</em> gene (+3214 to +3404) was increased in LS174T cells by treatment with cholesterol and 25-hydroxycholesterol. Specific binding of SREBP-2 to FXR was observed in glutathione-S-transferase (GST) pull-down assays. These results suggest that SREBP-2 negatively regulates the FXR-mediated transcriptional activation of the FGF<em>19</em> gene in human intestinal cells.

BACKGROUND

Non-alcoholic fatty liver disease (NAFLD) is common both in obese and overweight patients. <em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>), an intestinal hormone, could play a role in the complex pathogenesis of NAFLD. The aim of our study was to investigate responses of FGF<em>19</em> and bile acid (BA) synthesis after a body weight-adjusted oral fat tolerance test (OFTT) in overweight and obese NAFLD patients.

METHODS

For this study, we recruited 26 NAFLD patients; 14 overweight (median BMI 28.3 kg/m2), 12 obese (35.3 kg/m2) and 16 healthy controls (24.2 kg/m2). All individuals received 1 g fat (Calogen®) per kg body weight orally. Serum concentrations of FGF<em>19</em> were determined by ELISA. Concentrations of BAs and BA synthesis marker 7α-hydroxy-4-cholesten-3-one (C4) were measured by gas chromatography-mass spectrometry and high-performance liquid chromatography, respectively; all at 0 (baseline), 2, 4 and 6 h during the OFTT.

RESULTS

BMI correlated negatively with fasting FGF<em>19</em> concentrations (rho = - 0.439, p = 0.004). FGF<em>19</em> levels of obese NAFLD patients were significantly (p = 0.01) lower in the fasting state (median 116.0 vs. 178.5 pg/ml), whereas overweight NAFLD patients had significantly (p = 0.004) lower FGF<em>19</em> concentrations 2 h after the fat load (median 163.0 vs. 244.5 pg/ml), and lowest values at all postprandial time points as compared to controls. Baseline BA concentrations correlated positively with FGF<em>19</em> values (rho = 0.306, p = 0.048). In all groups, we observed BA increases during the OFTT with a peak at 2 h but no change in C4 levels in overweight/obese NAFLD patients.

CONCLUSIONS

Reduced basal gastrointestinal FGF<em>19</em> secretion and decreased postprandial response to oral fat together with blunted effect on BA synthesis indicate alterations in intestinal or hepatic FXR signaling in overweight and obese NAFLD subjects. The precise mechanism of FGF<em>19</em> signaling after oral fat load needs further evaluation.

BACKGROUND

We have registered the trial retrospectively on 30 Jan 2018 at the German clinical trials register ( http://www.drks.de /), and the following number has been assigned DRKS00013942 .

Intestinal fibrosis, caused by an excessive deposition of extracellular matrix components, and subsequent stricture development are a common complication of inflammatory bowel disease. However, currently there are no biomarkers which reliably predict the risk of developing intestinal strictures or identify early stages of fibrosis prior to clinical symptoms. Candidate biomarkers of intestinal fibrosis, including gene variants (i.e. nucleotide-binding oligomerization domain-2 gene), serum microRNAs (miR-<em>19</em>, miR-29), serum extracellular matrix proteins (i.e. collagen, fibronectin) or enzymes (i.e. tissue inhibitor of matrix metalloproteinase-1), serum <em>growth</em> <em>factors</em> (i.e. basic <em>fibroblast</em> <em>growth</em> <em>factor</em>, YKL-40), serum anti-microbial antibodies (i.e. anti-Saccharomyces cerevisiae) and circulating cells (i.e. fibrocytes) have shown conflicting results on relatively heterogeneous patients' cohorts, and none of them was proven to be strictly specific for fibrostenosis, but rather predictive of a disease disabling course. In this review we critically reassess the diagnostic and prognostic value of serum biomarkers of intestinal fibrosis in inflammatory bowel disease.

