Fibroblast Growth Factor Research Articles

Fibroblast growth factor 7 is a promising target in the process of ovarian cancer tumor attachment to prevent metastasis

Fibroblast growth factor 7 is a promising target in the process of ovarian cancer tumor attachment to prevent metastasis

Methionine Restriction Alleviates Diabetes-Associated Cognitive Impairment via Activation of FGF21

Glucose metabolism disturbances may result in diabetes-associated cognitive decline (DACI). Methionine restriction (MR) diet has emerged as a potential dietary strategy for managing glucose homeostasis. However, the effects and underlying mechanisms of MR on DACI have not been fully elucidated. Here, we found that a 13-week MR (0.17% methionine, w/w) intervention starting at 8 weeks of age improved peripheral insulin sensitivity in male db/db mice, a model for type 2 diabetes. Notably, MR significantly improved working as well as long-term memory in db/db mice, accompanied by increased PSD-95 level and reduced neuroinflammatory factors, malondialdehyde (MDA), and 8-hydroxy-2'-deoxyguanosine (8-OHdG). We speculate that this effect may be mediated by MR activating hepatic fibroblast growth factor 21 (FGF21) and the brain FGFR1/AMPK/GLUT4 signaling pathway to enhance brain glucose metabolism. To further delineate the mechanism, we used intracerebroventricular injection of adeno-associated virus to specifically knock down FGFR1 in the brain to verify the role of FGFR1 in MR-mediated DACI. It was found that the positive effects of MR on DACI were offset, reflected in decreased cognitive function, impaired synaptic plasticity, upregulated neuroinflammation, and balanced enzymes regulating reactive oxygen species (Sod1, Sod2, Nox4). Of note, the FGFR1/AMPK/GLUT4 signaling pathway and brain glucose metabolism were inhibited. In summary, our study demonstrated that MR increased peripheral insulin sensitivity, activated brain FGFR1/AMPK/GLUT4 signaling through FGF21, maintained normal glucose metabolism and redox balance in the brain, and thereby alleviated DACI. These results provide new insights into the effects of MR diet on cognitive dysfunction caused by impaired brain energy metabolism.

Drug treatment for MASLD: Progress and direction.

Metabolic dysfunction-associated steatotic liver disease (MASLD), also called non-alcoholic fatty liver disease, is the most epidemic chronic liver disease worldwide. Metabolic dysfunction-associated steatohepatitis (MASH) is the critical stage of MASLD, and early diagnosis and treatment of MASH are crucial for reducing the incidence of intrahepatic and extrahepatic complications. So far, pharmacotherapeutics for the treatment of MASH are still a major challenge, because of the complexity of the pathogenesis and heterogeneity of MASH. Many agents under investigation have shown impressive therapeutic effects by targeting different key pathways, including the attenuation of steatohepatitis or fibrosis or both. It is notable that thyroid hormone receptor-β agonist, resmetirom has become the first officially approved drug for treating MASH with fibrosis. Other agents such as peroxisome proliferator-activated receptor agonists, glucagon-like peptide-1 analogs, and fibroblast growth factor 21 analogs are awaiting approval. This review focuses on the current status of drug therapy for MASH and summarizes the latest results of new medications that have completed phase 2 or 3 clinical trials, and presents the future directions and difficulties of new drug research for MASH.

Cordycepin Activates Autophagy to Suppress FGF9-induced TM3 Mouse Leydig Progenitor Cell Proliferation.

Fibroblast growth factor 9 (FGF9) is a member of the human FGF family known for its pivotal roles in various biological processes, such as cell proliferation, tissue repair, and male sex determination including testis formation. Cordycepin, a bioactive compound found in Cordyceps sinensis, exhibits potent antitumor effects by triggering apoptosis and/or autophagy pathways. Our research has unveiled that FGF9 promotes proliferation and tumorigenesis in MA-10 mouse Leydig tumor cells, as the phenomena are effectively countered by cordycepin through apoptosis induction. Moreover, we have observed FGF9-mediated stimulation of proliferation and tumorigenesis in TM3 mouse Leydig progenitor cells, prompting an investigation into the potential inhibitory effect of cordycepin on TM3 cell proliferation under FGF9 treatment. Hence, we hypothesized that cordycepin induces cell death via apoptosis and/or autophagy in FGF9-treated TM3 cells. TM3 cells were treated with cordycepin and/or FGF9, and the flow cytometry, immunofluorescent plus western blotting assays were used to determine how cordycepin regulated Leydig cell death under FGF9 treatment. Our findings reveal that cordycepin restricts cell viability and colony formation while inducing morphological alterations associated with cell death in FGF9-treated TM3 cells. Surprisingly, cordycepin fails to elicit the expression of key apoptotic markers, suggesting an alternate mechanism of action. Although the expression of certain autophagy-related proteins remains unaltered, a significant up-regulation of LC3-II, indicative of autophagy, is observed in cordycepin-treated TM3 cells under FGF9 influence. Moreover, the inhibition of autophagy by chloroquine reverses cordycepin-induced TM3 cell death, highlighting the crucial role of autophagy in this process. Our study demonstrates that cordycepin activates autophagy to induce cell death in TM3 cells under FGF9 treatment conditions.

