Fibroblast Growth Factor Family Research Articles

Fibroblast growth factor-21 potentiates the stimulatory effects of 1,25-dihydroxyvitamin D3 on transepithelial calcium transport and TRPV6 Ca2+ channel expression

Fibroblast growth factor (FGF)-21 is a salient liver-derived endocrine regulator for metabolism of glucose and triglyceride as well as bone remodeling. Previously, certain peptides in the FGF family have been shown to modulate calcium absorption across the intestinal epithelia. Since FGF21 receptor, i.e., FGF receptor-1, is abundantly expressed in the enterocytes, there was a possibility that FGF21 might exert direct actions on the intestine. Herein, a large-scale production of recombinant FGF21 at the multi-gram level was developed in order to minimize variations among various batches. In the oral glucose tolerance test, recombinant FGF21 was found to reduce plasma glucose levels in mice fed high-fat diet. A series of experiments applying radioactive tracer 45Ca in Ussing chamber showed that FGF21 potentiated the stimulatory effect of low-dose 1,25-dihydroxyvitamin D3 [10 nM 1,25(OH)2D3] on the transepithelial calcium transport across intestinal epithelium-like Caco-2 monolayer. FGF21+1,25(OH)2D3 also decreased transepithelial resistance, but had no effect on epithelial potential difference or short-circuit current. Furthermore, 1,25(OH)2D3 alone upregulated the Caco-2 mRNA expression of the major apical calcium channels, i.e., transient receptor potential vanilloid subfamily member 6 (TRPV6), which was further elevated by a combination of FGF21 and 1,25(OH)2D3, consistent with the upregulated TRPV6 protein expression in enterocytes of FGF21-treated mice. However, FGF21 was without effects on the mRNA expression of voltage-gated calcium channel 1.3, calbindin-D9k, plasma membrane Ca2+-ATPase 1b, claudin-12 or claudin-15. In conclusion, FGF21 did exert a direct action on the intestinal epithelial cells by potentiating the 1,25(OH)2D3-enhanced calcium transport, presumably through the upregulation of TRPV6 expression.

Role of Rhodomyrtus tomentosa (Aiton) Hassk. in regulating the expression of fibroblast growth factor family in the liver of rat in a breast cancer model

Context: Cellular abnormalities in the ducts and breast tissue cause breast cancer to invade nearby tissues like the liver. The fibroblast growth factor (FGF) signals are sent to its receptor and regulate various cellular processes to maintain liver homeostasis. However, this condition has few and inefficient treatments. Breast cancer is characterized by the development of cellular abnormalities within the ducts and breast tissue, leading to the invasion of adjacent tissues, such as the liver. Aims: To examine the impact of Rhodomyrtus tomentosa administration on the expression of the FGF family in cancer animal models, with a specific focus on the liver. Methods: Cancer model rats were administered at dosages of 100, 200, and 300 mg/kg BW for 30 days. Liver tissue and blood serum samples were extracted from the rat. Liver tissue was stained for immunohistochemistry using FGF1, FGF15, FGF19, and FGF21, and blood samples were collected for ELISA analysis. Results: The study found that DMBA in hepatocyte cells degrades parenchyma, making it hydrophilic and necrosating. Hepatocyte cell function improved with the greatest dose of R. tomentosa. The elevation was associated with an area around the portal vein where recently dividing hepatocytes form clusters. Conclusions: The promise of R. tomentosa as a candidate for the development of hepatoprotective medicines in cancer treatment arises from its ability to influence the expression of crucial liver health markers, including FGF1, FGF15, FGF19, and FGF21.

Panoramic RNA expression of fibroblast growth factors in human glioblastoma tissues and the impact on the survival of patients.

