Expression of basic fibroblast growth factor,nerve growth factor,platelet-derived growth factor and transforming growth factor-β in human brain abscess

We correlated the histopathological findings of six human brain abscesses with the expression of basic fibroblast growth factor (bFGF), nerve growth factor (NGF), platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF). The clinical courses ranged from 1 month to 1 year and viridans streptoccus was the major pathogen. In early abscesses, we demonstrated strong bFGF and moderate NGF and PDGF immunoreactivities in neutrophils and monocytes/macrophages infiltrating the abscess wall and in the fibrin layer lining the abscess center. In the subacute cases, growth of capillaries and fibroblasts into the fibrin layer and deposition of collagen resulted in the formation of a mesodermal layer between the abscess center and the outer gliotic layer. The proliferative non-neural cells (endothelial cells, fibroblasts and glial cells) expressed mild to strong bFGF, NGF and PDGF immunoreactivities, while strong TGF staining was seen in the extracellular matrix. A loss of growth factor expression and increased fibrosis was seen in the chronic case. These findings suggest that bFGF, NGF, PDGF and TGF produced by the continued influx of leukocytes and by the proliferating non-neural cells may mediate various steps of defense mechanisms and wound healing such as angiogenesis, fibrogenesis and gliosis.Supported by NSC-82-0115-B-006-127 from the National Science Council, Republic of China     

The transforming growth factor-β receptor genes and the risk of intracranial aneurysms

Background Mutations in the receptor genes of the transforming growth factor β pathway, TGFBR1 and TGFBR2, cause syndromes with thoracic aortic aneurysms, while genetic variants in TGFBR1 and TGFBR2 are associated with abdominal aortic aneurysms. The transforming growth factor-β pathway may be involved in aneurysm development in general. Aims To analyze whether genetics variants in TGFBR1 and TGFBR2 are also involved in the pathogenesis of intracranial aneurysms. Methods Using tag single nucleotide polymorphisms, we analyzed all common genetic variants in TGFBR1 (five single nucleotide polymorphisms) and TGFBR2 (26 single nucleotide polymorphisms) in a Dutch intracranial aneurysm case-control population approach using a two-stage genotyping approach. Results In stage 1, on analyzing 481 patients and 648 controls, two of the five single nucleotide polymorphisms in TGFBR1 were associated with intracranial aneurysm with P<0·10. In an independent cohort of 310 intracranial aneurysm patients and 376 controls, a predominance of the allele of the two single nucleotide polymorphisms found more frequently in patients in stage 1 was also observed in patients of stage 2 but the associations were not statistically significant. On combined analyses of both stages, there was a statistically significant association of both single nucleotide polymorphisms with intracranial aneurysm (single nucleotide polymorphism rs1626340, odds ratio 1·24, 95% confidence intervals 1·05-1·46, P=0·01; single nucleotide polymorphism rs10819634, odds ratio 1·23, 95% confidence intervals 1·03-1·46, P=0·02) but these associations did not hold after multiple testing correction (i.e., P<0·0016, 0·05/31). Also, no differences in the single nucleotide polymorphism frequency were observed for TGFBR2 between patients and controls. Conclusions We found no evidence for TGFBR1 and TGFBR2 as susceptibility genes for intracranial aneurysm in the Dutch population.     

Repurposed anti-cancer epidermal growth factor receptor inhibitors: mechanisms of neuroprotective effects in Alzheimer’s disease

Numerous molecular mechanisms are being examined in an attempt to discover disease-modifying drugs to slow down the underlying neurodegeneration in Alzheimer’s disease.Recent studies have shown the beneficial effects of epidermal growth factor receptor inhibitors on the enhancement of behavioral and pathological sequelae in Alzheimer’s disease.Despite the promising effects of epidermal growth factor receptor inhibitors in Alzheimer’s disease,there is no irrefutable neuroprotective evidence in well-established animal models using epidermal growth factor receptor inhibitors due to many un-explored downstream signaling pathways.This caused controversy about the potential involvement of epidermal growth factor receptor inhibitors in any prospective clinical trial.In this review,the mystery beyond the under-investigation of epidermal growth factor receptor in Alzheimer’s disease will be discussed.Furthermore,their molecular mechanisms in neurodegeneration will be explained.Also,we will shed light on SARS-COVID-19 induced neurological manifestations mediated by epidermal growth factor modulation.Finally,we will discuss future perspectives and under-examined epidermal growth factor receptor downstream signaling pathways that warrant more exploration.We conclude that epidermal growth factor receptor inhibitors are novel effective therapeutic approaches that require further research in attempts to be repositioned in the delay of Alzheimer’s disease progression.     

