Roles of fibroblast growth factors in the treatment of diabetes

Diabetes affects about 422 million people worldwide,causing 1.5 million deaths each year.However,the incidence of diabetes is increasing,including several types of diabetes.Type 1 diabetes(5%-10%of diabetic cases)and type 2 diabetes(90%-95%of diabetic cases)are the main types of diabetes in the clinic.Accumulating evidence shows that the fibroblast growth factor(FGF)family plays important roles in many metabolic disorders,including type 1 and type 2 diabetes.FGF consists of 23 family members(FGF-1-23)in humans.Here,we review current findings of FGFs in the treatment of diabetes and management of diabetic complications.Some FGFs(e.g.,FGF-15,FGF-19,and FGF-21)have been broadly investigated in preclinical studies for the diagnosis and treatment of diabetes,and their therapeutic roles in diabetes are currently under investigation in clinical trials.Overall,the roles of FGFs in diabetes and diabetic complications are involved in numerous processes.First,FGF intervention can prevent high-fat diet-induced obesity and insulin resistance and reduce the levels of fasting blood glucose and triglycerides by regulating lipolysis in adipose tissues and hepatic glucose production.Second,modulation of FGF expression can inhibit renal and cardiac fibrosis by regulating the expression of extracellular matrix components,promote diabetic wound healing process and bone repair,and inhibit cancer cell proliferation and migration.Finally,FGFs can regulate the activation of glucoseexcited neurons and the expression of thermogenic genes.

Fibroblast growth factor 21 inhibits ferroptosis following spinal cord injury by regulating heme oxygenase-1

Interfering with the ferroptosis pathway is a new strategy for the treatment of spinal cord injury.Fibroblast growth factor 21 can inhibit ferro ptosis and promote neurofunctional recovery,while heme oxygenase-1 is a regulator of iron and reactive oxygen species homeostasis.The relationship between heme oxygenase-1and ferroptosis remains controve rsial.In this study,we used a spinal co rd injury rat model to show that the levels of fibroblast growth factor 21 in spinal co rd tissue decreased after spinal cord injury.In addition,there was a significant aggravation of ferroptosis and a rapid increase in heme oxygenase-1 expression after spinal cord injury.Furthe r,heme oxygenase-1 aggravated fe rroptosis after spinal cord injury,while fibroblast growth factor 21 inhibited fe rroptosis by downregulating heme oxygenase-1.Thus,the activation of fibroblast growth factor 21 may provide a potential treatment for spinal co rd injury.These findings could provide a new potential mechanistic explanation for fibroblast growth factor 21 in the treatment of spinal cord injury.

Overexpression of fibroblast growth factor 13 ameliorates amyloid-β-induced neuronal damage

Previous studies have shown that fibroblast growth factor 13 is downregulated in the brain of both Alzheimer’s disease mouse models and patients,and that it plays a vital role in the learning and memory.However,the underlying mechanisms of fibroblast growth factor 13 in Alzheimer’s disease remain unclear.In this study,we established rat models of Alzheimer’s disease by stereotaxic injection of amyloid-β(Aβ_(1-42))-induced into bilateral hippocampus.We also injected lentivirus containing fibroblast growth factor 13 into bilateral hippocampus to overexpress fibroblast growth factor 13.The expression of fibroblast growth factor 13 was downregulated in the brain of the Alzheimer’s disease model rats.After overexpression of fibroblast growth factor 13,learning and memory abilities of the Alzheimer’s disease model rats were remarkably improved.Fibroblast growth factor 13 overexpression increased brain expression levels of oxidative stress-related markers glutathione,superoxide dismutase,phosphatidylinositol-3-kinase,AKT and glycogen synthase kinase 3β,and anti-apoptotic factor BCL.Furthermore,fibroblast growth factor 13 overexpression decreased the number of apoptotic cells,expression of pro-apoptotic factor BAX,cleaved-caspase 3 and amyloid-βexpression,and levels of tau phosphorylation,malondialdehyde,reactive oxygen species and acetylcholinesterase in the brain of Alzheimer’s disease model rats.The changes were reversed by the phosphatidylinositol-3-kinase inhibitor LY294002.These findings suggest that overexpression of fibroblast growth factor 13 improved neuronal damage in a rat model of Alzheimer’s disease through activation of the phosphatidylinositol-3-kinase/AKT/glycogen synthase kinase 3βsignaling pathway.

