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The testis serves as the reproductive gland in male mammals, primarily tasked with the production of sperm and synthesis of androgens. A complex signaling network consisting of various cell types, including germ cells, Sertoli cells, and Leydig cells, supports the structure and maintains the function of the testis. Apart from the hypothalamic-pituitary-gonadal axis, various sex hormones and cytokines are also implicated in the regulation of testicular function. The fibroblast growth factor (FGF) represents a crucial class of active cytokines that stimulate cell proliferation, induce tissue differentiation, and govern organ development. This review summarizes the molecular mechanisms of FGF regulating testicular development and spermatogenesis and maintaining male fertility.

Growth factors are involved in the regulation of hair morphogenesis and cycle hair growth. The present study sought to investigate the hair growth promoting activities of three approved growth factor drugs, fibroblast growth factor 10 (FGF-10), acidic fibroblast growth factor (FGF-1), and basic fibroblast growth factor (FGF-2), and the mechanism of action. We observed that FGFs promoted hair growth by inducing the anagen phase in telogenic C57BL/6 mice. Specifically, the histomorphometric analysis data indicates that topical application of FGFs induced an earlier anagen phase and prolonged the mature anagen phase, in contrast to the control group. Moreover, the immunohistochemical analysis reveals earlier induction of β-catenin and Sonic hedgehog (Shh) in hair follicles of the FGFs-treated group. These results suggest that FGFs promote hair growth by inducing the anagen phase in resting hair follicles and might be a potential hair growth-promoting agent.

Fibroblast growth factor 21 (FGF21) is an important endogenous regulator involved in the regulation of glucose and lipid metabolism. FGF21 expression is strongly induced in animal and human subjects with metabolic diseases, but little is known about the molecular mechanism. Endoplasmic reticulum (ER) stress plays an essential role in metabolic homeostasis and is observed in numerous pathological processes, including type 2 diabetes, overweight, nonalcoholic fatty liver disease (NAFLD). In this study, we investigate the correlation between the expression of FGF21 and ER stress. We demonstrated that TG-induced ER stress directly regulated the expression and secretion of FGF21 in a dose- and time-dependent manner. FGF21 is the target gene for activating transcription factor 4 (ATF4) and CCAAT enhancer binding protein homologous protein (CHOP). Suppression of CHOP impaired the transcriptional activation of FGF21 by TG-induced ER stress in CHOP-/- mouse primary hepatocytes (MPH), and overexpression of ATF4 and CHOP resulted in FGF21 promoter activation to initiate the transcriptional programme. In mRNA stability assay, we indicated that ER stress increased the half-life of mRNA of FGF21 significantly. In conclusion, FGF21 expression is regulated by ER stress via ATF- and CHOP-dependent transcriptional mechanism and posttranscriptional mechanism, respectively.

Fibroblast growth factor (FGF)-21 is a novel regulator of insulin-independent glucose transport in 3T3-L1 adipocytes and has glucose and triglyceride lowering effects in rodent models of diabetes. In this study, we found that FGF-21 can significantly attenuate ischemia-reperfusion (I/R) induced damage in H9c2 cells (rat heart). However, it is unclear which signal transduction pathway is involved in the cardioprotective effect of FGF-21. Thus, this study was designed to investigate the potential mechanism induced by FGF-21. The results showed that FGF-21 treatment prevented the oxidative stress and apoptosis associated with I/R damage by reducing the levels of superoxide anions, inhibiting glycogen synthase kinase (GSK) 3β by activating Akt phosphorylation, and recovering the levels of ATP synthase pyruvate kinase isozymes M1 and protein kinase C, thereby improving energy supply. In summary, we conclude that FGF-21 protects H9c2 cells against I/R injury mainly through the Akt-GSK-3β-caspase-3 dependent pathway, preventing oxidative stress, and recovery of the energy supply.

