The stilbenoid resveratrol (1) was subjected to regioselective acetylation catalysed by Candida antarctica lipase (CAL) to obtain 4'-acetylresveratrol (2). CAL biocatalysed regioselective alcoholysis of 3,5,4'-triacetylresveratrol (3), 3,5,4'-tributanoylresveratrol (6), and 3, 4, 5'-trioctanoylresveratrol (9) afforded derivatives 4, 5, 7, 8, 10, and 11. Further resveratrol analogues (12-18) were obtained through methylation and hydrogenation reactions, whereas the 3,4,4'-trimethoxystilbene (<em>19</em>) was obtained by complete synthesis. Resveratrol and its lipophylic analogues were subjected to cell-<em>growth</em> inhibition bioassays towards DU-145 human prostate cancer cells. Compounds 2-<em>19</em> showed cell-<em>growth</em> inhibition activity comparable to or higher than resveratrol (GI(50)=24.09 microM), displaying low or very low toxicity against non-tumorigenic human <em>fibroblast</em> cells. Comparison of the trimethoxy stilbenes 12 (GI(50)=2.92 microM) and <em>19</em> (GI(50)=25.39 microM) indicates that the position of the substituents is important for the activity. The marked activity of methyl ethers 12, 13, and 18 in comparison with that of the corresponding esters suggests that the different chemical reactivity, rather than steric <em>factors</em>, strongly influences the activity.

OBJECTIVE

Phosphaturic mesenchymal tumour, mixed connective tissue variant (PMT-MCT), is a tumour of uncertain differentiation, characterised by 'smudgy/grungy' calcification and vitamin D-resistant phosphaturic osteomalacia. Fibroblast growth factor (FGF)23 is recognised as a reliable marker of PMT-MCT, but quantitative evaluation has never been performed. We reviewed cases of tumour-associated osteomalacia or histologically definitive PMT-MCT without osteomalacia using histological, immunohistochemical and genetic methods and evaluated the diagnostic significance of these findings.

RESULTS

A total of 19 tumours from 14 cases diagnosed previously as PMT-MCT were retrieved, on which immunohistochemical staining, reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence in-situ hybridisation (FISH) analysis were performed. Histologically, fibrous capsule, calcification and giant cell reaction tended to be observed in soft-tissue PMT-MCT, while PMT-MCT of bone and multiple PMT-MCT showed an infiltrative growth pattern. The immunohistochemical results were as follows: the tumour cells were positive for FGF23 (nine of 12, 75%), FGFR1 (11 of 11, 100%), CD56 (12 of 14, 85.7%) and E26 oncogene homologue (ERG) (5 of 13, 38.4%). The sole malignant tumour was positive for p53. FGF23 mRNA was detected in seven of 14 formalin-fixed paraffin-embedded (FFPE) specimens and all five frozen specimens by RT-PCR. The level of FGF23 mRNA, which was determined by real-time PCR, varied among the phosphaturic cases. Two of 17 tumours were positive for FGFR1 gene rearrangement.

CONCLUSIONS

It was considered that PMT-MCT is a histopathological entity with or without phosphaturia, with varying levels of FGF23 mRNA, and with or without fibronectin 1 (FN1)-FGFR1 fusion gene. The authors propose that the histology of PMT-MCT differs depending on its location, such as bone or soft tissue, which could complicate the differential diagnosis.

The ileal-derived hormone, <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF-<em>19</em>), may promote weight loss and facilitate type-2 diabetes mellitus remission in bariatric surgical patients. We investigated the effect of different bariatric procedures on circulating FGF-<em>19</em> levels and the resulting impact on mitochondrial health in white adipose tissue (AT).

Obese and type-2 diabetic women (n = 39, BMI>> 35 kg/m2) undergoing either biliopancreatic diversion (BPD), laparoscopic greater curvature plication (LGCP), or laparoscopic adjustable gastric banding (LAGB) participated in this ethics approved study. Anthropometry, biochemical, clinical data, serum, and AT biopsies were collected before and 6 months after surgery. Mitochondrial gene expression in adipose biopsies and serum FGF-<em>19</em> levels were then assessed.

All surgeries led to metabolic improvements with BPD producing the greatest benefits on weight loss (↓30%), HbA1c (↓28%), and cholesterol (↓25%) reduction, whilst LGCP resulted in similar HbA1c improvements (adjusted for BMI). Circulating FGF-<em>19</em> increased in both BPD and LGCP (χ2(2) = 8.088; P = 0.018), whilst, in LAGB, FGF-<em>19</em> serum levels decreased (P = 0.028). Interestingly, circulating FGF-<em>19</em> was inversely correlated with mitochondrial number in AT across all surgeries (n = 39). In contrast to LGCP and LAGB, mitochondrial number in BPD patients corresponded directly with changes in 12 of 14 mitochondrial genes assayed (P < 0.01).

Elevated serum FGF-<em>19</em> levels post-surgery were associated with improved mitochondrial health in AT and overall diabetic remission. Changes in circulating FGF-<em>19</em> levels were surgery-specific, with BPD producing the best metabolic outcomes among the study procedures (BPD>> LGCP>> LAGB), and highlighting mitochondria in AT as a potential target of FGF-<em>19</em> during diabetes remission.