Fibroblast growth factors (FGFs) have a key role in various critical steps of tumor growth and progression through effects on angiogenesis, inflammation and the growth and invasion of malignant cells. Nevertheless, the role of the FGF family in human glioblastoma (GBM) has been rarely studied. The objective of the present study was to assess the RNA expression of all FGF family members in tissues obtained from patients with GBM and to analyze the association between FGF expression and the survival of these patients. For this, the RNA expression of FGF family members in the malignant and proximal tissues of 12 patients with GBM was determined by analyzing high-throughput RNA transcriptome sequencing data uploaded to the National Center for Biotechnology Information database. The relationship between FGF genes and the survival of patients with GBM and glioma was also respectively studied by analyzing data from The Cancer Genome Atlas database using the Gene Expression Profiling Interactive Analysis tool. The results showed that the expression of FGF1, FGF17, FGF20 and FGF22 in GBM tissues was lower than that in adjacent tissues, with a difference of >2 times. Analysis of the overall survival of patients with GBM indicated there were no significant relationships between the expression of FGF1, FGF17, FGF20, FGF22 and overall survival. Analysis of the overall survival of patients with glioma showed that glioma patients with low FGF1 expression achieved a longer survival time than patients with high FGF1 expression; however, high expression of FGF17 and FGF22 indicated a longer survival time. In summary, the results of the present study demonstrated the panoramic expression of FGF family members in patients with GBM, and indicated that FGF1, FGF17 and FGF22 did not affect the survival of patients with GBM, but had a notable influence on the survival of patients with glioma.

Exploring the Impact of Fibroblast Growth Factor 17 on Functional Recovery and Neuroinflammation in Spinal Cord Injury

Spinal cord injury (SCI) affects more than 300,000 people in the United States, making it a significant and widespread problem. This includes injuries at the cervical level, which pose greater challenges due to respiratory in addition to mobility issues. Though there is a large societal impact there is still standard of care following spinal cord injury. While previous preclinical research has shown benefits from FGF1 and FGF2, there is weak data to suggest their clinical effcacy. A related compound, Fibroblast Growth Factor 17 (FGF17), has recently been described as a component within the CSF of young animals that when delivered to aged animals improved cognitive function. These improvements were associated with oligodendrogenesis. Spinal cord injury results in secondary demyelination, which may be mitigated by increasing oligodendrogenesis; this led us to examine how FGF17 may be used as a therapeutic agent following SCI. We used a rat C2 hemisection injury model to evaluate the effects of FGF17 at 4 hours, 2 and 6 weeks after injury. FGF17 was administered via intrathecal infusion at 25 μg/μl for 14 days at 0.5 μL/hour or a single application of 20 μL (4-hour timepoint). Following treatment, whole body plethysmography was performed weekly. Tissues were collected at endpoint to assess brainstem neuroinflammation via immunohistochemistry and molecular signaling pathways via western blotting. As anticipated, animals that were not treated with FGF17 had reduced tidal volume following spinal cord injury. Treatment with FGF17 partially preserved tidal volume as early as 3 days post injury. 6 weeks following spinal cord injury we observed a reduction in GFAP+ and IBA1+ staining in the brainstem near regions associated with respiratory control in animals treated with FGF17. Further, when we quantified the protein content in the spinal cord near the lesion epicenter we saw an increase in p-ERK 1/2 in all injured animals. However, in FGF17 treated animals we saw an increase in downstream transcription factors, STAT6 and Serum Response Factor. Serum Response Factor was implicated in oligodendrogenesis, ongoing studies will directly address this. These data suggest that FGF17 may be a viable alternative to the traditional fibroblast growth factor family members when treating spinal cord injury. R21NS121966, R01NS116068. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Fibroblast Growth Factor 6

Fibroblast Growth Factor 6 (FGF6), also referred to as HST2 or HBGF6, is a member of the Fibroblast Growth Factor (FGF), the Heparin Binding Growth Factor (HBGF) and the Heparin Binding Secretory Transforming Gene (HST) families. The genomic and protein structure of FGF6 is highly conserved among varied species, as is its expression in muscle and muscle progenitor cells. Like other members of the FGF family, FGF6 regulates cell proliferation, differentiation, and migration. Specifically, it plays key roles in myogenesis and muscular regeneration, angiogenesis, along with iron transport and lipid metabolism. Similar to others from the FGF family, FGF6 also possesses oncogenic transforming activity, and as such is implicated in a variety of cancers.

Roles of fibroblast growth factors in the treatment of diabetes.