Fibroblast growth factor 15,induced by elevated bile acids,mediates the improvement of hepatic glucose metabolism after sleeve gastrectomy

BACKGROUND Fibroblast growth factor(FGF)15/19,which is expressed in and secreted from the distal ileum,can regulate hepatic glucose metabolism in an endocrine manner.The levels of both bile acids(BAs)and FGF15/19 are elevated after bariatric surgery.However,it is unclear whether the increase in FGF15/19 is induced by BAs.Moreover,it remains to be understood whether FGF15/19 elevations contribute to improvements in hepatic glucose metabolism after bariatric surgery.AIM To investigate the mechanism of improvement of hepatic glucose metabolism by elevated BAs after sleeve gastrectomy(SG).METHODS By calculating and comparing the changes of body weight after SG with SHAM group,we examined the weight-loss effect of SG.The oral glucose tolerance test(OGTT)test and area under the curve of OGTT curves were used to assess the anti-diabetic effects of SG.By detecting the glycogen content,expression and activity of glycogen synthase as well as the glucose-6-phosphatase(G6Pase)and phosphoenolpyruvate carboxykinase(Pepck),we evaluated the hepatic glycogen content and gluconeogenesis activity.We examined the levels of total BA(TBA)together with the farnesoid X receptor(FXR)-agonistic BA subspecies in systemic serum and portal vein at week 12 post-surgery.Then the histological expression of ileal FXR and FGF15 and hepatic FGF receptor 4(FGFR4)with its corresponding signal pathways involved in glucose metabolism were detected.RESULTS After surgery,food intake and body weight gain of SG group was decreased compare with the SHAM group.The hepatic glycogen content and glycogen synthase activity was significantly stimulated after SG,while the expression of the key enzyme for hepatic gluconeogenesis:G6Pase and Pepck,were depressed.TBA levels in serum and portal vein were both elevated after SG,the FXR-agonistic BA subspecies:Chenodeoxycholic acid(CDCA),lithocholic acid(LCA)in serum and CDCA,DCA,LCA in portal vein were all higher in SG group than that in SHAM group.Consequently,the ileal expression of FXR and FGF15 were also advanced in SG group.Moreover,the hepatic expression of FGFR4 was stimulated in SG-operated rats.As a result,the activity of its corresponding pathway for glycogen synthesis:FGFR4-Ras-extracellular signal regulated kinase pathway was stimulated,while the corresponding pathway for hepatic gluconeogenesis:FGFR4-cAMP regulatory element-binding protein-peroxisome proliferator-activated receptorγcoactivator-1αpathway was suppressed.CONCLUSION Elevated BAs after SG induced FGF15 expression in distal ileum by activating their receptor FXR.Furthermore,the promoted FGF15 partly mediated the improving effects on hepatic glucose metabolism of SG.

Depletion of gut microbiota facilitates fibroblast growth factor 21-mediated protection against acute pancreatitis in diabetic mice