Therapeutic effects of FGF21 mimetic bFKB1 on MASH and atherosclerosis in Ldlr-/-.Leiden mice.

Fibroblast growth factor 21 (FGF21) is a promising target for treatment of obesity-associated diseases including metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerosis. We evaluated the effects of the bispecific anti-FGF21-β klotho (KLB) agonist antibody bFKB1 in a preclinical model of MASH and atherosclerosis. Low-density lipoprotein receptor knockout (Ldlr-/-).Leiden mice received a high-fat diet for 20 weeks, followed by treatment with an isotype control antibody or bFKB1 for 12 weeks. Effects on plasma risk markers and (histo)pathology of liver, adipose tissue, and heart were evaluated alongside hepatic transcriptomics analysis. bFKB1 lowered body weight (-21%) and adipose tissue mass (-22%) without reducing food intake. The treatment also improved plasma insulin (-80%), cholesterol (-48%), triglycerides (-76%), alanine transaminase (ALT: -79%), and liver weight (-43%). Hepatic steatosis and inflammation were strongly reduced (macrovesicular steatosis -34%; microvesicular steatosis -100%; inflammation -74%) and while the total amount of fibrosis was not affected, bFKB1 did decrease new collagen formation (-49%). Correspondingly, hepatic transcriptomics and pathway analysis revealed the mechanistic background underlying these histological improvements, demonstrating broad inactivation of inflammatory and profibrotic transcriptional programs by bFKB1. In epididymal white adipose tissue, bFKB1 reduced adipocyte size (-16%) and inflammation (-52%) and induced browning, signified by increased uncoupling protein-1 (UCP1) protein expression (8.5-fold increase). In the vasculature, bFKB1 had anti-atherogenic effects, lowering total atherosclerotic lesion area (-38%). bFKB1 has strong beneficial metabolic effects associated with a reduction in hepatic steatosis, inflammation, and atherosclerosis. Analysis of new collagen formation and profibrotic transcriptional programs indicate that bFKB1 treatment may have antifibrotic potential in a longer treatment duration as well.

Activation of fibroblast growth factor 21 by Canagliflozin reduces high-fat diet associated obesity-related cardiac injury: a translational study from bench to bedside

Abstract Aims/hypothesis Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are indicated for the treatment of type 2 diabetes, and evidence shows that they may confer a cardioprotective effect to reduce the incidence of cardiovascular conditions in obese type 2 diabetes patients. The mechanisms underlying this effect remain unclear, but an SGLT2i, canagliflozin (CANA), has been reported to increase levels of fibroblast growth factor-21 (FGF21) and enhance activation of its downstream target proteins. We thus aimed to study whether the effect on FGF21 by CANA can reduce obesity-related cardiac injury. Methods 1) Animal study: Sixteen-week-old normal diet and high-fat diet male mice were treated with or without 30 mg/kg CANA once a day for 24 weeks, and were subsequently examined for body weight, blood glucose levels, adipose tissue changes, lipid accumulation in the liver, and cardiac function. 2) Cell study: An in vitro study that treated H9c2 cardiomyocyte cells cultured in a simulated high-lipid environment containing palmitic acid (PA) with FGF21 recombinant protein was also conducted to examine protein expression profiles. Furthermore, the effect of CANA on FGF21 expression. 3) Human clinical trial: A randomized double-blinded control trial (NCT 05764811) was performed to test effect of CANA on MRI liver fibrosis scores of obese type 2 diabetes patients (n = 40). Results 1) High-fat diet mice treated with CANA for 24 weeks had lower average body weight than untreated controls (34 g vs. 40 g, p < 0.001). In addition, CANA treatment stimulated FGF21 protein production in liver tissue and plasma at higher levels for both normal diet and high-fat diet mice, and reduced expression levels of proteins associated with fibrosis and apoptosis. 2) H9c2 cardiomyocyte culture studies suggested that a simulated high-lipid environment with PA caused higher expression of apoptotic proteins, but the addition of FGF21 recombinant protein significantly reduced apoptosis signalling. 3) MRI before and after 4 weeks of CANA treatment in obese type 2 diabetes patients showed a significant reduction in liver fibrosis scores for those receiving CANA treatment. Conclusion CANA treatment stimulated FGF21 protein expression and reduced fibrosis and apoptosis signalling protein expression. Moreover, reductions in liver fibrosis scores were observed in obese type 2 diabetes patients treated with CANA. Taken together, this suggests that CANA-induced FGF21 expression may exert a cardioprotective effect against fibrosis and apoptosis and can potentially reduce the risk of obesity-related cardiac injury.