Diabetes affects about 422 million people worldwide, causing 1.5 million deaths each year. However, the incidence of diabetes is increasing, including several types of diabetes. Type 1 diabetes (5%-10% of diabetic cases) and type 2 diabetes (90%-95% of diabetic cases) are the main types of diabetes in the clinic. Accumulating evidence shows that the fibroblast growth factor (FGF) family plays important roles in many metabolic disorders, including type 1 and type 2 diabetes. FGF consists of 23 family members (FGF-1-23) in humans. Here, we review current findings of FGFs in the treatment of diabetes and management of diabetic complications. Some FGFs (e.g., FGF-15, FGF-19, and FGF-21) have been broadly investigated in preclinical studies for the diagnosis and treatment of diabetes, and their therapeutic roles in diabetes are currently under investigation in clinical trials. Overall, the roles of FGFs in diabetes and diabetic complications are involved in numerous processes. First, FGF intervention can prevent high-fat diet-induced obesity and insulin resistance and reduce the levels of fasting blood glucose and triglycerides by regulating lipolysis in adipose tissues and hepatic glucose production. Second, modulation of FGF expression can inhibit renal and cardiac fibrosis by regulating the expression of extracellular matrix components, promote diabetic wound healing process and bone repair, and inhibit cancer cell proliferation and migration. Finally, FGFs can regulate the activation of glucose-excited neurons and the expression of thermogenic genes.

Changes in the Concentrations of Proangiogenic Cytokines in Human Brain Glioma and Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) and glioma are some of the most common malignancies, with ALL most often affecting children and glioma affecting adult men. Proangiogenic cytokines and growth factors play an important role in the development of both of these tumors. Glioma is characterized by an extremely extensive network of blood vessels, which continues to expand mainly in the process of neoangiogenesis, the direct inducers of which are cytokines from the family of vascular endothelial growth factors, i.e., vascular endothelial growth factor (VEGF-A) and its receptor vascular endothelial growth factor receptor 2 (VEGF-R2), as well as a cytokine from the fibroblast growth factor family, fibroblast growth factor 2 (FGF-2 or bFGF). Growth factors are known primarily for their involvement in the progression and development of solid tumors, but there is evidence that local bone marrow angiogenesis and increased blood vessel density are also present in hematological malignancies, including leukemias. The aim of this study was to examine changes in the concentrations of VEGF-A, VEGF-R2, and FGF-2 (with a molecular weight of 17 kDa) in a group of patients divided into specific grades of malignancy (glioma) and a control group; changes of VEGF-A and FGF-2 concentrations in childhood acute lymphoblastic leukemia and a control group; and to determine correlations between the individual proteins as well as the influence of the patient's age, diet, and other conditions that may place the patient in the risk group. During the statistical analysis, significant differences in concentrations were found between the patient and control groups in samples from people with diagnosed glioma and from children with acute lymphoblastic leukemia, but in general, there are no significant differences in the concentrations of VEGF-A, VEGF-R2, and FGF-2 between different grades of glioma malignancy. Among individuals treated for glioma, there was no significant impact from the patient's gender and age, consumption of food from plastic packaging, frequency of eating vegetables and fruit, smoking of tobacco products, the intensity of physical exercise, or the general condition of the body (Karnofsky score) on the concentrations of the determined cytokines and receptor. The listed factors do not bring about an actual increase in the risk of developing brain glioma.

Acidic fibroblast growth factor inhibits reactive oxygen species-induced epithelial-mesenchymal transdifferentiation in vascular endothelial cells via the miR-155-5p/SIRT1/Nrf2/HO-1 pathway to promote wound healing in diabetic mice.

Diabetic chronic wounds are among the most common and serious complications of diabetes and are associated with significant morbidity and mortality. Endothelial-to-mesenchymal transition (EndMT) is a specific pathological state in which endothelial cells are transformed into mesenchymal cells in response to various stimuli, such as high glucose levels and high oxidative stress. Acidic fibroblast growth factor (aFGF), which is a member of the fibroblast growth factor family, possesses strong antioxidant properties and can promote the differentiation of mesenchymal stem cells into angiogenic cells. Therefore, we investigated the role of aFGF in EndMT in diabetic wounds and analysed the underlying mechanisms. A diabetic mouse model was used to verify the effect of aFGF on wound healing, and the effect of aFGF on vascular endothelial cells in a high-glucose environment was examined in vitro. We examined the expression of miR-155-5p in a high-glucose environment and the miR-155 downstream target gene SIRT1 by luciferase reporter assays. aFGF promoted wound closure and neovascularization in a mouse model of type 2 diabetes. In vitro, aFGF inhibited the production of total and mitochondrial reactive oxygen species (ROS) in vascular endothelial cells and alleviated epithelial-mesenchymal transdifferentiation in a high-glucose environment. Mechanistically, aFGF promoted the expression of SIRT1 and the downstream targets Nrf2 and HO-1 by negatively regulating miR-155-5p, thereby reducing ROS generation. In conclusion, our results suggest that aFGF inhibits ROS-induced epithelial-mesenchymal transdifferentiation in diabetic vascular endothelial cells via the miR-155-5p/SIRT1/Nrf2/HO-1 axis, thereby promoting wound healing.