<em>Fibroblast</em> <em>growth</em> <em>factor</em> (FGF) has been considered to modulate liver regeneration (LR) after partial hepatectomy (PH) at the tissue level. Previous studies have demonstrated that FGF15 and FGF<em>19</em> induce the activation of its receptor, FGF receptor 4 (FGFR4), which can promote hepatocellular carcinoma progression and regulate liver lipid metabolism. In this study, we aimed to explore the role of the ileal FGF15/<em>19</em>- hepatic FGFR4 axis in the LR after PH. Male C57BL/6 mice aged 8-12 weeks were partially hepatectomized and assessed for expression of ileal FGF15/<em>19</em> to hepatic FGFR4 signaling. We used recombinant human FGF<em>19</em> protein and a small interfering RNA (siRNA) of FGFR4 to regulate expression of the FGF15/<em>19</em>-FGFR4 axis in vitro and in vivo. The proliferation and cell cycle of hepatocytes, the expression levels of FGF15/<em>19</em>-FGFR4 downstream molecules, liver recovery, and lipid metabolism were assessed. We found that both ileal and serum FGF15 expression were upregulated and hepatic FGFR4 was activated after PH in mice. FGF15/<em>19</em> promoted cell cycle progression, enhanced proliferation, and reduced hepatic lipid accumulation of hepatocytes both in vitro and in vivo. Furthermore, the proliferative effect and lipid regulatory properties of FGF15/<em>19</em> were dependent on FGFR4 in hepatocytes. In addition, ileal FGF15/<em>19</em>-hepatic FGFR4 transduction during hepatocyte proliferation was regulated by extracellular regulated protein kinase (ERK) 1/2. In conclusion, the ileal FGF15/<em>19</em> to hepatic FGFR4 axis is activated and promotes LR after PH in mice, supporting the potential of ileal FGF15/<em>19</em> to hepatic FGFR4 axis-targeted therapy to enhance LR after PH.

BACKGROUND

<em>Fibroblast</em> <em>growth</em> <em>factor</em>-<em>19</em> (FGF<em>19</em>) is an intestinal hormone that mediates postprandial metabolic responses in the liver. The unusual orphan nuclear receptor, small heterodimer partner (SHP), acts as a co-repressor for many transcriptional <em>factors</em> and has been implicated in diverse biological pathways including FGF<em>19</em>-mediated repression of bile acid synthesis. To explore global functions of SHP in mediating FGF<em>19</em> action, we identify genome-wide SHP binding sites in hepatic chromatin in mice treated with vehicle or FGF<em>19</em> by ChIP-seq analysis.

RESULTS

The overall pattern of SHP binding sites between these two groups is similar, but SHP binding is enhanced at the sites by addition of FGF<em>19</em>. SHP binding is detected preferentially in promoter regions that are enriched in motifs for unexpected non-nuclear receptors. We observe global co-localization of SHP sites with published sites for SREBP-2, a master transcriptional activator of cholesterol biosynthesis. FGF<em>19</em> increases functional interaction between endogenous SHP and SREBP-2 and inhibits SREBP-2 target genes, and these effects were blunted in SHP-knockout mice. Furthermore, FGF<em>19</em>-induced phosphorylation of SHP at Thr-55 is shown to be important for its functional interaction with SREBP-2 and reduction of liver/serum cholesterol levels.

CONCLUSIONS

This study reveals SHP as a global transcriptional partner of SREBP-2 in regulation of sterol biosynthetic gene networks and provides a potential mechanism for cholesterol-lowering action of FGF<em>19</em>.

<AbstractText><em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) and <em>fibroblast</em> <em>growth</em> <em>factor</em> receptor 4 (FGFR4) signalling play critical roles in hepatocarcinogenesis. This study explored the potential of FGF<em>19</em>- and FGFR4-related biomarkers in predicting early tumour recurrence (ETR) and survival in patients with resectable hepatocellular carcinoma (HCC).</AbstractText><AbstractText>We examined the mRNA expressions of FGF<em>19</em>, FGFR4, klotho-beta (KLB), cyclin D1 (CCND1) and FGF4 in 151 surgically resected, primary unifocal HCCs through quantitative real-time polymerase chain reaction. Generalized additive models were fitted to detect nonlinear effects of continuous covariates and define thresholds of biomarker expressions. Univariate and multivariate analyses were performed to evaluate prognostic values of these biomarkers for tumour recurrence and patient survival.</AbstractText><AbstractText>Overexpression of FGF<em>19</em>, FGFR4, KLB, CCND1 and FGF4 mRNA was detected in 40%, 32%, 26%, 15% and 35% of 151 tumours respectively. ETR was the strongest prognostic <em>factor</em> predicting worse overall survival (hazard ratio [HR], 5.678; 95% confidence interval, 3.7-8.713; P < 0.001). Furthermore, we revealed that mRNA expression levels of KLB (HR, 3.857; P = 0.021) and FGF<em>19</em> (HR, 3.248; P = 0.017) were significantly associated with the occurrence of ETR.</AbstractText><AbstractText>Frequent overexpression of FGF<em>19</em>/FGFR4-related biomarkers was detected in resectable HCC. Expression levels of KLB and FGF<em>19</em> may determine patient survival outcomes through their effects on ETR.</AbstractText>

Chronic hepatitis B virus (HBV) infection is one of the major global health problems. Although the small protein of hepatitis B virus surface antigen (HBsAg), SHBs, is the most abundant HBV viral protein, its pathogenic role and molecular mechanism in malignant progression of HBV-related hepatocellular carcinoma (HCC) remain largely unknown. Here we reported that SHBs expression induced epithelial-mesenchymal transition (EMT) process in HCC cells and significantly increased their migratory and invasive ability as well as metastatic potential. Mechanistically, SHBs expression in HCC cells induced endoplasmic reticulum (ER) stress that activated the activating transcription <em>factor</em> 4 (ATF4) to increase the expression and secretion of <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>). The autocrine released FGF<em>19</em> in turn activated JAK2/STAT3 signaling for induction of EMT process in HCC. Notably, SHBs was positively correlated with the expression of mesenchymal markers, the phosphorylation status of JAK2 and STAT3 as well as FGF<em>19</em> levels in human HCC samples. HCC patients with SHBs positive had a more advanced clinical stage and worse prognosis. These results suggest an important role of SHBs in the metastasis and progression of HCC and may highlight a potential target for preventive and therapeutic intervention of HBV-related HCC and its malignant progression.

