BACKGROUND

Foot ulcers are a major complication of diabetes mellitus, often leading to amputation. Growth factors derived from blood platelets, endothelium, or macrophages could potentially be an important treatment for these wounds but they may also confer risks.

OBJECTIVE

To assess the benefits and harms of growth factors for foot ulcers in patients with type 1 or type 2 diabetes mellitus.

METHODS

In March 2015 we searched the Cochrane Wounds Group Specialised Register, The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), Ovid MEDLINE, Ovid MEDLINE (In-Process & Other Non-Indexed Citations, Ovid EMBASE and EBSCO CINAHL. There were no restrictions with respect to language, date of publication or study setting.

METHODS

Randomised clinical trials in any setting, recruiting people with type 1 or type 2 diabetes mellitus diagnosed with a foot ulcer. Trials were eligible for inclusion if they compared a growth factor plus standard care (e.g., antibiotic therapy, debridement, wound dressings) versus placebo or no growth factor plus standard care, or compared different growth factors against each other. We considered lower limb amputation (minimum of one toe), complete healing of the foot ulcer, and time to complete healing of the diabetic foot ulcer as the primary outcomes.

METHODS

Independently, we selected randomised clinical trials, assessed risk of bias, and extracted data in duplicate. We estimated risk ratios (RR) for dichotomous outcomes. We measured statistical heterogeneity using the I(2) statistic. We subjected our analyses to both fixed-effect and random-effects model analyses.

RESULTS

We identified 28 randomised clinical trials involving 2365 participants. The cause of foot ulcer (neurologic, vascular, or combined) was poorly defined in all trials. The trials were conducted in ten countries. The trials assessed 11 growth factors in 30 comparisons: platelet-derived wound healing formula, autologous growth factor, allogeneic platelet-derived growth factor, transforming growth factor β2, arginine-glycine-aspartic acid peptide matrix, recombinant human platelet-derived growth factor (becaplermin), recombinant human epidermal growth factor, recombinant human basic fibroblast growth factor, recombinant human vascular endothelial growth factor, recombinant human lactoferrin, and recombinant human acidic fibroblast growth factor. Topical intervention was the most frequent route of administration. All the trials were underpowered and had a high risk of bias. Pharmaceutical industry sponsored 50% of the trials.Any growth factor compared with placebo or no growth factor increased the number of participants with complete wound healing (345/657 (52.51%) versus 167/482 (34.64%); RR 1.51, 95% CI 1.31 to 1.73; I(2) = 51%, 12 trials; low quality evidence). The result is mainly based on platelet-derived wound healing formula (36/56 (64.28%) versus 7/27 (25.92%); RR 2.45, 95% 1.27 to 4.74; I(2) = 0%, two trials), and recombinant human platelet-derived growth factor (becaplermin) (205/428 (47.89%) versus 109/335 (32.53%); RR 1.47, 95% CI 1.23 to 1.76, I(2)= 74%, five trials).In terms of lower limb amputation (minimum of one toe), there was no clear evidence of a difference between any growth factor and placebo or no growth factor (19/150 (12.66%) versus 12/69 (17.39%); RR 0.74, 95% CI 0.39 to 1.39; I(2) = 0%, two trials; very low quality evidence). One trial involving 55 participants showed no clear evidence of a difference between recombinant human vascular endothelial growth factor and placebo in terms of ulcer-free days following treatment for diabetic foot ulcers (RR 0.64, 95% CI 0.14 to 2.94; P value 0.56, low quality of evidence)Although 11 trials reported time to complete healing of the foot ulcers in people with diabetes , meta-analysis was not possible for this outcome due to the unique comparisons within each trial, failure to report data, and high number of withdrawals. Data on quality of life were not reported. Growth factors showed an increasing risk of overall adverse event rate compared with compared with placebo or no growth factor (255/498 (51.20%) versus 169/332 (50.90%); RR 0.83; 95% CI 0.72 to 0.96; I(2) = 48%; eight trials; low quality evidence). Overall, safety data were poorly reported and adverse events may have been underestimated.

CONCLUSIONS

This Cochrane systematic review analysed a heterogeneous group of trials that assessed 11 different growth factors for diabetic foot ulcers. We found evidence suggesting that growth factors may increase the likelihood that people will have complete healing of foot ulcers in people with diabetes. However, this conclusion is based on randomised clinical trials with high risk of systematic errors (bias). Assessment of the quality of the available evidence (GRADE) showed that further trials investigating the effect of growth factors are needed before firm conclusions can be drawn. The safety profiles of the growth factors are unclear. Future trials should be conducted according to SPIRIT statement and reported according to the CONSORT statement by independent investigators and using the Foundation of Patient-Centered Outcomes Research recommendations.

OBJECTIVE

<em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) is a postprandial hormone released from the small intestine. FGF<em>19</em> improves glucose tolerance when overexpressed in mice with impaired glucose tolerance or diabetes. This review summarizes the recent advances in our understanding of the biology of FGF<em>19</em> and its role in glucose homeostasis, with emphasis on publications from 2010 to 2012.

RESULTS

Protein engineering was used to generate FGF<em>19</em> protein variants that allowed the separation of its mitogenic and metabolic functions. Its cognate receptor in the liver (FGFR4) mediated the effects of FGF<em>19</em> on proliferation and bile salt synthesis, while this receptor was dispensable for its effects on glucose homeostasis. New metabolic activities of FGF<em>19</em> were uncovered. FGF<em>19</em> signaling was shown to stimulate glycogen and protein synthesis, and inhibit gluconeogenesis. FGF<em>19</em> employed signaling routes distinct from those used by insulin to regulate these pathways. Mice with genetic disruption of Fgf15 (the mouse FGF<em>19</em> ortholog) were glucose intolerant but had normal insulin levels and normal insulin sensitivity. Reduced hepatic glycogen stores and elevated hepatic gluconeogenesis were observed in the knock-out mice under the conditions in which insulin signaling was active.

CONCLUSIONS

FGF<em>19</em> signaling regulates glucose homeostasis in mice. The (patho)physiological role of FGF<em>19</em> in glucose homeostasis in humans remains to be determined. Its novel insulin-mimetic actions, combined with the elimination of its mitogenic activity by protein engineering, make FGF<em>19</em> an attractive candidate for the treatment of type 2 diabetes.

<em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) and 21 (FGF21) have emerged as key regulators of energy homeostasis. Our aim was to analyze the impact of weight loss (WL) induced either by conventional dietary treatment (CDT) or bariatric surgery on FGF<em>19</em> and FGF21 concentrations. Furthermore, the diverse effect of sleeve gastrectomy (SG) versus RYGB (Roux-en-Y gastric bypass) as two surgical procedures that affect the gastrointestinal anatomy and physiology differently was also analyzed.

