Expression Of Fibroblast Growth Factor Research Articles

Inhibition of RIP3 increased ADSC viability under OGD and modified the competency of adipogenesis, angiogenesis, and inflammation regulation.

Adipose-derived stem cells (ADSCs) showed decreased cell viability and increased cell death under oxygen-glucose deprivation (OGD). Meanwhile, vital necroptotic proteins, including receptor-interacting protein kinase (RIP) 3 (RIP3) and mixed lineage kinase domain-like pseudokinase (MLKL), were expressed in the early stage. The present study aims to explore the effect of necroptosis inhibition on ADSCs. ADSCs were obtained from normal human subcutaneous fat and verified by multidirectional differentiation and flow cytometry. By applying cell counting kit-8 (CCK-8), calcein/propidium iodide (PI) staining and immunostaining, we determined the OGD treatment time of 4 h, a timepoint when the cells showed a significant decrease in viability and increased protein expression of RIP3, phosphorylated RIP3 (pRIP3) and phosphorylated MLKL (pMLKL). After pretreatment with the inhibitor of RIP3, necroptotic protein expression decreased under OGD conditions, and cell necrosis decreased. Transwell assays proved that cell migration ability was retained. Furthermore, the expression of the adipogenic transcription factor peroxisome proliferator-activated receptor γ (PPARγ) and quantitative analysis of Oil Red O staining increased in the inhibitor group. The expression of vascular endothelial growth factor-A (VEGFA) and fibroblast growth factor 2 (FGF2) and the migration test suggest that OGD increases the secretion of vascular factors, promotes the migration of human umbilical vein endothelial cells (HUVECs), and forms unstable neovascularization. ELISA revealed that inhibition of RIP3 increased the secretion of the anti-inflammatory factor, interleukin (IL)-10 (IL-10) and reduced the expression of the proinflammatory factor IL-1β. Inhibition of RIP3 can reduce the death of ADSCs, retain their migration ability and adipogenic differentiation potential, reduce unstable neovascularization and inhibit the inflammatory response.

CircSLC16A12 Absence Inhibits High Glucose-Induced Dysfunction in Retinal Microvascular Endothelial Cells through Mediating miR-140-3p/FGF2 Axis in Diabetic Retinopathy

PurposeDiabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus which can cause irreversible visual impairment and blindness. We intended to investigate the function of circular RNA (circRNA) solute carrier family 16 member 12 (SLC16A12) in DR progression.MethodsReverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot assay were applied to measure RNA and protein expression. Cell apoptosis was analyzed by flow cytometry (FCM) analysis. The angiogenesis ability was assessed by tube formation assay. Enzyme-linked immunosorbent assay (ELISA) was performed to analyze the release of inflammatory cytokines. Cell oxidative stress status was evaluated using commercial kits. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay, and RNA-pull down assay were conducted to confirm the intermolecular interactions.ResultsCircSLC16A12 level was enhanced in the serum samples of DR patients and high glucose (HG)-treated HRECs. CircSLC16A12 absence protected HRECs from HG-induced apoptosis, blood-retinal barrier (BRB) injury, tube formation, inflammatory response, and oxidative stress. CircSLC16A12 acted as a sponge for microRNA-140-3p (miR-140-3p), and circSLC16A12 knockdown-mediated effects were largely reversed by the absence of miR-140-3p in HRECs under HG condition. miR-140-3p interacted with the 3’ untranslated region (3’UTR) of fibroblast growth factor 2 (FGF2), and the overexpression of FGF2 largely overturned miR-140-3p overexpression-mediated effects in HRECs. CircSLC16A12 interference reduced the expression of FGF2 by up-regulating miR-140-3p in HRECs.ConclusionCircSLC16A12 silencing suppressed HG-induced dysfunction in HRECs partly by targeting miR-140-3p/FGF2 axis.

Periostin-related progression of different types of experimental pulmonary hypertension: A role for M2 macrophage and FGF-2 signalling.