<strong class="sub-title"> Keywords: </strong> Fibroblast <em>growth</em> <em>factor</em> <em>19</em>; HBV small Surface proteins; Hepatitis B virus; Invasion and metastasis; Liver cancer.

The global epidemic of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) and the high prevalence among individuals with type 2 diabetes has attracted the attention of clinicians specialising in liver disorders. Many drugs are in the pipeline for the treatment of NAFLD/NASH, and several glucose-lowering drugs are now being tested specifically for the treatment of liver disease. Among these are nuclear hormone receptor agonists (e.g. peroxisome proliferator-activated receptor agonists, farnesoid X receptor agonists and liver X receptor agonists), <em>fibroblast</em> <em>growth</em> <em>factor</em>-<em>19</em> and -21, single, dual or triple incretins, sodium-glucose cotransporter inhibitors, drugs that modulate lipid or other metabolic pathways (e.g. inhibitors of fatty acid synthase, diacylglycerol acyltransferase-1, acetyl-CoA carboxylase and 11β-hydroxysteroid dehydrogenase type-1) or drugs that target the mitochondrial pyruvate carrier. We have reviewed the metabolic effects of these drugs in relation to improvement of diabetic hyperglycaemia and fatty liver disease, as well as peripheral metabolism and insulin resistance.

Keywords: Farnesoid X receptor agonists; Fibrosis; Hepatokines; Incretins; Insulin resistance; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Peroxisome proliferator-activated receptor (PPAR) agonists; Review; SGLT2 inhibitors.

Mammary remodeling in dairy cows involves coordinated changes in stromal and epithelial tissue. Tissue remodeling is characterized by changes in cell proliferation, activation of <em>fibroblasts</em> into myo<em>fibroblasts</em>, and changes in extracellular matrix content. Transforming <em>growth</em> <em>factor</em> β-1 (TGF-β1) increases differentiation of <em>fibroblasts</em> to myo<em>fibroblasts</em>, regulates expression of extracellular matrix proteins and proteases, and has cell-type dependent effects on proliferation. The objective of this study was to determine whether TGF-β1 treatment of mammary tissue from cows in late lactation and the dry period affects cell proliferation, expression of matrix metalloproteinase-3 (MMP-3) and fibronectin (FN), and the differentiation of <em>fibroblasts</em> into myo<em>fibroblasts</em> that express smooth muscle α actin (SMA). Tissue was biopsied from 7 Holstein cows at 4 time points: late lactation, 1 wk after dry-off, 3 wk before expected calving, and 1 wk before expected calving. Explants of biopsied tissue were incubated for 2h in Waymouth's medium containing insulin, hydrocortisone, and 0 or 5 ng of TGF-β1/mL; a subset of cultures was also incubated with bromodeoxyuridine to measure epithelial and stromal cell proliferation. Tissues were fixed, embedded in paraffin, sectioned, and stained by immunohistochemistry. Stage at biopsy had an overall effect on rate of epithelial and stromal cell proliferation, and TGF-β1 treatment increased rate of bromodeoxyuridine incorporation more than 2-fold in both cell types at 1 wk after dry-off. The number of <em>fibroblasts</em> expressing SMA was <em>19</em>% higher in the intralobular stroma at 1 wk after dry-off compared with that at 1 wk before expected calving, and the percentage of activated <em>fibroblasts</em> tended to be higher in tissue incubated with TGF-β1. Biopsy stage had an overall effect on percentage area of epithelium expressing FN and MMP-3. Incubation with TGF-β1 had no effect on percentage intralobular stroma area expressing FN or MMP-3. Effects of TGF-β1 treatment were most apparent at 1 wk after dry-off, indicating that the first week of dry period may be an ideal target for testing effects in vivo.

<em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) is an important postprandial enterokine which regulates liver metabolism and hepatocyte proliferation. However, the precise mechanism by which FGF<em>19</em> regulates these cellular effects is poorly understood. Given that mechanistic target of rapamycin complex 1 (mTORC1) regulates numerous postprandial adaptations, we investigated the potential role of mTORC1 in FGF<em>19</em> action. We found that FGF<em>19</em> activated mTORC1 in HepG2 and HuH7 human hepatoma cells, differentiated 3T3-L1 adipocytes and mouse liver. FGF<em>19</em> activates the mTORC1-p70S6K and extracellular signal-regulated kinase (Erk)-p90RSK pathways independently to regulate S6 in an additive manner in hepatoma cells, but it uses mTORC1 as the primary pathway to regulate S6 in 3T3-L1 adipocytes. Thus, mTORC1 is a novel mediator of FGF<em>19</em> signaling, which can act in parallel with Erk or function as the primary pathway to regulate S6. The FGF<em>19</em>-induced mTORC1 pathway requires amino acids for efficient signaling; thus, involvement of mTORC1 confers amino acid sensitivity to FGF<em>19</em> signaling. Although Akt and Erk are known to activate mTORC1, we found that FGF<em>19</em> signals to mTORC1 through a third recently identified mTORC1 regulator, Ras-like (Ral) protein. Pharmacological or genetic inhibition of RalA or RalB abolished FGF<em>19</em>-induced mTORC1 activation, demonstrating that Ral proteins are required for FGF<em>19</em> to activate mTORC1. FGF<em>19</em> induced metabolic gene expression, fatty acid oxidation, cell <em>growth</em>, and proliferation in HepG2 cells; and these effects were abolished by mTORC1 inhibition, demonstrating an essential role of mTORC1 in FGF<em>19</em> action.