Serum concentrations of FGF<em>19</em> and FGF21 were measured in 137 obese patients with different degrees of insulin resistance matched by sex, age and body adiposity and compared to 33 lean individuals. Furthermore, FGF<em>19</em> and FGF21 were measured in 114 subjects before and one-year after WL induced either by CDT (n = 28), SG (n = 20) or RYGB (n = 66).

Circulating serum FGF<em>19</em> concentrations were decreased (P < 0.01) similarly in obese patients regardless of their degree of insulin resistance, while FGF21 levels were increased in obesity (P < 0.01), being further increased in obesity-associated T2D (P < 0.01). FGF<em>19</em> concentrations were increased in obese subjects after surgically-induced WL (P < 0.01), but not after WL achieved by CDT, while FGF21 levels were reduced after CDT- (P < 0.05) or SG-induced WL (P < 0.05), but not after RYGB. The change in FGF21 concentrations emerged as a significant predictor of the change in insulin resistance (HOMA) after WL.

Based on the circulating concentrations and their subsequent pattern of response following WL, we conclude that FGF<em>19</em> levels are mainly related to body adiposity, in particular visceral adiposity, while FGF21 is mainly related to glucose homeostasis. CLINICALTRIALS.

NCT01572090.

Astroglial cells contribute to neuronal maintenance and function in the normal and diseased brain. Gap junctions formed predominantly by connexin43 (cx43) provide important pathways to coordinate astroglial responses. We have previously shown that <em>fibroblast</em> <em>growth</em> <em>factor</em> (FGF)-2, which occurs ubiquitously in the CNS, downregulates gap junction communication in cortical and striatal, but not in mesencephalic astroglial cells in vitro (Reuss et al. Glia 22:<em>19</em>-30, <em>19</em>98). Other members of the FGF family expressed in the CNS include FGF-5 and FGF-9. We show that both FGF-5 and FGF-9, like FGF-2, downregulate astroglial gap junctions and functional coupling. However, their effects are strikingly different from different brain regions, with regard to astroglial cells. FGF-5 specifically affects mesencephalic astroglial cells without changing coupling of cortical and striatal astroglia, while FGF-9 reduces gap junctional coupling in astroglia from all three brain regions. Both cx43 mRNA and protein levels as well as functional coupling assessed by dye spreading are affected. To clarify whether brain region-specific effects of FGFs on astroglial coupling are due to differential expression of FGF receptors (FGFR), we monitored expression of the four known FGFR mRNAs in astroglial cultures by RT-PCR. Irrespective of their regional origin, astroglial cells express mRNAs for FGFR-2 and FGFR-3. In summary, our results provide evidence for an important role of FGF-2, -5, and -9 in a distinct, CNS region-specific regulation mechanism of astroglial gap junction communication. The molecular basis underlying the regionally distinct responsiveness of astrocytes to different FGFs may be sought beyond distinct FGFR expression.

As receptivity of the injured hippocampus to cell grafts decreases with time after injury, strategies that improve graft integration are necessary for graft-mediated treatment of chronic neurodegenerative conditions such as temporal lobe epilepsy. We ascertained the efficacy of two distinct graft-augmentation strategies for improving the survival of embryonic day <em>19</em> hippocampal CA3 cell grafts placed into the adult hippocampus at 4-months after kainic acid induced injury. The donor cells were labeled with 5'-bromodeoxyuridine, and pre-treated and grafted with either brain-derived neurotrophic <em>factor</em>, neurotrophin-3 and a caspase inhibitor or <em>fibroblast</em> <em>growth</em> <em>factor</em> and caspase inhibitor. The yield of surviving grafted cells and neurons were quantified at 2-months post-grafting. The yield of surviving cells was substantially greater in grafts treated with brain-derived neurotrophic <em>factor</em>, neurotrophin-3 and caspase inhibitor (84%) or <em>fibroblast</em> <em>growth</em> <em>factor</em> and caspase inhibitor (99% of injected cells) than standard cell grafts (26%). Because approximately 85% of surviving grafted cells were neurons, increased yield in augmented groups reflects enhanced survival of grafted neurons. Evaluation of the mossy fiber synaptic re-organization in additional kainic acid-lesioned rats receiving grafts enriched with brain-derived neurotrophic <em>factor</em>, neurotrophin-3 and caspase inhibitor at 3-months post-grafting revealed reduced aberrant dentate mossy fiber sprouting in the dentate supragranular layer than "lesion-only" rats at 4 months post-kainic acid, suggesting that some of the aberrantly sprouted mossy fibers in the dentate supragranular layer withdraw when apt target cells (i.e. grafted neurons) become available in their vicinity. Thus, the yield of surviving neurons from CA3 cell grafts placed into the adult hippocampus at an extended time-point after injury could be enhanced through apt neurotrophic supplementation and caspase inhibition. Apt grafting is also efficacious for reversing some of the abnormal synaptic reorganization prevalent in the hippocampus at later time-points after injury.

OBJECTIVE

Fibroblast growth factor 23 (FGF23), a phosphatonin, inhibits renal phosphate reabsorption and suppresses 1-α hydroxylase activity. Calcitriol stimulates FGF23 synthesis in bone. We aimed to determine the effect of vitamin D replacement therapy on serum FGF23 concentrations in vitamin D-deficient women and to compare the FGF23 concentrations of vitamin D-deficient patients with healthy subjects and patients with genetically determined hypophosphatemic rachitis.

METHODS

The study group was composed of vitamin D-deficient females (n=18, mean age 29.1 ± 9.9 years), vitamin D-sufficient healthy females (control group; n=19, mean age 28.5 ± 5.2 years), and patients with genetically determined hypophosphatemic rachitis (n=13, mean age 26.5 ± 15.1 years). The groups were compared for serum FGF23, 1,25-dihydroxyvitamin D3 (1,25(OH)2D), calcium, phosphate, bone turnover markers, intact parathyroid hormone (PTH), and urinary excretion of calcium and phosphate. The vitamin D-deficient group was re-evaluated after a standard treatment regimen.

RESULTS

Serum FGF23 concentrations were significantly lower in vitamin D-deficient patients than in vitamin D-sufficient women and hypophosphatemic rachitis group. Serum FGF23 and phosphate concentrations further decreased significantly during replacement of vitamin D (P<0.05). A significant negative correlation was evident between FGF23 and PTH before vitamin D replacement in the patients (r=-0.469, P<0.05).