Background and objectiveRemodelling of pulmonary arteries (PA) contributes to the progression of pulmonary hypertension (PH). Periostin, a matricellular protein, has been reported to be involved in the development of PH. We examined the role of periostin in the pathogenesis of PH using different types of experimental PH.MethodsPH was induced by vascular endothelial growth factor receptor antagonist (Sugen5416) plus hypoxic exposure (SuHx) and venous injection of monocrotaline‐pyrrole (MCT‐P) in wild‐type (WT) and periostin−/− mice. Pulmonary haemodynamics, PA remodelling, expression of chemokines and fibroblast growth factor (FGF)‐2, accumulation of macrophages to small PA and the right ventricle (RV) were examined in PH‐induced WT and periostin−/− mice. Additionally, the role of periostin in the migration of macrophages, human PA smooth muscle (HPASMCs) and endothelial cells (HPMVECs) was investigated.ResultsIn PH induced by SuHx and MCT‐P, PH and accumulation of M2 macrophage to small PA were attenuated in periostin−/− mice. PA remodelling post‐SuHx treatment was also mild in periostin−/− mice compared to WT mice. Expression of macrophage‐associated chemokines and FGF‐2 in lung tissue, and accumulation of CD68‐positive cells in the RV were less in SuHx periostin−/− than in SuHx WT mice. Periostin secretion in HPASMCs and HPMVECs was enhanced by transforming growth factor‐β. Periostin also augmented macrophage, HPASMCs and HPMVECs migration. Separately, serum periostin levels were significantly elevated in patients with PH compared to healthy controls.ConclusionPeriostin is involved in the development of different types of experimental PH, and may also contribute to the pathogenesis of human PH.

Exosomal miR-9-5p derived from BMSCs alleviates apoptosis, inflammation and endoplasmic reticulum stress in spinal cord injury by regulating the HDAC5/FGF2 axis

Exosomes derived from human bone marrow mesenchymal stem cells (BMSCs) play potential protective roles in spinal cord injury (SCI). However, the underlying mechanisms remain not fully elucidated. Herein, we isolated exosomes from BMSCs, and exosome morphology and marker protein levels were identified by transmission electron microscopy (TEM) and Western blot, respectively. PC12 cells were treated with lipopolysaccharide (LPS) to construct an injury model, and then incubated with BMSCs-derived exosomes. We found that exosome incubation increased miR-9-5p expression, and inhibited apoptosis and the levels of inflammation cytokines and ER stress marker proteins. Moreover, histone deacetylase 5 (HDAC5) was identified as a target gene of miR-9-5p by dual-luciferase reporter gene assay. Exosomal miR-9-5p upregulated fibroblast growth factor 2 (FGF2) expression by inhibiting HDAC5-mediated FGF2 deacetylation. Then, it was observed that HDAC5 overexpression or FGF2 inhibition reversed the inhibitory effects of exosomal miR-9-5p on apoptosis, inflammation and ER stress in PC12 cells. Additionally, an SCI rat model was established and exosomes were injected for treatment. Exosomal miR-9-5p treatment alleviated locomotor ability, histopathological damage, neuronal apoptosis, inflammation and ER stress in SCI rats. In conclusion, our findings indicated that exosomal miR-9-5p derived from BMSCs promoted FGF2 expression by inhibiting HDAC5-mediated deacetylation, thus inhibiting LPS-induced apoptosis, inflammation, and ER stress in PC12 cells, and alleviating SCI in rat model. Our study may provide a therapeutic direction for SCI.

HDAC7 promotes NSCLC proliferation and metastasis via stabilization by deubiquitinase USP10 and activation of \u03b2-catenin-FGF18 pathway