10-hydroxy-2-decenoic acid (10H2DA) is suggested to be a potential medication for rheumatoid arthritis (RA) by activation of matrix metalloproteinases (MMPs) via mitogen-activated protein kinase signaling pathways. The aim of the present work was to seek differentially expressed proteins in rheumatoid arthritis synovial <em>fibroblasts</em> (RASFs) treated with 10H2DA by comparative proteomics analysis. Two-dimensional electrophoresis (2-DE) and LC-MS/MS were performed to identify changes in protein expression after 24-h 10H2DA treatment. Differentially expressed proteins were identified by real-time PCR and Western blot analysis. Influence of down-regulation of connective tissue <em>growth</em> <em>factor</em> (CTGF) expression on MMPs was studied by RNAi. Ten proteins were up-regulated and 9 proteins were down-regulated after 24-h 10H2DA treatment. A total of <em>19</em> differentially expressed proteins were identified and found to be associated with glycolysis, lipid metabolism, cell adhesion, ATP synthesis, oxidation reduction, and anti-apoptosis. CTGF, a member of the C-terminal cystein-rich proteins (CCN) family, was down-regulated after 24-h 10H2DA treatment. MMPs were down-regulated after RNAi (CTGFi). These results suggest that CTGF is a regulator <em>factor</em> in the expression of MMPs, and 10H2DA down-regulate the concentration of MMPs probably by down-regulating the expression of CTGF.

<AbstractText>The nuclear farnesoid X receptor (FXR) agonist obeticholic acid (OCA) has been developed for the treatment of liver diseases. We aimed to determine whether OCA treatment increases the risk of gallstone formation.</AbstractText><AbstractText>Twenty patients awaiting laparoscopic cholecystectomy were randomized to treatment with OCA (25 mg/day) or placebo for 3 weeks until the day before surgery. Serum bile acids (BAs), the BA synthesis marker C4 (7α-hydroxy-4-cholesten-3-one), and <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) were measured before and after treatment. During surgery, biopsies from the liver and the whole bile-filled gallbladder were collected for analyses of gene expression, biliary lipids and FGF<em>19</em>.</AbstractText><AbstractText>In serum, OCA increased FGF<em>19</em> (from 95.0 ± 8.5 to 234.4 ± 35.6 ng/L) and decreased C4 (from 31.4 ± 22.8 to 2.8 ± 4.0 nmol/L) and endogenous BAs (from 1,312.2 ± 236.2 to 517.7 ± 178.9 nmol/L; all p <0.05). At surgery, BAs in gallbladder bile were lower in patients that received OCA than in controls (OCA, 77.9 ± 53.6 mmol/L; placebo, <em>19</em>6.4 ± 99.3 mmol/L; p <0.01), resulting in a higher cholesterol saturation index (OCA, 2.8 ± 1.1; placebo, 1.8 ± 0.8; p <0.05). In addition, hydrophobic OCA conjugates accounted for 13.6 ± 5.0% of gallbladder BAs after OCA treatment, resulting in a higher hydrophobicity index (OCA, 0.43 ± 0.09; placebo, 0.34 ± 0.07, p <0.05). Gallbladder FGF<em>19</em> levels were 3-fold higher in OCA patients than in controls (OCA, 40.3 ± 16.5 ng/L; placebo, 13.5 ± 13.1 ng/ml; p <0.005). Gene expression analysis indicated that FGF<em>19</em> mainly originated from the gallbladder epithelium.</AbstractText><AbstractText>Our results show for the first time an enrichment of FGF<em>19</em> in human bile after OCA treatment. In accordance with its murine homolog FGF15, FGF<em>19</em> might trigger relaxation and filling of the gallbladder which, in combination with increased cholesterol saturation and BA hydrophobicity, would enhance the risk of gallstone development.</AbstractText><AbstractText>Obeticholic acid increased human gallbladder cholesterol saturation and bile acid hydrophobicity, both decreasing cholesterol solubility in bile. Together with increased hepatobiliary levels of <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em>, our findings suggest that pharmacological activation of the farnesoid X receptor increases the risk of gallstone formation. Clinical trial number: NCT01625026.</AbstractText>

BACKGROUND

The poor glycemic status seems to be an important factor affecting implant complication rates, including peri-implant bone loss.

OBJECTIVE

This trial evaluated the influence of glycemic control of type 2 diabetes mellitus (T2DM) patients on implant stabilization and on the levels of bone markers in peri-implant fluid during the healing.