CONCLUSIONS

Decreased FGF23 concentrations, which further decline during vitamin D replacement therapy, may have favorable action on bone mineralization by counterregulatory effect on phosphate homeostasis. Lower 1,25(OH)2D concentrations at baseline and hypophosphatemia during treatment may have dominating effects on FGF23 concentrations in vitamin D deficiency, leading to decreased FGF23 concentrations at baseline and during replacement therapy.

The serine protease alpha-thrombin, a product of the circulating zymogen prothrombin, plays multiple roles in homeostasis and coagulation. During blood clotting, it is present within fibrin matrices and is likely to be presented to local cell populations. It is known to be a <em>fibroblast</em> mitogen, but its effects on <em>fibroblast</em> recruitment have not been assessed. Here we compared the effect of human alpha-thrombin on chemotaxis and proliferation of human and rat skin <em>fibroblasts</em> and assessed the mechanism of these actions. <em>Fibroblast</em> chemotaxis was assayed using a 48-well Boyden chamber and replication assessed by a spectrophotometric method, based upon the uptake and subsequent elution of methylene blue by <em>fibroblasts</em>. Two <em>fibroblast</em> cell lines were used; fetal rat skin (FR) and newborn human foreskin (HS68). Human alpha-thrombin stimulated FR <em>fibroblast</em> chemotaxis over a wide range of doses (10(-12) M to 10(-7) M). Maximal migration was seen at 10(-10) M; 39 +/- 2.5 cells/high power field (h.p.f.) compared with <em>19</em> +/- 3 cells/h.p.f. for media control. In the same assay platelet-derived <em>growth</em> <em>factor</em>, a well characterized <em>fibroblast</em> chemoattractant, caused a maximal stimulation of 44 +/- 5 cells/h.p.f. at a concentration of 3 x 10(-9) M. A similar stimulation was observed with HS68 <em>fibroblasts</em>, although for this cell line maximal chemotaxis (<em>19</em>0 +/- 12.5% of control) was seen at 10(-8) M thrombin. <em>Fibroblast</em> replication was optimal at 1.25 x 10(-9) M thrombin (134 +/- 4 and 127 +/- 5% of control for FR and HS68, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND

VIF-CAD randomized, placebo-controlled, double-blind trial was an attempt to induce therapeutic angiogenesis by percutaneous intramyocardial transfer of bicistronic (vascular endothelial growth factor/fibroblast growth factor [VEGF/FGF]) plasmid (pVIF) in patients with refractory heart ischemia. Myocardial perfusion, clinical symptoms, exercise tolerance, left ventricular function, and safety were assessed.

METHODS

Fifty-two patients with refractory coronary artery disease were randomized to receive VEGF/FGF plasmid (n = 33) or placebo plasmid (n = 19) into myocardial region showing stress-induced perfusion defects. Repeat stress and rest technetium Tc 99m sestamibi single-photon emission computed tomography at 5 months was the primary efficacy measure. Secondary assessment included Canadian Cardiovascular Society class and exercise tolerance at 5 and 12 months.

RESULTS

Rest- and stress-induced perfusion defects did not differ between groups. Canadian Cardiovascular Society functional class improved after 5 (P = .0210) and 12 months (P = .0607) in the treatment group. The exercise tolerance of treated patients improved: total exercise time increased marginally (P = .0541); maximum workload (P = .0419) and total test distance (P = .0473) increased significantly, compared to placebo.

CONCLUSIONS

Bicistronic VEGF/FGF plasmid therapy did not improve myocardial perfusion measured by single-photon emission computed tomography. However, treated patients experienced improvement with respect to exercise tolerance and clinical symptoms. Intramyocardial VEGF/FGF bicistronic plasmid transfer seemed safe throughout the follow-up period of 1 year.

Muenke syndrome, also known as FGFR3-associated coronal synostosis, is defined molecularly by the presence of a heterozygous nucleotide transversion, c.749C>G, encoding the amino acid substitution Pro250Arg, in the <em>fibroblast</em> <em>growth</em> <em>factor</em> receptor type 3 gene (FGFR3). This frequently occurs as a new mutation, manifesting one of the highest documented rates for any transversion in the human genome. To understand the biology of this mutation, we have investigated its parental origin, and the ages of the parents, in <em>19</em> families with de novo c.749C>G mutations. All ten informative cases originated from the paternal allele (95% confidence interval 74-100% paternal); the average paternal age at birth overall was 34.7 years. An exclusive paternal origin of mutations, and increased paternal age, were previously described for a different mutation (c.1138G>A) of the FGFR3 gene causing achondroplasia, as well as for mutations of the related FGFR2 gene causing Apert, Crouzon and Pfeiffer syndromes. We conclude that similar biological processes are likely to shape the occurrence of this c.749C>G mutation as for other mutations of FGFR3 as well as FGFR2.

The basic <em>fibroblast</em> <em>growth</em> <em>factor</em> (bFGF) gene locus is transcribed into a number of mRNA transcripts including an antisense mRNA derived from the opposite DNA strand of the bFGF gene. Expression of this natural antisense RNA has been implicated in regulation of the bFGF sense mRNA expression and turnover. In the present study we examined the developmental pattern of expression of the bFGF antisense transcript in fetal and postnatal rat tissues. Northern hybridization with a strand-specific cRNA probe detected a 1.5-kb polyadenylated antisense RNA in all tissues examined except brain, in which two transcripts were detected as a doublet of approximately 1.3-1.5 kb in size. The level of antisense transcript expression was markedly tissue- and age-dependent. In the developing brain, both sense and antisense transcripts were detected by Northern hybridization, but the pattern of their expression was inversely related. The 6.0-kb bFGF sense transcript increased in an age-dependent manner from days 3-30 of postnatal development while the antisense transcript decreased to nearly undetectable levels over the same period. In embryonic (days 15-<em>19</em>) liver, kidney, heart and intestine bFGF antisense RNA expression was low but increased dramatically at parturition, rising 5-10-fold over fetal levels by 10 days of age, then declined slowly to a new steady-state level in adult tissues. The level of antisense RNA in these tissues was much higher than that of bFGF sense mRNA, which was undetectable by Northern analysis. Sense and antisense trancripts were also detected in midgestational (11.5 days) embryos by RT-PCR. Antisense expression did not increase when embryos were explanted and cultured for 48 h (9.5-11.5 days). The apparent reciprocal relationship between the abundance of sense and antisense bFGF transcripts in developing brain supports the possibility of a regulatory role for the antisense transcript in this tissue. There was no evidence for a reciprocal relationship between sense and antisense expression in the other tissues examined, indicating that the relationship between sense and antisense RNA expression may be tissue-specific.