BackgroundHistone deacetylases (HDACs) play crucial roles in cancers, but the role and mechanism of HDAC7 in NSCLC have not been fully understood.MethodsA total of 319 patients with non-small cell lung cancer (NSCLC) who underwent surgery were enrolled in this study. Immunohistochemistry and Kaplan–Meier survival analysis were performed to investigate the relationship between HDAC7, fibroblast growth factor 18 (FGF18) expression, and clinicopathologic characteristics. Cell functional experiments were implemented both in vivo and in vitro to investigate the effects on NSCLC cell proliferation and metastasis. Recombinant lentivirus–meditated in vivo gene overexpression or knockdown, real-time polymerase chain reaction (PCR), western blotting, and coimmunoprecipitation assays were applied to clarify the underlying molecular mechanism of HDAC7 in promoting NSCLC progression.ResultsThe elevated expression of HDAC7 or FGF18 was positively correlated with poor prognosis, tumor–node–metastasis (TNM) stage, and tumor differentiation of NSCLC patients. NSCLC patients with co-expressed HDAC7 and FGF18 suffered the worst prognosis. HDAC7 overexpression promoted NSCLC proliferation and metastasis by upregulating FGF18. Conversely, overexpression of FGF18 reversed the attenuated ability in tumor growth and metastasis mediated by downregulating HDAC7. In terms of mechanism, our results suggested that the interaction of HDAC7 with β-catenin caused decreased β-catenin acetylation level at Lys49 and decreased phosphorylation level at Ser45. As a consequence, the HDAC7-mediated posttranslational modification of β-catenin facilitated nuclear transfer and activated FGF18 expression via binding to TCF4. Furthermore, deubiquitinase USP10 interacted with and stabilized HDAC7. The suppression of USP10 significantly accelerated the degradation of HDAC7 and weakened NSCLC growth and migration.ConclusionsOur findings reveal that HDAC7 promotes NSCLC progression through being stabilized by USP10 and activating the β-catenin-FGF18 pathway. Targeting this novel pathway may be a promising strategy for further developments in NSCLC therapy.

Next-Generation Sequencing of Circular RNAs Reveals the Molecular Mechanisms of Chondrogenic Differentiation in Human Adipose-derived Stem Cells.

Adipose-derived stem cells are one of the potential sources of cells for the treatment of cartilage defects. This study aimed to investigate the molecular mechanisms that account for the chondrogenic differentiation of human adipose-derived stem cells (hADSCs). We employed integrin β1 (ITGB1) overexpression to induce chondrogenic differentiation of hADSCs. Next-generation sequencing was used to determine the mRNAs and circular RNAs (circRNAs) expression profiles in ITGB1-overexpresing and negative control cells. The potential functions of differentially expressed mRNAs were analyzed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses. Moreover, differentially expressed circRNAs with the greatest fold change were validated by polymerase chain reaction (PCR), Sanger sequencing, and quantitative real-time PCR (qRT-PCR). These three circRNAs and their downstream microRNAs and mRNAs were used to construct a circRNA-microRNA-mRNA interaction network. The results showed that we identified 713 differentially expressed circRNAs (150 upregulated and 563 downregulated in ITGB1-overexpressing hADSCs versus negative control cells, respectively). Meanwhile, 2383 mRNAs were differentially expressed between two groups (1672 upregulated and 711 downregulated in ITGB1-overexpressing cells compared with the negative control cells). The GO and KEGG analysis results showed that the differentially expressed mRNAs were enriched in biological processes, cellular components, and molecular functions, especially in the phosphatidylinositol 3-kinase (PI3K)-AKT and mitogen-activated protein kinase signaling pathways. Three differentially expressed circRNAs, including hsa_circ_0071127, hsa_circ_0008637, and hsa_circ_0020028, were validated by qRT-PCR. Moreover, the circRNA-microRNA-mRNA network predicted that fibroblast growth factor 2 (FGF2) was a common node regulated by these three circRNAs through several microRNAs, including miR-195-3p, miR-205-3p, and miR-152-3p. We further found that the knockdown of hsa_circ_0020028, but not the two other circRNAs, significantly reduced FGF2 mRNA expression in hADSCs. Furthermore, the knockdown of hsa_circ_0020028 significantly inhibited the protein expression of FGF2, chondrogenic differentiation markers (COL II, aggrecan, and SOX9), and PI3K/AKT signaling in ITGB1-overexpressing hADSCs. This study uncovered the differentially expressed mRNA and circRNA profiles in the chondrogenic differentiation of hADSCs induced by ITGB1 overexpression. Our findings demonstrate that hsa_circ_0020028 regulates the ITGB1 overexpression-mediated chondrogenic differentiation of hADSCs through regulation of FGF2-related signaling pathways.

Canopy Homolog 2 contributes to liver oncogenesis by promoting unfolded protein response-dependent destabilization of tumor protein P53.