Lipid nanoparticles with solid matrix have been given increasing attention due to their biodegradable status and ability to entrap a variety of biologically active compounds. In this study, new phospholipid-based gelatin nanoparticles encapsulating basic fibroblast growth factor (bFGF) were developed to target the brain via nasal administration. Treatment effects were assessed by quantifying rotational behavior, monoamine neurotransmitter levels and tyrosine hydroxylase expression in 6-hydroxydopamine induced hemiparkinsonian rats. The gelatin nanostructured lipid carriers (GNLs) were prepared by a water-in-water emulsion method and then freeze-dried. The GNLs possessed better profile than gelatin nanoparticles (GNs), with particle size 143±1.14nm and Zeta potential −38.2±1.2mV. The intranasal GNLs efficiently enriched exogenous bFGF in olfactory bulb and striatum without adverse impact on the integrity of nasal mucosa and showed obvious therapeutic effects on hemiparkinsonian rats. Thus, GNLs are attractive carriers for nose-to-brain drug delivery, especially for unstable macromolecular drugs such as bFGF. From the Clinical Editor: This team of authors reports the development of phospholipid-based gelatin nanoparticles encapsulating basic fibroblast growth factor to target the brain via intranasal administration. A rat model of hemiparkinsonism was applied demonstrating a good safety profile and an obvious therapeutic effect. [ABSTRACT FROM AUTHOR]

Hypertrophic scars (HTS) and keloids are challenging problems. Their pathogenesis results from an overproduction of fibroblasts and excessive deposition of collagen. Studies suggest a possible anti-scarring effect of basic fibroblast growth factor (bFGF) during wound healing, but the precise mechanisms of bFGF are still unclear. In view of this, we investigated the therapeutic effects of bFGF on HTS animal model as well as human scar fibroblasts (HSF) model. We show that bFGF promoted wound healing and reduced the area of flattened non-pathological scars in rat skin wounds and HTS in the rabbit ear. We provide evidence of a new therapeutic strategy: bFGF administration for the treatment of HTS. The scar elevation index (SEI) and epidermal thickness index (ETI) was also significantly reduced. Histological reveal that bFGF exhibited significant amelioration of the collagen tissue. bFGF regulated extracellular matrix (ECM) synthesis and degradation via interference in the collagen distribution, the α-smooth muscle actin (α-SMA) and transforming growth factor-1 (TGF-β1) expression. In addition, bFGF reduced scarring and promoted wound healing by inhibiting TGFβ1/SMAD-dependent pathway. The levels of fibronectin (FN), tissue inhibitor of metalloproteinase-1 (TIMP-1) collagen I, and collagen III were evidently decreased, and matrix metalloproteinase-1 (MMP-1) and apoptosis cells were markedly increased. These results suggest that bFGF possesses favorable therapeutic effects on hypertrophic scars in vitro and in vivo, which may be an effective cure for human hypertrophic scars. [ABSTRACT FROM AUTHOR]

Aim To investigate the mechanism of endoplasmic reticulum (ER) stress-induced apoptosis as well as the protective action of basic fibroblast growth factor ( bFGF) both in vivo and in vitro. Methods and Results ER stress-induced apoptosis was involved in the injuries of spinal cord injury (SCI) model rat. bFGF administration improved the recovery and increased the survival of neurons in spinal cord lesions in model rat. The protective effect of bFGF is related to the inhibition of CHOP, GRP78 and caspase-12, which are ER stress-induced apoptosis response proteins. bFGF administration also increased the survival of neurons and the expression of growth-associated protein 43 (GAP43), which is related to neural regeneration. The protective effect of bFGF is related to the activation of downstream signals, PI3K/Akt/GSK-3β and ERK1/2, especially in the ER stress cell model. Conclusions This is the first study to illustrate that the role of bFGF in SCI recovery is related to the inhibition of ER stress-induced cell death via the activation of downstream signals. Our work also suggested a new trend for bFGF drug development in central neural system injuries, which are involved in chronic ER stress-induced apoptosis. [ABSTRACT FROM AUTHOR]

