Elevated fibroblast growth factor 23 (FGF23) in X-linked hypophosphatemia (XLH) results in rickets and phosphate wasting, manifesting by severe bone and dental abnormalities. Burosumab, a FGF23-neutralizing antibody, an alternative to conventional treatment (phosphorus and active vitamin D analogs), showed significant improvement in the long bone phenotype. Here, we examined whether FGF23 antibody (FGF23-mAb) also improved the dentoalveolar features associated with XLH. Four-week-old male Hyp mice were injected weekly with 4 or 16 mg·kg^-1 of FGF23-mAb for 2 months and compared to wild-type (WT) and vehicle (PBS) treated Hyp mice (n = 3-7 mice). Micro-CT analyses showed that both doses of FGF23-mAb restored dentin/cementum volume and corrected the enlarged pulp volume in Hyp mice, the higher concentration resulting in a rescue similar to WT levels. FGF23-mAb treatment also improved alveolar bone volume fraction and mineral density compared to vehicle-treated ones. Histology revealed improved mineralization of the dentoalveolar tissues, with a decreased amount of osteoid, predentin and cementoid. Better periodontal ligament attachment was also observed, evidenced by restoration of the acellular cementum. These preclinical data were consistent with the retrospective analysis of two patients with XLH showing that burosumab treatment improved oral features. Taken together, our data show that the dentoalveolar tissues are greatly improved by FGF23-mAb treatment, heralding its benefit in clinics for dental abnormalities.
Humans ; Male ; Mice ; Animals ; Familial Hypophosphatemic Rickets/pathology* ; Fibroblast Growth Factor-23 ; Retrospective Studies ; Fibroblast Growth Factors/metabolism* ; Bone and Bones/metabolism* ; Phosphates/therapeutic use*

Administration, Topical ; Alopecia/drug therapy* ; China ; Double-Blind Method ; Fibroblast Growth Factors/therapeutic use* ; Hair ; Humans ; Male ; Minoxidil/therapeutic use* ; Treatment Outcome

Bile acid diarrhea (BAD) is usually seen in patients with ileal Crohn's disease or ileal resection. However, 25% to 50% of patients with functional diarrhea or diarrhea-predominant irritable bowel syndrome (IBS-D) also have evidence of BAD. It is estimated that 1% of the population may have BAD. The causes of BAD include a deficiency in fibroblast growth factor 19 (FGF-19), a hormone produced in enterocytes that regulates hepatic bile acid (BA) synthesis. Other potential causes include genetic variations that affect the proteins involved in BA enterohepatic circulation and synthesis or in the TGR5 receptor that mediates the actions of BA in colonic secretion and motility. BAs enhance mucosal permeability, induce water and electrolyte secretion, and accelerate colonic transit partly by stimulating propulsive high-amplitude colonic contractions. There is an increased proportion of primary BAs in the stool of patients with IBS-D, and some changes in the fecal microbiome have been described. There are several methods of diagnosing BAD, such as 75selenium homotaurocholic acid test retention, serum C4, FGF-19, and fecal BA measurement; presently, therapeutic trials with BA sequestrants are most commonly used for diagnosis. Management involves the use of BA sequestrants including cholestyramine, colestipol, and colesevelam. FXR agonists such as obeticholic acid constitute a promising new approach to treating BAD.
Anticholesteremic Agents/therapeutic use ; Bile Acids and Salts/*physiology ; Crohn Disease/complications ; Diarrhea/*etiology/pathology/therapy ; Feces/chemistry ; Fibroblast Growth Factors/deficiency ; Gastrointestinal Microbiome ; Humans ; Irritable Bowel Syndrome/complications

OBJECTIVETo investigate the influence of aqueous extract of Aralia echinocaulis Hand.-Mazz on the expression of fracture healing-ralated factor receptors.

