Glial Cell Line-derived Neurotrophic Factor Research Articles

Enteric neural stem cell neurogenesis by glial cell-derived neurotrophic factor in experimental Hirschsprung's disease

Enteric neural stem cell neurogenesis by glial cell-derived neurotrophic factor in experimental Hirschsprung's disease

Inhibition of GDNF-Driven Macrophage-to-Myofibroblast Transition Protects Against Colitis-Associated Intestinal Fibrosis.

Glial cell line-derived neurotrophic factor (GDNF) has been demonstrated to promote the development of liver fibrosis, but its role in intestinal fibrosis is unknown. Macrophage-to-myofibroblast transition (MMT) is an important pathway contributing to fibrosis diseases. However, whether MMT cells, characterized by co-expressing both macrophage (CD68 or F4/80) and myofibroblast (α-SMA) markers, occurs in intestinal fibrosis remain to be addressed. Here, we showed that GDNF expression and the infiltration of MMT cells in intestinal tissues from patients with fibrostenotic Crohn's disease (CD) and a mouse model of chronic dextran sodium salt-induced intestinal fibrosis were significantly increased. GDNF induced bone marrow-derived macrophages (BMDMs) differentiation into MMT cells in vitro. Mechanistically, the Src pathway was activated by GDNF stimulation and contributed to GDNF-induced MMT in BMDMs. Moreover, pharmacological inhibition of GDNF by using antibody markedly decreased the infiltration of MMT cells following the decrease of collagen deposition and α-SMA and Col1 expression in the mouse model of colitis-associated intestinal fibrosis. In conclusion, GDNF is able to induce MMT and contributes to intestinal fibrosis in the context of chronic intestinal inflammation. Pharmacological inhibition of GDNF-driven MMT might provide a novel approach for the treatment of fibrosis complication in CD.

Investigation of Phytochemical and Antidepressants Activity of Cinnamon Powder Extract

Neurodegenerative disease is the most common type of mobility issue, but unfortunately, there is now no medication that can alter the course of the disease. We don't know what causes this ailment. In mouse models of Parkinson's disease induced with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine, the oral administration of cinnamon powder and sodium benzoate may prevent the death of dopaminergic cells, dysregulation of striatal neurotransmitters, and motor impairments. The mechanisms driving its function include controlling autophagy, antioxidant effects, Parkin, DJ-1, and glial cell line-derived neurotrophic factor activation, TLR/NF-κB pathway modulation, and excessive proinflammatory response prevention. Moreover, research carried out in both laboratory and living organism settings has shown that cinnamon extracts may impact the oligomerisation and aggregation of α-synuclein. This article's goal is to discuss recent findings about this phytochemical's potential as a novel treatment for Parkinson's disease (PD). We highlight additional areas of mechanism that require investigation and possible constraints that must be overcome before this phytochemical may be used in PD trials. Neurodegenerative disease is the most common type of mobility impairment, and unfortunately, there is now no medication that can alter this disease. We don't know what causes this ailment. There has been a recent uptick in interest in medicinal plant use because of the novelty, safety, and relative affordability of this field. The characteristic flavour and aroma of cinnamon, a spice that is often used, may have neuroprotective effects on people with Parkinson's disease (PD) and other neurodegenerative diseases. The essential oils of Cinnamomum species, such as cinnamaldehyde and sodium benzoate, have shown in vitro that they can protect cells from oxidative stress, ROS generation, and autophagy dysregulation. Consequently, these oils may exert a neuroprotective effect. The in vivo evidence suggests that cinnamon powder and sodium benzoate, when administered orally to Parkinson's disease models in mice, may prevent the death of dopaminergic cells, dysregulation of striatal neurotransmitters, and motor deficits. In this essay, we will go over the latest research on this phytochemical and its potential as a novel treatment for Parkinson's disease (PD). Incorporating this phytochemical into experimental PD treatments requires further investigation into additional molecular aspects and the potential overcoming of constraints and obstacles.