Abnormalities in the tumor protein P53(p53)gene and overexpression of mouse double minute 2 homolog (MDM2), a negative regulator of p53, are commonly observed in cancers. p53 destabilization is regulated by endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in cancer. However, the mechanisms remain enigmatic. Canopy homolog 2 (CNPY2) is a key UPR initiator that primarily involved in ER stress and is highly expressed in the liver, but its functional role in regulating liver carcinogenesis is poorly understood. Therefore, we aimed to investigate the role of CNPY2 in hepartocarcinogenesis through URP-dependent p53 destabilization. Here, we showed that CNPY2 expression is up-regulated in HCC and negatively correlated with survival rate in liver cancer patients. Deletion of Cnpy2 obliterates diethylnitrosamine (DEN)-induced HCC in mice. Mechanistic studies demonstrated that CNPY2 binds and prevents ribosome proteins from inhibiting MDM2 and enhances the UPR activity of protein kinase RNA-like endoplasmic reticulum kinase and inositol-requiring transmembrane kinase endoribonuclease-1α, leading to p53 destabilization and cell-cycle progression. In addition, transcriptome analyses uncovered that CNPY2 is also required for DEN-induced expression of oncogenes, including c-Jun and fibroblast growth factor 21. Intratumoral injection of nanoparticle-based CRISPR single-guide RNA/CRISPR-associated protein 9 mRNA against Cnpy2 has antitumor effects in HCC. These findings demonstrate that CNPY2 is crucial for liver oncogenesis through UPR-dependent repression of p53 and activation of oncogenes, providing insights into the design of a therapeutic target for HCC.

Downregulated exosome-associated gene FGF9 as a novel diagnostic and prognostic target for ovarian cancer and its underlying roles in immune regulation.

Exosome has been demonstrated to be secreted from cells and seized by targeted cells. Exosome could transmit signals and exert biological functions in cancer progression. Nevertheless, the underlying mechanisms of exosome in ovarian cancer (OC) have not been fully explored. In this study, we wanted to explore whether Fibroblast growth factor 9 (FGF9), as an exosome-associated gene, was importantly essential in OC progression and prognosis. Firstly, comprehensive bioinformatics platforms were applied to find that FGF9 expression was lower in OC tissues compared to normal ovarian tissues. Meanwhile, downregulated FGF9 displayed favorable prognostic values in OC patients. The gene enrichment of biological functions indicated that abnormally expressed FGF9 could be involved in the OC-related immune signatures, such as immunoinhibitors and chemokine receptors. Taken together, these findings could provide a novel insight into the significance of FGF9 in OC progress and supply a new destination of FGF9-related immunotherapy in clinical treatment.

Circular RNA circLMF1 regulates PDGF-BB-induced proliferation and migration of human aortic smooth muscle cells by regulating the miR-125a-3p/VEGFA or FGF1 axis.

Atherosclerosis is a major cause of cardiovascular disease, in which vascular smooth muscle cells (VSMCs) proliferation and migration play a vital role. Circular RNAs (circRNAs) have been reported to be correlated with the VSMCs function. Therefore, this study is designed to explore the role and mechanism of circRNA lipase maturation factor 1 (circLMF1) in Human aortic VSMCs (HASMCs). The microarray was used for detecting the expression of circLMF1 in proliferative and quiescent HASMCs. Levels of circLMF1, microRNA-125a-3p (miR-125a-3p), vascular endothelial growth factor A (VEGFA), and fibroblast growth factor 1 (FGF1) were determined by real-time quantitative polymerase chain reaction (RT-qPCR). Cell viability, cell cycle progression, and migration were assessed by Cell Counting Kit-8 (CCK-8), flow cytometry, wound healing, and transwell assays, respectively. Western blot assay determined proliferating cell nuclear antigen (PCNA), Cyclin D1, matrix metalloproteinase (MMP2), osteopontin (OPN), VEGFA, and FGF1 protein levels. The possible interactions between miR-125a-3p and circLMF1, and miR-125a-3p and VEGFA or FGF1 were predicted by circbank or targetscan, and then verified by a dual-luciferase reporter, RNA Immunoprecipitation (RIP), RNA pull-down assays. CircLMF1, VEGFA, and FGF1 were increased, and miR-125a-3p was decreased in platelet-derived growth factor-BB (PDGF-BB)-inducted HASMCs. Functionally, circLMF1 knockdown hindered cell viability, cell cycle progression, and migration in PDGF-BB-treated HASMCs. Mechanically, circLMF1 could regulate VEGFA or FGF1 expression through sponging miR-125a-3p. Our findings revealed that circLMF1 deficiency could inhibit cell viability, cell cycle progression, and migration of PDGF-BB stimulated atherosclerosis model partly through the miR-125a-3p/VEGFA or FGF1 axis, suggesting that targeting circLMF1 can be a feasible therapeutic strategy for atherosclerosis.