OBJECTIVE

Chronic diarrhoea resulting from primary idiopathic bile acid malabsorption (IBAM) is common, but its aetiology is largely unknown. We investigated possible mechanisms, first looking for common sequence variations in the cytoplasmic ileal bile acid-binding protein (IBABP, gene symbol FABP6), and secondly, determining the expression of ileal mucosal transcripts for the apical sodium-linked bile acid transporter (ASBT), IBABP, the putative basolateral transporters, OSTalpha and OSTbeta, and regulatory factors.

METHODS

Genomic DNA was prepared from two cohorts of patients and two control groups; the promoter and exonic regions of FABP6 were sequenced. In intestinal biopsies, transcript expression was measured by quantitative real time-PCR, using ileum from 17 patients and 21 controls.

RESULTS

Sequence variations were identified in FABP6, but overall frequencies were similar in patients and controls. Transcripts of ASBT and IBABP, but not OSTalpha and OSTbeta, were expressed at higher levels in ileum than duodenum. The transcription <em>factors</em> farnesoid-X-receptor (FXR) and liver-receptor-homologue (LRH-1) were also more abundant in ileum, as was <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>), unlike short heterodimer partner (SHP), c-Fos, or CDX2. No significant differences in mean or median values were found between the groups for any of these transcripts. However, findings on regression analysis suggested that these transporters differ in their regulation, particularly in the relationships of CDX2, LRH-1 and FXR with OSTalpha.

CONCLUSIONS

Most cases of IBAM are unlikely to be caused by genetic variation in FABP6 or by major differences in transporter transcript expression. Our evidence indicates that other factors, such as regulation of expression of the basolateral bile acid transporter, should be considered as possible causes.

CD123 (alpha-subunit of IL-3 receptor) expression on primitive and committed human hematopoietic cells was studied by multicolor sorting and single-cell culture. The sources of cells included fetal liver (FLV), fetal bone marrow, umbilical cord blood, adult bone marrow and mobilized peripheral blood. Three subsets of CD34+ cells were defined by the levels of surface CD123: CD123negative, CD123low, and CD123bright. Coexpression of lineage markers showed that a majority of CD34+CD123bright cells were myeloid and B-lymphoid progenitors, while erythroid progenitors were mainly in the CD34+CD123negative subset. The CD34+CD123low subset contained a heterogeneous distribution of early and committed progenitor cells. Single CD34+ cells from the CD123 subsets were cultured in a cytokine cocktail of stem cell <em>factor</em>, interleukin 3 (IL-3), IL-6, GM-CSF, erythropoietin, insulin-like <em>growth</em> <em>factor</em>-1, and basic <em>fibroblast</em> <em>growth</em> <em>factor</em>. After 14 days of incubation, a higher cloning efficiency (CE) was observed in the CD34+CD123negative and CD34+CD123low fractions (37+/-23% and 44+/-23%, respectively) than in the CD34+CD123bright fraction (15+/-21%). Using previously published criteria that colonies containing dispersed, translucent cells (dispersed <em>growth</em> pattern, DGP) were derived from primitive cells and that colonies composed solely of clusters were from committed cells, early precursors were distributed evenly in the CD34+CD123negative and CD34+CD123low subsets. When CD38 and CD90 (Thy-1) were used for further characterization of CD34+ cells from FLV, CE increased from 37+/-23% in CD123negative to 70+/-<em>19</em>% in CD123negativeCD38- and from 44+/-23% in CD123low to 66+/-<em>19</em>% in CD123lowCD38-. No significant increase in CE or DGP progenitors was observed when CD34+ cells were sorted by CD90 and CD123. We concluded that: A) high levels of CD123 were expressed on B-lymphoid and myeloid progenitors; B) early erythroid progenitors had little or no surface CD123, and C) primitive hematopoietic cells are characterized by CD123negative/low expression.

A <em>growing</em> body of literature suggests that the ubiquitously expressed Src family kinases (Src, Fyn and Yes) are required for agents such as platelet-derived <em>growth</em> <em>factor</em> (PDGF) to stimulate DNA synthesis. Yet Klinghoffer and colleagues recently presented evidence that <em>fibroblasts</em> derived from mice null for Src, Fyn and Yes responded normally to PDGF (Klinghoffer et al., <em>19</em>99, EMBO J., 18: 2459 - 2471). What is the reason for this discrepancy? We noted that Klinghoffer et al. (<em>19</em>99) used SV40 large T antigen (largeT) to facilitate derivation of cell lines from the embryos. We therefore tested the effect of largeT on PDGF receptor signaling. We found that expression of largeT overcame the inhibitory effects of interfering forms of both Ras (N17Ras) and Src (SrcK-). Furthermore, injection of SrcK- or the cst.1 antibody (which inhibits Src, Fyn and Yes) failed to inhibit PDGF-stimulated DNA synthesis in NIH3T3 cells expressing dominant negative p53, and <em>fibroblasts</em> derived from p53 null embryos. These data suggest firstly that caution should be used in interpretation of experiments conducted in cell lines expressing largeT, and secondly that the role of Src family kinases in <em>growth</em> <em>factor</em> signaling may be to oppose the effects of negative <em>growth</em> regulators such as p53. Oncogene (2000) <em>19</em>, 2867 - 2869

The extent to which plasma levels of angiogenic <em>factors</em> in healthy individuals and tumour volume-related variations in colorectal cancer affect the accuracy of circulating angiogenic <em>factors</em> as predictors of colorectal cancer vascularity is unknown. We used enzyme-linked immunosorbant assay to measure plasma vascular endothelial <em>growth</em> <em>factor</em> (VEGF) and basic <em>fibroblast</em> <em>growth</em> <em>factor</em> (bFGF) levels in colorectal liver metastasis (CLM) patients, and 'no cancer' controls. CLM volume was determined from computerized tomography scans, and tumour vessel count and vessel volume from anti-endothelial antibody-stained biopsies. There was a significant (P= 0.03) increase in plasma VEGF level in 29 CLM patients (median 180.3 pg/ml(-1), iqr 132.5-284.8 pg/ml(-1) compared with <em>19</em> controls (median 125.8 pg/ml(-1), iqr 58.2-235.9 pg/ml(-1). There were significant correlations between plasma VEGF and tumour vessel count (r = 0.66, P = 0.03), tumour vessel volume (r= 0.59, P = 0.03), and CLM volume (r= 0.53, P = 0.03). A VEGF level in the upper quartile of the plasma VEGF distribution had a 70% sensitivity and 75% specificity in predicting an upper quartile liver metastasis tumour vessel count. No relation was identified between CLM and plasma bFGF levels. Plasma VEGF level predicted CLM vascularity, despite an overlap with normal levels and tumour volume-related variations.