METHODSSingle factor model was set up in SD rat. Selecting 14 and 28 days in the experiment. Immunohistochemistry was employed to determine the expression of Fibroblast growth factor receptor 2 (FGFR2), Fms-like tyrosine kinase (Flt-1) and Fetal licer kinase (Flk-1) at 14 and 28 days after model establishing.

RESULTSThe expression of Flt-1 and Flk-1 at 14 days (the latter was more remarkable) were obviously promoted in High dose group of aqueous extract of Aralia echinocaulis Hand.-Mazz, and higher than that in normal group and model group. The expression of FGFR2 in the high dose group of Aralia echinocaulis Hand -Mazz was also promoted visibility, close to that in the compare group (traditional Chinese medicine), but higher than than in the model group. There was no significant difference among them. At 28 days, the expression of FGFR2, Flt-1 and Flk-1 in all groups decreased except normal group, and got higher expression in model groups than each control groups.

CONCLUSIONAqueous extract of Aralia echinocaulis Hand.-Mazz can promote angiogenesis in fracture healing, improve the activity and aggregation of fibroblasts, osteoblasts and chondrocytes. It also helps to quicken ossification in the cartilage and promote fracture healing.

Animals ; Aralia ; chemistry ; Drugs, Chinese Herbal ; chemistry ; pharmacology ; therapeutic use ; Female ; Fibroblast Growth Factors ; metabolism ; Immunohistochemistry ; Rats ; Rats, Sprague-Dawley ; Vascular Endothelial Growth Factor A ; metabolism ; Wound Healing ; drug effects

The aim of this study was to evaluate the efficacy of palifermin, an N-terminal truncated version of endogenous keratinocyte growth factor, in the control of oral mucositis during antiblastic therapy. Twenty patients undergoing allogeneic stem-cell transplantation for acute lymphoblastic leukaemia were treated with palifermin, and compared to a control group with the same number of subjects and similar inclusion criteria. Statistical analysis were performed to compare the outcomes in the treatment vs. control groups. In the treatment group, we found a statistically significant reduction in the duration of parenteral nutrition (P=0.002), duration of mucositis (P=0.003) and the average grade of mucositis (P=0.03). The statistical analysis showed that the drug was able to decrease the severity of mucositis. These data, although preliminary, suggest that palifermin could be a valid therapeutic adjuvant to improve the quality of life of patients suffering from leukaemia.
Adolescent ; Allografts ; transplantation ; Anti-Inflammatory Agents ; therapeutic use ; Case-Control Studies ; Child ; Cohort Studies ; Cyclophosphamide ; therapeutic use ; Female ; Fibroblast Growth Factor 7 ; therapeutic use ; Hematopoietic Stem Cell Transplantation ; methods ; Humans ; Male ; Myeloablative Agonists ; therapeutic use ; Parenteral Nutrition ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; therapy ; Radiotherapy Dosage ; Stomatitis ; classification ; drug therapy ; prevention & control ; Time Factors ; Transplantation Conditioning ; methods ; Treatment Outcome ; Whole-Body Irradiation

OBJECTIVETo explore the changes of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and angiogenesis, and the effects of bFGF, angiotensin converting enzyme inhibiter(ACEI) benazepril on the angiogenesis in acute myocardial infarction (AMI) model of rabbits, and to provide a probable evidence for the treatment of AMI.

METHODSAMI model was established by ligating anterior descending branch of coronary artery of Japan-Sino hybridization white rabbits. The postoperative rabbits were randomly divided into 6 groups and each group was treated with different drugs. Groups 1 and 2 were treated with normal saline (NS) for 28 and 14 days (d), group 3 and 4 with bFGF for 28 and 14 d, groups 5 with benazepril for 14 d, and group 6 with benazepril and bFGF for 14 d respectively. The rabbits were killed on the 14th or 28th d and their hearts were excised, sectioned and stained with HE, Masson trichrome to observe VEGF, bFGF and CD(34) under a microscope, which were quantified with a computer-assisted morphometry.