Adiponectin Influences FGF2 in the Developing Porcine Corpus Luteum.

Luteal angiogenesis is regulated by pro-angiogenic hormones including fibroblast growth factor 2 (FGF2) and angiopoietin 1 (Ang1), which are regulated by the adipokine leptin during development. Another adipokine, adiponectin, exhibits an inverse relationship with leptin and has been identified in the CL. Therefore, it is hypothesized that adiponectin will influence pro-angiogenic hormones in the developing porcine CL. Crossbred sows were randomly allocated to one of two days of the estrous cycle, day 5 (D5; n = 4) or day 7 (D7; n = 5) for CL collection. Tissue was processed for immunohistochemical localization of adiponectin receptor 2 (AdipoR2), gene expression of FGF2, Ang1, leptin, AdipoR2, and cell culture for adiponectin treatment. The expression of AdipoR2 tended (p = 0.09) to be higher in D7 lutea and was more prevalently localized to the cell surface of large and small luteal cells than in D5 tissue. Adiponectin influenced (p ≤ 0.05) FGF2, leptin, and AdipoR2 gene expression relative to the dose and day (D5 or D7). Collectively, the evidence supports the supposition that adiponectin influences angiogenic factors in the developing CL.

Alternate-day fasting alleviates high fat diet induced non-alcoholic fatty liver disease through controlling PPARα/Fgf21 signaling.

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that ultimately leads to cirrhosis and hepatocellular carcinoma. Intermittent fasting has been proposed as a nonpharmacological dietary approach against metabolic diseases, including NAFLD. In this study, we aimed to investigate the effect of alternate day fasting (ADF) on high-fat diet (HFD)-induced NAFLD in C57BL/6 mice. A mouse model of fatty liver disease was established by feeding the mice a HFD for 16weeks. The mice were administered by body weight, lipid accumulation and inflammation. PPARα, FGF21, serum triglycerides (TG), total cholesterol (TC), transaminase and lipogenesis were assessed. The results showed that long-term ADF can attenuate fatty liver disease by reducing hepatic inflammation and lipid accumulation in a mouse model. Meanwhile, fasting elevated the expression of serum and hepatic fibroblast growth Factor 21 (Fgf21), a circulating hormone produced predominantly in the liver, and could effectively prevent and ameliorate the pathogenesis of NAFLD. Serum starvation also enhanced Fgf21 expression and reduced free fatty acid (FFA)-induced lipid storage in hepatocytes. Moreover, refeeding inhibited the increase in Fgf21 expression induced by fasting. This fasted-to-refed transition is closely related to the expression of Fgf21. Further in vitro and in vivo studies showed that fasting-sensitive PPARα is indispensable for the expression of Fgf21 and its protective effect on NAFLD. These findings indicated that long-term ADF protects mouse livers against HFD induced fatty liver disease through controlling PPARα/Fgf21 signaling. In conclusion, ADF can emerge as a non-pharmacological dietary approach against fatty liver disease.

Endocrine Fibroblast Growth Factors in Relation to Stress Signaling.

Fibroblast growth factors (FGFs) play important roles in various growth signaling processes, including proliferation, development, and differentiation. Endocrine FGFs, i.e., atypical FGFs, including FGF15/19, FGF21, and FGF23, function as endocrine hormones that regulate energy metabolism. Nutritional status is known to regulate the expression of endocrine FGFs through nuclear hormone receptors. The increased expression of endocrine FGFs regulates energy metabolism processes, such as fatty acid metabolism and glucose metabolism. Recently, a relationship was found between the FGF19 subfamily and stress signaling during stresses such as endoplasmic reticulum stress and oxidative stress. This review focuses on endocrine FGFs and the recent progress in FGF studies in relation to stress signaling. In addition, the relevance of the stress–FGF pathway to disease and human health is discussed.