Neurons enhance blood–brain barrier function via upregulating claudin-5 and VE-cadherin expression due to glial cell line-derived neurotrophic factor secretion

Blood–brain barrier (BBB) prevents neurotoxins from entering central nervous system. We aimed to establish and characterize an in vitro triple co-culture BBB model consisting of brain endothelial cells hCMEC/D3, astrocytoma U251 cells, and neuroblastoma SH-SY5Y cells. Co-culture of SH-SY5Y and U251 cells markedly enhanced claudin-5 and VE-cadherin expression in hCMEC/D3 cells, accompanied by increased transendothelial electrical resistance and decreased permeability. Conditioned medium (CM) from SH-SY5Y cells (S-CM), U251 cells (U-CM), and co-culture of SH-SY5Y and U251 cells (US-CM) also promoted claudin-5 and VE-cadherin expression. Glial cell line-derived neurotrophic factor (GDNF) levels in S-CM and US-CM were significantly higher than CMs from hCMEC/D3 and U-CM. Both GDNF and US-CM upregulated claudin-5 and VE-cadherin expression, which were attenuated by anti-GDNF antibody and GDNF signaling inhibitors. GDNF increased claudin-5 expression via the PI3K/AKT/FOXO1 and MAPK/ERK pathways. Meanwhile, GDNF promoted VE-cadherin expression by activating PI3K/AKT/ETS1 and MAPK/ERK/ETS1 signaling. The roles of GDNF in BBB integrity were validated using brain-specific Gdnf silencing mice. The developed triple co-culture BBB model was successfully applied to predict BBB permeability. In conclusion, neurons enhance BBB integrity by upregulating claudin-5 and VE-cadherin expression through GDNF secretion and established triple co-culture BBB model may be used to predict drugs’ BBB permeability.

Neurons enhance blood-brain barrier function via upregulating claudin-5 and VE-cadherin expression due to glial cell line-derived neurotrophic factor secretion.

Blood-brain barrier (BBB) prevents neurotoxins from entering central nervous system. We aimed to establish and characterize an in vitro triple co-culture BBB model consisting of brain endothelial cells hCMEC/D3, astrocytoma U251 cells, and neuroblastoma SH-SY5Y cells. Co-culture of SH-SY5Y and U251 cells markedly enhanced claudin-5 and VE-cadherin expression in hCMEC/D3 cells, accompanied by increased transendothelial electrical resistance and decreased permeability. Conditioned medium (CM) from SH-SY5Y cells (S-CM), U251 cells (U-CM), and co-culture of SH-SY5Y and U251 cells (US-CM) also promoted claudin-5 and VE-cadherin expression. Glial cell line-derived neurotrophic factor (GDNF) levels in S-CM and US-CM were significantly higher than CMs from hCMEC/D3 and U-CM. Both GDNF and US-CM upregulated claudin-5 and VE-cadherin expression, which were attenuated by anti-GDNF antibody and GDNF signaling inhibitors. GDNF increased claudin-5 expression via the PI3K/AKT/FOXO1 and MAPK/ERK pathways. Meanwhile, GDNF promoted VE-cadherin expression by activating PI3K/AKT/ETS1 and MAPK/ERK/ETS1 signaling. The roles of GDNF in BBB integrity were validated using brain-specific Gdnf silencing mice. The developed triple co-culture BBB model was successfully applied to predict BBB permeability. In conclusion, neurons enhance BBB integrity by upregulating claudin-5 and VE-cadherin expression through GDNF secretion and established triple co-culture BBB model may be used to predict drugs' BBB permeability.

Accelerated innervation of biofabricated skeletal muscle implants containing a neurotrophic factor delivery system.

Volumetric muscle loss (VML) is one of the most severe and debilitating conditions in orthopedic and regenerative medicine. Current treatment modalities often fail to restore the normal structure and function of the damaged skeletal muscle. Bioengineered tissue constructs using the patient's own cells have emerged as a promising alternative treatment option, showing positive outcomes in fostering new muscle tissue formation. However, achieving timely and proper innervation of the implanted muscle constructs remains a significant challenge. In this study, we present a clinically relevant strategy aimed at enhancing and sustaining the natural regenerative response of peripheral nerves to accelerate the innervation of biofabricated skeletal muscle implants. We previously developed a controlled-release neurotrophic factor delivery system using poly (lactic-co-glycolic acid) (PLGA) microspheres encapsulating ciliary neurotrophic factor (CNTF) and glial cell line-derived neurotrophic factor (GDNF). Here, we incorporate this neurotrophic factor delivery system into bioprinted muscle constructs to facilitate innervation in vivo. Our results demonstrate that the neurotrophic factors released from the microspheres provide a chemical cue, significantly enhancing the neurite sprouting and functional innervation of the muscle cells in the biofabricated muscle construct within 12weeks post-implantation. Our approach provides a clinically applicable treatment option for VML through accelerated innervation of biomanufactured muscle implants and subsequent improvements in functionality.

