The optimized priming effect of FGF-1 and FGF-2 enhances preadipocyte lineage commitment in human adipose-derived mesenchymal stem cells.

The cell-assisted lipotransfer technique, integrating adipose-derived mesenchymal stem cells (ADMSCs), has transformed lipofilling, enhancing fat graft viability. However, the multipotent nature of ADMSCs poses challenges. To improve safety and graft vitality and to reduce unwanted lineage differentiation, this study refines the methodology by priming ADMSCs into preadipocytes-unipotent, self-renewing cells. We explored the impact of fibroblast growth factor-1 (FGF-1), fibroblast growth factor-2 (FGF-2), and epidermal growth factor (EGF), either alone or in combination, on primary human ADMSCs during the proliferative phase. FGF-2 emerged as a robust stimulator of cell proliferation, preserving stemness markers, especially when combined with EGF. Conversely, FGF-1, while not significantly affecting cell growth, influenced cell morphology, transitioning cells to a rounded shape with reduced CD34 expression. Furthermore, co-priming with FGF-1 and FGF-2 enhanced adipogenic potential, limiting osteogenic and chondrogenic tendencies, and possibly promoting preadipocyte commitment. These preadipocytes exhibited unique features: rounded morphology, reduced CD34, decreased preadipocyte factor 1 (Pref-1), and elevated C/EBPα and PPARγ, alongside sustained stemness markers (CD73, CD90, CD105). Mechanistically, FGF-1 and FGF-2 activated key adipogenic transcription factors-C/EBPα and PPARγ-while inhibiting GATA3 and Notch3, which are adipogenesis inhibitors. These findings hold the potential to advance innovative strategies for ADMSC-mediated lipofilling procedures.

FGF1 ameliorates obesity-associated hepatic steatosis by reversing IGFBP2 hypermethylation.

Obesity is a major contributing factor for metabolic-associated fatty liver disease (MAFLD). Fibroblast growth factor (FGF) 1 is the first paracrine FGF family member identified to exhibit promising metabolic regulatory properties capable of conferring glucose-lowering and insulin-sensitizing effect. This study explores the role and molecular underpinnings of FGF1 in obesity-associated hepatic steatosis. In a mouse high-fat diet (HFD)-induced MAFLD model, chronic treatment with recombinant FGF1(rFGF1) was found to effectively reduce the severity of insulin resistance, hyperlipidemia, and inflammation. FGF1 treatment decreased lipid accumulation in the mouse liver and palmitic acid-treated AML12 cells. These effects were associated with decreased mature form SREBF1 expression and its target genes FASN and SCD1. Interestingly, we uncovered that rFGF1 significantly induced IGFBP2 expression at both mRNA and protein levels in HFD-fed mouse livers and cultured hepatocytes treated with palmitic acid. Adeno-associated virus-mediated IGFBP2 suppression significantly diminished the therapeutic benefit of rFGF1 on MAFLD-associated phenotypes, indicating that IGFBP2 plays a crucial role in the FGF1-mediated reduction of hepatic steatosis. Further analysis revealed that rFGF1 treatment reduces the recruitment of DNA methyltransferase 3 alpha to the IGFBP2 genomic locus, leading to decreased IGFBP2 gene methylation and increased mRNA and protein expression. Collectively, our findings reveal FGF1 modulation of lipid metabolism via epigenetic regulation of IGFBP2 expression, and unravel the therapeutic potential of the FGF1-IGFBP2 axis in metabolic diseases associated with obesity.

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.

Beneficial Effects of Fibroblast Growth Factor-1 on Retinal Pigment Epithelial Cells Exposed to High Glucose-Induced Damage: Alleviation of Oxidative Stress, Endoplasmic Reticulum Stress, and Enhancement of Autophagy.