Possible role of transforming growth factor-β in relapsing-remitting multiple sclerosis

Abstract

Cerebrospinal fluid (CSFJ and serum levels of transforming growth factor (TGFJ-f3 and soluble intercellular adhesion molecule-1 (sICAM-l) were evaluated in ten patients with definite multiple sclerosis (MS) of the relapsing-remitting type. CSF TGF-β levels of MS patients in remission were significantly (p < 0.01) higher than of MS patients in active phase and there was a significant inverse correlation (p < 0.05) between TGF-β and sICAM-l levels in the CSF of patients in both remitting and relapsing type. This is consistent with a possible down-regulation of TGF-β on ICAM-l expression and suggests a possible synthesis in the central nervous system of TGF-β. [Neural Res 1997; 19: 599-600]     

Association between polymorphisms in transforming growth factor-β1 and sporadic Alzheimer's disease in a Chinese population

Alzheimer's disease (AD) is the most common neurodegenerative disorder of the brain. It causes the slow progressive loss of cognitive functions that ultimately leads to dementia and death in the elderly. The etiology and mechanism of late-onset AD (LOAD) are poorly understood, and genetic factors might play an important role in the development of AD. The aim of this study was to investigate the association between common polymorphisms in TGF-β1 with LOAD in a Chinese Han population. Two single nucleotide polymorphisms in TGF-β1 (rs1800469 and rs1982073) were genotyped in 202 patients with sporadic LOAD and 225 control subjects using polymerase chain reaction restriction fragment length polymorphism. Our results showed that rs1800469 in TGF-β1 were significantly associated with LOAD. The frequencies of the AC genotypes of rs1800469 were significantly higher in the LOAD patients than in the control subjects (42.5% vs 28.6%; P = 0.001). The minor allele (C) frequency was significantly higher in patients with LOAD than in control subjects (30.7% vs. 21.0%; P = 0.001). The genotypes and allele of rs1982073 in TGF-β1 were also significantly associated with LOAD. The frequency of the TG genotype of rs1982073 was significantly higher in the LOAD patients than in the control subjects (38.1% vs. 27.1%; P = 0.013). The minor allele (G) frequency was significantly higher in patients with LOAD than in control subjects (22.2% vs. 16.7%; P = 0.032). These results suggest that common variants in TGF-β1 might contribute to the development of LOAD in the Chinese population.     

Evaluation of serum transforming growth factor β1 and C-reactive protein levels in migraine patients

Background and purposeMigraine is a frequent form of headache. Although many mechanisms describing onset of migraine with and without visual aura have been suggested, the aetiology of migraine headaches is still not clear. Neurogenic inflammation may play a key role in the development of migraine headaches. We evaluated the discriminative power of serum levels of C-reactive protein (CRP) and transforming growth factor beta 1 (TGF-β1) in patients who presented to our clinic with migraine headaches with or without visual aura.Material and methodsWe designed a prospective case-control study of 51 patients with migraine (27 with migraine with aura and 24 with migraine without aura; all had headache) and compared them with 27 healthy subjects during the study period. Demographic and clinical characteristics recorded were age, sex, marital status, occupation, characteristics of headache, laboratory values, and serum CRP and TGF-β1 levels. Statistical analyses used Student t-test, the χ² test, and ANOVA followed by the post-hoc Bonferroni test for multiple comparisons. Receiver operator characteristic (ROC)-curve analysis for CRP and TGF-β1 was also conducted.ResultsThere was no difference between the groups in terms of demographic characteristics, marital status, and socioeconomic status. Statistically, white blood cell levels, serum glucose levels, triglyceride levels, high-density lipoprotein levels, and serum CRP and TGF-β1 were significantly higher in patients with migraine (p < 0.05). The ROC curve results in this study identified that CRP and TGF-β1 may discriminate patients who have different types of migraine headache.ConclusionsThis study suggests that serum CRP and TGF-β1 levels may be diagnostic factors to differentiate migraine patients with and without aura. These findings show that neurogenic inflammation may have a role in the aetiology of migraines.     

