Intracellular FGF1 protects cells from apoptosis through direct interaction with p53.

Fibroblast growth factor 1 (FGF1) acts by activating specific tyrosine kinase receptors on the cell surface. In addition to this classical mode of action, FGF1 also exhibits intracellular activity. Recently, we found that FGF1 translocated into the cell interior exhibits anti-apoptotic activity independent of receptor activation and downstream signaling. Here, we show that expression of FGF1 increases the survival of cells treated with various apoptosis inducers, but only when wild-type p53 is present. The p53-negative cells were not protected by either ectopically expressed or translocated FGF1. We also confirmed the requirement of p53 for the anti-apoptotic intracellular activity of FGF1 by silencing p53, resulting in loss of the protective effect of FGF1. In contrast, in p53-negative cells, intracellular FGF1 regained its anti-apoptotic properties after transfection with wild-type p53. We also found that FGF1 directly interacts with p53 in cells and that the binding region is located in the DBD domain of p53. We therefore postulate that intracellular FGF1 protects cells from apoptosis by directly interacting with p53.

Fibroblast Growth Factor-1 Activates Neurons in the Arcuate Nucleus and Dorsal Vagal Complex.

Central administration of fibroblast growth factor-1 (FGF1) results in long-lasting resolution of hyperglycemia in various rodent models, but the pre- and postsynaptic mechanisms mediating the central effects of FGF1 are unknown. Here we utilize electrophysiology recordings from neuronal populations in the arcuate nucleus of the hypothalamus (ARH), nucleus of the solitary tract (NTS), and area postrema (AP) to investigate the mechanisms underlying FGF1 actions. While FGF1 did not alter membrane potential in ARH-NPY-GFP neurons, it reversibly depolarized 83% of ARH-POMC-EGFP neurons and decreased the frequency of inhibitory inputs onto ARH-POMC-EGFP neurons. This depolarizing effect persisted in the presence of FGF receptor (R) blocker FIIN1, but was blocked by pretreatment with the voltage-gated sodium channel (VGSC) blocker tetrodotoxin (TTX). Non-FGF1 subfamilies can activate vascular endothelial growth factor receptors (VEGFR). Surprisingly, the VEGFR inhibitors axitinib and BMS605541 blocked FGF1 effects on ARH-POMC-EGFP neurons. We also demonstrate that FGF1 induces c-Fos in the dorsal vagal complex, activates NTS-NPY-GFP neurons through a FGFR mediated pathway, and requires VGSCs to activate AP neurons. We conclude that FGF1 acts in multiple brain regions independent of FGFRs. These studies present anatomical and mechanistic pathways for the future investigation of the pharmacological and physiological role of FGF1 in metabolic processes.

Exogenous fibroblast growth factor 1 ameliorates diabetes-induced cognitive decline via coordinately regulating PI3K/AKT signaling and PERK signaling.

BACKGROUND: Diabetes induces central nervous system damage, leading to cognitive decline. Fibroblast growth factor 1 (FGF1) has dual function of neuroprotection and normalizing hyperglycemia. To date, the precise mechanisms and potential treating strategies of FGF1 for diabetes-induced cognitive decline (DICD) hasn't been fully elucidated. METHODS: In this study, db/db mice were used as DICD animal model. We found that diabetes remarkably suppressed FGF1 expression in hippocampus. Thus, exogenous FGF1 had been treated for db/db mice and SH-SY5Y cells. RESULTS: FGF1 significantly ameliorates DICD with better spatial learning and memory function. Moreover, FGF1 blocked diabetes-induced morphological structure change, neuronal apoptosis and Aß1-42 deposition and synaptic dysfunction in hippocampus. But normalizing glucose may not the only contributed factor for FGF1 treating DICD with evidencing that metformin-treated db/db mice has a inferior cognitive function than that in FGF1 group. Current mechanistic study had found that diabetes inhibits cAMP-response element binding protein (CREB) activity and subsequently suppresses brain derived neurotrophic factor (BDNF) level via coordinately regulating PERK signaling and PI3K/AKT signaling in hippocampus, which were reversed by FGF1. CONCLUSION: We conclude that FGF1 exerts its neuroprotective role and normalizing hyperglycemia effect, consequently ameliorates DICD, implying FGF1 holds a great promise to develop a new treatment for DICD. Video abstract.

Fibroblast Growth Factor Type 1 (FGF1)-Overexpressed Adipose-Derived Mesenchaymal Stem Cells (AD-MSCFGF1) Induce Neuroprotection and Functional Recovery in a Rat Stroke Model.

Stroke, as the second most common cause of death, imposes a great financial burden on both the individual and society. Mesenchymal stem cells from rodents have demonstrated efficacy in experimental animal models of stroke due to enhanced neurological recovery. Since FGF1 (fibroblast growth factor 1) displays neuroprotective properties, for the first time, we investigated the effect of acute intravenous administration of FGF1 gene transfected adipose-derived mesenchymal stem cell (AD-MSCFGF1) on transient experimental ischemic stroke in rats. Stroke induction was made by transient middle cerebral artery occlusion (tMCAO). 2 × 106 AD-MSCFGF1 was administrated intravenously 30 min after carotid reperfusion. The ability of technetium99m-hexamethyl propylene amine oxime (99mTc-HMPAO)-labeled AD-MSCFGF1 to enter into ischemic brain was evaluated 2 h post injection. 24 h post operation, the neurological recovery (rotarod and Roger's tests), the infarct volume (2, 3, 5-triphenyltetrazolium chloride, TTC assay), apoptosis rate (TUNEL assay), and the expression of FGF1 protein (western blotting) in the ischemic hemisphere were assessed. The 99mTc-HMPAO-labeled AD-MSCFGF1 could enter into the ischemic brain. Ischemic hemisphere activity was significantly higher than that observed in the contralateral hemisphere (p = 0.002). The administration of AD-MSCFGF1 resulted in significant improvement of neurological function tests and increased density of FGF1 protein in the peri-infarct area, while the infarct volume and the apoptotic index were significantly decreased, in comparison to the other treated groups. In conclusion, acute intravenous administration of AD-MSCFGF1 can be a novel and promising candidate approach for the treatment of ischemic stroke.