Diabetic retinopathy (DR) severely affects vision in individuals with diabetes. High glucose (HG) induces oxidative stress in retinal cells, a key contributor to DR development. Previous studies suggest that fibroblast growth factor-1 (FGF-1) can mitigate hyperglycemia and protect tissues from HG-induced damage. However, the specific effects and mechanisms of FGF-1 on DR remain unclear. In our study, FGF-1-pretreated adult retinal pigment epithelial (ARPE)-19 cells were employed to investigate. Results indicate that FGF-1 significantly attenuated HG-induced oxidative stress, including reactive oxygen species, DNA damage, protein carbonyl content, and lipid peroxidation. FGF-1 also modulated the expression of oxidative and antioxidative enzymes. Mechanistic investigations showed that HG induced high endoplasmic reticulum (ER) stress and upregulated specific proteins associated with apoptosis. FGF-1 effectively alleviated ER stress, reduced apoptosis, and restored autophagy through the adenosine monophosphate-activated protein kinase/mammalian target of the rapamycin signaling pathway. We observed that the changes induced by HG were dose-dependently reversed by FGF-1. Higher concentrations of FGF-1 (5 and 10 ng/mL) exhibited increased effectiveness in mitigating HG-induced damage, reaching statistical significance (p < 0.05). In conclusion, our study underscores the promising potential of FGF-1 as a safeguard against DR. FGF-1 emerges as a formidable intervention, attenuating oxidative stress, ER stress, and apoptosis, while concurrently promoting autophagy. This multifaceted impact positions FGF-1 as a compelling candidate for alleviating retinal cell damage in the complex pathogenesis of DR.

Effect of recombinant human acidic fibroblast growth factor on nasal mucosal healing after endoscopic sinus surgery.

BACKGROUND: Postoperative nasal treatment is an important factor affecting the outcomes of endoscopic sinus surgery (ESS) in patients with chronic rhinosinusitis (CRS). This study aimed to determine the effect of recombinant human acidic fibroblast growth factor (rh-aFGF) on nasal mucosal healing after ESS. METHODS: This study is a prospective, single-blind, and randomized controlled clinical study. Fifty-eight CRS patients with nasal polyps (CRSwNP) with bilateral ESS were enrolled and randomly given 1 mL of budesonide nasal spray and 2 mL of rh-aFGF solution (rh-aFGF group) or 1 mL of budesonide nasal spray and 2 mL of rh-aFGF solvent (budesonide group)-infiltrated Nasopore nasal packing after ESS. Preoperative and postoperative scores for Sino-Nasal Outcome Test (SNOT-22), Visual Analogue Scale (VAS), and Lund-Kennedy were collected and analyzed. RESULTS: Forty-two patients completed the 12-week follow-up. Postoperative SNOT-22 scores and VAS scores showed no significant differences between the two groups. In terms of the Lund-Kennedy scores, there was a statistically significant difference between the two groups at the 2-, 4-, 8-, and 12-week postoperative visits, but not at the 1-week visit. Twelve weeks after surgery, the nasal mucosa had completely epithelialized in 18 patients in the rh-aFGF group and in 12 patients in the budesonide group (χ2 = 4.200, P = 0.040). CONCLUSION: The combined application of rh-aFGF and budesonide significantly improved postoperative endoscopic appearance in the nasal mucosal healing process.

FGF1 alleviates LPS-induced acute lung injury via suppression of inflammation and oxidative stress.

BACKGROUND: Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are devastating clinical disorders with high mortality, and for which more effective therapies are urgently needed. FGF1, the prototype member of the FGF family, is shown to exert protective effects against injurious stimuli in multiple disease models. Here we aimed to evaluate whether FGF1 pretreatment is protective against LPS-induced ALI and elucidate the potential underlying mechanisms. METHODS: For drug-treated groups, C57B/6 mice received a single i.p. injection of FGF1 (1 mg/kg) 1 h before the LPS challenge or not. To induce the ALI model, the mice were treated by intratracheal instillation of LPS (5 mg/kg). Then, histopathological changes in lung tissues were assessed by hematoxylin and eosin staining and transmission electron microscopy. ELISA and qPCR assays were used to detect pro-inflammatory cytokine levels in BALF and lung tissues, respectively. The total number of inflammatory cells (neutrophils and macrophages) in BALF were counted using the Wright-Giemsa method. The expressions of reactive oxygen species (ROS) and malondialdehyde (MDA) were measured using their respective kits. Western blot and immunostaining were used to evaluate the expressions of antioxidants (Nrf-2, HO-1, SOD2, GPX4, and Catalase), as well as the inflammatory and/or apoptosis-related factors (TLR4, NF-κB, and Cleaved- caspase 3). RESULTS: FGF1 pretreatment significantly ameliorated the LPS-induced histopathological changes, reduced lung wet/dry ratios, ROS and MDA levels, total BALF protein, inflammatory cell infiltration, proinflammatory cytokine levels, and significantly increased the expression of antioxidant proteins (Nrf-2, HO-1, Catalase, and SOD2). In addition, FGF1 pretreatment significantly reduced the expression of TLR4 and cleaved- caspase 3, inhibited NF-κB activation, and reduced LPS-induced cell apoptosis. CONCLUSIONS: Altogether, our results suggest that FGF1 pretreatment is protective against LPS-induced ALI through mediating anti-inflammatory and antioxidant effects, which may be attributed to the downregulation of TLR4 expression and inhibition of NF-κB activation, as well as promotion of antioxidant defenses. Therefore, FGF1 administration may prove beneficial in preventative strategies for ALI/ARDS.