METHODS

Systemically healthy patients (SH,n = 19), better-controlled T2DM (BCDM,n = 16), and poorly controlled T2DM (PCDM,n = 16) indicated for implant therapy were recruited. The implant stability quotient (ISQ) was determined at implant placement, 3, 6, and 12 months. Levels of transforming growth factor- β (TGF-β), fibroblast growth factor (FGF), osteopontin (OPN), osteocalcin (OC), and osteoprotegerin (OPG) in the peri-implant fluid were quantified at 15 days, and 3, 6, and 12 months, using the Luminex assay.

RESULTS

OPG and OPN levels were higher in SH at 12 months than at15 days (p < .05), whereas OC and TGF-β were lower in PCDM at 12 months compared with the 15-day and 3-month follow-ups, respectively (p < .05). Inter-group analyses showed lower OPN levels in PCDM compared with SH at 12 months (p < .05). The ISQ was higher at 12 months when compared with baseline and 3 months in SH (p < .05), whereas no differences were observed during follow-up in diabetics, regardless of glycemic control (p>> .05). No difference in ISQ was observed among groups over time (p>> .05).

CONCLUSIONS

Poor glycemic control negatively modulated the bone factors during healing, although T2DM, regardless of glycemic status, had no effect on implant stabilization.

OBJECTIVE

Human heparanase is an endo-D-glucuronidase that degrades heparan sulfate/heparin and has been implicated in a variety of biological processes. The objective was to investigate the expression of heparanase (Hps) and basic fibroblast growth factor (bFGF) and their relationship to neoangiogenesis and metastasis of human esophageal carcinoma.

METHODS

Seventy-nine patients who had undergone esophageal resection for esophageal carcinoma without preoperative treatment were included in the present study. Immunohistochemistry was used to study the expression of Hps, bFGF and microvessel density (MVD) in 79 cases of esophageal carcinoma. bFGF and Hps were quantitatively detected with immunohistochemistry in 79 cases of human esophageal carcinoma and 19 cases of adjacent normal human esophageal carcinoma. Cd34 was used to explore the MVD as a marker of endothelial cells.

RESULTS

Hps and bFGF expression in tumor tissue, being remarkably higher than that in normal esophageal tissue, were significantly correlated with clinicopathological features (depth of invasion, lymph-node metastasis and TNM stage) and MVD.

CONCLUSIONS

The results of this study suggest that the coexpression of Hps and bFGF plays a key role in angiogenesis, invasion and metastasis of esophageal carcinoma. Hps and bFGF may serve as a predictor of progression in esophageal carcinoma. The expression of heparanase in esophageal carcinoma enhances growth, invasion, and angiogenesis of the tumor, and bFGF seems to be a potent antigenic factor for esophageal carcinoma.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease of unknown aetiology and cure. Recent studies have reported a dysregulation of exosomal microRNAs (miRs) in the IPF context. However, the impact of IPF-related exosomal miRs on the progression of pulmonary fibrosis is unknown.

<strong class="sub-title"> Methods: </strong> Two independent cohorts were enrolled at the ambulatory care polyclinic of Liège University. Exosomes from sputum were obtained from <em>19</em> patients with IPF and 23 healthy subjects (HSs) (cohort 1), and the ones from plasma derived from 14 patients with IPF and 14 HSs (cohort 2). Exosomal miR expression was performed by quantitative reverse transcription-PCR. The functional role of exosomal miRs was assessed in vitro by transfecting miR mimics in human alveolar epithelial cells and lung <em>fibroblasts</em>.

Results: Exosomal miR analysis showed that miR-142-3p was significantly upregulated in sputum and plasma of patients with IPF (8.06-fold, p<0.0001; 1.64 fold, p=0.008, respectively). Correlation analysis revealed a positive association between exosomal miR-142-3p and the percentage of macrophages from sputum of patients with IPF (r=0.576, p=0.012), suggesting macrophage origin of exosomal miR-142-3p upregulation. The overexpression of miR-142-3p in alveolar epithelial cells and lung fibroblasts was able to reduce the expression of transforming growth factor β receptor 1 (TGFβ-R1) and profibrotic genes. Furthermore, exosomes isolated from macrophages present antifibrotic properties due in part to the repression of TGFβ-R1 by miR-142-3p transfer in target cells.

Discussion: Our results suggest that macrophage-derived exosomes may fight against pulmonary fibrosis progression via the delivery of antifibrotic miR-142-3 p to alveolar epithelial cells and lung fibroblasts.