Electroacupuncture suppresses spinal nerve ligation-induced neuropathic pain via regulation of synaptic plasticity through upregulation of basic fibroblast growth factor expression.

Improving synaptic plasticity is a good way to alleviate neuropathic pain. Electroacupuncture (EA) is currently used worldwide to treat this disease, but its specific mechanisms of action need further investigation. Evidence has suggested that basic fibroblast growth factor (bFGF) plays an important role in promoting nerve regeneration and can promote the expression of vascular endothelial growth factor (VEGF). In this study, we examined the effects of EA on synaptic plasticity and its underlying mechanism. A spinal nerve ligation (SNL) rat model was established. NSC37204 (a specific inhibitor of bFGF) was used to determine the relationship between bFGF and putative EA-mediated improvements in synaptic plasticity. Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were assessed to evaluate hyperalgesia in rats with SNL. Tissue morphology was detected by hematoxylin-eosin (HE) and Nissl staining, while neural plasticity and its molecular mechanisms were examined by Western blotting, quantitative real-time polymerase chain reaction (qPCR), dual-label immunohistochemistry and transmission electron microscopy. We found that EA improved synaptic plasticity, consistent with higher levels of expression of bFGF and VEGF. Contrary to the beneficial effects of EA, NSC37204 promoted synaptic reconstruction. Furthermore, EA-induced improvements in the neurobehavioral state and improved synaptic plasticity were blocked by NSC37204, consistent with lower expression levels of bFGF and VEGF. These findings indicate that EA suppresses SNL-induced neuropathic pain by improving synaptic plasticity via upregulation of bFGF expression.

Bromodomain Inhibition Reveals FGF15/19 As a Target of Epigenetic Regulation and Metabolic Control.

Epigenetic regulation is an important factor in glucose metabolism, but underlying mechanisms remain largely unknown. Here we investigated epigenetic control of systemic metabolism by bromodomain-containing proteins (Brds), which are transcriptional regulators binding to acetylated histone, in both intestinal cells and mice treated with the bromodomain inhibitor JQ-1. In vivo treatment with JQ-1 resulted in hyperglycemia and severe glucose intolerance. Whole-body or tissue-specific insulin sensitivity was not altered by JQ-1; however, JQ-1 treatment reduced insulin secretion during both in vivo glucose tolerance testing and ex vivo incubation of isolated islets. JQ-1 also inhibited expression of fibroblast growth factor (FGF) 15 in the ileum and decreased FGF receptor 4-related signaling in the liver. These adverse metabolic effects of Brd4 inhibition were fully reversed by in vivo overexpression of FGF19, with normalization of hyperglycemia. At a cellular level, we demonstrate Brd4 binds to the promoter region of FGF19 in human intestinal cells; Brd inhibition by JQ-1 reduces FGF19 promoter binding and downregulates FGF19 expression. Thus, we identify Brd4 as a novel transcriptional regulator of intestinal FGF15/19 in ileum and FGF signaling in the liver and a contributor to the gut-liver axis and systemic glucose metabolism.

FGF2 is overexpressed in asthma and promotes airway inflammation through the FGFR/MAPK/NF-\u03baB pathway in airway epithelial cells