mTORC1 is a novel and essential mediator of FGF<em>19</em> action on metabolic and mitogenic programs; thus, the involvement of mTORC1 in FGF<em>19</em> signaling is an important <em>factor</em> to consider when targeting the pathway for cancer or diabetes therapy. (Hepatology 2016;64:1289-1301).

BACKGROUND

Receptor-interacting serine/threonine protein kinase-2 (RIPK2) has been reported to be an important regulator of tumor proliferation, differentiation and wound repair. We investigated the effects of RIPK2 knockdown in human hepatoma cells on epithelial-to-mesenchymal transition (EMT)-associated gene expression.

METHODS

HepG2 cells stably expressing RIPK2-shRNA (HepG2-shRIPK2) were generated after puromycin selection. Total RNAs from HepG2-shRIPK2 and from HepG2-shcontrol cells were isolated and PCR-based arrays were performed to compare the 84 EMT-associated gene expressions.

RESULTS

We observed that knockdown of RIPK2 down-regulated mRNA expression of jagged 1 (JAG1); plasminogen activator inhibitor-1 (PAI1); regulator of G-protein signalling 2, 24 kDa (RGS2); E-cadherin (CDH1); <em>fibroblast</em> <em>growth</em> <em>factor</em> binding protein 1 (FGFBP1); snail homolog 2 (SNAI2); protein tyrosine phosphatase type IVA, member 1 (PTP4A1); keratin <em>19</em> (KRT<em>19</em>); vimentin (VIM); and survival of motor neuron protein-interacting protein 1 (SIP1).

CONCLUSIONS

We found that knockdown of RIPK2 down-regulated nuclear factor kappa B (NF-κB)-dependent PAI1 and VIM gene expressions. RIPK2 might play an important role in hepatic cell migration. These findings could shed new light on carcinogenesis and on liver regeneration.

OBJECTIVE

We sought to develop a minimally invasive intra-amniotic therapy for prenatal treatment of myelomeningocele (MMC) in an established rat model.

METHODS

Time-dated pregnant rats were gavage-fed retinoic acid to induce MMC. Groups received intraamniotic injections at E17.5 with alginate particles loaded with fluorescent dye, basic fibroblast growth factor (Alg-HSA-bFGF), fluorescently tagged albumin (Alginate-BSA-TR), free bFGF, blank alginate particles (Alg-Blank), or PBS. Groups were analyzed at 3 h for specific particle binding or at term (E21) to determine MMC coverage.

RESULTS

Alginate microparticles demonstrated robust binding to the MMC defect 3 h after injection. Of those specimens analyzed at E21, 150 of 239 fetuses (62.8%) were viable. Moreover, 18 of 61 (30%) treated with Alg-HSA-bFGF showed evidence of soft tissue coverage compared to 0 of 24 noninjected (P = 0.0021), 0 of 13 PBS (P = 0.0297), and 0 of 42 free bFGF (P = P < 0.0001). Scaffolds of aggregated particles associated with disordered keratinized tissue were observed covering the defect in 2 of 18 (11%) Alg-BSA-TR and 3 of 19 (16%) Alg-Blank specimens.

CONCLUSIONS

Injection of microparticles loaded with bFGF resulted in significant soft tissue coverage of the MMC defect compared to controls. Alginate microparticles without growth factors might result in scaffold development over the fetal MMC.

METHODS

Basic science.

METHODS

N/A.

Alcoholic liver disease (ALD) is the most prevalent form of liver disease, encompassing a spectrum of progressive pathological changes from steatosis to steatohepatitis to fibrosis/cirrhosis and hepatocellular carcinoma. Alcoholic steatosis/steatohepatitis is the initial stage of ALD and a major risk <em>factor</em> for advanced liver injuries. Adiponectin is a hormone secreted from adipocytes. <em>Fibroblast</em> <em>growth</em> <em>factor</em> (FGF) 15 (human homolog, FGF<em>19</em>) is an ileum-derived hormone. Adipocyte-derived adiponectin and gut-derived FGF15/<em>19</em> regulate each other, share common signaling cascades, and exert similar beneficial functions. Emerging evidence has revealed that dysregulated adiponectin-FGF15/<em>19</em> axis and impaired hepatic adiponectin-FGF15/<em>19</em> signaling are associated with alcoholic liver damage in rodents and humans. More importantly, endocrine adiponectin-FGF15/<em>19</em> signaling confers protection against ethanol-induced liver damage via fine tuning the adipose-intestine-liver crosstalk, leading to limited hepatic inflammatory responses, and ameliorated alcoholic liver injury. This review is focused on the recently discovered endocrine adiponectin-FGF15/<em>19</em> axis that is emerging as an essential adipose-gut-liver coordinator involved in the development and progression of alcoholic steatohepatitis.