Activating Adenosine Monophosphate-Activated Protein Kinase Mediates Fibroblast Growth Factor 1 Protection From Nonalcoholic Fatty Liver Disease in Mice.

BACKGROUND AND AIMS: Fibroblast growth factor (FGF) 1 demonstrated protection against nonalcoholic fatty liver disease (NAFLD) in type 2 diabetic and obese mice by an uncertain mechanism. This study investigated the therapeutic activity and mechanism of a nonmitogenic FGF1 variant carrying 3 substitutions of heparin-binding sites (FGF1△HBS ) against NAFLD. APPROACH AND RESULTS: FGF1△HBS administration was effective in 9-month-old diabetic mice carrying a homozygous mutation in the leptin receptor gene (db/db) with NAFLD; liver weight, lipid deposition, and inflammation declined and liver injury decreased. FGF1△HBS reduced oxidative stress by stimulating nuclear translocation of nuclear erythroid 2 p45-related factor 2 (Nrf2) and elevation of antioxidant protein expression. FGF1△HBS also inhibited activity and/or expression of lipogenic genes, coincident with phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and its substrates. Mechanistic studies on palmitate exposed hepatic cells demonstrated that NAFLD-like oxidative damage and lipid accumulation could be reversed by FGF1△HBS . In palmitate-treated hepatic cells, small interfering RNA (siRNA) knockdown of Nrf2 abolished only FGF1△HBS antioxidative actions but not improvement of lipid metabolism. In contrast, AMPK inhibition by pharmacological agent or siRNA abolished FGF1△HBS benefits on both oxidative stress and lipid metabolism that were FGF receptor (FGFR) 4 dependent. Further support of these in vitro findings is that liver-specific AMPK knockout abolished therapeutic effects of FGF1△HBS against high-fat/high-sucrose diet-induced hepatic steatosis. Moreover, FGF1△HBS improved high-fat/high-cholesterol diet-induced steatohepatitis and fibrosis in apolipoprotein E knockout mice. CONCLUSIONS: These findings indicate that FGF1△HBS is effective for preventing and reversing liver steatosis and steatohepatitis and acts by activation of AMPK through hepatocyte FGFR4.

Multimodal treatment combining cold atmospheric plasma and acidic fibroblast growth factor for multi-tissue regeneration.

Cold atmospheric plasma (CAP) is an emerging technology for biomedical applications, exemplified by its antimicrobial and antineoplastic potentials. On the contrary, acidic fibroblast growth factor (aFGF) has been a long-standing potent mitogen for cells from various origins. In this study, we are the first to develop a multimodal treatment combining the aforementioned physicochemical and pharmacological treatments and investigated their individual and combined effects on wound healing, angiogenesis, neurogenesis, and osteogenesis. This work was performed at the tissue, cellular, protein, and gene levels, using histochemical staining, flow cytometry, ELISA, and PCR, respectively. Depending on the type of target tissue, various combinations of aforementioned methods were used. The results showed that the enhancement on would healing and angiogenesis by CAP and aFGF were synergistic. The former was manifested by increased murine fibroblast proliferation and reduced cutaneous tissue inflammation, whereas the latter by upregulated proangiogenic markers in vivo, for example, CD31, VEGF, and TGF-ß, and downregulated antiangiogenic proteins in vitro, for example, angiostatin and angiopoietin-2, respectively. In addition, aFGF outperformed CAP during neurogenesis, which was evidenced by superior neurite outgrowth, while CAP exceeded aFGF in osteogenesis which was demonstrated by more substantial bone nodule formation. These novel findings not only support the fact that CAP and aFGF are both multipotent agents during tissue regeneration, but also highlight the potential of our multimodal treatment combining the individual advantages of CAP and aFGF. The versatile administration route, that is, topical and/or systemic, might further broaden its applications.