Enhancement of enteric neural stem cell neurogenesis by glial cell-derived neurotrophic factor in experimental Hirschsprung's disease.

Stem cell therapy offers a promising solution for congenital diseases like Hirschsprung's disease (HSCR). Optimizing stem cell efficacy by modifying the cells and their environment is crucial, but in vitro culture conditions need to be further improved. Glial cell-derived neurotrophic factor (GDNF) plays an important role in neuronal survival, proliferation, migration and differentiation during enteric nervous system (ENS) development. In this study, the effects of GDNF on neurites derived from an Ednrb knockout model were investigated with the aim of enhancing the neurogenic potential of enteric neural crest cells (ENCCs). Neurospheres were generated form Ednrb+/+ (control) and Ednrb-/- mice at embryonic day13.5 (E13.5) with Sox10-green fluorescent protein (Venus) transgenic expression. These neurospheres were cultured in control media and neurospheres from Ednrb-/- were cultured with either control media or media supplemented with GDNF. ENCCs differentiation was assessed using immunofluorescence staining after 18days. GDNF-treated Ednrb-/- neurospheres showed increased size and higher density of Sox10-positive ENCCs compared to untreated Ednrb-/- neurospheres. GDNF also enhanced the distribution of both TUJ1-positive neurons and S100-positive glial cells. GDNF effectively enhanced the neurogenic potential of ENCCs from HSCR animal model. This finding is crucial for the development of cell therapy in HSCR.

Bidirectional two-sample Mendelian randomization analysis unveils causal association between inflammatory cytokines and the risk of diabetic nephropathy

ObjectivePrevious observational studies have indicated associations between various inflammatory cytokines and diabetic nephropathy (DN) caused by type 2 diabetes mellitus (T2DM). However, the causality remains unclear. We aimed to further evaluate the causal association between 91 inflammatory cytokines and DN using bidirectional two-sample Mendelian randomization (MR) analysis.MethodSummary statistics for DN were obtained from a publicly available genome-wide association study (GWAS) analysis. Data pertaining to inflammatory cytokines were derived from a GWAS protein quantitative trait locus (pQTL) study. The primary analytical approach employed the inverse variance weighted (IVW) method, complemented by MR-Egger regression, weighted mode (WM), and weighted median (WME) methods to evaluate the causal association between inflammatory cytokines and DN. Sensitivity analyses were conducted to validate the robustness of the findings.ResultAmong individuals of European ancestry, the IVW method results revealed a positive causal association between the gene expression of tumor necrosis factor ligand superfamily member 14 (TNFSF14), and TNF-related activation-induced cytokine (TRANCE) with DN. Conversely, a negative causal association was observed between the gene expression of interleukin-1-alpha (IL-1α), and transforming growth factor-alpha (TGF-α) with DN. Among individuals of East Asian ancestry, the IVW method results indicated a negative causal association between the gene expression of glial cell line-derived neurotrophic factor (GDNF) and DN. Notably, these findings persisted without evidence of horizontal pleiotropy or heterogeneity, ensuring their robustness and reliability.ConclusionThe MR analysis underscores a causal association between inflammatory cytokines and DN, providing an important reference and evidence for the study of DN.

