Search Results (47)

FGFRL1 (fibroblast growth factor receptor-like 1) is a newly identified member of the FGFR family. Its extracellular domain resembles the four conventional FGFRs, while its intracellular part lacks the tyrosine kinase domain necessary for FGF-mediated signal transduction. At first, it was only considered a “decoy receptor”. However, recent studies have demonstrated that FGFRL1 is a multifunctional molecule involved in prenatal and postnatal growth of cartilage and osteogenesis, the development of embryonic kidney and diaphragm, the modulation of cellular biological behaviors, and cell signal transduction. The functional abnormalities of FGFRL1 contribute to human diseases including congenital disease, hypertension, osteoporosis, degenerative diseases of the central nervous system, and different kinds of tumors. The present review summarizes the research progress of FGFRL1, especially its subcellular location, molecular function, and associated human disease. These data may offer valuable resources for further studying the molecular function of FGFRL1 and disclosing the mechanism of its related human diseases. Full article

Titanium is widely recognized for its biocompatibility and utility in maxillofacial and orthopedic surgery; however, its influence on bone remodeling biomarkers remains underexplored. This study investigates the effects of uncoated titanium plates on both the growth factors and diacylglycerols (DAGs) in the periostea of the maxilla and mandible, as DAG signaling is an essential secondary messenger molecule involved in intracellular signaling connected to various growth factors. The study group comprised 20 patients undergoing bimaxillary osteotomies using miniplates and screws made of Ti6Al4V titanium, from whom bone fixations were removed, while the control group included 20 patients operated on for dentofacial deformities (before the insertion of titanium fixations). Diacylglycerol levels in the serum and periosteum were analyzed using tandem mass spectrometry coupled with ultra-high performance liquid chromatography. Growth factors in the periosteum were measured via ELISA with commercially available assay kits. Our findings demonstrate a significant reduction in growth factors, including IGF-1, PDGF, and FGF-23, alongside decreased total DAG levels, suggesting titanium plate stabilization may modulate bone remodeling dynamics. Notably, while overall DAG levels declined, specific DAG species such as C16:0/16:0 and C18:0/18:0 were elevated, whereas polyunsaturated DAGs showed reductions, indicating selective regulation of lipid signaling pathways. Correlation analyses highlighted complex interactions between growth factors and DAGs, with distinct regional differences observed in the mandibular and maxillary periostea. These alterations may result from chronic titanium exposure, potentially inducing a low-grade immune response or modifying the local biochemical environment. This study emphasizes the need for further research into the long-term effects of titanium implants, particularly their influence on lipid metabolism, growth factor dynamics, and bone healing. Full article

Background: Despite significant strides in anti-melanoma therapies, resistance and recurrence remain major challenges. A deeper understanding of the underlying biology of these challenges is necessary for developing more effective treatment paradigms. Methods: Melanoma single-cell data were retrieved from the Broad Single Cell Portal (SCP11). High-dimensional weighted gene co-expression network analysis (hdWGCNA), CellChat, and ligand-receptor relative crosstalk (RC) scoring were employed to evaluate intercellular and intracellular signaling. The prognostic value of key regulatory genes was assessed via Kaplan-Meier (KM) survival analysis using the ‘SKCM-TCGA’ dataset. Results: Twenty-seven (27) gene co-expression modules were identified via hdWGCNA. Notable findings include NRAS Q61L melanomas being enriched for modules involving C19orf10 and ARF4, while BRAF V600E melanomas were enriched for modules involving ALAS1 and MYO1B. Additionally, CellChat analysis highlighted several dominant signaling pathways, namely MHC-II, CD99, and Collagen-receptor signaling, with numerous significant ligand-receptor interactions from melanocytes, including CD99-CD99 communications with cancer-associated fibroblasts, endothelial cells, NK cells, and T-cells. KM analysis revealed that higher expression of SELL, BTLA, IL2RG, PDGFA, CLDN11, ITGB3, and SPN improved overall survival, while higher FGF5 expression correlated with worse survival. Protein-protein interaction network analysis further indicated significant interconnectivity among the identified prognostic genes. Conclusions: Overall, these insights underscore critical immune interactions and potential therapeutic targets to combat melanoma resistance, paving the way for more personalized and effective treatment strategies. Full article