G-coupled protein receptors (GPCRs) comprise the largest class of druggable targets. Signaling by GPCRs is initiated from subcellular hot spots including the plasma membrane, signalosomes and endosomes to contribute to vascular inflammation. GPCR-G protein signaling at the plasma membrane causes endothelial barrier disruption and also cross-talks with <em>growth</em> <em>factor</em> receptors to promote proinflammatory signaling. A second surge of GPCR signaling is initiated by cytoplasmic NFκB activation mediated by β-arrestins and CARMA-Bcl10-MALT1 signalosomes. Once internalized, ubiquitinated GPCRs initiate signaling from endosomes via assembly of the transforming <em>growth</em> <em>factor</em>-β-activated kinase binding protein-1 (TAB1)-TAB2-p38 MAPK complex to promote vascular inflammation. Understanding the complexities of GPCR signaling is critical for development of new strategies to treat vascular inflammation such as that associated with COVID-<em>19</em>.

<strong class="sub-title"> Keywords: </strong> (Bcl10), mucosa-associated lymphoid tissue lymphoma translocation protein 1; (MALT1), CBM; Angiotensin converting enzyme-2, ACE2; CARMA, B-cell lymphoma protein 10; COVID-<em>19</em>; G protein-coupled receptor, GPCR; JAK-STAT; Janus kinase, JAK; MALT1; NFκB; adherens junctions, AJ; angiotensin II type 1 receptor, AT1: domain-containing protein; arrestins; coronavirus disease of 20<em>19</em>, COVID-<em>19</em>; endosomes; endothelial; fibroblast-<em>growth</em>-<em>factor</em>, FGF; inhibitor of NFκB kinase, IKK; mitogen-activated protein kinase, MAPK; neural precursor cell expressed developmentally down-regulated protein 4, NEDD4; nuclear <em>factor</em> kappa-light-chain-enhancer of activated B cells, NFκB; p38 MAPK; platelet activating <em>factor</em>, PAF; protease-activated receptor-1, PAR1; severe acute respiratory syndrome coronavirus 2, SARS-CoV-2; signal transducer and activator of transcription, STAT; transforming <em>growth</em> <em>factor</em>-α-activated kinase binding protein-1, TAB1.

<AbstractText>The nuclear receptor subfamily 0 group B member 2 (NR0B2, also called SHP) is expressed at high levels in the liver and intestine. Postprandial <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (human FGF<em>19</em>, mouse FGF15) signaling increases the transcriptional activity of SHP. We studied the functions of SHP and FGF<em>19</em> in the intestines of mice, including their regulation of expression of the cholesterol transporter NPC1L1 )NPC1-like intracellular cholesterol transporter 1) and cholesterol absorption.</AbstractText><AbstractText>We performed histologic and biochemical analyses of intestinal tissues from C57BL/6 and SHP-knockout mice and performed RNA-sequencing analyses to identify genes regulated by SHP. The effects of fasting and refeeding on intestinal expression of NPC1L1 were examined in C57BL/6, SHP-knockout, and FGF15-knockout mice. Mice were given FGF<em>19</em> daily for 1 week; fractional cholesterol absorption, cholesterol and bile acid (BA) levels, and composition of BAs were measured. Intestinal organoids were generated from C57BL/6 and SHP-knockout mice, and cholesterol uptake was measured. Luciferase reporter assays were performed with HT29 cells.</AbstractText><AbstractText>We found that the genes that regulate lipid and ion transport in intestine, including NPC1L1, were up-regulated and that cholesterol absorption was increased in SHP-knockout mice compared with C57BL/6 mice. Expression of NPC1L1 was reduced in C57BL/6 mice after refeeding after fasting but not in SHP-knockout or FGF15-knockout mice. SHP-knockout mice had altered BA composition compared with C57BL/6 mice. FGF<em>19</em> injection reduced expression of NPC1L1, decreased cholesterol absorption, and increased levels of hydrophilic BAs, including tauro-α- and -β-muricholic acids; these changes were not observed in SHP-knockout mice. SREBF2 (sterol regulatory element binding transcription <em>factor</em> 2), which regulates cholesterol, activated transcription of NPC1L1. FGF<em>19</em> signaling led to phosphorylation of SHP, which inhibited SREBF2 activity.</AbstractText><AbstractText>Postprandial FGF<em>19</em> and SHP inhibit SREBF2, which leads to repression of intestinal NPC1L1 expression and cholesterol absorption. Strategies to increase FGF<em>19</em> signaling to activate SHP might be developed for treatment of hypercholesterolemia.</AbstractText>

The effects of 13 phenothiazines, and 8 benzo[a]phenothiazines on the <em>growth</em> and differentiation of various human cultured cell lines were investigated. Perphenazine dimaleate and chlorpromazine hydrochloride were more cytotoxic against human normal <em>fibroblasts</em> and glioma cells than <em>19</em> other related compounds. The differentiation of three human myelogenous leukemic cell lines (ML-1, U-937, THP-1) into maturing monocytes/macrophages was potently induced by 12H- benzo[a]phenothiazine and 5-oxo-5H-benzo[a]phenothiazine. The differentiation--inducing activity of phenothiazine, and other benzo[a]phenothiazine derivatives was much less, and that of phenothiazine derivatives without the benzyl group was undetectable. Simultaneous treatment with 12H- benzo[a]phenothiazine and tumor necrosis <em>factor</em> produced additive, but not synergistic differentiation--induction of these cells.