Keywords: Airway Epithelium; Idiopathic pulmonary fibrosis; Interstitial Fibrosis; Macrophage Biology.

<AbstractText>Precision medicine (PM) represents a new paradigm in disease diagnosis, prevention, and treatment. To apply PM premises in an emerging coronavirus pandemic acquires potentially greater relevance in order to allow the selection of specific preventive measures as well as biomarkers that will be useful in disease management.</AbstractText><AbstractText>The identification of the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as the responsible for the coronavirus disease 20<em>19</em> (COVID-<em>19</em>) pandemic had led to a plethora of strategies to contain viral dissemination, affecting life styles and personal behaviors. Viral genomic sequencing has shown that SARS-CoV-2 spike protein utilizes angiotensin-converting enzyme 2 (ACE2) found on ciliated epithelial cells of the human lungs as its specific receptor. Neutralizing antibodies to the receptor-binding domain of the spike protein were detected in patients recovered from COVID-<em>19</em>; however, both T cells and NK cells were reduced in severe cases. Excessive and uncontrolled releases of pro-inflammatory cytokines such as IL-1B, IL-1RA, IL-7, IL-8, IL-9, IL-10, <em>fibroblast</em> <em>growth</em> <em>factor</em> (FGF), granulocyte-macrophage colony-stimulating <em>factor</em> (GM-CSF), and tumor necrosis <em>factor</em> (TNFα) were increased in severe patients. These cytokines might be useful biomarkers of disease worsening and potential targets for new biological therapies currently under investigation.</AbstractText><AbstractText>Present knowledge and recent developments in PM approach to COVID-<em>19</em> disease prevention, evaluation, and management are pointed out. Better understanding of pathogenic pathways together with an accurate phenotype classification of patients presented with SARS-CoV-2 infection and symptoms might contribute to a more accurate definition of biomarkers and other diagnostic tools, which may lead to more precise mitigation strategies, personalized pharmacologic options, as well as new biological therapy developments.</AbstractText>

Nonalcoholic steatohepatitis (NASH), a progressive form of nonalcoholic fatty liver disease, is one of the most common hepatic diseases in children. We conducted a randomized controlled clinical trial on children with biopsy-proven NASH based on a combinatorial nutritional approach compared with placebo. Participants were assigned to lifestyle modification plus placebo or lifestyle modification plus a mix containing docosahexaenoic acid, choline, and vitamin E (DHA-CHO-VE). Forty children and adolescents participated in the entire trial. The primary outcome was the improvement of liver hyperechogenicity. Secondary outcomes included alterations of alanine aminotransferase (ALT) and other metabolic parameters. Furthermore, changes of serum bile acids (BA) and plasma <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) levels were evaluated as inverse biomarkers of disease severity. At the end of the study, we observed a significant decrease in severe steatosis in the treatment group (50% to 5%, p = 0.001). Furthermore, although the anthropometric and biochemical measurements in the placebo and DHA-CHO-VE groups were comparable at baseline, at the end of the study ALT and fasting glucose levels improved only in the treatment group. Finally, we found that BA levels were not influenced whereas FGF<em>19</em> levels were significantly increased by DHA-CHO-VE. The results suggest that a combination of DHA, VE, and CHO could improve steatosis and reduce ALT and glucose levels in children with NASH. However, further studies are needed to assess the impact of a DHA and VE combination on repair of liver damage in paediatric NASH.