Unveiling the Therapeutic Potential of Small Molecule of SVAK-12: A Comprehensive In Silico, In Vitro, and In Vivo Studies on its Neuroprotective Effects and Molecular Interactions in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder associated with a progressive loss of dopaminergic cells and as of now, there is no established definitive treatment available for this condition. In this study, the focus was on investigating the impact of SVAK-12, a small molecule that can cross the blood-brain barrier and remain stable without structural changes. The effect of SVAK-12 was investigated in vitro on neurotoxicity, in vivo model of Parkinson's Diseases and in silico. Through in vitro and in vivo experiments, as well as molecular docking simulations, it was found that SVAK-12 (375 ng.ml) led to increased cell viability, reduced cellular damage, and decreased production of NO and ROS. Additionally, it boosted levels of important neurotrophic factors like BDNF (130.49%) and GDNF (116.38%), potentially aiding in alleviating motor disability and depression. The study also highlighted SVAK-12's potential as a therapeutic candidate for neurological disorders due to its ability to increase tyrosine hydroxylase expression and dopamine levels (4.84 times). While it did not significantly improve motor symptoms in vivo, it did enhance motor asymmetry in the forelimbs and gene expression related to brain regions. Besides, it induced significant BMP-2 gene expression in substantial nigra regions without significant changes in GDNF and Nurr1 gene expression in the striatum expression. The docking of SVAK-12, Levodopa, Amantadine, Biperiden, Selegiline, and Rasagiline to the binding site of GFRα1, sortilin, and TrkB showed that SVAK-12 had greater MolDock score than Selegiline and Amantadine for GFRα1 and greater than amantadine for Sortilin and TrKB. Overall, the study suggests that SVAK-12's neuro-biocompatibility, ability to reduce free radicals, and enhanced neurotrophic factors make it a promising candidate as a neuroprotective drug.

Exploring the Gene Expression and Plasma Protein Levels of HSP90, HSP60, and GDNF in Multiple Sclerosis Patients and Healthy Controls.

Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by immune-mediated inflammation and neurodegeneration in the central nervous system (CNS). In this study; we aimed to investigate the gene expression and plasma protein levels of three neuroprotective genes-heat shock proteins (HSP90 and HSP60) and glial cell line-derived neurotrophic factor (GDNF)-in MS patients compared to healthy controls. Forty patients with relapsing-remitting MS and 40 healthy volunteers participated in this study. Gene expression was measured using reverse transcription quantitative real-time PCR, and protein levels were assessed via ELISA. The results showed a significant increase in HSP90 (1.7-fold) and HSP60 (2-fold) gene expression in MS patients compared to controls, along with corresponding increases in protein levels (1.5-fold for both HSP90 and HSP60). In contrast, GDNF gene expression and protein levels were significantly reduced in MS patients, with a 7-fold decrease in gene expression and a 1.6-fold reduction in protein levels. Notably, a non-linear relationship between GDNF gene expression and protein concentration was observed in MS patients, suggesting complex regulatory mechanisms influencing GDNF in the disease. The upregulation of HSP90 and HSP60 in MS highlights their roles in immune regulation and stress responses, while the reduction in GDNF indicates impaired neuroprotection. These findings suggest that HSP90, HSP60, and GDNF could serve as biomarkers for disease progression and as potential therapeutic targets in MS, offering promising avenues for future research and treatment development.

Androgen blockage impairs proliferation and function of Sertoli cells via Wee1 and Lfng

BackgroundAndrogens are essential hormones for testicular development and the maintenance of male fertility. Environmental factors, stress, aging, and psychological conditions can disrupt androgen production, impacting the androgen signaling pathway and consequently spermatogenesis. Within the testes, testosterone is produced by Leydig cells and acts on Sertoli cells by activating the androgen receptor (AR), which then translocates to the nucleus to function as a transcription factor. Despite clinical correlations between low testosterone levels and diminished sperm quality, the precise mechanism remains unclear.MethodsThis study explores the hypothesis that reduced androgen levels impair Sertoli cell function by disrupting AR transcriptional regulation. Using an androgen blockade model with enzalutamide, we investigated the impact of low androgen levels on AR target genes in Sertoli cells through ChIP-seq and RNA-seq assays.ResultsOur results reveal that androgen blockage increases AR enrichment on the promoter region of Wee1, promoting Wee1 expression, while decreasing binding to the promoter region of Lfng, inhibiting its expression. Increased WEE1 protein inhibits Sertoli cell proliferation, whereas reduced LFNG affects Notch modification, leading to decreased production of glial cell line-derived neurotrophic factor (GDNF), a key growth factor for spermatogonial stem cell self-renewal.ConclusionsThese findings provide new insights into the molecular mechanisms by which low androgen levels interfere with Sertoli cell functions, offering novel perspectives for the clinical treatment of male reproductive disorders.