Amniotic fluid is a complex and dynamic biological matrix that surrounds the fetus during the pregnancy. From this fluid, is possible to isolate various cell types with particular interest directed towards stem cells (AF-SCs). These cells are highly appealing due to their numerous potential applications in the field of regenerative medicine for tissues and organs as well as for treating conditions such as traumatic or ischemic injuries to the nervous system, myocardial infarction, or cancer. AF-SCs, when subcultured in the presence of basic Fibroblast Growth Factor (bFGF), have been shown to survive and migrate when transplanted into the striatum of the rat brain, exhibiting behavior characteristics of neuronal/glial progenitor cells. In this work, we performed an electrophysiological characterization to ascertain the propensity of AF-SCs to differentiate into glial and neuronal cells by bFGF. By using patch clamp technique we characterized a fibroblast-like morphology that display a barium-sensitive inward-rectifying potassium current (Kir) and calcium-activated potassium currents (KCa). The electrophysiological and calcium dynamics of histamine, a marker of undifferentiated neural progenitors, was further studied. Histamine promoted intracellular calcium increase by Fura-2 recording and calcium-activated potassium current activation with a similar temporal profile in AF-SC. The data presented in this paper ultimately confirm the expression in AF-SCs of the Kir and KCa currents, also showing regulation by endogenous stimuli such as histamine for the latter. Full article

Autophagy is a critical biological process in which cytoplasmic components are sequestered in autophagosomes and degraded in lysosomes. This highly conserved pathway controls intracellular recycling and is required for cellular homeostasis, as well as the correct functioning of a variety of cellular differentiation programs, including cardiomyocyte differentiation. By decreasing oxidative stress and promoting energy balance, autophagy is triggered during differentiation to carry out essential cellular remodeling, such as protein turnover and lysosomal degradation of organelles. When it comes to controlling cardiac differentiation, the crosstalk between autophagy and other signaling networks such as fibroblast growth factor (FGF), Wnt, Notch, and bone morphogenetic proteins (BMPs) is essential, yet the interaction between autophagy and epigenetic controls remains poorly understood. Numerous studies have shown that modulating autophagy and precisely regulating it can improve cardiac differentiation, which can serve as a viable strategy for generating mature cardiac cells. These findings suggest that autophagy should be studied further during cardiac differentiation. The purpose of this review article is not only to discuss the relationship between autophagy and other signaling pathways that are active during the differentiation of cardiomyocytes but also to highlight the importance of manipulating autophagy to produce fully mature cardiomyocytes, which is a tough challenge. Full article

Fibroblast growth factors (FGFs) have been widely studied by virtue of their ability to regulate many essential cellular activities, including proliferation, survival, migration, differentiation and metabolism. Recently, these molecules have emerged as the key components in forming the intricate connections within the nervous system. FGF and FGF receptor (FGFR) signaling pathways play important roles in axon guidance as axons navigate toward their synaptic targets. This review offers a current account of axonal navigation functions performed by FGFs, which operate as chemoattractants and/or chemorepellents in different circumstances. Meanwhile, detailed mechanisms behind the axon guidance process are elaborated, which are related to intracellular signaling integration and cytoskeleton dynamics. Full article

Fibroblast growth factors (FGFs) encode a large family of growth factor proteins that activate several intracellular signaling pathways to control diverse physiological functions. The human genome encodes 22 FGFs that share a high sequence and structural homology with those of other vertebrates. FGFs orchestrate diverse biological functions by regulating cellular differentiation, proliferation, and migration. Dysregulated FGF signaling may contribute to several pathological conditions, including cancer. Notably, FGFs exhibit wide functional diversity among different vertebrates spatiotemporally. A comparative study of FGF receptor ligands and their diverse roles in vertebrates ranging from embryonic development to pathological conditions may expand our understanding of FGF. Moreover, targeting diverse FGF signals requires knowledge regarding their structural and functional heterogeneity among vertebrates. This study summarizes the current understanding of human FGF signals and correlates them with those in mouse and Xenopus models, thereby facilitating the identification of therapeutic targets for various human disorders. Full article

Oocyte maturation is a critical step in the completion of female gametogenesis in the ovary; thus, for subsequent fertilization and embryogenesis. Vitrification of embryo also has been shown to be closely associated with oocyte maturation. To improve the quality and developmental potential of bovine oocytes derived from in vitro maturation (IVM), Pre-IVM with C-type natriuretic peptide (CNP), melatonin (MT) and in combination, IGF1, FGF2, LIF (FLI) were supplemented in the IVM medium. In this current study, we cultured bovine oocytes in Pre-IVM with CNP for 6 h before transferring them to the IVM medium supplemented with MT and FLI. The developmental potential of bovine oocytes was then investigated by measuring the reactive oxygen species (ROS), the intracellular glutathione (GSH) and ATP levels, the transzonal projections (TZP), the mitochondrial membrane potential (ΔΨm), cacline-AM, and the expression of related genes (cumulus cells (CCs), oocytes, blastocysts). The results revealed that oocytes treated with a combination of CNP, MT, and FLI had dramatically improved the percentage of oocytes developed to blastocyst, ATP content, GSH levels, TZP intensity, the ΔΨm, cacline-AM fluorescence intensity, and considerably reduced ROS levels of oocytes. Furthermore, the survival rate and the hatched rate after vitrification of the CNP+MT+FLI group were significantly higher than those other groups. Thus, we speculated that CNP+MT+FLI increases the IVM of bovine oocytes. In conclusion, our findings deepen our understanding and provide new perspectives on targeting the combination of CNP, MT and FLI to enhance the quality and developmental potential of bovine oocytes. Full article