To understand metformin's effects on <em>fibroblast</em> <em>growth</em> <em>factors</em> (FGFs) and <em>fibroblast</em> <em>growth</em> <em>factor</em> receptor 1 (FGFR1), we investigated circulating <em>fibroblast</em> <em>growth</em> <em>factor</em>-<em>19</em> (FGF<em>19</em>), FGF21 levels, and FGFR1 in type 2 diabetes mellitus (T2DM). In addition, protein kinase B (Akt) signaling pathway was detected to explain the possible mechanisms. T2DM was induced by feeding rats with high-fat diet for 11 weeks, followed by a low dose of streptozotocin (STZ, 30-35 mg/kg, intraperitoneally). Control rats (Con) were fed on a normal chow; diabetic rats (DM) were fed on high-fat diet supplemented with or without metformin (METF) for 12 weeks (500 mg·kg-1·d-1). Biochemical parameters were detected at the end of 24th weeks. FGFR1 expression and protein kinase B (Akt) phosphorylation in the pancreas and visceral adipose tissues were detected using either Western blot (WB) or immunohistochemistry (IHC). Serum FGF<em>19</em> and FGF21 were measured using enzyme-linked immune sorbent assay (ELISA). Metformin treated DM rats showed improved glucose, lipid and bile acid metabolism. Besides, significantly decreased FGF<em>19</em> and increased FGF21 were observed in DM+METF rats. DM rats showed significantly increased FGFR1 both in the pancreas and visceral adipose tissues. While in DM+METF rats, FGFR1 was almost remained at a normal level in the pancreas and increased in the visceral adipose tissue compared to that in DM rats. Besides, metformin treatment restores Akt phosphorylation in both tissues. The altered glucose and lipid profiles by metformin treatment may be associated with the increased circulating FGF21 and tissue-specific expressions of FGFR1.

<AbstractText>Gastric bypass (GBP) and sleeve gastrectomy (SG) are both effective bariatric treatments that cause sustained weight loss as well as improvement of type 2 diabetes mellitus (T2DM). The underlying mechanisms are under investigation, including the contribution of alterations in bile acids (BAs) in achieving or maintaining the beneficial metabolic effects after bariatric surgery.</AbstractText><AbstractText>The aim of this study is to investigate the acute and short-term effects of GBP and SG on BA compositions and <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) in obese individuals with T2DM and to evaluate any correlations between changes in these measures with glucose metabolic improvements.</AbstractText><AbstractText>The levels of both fasting and postprandial plasma BA compositions after oral glucose tolerance test (OGTT), fasting FGF<em>19</em> and various metabolic indices were measured 1 day before and at 3 days and 3 months after GBP and SG in <em>19</em> obese patients (GBP = 8, SG = 11) with T2DM.</AbstractText><p><div><b>RESULTS</b></div>Body weight loss was observed after both GBP and SG 3 months post-operatively, with no significant difference between the two intervention groups (15.0 ± 3.1% vs. 13.9 ± 5.2%, P = 0.761). At 3 days post-operation, FGF<em>19</em> levels increased significantly in both surgery groups (GBP, 118.3 ± 57.3 vs. 363.6 ± 131.0 pg mL^-1, post-operation P = 0.008; SG, 173.2 ± 127.8 vs. 422.0 ± 243.6 pg mL^-1, post-operation P = 0.001). Fasting and postprandial increases from pre-operative values in secondary (r = 0.57, P = 0.02; r = 0.58, P = 0.01), conjugated (r = 0.50, P = 0.01; r = 0.48, P = 0.04), glycine-conjugated (r = 0.52, P = 0.05; r = 0.46, P = 0.05) and secondary-conjugated (r = 0.53, P = 0.02; r = 0.60, P = 0.01) BAs correlated with decreases in the postprandial states of glucose (defined by area under the curve (AUC) over 120 min (AUC_0-120min)). Increases in postprandial primary-conjugated BAs were found to be associated with decreases in HOMA-IR (r = 0.45, P = 0.05). However, increases in fasting and postprandial taurine-conjugated BA correlated with decreases in both basal insulin secretion rate (r = 0.47, P = 0.04; r = 0.48, P = 0.04) and C-peptide level (r = 0.45, P = 0.05; r = 0.47, P = 0.04). After 3 months, fasting and postprandial increases in secondary (r = 0.51, P = 0.03; r = 0.48, P = 0.04), secondary-conjugated (r = 0.52, P = 0.02; r = 0.51, P = 0.03) and non-12α-OH (r = 0.51, P = 0.02; r = 0.58, P = 0.01) BAs were found to correlate with increases in Stumvoll Insulin Sensitivity Index. Increases in both fasting and postprandial 12α-OH BAs were correlated with the decreases in glucose AUC (r = 0.46, P = 0.05; r = 0.41, P = 0.04).</p><AbstractText>Both GBP and SG achieve increases in many BA species as early as 3 days post-operation, which are sustained at 3 months post-operation. Rises in secondary BA and conjugated forms are correlated with early improvements in glucose metabolism at 3 days post-operation. These along with 12α-OH BA correlated with improved glucose metabolism at 3 months post-operation, suggesting they may contribute to the observed T2DM remission after bariatric surgery.</AbstractText>