Beneficial Effects of Oleosomes Fused with Human Fibroblast Growth Factor 1 on Wound Healing via the Promotion of Angiogenesis.

In our previous study, human fibroblast growth factor 1 was successfully fused with oleosomes, energy-storing organelles of seeds, which are considered to be excellent "expression carriers" for substances with a convenient purification process. The present work aimed to explore the beneficial effects of oleosomes fused with human fibroblast growth factor 1 (OLAF) on wound healing. The data showed marked improvements in terms of the angiogenesis, vascular integrity, collagen and inflammation on the wound sites of rats with a full-thickness skin defect. Moreover, the positive role of OLAF in promoting angiogenesis and its possible pathways were clarified in vivo and in vitro. The results showed that the number, length and branches of the blood vessels of the chick embryo chorioallantoic membrane were markedly increased after OLAF treatment. Meanwhile, the in vitro results also revealed that 100 ng/mL OLAF exhibited a promoting effect on the proliferation, migration and tube formation of human umbilical vein endothelial cells. In addition, the potential of OLAF to improve wound angiogenesis was demonstrated to be associated with an up-regulated PI3K/Akt pathway by transcriptome sequencing analysis and the introduction of a PI3K/Akt pathway inhibitor (LY294002). These findings suggest that OLAF has many prospects in the development of drugs for wound healing.

RAGE: A potential therapeutic target during FGF1 treatment of diabetes-mediated liver injury.

As a serious metabolic disease, diabetes causes series of complications that seriously endanger human health. The liver is a key organ for metabolizing glucose and lipids, which substantially contributes to the development of insulin resistance and type 2 diabetes mellitus (T2DM). Exogenous fibroblast growth factor 1 (FGF1) has a great potential for the treatment of diabetes. Receptor of advanced glycation end products (RAGE) is a receptor for advanced glycation end products that involved in the development of diabetes-triggered complications. Previous study has demonstrated that FGF1 significantly ameliorates diabetes-mediated liver damage (DMLD). However, whether RAGE is involved in this process is still unknown. In this study, we intraperitoneally injected db/db mice with 0.5 mg/kg FGF1. We confirmed that FGF1 treatment not only significantly ameliorates diabetes-induced elevated apoptosis in the liver, but also attenuates diabetes-induced inflammation, then contributes to ameliorate liver dysfunction. Moreover, we found that diabetes triggers the elevated RAGE in hepatocytes, and FGF1 treatment blocks it, suggesting that RAGE may be a key target during FGF1 treatment of diabetes-induced liver injury. Thus, we further confirmed the role of RAGE in FGF1 treatment of AML12 cells under high glucose condition. We found that D-ribose, a RAGE agonist, reverses the protective role of FGF1 in AML12 cells. These findings suggest that FGF1 ameliorates diabetes-induced hepatocyte apoptosis and elevated inflammation via suppressing RAGE pathway. These results suggest that RAGE may be a potential therapeutic target for the treatment of DMLD.

Regenerative responses of rabbit corneal endothelial cells to stimulation by fibroblast growth factor 1 (FGF1) derivatives, TTHX1001 and TTHX1114.

Utilising rabbit corneal endothelial cells (CEC) in three different paradigms, two human FGF1 derivatives (TTHX1001 and TTHX1114), engineered to exhibit greater stability, were tested as proliferative agents. Primary CECs and mouse NIH 3T3 cells treated with the two FGF1 derivatives showed equivalent EC50 ranges (3.3-24 vs.1.9-16. ng/mL) and, in organ culture, chemically lesioned corneas regained half of the lost endothelial layer in three days after treatment with the FGF1 derivatives as compared to controls. In vivo, following cryolesioning, the CEC monolayer, as judged by specular microscopy, regenerated 10-11 days faster when treated with TTHX1001. Over two weeks, all treated eyes showed clearing of opacity about twice that of untreated controls. In all three rabbit models, both FGF1 derivatives were effective in inducing CEC proliferation over control conditions, supporting the prediction that these stabilised FGF1 derivatives can potentially regenerate corneal endothelial deficits in humans.

