Fibroblast Growth Factor 1 Levels Research Articles

Evaluation of adropin, fibroblast growth factor-1 (FGF-1), and Toll-like receptor-1 (TLR1) biomarkers in patients with inflammatory bowel disease: gene expression of TNF-α as a marker of disease severity

BackgroundInflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder of unknown etiology and unpredictable course. The aim of the work was to assess the levels of adropin, fibroblast growth factor-1 (FGF-1), and Toll-like receptor-1 (TLR1) biomarkers in IBD patients compared to controls and evaluate the gene expression of TNF-α as a marker of disease severity.MethodsAdropin, fasting serum FGF-1 levels, TLR1, and TNF-α were measured in 60 IBD patients. They were also compared with 58 healthy controls matching age and gender. Moreover, the blood cells cDNA copy number of TNF-α were determined as a marker of severity.ResultsAdropin and TLR1 levels were significantly lower in patients than controls. FGF-1 was reduced but not statistically significant. The expression of TNF-α gene in the IBD patients was significantly increased (42%) in comparison with control samples (P < 0.001).ConclusionsAdropin, IGF-I, and Toll-like receptor-1 biomarkers may have a role in the intricate pathophysiology of IBD and may possibly operate as predictors of disease activity. Thus, they may be therapeutic targets for IBD. Moreover, the expression of TNF-α gene can be used as a marker of severity.

Design, Synthesis and Biological Evaluation of Novel Gypsogenin Derivatives as Potential Anticancer and Antimicrobial Agents.

Natural compounds are important sources for the treatment of chronic disorders such as cancer and microbial infectious disorders. In this research, Gypsogenin and its derivatives (2 a-2 f) have been tested against different cancer cell lines (MCF-7, HeLa, Jurkat and K562 cell lines) and further analyzed for cell proliferation, cell death type, and for act of the mechanism. Cell proliferation was determined by the MTT method and cell death types were analyzed with HO/PI staining. Fibroblast Growth Factor 1 (FGF-1), Interleukin 1 (IL-1), Interleukin 6 (IL-6), and Tumor Necrosis Factor Alpha (TNF-α), key players in breast cancer development and progression, were determined by Elisa kits. Results showed that compound 2 e inhibited the MCF-7 cell line proliferation with an IC50 value of 0.66±0.17 μM with 93.38 % apoptosis rate. Compound 2 e also decreased FGF-1, IL-1, IL-6, and TNF-α levels. Molecular docking studies performed in the binding site of FGFR-1 indicated that compound 2 e formed key hydrogen bonding with Arg627 and Asn568. Besides, compounds 2 a-2 f were evaluated for their antimicrobial activities against gram-negative and gram-positive bacteria and C. albicans via the microdilution method. Overall, compound 2 e stands out as a potential anticancer agent for future studies.

Serum fibroblast growth factor 1 and its association with pancreatic beta cell function and insulin sensitivity in adults with glucose intolerance.

Beneficial role of fibroblast growth factor 1 (FGF1) in the regulation of glucose metabolism and adipose tissue remodeling was suggested in rodents. This study aimed to investigate the association between serum FGF1 levels and metabolic parameters in adults with glucose intolerance. Serum FGF1 levels were examined using an enzyme-linked immunosorbent assay in 153 individuals with glucose intolerance. Associations between serum FGF1 levels and metabolic parameters, including body mass index (BMI), glycated hemoglobin (HbA1c), and 75 g oral glucose tolerance test-derived parameters, including insulinogenic index (IGI), Matsuda insulin sensitivity index (ISI), and disposition index (DI), were examined. Serum FGF1 was detected in 35 individuals (22.9%), possibly due to the autocrine/paracrine nature of the peptide. IGI and DI levels were significantly lower in individuals with higher FGF1 levels than in those with lower FGF1 levels or undetectable FGF1 (p=0.006 and 0.005 for IGI and DI, respectively, after adjustment for age, sex, and BMI). Univariable and multivariable analyses using the Tobit regression model also revealed a negative association between FGF1 levels and IGI and DI. The regression coefficients per 1-SD of log-transformed IGI and DI were -0.461 (p=0.013) and -0.467 (p=0.012), respectively, after adjustment for age, sex, and BMI. In contrast, serum FGF1 levels were not significantly associated with ISI, BMI, or HbA1c. The serum concentration of FGF1 was significantly elevated in individuals with low insulin secretion, suggesting a possible interaction between FGF1 and beta cell function in humans.