Glial-derived transforming growth factor β1(TGF-β1):a key factor in multiple sclerosis neuroinflammation

正Glial cell activation and neuroinflammation in multiple sclerosis (MS):MS is an irreversible and progressive central nervous system (CNS) disease which originates in the autoimmune attack of lymphocytes against CNS myelin.This specialized membrane,synthesized by oligodendrocytes (OL) in the CNS,provides metabolic support to axons and allows for     

Serum epidermal growth factor predicts cognitive functions in early, drug-naive Parkinson’s disease patients

Epidermal growth factor (EGF) has been proposed as a candidate biomarker for cognitive impairment in Parkinson’s disease (PD). We aimed to assess the relationship between serum EGF and cognitive functions in early, drug-naive PD patients and evaluate the predictive value of EGF on cognitive functions in a 2-year follow-up study. Serum EGF was measured in 65 early, drug-naive PD patients, that underwent a comprehensive neuropsychological battery. Motor symptoms were assessed by means of the Unified Parkinson’s Disease Rating Scale, Part III (UPDRS-III). Neuropsychological evaluation was repeated after 2 years. Spearman’s rank correlation was used to assess the relationship between serum EGF levels and neuropsychological variables. Linear regression analysis was used to evaluate the relationship between EGF and neuropsychological scores as well as other variables (age, gender, UPDRS-III, levodopa equivalent dose, and type of treatment at follow-up) potentially affecting cognitive performance. Variation over time in cognitive scores was analyzed using repeated-measures ANOVA. At baseline, EGF was the only significant variable associated with performance on semantic fluency (R ² = 0.131; p = 0.005). EGF levels (p = 0.025), together with UPDRS-III (p = 0.009) and age (p = 0.011), were associated with performance on frontal assessment battery (R ² = 0.260). At 2-year follow-up, EGF was the only significant variable to predict performance on semantic fluency (R ² = 0.147; p = 0.025) and color naming task of Stroop color-word test (R ² = 0.121; p = 0.044). Serum EGF levels are related to frontal and temporal cognitive functions in early, drug-naive PD patients and predict performance on frontal and posterior cognitive functions at 2-year follow-up. EGF is proposed as a potential serum biomarker for early cognitive impairment in PD.     

Effect of epidermal growth factor on the migration of neural stem cells

INTRODUCTION Since neural stem cells (NSCs) are separated from corpus striatum of adult rats in 1992 [1], researches on NSCs become a hot topic all over the world because they are characterized by excellent superiority and complete cure on treating geneti…     

Potential role of transforming growth factor-β1 in terminating the immune response in patients with Guillain-Barré syndrome

T-cell activation and proinflammatory cytokines seem to be important in promoting the disease activity in Guillain-Barré syndrome (GBS). Transforming growth factor-1 (TGF-1) is a multifunctional peptide with potent immunosuppressive activity, and can therefore be considered a putative disease-limiting cytokine. We determined levels of soluble TGF-1 in the serum of 12 patients with GBS in serial investigations during the course of the disease, in 12 patients with other non-inflammatory neurological diseases (OND), and in 12 healthy control subjects. Levels of biologically active and total TGF-1 were significantly increased in patients with GBS compared with patients with OND and healthy controls. During the course of GBS, levels of TGF-1 peaked in the plateau phase before onset of recovery. During the recovery phase levels of TGF-1 decreased but still exceeded significantly the levels in patients with OND and healthy controls. The differences were more marked with biologically active than with total TGF-1. The temporal relationship between increased serum levels of TGF-1 and the end of the progressive phase indicates that TGF-1 has a role in terminating the pathological immune response in GBS. These findings suggest that TGF-1 may be important in recovery from GBS.     