Bile acids are endogenous ligands of nuclear receptors pregnane X (PXR) and farnesoid X (FXR). PXR and FXR regulate pathways that are impaired in inflammatory bowel disease (IBD). Decreases in PXR and FXR activity are documented in IBD; however reasons for this are unknown. We aimed to assess the effect of Crohn's disease (CD) on the plasma bile acid composition in vivo and the resultant impact on PXR and FXR activation. A cross-sectional study evaluated the plasma concentrations of 12 bile acids in addition to 4β-hydroxycholesterol (4βOHC), an in vivo probe of the PXR target-gene cytochrome 3A4 (CYP3A4) and the FXR target-gene, <em>fibroblast</em> <em>growth</em> <em>factor</em> (FGF) <em>19</em> in individuals with (n = 74) and without (n = 71) CD. An in vitro model was used to assess the impact of CD-specific changes in the plasma bile acid composition on PXR and FXR activation. Decreases in glycochenodeoxycholic acid, taurocholic acid and lithocholic acid were seen in CD with increases in glycodeoxycholic acid and glycocholic acid relative to the total plasma bile acid profile. In vitro, increasing concentrations of bile acids applied in the same ratio as seen in the study cohorts resulted in decreased activation of both PXR and FXR in the CD model. In vivo, plasma 4βOHC (CD = 18.68 ng/ml ± 13.02 ng/ml, non-CD = 46.38 ng/ml ± 40.70 ng/ml, p ≤ 0.0001) and FGF<em>19</em> (CD = 0.276 pg/L ± 0.189 pg/L, non-CD = 0.485 pg/L ± 0.42 pg/L, p = 0.0002) concentrations were lower in CD versus controls. Ultimately, CD-specific changes in the plasma bile acid composition lead to reduced activation of FXR and PXR target genes in vitro and in vivo.

<AbstractText>To investigate the role of <em>fibroblast</em> <em>growth</em> <em>factors</em> (FGFs) in the production of neural retina (NR) and retinal pigmented epithelium (RPE) in a human pluripotent stem cell model of early retinal development.</AbstractText><AbstractText>Human induced pluripotent stem cell (hiPSC) lines from an individual with microphthalmia caused by a functional null mutation (R200Q) in Visual systems homeobox 2 (VSX2), a transcription <em>factor</em> involved in early NR progenitor cell (NRPC) production, and a normal sibling were differentiated along the retinal and forebrain lineages using an established protocol. Quantitative and global gene expression analyses (microarray and RNAseq) were used to investigate endogenous FGF expression profiles in these cultures over time. Based on these results, mutant and control hiPSC cultures were treated exogenously with selected FGFs and subjected to gene and protein expression analyses to determine their effects on RPE and NR production.</AbstractText><AbstractText>We found that FGF9 and <em>19</em> were selectively increased in early hiPSC-derived optic vesicles (OVs) when compared to isogenic cultures of hiPSC-derived forebrain neurospheres. Furthermore, these same FGFs were downregulated over time in (R200Q)VSX2 hiPSC-OVs relative to sibling control hiPSC-OVs. Interestingly, long-term supplementation with FGF9, but not FGF<em>19</em>, partially rescued the mutant retinal phenotype of the (R200Q)VSX2 hiPSC-OV model. However, antagonizing FGF9 in wildtype control hiPSCs did not alter OV development.</AbstractText><AbstractText>Our results show that FGF9 acts in concert with VSX2 to promote NR differentiation in hiPSC-OVs and has potential to be used to manipulate early retinogenesis and mitigate ocular defects caused by functional loss of VSX2 activity.</AbstractText>

<AbstractText>Renal osteodystrophy (ROD) develops early in chronic kidney disease (CKD) and progresses with loss of kidney function. While intact parathyroid hormone (PTH), 1,25-dihydroxyvitamin D3 (1,25D), and <em>fibroblast</em> <em>growth</em> <em>factor</em>-23 (FGF-23) levels are usually considered the primary abnormalities in ROD development, the role of serum activin A elevations in CKD and its relationships to ROD have not been explored. The aims of this study were to evaluate serum activin A at different CKD stages, and to establish the relationships between activin A, bone biomarkers, and bone histomorphometric parameters.</AbstractText><AbstractText>104 patients with CKD stages 2 - 5D underwent bone biopsies. We measured in the serum activin A, BSAP, DKK1, FGF-23, α-Klotho, intact PTH, sclerostin, TRAP-5b, and 1,25D. Biochemical results were compared across CKD stages and with <em>19</em> age-matched controls with normal kidney function.</AbstractText><AbstractText>Median activin A levels were increased in all stages of CKD compared to controls from 544 pg/mL in CKD 2 (431 - 628) to 1,135 pg/mL in CKD 5D (816 - 1,456), compared to 369 pg/mL in controls (316 - 453, p < 0.01). The increase of activin A in CKD 2 (p = 0.016) occurred before changes in the other measured biomarkers. Activin A correlated with intact PTH and FGF-23 (r = 0.65 and 0.61; p < 0.01) and with histomorphometric parameters of bone turnover (BFR/BS, Acf, ObS/BS and OcS/BS; r = 0.47 - 0.52; p < 0.01). These correlations were comparable to those found with intact PTH and FGF-23.</AbstractText><AbstractText>Serum activin A levels increase starting at CKD 2 before elevations in intact PTH and FGF-23. Activin A correlates with bone turnover similar to intact PTH and FGF-23. These findings suggest a role for activin A in early development of ROD.</AbstractText>