RESULTSCompared with group 1, the granulation tissue of infarction zone (IZ) in group 2 freshened up, and the capillary density (CD) in IZ was increased (P = 0.002). The CD in the IZ as well as VEGF and bFGF in groups 3 and 4 were increased respectively (P = 0.011-0.037). In group 5 the changes of VEGF and bFGF were not found in the IZ and the border zone (BZ) while CD was significantly increased (35.4% and 25.6%, P = 0.036 and 0.037). Compared with group 2, the CD in the IZ and BZ of group 6 was significantly increased (63.4% and 44.3% P = 0.007 and 0.007), meanwhile VEGF and bFGF were increased. Compared with group 5, only VEGF was increased.

CONCLUSIONIntravenous bFGF may increase VEGF and bFGF significantly, thus promoting the angiogenesis in the IZ and BZ in cardiac infarction as VEGF and bFGF are the potent angiogenic growth factors. Benazepril may promote angiogenesis in the IZ and BZ in cardiac infarction, but its mechanism is irrelative to the expression of VEGF and bFGF. The combination of benazepril and bFGF may promote, to some extent, the expression of VEGF and bFGF, but their effect on angiogenesis has not been found.

Angiotensin-Converting Enzyme Inhibitors ; pharmacology ; Animals ; Benzazepines ; metabolism ; pharmacology ; therapeutic use ; Coronary Circulation ; drug effects ; Coronary Vessels ; drug effects ; metabolism ; Disease Models, Animal ; Fibroblast Growth Factor 2 ; metabolism ; therapeutic use ; Myocardial Infarction ; metabolism ; Neovascularization, Physiologic ; Rabbits ; Time Factors ; Vascular Endothelial Growth Factor A ; metabolism ; therapeutic use

OBJECTIVETo investigate the role of metronomic chemotherapy of S-1 on angiogenesis of hepatocellular carcinoma in animal model.

METHODS-1 was dissolved in a 0.5% (w/v) HPMC solution. 30 LCI-D20 were randomly devided into five groups: control group(O), 10 mg * kg(-1) * d(-1) S-1 group (A), 1 mg * kg(-1) * d(-1) S-1 group (B), 0.5 mg * kg(-1) * d(-1) S-1 group (C) and 0.25 mg * kg(-1) * d S-1 group (D). 28 days after the treatment with 0.5% (w/v) HPMC solution, tumors in LCI-D20 mice were moved out. Tumor mass was measured and microvessel density (MVD) was used to evaluate angiogenesis in tumor. The cellular apoptosis was determined using flow cytometry. The expression of VEGF, bFGF and TSP-1 was measured by RT-PCR.

RESULTSThe mean tumor mass was 2.01, 0.38, 1.12, 1.38, 2.27 g in O, A, B, C, D group, respectively. The mean MVD was 39.57, 19.90, 5.93, 17.10, 29.53 in O, A, B, C, D respectively. The mean tumor cellular apoptosis rate was 4.08%, 44.37%, 31.73%, 19.83%, and 8.25% in O, A, B, C, D respectively. The expression of VEGF and bFGF in O group was highest, and A was slightly low, and C and D taked the third place, and B was the lowst; The expression of TSP-1 in B was highest, and C and D were slightly low, and A taked the third place, and O was the lowst.

CONCLUSIONMetronomic chemotherapy of S-1 destabilizes pre-existing tumor vasculature and inhibits ongoing angiogenesis.

Animals ; Antimetabolites, Antineoplastic ; therapeutic use ; Apoptosis ; Carcinoma, Hepatocellular ; blood supply ; drug therapy ; pathology ; Drug Combinations ; Fibroblast Growth Factor 2 ; genetics ; metabolism ; Liver Neoplasms, Experimental ; blood supply ; drug therapy ; pathology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Transplantation ; Neovascularization, Pathologic ; Oxonic Acid ; administration & dosage ; therapeutic use ; RNA, Messenger ; genetics ; metabolism ; Random Allocation ; Reverse Transcriptase Polymerase Chain Reaction ; Tegafur ; administration & dosage ; therapeutic use ; Vascular Endothelial Growth Factors ; genetics ; metabolism