Ultrasound (US)-mediated cavitation of microbubbles has evolved into a new tool for organ-specific gene and drug delivery. This paper was to investigate the feasibility of acidic fibroblast growth factor (aFGF) intravenous delivery to the ischemic myocardium of rats by ultrasonic microbubbles modified with heparin. Heparin modified microbubbles (HMB) were prepared by the freeze-dried method. Acute myocardial infarction (AMI) model was established and the cardio protective effect of the aFGF combing with HMB (aFGF-HMB) under US-mediated cavitation technique was investigated. aFGF-HMB combined with US-mediated cavitation technique was examined by ECG. Ejection fraction (EF), fractional shortening (FS) and left ventricular diastolic diameter (LVDd) were measured to monitor the improvement of global myocardial contractile function. Myocardial tissue was stained with hematoxylin and eosine (HE) to evaluate the elaborate general morphology of the ischemic myocardium. From morphologic observation and echocardiography in rat heart, aFGF-HMB had suitable size distribution, physical stability and good acoustic resonance function. From AMI rat experiments, aFGF-HMB under US-mediated cavitation technique exerted aFGF cardio protective effect in ischemic myocardium. From histological evaluation, US-mediated cavitation of aFGF-HMB showed improvement of myocardial ischemia. With the visual imaging and US-triggered drug release advantages, US-mediated cavitation of aFGF-HMB might be developed as a novel technique for targeting delivery of aFGF into ischemic myocardium. [ABSTRACT FROM AUTHOR]

Abstract: Basic fibroblast growth factor (bFGF) is a known neuroprotectant against a number of brain injury conditions such as cerebral ischemia. However, bFGF also regulates a plethora of brain developmental processes and functions as a strong mitogen. Therefore, unregulated long-term expression of bFGF in brain may potentially be tumorigenic, limiting its utility in brain therapy. Here, we report the successful construction of an adenoviral vector (Ad-5HRE-bFGF) expressing bFGF under the regulation of five hypoxia-responsive elements (5HRE) and a minimal cytomegalovirus promoter (CMVmp). Following hypoxia treatment in a hypoxic chamber with less than 1% of oxygen, Ad-5HRE-bFGF induced a significant and time-dependent expression of bFGF protein and the fluorescent tag, humanized GFP (hrGFP) protein, in infected PC12 cells. In contrast, normoxia treatment evoked extremely low level of bFGF and hrGFP expression, demonstrating that the 5HRE-CMVmp cassette was effective in regulating the expression of bFGF gene in response to hypoxia. More importantly, bFGF expressed by the Ad-5HRE-bFGF viral vector under the regulation of hypoxia was significantly neuroprotective against PC12 cell death evoked by serum deprivation. Taken together, these studies demonstrated the feasibility to express bFGF in a hypoxia-regulated fashion to provide neuroprotection. The Ad-5HRE-bFGF can be further developed as an effective tool to provide neuroprotection against hypoxia-induced brain diseases, such as cerebral ischemia. [Copyright &y& Elsevier]

Abstract: Objective: To investigate the protective effect of a mutant of acidic fibroblast growth factor (MaFGF) against cerebral ischaemia-reperfusion injury in rats. Methods: Sixty male Sprague–Dawley rats were randomly divided into six groups as follows: sham-operated group, untreated group, 20μg/kg, 40μg/kg and 80μg/kg MaFGF-treated groups and also the positive control group. Cerebral ischaemia-reperfusion injury was induced by middle cerebral artery occlusion (MCAO) for 2h followed by reperfusion for 24h. Different dose of MaFGF were infused intravenously at 1h after middle cerebral artery (MCA) occlusion. Nimodipine was used as positive control. The behaviour deficit score, brain-infarcted area, brain oedema degree, malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were detected at 24h after reperfusion. Results: The results showed that MaFGF at the dose of 20μg/kg, 40μg/kg and 80μg/kg significantly alleviated brain injury. Compared to untreated group, the behaviour deficits were much less severe, the brain oedema alleviated obviously, the MDA contents decreased and SOD activity increased dramatically in MaFGF-treated groups respectively. The efficacy of MaFGF was similar to that of nimodipine. Conclusion: The results demonstrate that MaFGF has neuroprotective effect against brain injury resulting from focal ischaemia-reperfusion in Sprague–Dawley rats. [Copyright &y& Elsevier]