Elevation of circulating FGF23 in chronic kidney disease promotes atrial fibrosis through the AKT pathway

Abstract Background The relationship between chronic kidney disease (CKD) and atrial fibrillation (AF) remains unclear. Elevated level of fibroblast growth factor 23 (FGF23) is highly associated with increased cardiovascular disease and mortality in patients suffering from CKD. In recent years, studies have shown that FGF23 promotes cardiac hypertrophy through FGFR4, suggesting that FGF23 may be an important bridge between the heart and kidney. Purpose In this study, we sought to use a well-established rat model of CKD to further characterize the effects of CKD on AF and to identify potential drivers of CKD-induced AF. Methods 14 SD rats were randomly selected to undergo 5/6 nephrectomy and fed for 15 weeks to establish a CKD model, while the SHAM group (8 rats) underwent the same surgery without removing kidney tissue. Body weight, blood pressure, renal function, cardiac ultrasound, epicardial electrocardiography, and pathological indices were monitored in both groups. Gene sequencing was performed on the left atria to search for differentially expressed genes. Rat atrial fibroblasts were selected for further mechanism exploration. We chose TGF-β to stimulate fibroblasts to mimic the process of fibrosis in vivo, and then administered FGFR inhibitors to explore the downstream molecular mechanisms. Results Systolic blood pressure and creatinine were elevated in the CKD group. Compared with the SHAM group, the incidence of AF was significantly higher, left atrial diameter was significantly larger, and epicardial electrical markers showed that left atrial electrical conduction velocity was significantly slower and conduction heterogeneity was significantly increased in the CKD group. Pathologic staining of the left atrium showed significant fibrosis in the CKD group. Consistent with previous findings, FGF23 was significantly elevated in CKD rats. Transcriptomic sequencing revealed that FGFR4 expression was significantly upregulated in the left atrium of CKD rats, The results in rat atrial fibroblasts showed that blocking FGFR4 expression inhibited TGF-β-induced fibrosis and was mediated by the AKT pathway. Conclusions The mechanism of CKD-induced AF is that CKD promotes both structural and electrical remodeling of the atria. Further investigation of its possible downstream molecules revealed that elevated FGF23 in the CKD circulation promotes the development of atrial fibrosis by binding to FGFR4 through the AKT pathway.

Causal association of serum calcium, phosphate, vitamin D, parathyroid hormone, and FGF23 with the risk of aortic stenosis

Abstract Aim Disorders of mineral metabolism, including elevated levels of serum calcium, phosphate, 25-hydroxyvitamin D (25OH-VitD), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23), have been reported in patients with calcific aortic valve stenosis (CAVS). However, evidence of the causal role of mineral metabolism in CAVS is still lacking. We aimed to investigate the causality between mineral metabolism and CAVS. Methods A systematic pipeline combining Mendelian randomization (MR), Steiger directionality test, colocalization analysis, protein-protein network, and enrichment analysis was applied to investigate the causal effect. Genome-wide association study (GWAS) and protein quantitative trait loci data for mineral metabolism markers were extracted from large-scale meta-analyses. Summary statistics for CAVS were obtained from two independent GWAS datasets as discovery and replication cohorts (n=374,277 and 653,867). Results In MR analysis, genetic mimicry of serum FGF23 elevation was associated with increased CAVS risk [ORdiscovery=3.081 (1.649-5.760), Pdiscovery=4.21×10-4; ORreplication=2.280 (1.461-3.558), Preplication=2.82×10-4] without evidence of reverse causation (Psteiger=7.21×10-98). Strong colocalisation association with CAVS was observed for FGF23 expression in the blood (PP.H4 = 0.96). Additionally, we identified some protein-protein interactions between FGF23 and known CAVS causative genes. Serum calcium, phosphate, 25OH-VitD, and PTH failed to show causal effects on CAVS at Bonferroni-corrected significance (all P>0.05/5=0.01). Conclusions Elevated serum FGF23 level is a causal risk factor for CAVS, and its mechanism of action in CAVS development may be independent of its function in regulating mineral metabolism. Hence, FGF23 may serve as a circulating marker and a promising preventive target for CAVS, warranting further investigation.