BackgroundAirway inflammation is the core pathological process of asthma, with the key inflammatory regulators incompletely defined. Recently, fibroblast growth factor 2 (FGF2) has been reported to be an inflammatory regulator; however, its role in asthma remains elusive. This study aimed to investigate the immunomodulatory role of FGF2 in asthma.MethodsFirst, FGF2 expression was characterised in clinical asthma samples and the house dust mite (HDM)-induced mouse chronic asthma model. Second, recombinant mouse FGF2 (rm-FGF2) protein was intranasally delivered to determine the effect of FGF2 on airway inflammatory cell infiltration. Third, human airway epithelium-derived A549 cells were stimulated with either HDM or recombinant human interleukin-1β (IL-1β) protein combined with or without recombinant human FGF2. IL-1β-induced IL-6 or IL-8 release levels were determined using enzyme-linked immunosorbent assay, and the involved signalling transduction was explored via Western blotting.ResultsCompared with the control groups, the FGF2 protein levels were significantly upregulated in the bronchial epithelium and alveolar areas of clinical asthma samples (6.70 ± 1.79 vs. 16.32 ± 2.40, P = 0.0184; 11.20 ± 2.11 vs. 21.00 ± 3.00, P = 0.033, respectively) and HDM-induced asthmatic mouse lung lysates (1.00 ± 0.15 vs. 5.14 ± 0.42, P < 0.001). Moreover, FGF2 protein abundance was positively correlated with serum total and anti-HDM IgE levels in the HDM-induced chronic asthma model (R2 = 0.857 and 0.783, P = 0.0008 and 0.0043, respectively). Elevated FGF2 protein was mainly expressed in asthmatic bronchial epithelium and alveolar areas and partly co-localised with infiltrated inflammatory cell populations in HDM-induced asthmatic mice. More importantly, intranasal instillation of rm-FGF2 aggravated airway inflammatory cell infiltration (2.45 ± 0.09 vs. 2.88 ± 0.14, P = 0.0288) and recruited more subepithelial neutrophils after HDM challenge [(110.20 ± 29.43) cells/mm2 vs. (238.10 ± 42.77) cells/mm2, P = 0.0392] without affecting serum IgE levels and Th2 cytokine transcription. In A549 cells, FGF2 was upregulated through HDM stimulation and promoted IL-1β-induced IL-6 or IL-8 release levels (up to 1.41 ± 0.12- or 1.44 ± 0.14-fold change vs. IL-1β alone groups, P = 0.001 or 0.0344, respectively). The pro-inflammatory effect of FGF2 is likely mediated through the fibroblast growth factor receptor (FGFR)/mitogen-activated protein kinase (MAPK)/nuclear factor kappa B (NF-κB) pathway.ConclusionOur findings suggest that FGF2 is a potential inflammatory modulator in asthma, which can be induced by HDM and acts through the FGFR/MAPK/NF-κB pathway in the airway epithelial cells.

Mast cells and basic fibroblast growth factor in physiological aging of rat heart and kidney

ABSTRACT Age-related morphological and physiological changes occur in cells, tissues and organs with high metabolic or mitotic activity; these changes decrease their regenerative capacity. One such change is interstitial fibrosis. Mast cells contain basic fibroblast growth factor and have been related to pro-fibrotic activity. We investigated the role of mast cells in physiological aging of the heart and kidney. We analyzed changes in mast cell number and compared the left and right heart ventricles and kidneys of 6- and 12-month-old Wistar rats. We also evaluated the immunohistochemical expression of basic fibroblast growth factor. Finally, we analyzed changes in the extent of interstitial fibrosis and in the glomerular sclerosis index as nonspecific markers of aging and correlated these parameters with of mast cells. Mast cells were visualized by toluidine blue staining and specific immunohistochemical expression of tryptase. The expression of basic fibroblast growth factor was assessed semiquantitatively. The extent of interstitial fibrosis was investigated using Mallory’s trichrome staining. Glomerular sclerosis was evaluated using periodic acid-Schiff staining. We found that the number of mast cells increased significantly in the older rats. We also found that the number of mast cells was greatest in the left ventricle followed by the right ventricle, then the kidney. The immunoreactivity of basic fibroblast growth factor also increased in older animals. Correlations between the number of mast cells and immunoreactivity of basic fibroblast growth factor, extent of interstitial fibrosis and glomerular sclerosis index demonstrated the association between mast cells and age-related tissue remodeling of the heart and kidney.

Enhanced growth factor expression in chronic diabetic wounds treated by cold atmospheric plasma.