Abstract: Background: In our previous study, a mutant human acidic fibroblast growth factor without mitogenic action (nonmitogenic human acidic fibroblast growth factor) was created, and its protection from the cytotoxic effect of hydrogen peroxide treatment was confirmed in cultured cardiomyocytes. Methods: The present study was performed to further investigate whether genetically overexpressing nonmitogenic human acidic fibroblast growth factor in cardiomyocytes provides similar protection from the cytotoxic effect of hydrogen peroxide and whether in vivo administration of nonmitogenic human acidic fibroblast growth factor attenuates ischemia/reperfusion-induced cardiac dysfunction and tissue damage and protects the carotid sinus baroreceptor from alcohol-induced damage, as shown by a reduced response of blood pressure to short carotid artery occlusion. Results and conclusions: Cardiomyocytes transfected by nonmitogenic human acidic fibroblast growth factor, with significant increases in the cellular expression and secretion of nonmitogenic human acidic fibroblast growth factor into a culture medium, were resistant to hydrogen-peroxide-induced cytotoxicity, as measured by cell viability. Hearts isolated from rats pretreated with saline, human acidic fibroblast growth factor, or nonmitogenic human acidic fibroblast growth factor for 24 h were subjected to ischemia/reperfusion in the Langendorff system. Ischemia/reperfusion induced cardiac dysfunction in the saline group, but not in the group pretreated with human acidic fibroblast growth factor or nonmitogenic human acidic fibroblast growth factor. Ischemia/reperfusion also caused a release of the cardiac enzyme lactic dehydrogenase into—and an increase in lipid peroxide content in the efflux of—the hearts of saline-treated rats, but not in rats pretreated with human acidic fibroblast growth factor or nonmitogenic human acidic fibroblast growth factor. There was no difference in cardioprotective effects between human acidic fibroblast growth factor and nonmitogenic human acidic fibroblast growth factor. Furthermore, the protective effect of in-vivo-administered nonmitogenic acidic fibroblast growth factor on alcohol-induced damage to the carotid sinus baroreceptor, as shown by the reduced response of blood pressure to short carotid artery occlusion, was also observed. These results suggest that nonmitogenic human acidic fibroblast growth factor, similar to the native human acidic fibroblast growth factor, provides significant cardiovascular protection from oxidative damage in vitro and in vivo. [Copyright &y& Elsevier]

Fibroblast migration is a central process in skin wound healing, which requires the coordination of several types of growth factors. bFGF, a well-known fibroblast growth factor (FGF), is able to accelerate fibroblast migration; however, the underlying mechanism of bFGF regulation fibroblast migration remains unclear. Through the RNA-seq analysis, we had identified that the hedgehog (Hh) canonical pathway genes including Smoothened (Smo) and Gli1, were regulated by bFGF. Further analysis revealed that activation of the Hh pathway via up-regulation of Smo promoted fibroblast migration, invasion, and skin wound healing, but which significantly reduced by GANT61, a selective antagonist of Gli1/Gli2. Western blot analyses and siRNA transfection assays demonstrated that Smo acted upstream of phosphoinositide 3-kinase (PI3K)-c-Jun N-terminal kinase (JNK)-β-catenin to promote cell migration. Moreover, RNA-seq and qRT-PCR analyses revealed that Hh pathway genes including Smo and Gli1 were under control of β-catenin, suggesting that β-catenin turn feedback activates Hh signaling. Taken together, our analyses identified a new bFGF-regulating mechanism by which Hh signaling regulates human fibroblast migration, and the data presented here opens a new avenue for the wound healing therapy. [ABSTRACT FROM AUTHOR]

Acidic fibroblast growth factor (aFGF) has shown the great potential to prevent the structural and functional injuries caused by diabetic cardiomyopathy (DCM). The present study sought to investigate the preclinical performance and mechanism of the combination therapy of aFGF-nanoparticles (aFGF-NP) and ultrasound-targeted microbubble destruction (UTMD) technique for DCM prevention. From Mason staining and TUNEL staining, aFGF-NP + UTMD group showed significant differences from the diabetes group and other groups treated with aFGF or aFGF-NP. The cardiac collagen volume fraction (CVF) and cardiac myocyte apoptosis index in aFGF-NP + UTMD group reduced to 4.15% and 2.31% respectively, compared with those in the diabetes group (20.5% and 11.3% respectively). Myocardial microvascular density (MCD) in aFGF-NP + UTMD group was up to 35 n/hpf, much higher than that in the diabetes group (14 n/hpf). The diabetes group showed similar results (MCD, CVF and cardiac myocyte apoptosis index) to other aFGF treatment groups (free aFGF ± UTMD or aFGF-NP). Indexes from transthoracic echocardiography and hemodynamic evaluation also proved the same conclusion. These results confirmed that the abnormalities including diastolic dysfunctions, myocardial fibrosis and metabolic could be suppressed by the different extents of twice weekly aFGF treatments for 12 consecutive weeks (free aFGF or aFGF-NP ± UTMD), with the strongest improvements observed in the aFGF-NP + UTMD group. Western blot and immunohistochemical analyses of heart tissue samples further revealed the high efficiency of heart-targeted delivery and effective cardioprotection with this combination approach. Overall, this study has generated supportive data that are critical for the translation of a promising DCM prevention strategy. [ABSTRACT FROM AUTHOR]