Plain language summary: an analysis of the safety of futibatinib treatment in people with different types of cancer.

Researchers combined information from three separate phase 1 and 2 clinical trials, including over 400 people who had one of 33 different cancer types and who all received futibatinib in their clinical trial. This type of study is called a pooled analysis. Futibatinib is taken orally (by mouth) as a tablet and works by reducing the activity of a group of proteins called fibroblast growth factor receptors (FGFRs). FGFRs drive the growth of some cancers, especially cancer cells with changes in FGFR genes that make the proteins more active. Researchers wanted to look at how common some side effects were in people treated with futibatinib, how soon the side effects happened after taking futibatinib, and how they could be managed. Researchers also wanted to provide recommendations to other health care professionals on how to manage these side effects in people with cancer. In this analysis, the researchers focused on side effects that they had seen in previously completed trials of futibatinib. Overall, futibatinib was safe and tolerable. Most people (82%) had a high phosphate level in their blood (hyperphosphatemia), 27% had nail disorders, 27% had liver side effects (changes in liver-related laboratory tests), 19% had a sore mouth (stomatitis), 13% had hand-foot syndrome (palmar-plantar erythrodysesthesia syndrome), 9% had a rash, 8% developed changes in the back of the eye (retinal disorders), and 4% of people developed cataracts. Most side effects were mild/moderate and reversible. The median time it took from starting treatment to experiencing a severe side effect ranged from 9days (hyperphosphatemia) to 125days (cataracts). Some side effects tended to occur early, while others developed later. Only 2% of people stopped taking futibatinib due to treatment-related side effects, and futibatinib caused no deaths. The side effects from taking futibatinib were manageable and similar in people with different types of cancer. To fully understand the safety of futibatinib, researchers will need to look at what side effects are reported in people taking futibatinib over a longer time in the real-world setting (outside of clinical trials).

Growth plate closure and therapeutic interventions.

Height gains result from longitudinal bone growth, which is largely dependent on chondrocyte differentiation and proliferation within the growth plates of long bones. The growth plate, that is, the epiphyseal plate, is divided into resting, proliferative, and hypertrophic zones according to chondrocyte characteristics. The differentiation poten-tial of progenitor cells in the resting zone, continuous capacity for chondrocyte differentiation and proliferation within the proliferative zone, timely replacement by osteocytes, and calcification in the hypertrophic zone are the 3 main factors controlling longitudinal bone growth. Upon ade quate longitudinal bone growth, growth plate senescence limits human body height. During growth plate senescence, progenitor cells within the resting zone are deplet ed, proliferative chondrocyte numbers de crease, and hypertrophic chondrocyte number and size decrease. After senescence, hypertrophic chondrocytes are replaced by osteocytes, the extracellular matrix is calcified and va-scularized, the growth plate is closed, and longitudinal bone growth is complete. To date, go nadotropin-releasing hormone analogs, aromatase inhi bitors, C-type natriuretic peptide analogs, and fibroblast growth factor receptor 3 inhibitors have been studied or used as therapeutic interv-entions to delay growth plate closure. Complex networks of cellular, genetic, paracrine, and endocrine signals are involved in growth plate closure. However, the detailed mechanisms of this process remain unclear. Further eluci-dation of these mechanisms will enable the development of new thera peutic modalities for the treatment of short stature, precocious puberty, and skeletal dysplasia.