Neurulation is a crucial process in the formation of the central nervous system (CNS), which begins with the folding and fusion of the neural plate, leading to the generation of the neural tube and subsequent development of the brain and spinal cord. Environmental and genetic factors that interfere with the neurulation process promote neural tube defects (NTDs). Connexins (Cxs) are transmembrane proteins that form gap junctions (GJs) and hemichannels (HCs) in vertebrates, allowing cell-cell (GJ) or paracrine (HCs) communication through the release of ATP, glutamate, and NAD⁺; regulating processes such as cell migration and synaptic transmission. Changes in the state of phosphorylation and/or the intracellular redox potential activate the opening of HCs in different cell types. Cxs such as Cx43 and Cx32 have been associated with proliferation and migration at different stages of CNS development. Here, using molecular and cellular biology techniques (permeability), we demonstrate the expression and functionality of HCs-Cxs, including Cx46 and Cx32, which are associated with the release of ATP during the neurulation process in Xenopus laevis. Furthermore, applications of FGF2 and/or changes in intracellular redox potentials (DTT), well known HCs-Cxs modulators, transiently regulated the ATP release in our model. Importantly, the blockade of HCs-Cxs by carbenoxolone (CBX) and enoxolone (ENX) reduced ATP release with a concomitant formation of NTDs. We propose two possible and highly conserved binding sites (N and E) in Cx46 that may mediate the pharmacological effect of CBX and ENX on the formation of NTDs. In summary, our results highlight the importance of ATP release mediated by HCs-Cxs during neurulation. Full article

NMR-based approaches play a pivotal role in providing insight into molecular recognition mechanisms, affording the required atomic-level description and enabling the identification of promising inhibitors of protein–protein interactions. The aberrant activation of the fibroblast growth factor 2 (FGF2)/fibroblast growth factor receptor (FGFR) signaling pathway drives several pathologies, including cancer development, metastasis formation, resistance to therapy, angiogenesis-driven pathologies, vascular diseases, and viral infections. Most FGFR inhibitors targeting the intracellular ATP binding pocket of FGFR have adverse effects, such as limited specificity and relevant toxicity. A viable alternative is represented by targeting the FGF/FGFR extracellular interactions. We previously identified a few small-molecule inhibitors acting extracellularly, targeting FGFR or FGF. We have now built a small library of natural and synthetic molecules that potentially act as inhibitors of FGF2/FGFR interactions to improve our understanding of the molecular mechanisms of inhibitory activity. Here, we provide a comparative analysis of the interaction mode of small molecules with the FGF2/FGFR complex and the single protein domains. DOSY and residue-level NMR analysis afforded insights into the capability of the potential inhibitors to destabilize complex formation, highlighting different mechanisms of inhibition of FGF2-induced cell proliferation. Full article

Aging has been recently reported to promote lung cancer initiation and progression. Senescent fibroblasts gain a cancer-associated fibroblast (CAF) phenotype, and exert a powerful influence on cancer behavior, such as tumor cell growth and metastasis. However, mechanisms linking fibroblast senescence with CAF activation remain poorly understood. Our study shows that senescent fibroblasts displayed CAF properties, including the highly expressed CAF markers, α-SMA and Vimentin, and CAF-specific factors, CXCL12, FGF10, IL6 and COL1A1, which significantly increased collagen contractile activity and promoted the migration and invasion of lung cancer cells, H1299 and A549. We were further able to show that CAF characteristics in senescent fibroblasts could be regulated by the Stat3 pathway. Intracellular ROS accumulation activates the Stat3 pathway during senescence. Thus, our findings indicate that senescent fibroblasts mediate a CAF function with the Stat3 pathway. We further propose a novel Stat3 dependent targetable mechanism, which is instrumental in mediating the migration and invasion of lung cancer cells. Full article