Protective effects of resveratrol on permethrin-induced fetotoxicity in rats

Synthetic pyrethroid insecticides have been widely used for years to prevent harmful effects of insects and control disease vectors. In this study, the effects of resveratrol against the potential toxicity of permethrin, an effective pyrethroid derivative, on the fetus were investigated. Accordingly, Wistar female rats were divided into four groups as Control, Sham, Permethrin, and Permethrin + Resveratrol. Lung, liver, kidney and small intestine of developing fetuses were evaluated histopathologically. Also, Bone Morphogenetic Protein-4 (BMP-4) in bone tissue development and Fibroblast Growth Factor-1 (FGF-1) expressions in lung were examined immunohistochemically. All structures in the Control and Sham groups were normal. Permethrin caused epithelial damage, regression in bronchial and primitive alveolar development in the lung; congestion, edema and sinusoidal dilatation around the central vein in the liver; tubular epithelial degeneration, regression in glomeruli and tubule formation in the kidney; epithelial degeneration and irregularity in the villus structure in the small intestine. Immunohistochemical results indicated that permethrin administration decreased BMP-4 levels in bone tissue and FGF-1 levels in lung. Resveratrol application was found to greatly alleviate histopathological and immunohistopathological variability in all tissues. Oral consumption of permethrin by pregnant rats caused growth retardation and tissue damage in many different tissues in offspring. Intake of resveratrol during pregnancy showed protective effects against fetotoxicity caused by permethrin.

Intracellular FGF1 promotes invasion and migration in thyroid carcinoma via HMGA1 independent of FGF receptors.

Fibroblast growth factor 1 (FGF1) is extensively amplified in many tumors and accelerates tumor invasion and metastasis. However, the role and precise molecular mechanism by which FGF1 participates in thyroid cancer (TC) are still unclear. Quantitative real-time polymerase chain reaction- and western blotting were used to detect the mRNA and protein levels of FGF1, high mobility group A (HMGA1), epithelial-to-mesenchymal transition (EMT)-related factors, and FGFs in both TC tissues and cell lines. Immunohistochemistry was conducted to examine the expression of FGF1 and HMGA1. Immunofluorescence staining was used to detect the coexpression of FGF1 and HMGA1. Transwell and wound healing assays were conducted to evaluate the effects of FGF1 on the capacity of invasion and migration in cells. FGF1 was upregulated in papillary thyroid carcinoma (PTC) tissues and cell lines and was relatively higher in PTC tissues with cervical lymph node metastasis. Furthermore, FGF1 promotes invasion and metastasis through the EMT pathway. Mechanistically, FGF1 promotes EMT through intracellular function independent of FGF receptors. Interestingly, we demonstrated that FGF1 could upregulate HMGA1 in TC cells, and the correlation of FGF1 and HMGA1 was positive in PTC tissues. FGF1 and HMGA1 had obvious colocalization in the nucleus. We further revealed that FGF1 promotes the invasion and migration of TC cells through the upregulation of HMGA1. Intracellular FGF1 could promote invasion and migration in TC by mediating the expression of HMGA1 independent of FGF receptors, and FGF1 may be an effective therapeutic target in TC.

1384-P: Serum Fibroblast Growth Factor 1 Levels and Its Association with ß-Cell Function and Insulin Sensitivity in Adults with Glucose Intolerance