Assessment of experimental circulating biomarkers in volume and pressure overload: insights from a cohort study

Abstract Introduction Experimental biomarkers including Angiopoietin-2 (ANG2), bone morphogenetic protein 10 (BMP10), fibroblast growth factor 23 (FGF23), and insulin-like growth factor-binding protein 7 (IGFBP7) are hypothesized to reflect cardiac pathophysiological processes that are potentially present in adverse cardiac remodeling in volume or pressure overload. This study aims to elucidate the relationship between these circulating biomarkers and the presence of hemodynamically significant pressure or volume overload and adverse outcomes and compare it to N-terminal pro B-type natriuretic peptide (NT-proBNP). Methods We studied the association between the four experimental circulating biomarkers in patients with pressure or volume overload with reference to none/mild valvular disease in N=1302 of an observational outpatient cardiology cohort. The median age was 63.0 (25th/75th quartile 51.5, 71.4) years, 445 (34.2%) were women. Circulating biomarkers were quantified using a novel antibody-based method. Logistic regression models with cox regression plots were employed to assess the association of each biomarker with the severity of valve disease concerning volume or pressure overload, adjusted for age and sex. Results In the overall population, elevated levels of ANG2, BMP10, FGF23 and IGFB7 were positively associated with the presence of significant volume overload (ANG2: Odds ratio (OR) 1.26 (95% confidence interval (CI) 1.17-1.35), p<0.001; BMP10: OR 2.57 (CI 1.89-3.48), p<0.001; FGF23: OR 1.51 (CI 1.14-1.20), p=0.004; IGFBP7: OR 1.39 (CI 1.14-1.69), p=0.001, NT-proBNP: OR 1.69 (CI 1.47-1.95), p<0.001). No statistically significant association between circulating biomarkers and pressure overload was observed. Over a median follow-up of 4 years, 31 (20.1%) participants died in the group of volume overload and 9 (40.9%) individuals in the group of pressure overload. After multivariable-adjustment, elevated levels of BMP 10 showed a borderline association with an increased risk of all-cause mortality in individuals with volume overload compared to none/mild valvular disease: hazard ratio (HR) 1.51 (CI 0.96- 2.38), p=0.075. Higher concentrations of all biomarkers were predictive of all-cause mortality for both individuals with volume overload and those with none/mild valvular disease (ANG2: HR 3.72 (CI 1.67-8.33), p=0.001; BMP10: HR 1.65 (CI 1.20-2.26), p=0.002; FGF23: HR 2.08 (CI 1.65-2.62), p<0.001; IGFBP7: HR 1.55 (CI 1.25-1.91), p<0.001; NT-proBNP: HR 1.72 (CI 1.47-2.00), p<0.001). Conclusions This study demonstrates that circulating biomarkers involved in distinct pathophysiological pathways of inflammation, fibrosis and calcification are elevated in patients with hemodynamically significant volume overload. Since they are also related to mortality, their clinical role needs to be explored further, also in context with the routine biomarker NT-proBNP.

FGFR2 in the Development and Progression of Cutaneous Squamous Cell Cancer.

Cutaneous squamous cell carcinoma (cSCC) is an increasingly common malignancy of the skin and the leading cause of death from skin cancer in adults over the age of 85. Fibroblast growth factor receptor 2 (FGFR2) has been identified as an important effector of signaling pathways that lead to the growth and development of cSCC. In recent years, there have been numerous studies evaluating the role FGFR2 plays in multiple cancers, its contribution to resistance to anticancer therapy, and new drugs that may be used to inhibit FGFR2. This review will provide an overview of our current understanding of FGFR2 and potential mechanisms in which we can target FGFR2 in cSCC. The goals of this review are the following: (1) to highlight our current knowledge of the role of FGFR2 in healthy skin and contrast this with its role in the development of cancer; (2) to further explain the specific molecular mechanisms that FGFR2 uses to promote tumorigenesis; (3) to describe how FGFR2 contributes to more invasive disease; (4) to describe its immunosuppressive effects in skin; and (5) to evaluate its effect on current anticancer therapy and discuss therapies on the horizon to target FGFR2 related malignancy.

Tasurgratinib in patients with cholangiocarcinoma or gastric cancer: Expansion part of the first-in-human phase I study.