Regulatory role of endogenous and exogenous fibroblast growth factor 1 in the cardiovascular system and related diseases.

Fibroblast growth factor 1 (FGF1) has a critical regulatory role in the development of the cardiovascular system (CVS) and is strongly associated with the progression or treatment of cardiovascular diseases (CVDs). However, the regulatory mechanisms of FGF1 in CVS and CVDs have not yet been fully elucidated. Therefore, this review article summarized the existing literature reports on the role of FGF1 in CVS under physiological and pathological conditions. First, the expression and physiological functions of endogenous FGF1 is fully demonstrated. Then, we analyzed the role of exogenous FGF1 in normal CVS and related pathological processes. Specifically, the potential signaling pathways might be mediated by FGF1 in CVDs treatment is discussed in detail. In addition, the barriers and feasible solutions for the application of FGF1 are further analyzed. Finally, we highlight therapeutic considerations of FGF1 for CVDs in the future. Thus, this article may be as a reference to provide some ideas for the follow-up research.

Fibroblast Growth Factor Type 1 Ameliorates High-Glucose-Induced Oxidative Stress and Neuroinflammation in Retinal Pigment Epithelial Cells and a Streptozotocin-Induced Diabetic Rat Model.

Diabetic retinopathy (DR) is a common complication of diabetes that causes severe visual impairment globally. The pathogenesis of DR is related to oxidative stress and chronic inflammation. The fibroblast growth factor type 1 (FGF-1) mitogen plays crucial roles in cell function, development, and metabolism. FGF-1 is involved in blood sugar regulation and exerts beneficial antioxidative and anti-inflammatory effects on various organ systems. This study investigated the antioxidative and anti-inflammatory neuroprotective effects of FGF-1 on high-glucose-induced retinal damage. The results revealed that FGF-1 treatment significantly reversed the harmful effects of oxidative stress and inflammatory mediators in retinal tissue in a streptozotocin-induced diabetic rat model. These protective effects were also observed in the in vitro model of retinal ARPE-19 cells exposed to a high-glucose condition. We demonstrated that FGF-1 attenuated p38 mitogen-activated protein kinase and nuclear factor-κB pathway activation under the high-glucose condition. Our results indicated that FGF-1 could effectively prevent retinal injury in diabetes. The findings of this study could be used to develop novel treatments for DR that aim to reduce the cascade of oxidative stress and inflammatory signals in neuroretinal tissue.

CHIR99021 and fibroblast growth factor 1 enhance the regenerative potency of human cardiac muscle patch after myocardial infarction in mice.

BACKGROUND: We have shown that genetic overexpression of cell cycle proteins can increase the proliferation of transplanted cardiomyocytes derived from human induced-pluripotent stem cells (hiPSC-CMs) in animal models of myocardial infarction (MI). Here, we introduce a new, non-genetic approach to promote hiPSC-CM cell cycle activity and proliferation in transplanted human cardiomyocyte patches (hCMPs). METHODS: Mice were randomly distributed into 5 experimental groups (n = 10 per group). One group underwent Sham surgery, and the other 4 groups underwent MI induction surgery followed by treatment with hCMPs composed of hiPSC-CMs and nanoparticles that contained CHIR99021 and FGF1 (the NPCF-hCMP group), with hCMPs composed of hiPSC-CMs and empty nanoparticles (the NPE-hCMP group); with patches containing the CHIR99021/FGF-loaded nanoparticles but lacking hiPSC-CMs (the NPCF-Patch group), or patches lacking both the nanoparticles and cells (the E-Patch group). Cell cycle activity was evaluated via Ki67 and Aurora B expression, bromodeoxyuridine incorporation, and phosphorylated histone 3 levels (immunofluorescence); engraftment via human cardiac troponin T or human nuclear antigen expression (immunofluorescence) and bioluminescence imaging; cardiac function via echocardiography; infarct size and wall thickness via histology; angiogenesis via isolectin B4 expression (immunofluorescence); and apoptosis via TUNEL and caspace 3 expression (immunofluorescence). RESULTS: Combined CHIR99021- and FGF1-treatment significantly increased hiPSC-CM cell cycle activity both in cultured cells (by 4- to 6-fold) and in transplanted hCMPs, and compared to treatment with NPE-hCMPs, NPCF-hCMP transplantation increased hiPSC-CM engraftment by ~4-fold and was associated with significantly better measurements of cardiac function, infarct size, wall thickness, angiogenesis, and hiPSC-CM apoptosis four weeks after MI induction. CONCLUSIONS: Nanoparticle-mediated CHIR99021 and FGF1 delivery promotes hiPSC-CM cell cycle activity and proliferation, as well as the engraftment and regenerative potency of transplanted hCMPs, in a mouse MI model.