The role of thrombospondin-1 and transforming growth factor-β after spinal cord injury in the rat

Spinal cord injury (SCI) continues to result in high morbidity and mortality throughout the world. An effective neuroprotective agent is still not available to counteract secondary damage caused by traumatic injury. Thrombospondin-1 (TSP-1) and transforming growth factor-β (TGF-β) have a role in angiogenesis, scar deposition, inflammation and may affect astrocyte phenotype and mobility. We investigated the role of TSP-1 and TGF-β in a model of spinal cord injury in rats. Forty female Sprague-Dawley rats were randomly divided into two equal groups: the experimental group was subject to SCI using an impactor and the sham-operated group was not subject to SCI. These animals were sacrificed at 12 h and 24 h after SCI for immunochemistry and Western blot analysis of the injured spinal segment for the expression of the TSP-1 and TGF-β proteins. We found that TSP-1 and TGF-β expression increased immediately after SCI in the injured segment. After 12 h, TSP-1 concentrations increased more rapidly and dramatically than TGF-β in the injured segment of the spinal cord. Elevations in TSP-1 and TGF-β concentrations persisted for 24 h after injury. These results show that elevated expression of TSP-1 and TGF-β can be detected in the injured segment of the spinal cord 12 and 24 h after injury. Thus, TSP-1 and TGF-β may have a role in SCI.     

Antiparkinsonian trophic action of glial cell line-derived neurotrophic factor and transforming growth factor β1 is enhanced after co-infusion in rats

The objective was to analyze functional effects of the combination of GDNF and TGF-β1 in the retrograde model of Parkinsonism in rats, based on the intrastriatal infusion of 6-hydroxydopamine, which leads to protracted and progressive cell death in the substantia nigra. Hemiparkinsonian rats were implanted with osmotic minipumps 2 months after striatal lesion, pumps delivering GDNF alone (10 ng/day), TGF-β1 alone (2 ng/day), or a GDNF and TGF-β1 combination. The findings confirmed that GDNF alone has potent dopaminotrophic effects but they also revealed, for the first time, that GDNF and TGF-β1 co-infusion led to stronger trophic effects relative to the infusion of GDNF alone. TGF-β1 allowed further reducing dopamine receptor hypersensitivity, and potentiated GDNF-mediated effects. This cooperation could be accounted for by the recruitment of GFRα1 on striatal membranes, and by enhanced expression and activation of TH through augmented pSer31TH and pSer40TH. Co-infusion induced striatal sprouting, as revealed by augmentation of p21-Arc, stathmin, and synaptophysin, and led to a reliable recovery of phenotypic expression of TH in surviving nigral neurons. Functional recovery and improvement of TH signal in the nigrostriatal system were long-lasting and sustained, remaining after cessation of trophic infusion.     

Are there fibroblast growth factor receptor 1 mutations in a Chinese Kallmann syndrome family?

The present study examined 58 members of a Kallmann syndrome family and investigated whether there are fibroblast growth factor receptor 1 (FGFR1) gene mutations in this family.Genomic DNA from the proband and family members was subjected to PCR to amplify 18 exons of FGFR1,and the amplified products were sequenced to identify potential mutations.MRI of the olfactory bulb region was performed on suspected subjects.The patient and his father were diagnosed with Kallmann syndrome.A polymorphic site was found at 39542,with the proband and his parents being heterozygous (guanine + cytosine).However,healthy controls and the other members of this family were homozygous for guanine at this position.     

Examination of glucose transporter-1, transforming growth factor-β and neuroglobin immunoreactivity in the orbitofrontal cortex in late-life depression

Aims: This study immunohistochemically examined the orbitofrontal cortex for three possible candidates in hypoxic/ischemic signaling: the cytokine transforming growth factor‐β, the glucose transporter‐1 and the neuron‐specific oxygen‐binding protein neuroglobin. Methods: Post‐mortem tissue from 20 depressed and 20 non‐depressed individuals was obtained and the expression of the three proteins was analyzed using image analysis software. Results: No significant changes were found in transforming growth factor‐β or neuroglobin in the orbitofrontal cortex between depressed and non‐depressed individuals. There was, however, a trend towards a reduction in glucose transporter‐1 in the depressed group. Conclusions: This study does not clearly support the hypothesis that hypoxic/ischemic processes are behind the pathological deficits in the frontal‐subcortical circuitry associated with depression and therefore does not provide evidence to support the ‘vascular depression’ hypothesis.     