Fibroblast growth factor receptors (FGFRs) are a highly conserved family of transmembrane receptor tyrosine kinases with multiple roles in the regulation of key cellular processes. Specific FGFR mutations have been observed in several types of cancers, including gastric carcinoma and cholangiocarcinoma. Dose escalation data of 24 Japanese patients with solid tumors treated with Tasurgratinib (previously known as E7090), a potent, selective FGFR1-3 inhibitor, was reported in a phase I, first-in-human, single-center study. Based on the safety, pharmacokinetic, and pharmacodynamic profiles observed in this study, the recommended dose of 140 mg once daily was selected for the expansion part (Part 2), a multicenter expansion of the dose-finding study restricted to patients with tumors harboring FGFR gene alterations. Safety and preliminary efficacy were assessed in Part 2. Pharmacodynamic pharmacogenomic markers (serum phosphate, FGF23, and 1,25-(OH)2-vitamin D, circulating tumor DNA) and pharmacokinetic profiles were also evaluated. A total of 16 patients were enrolled in Part 2, six with cholangiocarcinoma and 10 with gastric cancer. The most common treatment-emergent adverse events were hyperphosphatemia, palmar-plantar erythrodysesthesia syndrome, and paronychia. Five partial responses (83.3%) in cholangiocarcinoma patients and one partial response (11.1%) in gastric cancer patients were observed; median progression-free survival was 8.26 months (95% confidence interval [CI] 3.84, not evaluable [NE]) and 3.25 months (95% CI 0.95, 4.86), and overall survival was 22.49 months (95% CI 6.37, NE) and 4.27 months (95% CI 2.23, 7.95), respectively, in the two groups. In conclusion, Tasurgratinib 140 mg has a tolerable safety profile with good clinical efficacy in patients with cholangiocarcinoma harboring FGFR2 gene rearrangements.

Overexpression of Fibroblast Growth Factor 8 Is a Predictor of Impaired Survival in Esophageal Squamous Cell Carcinoma and Correlates with ALK/EML4 Alteration

FGF8, ALK, and EML4 have been identified as promising biomarkers in a number of malignancies. The aim of this study was to examine the prognostic role of FGF8, ALK, and EML4 in esophageal squamous cell carcinoma (ESCC). Methods: Consecutive patients with ESCC who underwent upfront resection were included in this study. ALK and EML4 gene status was evaluated by fluorescence in situ hybridization (FISH) using a triple-color break-apart single-fusion probe and a probe against 2p11. FGF8, ALK, and EML4 protein expression was determined by immunohistochemistry. Results: A total of 122 patients were included in this study. Multivariate analysis revealed that FGF8 overexpression is an independent negative prognostic factor for patients’ overall survival (OS) (p = 0.04). Furthermore, a significant correlation between the expression of FGF8, and ALK (p = 0.04) and EML4 (p = 0.01) alteration was found. Conclusions: FGF8 overexpression is an adverse independent prognostic factor in patients with upfront resected ESCC. Furthermore, FGF8 expression significantly correlates with ALK and EML4 amplification and may therefore qualify as a future therapeutic target.

Supplementation of 3'-Sialyllactose During the Growth Period Improves Learning and Memory Development in Mice.

3'-Sialyllactose (3'-SL), a major acidic oligosaccharide found in human milk, has been investigated to improve cognitive-enhancing effects with 3 weeks old C57BL/6 mice by administering 3'-SL orally at a dose of 350 mg/kg/day for 6 weeks. Behavioral tests indicated that supplementation with 3'-SL promoted cognitive and memory development in young mice. Through interaction network and coenrichment analysis, nine differentially expressed genes (DEGs) related to memory and cognition were identified and localized in the hippocampal tissue of mice. The intervention of 3'-SL significantly increased the metabolism of sialic acid in mouse hippocampal tissue and promoted the expression of learning-related genes (p < 0.05). Notably, it increased the expression of genes associated with neural cell adhesion molecule (NCAM, p < 0.05), glutamate receptors, and fibroblast growth factor receptor (FGFR, p < 0.05). This suggests that 3'-SL may elevate polysialylated NCAM (PSA-NCAM) levels, which could subsequently interact with FGFR and glutamate receptors, thereby enhancing synaptic growth and plasticity. Additionally, 3'-SL altered the composition of the mouse intestinal microbiota. The synergistic action of gut microbiota and intestinal sialidase promoted the production of free sialic acid, providing essential nutritional elements for the development of the brain's nervous system. In conclusion, our findings provide new insights into the promoting effect of 3'-SL on cognitive development in growing mice and elucidate its molecular mechanisms.

Compromised macrophages contribute to progression of MASH to hepatocellular carcinoma in FGF21KO mice.