FGF19/FGFR4 signaling contributes to hepatocellular carcinoma survival and immune escape by regulating IGF2BP1-mediated expression of PD-L1

Immune-checkpoint blockade (ICB) therapies have been widely used in clinical treatment of cancer patients, but only 20–30% of patients benefit from immunotherapy. Therefore, it is important to decipher the molecular mechanism of resistance to ICB and develop new combined treatment strategies. PD-L1 up-regulation in tumor cells contributes to the occurrence of immune escape. Increasing evidence shows that its transcription level is affected by multiple factors, which limits the objective response rate of ICB. Fibroblast growth factor 19 (FGF19), a member of the fibroblast growth factor family, is widely involved in the malignant progression of many tumors by binding to fibroblast growth factor receptor 4 (FGFR4). In this study, we confirmed that FGF19 acts as a driver gene in hepatocellular carcinoma (HCC) progression by binding to FGFR4. The up-regulation of FGF19 and FGFR4 in HCC is associated with poor prognosis. We found that FGF19/FGFR4 promoted the proliferation and invasion of HCC cells by driving IGF2BP1 to promote PD-L1 expression. Knockdown of FGFR4 significantly reduced the expression of IGF2BP1/PD-L1 and inhibited the proliferation and invasion of HCC cells. These biological effects are achieved by inhibiting the PI3K/AKT pathway. The combination of FGFR4 knockdown and anti-PD-1 antibody greatly suppressed tumor growth and enhanced the sensitivity of immunotherapy, highlighting the clinical significance of FGF19/FGFR4 activation in immunotherapy.

Fibroblast growth factor 9 (FGF9)-mediated neurodegeneration: Implications for progressive multiple sclerosis?

Fibroblast growth factor (FGF) signalling is dysregulated in multiple sclerosis (MS) and other neurological and psychiatric conditions, but there is little or no consensus as to how individual FGF family members contribute to disease pathogenesis. Lesion development in MS is associated with increased expression of FGF1, FGF2 and FGF9, all of which modulate remyelination in a variety of experimental settings. However, FGF9 is also selectively upregulated in major depressive disorder (MDD), prompting us to speculate it may also have a direct effect on neuronal function and survival. Transcriptional profiling of myelinating cultures treated with FGF1, FGF2 or FGF9 was performed, and the effects of FGF9 on cortical neurons investigated using a combination of transcriptional, electrophysiological and immunofluorescence microscopic techniques. The in vivo effects of FGF9 were explored by stereotactic injection of adeno-associated viral (AAV) vectors encoding either FGF9 or EGFP into the rat motor cortex. Transcriptional profiling of myelinating cultures after FGF9 treatment revealed a distinct neuronal response with a pronounced downregulation of gene networks associated with axonal transport and synaptic function. In cortical neuronal cultures, FGF9 also rapidly downregulated expression of genes associated with synaptic function. This was associated with a complete block in the development of photo-inducible spiking activity, as demonstrated using multi-electrode recordings of channel rhodopsin-transfected rat cortical neurons in vitro and, ultimately, neuronal cell death. Overexpression of FGF9 in vivo resulted in rapid loss of neurons and subsequent development of chronic grey matter lesions with neuroaxonal reduction and ensuing myelin loss. These observations identify overexpression of FGF9 as a mechanism by which neuroaxonal pathology could develop independently of immune-mediated demyelination in MS. We suggest targeting neuronal FGF9-dependent pathways may provide a novel strategy to slow if not halt neuroaxonal atrophy and loss in MS, MDD and potentially other neurodegenerative diseases.