Small molecule inhibitor of type I transforming growth factor-β receptor kinase ameliorates the inhibitory milieu in injured brain and promotes regeneration of nigrostriatal dopaminergic axons

Transforming growth factor-β (TGF-β), a multifunctional cytokine, plays a crucial role in wound healing in the damaged central nervous system. To examine effects of the TGF-β signaling inhibition on formation of scar tissue and axonal regeneration, the small molecule inhibitor of type I TGF-β receptor kinase LY-364947 was continuously infused in the lesion site of mouse brain after a unilateral transection of the nigrostriatal dopaminergic pathway. At 2 weeks after injury, the fibrotic scar comprising extracellular matrix molecules including fibronectin, type IV collagen, and chondroitin sulfate proteoglycans was formed in the lesion center, and reactive astrocytes were increased around the fibrotic scar. In the brain injured and infused with LY-364947, fibrotic scar formation was suppressed and decreased numbers of reactive astrocytes occupied the lesion site. Although leukocytes and serum IgG were observed within the fibrotic scar in the injured brain, they were almost absent in the injured and LY-364947-treated brain. At 2 weeks after injury, tyrosine hydroxylase (TH)-immunoreactive fibers barely extended beyond the fibrotic scar in the injured brain, but numerous TH-immunoreactive fibers regenerated over the lesion site in the LY-364947-treated brain. These results indicate that inhibition of TGF-β signaling suppresses formation of the fibrotic scar and creates a permissive environment for axonal regeneration.     

Changes of insulin-like growth factor-Ⅱ and insulin-like growth factor binding protein-3 in cerebrospinal fluid of children with tuberculous meningitis

BACKGROUND: Recent studies have found that insulin-like growth factors (IGFs) and insulin-like growth factor binding protein-3 (IGFBP-3) have stronger neurotrophic and neuroprotective effects. But whether their levels in cerebrospinal fluid could be used as an auxiliary indicator in differentially diagnosing tuberculous meningitis and viral encephalitis is not yet clear. OBJECTIVE: To explore the changes of insulin-like growth factor-Ⅱ (IGF-Ⅱ) and IGFBP-3 in cerebrospinal fluid (CSF) of children with tuberculous meningitis and the significance of the changes. DESIGN: A non-randomized concurrent controlled study. SETTING: Department of Pediatric Internal Medicine, the First Affiliated Hospital of Xinxiang Medical College. PARTICIPANTS: Thirty children with tuberculous meningitis (14 males and 16 females) were selected from the Department of Pediatric Internal Medicine, the First Affiliated Hospital of Xinxiang Medical College from January 2005 to December 2006. Tuberculous meningitis was diagnosed according to their clinical manifestations, the history of close contact with tuberculosis, typical cerebrospinal fluid changes of tuberculous meningitis, positive tuberculosis antibody and effective antituberculosis treatment. There were 30 children (13 males and 17 females) with viral encephalitis, and viral encephalitis was diagnosed according to epidemiological history, clinical manifestations, conventional and biochemical changes of cerebrospinal fluid, and negative bacteriology judgment. Meanwhile, 30 children (13 males and 17 females) without infectious and central nervous system disease were selected as the control group. Informed consent was obtained from the parents of all the enrolled children. METHODS: ① The lumbar puncture operation was implemented immediately to obtain cerebrospinal fluid (3 mL). The contents of IGF-Ⅱ and IGFBP-3 were detected with immunoradiometric assay. The concentrations of glucose and protein in cerebrospinal fluid were determined with a dry-chemical method. The number of white blood cells was counted by Fushi Method. ② The Pearson correlation analysis was used to analyze the correlation of the contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid with the leucocyte counting and the concentrations of glucose and protein in cerebrospinal fluid. MAIN OUTCOME MEASURES: The contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid, and their correlation with the leucocyte counting and the concentrations of glucose and protein in cerebrospinal fluid. RESULTS: ① Contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid: The contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid in the tuberculous meningitis group were significantly higher than those in the encephalitis virus group and control group (P < 0.05). There was no significant difference in the contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid between the viral encephalitis group and control group (P > 0.05). ② Correlation: The IGF-Ⅱ and IGFBP-3 contents in cerebrospinal fluid were positively correlated with the protein concentration in cerebrospinal fluid (r =0.821, 0.855, P < 0.01), but negatively with the glucose (r =0.742, –0.605, P < 0.01). CONCLUSION: ① IGFs and IGFBPs are involved in the pathophysiological process of tuberculous meningitis, as well as the glucose and protein metabolism in cerebrospinal fluid. ② The IGF-Ⅱ and IGFBP-3 contents in cerebrospinal fluid can be used as the auxiliary indicators to differentially diagnose tuberculous meningitis and viral encephalitis.