Blood Growth Factor Levels in Patients with Systemic Lupus Erythematosus: High Neuregulin-1 Is Associated with Comorbid Cardiovascular Pathology.

Patients with systemic lupus erythematosus (SLE) are known to frequently suffer from comorbid cardiovascular diseases (CVDs). There are abundant data on cytokine levels and their role in the pathogenesis of SLE, while growth factors have received much less attention. The aim of this study was to analyze growth factor levels in SLE patients and their association with the presence of comorbid CVDs. The serum concentrations for the granulocyte-macrophage colony-stimulating factor (GM-CSF), nerve growth factor β (NGFβ), glial cell line-derived neurotrophic factor (GDNF), and neuregulin-1 β (NRG-1β) were determined in the SLE patients (n = 35) and healthy individuals (n = 38) by a Luminex multiplex assay. The NGFβ and NRG-1β concentrations were shown to be significantly higher in the total group of SLE patients (median [Q1-Q3]: 3.6 [1.3-4.5] and 52.5 [8.5-148], respectively) compared with the healthy individuals (2.9 [1.3-3.4] and 13.7 [4.4-42] ng/mL, respectively). The GM-CSF and GDNF levels did not differ. Interestingly, elevated NRG-1β levels were associated with the presence of CVDs, as SLE patients with CVDs had significantly higher NRG-1β levels (99 [22-242]) compared with the controls (13.7 [4.4-42]) and patients without CVDs (19 [9-80] ng/mL). The model for the binary classification of SLE patients with and without CVDs based on the NRG-1β level had an average predictive ability (AUC = 0.67). Thus, altered levels of growth factors may be associated with comorbid CVDs in SLE patients.

Mechanisms of Electroacupuncture in Alleviating Visceral Hypersensitivity in Post-Infectious Irritable Bowel Syndrome Mice: The Role of GDNF Signaling Pathway and Gut Microbiota

Introduction: Post-infectious irritable bowel syndrome (PI-IBS) is a functional bowel disease that develops following an acute gastrointestinal infection. Electroacupuncture (EA) can regulate the gut microbiota and alleviate visceral hypersensitivity. Glial cell-derived neurotrophic factor (GDNF) is a potential factor in visceral hypersensitivity reactions. The aim of this study was to explore whether EA could alleviate visceral hypersensitivity in PI-IBS by regulating gut microbiota through GDNF signaling. Methods: 2,4,6-trinitrobenzene sulfonic acid was used to induce visceral hypersensitivity in PI-IBS mice. Intestinal visceral sensitivity was assessed by using the abdominal withdrawal reflex (colorectal distention). 16S ribosomal RNA sequencing profiles the gut microbiome community. Results: GDNF can exacerbate the imbalances of the gut microbiota and increase visceral hypersensitivity compared with the model group. Whereas EA treatment increases the richness and diversity of the gut microbiota, decreases differences among species and alleviates visceral sensitivity. Conclusion: EA can alleviate visceral hypersensitivity in PI-IBS by regulating the gut microbiota via GDNF signaling, providing new insights for mechanistic research on EA in PI-IBS treatment.

Advances in glial cell line-derived neurotrophic factor

Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor with significant research value due to its profound effects on dopaminergic, cholinergic, and motor neurons. Initially identified for its neuroprotective role in dopaminergic neurons, GDNF has been found to support various neuronal populations and plays a crucial role in neural development, maintenance, and repair. This review provides a comprehensive overview of the molecular characteristics, tissue distribution, physiological function of GDNF and its protective effect on a series of diseases, emphasizing its potential therapeutic applications. Meanwhile, this study discusses the challenges in delivering GDNF across the blood-brain barrier and explores current strategies to enhance its clinical efficacy, including the use of gene therapy and innovative delivery methods. In summary, the review underscores the promise of GDNF as a therapeutic agent for neurodegenerative diseases and nerve injuries, highlighting the need for further research to translate these findings into clinical practice.