Circulating biomarkers of extracellular matrix dysregulation are associated with adverse post-stage 2 outcomes in infants with single ventricle heart disease

Children with single ventricle heart disease (SVHD) experience morbidity due to inadequate pulmonary blood flow. Using proteomic screening, our group previously identified members of the matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinase (TIMP), and fibroblast growth factor (FGF) families as potentially dysregulated in SVHD. No prior study has taken a targeted approach to mapping circulating levels of these protein families or their relationship to pulmonary vascular outcomes in SVHD. We performed a prospective cohort study of 70 SVHD infants pre-Stage 2 palliation and 24 healthy controls. We report targeted serum quantification of 39 proteins in the MMP, TIMP, and FGF families using the SomaScan platform. Clinical variables were extracted from the medical record. Twenty of 39 tested proteins (7/14 MMPs, 2/4 TIMPs, and 11/21 FGFs) differed between cases and controls. On single variable testing, 6 proteins and no clinical covariates were associated with both post-Stage 2 hypoxemia and length of stay. Multiple-protein modeling identified increased circulating MMP 7 and MMP 17, and decreased circulating MMP 8 and FGFR2 as most associated with post-Stage 2 hypoxemia; increased MMP 7 and TIMP 4 and decreased circulating MMP 1 and MMP 8 were most associated with post-operation length of stay. The MMP, TIMP, and FGF families are altered in SVHD. Pre-Stage 2 imbalance of extracellular matrix (ECM) proteins—increased MMP 7 and decreased MMP 8—was associated with multiple adverse post-operation outcomes. Maintenance of the ECM may be an important pathophysiologic driver of Stage 2 readiness in SVHD.

Fibroblast growth factor 5 expression predicts the progression of oral squamous cell carcinoma

Fibroblast growth factor (FGF) 5 is a member of the FGF family that functions as a regulator of tissue growth and regeneration. Aberrant FGF5 expression has been previously associated with the progression of a number of different malignancies. However, its potential role in oral cancer remains unclear. In this study, we explored the relationship between the expression of FGF5 protein in oral squamous cell carcinomas (OSCCs) and the clinicopathological parameters of OSCCs and whether the expression of FGF5 protein in OSCCs could be a prognostic factor for OSCC patients. The FGF5 protein expression was examined in 64 OSCC and 34 normal oral mucosal specimens by immunohistochemical staining. Stress induced upregulation and intracellular redistribution of FGF5 were verified using xenograft animal model and OSCC cell lines. The mean FGF5 protein labelling index was significantly higher in OSCC than in normal oral mucosal samples, with high FGF5 protein labelling index (>58%) being correlated with advanced stage and poor survival of OSCC patients. Apart from the peri-cytoplasmic staining pattern characteristic of paracrine growth factors, FGF5 protein was localized as distinct punctate structures in the cytoplasm of advanced stage or stressed-induced cells. This redistribution and upregulation of FGF5 protein could be sustained after termination of the stress induction in cell line and xenograft animal models. FGF5 can be induced by cellular stress and risk factors of OSCC, where high expression levels of FGF5 is potentially a useful parameter for predicting OSCC progression and patient survival.

Craniofacial anomalies in a murine model of heterozygous fibroblast growth factor 10 gene mutation.

Dysregulation of Fibroblast Growth Factor 10 (FGF10), a member of the family of Fibroblast Growth Factor (FGF) proteins, has been implicated in craniofacial and dental anomalies, including craniosynostosis, cleft palate, and Lacrimo-Auriculo-Dento-Digital Syndrome. The aim of this murine study was to assess the craniofacial and dental phenotypes associated with a heterozygous FGF10 gene (FGF10+/- ) mutation at skeletal maturity. Skulls of 40 skeletally mature mice, comprising two genotypes (heterozygous FGF10+/- mutation, n = 22; wildtype, n = 18) and two sexes (male, n = 23; female, n = 17), were subjected to micro-computed tomography. Landmark-based linear dimensions were measured for the cranial vault, maxilla, mandible, and first molar teeth. Multivariate analysis of variance was performed to assess whether there were significant differences in the craniofacial and dental structures between genotypes and sexes. The craniomaxillary skeleton and the first molar teeth were smaller in the FGF10+/- mice (P < .05), but the mandible was unaffected. Sex did not have a significant effect on these structures (P > .05). Cranial sutural defects were noted in 5/22 (22.7%) mutant versus 2/18 (11.1%) wildtype mice, and cleft palate in only one (4.5%) mutant mouse. None of the mice displayed craniosynostosis, expansive bony lesions, bifid condyles, or impacted teeth. The FGF10+/- mutation was associated with craniomaxillary skeletal hypoplasia thatprobably arose from deficient (delayed) intramembranous ossification of the sutured bones. Overall, theskeletal and dental data suggest that the FGF10 gene plays an important role in the aetiology of craniofacial dysmorphology and malocclusion.