Objectives: Beneficial role of Fibroblast growth factor 1 (FGF1) in the regulation of glucose metabolism and adipose tissue remodeling was suggested in rodents. We investigated an association between serum FGF1 levels and metabolic parameters in adults with glucose intolerance. Research Designs and Methods: Serum FGF1 levels were examined using enzyme-linked immunosorbent assay in 92 individuals with glucose intolerance. Associations between serum FGF1 levels and metabolic parameters including body mass index (BMI) , waist circumference (WC) , glycated hemoglobin (HbA1c) and 75g oral glucose tolerance test-derived parameters including insulinogenic index (IGI) , Matsuda insulin sensitivity index (ISI) , and disposition index (DI) were examined. Results: Mean age was 49.8 years, and mean BMI was 30.7 kg/m2 of 92 participants. Among them, 87% had type 2 diabetes. There was no significant association between serum FGF1 level and BMI or WC by using censored regression analysis. On the other hand, serum FGF1 level was higher in patients with higher HbA1c (β=0.369, p=0.014) . This association was significant after adjusting for age, sex, and BMI (p=0.005) . Notably, serum FGF1 level was negatively associated with IGI and DI (β=−0.462, p=0.017; β=−0.469, p=0.014, respectively) , but not with ISI. Mean FGF1 concentrations were significantly lower with higher quartiles of IGI and DI (p for trend=0.035 and 0.015 for IGI and DI, respectively) . Conclusion: Serum concentration of FGF1 was significantly higher in individuals with higher blood glucose and lower insulin secretion, which suggests a possible role of FGF1 in the glucose metabolism, especially in the regulation of β cell function in humans. Disclosure J.Kim: None. J.Choi: None. S.Kim: None. N.Kim: None.

FGF1\u0394HBS prevents diabetic cardiomyopathy by maintaining mitochondrial homeostasis and reducing oxidative stress via AMPK/Nur77 suppression

As a classically known mitogen, fibroblast growth factor 1 (FGF1) has been found to exert other pleiotropic functions such as metabolic regulation and myocardial protection. Here, we show that serum levels of FGF1 were decreased and positively correlated with fraction shortening in diabetic cardiomyopathy (DCM) patients, indicating that FGF1 is a potential therapeutic target for DCM. We found that treatment with a FGF1 variant (FGF1∆HBS) with reduced proliferative potency prevented diabetes-induced cardiac injury and remodeling and restored cardiac function. RNA-Seq results obtained from the cardiac tissues of db/db mice showed significant increase in the expression levels of anti-oxidative genes and decrease of Nur77 by FGF1∆HBS treatment. Both in vivo and in vitro studies indicate that FGF1∆HBS exerted these beneficial effects by markedly reducing mitochondrial fragmentation, reactive oxygen species (ROS) generation and cytochrome c leakage and enhancing mitochondrial respiration rate and β-oxidation in a 5’ AMP-activated protein kinase (AMPK)/Nur77-dependent manner, all of which were not observed in the AMPK null mice. The favorable metabolic activity and reduced proliferative properties of FGF1∆HBS testify to its promising potential for use in the treatment of DCM and other metabolic disorders.

Evaluation of GLUT1, IGF-2, VEGF, FGF 1, and angiopoietin 2 in infantile hemangioma

IntroductionInfantile hemangioma (IH) is a common vascular tumor in children. It is reported that IHs are associated with immunochemical markers such as vascular endothelial growth factor (VEGF)-A, glucose transporter isoform 1 (GLUT1), and insulin-like growth factor-2 (IGF-2). Material and methodsThis cross-sectional study focused on pediatric patients with IH. A total of 46 patients (mean age 14.2±21.9 months) with IH and 45 healthy controls (mean age 21.8±15.08 months) were enrolled. Demographic data, clinical findings, and laboratory parameters were recorded. Blood samples were collected. Serum GLUT1, IGF-2, VEGF-A, fibroblast growth factor 1 (FGF1), and angiopoietin 2 levels were assessed by enzyme-linked immunosorbent assay. ResultsSerum GLUT1, IGF-2, and VEGF-A levels were significantly higher in patients with IH than in healthy controls (8.80±4.07pg/mL vs. 5.66±4.34pg/mL, 281.10±84.12pg/mL vs. 234.19±75.38pg/mL, 1196.99±389.34pg/mL vs. 996.99±349.16pg/mL, respectively, p=0.026, p=0.030, and p=0.036). Serum GLUT1, IGF-2, and VEGF-A levels in patients with complicated hemangioma were significantly higher than in healthy controls (9.69±3.94pg/mL vs. 5.66±4.34pg/mL, 289.94±83.18pg/mL vs. 234.19±75.38pg/mL, 1276.22±388.24pg/mL vs. 996.99±349.16pg/mL, respectively, p=0.017, p=0.022, and p=0.011). Serum GLUT1, IGF-2, and VEGF-A levels in patients with hemangioma receiving propranolol treatment were significantly higher than in healthy controls. Serum FGF1 levels were higher in patients with IH, complicated hemangioma, and hemangioma receiving propranolol treatment than in healthy controls but the difference was not statistically significantly. ConclusionSerum GLUT1, IGF-2, and VEGF-A levels were positively correlated with disease severity in patients with hemangioma, for example, in complicated hemangioma and hemangioma requiring propranolol treatment. However, further research on larger and different age subgroups is warranted to assess these markers.