BACKGROUND Fibroblast growth factor 21(FGF21),primarily secreted by the pancreas,liver,and adipose tissues,plays a pivotal role in regulating glucose and lipid metabolism.Acute pancreatitis(AP)is a common inflammatory disease with specific clinical manifestations.Many patients with diabetes present with concurrent inflammatory symptoms.Diabetes exacerbates intestinal permeability and intestinal inflammation,thus leading to the progression to AP.Our previous study indicated that FGF21 significantly attenuated susceptibility to AP in mice.AIM To investigate the potential protective role of FGF21 against AP in diabetic mice.METHODS In the present study,a mouse model of AP was established in diabetic(db)/db diabetic mice through ceruletide injections.Thereafter,the protective effects of recombinant FGF21 protein against AP were evaluated,with an emphasis on examining serum amylase(AMS)levels and pancreatic and intestinal inflammatory cytokines[interleukin(IL)-6,tumor necrosis factor-alpha(TNF-),and intestinal IL-1β].Additionally,the impact of this treatment on the histopathologic changes of the pancreas and small intestinal was examined to elucidate the role of FGF21 in diabetic mice with AP.An antibiotic(Abx)cocktail was administered in combination with FGF21 therapy to investigate whether the effect of FGF21 on AP in diabetic mice with AP was mediated through the modulation of the gut microbiota. Subsequently, thePhylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt), a bioinformaticssoftware package, was used to predict different pathways between the groups and to explore the potentialmechanisms by which the gut microbiota influenced the protective effect of FGF21.RESULTSThe results indicated that FGF21 notably diminished the levels of serum AMS (944.5 ± 15.9 vs 1732 ± 83.9, P < 0.01)and inflammatory factors including IL-6 (0.2400 ± 0.55 vs 1.233 ± 0.053, P < 0.01), TNF- (0.7067 ± 0.22 vs 1.433 ±0.051, P < 0.01), and IL-1β (1.377 ± 0.069 vs 0.3328 ± 0.02542, P < 0.01) in diabetic mice with AP. Moreover, notablesigns of recovery were observed in the pancreatic structure of the mice. The histologic evidence of inflammation inthe small intestine, including edema and villous damage, was significantly alleviated. FGF21 also significantlyaltered the composition of the gut microbiota, reestablishing the Bacteroidetes/Firmicutes ratio. Upon treatment withan Abx cocktail to deplete the gut microbiota, the FGF21 + Abx group showed lower levels of serum AMS (0.9328 ±0.075 vs 0.2249 ± 0.023, P < 0.01) and inflammatory factors (1.083 ± 0.12 vs 0.2799 ± 0.032, p < 0.01) than the FGF21group. Furthermore, the FGF21 + Abx group exhibited diminished injury to the pancreatic and small intestinaltissues, accompanied by a significant decrease in blood glucose levels (17.50 ± 1.1 vs 9.817 ± 0.69 mmol/L, P <0.001). These findings underscored the superior protective effects of the combination therapy involving an Abxcocktail with FGF21 over the FGF21 treatment alone in diabetic mice with AP. The gut microbiota compositionacross different groups was further characterized, and a differential expression analysis of gene functions wasundertaken using the PICRUSt2 prediction method. These findings suggested that FGF21 could potentially confertherapeutic effects on diabetic mice with AP by modulating the sulfate reduction I pathway and the superpathwayof n-acetylceramide degradation in the gut microbiota.CONCLUSION This study reveals the potential of FGF21 in improving pancreatic and intestinal damage recovery, reducing bloodglucose levels, and reshaping gut microbiota composition in diabetic mice with AP. Notably, the protective effectsof FGF21 are augmented when combined with the Abx cocktail.

Assessment of fibroblast growth factor 19 as a non-invasive serum marker for hepatocellular carcinoma

BACKGROUND Fibroblast growth factor 19(FGF-19)is one of the founding members of the endocrine FGF subfamily.Recently,it has been the subject of much interest owing to its role in various physiological processes affecting glucose and lipid metabolism and the regulation of bile acid secretion as well as cell proliferation,differentiation,and motility.Additionally,FGF-19 secretion in an autocrine style has reportedly contributed to cancer progression in various types of malignancies including hepatocellular carcinoma(HCC).AIM To estimate the serum FGF-19 concentrations in HCC cases and assess its diagnostic performance for the detection of HCC.METHODS We recruited 90 adult participants and divided them into three equal groups:Healthy controls,cirrhosis patients,and HCC patients.Serum FGF-19 concentrations were measured using the Human FGF-19 ELISA kit.RESULTS We detected a high statistically significant difference in serum FGF-19 levels among the three groups.The highest level was observed in the HCC group,followed by the cirrhosis and control groups(236.44±40.94 vs 125.63±31.54 vs 69.60±20.90 pg/mL,respectively,P≤0.001).FGF-19 was positively correlated with alpha fetoprotein(AFP;r=0.383,P=0.003)and international normalised ratio(r=0.357,P=0.005),while it was negatively correlated with albumin(r=-0.500,P≤0.001).For the detection of HCC,receiver operating characteristic curve analysis showed that the best cut-off point of AFP was>8.2 ng/mL with an area under the curve(AUC)of 0.78,sensitivity of 63.33%,specificity of 83.33%,positive predictive value(PPV)of 79.2%,negative predictive value(NPV)of 69.4%,and total accuracy of 78%.However,FGF-19 at a cut-off point>180 pg/mL had an AUC of 0.98,sensitivity of 100%,specificity of 90.0%,PPV of 90.0%,NPV of 100%,and total accuracy of 98%.CONCLUSION FGF-19 represents a possible novel non-invasive marker for HCC.It may improve the prognosis of HCC patients due to its utility in several aspects of HCC detection and management.