FGF homologous factors are secreted from cells to induce FGFR-mediated anti-apoptotic response.

FGF homologous factors (FHFs) are the least described group of fibroblast growth factors (FGFs). The FHF subfamily consists of four proteins: FGF11, FGF12, FGF13, and FGF14. Until recently, FHFs were thought to be intracellular, non-signaling molecules, despite sharing structural and sequence similarities with other members of FGF family that can be secreted and activate cell signaling by interacting with surface receptors. Here, we show that despite lacking a canonical signal peptide for secretion, FHFs are exported to the extracellular space. Furthermore, we propose that their secretion mechanism is similar to the unconventional secretion of FGF2. The secreted FHFs are biologically active and trigger signaling in cells expressing FGF receptors (FGFRs). Using recombinant proteins, we demonstrated their direct binding to FGFR1, resulting in the activation of downstream signaling and the internalization of the FHF-FGFR1 complex. The effect of receptor activation by FHF proteins is an anti-apoptotic response of the cell.

Deciphering transcriptional dynamics of cardiac hypertrophy and failure in a chamber-specific manner.

Pressure overload-induced pathological cardiac hypertrophy (CH) is a complexed and adaptive remodeling of the heart, predominantly involving an increase in cardiomyocyte size and thickening of ventricular walls. Over time, these changes can lead to heart failure (HF). However, the individual and shared biological mechanisms of both processes remain poorly understood. This study aimed to identify key genes and signaling pathways associated with CH and HF following aortic arch constriction (TAC) at four weeks and six weeks, respectively, and to investigate potential underlying molecular mechanisms in this dynamic transition from CH to HF at the whole cardiac transcriptome level. Initially, a total of 363, 482, and 264 differentially expressed genes (DEGs) for CH, and 317, 305, and 416 DEGs for HF were identified in the left atrium (LA), left ventricle (LV), and right ventricle (RV), respectively. These identified DEGs could serve as biomarkers for the two conditions in different heart chambers. Additionaly, two communal DEGs, elastin (ELN) and hemoglobin beta chain-beta S variant (HBB-BS), were found in all chambers, with 35 communal DEGs in the LA and LV and 15 communal DEGs in the LV and RV in both CH and HF. Functional enrichment analysis of these genes emphasized the crucial roles of the extracellular matrix and sarcolemma in CH and HF. Lastly, three groups of hub genes, including the lysyl oxidase (LOX) family, fibroblast growth factors (FGF) family, and NADH-ubiquinone oxidoreductase (NDUF) family, were determined to be essential genes of dynamic changes from CH to HF.

A Low-Protein, High-Carbohydrate Diet Exerts a Neuroprotective Effect on Mice with 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Parkinson's Disease by Regulating the Microbiota-Metabolite-Brain Axis and Fibroblast Growth Factor 21.

Parkinson's disease (PD) is closely linked to lifestyle factors, particularly dietary patterns, which have attracted interest as potential disease-modifying factors. Eating a low-protein, high-carbohydrate (LPHC) diet is a promising dietary intervention against brain aging; however, its protective effect on PD remains elusive. Here, we found that an LPHC diet ameliorated 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-induced motor deficits, decreased dopaminergic neuronal death, and increased the levels of striatal dopamine, serotonin, and their metabolites in PD mice. Levels of fibroblast growth factor 21 (FGF-21), a member of the fibroblast growth factor family, were elevated in PD mice following LPHC treatment. Furthermore, the administration of FGF-21 exerted a protective effect on MPTP-induced PC12 cells, similar to the effect of an LPHC diet in MPTP-induced mice. Sequencing of the 16S rDNA from fecal microbiota revealed that an LPHC diet normalized the gut bacterial composition imbalance in PD mice, as evidenced by the increased abundance of the genera Bifidobacterium, Ileibacterium, Turicibacter, and Blautia and decreased abundance of Bilophila, Alistipes, and Bacteroides. PICRUSt-predicted fecal microbiome function revealed that an LPHC diet suppressed lipopolysaccharide biosynthesis and the citrate cycle (TCA cycle), biosynthesis of ubiquinone and other terpenoid-quinones, and oxidative phosphorylation pathways caused by MPTP, and enhanced the biosynthesis of amino acids, carbohydrate metabolism, and biosynthesis of other secondary metabolites. A nonmetabolomic analysis of the serum and feces showed that an LPHC diet significantly increased the levels of aromatic amino acids (AAAs), including tryptophan, tyrosine, and phenylalanine. In addition, an LPHC diet elevated the serum concentrations of bile acids (BAs), particularly tauroursodeoxycholic acid (TUDCA) and taurine. Collectively, our current findings point to the potential mechanism of administering an LPHC diet in attenuating movement impairments in MPTP-induced PD mice, with AAAs, microbial metabolites (TUDCA and taurine), and FGF-21 as key mediators along the gut-microbiota-brain axis.