Increased irisin versus reduced fibroblast growth factor1 (FGF1) in relation to adiposity, atherogenicity and hematological indices in metabolic syndrome patients with and without prediabetes.

Background Irisin and fibroblast growth factor 1 (FGF1) are intricately involved in metabolic syndrome (MetS) and prediabetes (preDM) pathophysiology. This study aimed to compare and correlate irisin and FGF1 plasma levels, adiposity, atherogenicity and hematological indices in 29 normoglycemic MetS and 30 newly diagnosed drug naive prediabetic (PreDM) MetS patients vs. 29 lean and normoglycemic controls. Materials and methods Irisin and FGF1 plasma levels were measured using colorimetric assays. Intergroup comparisons were conducted by analysis of variance (ANOVA). Spearman's rank correlation was also examined. Results The mean circulating irisin levels (ng/mL) were significantly higher in the normoglycemic (but not prediabetic) MetS group (p < 0.01), while the mean circulating FGF1 levels (pg/mL) were markedly lower in the prediabetic (but not normoglycemic) MetS group (p < 0.05). Of note unlike FGF1, irisin in the MetS (both normoglycemic and prediabetic;N=59) groups correlated significantly and positively with each of waist circumference (WC), hip circumference (HC), body mass index (BMI), body adiposity index (BAI) and high-density lipoprotein-cholesterol (HDL-C) but not the non-HDL-C. Distinctively MetS-irisin negatively associated with the non-HDL-C/HDL-C ratio, total cholesterol (TC)/HDL-C ratio and the low-density lipoprotein-cholesterol (LDL-C)/HDL-C ratio, but positively with the red cell distribution width (RDW). In the same pool of 59 MetS reruits; Neither biomarker had a relationship with the visceral adiposity index (VAI), the lipid accumulation product (LAP), the conicity index (CI), the waist-hip ratio (WHR), the waist-to-height ratio (WHtR), the blood ratios or the atherogenicity index of plasma (AIP). Conclusions As any potential molecular crosstalk of irisin and FGF1 in MetS or its related dysregularities cannot be ruled out; Conversely the utility of irisin and FGF1 as surrogate prognostic biomarkers and putative pharmacotherapeutic targets in the predtion/prevention/management of diabetes and MetS is strongly suggested.

INAVA promotes aggressiveness of papillary thyroid cancer by upregulating MMP9 expression

BackgroundInnate immunity activator (INAVA) has been shown to be elevated in lung adenocarcinoma. However, its expression pattern and function in papillary thyroid cancer (PTC) are unknown. This study aimed to identify the clinical, biological, and mechanistic impacts of INAVA on PTC.MethodsUsing The Cancer Genome Atlas dataset, real time PCR, and immunohistochemistry, the expression of INAVA in PTC was analyzed. Gain- and loss-of-function assays were performed to investigate the role of INAVA in PTC cell invasion, migration, and metastasis. We explored the molecular mechanisms underlying the roles of INAVA in PTC cells using transcriptome resequencing, real time PCR, western blotting and immunohistochemistry.ResultsWe found that INAVA expression was significantly upregulated in PTC and was significantly associated with lymph node metastasis. Loss- and gain-of-function experiments demonstrated that INAVA promoted the aggressive phenotype of PTC cells in vitro and in vivo. Mechanistic study suggested that upregulation of INAVA resulted in elevated fibroblast growth factor 1 (FGF1), which in turn increased the expression level of matrix metalloproteinases 9 (MMP9). We further identified that the level of INAVA was positively correlated with the levels of FGF1 and MMP9 in clinical PTC specimens.ConclusionThese data establish a novel role for INAVA in promoting PTC progression and suggest that INAVA may represent a therapeutic target for the disease.