Exploring the Mechanisms of Neuronal Protection by Glial Cell Line-Derived Neurotrophic Factor in Autism Spectrum Disorder.

A complicated neurological disease known as autism spectrum disorder (ASD) is typified by issues with social interaction, communication, and repetitive behavior. The neural protective mechanisms in ASD are thought to be influenced by genetic variables, including the expression of neurotrophic genes such as glial cell line-derived neurotrophic factor (GDNF). The aim was to examine the relationship between neuronal protection and cognitive functioning by crosslinking GDNF gene expression and serum levels in individuals with relation to Mini-Mental State Examination (MMSE) scores in ASD patients. After getting study approval and informed consent of patients, this case-control study experimental study was conducted for six months between July 2023 and December 2023. The blood samples (5 ml each) were drawn from the study population (n = 140), including 100 ASD patients with a disease course of30 months based on patients' reports data and 40 healthy controls from four major clinical and hospital settings in Lahore, Karachi, and Bahawalpur from Pakistan. The analytical procedures included nucleic acid extraction, primer design and optimization, and GDNF-targeted real-time quantitative polymerase chain reaction expression analysis. To measure cognitive and behavioral deficits, enzyme-linked immunosorbent assay-based serum GDNF levels (pg/ml) and MMSE scores were compared, concluding the neuronal protection potential of GDNF. In patients with ASD, lower serum levels of GDNF (9.371 ± 2.388 pg/ml) were linked to more severe behavioral and cognitive deficits confirmed by MMSE scores (13.6 ± 3.5) of ASD patients in comparison with the control group (27.1 ± 2.1). Healthy individuals showed higher relative gene fold expression (11.71) compared to the ASD patients (5.51). There is a notable decrease in GDNF gene expression in people with ASD, which raises the possibility that GDNF is important for both cognitive performance and neuronal protection in these people. GDNF may be a useful biomarker for identifying ASD and comprehending its molecular causes, opening the door for focused treatment approaches.

Multi-loaded PLGA microspheres as neuroretinal therapy in a chronic glaucoma animal model.

This work focused on the co-encapsulation and simultaneous co-delivery of three different neuroprotective drugs in PLGA (poly(lactic-co-glycolic acid) microspheres for the treatment of glaucoma. For formulation optimization, dexamethasone (anti-inflammatory) and ursodeoxycholic acid (anti-apoptotic) were co-loaded by the solid-in-oil-in-water emulsion solvent extraction-evaporation technique as a first step. The incorporation of a water-soluble co-solvent (ethanol) and different amounts of dexamethasone resulted critical for the encapsulation of the neuroprotective agents and their initial release. The optimized formulation was obtained with 60mg of dexamethasone and using an 80:20 dichloromethane:ethanol ratio. In the second step in the microencapsulation process, the incorporation of the glial cell line-derived neurotrophic factor (GDNF) was performed. The final prototype showed encapsulation efficiencies for each component above 50% with suitable properties for long-term application for at least 3months. Physicochemical studies were performed by SEM, TEM, DSC, XRD, and gas chromatography. The evaluation of the kinetic release by the Gallagher-Corrigan analysis with Gorrasi correction helped to understand the influence of the co-microencapsulation on the delivery of the different actives from the optimized formulation. The final prototype was tested in a chronic glaucoma animal model. Rats received two intravitreal injections of the neuroprotective treatment within a 24-week follow-up study. The proposed formulation improved retinal ganglion cell (RGC) functionality examined by electroretinography. Also, it was able to maintain a neuroretinal thickness similar to that of healthy animals scanned by in vivo optical coherence tomography, and a higher RGC count on histology compared to glaucomatous animals at the end of the study.

Mechanisms of RET mediated signal transduction.

The RET receptor tyrosine kinase is physiologically stimulated by growth factors belonging to the glial cell line-derived neurotrophic factor (GDNF) family (GFLs) and by the growth differentiation factor-15 (GDF15) cytokine. RET plays a critical role in normal development as well as in various human tumors and developmental disorders. This review focuses on mechanisms of RET signaling and their alterations in human diseases.