The role of fibroblast growth factor 18 in cancers: functions and signaling pathways.

Fibroblast growth factor 18(FGF18) is a member of the fibroblast growth factor family (FGFs). FGF18 is a class of bioactive substances that can conduct biological signals, regulate cell growth, participate in tissue repair and other functions, and can promote the occurrence and development of different types of malignant tumors through various mechanisms. In this review, we focus on recent studies of FGF18 in the diagnosis, treatment, and prognosis of tumors in digestive, reproductive, urinary, respiratory, motor, and pediatric systems. These findings suggest that FGF18 may play an increasingly important role in the clinical evaluation of these malignancies. Overall, FGF18 can function as an important oncogene at different gene and protein levels, and can be used as a potential new therapeutic target and prognostic biomarker for these tumors.

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.

Genome-Wide Identification and Characterization of Bovine Fibroblast Growth Factor (FGF) Gene and Its Expression during Adipocyte Differentiation.

Fibroblast growth factor (FGF) family genes are a class of polypeptide factors with similar structures that play an important role in regulating cell proliferation and differentiation, nutritional metabolism, and neural activity. In previous studies, the FGF gene has been widely studied and analyzed in many species. However, the systematic study of the FGF gene in cattle has not been reported. In this study, 22 FGF genes distributed on 15 chromosomes were identified in the Bos taurus genome and clustered into seven subfamilies according to phylogenetic analysis and conservative domains. Collinear analysis showed that the bovine FGF gene family was homologous to Bos grunniens, Bos indicus, Hybrid-Bos taurus, Bubalus bubalis, and Hybrid-Bos indicus, and tandem replication and fragment replication were the key driving forces for the expansion of the gene family. Tissue expression profiling showed that bovine FGF genes were commonly expressed in different tissues, with FGF1, FGF5, FGF10, FGF12, FGF16, FGF17, and FGF20 being highly expressed in adipose tissue. In addition, real-time fluorescence quantitative PCR (qRT-PCR) detection showed that some FGF genes were differentially expressed before and after adipocyte differentiation, indicating their diverse role in the formation of lipid droplets. This study made a comprehensive exploration of the bovine FGF family and laid a foundation for further study on the potential function in the regulation of bovine adipogenic differentiation.

Polymorphic Variants of Genes Encoding Angiogenesis-Related Factors in Infertile Women with Recurrent Implantation Failure

Recurrent implantation failure (RIF) is a global health issue affecting a significant number of infertile women who undergo in vitro fertilization (IVF) cycles. Extensive vasculogenesis and angiogenesis occur in both maternal and fetal placental tissues, and vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) family molecules and their receptors are potent angiogenic mediators in the placenta. Five single nucleotide polymorphisms (SNPs) in the genes encoding angiogenesis-related factors were selected and genotyped in 247 women who had undergone the ART procedure and 120 healthy controls. Genotyping was conducted by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). A variant of the kinase insertion domain receptor (KDR) gene (rs2071559) was associated with an increased risk of infertility after adjusting for age and BMI (OR = 0.64; 95% CI: 0.45-0.91, p = 0.013 in a log-additive model). Vascular endothelial growth factor A (VEGFA) rs699947 was associated with an increased risk of recurrent implantation failures under a dominant (OR = 2.34; 95% CI: 1.11-4.94, padj. = 0.022) and a log-additive model (OR = 0.65; 95% CI 0.43-0.99, padj. = 0.038). Variants of the KDR gene (rs1870377, rs2071559) in the whole group were in linkage equilibrium (D' = 0.25, r2 = 0.025). Gene-gene interaction analysis showed the strongest interactions between the KDR gene SNPs rs2071559-rs1870377 (p = 0.004) and KDR rs1870377-VEGFA rs699947 (p = 0.030). Our study revealed that the KDR gene rs2071559 variant may be associated with infertility and rs699947 VEGFA with an increased risk of recurrent implantation failures in infertile ART treated Polish women.