Long non-coding RNA Gas5 regulates proliferation and apoptosis in HCS-2/8 cells and growth plate chondrocytes by controlling FGF1 expression via miR-21 regulation

BackgroundLncRNA Gas5 is known to be a key control element during growth, differentiation and development in mammalian species. However, the role and function of Gas5 in growth plate chondrocytes has not been determined.MethodsThe overexpression and knockdown models of Gas5 and miR-21 in cells and animals were constructed. Cell survival was determined by MTT assay and flow cytometry. Animal biochemical indices were measured by enzyme-linked immunosorbent assay, hematoxylin/eosin staining, immunohistochemistry or in situ hybridisation. Dual luciferase reporter gene assay was carried out to study targeting.ResultsFirst, we found the expression levels of fibroblast growth factor 1(FGF1) were up-regulated and miR-21 were down-regulated in Gas5 overexpressing model cells. Meanwhile, the expression levels of FGF1 and Gas5 were up-regulated in miR-21 knockdown model cells. Furthermore, cell proliferation was significantly promoted after Gas5 knockdown or miR-21 overexpression. Subsequently, Gas5 promoted apoptosis, while miR-21 suppressed apoptosis. Animal assays demonstrated that both Gas5 and dexamethasone suppressed proliferation and promoted apoptosis of growth plate chondrocytes, up-regulated FGF1 expression but reduced miR-21 expression. Finally, there was a binding relationship between Gas5, miR-21 and FGF1.ConclusionWe concluded that Gas5 regulated proliferation and apoptosis in growth plate by controlling FGF1 expression via miR-21 regulation.

Fibroblast growth factor-1 attenuates TGF-β1-induced lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive fibroblast and myofibroblast proliferation, and extensive deposition of extracellular matrix (ECM). Fibroblast growth factor-1 (FGF-1) belongs to the FGF family and has been shown to inhibit fibroblast collagen production and differentiation into myofibroblasts, and revert epithelial-mesenchymal transition by inhibiting TGF-β1 signalling pathways. However, the precise role of FGF-1 in pulmonary fibrosis has not yet been elucidated. In this study, we explore the mechanisms underlying the anti-fibrogenic effect of FGF-1 in pulmonary fibrosis in vitro and in vivo by prolonged transient overexpression of FGF-1 (AdFGF-1) and TGF-β1 (AdTGF-β1) using adenoviral vectors. In vivo, FGF-1 overexpression markedly attenuated TGF-β1-induced pulmonary fibrosis in rat lungs when given both concomitantly, or delayed, by enhancing proliferation and hyperplasia of alveolar epithelial cells (AECs). AdFGF-1 also attenuated the TGF-β1 signalling pathway and induced FGFR1 expression in AECs. In vitro, AdFGF-1 prevented the increase in α-SMA and the decrease in E-cadherin induced by AdTGF-β1 in normal human lung fibroblasts, primary human pulmonary AECs, and A549 cells. Concomitantly, AdTGF-β1-induced Smad2 phosphorylation was significantly reduced by AdFGF-1 in both cell types. AdFGF-1 also attenuated the increase in TGFβR1 protein and mRNA levels in fibroblasts. In AECs, AdFGF-1 decreased TGFβR1 protein by favouring TGFβR1 degradation through the caveolin-1/proteasome pathway. Furthermore, FGFR1 expression was increased in AECs, whereas it was decreased in fibroblasts. In serum of IPF patients, FGF-1 levels were increased compared to controls. Interestingly, FGF-1 expression was restricted to areas of AEC hyperplasia, but not α-SMA-positive areas in IPF lung tissue. Our results demonstrate that FGF-1 may have preventative and therapeutic effects on TGF-β1-driven pulmonary fibrosis via inhibiting myofibroblast differentiation, inducing AEC proliferation, regulating TGF-β1 signalling by controlling TGFβR1 expression and degradation, and regulating FGFR1 expression. Thus, modulating FGF-1 signalling represents a potential therapy for the treatment of pulmonary fibrosis. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Activation of heat shock response augments fibroblast growth factor-1 expression in wounded lung epithelium.