<AbstractText>Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in adults and children. Along with obesity, diabetes and insulin resistance, genetic <em>factors</em> strongly impact on NAFLD development and progression. Dysregulated bile acid metabolism and the <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) pathway play a pivotal role in NAFLD pathogenesis. However, it remains to be defined the mechanism through which the FGF<em>19</em> receptor system is associated with liver damage in NAFLD.</AbstractText><AbstractText>We evaluated the impact of the rs17618244 G>A β-Klotho (KLB) variant on liver damage in 249 pediatric patients with biopsy-proven NAFLD and the association of this variant with the expression of hepatic and soluble KLB. In vitro models were established to investigate the role of KLB mutant.</AbstractText><AbstractText>The KLB rs17618244 variant was associated with increased risk of ballooning and lobular inflammation. KLB plasma levels were lower in carriers of the rs17618244 minor A allele and were associated with lobular inflammation, ballooning and fibrosis. In HepG2 and Huh7 hepatoma cell lines, exposure to free fatty acids caused a severe reduction of intracellular and secreted KLB. Finally, KLB down-regulation obtained by the expression of KLB mutant in HepG2 and Huh7 cells induced intracellular lipid accumulation and up-regulation of p62, ACOX1, ACSL1, IL-1β and TNF-α gene expression.</AbstractText><AbstractText>In conclusion, we showed an association between the rs17618244 KLB variant, which leads to reduced KLB expression, and the severity of NAFLD in pediatric patients. We can speculate that KLB protein may exert a protective role against lipotoxicity and inflammation in hepatocytes.</AbstractText><AbstractText>Genetic and environmental <em>factors</em> strongly impact on NAFLD pathogenesis and progression. The FGF<em>19</em>/FGFR4/KLB pathway plays a pivotal role in NAFLD pathogenesis, thus, it has been identified as a therapeutic target. Therefore, the aim of the study was to investigate the impact of the KLB rs17618244 G>A genetic variant on liver damage severity in pediatric patients with NAFLD, and the effect of KLB mutant on hepatocellular damage.</AbstractText>

BACKGROUND

Fibroblast growth factors (FGFs) belong to the FGF superfamily with diverse biological functions, including proliferation, cellular differentiation, wound repair, angiogenesis and tumorigenesis. The ability to reduce liver fat content and concentrations of triglycerides, total cholesterol and plasma glucose, and to improve sensitivity and limit pro-lipogenic properties of insulin, makes FGF19 a promising therapeutic target for the treatment of metabolic syndrome. FGF19 regulates bile acid biosynthesis in the bile duct, glucose metabolism and vitamin D and phosphate homeostasis, raises the metabolic rate, reduces body weight, and ameliorates diabetes in mice. The therapeutic potential of FGF19 to treat metabolic disorders has been widely studied in animal models, but currently there are no reports concerning its use in humans.

METHODS

The following article highlights the metabolic effects and mechanism of action of FGF19. It also discusses the potential therapies that target FGF19.

CONCLUSIONS

FGF19 is emerging as a new target for the therapy of metabolic disorders, including diabetes. The results obtained from animal models are promising. However, there is still much to be done before the translation of these effects into practice will be possible.

The natural farnesoid X receptor (FXR) agonist chenodeoxycholic acid (CDCA) suppresses hepatic cholesterol and bile acid synthesis and reduces biliary cholesterol secretion and triglyceride production. Animal studies have shown that bile acids downregulate hepatic LDL receptors (LDLRs); however, information on LDL metabolism in humans is limited.

Kinetics of autologous 125 I-LDL were determined in 12 male subjects at baseline and during treatment with CDCA (15 mg kg-1 day-1 ). In seven patients with gallstones treated with CDCA for 3 weeks before cholecystectomy, liver biopsies were collected and analysed for enzyme activities and for specific LDLR binding. Serum samples obtained before treatment and at surgery were analysed for markers of lipid metabolism, lipoproteins and the LDLR modulator proprotein convertase subtilisin/kexin type 9 (PCSK9).

Chenodeoxycholic acid treatment increased plasma LDL cholesterol by ~10% as a result of reduced clearance of plasma LDL-apolipoprotein (apo)B; LDL production was somewhat reduced. The reduction in LDL clearance occurred within 1 day after initiation of treatment. In CDCA-treated patients with gallstones, hepatic microsomal cholesterol 7α-hydroxylase and HMG-CoA reductase activities were reduced by 83% and 54%, respectively, and specific LDLR binding was reduced by 20%. During treatment, serum levels of <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> and total and LDL cholesterol increased, whereas levels of 7α-hydroxy-4-cholesten-3-one, lathosterol, PCSK9, apoA-I, apoC-III, lipoprotein(a), triglycerides and insulin were reduced.

Chenodeoxycholic acid has a broad influence on lipid metabolism, including reducing plasma clearance of LDL. The reduction in circulating PCSK9 may dampen its effect on hepatic LDLRs and plasma LDL cholesterol. Further studies of the effects of other FXR agonists on cholesterol metabolism in humans seem warranted, considering the renewed interest for such therapy in liver disease and diabetes.

