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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. [ABSTRACT FROM AUTHOR]

The human amniotic membrane dressing has been shown to accelerate the wound healing process in the clinic. In this study, heparin was conjugated to a human Acellular Amniotic Membrane (hAAM) to provide affinity binding sites for immobilizing growth factors. To study the acceleration of the wound healing process, we bound epidermal growth factor and fibroblast growth factor 1 to heparinized hAAMs (GF‐Hep‐hAAMs). The heparinized hAAMs (Hep‐hAAMs) were characterized by toluidine blue staining and infrared spectroscopy. The quality control of hAAM was performed by hematoxylin staining, swelling capacity test and biomechanical evaluation. The cytotoxicity, adhesion, and migration in vitro assays of GF‐Hep‐hAAMs on L‐929 fibroblast cells were also studied by MTT assay, scanning electron microscopy, and scratch assay, respectively. Finally, in vivo skin wound healing study was performed to investigate the wound closure rate, re‐epithelization, collagen deposition, and formation of new blood vessels. The results showed that GF‐Hep‐hAAMs enhance the rate of wound closure and epidermal regeneration in BALB/c mice. In conclusion, GF‐Hep‐hAAMs could accelerate the wound healing process, significantly in the first week. [ABSTRACT FROM AUTHOR]

Abstract 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 Aβ1–42 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

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 Aβ1–42 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 [ABSTRACT FROM AUTHOR]

Anna Szlachcic, Malgorzata Zakrzewska, Michal Lobocki, Piotr Jakimowicz, Jacek Otlewski Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland Abstract: Fibroblast growth factor receptors (FGFRs) are attractive candidate cancer therapy targets as they are overexpressed in multiple types of tumors, such as breast, prostate, bladder, and lung cancer. In this study, a natural ligand of FGFR, an engineered variant of fibroblast growth factor 1 (FGF1V), was conjugated to a potent cytotoxic drug, monomethyl auristatin E (MMAE), and used as a targeting agent for cancer cells overexpressing FGFRs, similar to antibodies in antibody–drug conjugates. The FGF1V–valine–citrulline–MMAE conjugate showed a favorable stability profile, bound FGFRs on the cell surface specifically, and efficiently released the drug (MMAE) upon cleavage by the lysosomal protease cathepsin B. Importantly, the conjugate showed a prominent cytotoxic effect toward cell lines expressing FGFR. FGF1V–vcMMAE was highly cytotoxic at concentrations even an order of magnitude lower than those found for free MMAE. This effect was FGFR-specific as cells lacking FGFR did not show any increased mortality. Keywords: fibroblast growth factor 1, FGF receptor, targeted cancer therapy, cytotoxic conjugates, FGFR-dependent cancer, MMAE, auristatin

Diabetic nephropathy (DN) is one of general and common complication of diabetes, which severely affects the physical and mental health of diabetic patients. Fibroblast growth factor 1 (FGF1), an effective control agent of blood glucose, plays an effective treatment role on diabetes‐induced renal injury. But the specific molecule mechanism underlying it is still unclear. Since induction of cellular stress is the main and common mechanism of diabetes‐induced complication, we hypothesized that reduction of cellular stress is also the molecular mechanism of FGF1 treatment for DN. Here, we have further confirmed that FGF1 significantly ameliorated the diabetes‐induced renal interstitial fibrosis and glomerular damage. The expression levels of collagen and α‐smooth muscle actin (α‐SMA) also dramatically induced in kidney from db/db mice, but these effects were blocked by FGF1 administration. Our mechanistic investigation had further revealed that diabetes significantly induced oxidative stress, nitrosative stress, and endoplasmic reticulum (ER) stress with upregulation of malondialdehyde (MDA), nitrotyrosine level, ER stress makers and downregulation of antioxidant capacity (AOC). FGF1 treatment significantly attenuated the effect of diabetes on cellular stress. We conclude that FGF1‐associated glucose decreases and subsequent reduction of cellular stress is the another potential molecule mechanism underlying FGF1 treatment for DN. [ABSTRACT FROM AUTHOR]

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-MSC) on transient experimental ischemic stroke in rats. Stroke induction was made by transient middle cerebral artery occlusion (tMCAO). 2 × 10 AD-MSC was administrated intravenously 30 min after carotid reperfusion. The ability of technetium-hexamethyl propylene amine oxime (Tc-HMPAO)-labeled AD-MSC 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 Tc-HMPAO-labeled AD-MSC 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-MSC 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-MSC can be a novel and promising candidate approach for the treatment of ischemic stroke. [ABSTRACT FROM AUTHOR]

Background: As a transducer of PPAR? signaling, recent evidence supports that fibroblast growth factor 1 (FGF1) mediates adipose tissue remodeling and insulin sensitivity. Aims: This study is to assess the role of serum FGF1 in obesity. Methods: A hospital-based case-control study of 154 subjects was conducted. Serum level of FGF1 was measured by enzyme-linked immunosorbent assay. Results: The serum level of FGF1 in the lean (119.0 [103.1-146.1] pg/ml) was higher than it in the subjects with overweight/obesity (111.9 [80.3-127.4] pg/ml, P = 0.009). Binary logistic regression models found a reverse association between serum FGF1 level and the risk of overweight/obesity (adjusted odds ratio = 0.990, 95% confidence interval [0.981-0.998], P = 0.019). Furthermore, serum FGF1 reversely correlated with body mass index (r = - 0.176, P = 0.029), systolic blood pressure (r = - 0.224, P = 0.005), diastolic blood pressure (r = - 0.185, P = 0.022) and triglycerides (r = - 0.162, P = 0.044). Multiple stepwise linear regression analysis found serum level of FGF1 was dependent on anti-diabetic drugs, hemoglobin A1C, body mass index and sex. Conclusions: Serum level of FGF1 is associated with the decreased risk of obesity in human. [ABSTRACT FROM AUTHOR]

Abstract: Several lines of evidence indicate that fibroblast growth factor 1 (FGF1) confers neuroprotection against excitotocity and contributes to the selective vulnerability of neurons in entorhinal cortex in Alzheimer''s disease (AD). Especially, FGF1 is related to Apolipoprotein E (ApoE) expression in reactive astrocytes. Therefore, FGF1 is a promising candidate gene for AD. Two studies reported the association of a polymorphism that is located 1385bp upstream from the initial code of FGF1 gene (FGF1 −1385 C>T) polymorphism with AD. To determine whether this polymorphism could affect AD development, we investigated the association between this polymorphism and AD risk in 372 sporadic AD patients and 349 controls in a Chinese Han population. No significant difference of allele and genotype distributions between the AD cases and the controls was observed in the total samples (for the alleles, χ 2 =0.126; p =0.722; for the genotypes, χ 2 =0.089; p =0.765), neither when the samples were stratified by ApoE ε4-carrying status, age/age at onset and gender. Our data suggested no association between the FGF1 −1385 C>T polymorphism and AD risk in Chinese Han population. [Copyright &y& Elsevier]