We previously showed that coincident exposure to heat shock (HS; 42°C for 2 h) and TNF-α synergistically induces apoptosis in mouse lung epithelium. We extended this work by analyzing HS effects on human lung epithelial responses to clinically relevant injury. Cotreatment with TNF-α and HS induced little caspase-3 and poly(ADP-ribose) polymerase cleavage in human small airway epithelial cells, A549 cells, and BEAS2B cells. Scratch wound closure rates almost doubled when A549 and BEAS2B cells and air-liquid interface cultures of human bronchial epithelial cells were heat shocked immediately after wounding. Microarray, qRT-PCR, and immunoblotting showed fibroblast growth factor 1 (FGF1) to be synergistically induced by HS and wounding. Enhanced FGF1 expression in HS/wounded A549 was blocked by inhibitors of p38 MAPK (SB203580) or HS factor (HSF)-1 (KNK-437) and in HSF1 knockout BEAS2B cells. PCR demonstrated FGF1 to be expressed from the two most distal promoters in wounded/HS cells. Wound closure in HS A549 and BEAS2B cells was reduced by FGF receptor-1/3 inhibition (SU-5402) or FGF1 depletion. Exogenous FGF1 accelerated A549 wound closure in the absence but not presence of HS. In the presence of exogenous FGF1, HS slowed wound closure, suggesting that it increases FGF1 expression but impairs FGF1-stimulated wound closure. Frozen sections from normal and idiopathic pulmonary fibrosis (IPF) lung were analyzed for FGF1 and HSP70 by immunofluorescence confocal microscopy and qRT-PCR. FGF1 and HSP70 mRNA levels were 7.5- and 5.9-fold higher in IPF than normal lung, and the proteins colocalized to fibroblastic foci in IPF lung. We conclude that HS signaling may have an important impact on gene expression contributing to lung injury, healing, and fibrosis.

Enlisting the brain to treat diabetes

Some patients with diabetes inject themselves with insulin multiple times each day to keep their blood sugar at healthy levels. Researchers now report that a single injection of a protein called fibroblast growth factor 1 (FGF1) into the brains of diabetic rodents normalizes the animals’ blood glucose levels for at least 18 weeks (Nat. Med. 2016, DOI: 10.1038/nm.4101). The findings, the scientists say, suggest the brain plays a role in regulating how the liver and muscle handle glucose, and they point to the brain as a possible target for a diabetes therapy with sustained effects. Previous studies have shown that FGF1 plays a role in metabolism. Levels of FGF1 in the blood “go up when you eat and go down when you’re starving,” says Ronald Evans of the Salk Institute for Biological Studies, who was not involved in the new work. In 2014, Evans and colleagues showed that injecting FGF1

Fibroblast growth factor 1 levels are elevated in newly diagnosed type 2 diabetes compared to normal glucose tolerance controls.

Fibroblast growth factor 1 (FGF1) has been recently characterized as a potent insulin sensitizer that regulates adipose tissue remodeling, but the physiological role of FGF1 remains unclear. This study measured serum FGF1 levels for the first time in patients with newly diagnosed type 2 diabetes mellitus (T2DM), and further explored the correlations between FGF1 levels and various metabolic parameters in T2DM. Serum FGF1 levels were determined using ELISA in age-, sex- and BMI- matched subjects with normal glucose tolerance (NGT) (n=80) and newly diagnosed T2DM (n=80). Oral glucose tolerance test (OGTT), glycosylated hemoglobin (HbA1C), blood lipids, and insulin secretion were also measured. Insulin resistance and pancreatic β-cell function were assessed by homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of beta cell function (HOMA-β), respectively. Serum FGF1 levels were significantly higher in T2DM patients than in normal glucose tolerance subjects (74.52 [55.91∼101.34] vs. 60.31 [48.99∼83.91] pg/mL; P<0.05). In addition, serum FGF1 level positively correlated with body mass index (BMI), waist circumference (WC), waist to hip ratio (WHR), fasting plasma glucose (FPG), 2-h post-OGTT glucose (2h PG), and HbA1C (all P values <0.05) in T2DM subjects. Multivariate regression analyses showed that BMI and HbA1C were the independent factors influencing serum FGF1 levels. Logistic regression analyses demonstrated that serum FGF1 was significantly associated with type 2 diabetes (P<0.01). Circulating concentrations of FGF1 are significantly increased in T2DM patients. Our results suggest that FGF1 may play a role in the pathogenesis of T2DM.