The current focus on cardiovascular research reflects society's concerns regarding the alarming incidence of cardiac-related diseases and mortality in the industrialized world and, notably, an urgent need to combat them by more efficient therapies. To pursue these therapeutic approaches, a comprehensive understanding of the mechanism of action for multifunctional <em>fibroblast</em> <em>growth</em> <em>factor</em> (FGF) signaling in the biology of the heart is a matter of high importance. The roles of FGFs in heart development range from outflow tract formation to the proliferation of cardiomyocytes and the formation of heart chambers. In the context of cardiac regeneration, FGFs 1, 2, 9, 16, <em>19</em>, and 21 mediate adaptive responses including restoration of cardiac contracting rate after myocardial infarction and reduction of myocardial infarct size. However, cardiac complications in human diseases are correlated with pathogenic effects of FGF ligands and/or FGF signaling impairment. FGFs 2 and 23 are involved in maladaptive responses such as cardiac hypertrophic, fibrotic responses and heart failure. Among FGFs with known causative (FGFs 2, 21, and 23) or protective (FGFs 2, 15/<em>19</em>, 16, and 21) roles in cardiac diseases, FGFs 15/<em>19</em>, 21, and 23 display diagnostic potential. The effective role of FGFs on the induction of progenitor stem cells to cardiac cells during development has been employed to boost the limited capacity of postnatal cardiac repair. To renew or replenish damaged cardiomyocytes, FGFs 1, 2, 10, and 16 were tested in (induced-) pluripotent stem cell-based approaches and for stimulation of cell cycle re-entry in adult cardiomyocytes. This review will shed light on the wide range of beneficiary and detrimental actions mediated by FGF ligands and their receptors in the heart, which may open new therapeutic avenues for ameliorating cardiac complications.

Keywords: FGF (fibroblast growth factor); cardiac adaptive and maladaptive responses; cardiac diseases; cardiac regeneration; heart development; stem cells.

<AbstractText>Observational studies have shown that diets high in fat and low in dietary fiber, might have an unfavorable impact on bile acid (BA) profiles, which might further affect host cardiometabolic health. In the current study, we aimed to evaluate the effects of dietary fat content on BA profiles and associated gut microbiota, and their correlates with cardiometabolic risk <em>factors</em>.</AbstractText><AbstractText>In a randomized controlled-feeding trial, healthy young adults were assigned to one of the three diets: a lower-fat diet (fat 20%, carbohydrate 66% and protein 14%), a moderate-fat diet (fat 30%, carbohydrate 56% and protein 14%) and a higher-fat diet (fat 40%, carbohydrate 46% and protein 14%) for 6 months. All the foods were provided during the entire intervention period. The BA profiles, associated gut microbiota and markers of cardiometabolic risk <em>factors</em> were determined before and after intervention.</AbstractText><AbstractText>The higher-fat diet resulted in an elevated concentration of total BAs (p < 0.001), and unconjugated BAs (p = 0.03) compared with lower-fat diet. Secondary BAs, such as deoxycholic acid (DCA), taurodeoxycholic acid (TDCA), 12ketolithocholic acid (12keto-LCA), 3β-DCA and taurolithocholic acid (TLCA) (p < 0.05 after FDR correction) were significantly increased in the higher-fat diet group after the 6-month intervention. Consistently, the abundances of gut bacteria (Bacteroides, Clostridium, Bifidobacterium and Lactobacillus) which affect bile salt hydrolase gene expression were significantly increased after higher-fat consumption. The change of DCA was positively associated with the relative abundance of Bacteroides (r = 0.31, p = 0.08 after FDR correction). In addition, the changes of fecal concentrations of DCA and 12keto-LCA were positively associated with serum total cholesterol (r > 0.3, p = 0.02 and p = 0.008 after FDR correction, respectively). In line with these findings, serum <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) was marginally significantly elevated in the higher-fat group after intervention (p = 0.05).</AbstractText><AbstractText>The higher-fat diet resulted in an alteration of BAs, especially unconjugated BAs and secondary BAs, most likely through actions of gut microbiota. These alterations might confer potentially unfavorable impacts on colonic and host cardiometabolic health in healthy young adults. Clinical trial registry number: NCT02355795 listed on NIH website: ClinicalTrials.gov.</AbstractText>

BACKGROUND

Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor (FGF) family. KGF is a stromally derived, paracrine growth factor specifically mitogenic for a variety of epithelial cells. The KGF receptor (KGFR), which is a splice variant of the FGF receptor-2 (FGFR-2)/bek gene, is expressed only in epithelial cells. In this study, the expression of mRNAs encoding KGF, KGFR, and FGFR-2 in endometrial adenocarcinoma and in carcinosarcoma tissues was examined and the expression of the same mRNAs was compared with cycling endometrium.

METHODS

Specimens of tumor tissue were collected from 14 women with well differentiated endometrial adenocarcinoma and from 4 women with carcinosarcoma. All samples were obtained at the primary surgery before any treatment was initiated. In addition, endometrial tissues from 19 premenopausal women with normal menstrual cycles were examined. The expression of specific mRNAs in the endometrial samples was assessed using quantitative reverse transcriptase polymerase chain reaction. The results were analyzed by the nonparametric Kruskal-Wallis statistic.

RESULTS

The KGF mRNA expression was significantly lower in endometrial adenocarcinoma tissue compared with cycling endometrial tissues, whereas no difference was found between carcinosarcoma tissue and cycling endometrium. The relative level of KGFR mRNA in endometrial adenocarcinoma did not differ from that in cycling endometrium, but was significantly higher compared with carcinosarcomas. No differences were observed in FGFR-2 mRNA expression between cycling endometrium and tumor tissues.

CONCLUSIONS

To the authors' knowledge, this study demonstrates for the first time the expression of KGF, KGFR, and FGFR-2 mRNAs in endometrial adenocarcinoma and in carcinosarcoma tissues. The relative level of KGF mRNA expression in adenocarcinoma tissue is decreased compared with that in cycling endometrium. The change in epithelial/stromal cell prominence between cycling endometrium and adenocarcinoma tissue may account for the difference in KGF expression but does not explain why KGF receptor expression in same tissues remains unchanged. The impact of altered KGF expression for endometrial tumorigenesis is still unknown.