Cytotoxic ether lipid analogues have been studied for their ability to inhibit <em>growth</em> <em>factor</em>-dependent [Ca2+]i signaling in Swiss 3T3 <em>fibroblasts</em>. 1-Octadecyl-2-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3) inhibited 45Ca2+ uptake and inositol(1,4,5)trisphosphate-induced 45Ca2+ release in saponin permeabilized cells with concentration producing 50% inhibition values of 55 and 360 microM, respectively. When cells were exposed to ET-18-OCH3 for 18 h before permeabilization there was selective inhibition of inositol(1,4,5)trisphosphate-induced 45Ca2+ release with a concentration producing 50% inhibition value of 20 microM, but no effect on 45Ca2+ uptake, or on 45Ca2+ release by arachidonic acid. The concentration of ET-18-OCH3 with continuous exposure to inhibit cell <em>growth</em> 50% was <em>19</em> microM. The ether lipid analogues 1-hexadecylthio-2-ethyl-rac-glycero-3- phosphocholine and 1-S-octadecyl-2-O-methylthiopropyl-3-N,N-dimethyl-gamma-hydroxy pro pyl ammonium iodide had effects similar to those of ET-18-OCH3 but the noncytotoxic analogue 1-alkyl-2-hydroxy-sn-glycero-3- phosphocholine was without effect. Exposure of cells to 10 microM ET-18-OCH3 produced 81% inhibition of platelet-derived <em>growth</em> <em>factor</em>-stimulated inositol phosphate formation and 66% inhibition of fluoroaluminate anion-stimulated inositol phosphate formation. Addition of ET-18-OCH3 to cells in medium with 10% fetal calf serum gave a transient increase in [Ca2+]i without causing an increase in resting [Ca2+]i, while the addition of ET-18-OCH3 to cells in medium without serum gave a sustained increase in resting [Ca2+]i. Cells exposed to 5 microM ET-18-OCH3 for 18 h showed no increase in resting [Ca2+]i but there was 95% inhibition of the [Ca2+]i response to platelet-derived <em>growth</em> <em>factor</em>, 63% inhibition of the response to bradykinin, and 55% inhibition of the response to vasopressin. The block by ether lipid analogues of inositol phosphate-mediated [Ca2+]i signaling suggests a mechanism for preventing the action of <em>growth</em> <em>factors</em> that could contribute to the inhibition of cell proliferation by the agents.

<em>Fibroblast</em> <em>growth</em> <em>factors</em> (FGFs) are a family of 21 cytokines with a broad spectrum of activities, including regulation of cell proliferation, differentiation, and migration. The various FGFs bind to one or more of four different tyrosine kinase receptor types. FGFs 1, 2, 5, 7, and 10 are up-regulated during adult cutaneous wound healing. However, the expression of FGFs during fetal skin development and scarless wound healing has not been characterized. It was hypothesized that differential expression of FGF isoforms and receptors occurs during fetal skin development and that this differential expression pattern may regulate the transition from scarless repair to healing with scar formation. Excisional wounds (2 mm) were created on fetal rats at gestational days 16.5 (scarless) (one wound per fetus, n = 36 fetuses) and <em>19</em>.5 (scarring) (one wound per fetus, n = 36 fetuses). Wounds were harvested at 24, 48, and 72 hours. Survival until wound harvest ranged from 66 to 75 percent for the gestational day 16 fetuses, and from 83 to 92 percent for the gestational day <em>19</em> fetuses. Nonwounded fetal skin from littermates (n = 12 fetuses per wound harvest time point) was used as the control. Wounds/skins were pooled by harvest time point, and RNA was isolated from pooled wounds/skins. Reduced-cycle, specific-primer reverse transcriptase-polymerase chain reaction was performed to determine the expression of FGF isoforms 2, 5, 7, 9, and 10 and FGF receptors 1, 2, and 4 in wounds relative to unwounded skin.In unwounded fetal skin, FGF isoform 5 expression more than doubled at birth. FGF 10 expression doubled during the transition period. FGF 7 expression increased more than sevenfold at birth. Expression of FGF isoforms 2 and 9 did not change during late fetal skin development. The expression of FGF receptors 1, 2, and 4 increased at birth. After wounding, expression of FGF isoforms 7 and 10 was down-regulated in scarless wounds, whereas FGF receptor 2 expression decreased in both scarless and scar-forming wounds. Expression of FGF isoforms 5 and 9 did not change in scarless wounds. FGF receptor 2 expression was down-regulated in both scarless and scarring wounds, but at an earlier and more sustained level in scarless wounds. Receptor type 4 expression increased in scarring wounds, whereas type 1 expression did not change in either scarless or scarring wounds. These results demonstrate an overall down-regulation of FGF expression during scarless healing.

BACKGROUND

Decidualization, the differentiation of endometrial stromal cells is a crucial step for successful implantation of an embryo, development of the placenta and completion of pregnancy to term. Epigenetic mechanisms are thought to be strongly involved in the regulation of processes controlling implantation, placentation, organ formation and foetal growth. Recent studies suggest that decreased DNA methylation facilitates a receptive endometrium. Hence, the aim of this project was to compare the transcriptional profile changes induced by the inhibitor of DNA methylation, 5-Aza-2'-deoxycytidine (AZA) to the transcriptional changes that happen during decidualization.

RESULTS

When DNA methylation was inhibited in a human endometrial stromal cell (HESC) line with AZA, it resulted in the fibroblast-like stromal cells being transformed into decidual-like morphology after 9 days. Expression of both prolactin and insulin-like growth factor binding protein-1, the two established decidualization marker genes, were minimally up-regulated by AZA after 10 days of treatment. In a microarray of a three-way experiment between AZA-treated and oestradiol/progestin/cAMP-treated [medroxy-progesterone acetate (MPA)-mix] HESC and the untreated controls, we detected more than 1000 common genes that had a significant difference of expression compared with the controls. AZA-treated cells in the microarray significantly expressed 76 genes in common with the MPA-mix treated cells, and AZA treatment also differentially regulated 148 genes independently to that of MPA-mix treatment. The MPA-mix regulated at least 36 genes in the cell adhesion, extracellular matrix remodelling and RhoGTPase cytoskeletal reorganization pathway; AZA regulated 19 of these genes in common and 15 other RhoGTPase pathway genes.