ω-3 Fatty Acids Reduce Chemotherapy-Induced Hematological Toxicity by Bone Marrow Stimulation in Mice.

ω-3 Fatty acids exert several benefits during chemotherapy, such as preventing intestinal mucosal damage and improving response to chemotherapy. However, little is known about the effect of ω-3 fatty acids on chemotherapy-induced hematological toxicities. Mice that had consumed either an ω-3-rich or an ω-3-poor diet for 2 weeks were intraperitoneally administered cisplatin. The resultant changes in blood cell count, bone marrow cell count, and cytokine levels in bone marrow supernatant were analyzed. The effect of ω-3 fatty acids on human peripheral blood mononuclear cells (PBMCs) exposed to cisplatin was also examined. Although peripheral blood cell counts decreased after cisplatin treatment in both groups of mice, the decrease in white blood cell count was significantly lower in mice that consumed the ω-3-rich diet. The decrease in bone marrow cells after cisplatin treatment was also reduced in mice that consumed the ω-3-rich diet. Levels of stem cell factor (SCF) and fibroblast growth factor 1 (FGF-1) were significantly higher in bone marrow supernatants from mice that consumed the ω-3-rich diet. The rate of apoptosis in PBMCs (after exposure to cisplatin) cultured in medium containing ω-3 fatty acids was significantly lower than in PBMCs cultured in control medium. ω-3-Rich diets reduced chemotherapy-induced leukopenia in mice. This may be the result of increased numbers of bone marrow cells due to higher levels of SCF and FGF-1 in the bone marrow.

Upregulation of fibroblast growth factor 1 in the synovial membranes of patients with late stage osteoarthritis.

Osteoarthritis (OA) is a degenerative disease of the systemic joint that involves multiple cytokines and growth factors. Fibroblast growth factor 1 (FGF-1) is increased in patients with rheumatic arthritis. The aim of this study was to determine whether the expression and secretion of FGF-1 differed in synovial tissue from patients with late stage OA from that in normal tissues. We selected eight patients with late stage OA and eight healthy donors for this study. An enzyme-linked immunosorbent assay was used to determine the amount of FGF-1 in the synovial fluid and in the culture medium of synovial fibroblasts. Real time quantitative polymerase chain reaction (qPCR) analysis was performed to examine the expression levels of FGF-1 and FGF receptor 2 (FGFR2) in synovial and cartilage tissues. We detected FGF-1 in the synovial fluid from all eight donors, as well as in the culture medium of synovial fibroblasts. Synovial fluid from patients with OA and culture medium of OA synovial fibroblasts contained significantly more FGF-1 than those from controls. FGF-1 expression was also lower in the synovial membranes of normal donors than in those of OA patients. FGFR2 expression was also higher in OA cartilage than in normal cartilage. Overall, these results demonstrated that FGF-1 synthesis and secretion by synovial fibroblasts were significantly increased in OA. FGFR2 expression was also shown to be upregulated in patients with OA. These findings suggest that increased FGF-1 signaling correlates with an OA pathological condition.

Hyperglycemia is associated with lower levels of urokinase-type plasminogen activator and urokinase-type plasminogen activator receptor in wound fluid