This study is to evaluate the therapeutic effect of fibroblast growth factor 21 (FGF21) on hypertension induced by insulin resistance in rats and to provide mechanistic insights into its therapeutic effect. Male Sprague-Dawley (SD) rats were fed with high-fructose (10%) water to develop mild hypertensive models within 4 weeks, then randomized into 4 groups: model control, FGF21 0.25, 0.1 and 0.05 micromol x kg(-1) x d(-1) groups. Five age-matched normal SD rats administrated with saline were used as normal controls. The rats in each group were treated once a day for 4 weeks. Body weight was measured weekly, systolic blood pressure (SBP) was measured noninvasively using a tail-cuff method, insulin sensitivity was assessed using oral glucose tolerance test (OGTT) and HOMA-IR assay. At the end of the treatment, blood samples were collected, and blood glucose, serum cholesterol, serum triglyceride and serum insulin were measured. The results showed that blood pressure of the rats treated with different doses of FGF21 returned to normal levels [(122.2 +/- 3.5) mmHg, P < 0.01] after 4-week treatment, whereas, SBP of untreated (model control) rats maintained a high level [(142.5 +/- 4.5) mmHg] throughout the treatment. The observation of blood pressure in 24 h revealed that SBP of FGF21 treated-rats maintained at (130 +/- 4.5) mmHg vs. (143 +/- 5.5) mmHg for model control (P < 0.01). FGF21 treatment groups improved serum lipids obviously, total cholesterol (TC) and triglyceride (TG) levels decreased significantly to normal levels. The serum NO levels of three different doses FGF21 treatment group were significantly higher than that of the model control group [(7.32 +/- 0.11), (7.24 +/- 0.13), (6.94 +/- 0.08) vs. (6.56 +/- 0.19) micromol x L(-1), P < 0.01], and the degree of improvement showed obvious dose-dependent manner, indicating that FGF21 can significant increase serum NO in fructose-induced hypertension rat model and improve endothelial NO release function. The results of OGTT and HOMA-IR showed that insulin resistance state was significantly relieved in a dose-dependent manner. Thus, this study demonstrates that FGF21 significantly ameliorates blood pressure in fructose-induced hypertension model by relieving insulin resistance. This finding provides a theoretical support for clinical application of FGF21 as a novel therapeutics for treatment of essential hypertension.
Animals ; Antihypertensive Agents ; administration & dosage ; therapeutic use ; Blood Glucose ; metabolism ; Blood Pressure ; drug effects ; Body Weight ; drug effects ; Cholesterol ; blood ; Dose-Response Relationship, Drug ; Fibroblast Growth Factors ; administration & dosage ; therapeutic use ; Fructose ; Glucose Tolerance Test ; Hypertension ; blood ; chemically induced ; drug therapy ; Insulin Resistance ; Male ; Nitric Oxide ; blood ; Rats ; Rats, Sprague-Dawley ; Triglycerides ; blood

This study is to evaluate the therapeutic effect of fibroblast growth factor 21 (FGF21) on NAFLD in MSG-IR mice and to provide mechanism insights into its therapeutic effect. The MSG-IR mice with insulin resistance were treated with high dose (0.1 micromol.kg-1d-1) and low dose (0.025 micromol.kg-1d-1) of FGF21 once a day for 5 weeks. Body weight was measured weekly. At the end of the experiment, serum lipids, insulin and aminotransferases were measured. Hepatic steatosis was observed. The expression of key genes regulating energy metabolism were detected by real-time PCR. The results showed that after 5 weeks treatment, both doses of FGF21 reduced body weight (P<0.01), corrected dyslipidemia (P<0.01), reversed steatosis and restored the liver morphology in the MSG model mice and significantly ameliorated insulin resistance. Additionally, real-time PCR showed that FGF21 significantly reduced transcription levels of fat synthetic genes, decreased fat synthesis and promoted lipolysis and energy metabolism by up-regulating key genes of lipolysis, thereby liver fat accumulation was reduced and liver function was restored to normal levels. In conclusion, FGF21 significantly reduces body weight of the MSG-IR mice, ameliorates insulin resistance, reverses hepatic steatosis. These findings provide a theoretical support for clinical application of FGF21 as a novel therapeutics for treatment of NAFLD.
Animals ; Body Weight ; drug effects ; Dose-Response Relationship, Drug ; Dyslipidemias ; metabolism ; Energy Metabolism ; drug effects ; Fatty Liver ; chemically induced ; complications ; Female ; Fibroblast Growth Factors ; administration & dosage ; pharmacology ; therapeutic use ; Insulin Resistance ; Lipolysis ; drug effects ; Liver ; metabolism ; pathology ; Male ; Mice ; Non-alcoholic Fatty Liver Disease ; drug therapy ; Sodium Glutamate