CONCLUSIONS

AZA induced some decidualization-like responses of endometrial stromal cells independently of progestins or cAMP, possibly via the cytoskeletal reorganization pathway of the RhoGTPase family.

BACKGROUND

Rodent mesenchymal stem/stromal cells (MSCs) enhance repair after ventilator-induced lung injury (VILI). We wished to determine the therapeutic potential of human MSCs (hMSCs) in repairing the rodent lung.

METHODS

In series 1, anesthetized rats underwent VILI (series 1A, n = 8 to 9 per group) or protective ventilation (series 1B, n = 4 per group). After VILI, they were randomized to intravenous administration of (1) vehicle (phosphate-buffered saline); (2) fibroblasts (1 × 10 cells/kg); or (3) human MSCs (1 × 10 cells/kg) and the effect on restoration of lung function and structure assessed. In series 2, the efficacy of hMSC doses of 1, 2, 5, and 10 million/kg was examined (n = 8 per group). Series 3 compared the efficacy of both intratracheal and intraperitoneal hMSC administration to intravascular delivery (n = 5-10 per group). Series 4 examined the efficacy of delayed hMSC administration (n = 8 per group).

RESULTS

Human MSC's enhanced lung repair, restoring oxygenation (131 ± 19 vs. 103 ± 11 vs. 95 ± 11 mmHg, P = 0.004) compared to vehicle or fibroblast therapy, respectively. hMSCs improved lung compliance, reducing alveolar edema, and restoring lung architecture. hMSCs attenuated lung inflammation, decreasing alveolar cellular infiltration, and decreasing cytokine-induced neutrophil chemoattractant-1 and interleukin-6 while increasing keratinocyte growth factor concentrations. The lowest effective hMSC dose was 2 × 10 hMSC/kg. Intraperitoneal hMSC delivery was less effective than intratracheal or intravenous hMSC. hMSCs enhanced lung repair when administered at later time points after VILI.

CONCLUSIONS

hMSC therapy demonstrates therapeutic potential in enhancing recovery after VILI.

COVID-<em>19</em> rapidly emerged as a crippling public health crisis in the last few months, which has presented a series health risk. Understanding of the immune response and biomarker analysis is needed to progress toward understanding disease pathology and developing improved treatment options. The goal of this study is to identify pathogenic <em>factors</em> that are linked to disease severity and patient characteristics. Patients with COVID-<em>19</em> who were hospitalized from March 17 to June 5, 2020 were analyzed for clinical features of disease and soluble plasma cytokines in association with disease severity and sex. Data from COVID-<em>19</em> patients with acute illness were examined along with an age- and gender-matched control cohort. We identified a group of 16 soluble <em>factors</em> that were found to be increased in COVID-<em>19</em> patients compared to controls, whereas 2 <em>factors</em> were decreased. In addition to inflammatory cytokines, we found significant increases in <em>factors</em> known to mediate vasculitis and vascular remodeling (PDGF-AA, PDGF-AB-BB, soluble CD40L (sCD40L), FGF, and IP10). Four <em>factors</em> such as platelet-derived <em>growth</em> <em>factors</em>, <em>fibroblast</em> <em>growth</em> <em>factor</em>-2, and IFN-γ-inducible protein 10 were strongly associated with severe disease and ICU admission. Th2-related <em>factors</em> (IL-4 and IL-13) were increased with IL-4 and sCD40L present at increased levels in males compared with females. Our analysis revealed networking clusters of cytokines and <em>growth</em> <em>factors</em>, including previously unknown roles of vascular and stromal remodeling, activation of the innate immunity, as well activation of type 2 immune responses in the immunopathogenesis of COVID-<em>19</em>. These data highlight biomarker associations with disease severity and sex in COVID-<em>19</em> patients.

Keywords: .

Keratin (K) <em>19</em>-positive hepatocellular carcinoma (HCC) is well known to have a higher malignant potential than K<em>19</em>-negative HCC: However, the molecular mechanisms involved in K<em>19</em>-mediated progression of HCC remain unclear. We attempted to clarify whether K<em>19</em> directly affects cell survival and invasiveness in association with cellular senescence or epithelial-mesenchymal transition (EMT) in K<em>19</em>-positive HCC.

K<em>19</em> expression was analysed in 136 HCC surgical specimens. The relationship of K<em>19</em> with clinicopathological factors and survival was analysed. Further, the effect of K<em>19</em> on cell proliferation, invasion, and angiogenesis was examined by silencing K<em>19</em> in the human HCC cell lines, HepG2, HuH-7, and PLC/PRF/5. Finally, we investigated HCC invasion, proliferation, and angiogenesis using K<em>19</em>-positive HCC specimens.

Analysis of HCC surgical specimens revealed that K<em>19</em>-positive HCC exhibited higher invasiveness, metastatic potential, and poorer prognosis. In vitro experiments using the human HCC cell lines revealed that K<em>19</em> silencing suppressed cell growth by inducting apoptosis or upregulating p16 and p27, resulting in cellular senescence. In addition, transfection with K<em>19</em> siRNA upregulated E-cadherin gene expression, significantly inhibited the invasive capacity of the cells, downregulated angiogenesis-related molecules such as vasohibin-1 (VASH1) and fibroblast growth factor 1 (FGFR1), and upregulated vasohibin-2 (VASH2). K<em>19</em>-positive HCC specimens exhibited a high MIB-1 labelling index, decreased E-cadherin expression, and high microvessel density around cancer foci.

K<em>19</em> directly promotes cancer cell survival, invasion, and angiogenesis, resulting in HCC progression and poor clinical outcome. K<em>19</em> may therefore be a novel drug target for the treatment of K<em>19</em>-positive HCC.