AimsWounds in patients with hyperglycemia show impaired healing. Plasminogen activation is crucial in several overlapping phases of wound healing process. In this study, we aimed i) to compare acute wound fluid in patients with hyperglycemia and normoglycemia, ii) to focus on the elements of plasminogen activation in the wound fluid, and iii) to determine if the acute wound fluid characteristics are associated with surgical site infections. MethodsIn a cohort of 54 patients, a closed suction drain was placed in the wound above the anterior abdominal wall fascia under the skin in order to collect postoperative acute wound fluid samples for 3 following days after colorectal surgery. Patients were classified as normoglycemic (n=25) or hyperglycemic (n=29; 17 with type 2 diabetes and 12 with stress induced hyperglycemia). Surgical site infection was defined according to the Centers for Disease Control criteria. The levels of urokinase-type plasminogen activator (uPA), urokinase-type plasminogen activator receptor (uPAr), plasminogen activator inhibitor-1 (PAI-1), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and fibroblast growth factor-1 (FGF-1) were measured in the wound fluid. ResultsCompared to normoglycemic subjects, patients with hyperglycemia had significantly lower levels of uPA and uPAr in the wound fluid despite similar or even higher circulating levels. There was no significant difference in IL-1β, TNF-α, PAI-1 and FGF-1 levels. In the whole study population, the wound fluid levels of uPA and uPAr were negatively correlated with circulating glucose levels. No difference was detected in the wound fluid characteristics of patients with and without surgical site infection. ConclusionPatients with hyperglycemia exhibit decreased levels of uPA and uPAr in the wound fluid, suggesting a local failure in plasminogen activation at the wound site.

Reproductive toxicity of Rhizoma Sparganii (Sparganium stoloniferum Buch.-Ham.) in mice: Mechanisms of anti-angiogenesis and anti-estrogen pharmacologic activities

Ethnopharmacological relevanceIndications and preliminary studies of Rhizoma Sparganii (RS) suggest its pharmacological mechanism is involved with endocrine/angiogenesis functions. We therefore studied its potential toxicity on reproduction in mice. Materials and methodsReproductive toxicity of 100, 200 and 400mg/kg RS extract were studied in pregnant ICR mice and its offspring. The embryos’ fibroblast growth factor-1 (FGF-1), vascular endothelial growth factor (VEGF) and estrogen receptor-α (ER-α) were evaluated as targets of endocrine/angiogenesis by immunohistochemical test. ResultsThe offspring of treated mice (100, 200 and 400mg/kg RS extract) during their pregnancy had various pathological conditions, suggesting an abnormal FGF signaling phenomenon during pregnancy. Embryos from the 400mg/kg group had significantly depressed levels of FGF-1 (P<0.01) and VEGF (P<0.05) expression levels as compared to controls by immunohistochemical test. Dysplasia in the heart (12.9%), craniofacial region (18.3%) and vertebrae (32.5%) presented in embryos of the 400mg/kg group. Furthermore, the ER-α expression was inversely proportional to FGF-1 levels in the same embryo (P<0.01). ConclusionsThese results implicate a FGF signaling abnormality in vivo and indicate that RS has anti-angiogenesis and anti-estrogen toxicity effects in pregnant rodents.

Regulation of FGF1 Gene Promoter through Transcription Factor RFX1

Fibroblast growth factor 1 (FGF1) has been suggested to have an important role in cell growth, proliferation, and neurogenesis. Human FGF1 gene 1B promoter (−540 to +31)-driven green fluorescence (F1BGFP) has been shown to monitor endogenous FGF1 expression. F1BGFP could also be used to isolate neural stem/progenitor cells from embryonic, neonatal, and adult mouse brains or to isolate glioblastoma stem cells (GBM-SCs) from human glioblastoma tissues. Here, we present evidence that transcription factor RFX1 could bind the 18-bp cis-elements (−484 to −467) of the F1B promoter, modulate F1BGFP expression and endogenous FGF1 expression, and further regulate the maintenance of GBM-SCs. These observations were substantiated by using yeast one-hybrid assay, electrophoretic mobility shift assay, chromatin immunoprecipitation assay, gain- and loss-of-function assays, and neurosphere assays. Overexpression of RFX1 was shown to down-regulate FGF-1B mRNA expression and neurosphere formation in human glioblastoma cells, whereas RNA interference knockdown of RFX1 demonstrated the opposite effects. Our findings provide insight into FGF1 gene regulation and suggest that the roles of FGF1 and RFX1 in the maintenance of GBM-SCs. RFX1 may negatively regulate the self-renewal of GBM-SCs through modulating FGF-1B and FGF1 expression levels by binding the 18-bp cis-elements of the F1B promoter.