Cushing’s syndrome, or hypercortisolism (HC), a common endocrinopathy in adult dogs, is caused by chronic hypercortisolemia. Among different metabolic disorders, this syndrome is associated with enhanced subcutaneous lipolysis and visceral adiposity. However, effects of HC in adipose tissue, especially regarding visceral adipose tissue (VAT), are still poorly understood. Herein, the transcriptomic effects of chronic HC on VAT of dogs were evaluated. For this, subcutaneously implanted ACTH-releasing pumps were used, followed by deep RNA sequencing of the canine VAT. Prolonged HC seems to affect a plethora of regulatory mechanisms in VAT of treated dogs, with 1190 differentially expressed genes (DEGs, p and FDR < 0.01) being found. The 691 downregulated DEGs were mostly associated with functional terms like cell adhesion and migration, intracellular signaling, immune response, extracellular matrix and angiogenesis. Treatment also appeared to modulate local glucocorticoid and insulin signaling and hormonal sensitivity, and several factors, e.g., TIMP4, FGF1, CCR2, CXCR4 and HSD11B1/2, were identified as possible important players in the glucocorticoid-related expansion of VAT. Modulation of their function during chronic HC might present interesting targets for further clinical studies. Similarities in the effects of chronic HC on VAT of dogs and humans are highlighted. Full article

Glycogen synthase kinase 3β (GSK3) is a multifaceted serine/threonine (S/T) kinase expressed in all eukaryotic cells. GSK3β is highly enriched in neurons in the central nervous system where it acts as a central hub for intracellular signaling downstream of receptors critical for neuronal function. Unlike other kinases, GSK3β is constitutively active, and its modulation mainly involves inhibition via upstream regulatory pathways rather than increased activation. Through an intricate converging signaling system, a fine-tuned balance of active and inactive GSK3β acts as a central point for the phosphorylation of numerous primed and unprimed substrates. Although the full range of molecular targets is still unknown, recent results show that voltage-gated ion channels are among the downstream targets of GSK3β. Here, we discuss the direct and indirect mechanisms by which GSK3β phosphorylates voltage-gated Na⁺ channels (Na_v1.2 and Na_v1.6) and voltage-gated K⁺ channels (K_v4 and K_v7) and their physiological effects on intrinsic excitability, neuronal plasticity, and behavior. We also present evidence for how unbalanced GSK3β activity can lead to maladaptive plasticity that ultimately renders neuronal circuitry more vulnerable, increasing the risk for developing neuropsychiatric disorders. In conclusion, GSK3β-dependent modulation of voltage-gated ion channels may serve as an important pharmacological target for neurotherapeutic development. Full article

During the periparturient period, dairy cows suffer drastic metabolic stress because of plasma increased non-esterified fatty acids (NEFAs) that stem from a negative energy balance. Fibroblast growth factor 21 (FGF21) is a hepatokine that activates the AMP-activated protein kinase (AMPK) signaling pathway to maintain intracellular energy balance and tissue integrity via the promotion of catabolism and the inhibition of anabolic regulation. FGF21 treatment caused a 50% reduction in triglyceride (TG) content in liver in dairy cows. However, it is not clear whether FGF21 regulates lipid metabolism in bovine liver. The purpose of this study was to evaluate the influence of FGF21 on lipid metabolism via AMPK signaling in bovine hepatocytes. The hepatocytes isolated from calves were treated with different concentrations of FGF21 or co-treated with AMPK inhibitor (BML-275). Herein, the study showed that FGF21 significantly reduced TG content in a dose–response manner and promoted very-low-density lipoprotein (VLDL) secretion via an up-regulation of the proteins (ApoB 100, ApoE and MTTP) involved in VLDL secretion. Otherwise, the genes associated with lipid transport (LDLR and CD36) and lipid oxidation (PPARGC1A, ACOX1 and CPT1A), were up-regulated following FGF21 treatment. Moreover, FGF21 treatment inhibited lipogenesis via SREBF1, ACACA, FASN and ACLY inhibition. After being co-treated with the AMPK inhibitor, FGF21-induced changes were reversed in some genes. In conclusion, these results indicate that FGF21 adaptively regulates energy metabolism for a negative impact on lipogenesis, strengthens lipid oxidation, and inhibited lipid transportation via AMPK signaling in bovine hepatocytes. The present data suggest the possibility that FGF21 has potential value in alleviating perinatal metabolic diseases in dairy cows, and specific research in vivo should be studied in more detail. Full article

In the present study, we investigated the molecular mechanisms of adenosine for its hair growth promoting effect. Adenosine stimulated the Wnt/β-catenin pathway by modulating the activity of Gsk3β in cultured human dermal papilla cells. It also activated adenosine receptor signaling, increasing intracellular cAMP level, and subsequently stimulating the cAMP mediated cellular energy metabolism. The phosphorylation of CREB, mTOR, and GSK3β was increased. Furthermore, the expression of β-catenin target genes such as Axin2, Lef1, and growth factors (bFGF, FGF7, IGF-1) was also enhanced. The inhibitor study data conducted in Wnt reporter cells and in cultured human dermal papilla cells demonstrated that adenosine stimulates Wnt/β-catenin signaling through the activation of the adenosine receptor and Gsk3β plays a critical role in transmitting the signals from the adenosine receptor to β-catenin, possibly via the Gαs/cAMP/PKA/mTOR signaling cascade. Full article