Metabolic dysfunction-associated steatohepatitis is well accepted as a potential precursor of hepatocellular carcinoma. Previously, we reported that fibroblast growth factor 21 (FGF21) revealed a novel anti-inflammatory activity via inhibiting the TLR4-IL-17A signaling, which could be a potential anticarcinogenetic mechanism to prevent to MASH-HCC transition. Here, we set out to determine whether FGF21 has a major impact on Kupffer cells' (KCs) ability during MASH-HCC transition. We found aberrant hepatic FGF21 and KC pool in human MASH-HCC. Lack of FGF21 up-regulated ALOX15, which converted the oxidized fatty acids to induce excessive KC death and mobilization of monocyte-derived macrophages (MoMFs) for KC replacement. Lack of FGF21 oversupplied free fatty acids for sphingosine-1-phosphate (S1P) cascade synthesis to mediate MASH-HCC transition via S1P-YAP signaling and cross-talk between tumor cells and macrophages. In conclusion, lack of FGF21 accelerated MASH-HCC transition via the S1P-AP signaling. Compromised MoMFs could present as tumor-associated macrophage phenotype rendering tumor immune microenvironment for MASH-HCC transition.

Structural analysis of the stable form of fibroblast growth factor 2 – FGF2-STAB

Fibroblast growth factor 2 (FGF2) is a signaling protein that plays a significant role in tissue development and repair. FGF2 binds to fibroblast growth factor receptors (FGFRs) alongside its co-factor heparin, which protects FGF2 from degradation. The binding between FGF2 and FGFRs induces intracellular signaling pathways such as RAS-MAPK, PI3K-AKT, and STAT. FGF2 has strong potential for application in cell culturing, wound healing, and cosmetics but the potential is severely limited by its low protein stability. The thermostable variant FGF2-STAB was constructed by computer-assisted protein engineering to overcome the natural limitation of FGF2. Previously reported characterization of FGF2-STAB revealed an enhanced ability to induce MAP/ERK signaling while having a lower dependence on heparin when compared with FGF2-wt. Here we report the crystal structure of FGF2-STAB solved at 1.3 Å resolution. Protein stabilization is achieved by newly formed hydrophobic interactions, polar contacts, and one additional hydrogen bond. The overall structure of FGF2-STAB is similar to FGF2-wt and does not reveal information on the experimentally observed lower dependence on heparin. A noticeable difference in flexibility in the receptor binding region can explain the differences in signaling between FGF2-STAB and its wild-type counterpart. Our structural analysis provided molecular insights into the stabilization and unique biological properties of FGF2-STAB.

Low-Energy extracorporeal shockwave therapy improves locomotor functions, tissue regeneration and modulating the inflammation induced FGF1 and FGF2 signaling to protect damaged tissue in spinal cord injury of rat model: An experimental animal study.

Spinal cord injury (SCI) is a debilitating condition that results in severe motor function impairments. Current therapeutic options remain limited, underscoring the need for novel treatments. Extracorporeal shockwave therapy (ESWT) has emerged as a promising noninvasive approach for treating musculoskeletal disorders and nerve regeneration. This study explored the effects of low-energy ESWT on locomotor function, tissue regeneration, inflammation, and mitochondrial function in a rat SCI model. Experiments were performed using locomotor function assays, CatWalk gait analysis, histopathological examination, immunohistochemical and immunofluorescence staining. The findings demonstrated that low-energy ESWT had a dose-dependent effect, with three treatment sessions (ESWT3) showing superior outcomes compared to a single session. ESWT3 significantly improved motor functions (run patterns, run average speed, and maximum variation, as well as the Basso, Beattie, and Bresnahan (BBB) score) and promoted tissue regeneration while reducing inflammation. ESWT3 significantly decreased levels of IL-1β, IL6 and macrophages (CD68) while increasing leucocyte (CD45) infiltration. Additionally, ESWT3 upregulated NueN and mitofusin 2 (MFN2), suggesting enhanced neuronal health and mitochondrial function. Moreover, ESWT3 modulated the expression of fibroblast growth factor 1 (FGF1), FGF2, their receptor FGFR1 and phosphorylation of ERK, aiding tissue repair and regeneration in SCI. This study highlights the potential of low-energy ESWT as an effective noninvasive treatment for SCI, demonstrating significant improvements in motor recovery, tissue regeneration, anti-inflammatory effects, and mitochondrial protection. These findings provide valuable insights into the mechanisms of ESWT and its therapeutic application for SCI recovery.