Cold atmospheric plasma (CAP) has been proven to enhance wound healing in superficial, chronically infected, diabetic foot ulcers. We aimed to investigate the molecular drivers responsible for this macroscopically observed improvement in diabetic wound healing. Wound exudate was available from each change of dressing within a prospective, randomised, patient-blinded clinical trial. Specific protein level analyses were conducted via multiplex ELISA for wound samples of a representative subcohort (placebo: n=13; CAP: n=14). Expression of fibroblast growth factor 2 (FGF-2), vascular endothelial growth factor A (VEGF-A), cytokines and matrix metalloproteinases (MMPs) were evaluated over a treatment period of about 14days. Analysis revealed increased levels of the growth factors FGF-2 (placebo: median 46.9 range [32.0-168.6] AU vs. CAP: 113.7[55.8-208.1] AU) and VEGF-A (placebo: 79.7 [52.4-162.7] AU vs. CAP: 120.8 [51.1-198.1] AU) throughout the treatment period and in head-to-head comparison in a daily assessment. CAP-treated wounds showed increased levels of tumour necrosis factor-alpha, interleukins 1α and 8. However, the total protein amounts were not significantly elevated. The total protein amounts of MMPs were not altered by CAP. Induction of crucial growth factors, like FGF-2 and VEGF-A, and interleukins appears to be an important component of CAP-mediated promotion of granulation, vascularisation and reepithelialisation in the diabetic foot. These findings demonstrate for the first time that CAP-mediated growth factor induction also occurs in persons with diabetes, as previously described only in several in vitro and rodent experiments. Clinical Trial registration KPWTRIAL: NCT04205942, ClinicalTrials.gov.

The Role of FGF19 and MALRD1 in Enterohepatic Bile Acid Signaling.

Bile acids are the catabolic end products of cholesterol metabolism that are best known for their role in the digestion of lipids. In the last two decades, extensive investigation has shown bile acids to be important signaling molecules in metabolic processes throughout the body. Bile acids are ligands that can bind to several receptors, including the nuclear receptor farnesoid X receptor (FXR) in ileal enterocytes. FXR activation induces the expression of fibroblast growth factor (FGF) 15/19, a hormone that can modulate bile acid levels, repress gluconeogenesis and lipogenesis, and promote glycogen synthesis. Recent studies have described a novel intestinal protein, MAM and LDL Receptor Class A Domain containing 1 (MALRD1) that positively affects FGF15/19 levels. This signaling pathway presents an exciting target for treating metabolic disease and bile acid-related disorders.

Oral administration of megestrol acetate can increase fat graft survival in a rat model

Insufficient and inconsistent survival is a significant shortcoming of fat grafts. Reportedly, megestrol acetate (MA) could induce proliferation, migration, and adipogenic differentiation of adipose-derived stem cells in vitro. Thus, we tested whether MA could promote fat graft survival in a rat model. Twenty-eight Sprague-Dawley rats (8 weeks old, male) were divided into two groups: experimental (MA group, n=14) and control (n=14). The inguinal fat pad (1g) was extracted en bloc and re-implanted under the scalp in both groups. MA (100mg/kg/day) was administered orally for 14 postoperative days in the experimental group. After 6 weeks, the volume and weight of the grafted fat were measured. Histologic examination with hematoxylin and eosin (HE) and real-time polymerase chain reaction (PCR) for vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), and CCAAT/enhancer-binding protein alpha (C/EBP-α) were performed. Perilipin staining was performed to check the viability of grafted fat. Graft fat volume was greater in the MA group, compared with that in the control (P=0.023). The MA group also had more viable cells, including more adipocytes, and less fibrosis or vacuoles than the control on HE and perilipin staining. MA upregulated the expression of FGF2 (P<0.001), VEGF (P=0.008), and C/EBP-α (P=0.002) at the second postoperative week. MA increased survival of grafted fat in an animal model. Increased vascularization and adipogenesis were related to these results. Further human clinical trials are necessary to evaluate adjunctive oral administration of MA after fat grafting to promote graft survival.

RETRACTED ARTICLE: Inhibition of Long non-coding RNA zinc finger antisense 1 improves functional recovery and angiogenesis after focal cerebral ischemia via microRNA-144-5p/fibroblast growth factor 7 axis

Statement of Retraction Tong Li, Bai Ling Qing, Yan Deng, Xian Ting Que, Cheng Zhi Wang, Hua Wen Lu, Shao Hua Wang & Zi Jun Wang (2022) Inhibition of Long non-coding RNA zinc finger antisense 1 improves functional recovery and angiogenesis after focal cerebral ischemia via microRNA-144-5p/fibroblast growth factor 7 axis, Bioengineered, 13:1, 1702-1716, DOI: 10.1080/21655979.2021.2018093 Since publication, significant concerns have been raised about the integrity of the data and reported results in the article. When approached for an explanation, the authors did not provide their original data or any necessary supporting information. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article. All authors listed in this publication have been informed. We have been informed in our decision-making by our editorial policies and the COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.