Fibroblast growth factor 1 ameliorates adipose tissue inflammation and systemic insulin resistance via enhancing adipocyte mTORC2/Rictor signal.

Obesity-induced activation and proliferation of resident macrophages and infiltration of circulating monocytes in adipose tissues contribute to adipose tissue inflammation and insulin resistance. These effects further promote the development of metabolic syndromes, such as type 2 diabetes, which is one of the most prevalent health conditions severely threatening human health worldwide. Our study examined the potential molecular mechanism employed by fibroblast growth factor 1 (FGF1) to improve insulin sensitivity. The leptin receptor-deficient obese mice (db/db) served as an insulin-resistant model. Our results demonstrated that FGF1-induced amelioration of insulin resistance in obese mice was related to the decreased levels of pro-inflammatory adipose tissue macrophages (ATMs) and plasma inflammatory factors. We found that FGF1 enhanced the adipocyte mTORC2/Rictor signalling pathway to inhibit C-C chemokine ligand 2 (CCL2) production, the major cause of circulating monocytes infiltration, activation and proliferation of resident macrophages in adipose tissues. Conversely, these alleviating effects of FGF1 were substantially abrogated in adipocytes with reduced expression of mTORC2/rictor. Furthermore, a model of adipocyte-specific mTORC2/Rictor-knockout (AdRiKO) obese mice was developed to further understand the in vitro result. Altogether, these results demonstrated adipocyte mTORC2/Rictor was a crucial target for FGF1 function on adipose tissue inflammation and insulin sensitivity.

Fibroblast growth factor 1 ameliorates diabetes-induced splenomegaly via suppressing inflammation and oxidative stress.

Type-2 diabetes (T2D) is a common metabolic disorder, which causes several physiological and pathological complications. Spleen is regarded as an important organ, which regulates immune system and iron metabolism in the body. Precious few studies have been conducted to explore the pathological and deleterious roles of diabetes on spleen. In our current study, we have explored and confirmed the pathological effects of diabetes on spleen in db/db experimental mice model. In our current study, 0.5 mg/kg fibroblast growth factor 1 (FGF1) dose was intraperitoneally administrated to db/db mice. We found that diabetes evidently induced spleen enlargement and fibrosis progression in the db/db mice. Additionally, our studies demonstrate that iron has hugely deposited in the spleen in db/db mice. Several studies have documented that diabetes largely disrupts the inflammatory cells distribution, immune homeostasis, proliferation and oxidative stress with the down-regulation of anti-inflammatory cytokines and antioxidant activities. Moreover, we have observed that FGF1 administration significantly reversed the deleterious effect of diabetes on spleen enlargement and dysfunction. In summary, these substantial findings clearly demonstrate that diabetes plays deleterious roles in maintaining the spleen structure and functions. Therefore, our investigations suggest that FGF1 can effectively prevent diabetes-mediated splenomegaly progression.

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.

Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer.