Basic fibroblast growth factor attenuates the degeneration of injured spinal cord motor endplates

The distal end of the spinal cord and neuromuscular junction may develop secondary degeneration and damage following spinal cord injury because of the loss of neural connections. In this study, a rat model of spinal cord injury, established using a modified Allen＇s method, was injected with basic fibroblast growth factor solution via subarachnoid catheter. After injection, rats with spinal cord injury displayed higher scores on the Basso, Beattie and Bresnahan locomotor scale. Motor function was also well recovered and hematoxylin-eosin staining showed that spinal glial scar hyperplasia was not apparent. Additionally, anterior tibial muscle fibers slowly, but progressively, atrophied. Immu- nohistochemical staining showed that the absorbance values of calcitonin gene related peptide and acetylcholinesterase in anterior tibial muscle and spinal cord were similar, and injection of basic fi- broblast growth factor increased this absorbance. Results showed that after spinal cord injury, the distal motor neurons and motor endplate degenerated. Changes in calcitonin gene related peptide and acetylcholinesterase in the spinal cord anterior horn motor neurons and motor endplate then occurred that were consistent with this regeneration. Our findings indicate that basic fibroblast growth factor can protect the endplate through gene related peptide and acetylcholinesterase cord. attenuating the decreased expression of calcitonin n anterior horn motor neurons of the injured spinal

Changes in expression and secretion patterns of fibroblast growth factor 8 and Sonic Hedgehog signaling pathway molecules during murine neural stem/progenitor cell differentiation in vitro

In the present study, we investigated the dynamic expression of fibroblast growth factor 8 and Sonic Hedgehog signaling pathway related factors in the process of in vitro hippocampal neural stem/progenitor cell differentiation from embryonic Sprague-Dawley rats or embryonic Kunming species mice, using fluorescent quantitative reverse transcription-PCR and western blot analyses. Results demonstrated that the dynamic expression of fibroblast growth factor 8 was similar to fibroblast growth factor receptor 1 expression but not to other fibroblast growth factor receptors. Enzyme-linked immunosorbent assay demonstrated that fibroblast growth factor 8 and Sonic Hedgehog signaling pathway protein factors were secreted by neural cells into the intercellular niche. Our experimental findings indicate that fibroblast growth factor 8 and Sonic Hedgehog expression may be related to the differentiation of neural stem/progenitor cells.

Fibroblast growth factor signaling in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis:Paving the way to hepatocellular carcinoma

Metabolic disorders are increasingly leading to non-alcoholic fatty liver disease,subsequent steatohepatitis,cirrhosis and hepatocellular carcinoma.Fibroblast growth factors and their receptors play an important role in maintaining metabolic homeostasis also in the liver and disorders in signaling have been identified to contribute to those pathophysiologic conditions leading to hepatic lipid accumulation and chronic inflammation.While specific and well tolerated inhibitors of fibroblast growth factor receptor activity are currently developed for(non-liver)cancer therapy,treatment of non-alcoholic fatty liver disease and nonalcoholic steatohepatitis is still limited.Fibroblast growth factor-mimicking or restoring approaches have recently evolved as a novel therapeutic option and the impact of such interactions with the fibroblast growth factor receptor signaling network during non-alcoholic fatty liver disease/non-alcoholic steatohepatitis development is reviewed here.

The hypoxia-inducible factor-1α activates ectopic production of fibroblast growth factor 23 in tumor-induced osteomalacia

Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-la （HIF-la） in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-la mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-la and FGF23 were co-localized in spindle- shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-la protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-la expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-la inhibitors decreased HIF-la and FGF23 protein accumulation and inhibited HIF-la-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-la consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-la inhibitor. These results show for the first time that HIF-la is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-la activity in TIO contributes to the aberrant FGF23 production in these patients.

Effect of electro-acupuncture on basic fibroblast growth factor protein and mRNA expression in hippocampal dentate gyrus of spleen deficiency rats