The farnesoid X receptor (FXR, NR1H4) is a bile acid (BA)-activated transcription <em>factor</em>, which is essential for BA homeostasis. FXR and its hepatic and intestinal target genes, small heterodimer partner (SHP, NR0B2) and <em>fibroblast</em> <em>growth</em> <em>factor</em> 15/<em>19</em> (Fgf15 in mice, FGF<em>19</em> in humans), transcriptionally regulate BA synthesis, detoxification, secretion, and absorption in the enterohepatic circulation. Furthermore, FXR modulates a large variety of physiological processes, such as lipid and glucose homeostasis as well as the inflammatory response. Targeted deletion of FXR renders mice highly susceptible to cholic acid feeding resulting in cholestatic liver injury, weight loss, and increased mortality. Combined deletion of FXR and SHP spontaneously triggers early-onset intrahepatic cholestasis in mice resembling human progressive familial intrahepatic cholestasis (PFIC). Reduced expression levels and activity of FXR have been reported in human cholestatic conditions, such as PFIC type 1 and intrahepatic cholestasis of pregnancy. Recently, two pairs of siblings with homozygous FXR truncation or deletion variants were identified. All four children suffered from severe, early-onset PFIC and liver failure leading to death or need for liver transplantation before the age of 2. These findings underscore the central role of FXR as regulator of systemic and hepatic BA levels. Therefore, targeting FXR has been exploited in different animal models of both intrahepatic and obstructive cholestasis, and the first FXR agonist obeticholic acid (OCA) has been approved for the treatment of primary biliary cholangitis (PBC). Further FXR agonists as well as a FGF<em>19</em> analogue are currently tested in clinical trials for different cholestatic liver diseases. This chapter will summarize the current knowledge on the role of FXR in cholestasis both in rodent models and in human diseases.

Normal and ischaemic incisional wounds in rats were treated with recombinant human basic <em>fibroblast</em> <em>growth</em> <em>factor</em> (rbFGF) in fibrin adhesive vehicle. After 10 days of healing the maximum load*S and stress*S (S denotes correction for shrinkage) of ischaemic wounds were increased by 45% and 39%, respectively, after treatment with 20 micrograms rbFGF and by 67% and 56% after treatment with 60 micrograms rbFGF. After 20 days only 20 micrograms rbFGF had any effect and increased maximum load*S by 31% and energy at maximum (load*S, stress*S) by 40%-48%. In normal wounds 0.6-20 micrograms and 60 micrograms rbFGF decreased the strength parameters by <em>19</em>%-34% and 49%-52%, respectively, after 10 days. After 20 days there was no negative influence but 60 micrograms rbFGF increased the biomechanical properties by 15%-24%. Treatment with the fibrin adhesive vehicle alone decreased the biomechanical properties of ischaemic wounds after 20 days, and of normal wounds after both 10 and 20 days. In conclusion, rbFGF can improve the healing of ischaemic wounds and may be used in the treatment of ischaemic wounds in patients, but it can have negative effects on normal wound healing.

Dactylaplasia, or Dac, was recently mapped to the distal portion of mouse chromosome <em>19</em> and shown to be inherited as an autosomal semi-dominant trait characterized by missing central digital rays. The most common locus for human split hand split foot malformation, also typically characterized by missing central digital rays, is 10q25, a region of synteny to the Dac locus. The Dac mouse appears to be an ideal genotypic and phenotypic model for this human malformation syndrome. Several genes lie in this region of synteny, however, only <em>Fibroblast</em> <em>Growth</em> <em>Factor</em> 8, or Fgf-8, has been implicated to have a role in limb development. We demonstrate that the developmental mechanism underlying loss of central rays in Dac limbs is dramatic cell death of the apical ectodermal ridge, or AER. This cell death pattern is apparent in E10.5-11.5 Dac limb buds stained with the supravital dye Nile Blue Sulfate. We demonstrate that Fgf8 expression in wild type limbs colocalizes spatially and temporally with AER cell death in Dac limbs. Furthermore, in our mapping panel, there is an absence of recombinants between Fgf-8 and the Dac locus in 133 backcross progeny with a median linkage estimate of approximately 0.5 cM. Thus, our results demonstrate that cell death of the AER in Dac limbs silences the role of the AER as key regulator of limb outgrowth, and that Fgf-8 is a strong candidate for the cause of the Dac phenotype.