Expression of Neurotrophic Factors and Their Receptors in the Rat Spinal Trigeminal Nucleus

The spinal trigeminal nucleus as part of the trigeminal sensory nuclear complex is associated with the transmission of discriminative tactile sensations, primarily pain, and temperature, from the orofacial region. It is divided into three parts – caudal, interpolar, and oral subnucleus which process pain and temperature stimulate. Our previous experiments have revealed the presence of certain neurotrophic factors such as the nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) in this nucleus. These neurotrophins facilitate neuronal differentiation, survival, and plasticity by signalling through high-affinity transmembrane receptors. By using primary antibodies against NGF, BDNF, NT-3, and glial-derived neurotrophic factor (GDNF), and their corresponding receptors of the tyrosine receptor kinase (Trk) proto-oncogene family and GFRα1, we found immunoreactive cells scattered along the whole length of the nucleus in rats in all three subnuclei. In particular, we observed that the majority of spinal trigeminal neurons were intensely immunostained for all the neurotrophic factors examined and that they were richly endowed with their Trk receptors. Our results also showed that NGF, NT-3, TrkC and GFRα1 expression did not differ between different topographic regions of the nucleus, while BDNF, GDNF, and TrkA expression was highest in the SpVo, and TrkB expression was highest in the SpVi and SpVc. Given that these neurotrophic factors are involved in mechanisms of central sensitization in trigeminal nociceptive pathways, it can be inferred that neurotrophins may contribute to a better understanding of the fundamental mechanisms of orofacial pain.

Effects of glial-derived neurotrophic factor on remodeling and mitochondrial function in human airway smooth muscle cells.

Airway smooth muscle (ASM) cells play important roles in airway remodeling of asthma. Our previous studies show that in vivo administration of glial-derived neurotrophic factor (GDNF) in mice induces thickening and collagen deposition in bronchial airways, whereas chelation of GDNF by GFRα1-Fc attenuates airway remodeling in the context of allergen exposure. To determine whether GDNF has direct effects on ASM, in this study, we examined GDNF in ASM cells from normal versus asthmatic humans. We found that GDNF treatment of human ASM cells had only minor effects on cell proliferation and migration, intracellular expression or extracellular deposition of collagen I (COL1), collagen III (COL3), and fibronectin. Endoplasmic reticulum (ER) stress response and mitochondrial function have been implicated in asthma. We investigated whether GDNF regulates these aspects in human ASM. We found that GDNF treatment did not affect ER stress protein expression in normal or asthmatic cells. However, GDNF treatment impaired mitochondrial morphology in ASM but without significant effects on mitochondrial respiration. Thus, it is likely that in vivo effects of GDNF on airway remodeling per se involve cell types other than those on ASM, and thus ASM may serve more as a source of GDNF rather than a target.NEW & NOTEWORTHY Our previous study suggests that glial-derived neurotrophic factor (GDNF) is involved in allergen-induced airway hyperreactivity and remodeling in vivo. Here, we show that GDNF has no direct effects in remodeling of human airway smooth muscle (ASM) but GDNF dysregulates mitochondrial morphology in human ASM in the context of asthma.

Glial-Cell-Line-Derived Neurotrophic Factor Promotes Glioblastoma Cell Migration and Invasion via the SMAD2/3-SERPINE1-Signaling Axis.

Glial-cell-line-derived neurotrophic factor (GDNF) is highly expressed and is involved in the malignant phenotype in glioblastomas (GBMs). However, uncovering its underlying mechanism for promoting GBM progression is still a challenging work. In this study, we found that serine protease inhibitor family E member 1 (SERPINE1) was a potential downstream gene of GDNF. Further experiments confirmed that SERPINE1 was highly expressed in GBM tissues and cells, and its levels of expression and secretion were enhanced by exogenous GDNF. SERPINE1 knockdown inhibited the migration and invasion of GBM cells promoted by GDNF. Mechanistically, GDNF increased SERPINE1 by promoting the phosphorylation of SMAD2/3. In vivo experiments demonstrated that GDNF facilitated GBM growth and the expressions of proteins related to migration and invasion via SERPINE1. Collectively, our findings revealed that GDNF upregulated SERPINE1 via the SMAD2/3-signaling pathway, thereby accelerating GBM cell migration and invasion. The present work presents a new mechanism of GDNF, supporting GBM development.