BACKGROUNDThe FIP1L1-PDGFRalpha fusion gene plays an important role in the pathogenesis of chronic eosinophilic leukemia (CEL) and is a direct therapeutic target of the tyrosine kinase inhibitor imatinib mesylate.

METHODSIn 24 hypereosinophilic syndromes (HES) patients, using reverse transcriptase-polymerase chain reaction (RT-PCR), nested PCR and sequence analysis, we investigated the frequency of FIP1L1-PDGFRalpha and other abnormalities of tyrosine kinase family genes like PDGFRalpha, PDGFRbeta, C-KIT, FGFR1, ABL and FLT3 as well as gene mutation "hotspots", like MPL515 and JAK2V617F, frequently involved in myeloproliferative diseases. Fluorescence in situ hybridization was used to confirm the 4q12 deletion.

RESULTSThe FIP1L1-PDGFRalpha fusion transcript was found in 8 (33%) of 24 patients with HES, corresponding to the chromosome 4q12 deletion identified by FISH. The FIP1L1-PDGFRalpha-associated patients diagnosed with CEL, frequently had hepatosplenomegaly, eosinophil-related tissue damage, anemia, thrombocytopenia, myelofibrosis and a short overall survival time. Nevertheless, imatinib mesylate induced rapid and complete hematological responses in treated FIP1L1-PDGFRalpha cases, followed by molecular remission and reversal of myelofibrosis. FIP1L1-PDGFRalpha fusion could co-exist with other mutations of tyrosine kinase family genes, like FLT3 or PDGFRbeta. We also demonstrated that the SNPs of PDGFRbeta were associated with selective splicing of exon 19 in case 20.

CONCLUSIONSCorrelating the CEL genotype with phenotype, FIP1L1-PDGFRalpha emerges as a relatively homogeneous clinicobiological entity that co-exists with other abnormalities of tyrosine kinase family genes. It reflects the disease progression and there is a good response to imatinib. Detection of the FIP1L1-PDGFRalpha fusion gene is valid for both CEL diagnosis and therapy surveillance.

Adolescent ; Adult ; Aged ; Antineoplastic Agents ; therapeutic use ; Benzamides ; Chronic Disease ; Disease Progression ; Female ; Genotype ; Humans ; Hypereosinophilic Syndrome ; drug therapy ; genetics ; pathology ; Imatinib Mesylate ; In Situ Hybridization ; Male ; Middle Aged ; Mutation ; Oncogene Proteins v-abl ; genetics ; Oncogene Proteins, Fusion ; genetics ; Phenotype ; Piperazines ; therapeutic use ; Polymorphism, Single Nucleotide ; Proto-Oncogene Proteins c-kit ; genetics ; Pyrimidines ; therapeutic use ; Receptor, Fibroblast Growth Factor, Type 1 ; genetics ; Receptor, Platelet-Derived Growth Factor alpha ; genetics ; Reverse Transcriptase Polymerase Chain Reaction ; fms-Like Tyrosine Kinase 3 ; genetics ; mRNA Cleavage and Polyadenylation Factors ; genetics