Capsicum-derived ingredients function as skin-conditioning agents--miscellaneous, external analgesics, flavoring agents, or fragrance components in cosmetics. These ingredients are used in <em>19</em> cosmetic products at concentrations as high as 5%. Cosmetic-grade material may be extracted using hexane, ethanol, or vegetable oil and contain the full range of phytocompounds that are found in the Capsicum annuum or Capsicum frutescens plant (aka red chiles), including Capsaicin. Aflatoxin and N-nitroso compounds (N-nitrosodimethylamine and N-nitrosopyrrolidine) have been detected as contaminants. The ultraviolet (UV) absorption spectrum for Capsicum Annuum Fruit Extract indicates a small peak at approximately 275 nm, and a gradual increase in absorbance, beginning at approximately 400 nm. Capsicum and paprika are generally recognized as safe by the U.S. Food and Drug Administration for use in food. Hexane, chloroform, and ethyl acetate extracts of Capsicum Frutescens Fruit at 200 mg/kg resulted in death of all mice. In a short-term inhalation toxicity study using rats, no difference was found between vehicle control and a 7% Capsicum Oleoresin solution. In a 4-week feeding study, red chilli (Capsicum annuum) in the diet at concentrations up to 10% was relatively nontoxic in groups of male mice. In an 8-week feeding study using rats, intestinal exfoliation, cytoplasmic fatty vacuolation and centrilobular necrosis of hepatocytes, and aggregation of lymphocytes in the portal areas were seen at 10% Capsicum Frutescens Fruit, but not 2%. Rats fed 0.5 g/kg day-1 crude Capsicum Fruit Extract for 60 days exhibited no significant gross pathology at necropsy, but slight hyperemia of the liver and reddening of the gastric mucosa were observed. Weanling rats fed basal diets supplemented with whole red pepper at concentrations up to 5.0% for up to 8 weeks had no pathology of the large intestines, livers, and kidneys, but destruction of the taste buds and keratinization and erosion of the gastrointestinal (GI) tract were noted in groups fed 0.5% to 5.0% red pepper. The results of 9-and 12-month extension of this study showed normal large intestines and kidneys. In rabbits fed Capsicum Annuum Powder at 5 mg/kg day-1 in the diet daily for 12 months damage to the liver and spleen was noted. A rabbit skin irritation test of Capsicum Annuum Fruit Extract at concentrations ranging from 0.1% to 1.0% produced no irritation, but Capsicum Frutescens Fruit Extract induced concentration-dependent (at 25 to 500 microg/ml) cytotoxicity in a human buccal mucosa <em>fibroblast</em> cell line. An ethanol extract of red chili was mutagenic in Salmonella typhimurium TA98, but not in TA100, or in Escherichia coli. Other genotoxicity assays gave a similar pattern of mixed results. Adenocarcinoma of the abdomen was observed in 7/20 mice fed 100 mg red chilies per day for 12 months; no tumors were seen in control animals. Neoplastic changes in the liver and intestinal tumors were observed in rats fed red chili powder at 80 mg/kg day-1 for 30 days, intestinal and colon tumors were seen in rats fed red chili powder and 1,2-dimethyl hydrazine, but no tumors were observed in controls. In another study in rats, however, red chile pepper in the diet at the same dose decreased the number of tumors seen with 1,2-dimethylhydrazine. Other feeding studies evaluated the effect of red chili peppers on the incidence of stomach tumors produced by N-methyl-N'-nitro-N-nitrosoguanidine, finding that red pepper had a promoting effect. Capsicum Frutescens Fruit Extract promoted the carcinogenic effect of methyl(acetoxymethyl)nitrosamine (carcinogen) or benzene hexachloride (hepatocarcinogen) in inbred male and female Balb/c mice dosed orally (tongue application). Clinical findings include symptoms of cough, sneezing, and runny nose in chili <em>factor</em>y workers. Human respiratory responses to Capsicum Oleoresin spray include burning of the throat, wheezing, dry cough, shortness of breath, gagging, gasping, inability to breathe or speak, and, rarely, cyanosis, apnea, and respiratory arrest. A trade name mixture containing 1% to 5% Capsicum Frutescens Fruit Extract induced very slight erythema in 1 of 10 volunteers patch tested for 48 h. Capsicum Frutescens Fruit Extract at 0.025% in a repeated-insult patch test using 103 subjects resulted in no clinically meaningful irritation or allergic contact dermatitis. One epidemiological study indicated that chili pepper consumption may be a strong risk <em>factor</em> for gastric cancer in populations with high intakes of chili pepper; however, other studies did not find this association. Capsaicin functions as an external analgesic, a fragrance ingredient, and as a skin-conditioning agent--miscellaneous in cosmetic products, but is not in current use. Capsaicin is not generally recognized as safe and effective by the U.S. Food and Drug Administration for fever blister and cold sore treatment, but is considered to be safe and effective as an external analgesic counterirritant. Ingested Capsaicin is rapidly absorbed from the stomach and small intestine in animal studies. Subcutaneous injection of Capsaicin in rats resulted in a rise in the blood concentration, reaching a maximum at 5 h; the highest tissue concentrations were in the kidney and lowest in the liver. In vitro percutaneous absorption of Capsaicin has been demonstrated in human, rat, mouse, rabbit, and pig skin. Enhancement of the skin permeation of naproxen (nonsteroidal anti-inflammatory agent) in the presence of Capsaicin has also been demonstrated. Pharmacological and physiological studies demonstrated that Capsaicin, which contains a vanillyl moiety, produces its sensory effects by activating a Ca2 +-permeable ion channel on sensory neurons. Capsaicin is a known activator of vanilloid receptor 1. Capsaicin-induced stimulation of prostaglandin biosynthesis has been shown using bull seminal vesicles and rheumatoid arthritis synoviocytes. Capsaicin inhibits protein synthesis in Vero kidney cells and human neuroblastoma SHSY-5Y cells in vitro, and inhibits <em>growth</em> of E. coli, Pseudomonas solanacearum, and Bacillus subtilis bacterial cultures, but not Saccharomyces cerevisiae. Oral LD50 values as low as 161.2 mg/kg (rats) and 118.8 mg/kg (mice) have been reported for Capsaicin in acute oral toxicity studies, with hemorrhage of the gastric fundus observed in some of the animals that died. Intravenous, intraperitoneal, and subcutaneous LD50 values were lower. In subchronic oral toxicity studies using mice, Capsaicin produced statistically significant differences in the <em>growth</em> rate and liver/body weight increases. Capsaicin is an ocular irritant in mice, rats, and rabbits. Dose-related edema was observed in animals receiving Capsaicin injections into the hindpaw (rats) or application to the ear (mice). In guinea pigs, dinitrochlorobenzene contact dermatitis was enhanced in the presence of Capsaicin, injected subcutaneously, whereas dermal application inhibited sensitization in mice. Immune system effects have been observed in neonatal rats injected subcutaneously with Capsaicin. Capsaicin produced mixed results in S. typhimurium micronucleus and sister-chromatid exchange genotoxicity assays. Positive results for Capsaicin were reported in DNA damage assays. Carcinogenic, cocarcinogenic, anticarcinogenic, antitumorigenic, tumor promotion, and anti-tumor promotion effects of Capsaicin have been reported in animal studies. Except for a significant reduction in crown-rump length in day 18 rats injected subcutaneously with Capsaicin (50 mg/kg) on gestation days 14, 16, 18, or 20, no reproductive or developmental toxicity was noted. In pregnant mice dosed subcutaneously with Capsaicin, depletion of substance P in the spinal cord and peripheral nerves of pregnant females and fetuses was noted. In clinical tests, nerve degeneration of intracutaneous nerve fibers and a decrease in pain sensation induced by heat and mechanical stimuli were evident in subjects injected intradermally with Capsaicin. An increase in mean inspiratory flow was reported for eight normal subjects who inhaled nebulized 10(-7) M Capsaicin. The results of provocative and predictive tests involving human subjects indicated that Capsaicin is a skin irritant. Overall, studies suggested that these ingredients can be irritating at low concentrations. Although the genotoxicity, carcinogenicity, and tumor promotion potential of Capsaicin have been demonstrated, so have opposite effects. Skin irritation and other tumor-promoting effects of Capsaicin appear to be mediated through interaction with the same vanilloid receptor. Given this mechanism of action and the observation that many tumor promoters are irritating to the skin, the Panel considered it likely that a potent tumor promoter may also be a moderate to severe skin irritant. Thus, a limitation on Capsaicin content that would significantly reduce its skin irritation potential is expected to, in effect, lessen any concerns relating to tumor promotion potential. Because Capsaicin enhanced the penetration of an anti-inflammatory agent through human skin, the Panel recommends that care should be exercised in using ingredients that contain Capsaicin in cosmetic products. The Panel advised industry that the total polychlorinated biphenyl (PCB)/pesticide contamination should be limited to not more than 40 ppm, with not more than 10 ppm for any specific residue, and agreed on the following limitations for other impurities: arsenic (3 mg/kg max), heavy metals (0.002% max), and lead (5 mg/kg max). Industry was also advised that aflatoxin should not be present in these ingredients (the Panel adopted < or =15 ppb as corresponding to "negative" aflatoxin content), and that ingredients derived from Capsicum annuum and Capsicum Frutescens Plant species should not be used in products where N-nitroso compounds may be formed. (ABSTRACT TRUNCATED)