BACKGROUND： Spleen deficiency in traditional Chinese medicine refers to the functional disorder of spleen, pancreas, intestines, and nervous system in modern medicine. OBJECTIVE; To test whether electro-acupuncture could alter basic fibroblast growth factor （bFGF） protein and mRNA expression in the hippocampal dentate gyrus of spleen deficiency rats. DESIGN, TIME AND SETTING： The randomized, controlled, in vivo animal experiment was performed at the National LeveI-B Laboratory of Clinical Cell Molecule and Biology in Shenzhen Hospital of Traditional Chinese Medicine, between March and November in 2008. MATERIALS： Reserpine injection was produced by Guangdong Bangmin Pharmaceutical Co. Rhubarb extract granule preparation was produced by Guangdong Yifang Pharmaceutical. Huanqiu Brand sterile acupuncture pin was provided by Suzhou Acupuncture Supplies, China. Huatuo Brand electroacupuncture instrument （type SDZ-II） was purchased from Suzhou Medical Appliance Factory, China. METHODS： A total of 96 male Sprague Dawley rats were randomly assigned to control （n = 32） and induction （n = 64） groups. Spleen deficiency was induced via intraperitoneal injection of reserpine and intragastric administration of rhubarb. The successful models were randomized into two groups： model and electro-acupuncture, with 32 rats in each group. Electro-acupuncture was administered at Zusanfi （ST 36） and Sanyinjiao （SP 6） acupoints using a condensation wave and rarefaction （condensation wave 15 Hz） at a strength of 6-15 V for 20 minutes, once per day. The appearance of a slight shiver in the corresponding locus was taken as the standard. According to electro- acupuncture time points, each group was assigned to four subgroups at 7, 14, 28, and 49 days, respectively, with eight rats in each subgroup. Immunohistochemical staining, image analysis, and reverse-transcription polymerase chain reaction were performed at different time points. MAIN OUTCOME MEASURES： bFGF protein and mRNA expression in the hippocampal dentate gyrus of spleen deficiency rats. RESULTS： After 7 days of electro-acupuncture therapy, bFGF protein and mRNA expression significantly increased compared with the model and control groups （P 〈 0.05）. After 14 days, bFGF protein and mRNA expression decreased until 28 days, where levels were then equal to the model group and greater than the control group （P 〈 0.05）. After 49 days, the above indices remained increased in the electro-acupuncture group compared to the model and control groups （P 〈 0.05）. CONCLUSION： Continuous electro-acupuncture maintained a high level of bFGF protein and mRNA expression in the hippocampal dentate gyrus of spleen deficiency rats.

The effect of basic fibroblast growth factor on regeneration in a surgical wound model of rat submandibular glands

This study developed an animal model of surgically wounded submandibular glands （SMGs） and investigated the effects of collagen gel with basic fibroblast growth factor （bFGF） on tissue regeneration of surgically wounded SMGs in vivo. The animal model was produced by creating a surgical wound using a 3-mm diameter biopsy punch in SMGs. The wound was filled with collagen gel with bFGF （bFGF group） or without bFGF （control group）. In the animal model of surgically wounded SMGs, salivary glands without scar tissue around the wound area were observed with smaller areas of collagen gel. Small round and spindle-shape cells invaded the collagen gel in both groups after operation day （AOD） 5, and this invasion dramatically increased at AOD 7. Host tissue completely replaced the collagen gel at AOD 21. The invading immune cells in the group treated with collagen gel with bFGF were positive for vimentin, g-smooth muscle actin （αSMA）, CD49f, c-kit and AQP5 at AOD 7. Similarly, the mRNA expression of vimentin, αSMA, CD49f, keratin 19 and AQP5 was also increased. This study suggests that the use of collagen gels with bFGF improves salivary gland regeneration.

Distribution and localization of fibroblast growth factor-8 in rat brain and nerve cells during neural stem/progenitor cell differentiation

The present study explored the distribution and localization of fibroblast growth factor-8 and its potential receptor, fibroblast growth factor receptor-3, in adult rat brain in vivo and in nerve cells during differentiation of neural stem/progenitor cells in vitro. Immunohistochemistry was used to examine the distribution of fibroblast growth factor-8 in adult rat brain in vivo. Localization of fibroblast growth factor-8 and fibroblast growth factor receptor-3 in cells during neural stem/progenitor cell differentiation in vitro was detected by immunofluorescence. Flow cytometry and immunofluorescence were used to evaluate the effect of an anti-fibroblast growth factor-8 antibody on neural stem/progenitor cell differentiation and expansion in vitro. Results from this study confirmed that fibroblast growth factor-8 was mainly distributed in adult midbrain, namely the substantia nigra, compact part, dorsal tier, substantia nigra and reticular part, but was not detected in the forebrain comprising the caudate putamen and striatum. Unusual results were obtained in retrosplenial locations of adult rat brain. We found that fibroblast growth factor-8 and fibroblast growth factor receptor-3 were distributed on the cell membrane and in the cytoplasm of nerve cells using immunohistochemistry and immunofluorescence analyses. We considered that the distribution of fibroblast growth factor-8 and fibroblast growth factor receptor-3 in neural cells corresponded to the characteristics of fibroblast growth factor-8, a secretory factor. Addition of an anti-fibroblast growth factor-8 antibody to cultures significantly affected the rate of expansion and differentiation of neural stem/progenitor cells. In contrast, addition of recombinant fibroblast growth factor-8 to differentiation medium promoted neural stem/progenitor cell differentiation and increased the final yields of dopaminergic neurons and total neurons. Our study may help delineate the important roles of fibroblast growth factor-8 in brain activities and neural stem/progenitor cell differentiation.