Abstract: Diabetic cardiomyopathy (DCM) is the leading cause of morbidity and mortality among the diabetic patients and currently there is no effective means to reverse its pathological progress. Basic fibroblast growth factor (bFGF) has shown promise as a molecular therapy for DCM, but its delivery is inefficient and non-specific. In the present study, a therapy combining nanoparticle (NP) carrier and ultrasound-targeted microbubble destruction (UTMD) was reported the first time for bFGF delivery to the heart of diabetic rats. bFGF-loaded NP (bFGF-NP) were prepared with Poloxamer 188-grafted heparin copolymer using water-in-water technique, and the morphology, encapsulation efficiency, and bioactivity of bFGF-NP were studied. The cellular uptake and cytotoxicity of bFGF-NP were evaluated with primary cultures of the left ventricular (LV) cardiomyocytes in vitro. Therapeutic effects of bFGF-NP/UTMD on the heart of DCM rats were studied by measuring LV systolic and diastolic functions, hemodynamic characteristics and indicators of cardiac remodeling including myocardial collagen volume fraction and capillary density. Results demonstrated that bFGF-NP showed good round morphology, efficient bFGF encapsulation and stable bioactivity of bFGF in vitro. bFGF-NP/UTMD combined treatment significantly enhanced the efficiency of bFGF cellular uptake (P <0.05) without obvious cytotoxicity. Significant improvements (P <0.05) in both cardiac functions and tissue morphology in the DCM rats were observed in bFGF-NP/UTMD group. These were not achievable using free bFGF, bFGF-NP or UTMD treatment alone. Our results show that combining a non-viral vector with UTMD technique is an effective strategy to deliver bFGF to the heart, and the resulting growth factor therapy has demonstrated potential to reverse the progress of DCM by restoring the cardiac functions and even the structure of damaged cardiac tissues. [Copyright &y& Elsevier]

Hypertrophic scars (HTS) and keloids are challenging problems. Their pathogenesis results from an overproduction of fibroblasts and excessive deposition of collagen. Studies suggest a possible anti-scarring effect of basic fibroblast growth factor (bFGF) during wound healing, but the precise mechanisms of bFGF are still unclear. In view of this, we investigated the therapeutic effects of bFGF on HTS animal model as well as human scar fibroblasts (HSF) model. We show that bFGF promoted wound healing and reduced the area of flattened non-pathological scars in rat skin wounds and HTS in the rabbit ear. We provide evidence of a new therapeutic strategy: bFGF administration for the treatment of HTS. The scar elevation index (SEI) and epidermal thickness index (ETI) was also significantly reduced. Histological reveal that bFGF exhibited significant amelioration of the collagen tissue. bFGF regulated extracellular matrix (ECM) synthesis and degradation via interference in the collagen distribution, the α-smooth muscle actin (α-SMA) and transforming growth factor-1 (TGF-β1) expression. In addition, bFGF reduced scarring and promoted wound healing by inhibiting TGFβ1/SMAD-dependent pathway. The levels of fibronectin (FN), tissue inhibitor of metalloproteinase-1 (TIMP-1) collagen I, and collagen III were evidently decreased, and matrix metalloproteinase-1 (MMP-1) and apoptosis cells were markedly increased. These results suggest that bFGF possesses favorable therapeutic effects on hypertrophic scars in vitro and in vivo, which may be an effective cure for human hypertrophic scars. [ABSTRACT FROM AUTHOR]