BACKGROUND

This study aims to quantify changes in <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) and bile acids (BAs) in patients with uncontrolled type 2 diabetes randomized to Roux-en-Y gastric bypass (RYGB) vs intensive medical management (IMM) and matched for similar reduction in HbA1c after 1 year of treatment.

METHODS

Blood samples were drawn from patients who underwent a test meal challenge before and 1 year after IMM (n = 15) or RYGB (n = 15).

RESULTS

Mean HbA1c decreased from 9.7 to 6.4% after RYGB and from 9.1 to 6.1% in the IMM group. At 12 months, the number of diabetes medications used per subject in the RYGB group (2.5 ± 0.5) was less than in the IMM group (4.6 ± 0.3). After RYGB, FGF<em>19</em> increased in the fasted (93 ± 15 to 152 ± <em>19</em> pg/ml; P = 0.008) and postprandial states (area under the curve (AUC), 10.8 ± 1.9 to 23.4 ± 4.1 pg × h/ml × 10(3); P = 0.006) but remained unchanged following IMM. BAs increased after RYGB (AUC ×10(3), 6.63 ± 1.3 to 15.16 ± 2.56 μM × h; P = 0.003) and decreased after IMM (AUC ×10(3), 8.22 ± 1.24 to 5.70 ± 0.70; P = 0.01). No changes were observed in the ratio of 12α-hydroxylated/non-12α-hyroxylated BAs. Following RYGB, FGF<em>19</em> AUC correlated with BAs (r = 0.54, P = 0.04) and trended negatively with HbA1c (r = -0.44; P = 0.09); these associations were not observed after IMM.

CONCLUSIONS

BA and FGF<em>19</em> levels increased after RYGB but not after IMM in subjects who achieved similar improvement in glycemic control. Further studies are necessary to determine whether these hormonal changes facilitate improved glucose homeostasis.

<em>Fibroblast</em> <em>growth</em> <em>factor</em> 15/<em>19</em> (FGF15/<em>19</em>), an enterokine that regulates synthesis of hepatic bile acids (BA), has been proposed to influence fat metabolism. Without FGF15/<em>19</em>, mouse liver regeneration after partial hepatectomy (PH) is severely impaired. We studied the role of FGF15/<em>19</em> in response to a high fat diet (HFD) and its regulation by saturated fatty acids. We developed a fusion molecule encompassing FGF<em>19</em> and apolipoprotein A-I, termed Fibapo, and evaluated its pharmacological properties in fatty liver regeneration.

Fgf15-/- mice were fed a HFD. Liver fat and the expression of fat metabolism and endoplasmic reticulum (ER) stress-related genes were measured. Influence of palmitic acid (PA) on FGF15/<em>19</em> expression was determined in mice and in human liver cell lines. In vivo half-life and biological activity of Fibapo and FGF<em>19</em> were compared. Hepatoprotective and proregenerative activities of Fibapo were evaluated in obese db/db mice undergoing PH.

Hepatosteatosis and ER stress were exacerbated in HFD-fed Fgf15-/- mice. Hepatic expression of Pparγ2 was elevated in Fgf15-/- mice, being reversed by FGF<em>19</em> treatment. PA induced FGF15/<em>19</em> expression in mouse ileum and human liver cells, and FGF<em>19</em> protected from PA-mediated ER stress and cytotoxicity. Fibapo reduced liver BA and lipid accumulation, inhibited ER stress and showed enhanced half-life. Fibapo provided increased db/db mice survival and improved regeneration upon PH.

FGF15/<em>19</em> is essential for hepatic metabolic adaptation to dietary fat being a physiological regulator of Pparγ2 expression. Perioperative administration of Fibapo improves fatty liver regeneration.

Bile acids are best known as detergents involved in the digestion of lipids. In addition, new data in the last decade have shown that bile acids also function as gut hormones capable of influencing metabolic processes via receptors such as FXR (farnesoid X receptor) and TGR5 (Takeda G protein-coupled receptor 5). These effects of bile acids are not restricted to the gastrointestinal tract, but can affect different tissues throughout the organism. It is still unclear whether these effects also involve signaling of bile acids to the central nervous system (CNS). Bile acid signaling to the CNS encompasses both direct and indirect pathways. Bile acids can act directly in the brain via central FXR and TGR5 signaling. In addition, there are two indirect pathways that involve intermediate agents released upon interaction with bile acids receptors in the gut. Activation of intestinal FXR and TGR5 receptors can result in the release of <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) and glucagon-like peptide 1 (GLP-1), both capable of signaling to the CNS. We conclude that when plasma bile acids levels are high all three pathways may contribute in signal transmission to the CNS. However, under normal physiological circumstances, the indirect pathway involving GLP-1 may evoke the most substantial effect in the brain.