Effects of 530 nm monochromatic light on basic fibroblast growth factor and transforming growth factor-β1 expression in Müller cells

AIMTo expose rat retinal M&#x000fc;ller cells to 530 nm monochromatic light and investigate the influence of varying light illumination times on basic fibroblast growth factor (bFGF) and transforming growth factor-&#x003b2;1 (TGF-&#x003b2;1) expression.METHODSThree groups of rat retinal M&#x000fc;ller cells cultured in vitro under a 530 nm monochromatic light were divided into 6, 12 and 24h experimental groups, while cells incubated under dark conditions served as the control group. The bFGF and TGF-&#x003b2;1 mRNA expression, protein levels and fluorescence intensity of the M&#x000fc;ller cells were analyzed.RESULTSThe bFGF mRNA expression and protein levels were significantly upregulated in M&#x000fc;ller cells in all three experimental groups compared with the control group (P&#x0003c;0.05), while that of TGF-&#x003b2;1 was downregulated (P&#x0003c;0.05). Also, bFGF expression was positively correlated, but TGF-&#x003b2;1 expression was negatively correlated with illumination time. The largest changes for both cytokines were seen in the 24h group. The changes in bFGF and TGF-&#x003b2;1 fluorescence intensity were highest in the 24h group, and significant differences were observed among the experimental groups (P&#x0003c;0.05).CONCLUSIONThe expressions of bFGF and TGF-&#x003b2;1 changed in a time-dependent manner in M&#x000fc;ller cells exposed to 530 nm monochromatic light with 250 lx illumination intensity. M&#x000fc;ller cells might play a role in the development of myopia by increasing bFGF expression or decreasing TGF-&#x003b2;1 expression. Changes in cytokine expression in retinal M&#x000fc;ller cells may affect monochromatic light-induced myopia.

Role of Fibroblast Growth Factor 19 in Maintaining Nutrient Homeostasis and Disease

Fibroblast growth factor 19 （FGF19） is a kind of gut-derived postprandial hormone. As an atypical member of the FGF family, FGF19 functions as an endocrine hormone except regulating cell growth and differentiation. FGF19 plays a key role in coordination of liver bile acid biosynthesis and gallbladder motility, and acts as a regulator of metabolic homeostasis, including strengthening insulin sensitivity, decreasing triglyceride concentration and reducing body weight.

Noggin versus basic fibroblast growth factor on the differentiation of human embryonic stem cells

The difference between Noggin and basic fibroblast growth factor for the neural precursor differen- tiation from human embryonic stem cells has not been studied. In this study, 100 tJg/L Noggin or 20 IJg/L basic fibroblast growth factor in serum-free neural induction medium was used to differen- tiate human embryonic stem cells H14 into neural precursors using monolayer differentiation. Two weeks after induction, significantly higher numbers of neural rosettes formed in the Noggin-induced group than the basic fibroblast growth factor-induced group, as detected by phase contrast micro- scope. Immunofluorescence staining revealed expression levels of Nestin, [3-111 Tubulin and Sox-1 were higher in the induced cells and reverse-transcription PCR showed induced cells expressed Nestin, Sox-1 and Neurofilament mRNA. Protein and mRNA expression in the Noggin-induced group was increased compared with the basic fibroblast growth factor-induced group. Noggin has a greater effect than basic fibroblast growth factor on the induction of human embryonic stem cell differentiation into neural precursors by monolayer differentiation, as Noggin accelerates and in- creases the differentiation of neural precursors.