Fibroblast growth factor 1 (FGF1) is an autocrine/paracrine regulator whose binding to heparan sulphate proteoglycans effectively precludes its circulation. Although FGF1 is known as a mitogenic factor, FGF1 knockout mice develop insulin resistance when stressed by a high-fat diet, suggesting a potential role in nutrient homeostasis. Here we show that parenteral delivery of a single dose of recombinant FGF1 (rFGF1) results in potent, insulin-dependent lowering of glucose levels in diabetic mice that is dose-dependent but does not lead to hypoglycaemia. Chronic pharmacological treatment with rFGF1 increases insulin-dependent glucose uptake in skeletal muscle and suppresses the hepatic production of glucose to achieve whole-body insulin sensitization. The sustained glucose lowering and insulin sensitization attributed to rFGF1 are not accompanied by the side effects of weight gain, liver steatosis and bone loss associated with current insulin-sensitizing therapies. We also show that the glucose-lowering activity of FGF1 can be dissociated from its mitogenic activity and is mediated predominantly via FGF receptor 1 signalling. Thus we have uncovered an unexpected, neomorphic insulin-sensitizing action for exogenous non-mitogenic human FGF1 with therapeutic potential for the treatment of insulin resistance and type 2 diabetes.

Heparinized silk fibroin hydrogels loading FGF1 promote the wound healing in rats with full-thickness skin excision.

BACKGROUND: Silk fibroin hydrogel, derived from Bombyx mori cocoons, has been shown to have potential effects on wound healing due to its excellent biocompatibility and less immunogenic and biodegradable properties. Many studies suggest silk fibroin as a promising material of wound dressing and it can support the adhesion and proliferation of a variety of human cells in vitro. However, lack of translational evidence has hampered its clinical applications for skin repair. Herein, a heparin-immobilized fibroin hydrogel was fabricated to deliver FGF1 (human acidic fibroblast growth factor 1) on top of wound in rats with full-thickness skin excision by performing comprehensive preclinical studies to fully evaluate its safety and effectiveness. The wound-healing efficiency of developed fibroin hydrogels was evaluated in full-thickness wound model of rats, compared with the chitosan used clinically. RESULTS: The water absorption, swelling ratio, accumulative FGF1 releasing rate and biodegradation ratio of fabricated hydrogels were measured. The regenerated fibroin hydrogels with good water uptake properties rapidly swelled to a 17.3-fold maximum swelling behavior over 12 h and a total amount of 40.48 ± 1.28% hydrogels was lost within 15 days. Furthermore, accumulative releasing data suggested that heparinized hydrogels possessed effective release behavior of FGF1. Then full-thickness skin excision was created in rats and left untreated or covered with heparinized fibroin hydrogels-immobilized recombinant human FGF1. The histological evaluation using hematoxylin and eosin (HE) and Masson's trichrome (MT) staining was performed to observe the dermic formation and collagen deposition on the wound-healing site. To evaluate the wound-healing mechanisms induced by fibroin hydrogel treatment, wound-healing scratch and cell proliferation assay were performed. it was found that both fibroin hydrogels and FGF1 can facilitate the migration of fibroblast L929 cells proliferation and migration. CONCLUSION: This study provides systematic preclinical evidence that the silk fibroin promotes wound healing as a wound-healing dressing, thereby establishing a foundation toward its further application for new treatment options of wound repair and regeneration.

FGF1 improves functional recovery through inducing PRDX1 to regulate autophagy and anti-ROS after spinal cord injury.

Fibroblast growth factor 1 (FGF1) is thought to exert protective and regenerative effects on neurons following spinal cord injury (SCI), although the mechanism of these effects is not well understood. The use of FGF1 as a therapeutic agent is limited by its lack of physicochemical stability and its limited capacity to cross the blood-spinal cord barrier. Here, we demonstrated that overexpression of FGF1 in spinal cord following SCI significantly reduced tissue loss, protected neurons in the ventricornu, ameliorated pathological morphology of the lesion, dramatically improved tissue recovery via neuroprotection, and promoted axonal regeneration and remyelination both in vivo and in vivo. In addition, the autophagy and the expression levels of PRDX1 (an antioxidant protein) were induced by AAV-FGF1 in PC12 cells after H2 O2 treatment. Furthermore, the autophagy levels were not changed in PRDX1-suppressing cells that were treated by AAV-FGF1. Taken together, these results suggest that FGF1 improves functional recovery mainly through inducing PRDX1 expression to increase autophagy and anti-ROS activity after SCI.