Cataracts Associated With Fibroblast Growth Factor Receptor Inhibitors for Cholangiocarcinoma

Since fibroblast growth factor receptor inhibitors (FGFRi) are used for treatment of intrahepatic cholangiocarcinoma (iCCA), understanding potential complications following longer-term use in clinical practice settings is warranted. This study describes cataract formation or progression as a complication of FGFRi use for the treatment of iCCA, even after treatment discontinuation. To describe cases of cataract formation or worsening in patients with iCCA treated with FGFRi and to characterize the ophthalmologic features, risk factors, and outcomes for FGFRi-associated cataracts. This retrospective case series study used data from patients with iCCA harboring FGFR2 aberrations who received FGFRi in clinical trials or as standard therapy from the University of California, San Francisco, Hepatobiliary Tissue Bank and Registry. Data were collected from patient visits between February 2015 and October 2021, and this retrospective investigation was conducted from September 6, 2022, to May 4, 2023. Data analysis was conducted from May 5, 2023, to September 6, 2023. Use of an FGFRi for the treatment of iCCA. The primary outcome was designated as development of a new or worsening cataract after FGFRi initiation. Statistical analysis for the association between cataract formation and clinical covariates was performed using unpaired t tests and Fisher exact tests. A single bivariate logistic regression model was used to examine total duration of FGFRi therapy and age at the conclusion of FGFRi therapy as predictors of cataract development. A total of 18 patients were included in the study; median (range) patient age was 54 (27-81) years, and 13 patients (72%) were female. Nine patients (50%) developed a cataract or had cataract progression in at least 1 eye after initiation of FGFRi. Of 17 eyes with cataract, 8 eyes (47%) required cataract surgery. One patient rapidly developed a cataract associated with phacomorphic glaucoma, which required urgent surgery. The median (range) time to cataract onset or worsening from initiation of FGFRi was approximately 18 (1-23) months. Five of 9 patients (56%) who developed cataracts or had cataract progression were diagnosed with new or worsening cataracts after discontinuation of FGFRi. Patients who developed cataracts had longer median (range) duration of FGFRi treatment compared with patients who did not develop cataracts (13 months [2-26] vs 5 months [1-11]; odds ratio, 1.01; 95% CI, 1.00-1.02; P = .02). While this retrospective case series study cannot prove cause and effect conclusively due to the study design, study results highlight cataract formation or progression as a potential adverse effect of FGFRi therapy, supporting consideration of periodic eye examinations in patients who have received this treatment.

Preparation and characterization of bovine dental pulp-derived extracellular matrix hydrogel for regenerative endodontic applications: an in vitro study

BackgroundThe use of biological scaffolds in regenerative endodontics has gained much attention in recent years. The search for a new biomimetic scaffold that contains tissue-specific cell homing factors could lead to more predictable tissue regeneration. The aim of this study was to prepare and characterize decellularized bovine dental pulp-derived extracellular matrix (P-ECM) hydrogels for regenerative endodontic applications.MethodsFreshly extracted bovine molar teeth were collected. Bovine dental pulp tissues were harvested, and stored at -40º C. For decellularization, a 5-day protocol was implemented incorporating trypsin/EDTA, deionized water and DNase treatment. Decellularization was evaluated by DNA quantification and histological examination to assess collagen and glycosaminoglycans (GAGs) content. This was followed by the preparation of P-ECM hydrogel alone or combined with hyaluronic acid gel (P-ECM + HA). The fabricated scaffolds were then characterized using protein quantification, hydrogel topology and porosity, biodegradability, and growth factor content using Enzyme-linked immunosorbent assay (ELISA): transforming growth factor beta-1(TGF-β1), basic fibroblast growth factor (bFGF), bone morphogenetic protein 2 (BMP-2) and vascular endothelial growth factor (VEGF).ResultsDecellularization was histologically confirmed, and DNA content was below (50 ng/mg tissue). P-ECM hydrogel was prepared with a final ECM concentration of 3.00 mg/ml while P-ECM + HA hydrogel was prepared with a final ECM concentration of 1.5 mg/ml. Total protein content in P-ECM hydrogel was found to be (439.0 ± 123.4 µg/µl). P-ECM + HA showed sustained protein release while the P-ECM group showed gradual decreasing release. Degradation was higher in P-ECM + HA which had a significantly larger fiber diameter, while P-ECM had a larger pore area percentage. ELISA confirmed the retention and release of growth factors where P-ECM hydrogel had higher BMP-2 release, while P-ECM + HA had higher release of TGF-β1, bFGF, and VEGF.ConclusionsBoth P-ECM and P-ECM + HA retained their bioactive properties demonstrating a potential role as functionalized scaffolds for regenerative endodontic procedures.