Fibroblast growth factor 23 and bone mineralisation

Fibroblast growth factor 23 （FGF23） is a hormone that is mainly secreted by osteocytes and osteoblasts in bone. The critical role of FGF23 in mineral ion homeostasis was first identified in human genetic and acquired rachitic diseases and has been further characterised in animal models. Recent studies have revealed that the levels of FGF23 increase significantly at the very early stages of chronic kidney disease （CKD） and may play a critical role in mineral ion disorders and bone metabolism in these patients. Our recent publications have also shown that FGF23 and its cofactor, Klotho, may play an independent role in directly regulating bone mineralisation instead of producing a systematic effect. In this review, we will discuss the new role of FGF23 in bone mineralisation and the pathophysiology of CKD-related bone disorders.

Fibroblast Growth Factor-2 Counteracts the Effect of Ciliary Neurotrophic Factor on Spontaneous Differentiation in Adult Hippocampal Progenitor Cells

Neural stem/progenitor cells (NSCs) can spontaneously differentiate into neurons and glial cells in the absence of mitogen fibroblast growth factor-2 (FGF-2) or epidermal growth factor (EGF) in medium and the spontaneous differentiation of NSCs is mediated partially by endogenous ciliary neuro-trophic factor (CNTF). This study examined the relationship of FGF-2 and CNTF in the spontaneous differentiation of adult hippocampal progenitor cells (AHPs). AHPs were cultured in the medium containing different concentration of FGF-2 (1–100 ng/mL). Western blotting and immunofluorescence staining were applied to detect the expression of the astrocytic marker GFAP, the neuronal marker Tuj1, the oligodendrocytic marker CNPase and, Nestin, the marker of AHPs. The expression of endogenous CNTF in AHPs at early (passage 4) and late stage (passage 22) was also measured by Western blotting. The results showed that FGF-2 increased the expression of Nestin, dramatically inhibited the expression of GFAP and Tuj1 and slightly suppressed the expression of CNPase. FGF-2 down-regulated the expression of endogenous CNTF in AHPs at both early (passage 4) and late stage (passage 22). These results suggested that FGF-2 could inhibit the spontaneous differentiation of cultured AHPs by negatively regulating the expression of endogenous CNTF in AHPs.

Recombinant human fibroblast growth factor-2 promotes nerve regeneration and functional recovery after mental nerve crush injury

Several studies have shown that fibroblast growth factor-2 （FGF2） can directly affect axon regeneration after peripheral nerve damage. In this study, we performed sensory tests and histological analyses to study the effect of recombinant human FGF-2 （rhFGF2） treatment on damaged mental nerves. The mental nerves of 6-week-old male Sprague-Dawley rats were crush-injured for 1 minute and then treated with 10 or 50 μg/mL rhFGF2 or PBS in crush injury area with a mini Osmotic pump. Sensory test using von Frey filaments at 1 week revealed the presence of sensory degeneration based on decreased gap score and increased difference score. However, at 2 weeks, the gap score and difference score were significantly rebounded in the mental nerve crush group treated with 10 μg/mL rhFGF2. Interestingly, treatment with 10 μg/mL rhFGF had a more obviously positive effect on the gap score than treatment with 50 μg/mL rhFGF2. In addition, retrograde neuronal tracing with Dil revealed a significant increase in nerve regeneration in the trigeminal ganglion at 2 and 4 weeks in the rhFGF2 groups （10 μg/mL and 50 μg/mL） than in the PBS group. The 10 μg/mL rhFGF2 group also showed an obviously robust regeneration in axon density in the mental nerve at 4 weeks. Our results demonstrate that 10 μg/mL rhFGF induces mental nerve regeneration and sensory recovery after mental nerve crush injury.

Effects of leukemia inhibitory factor and basic fibroblast growth factor on free radicals and endogenous stem cell proliferation in a mouse model of cerebral infarction

The present study established a mouse model of cerebral infarction by middle cerebral artery occlusion, and monitored the effect of 25 tJg/kg leukemia inhibitory factor and （or） basic fibroblast growth factor administration 2 hours after model establishment. Results showed that following administration, the number of endogenous neural stem cells in the infarct area significantly increased, malondialdehyde content in brain tissue homogenates significantly decreased, nitric oxide content, glutathione peroxidase and superoxide dismutase activity significantly elevated, and mouse motor function significantly improved as confirmed by the rotarod and bar grab tests. In particular, the effect of leukemia inhibitory factor in combination with basic fibroblast growth factor was the most significant. Results indicate that leukemia inhibitory factor and basic fibroblast growth factor can improve the microenvironment after cerebral infarction by altering free radical levels, improving the quantity of endogenous neural stem cells, and promoting neurological function of mice with cerebral infarction.