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1.
Heliyon ; 9(4): e14777, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37025807

RESUMO

The extracellular matrix (ECM) components present within all tissues and organs help to maintain the cytoskeletal architecture and tissue morphology. Although the ECM plays a role in cellular events and signaling pathways, it has not been well studied due its insolubility and complexity. Brain tissue has a higher cell density and weaker mechanical strength than other tissues in the body. When removing cells using a general decellularization method to produce scaffolds and obtain ECM proteins, various problems must be considered because tissues are easily damaged. To retain the brain shape and ECM components, we performed decellularization in combination with polymerization. We immersed mouse brains in oil for polymerization and decellularization via O-CASPER (Oil-based Clinically and Experimentally Applicable Acellular Tissue Scaffold Production for Tissue Engineering and Regenerative Medicine) and then isolated ECM components using sequential matrisome preparation reagents (SMPRs), namely, RIPA, PNGase F, and concanavalin A. Adult mouse brains were preserved with our decellularization method. Western blot and LC-MS/MS analyses revealed that ECM components, including collagen and laminin, were isolated efficiently from decellularized mouse brains using SMPRs. Our method will be useful to obtain matrisomal data and perform functional studies using adult mouse brains and other tissues.

2.
Exp Neurobiol ; 32(1): 1-7, 2023 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-36919331

RESUMO

In 1998, Korea implemented the Brain Research Promotion Act (BRPA), a law to revamp the field of neuroscience at the national level. However, despite numerous revisions including the definition and classification of neuroscience and the national plans for the training and education systems, the governance for neuroethics has not been integrated into the Act. The ethical issues raised by neuroscience and neurotechnology remain unchallenged, especially given the focus on the industrial purpose of the technology. In the current study, we analyzed the BRPA revision process by using Kingdon's Multiple Streams Framework to determine the problems faced by the process. We propose a new strategy, including neuroethics governance and a national committee, to promote interdisciplinary neuroscience research and strengthen neuroethics in Korea.

3.
Medicina (Kaunas) ; 58(9)2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36143916

RESUMO

Background: Cervical interlaminar epidural steroid injection (CIESI) is increasingly used as an interventional treatment for pain originating from the cervical spine. However, serious neurological complications may occur during CIESI because of direct nerve damage following inappropriate needle placement. Case report: A 35-year-old woman presented with posterior neck pain radiating to the left upper arm. Cervical magnetic resonance imaging (MRI) revealed left C6 nerve impingement. CIESI under fluoroscopic guidance was performed at another hospital using the left C5/6 interlaminar approach. Immediately after the procedure, the patient experienced dizziness, decreased blood pressure, motor weakness in the left upper arm, and sensory loss. She visited our emergency department with postdural puncture headache (PDPH) that worsened after the procedure. Post-admission cervical MRI revealed intramedullary T2 high signal intensity and cord swelling from the C4/5 to C6/7 levels; thus, a diagnosis of spinal cord injury was made. The patient's PDPH spontaneously improved after 48 h. However, despite conservative treatment with steroids, the decrease in abduction of the left fifth finger and loss of sensation in the dorsum of the left hand persisted for up to 6 months after the procedure. As noticed in the follow-up MRI performed 6 months post-procedure, the T2 high signal intensity in the left intramedullary region had decreased compared to that observed previously; however, cord swelling persisted. Furthermore, left C7/8 radiculopathy with acute denervation was confirmed by electromyography performed 6 months after the procedure. Conclusions: Fluoroscopy does not guarantee the prevention of spinal cord penetration during CIESI. Moreover, persistent neurological deficits may occur, particularly due to intrathecal perforation or drug administration during CIESI. Therefore, in accordance with the recommendations of the Multisociety Pain Workgroup, we recommend performing CIESI at the C6/7 or C7/T1 levels, where the epidural space is relatively large, rather than at the C5/6 level or higher.


Assuntos
Cefaleia Pós-Punção Dural , Traumatismos da Medula Espinal , Adulto , Feminino , Humanos , Injeções Epidurais/efeitos adversos , Injeções Epidurais/métodos , Dor , Cefaleia Pós-Punção Dural/tratamento farmacológico , Cefaleia Pós-Punção Dural/etiologia , Esteroides
4.
Medicine (Baltimore) ; 101(49): e32018, 2022 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-36626490

RESUMO

Kyphoplasty (KP) has been widely used to treat vertebral compression fractures (VCFs). However, the issue of new VCFs after KP remains controversial. Identification of risk factors for new VCF after KP may help prevent their occurrence in patients. This study aimed to retrospectively determine the major risk factors for new VCF after KP, including those associated with osteoporosis drugs used after kyphoplasty. We reviewed 117 patients who underwent single-level KP. During the follow-up period of 1 year after KP, the demographic data of these patients were compared by dividing them into two groups: those with new fractures (n = 19) and those without new fractures (n = 98). We investigated the age, sex, fracture location, medical history, steroid use history, bone mineral density (BMD), type of osteoporosis treatment, period from fracture to KP, KP method (unilateral or bilateral), bone cement dose, intradiscal cement leakage, preoperative and postoperative compression ratio, kyphotic angle (KA), and lowest vertebral body height in the fractured vertebrae. Based on these data, the factors related to new VCFs after KP were investigated using univariate and multivariate logistic regression analyses. We also investigated whether there were differences in new VCFs according to the type of osteoporosis treatment. During the 1-year follow-up period after KP, the rate of new VCFs was 16.2%. Factors related to new VCFs were BMD, intradiscal cement leakage, KA recovery rate after 1 day, and baseline height in the univariate and multivariate logistic regression analyses. The group treated with zoledronate after KP tended to show a lower frequency of developing new VCFs than the groups treated with alendronate (P = .07), calcium (P = .05), selective estrogen receptor modulator (SERM) (P = .15), and risendronate (P = .02). This study showed that for patients with new VCFs after KP, lower BMD, greater intradiscal cement leakage, greater KA recovery rate, and lower baseline vertebral height were likely risk factors for the development of new VCFs. Additionally, among the drugs used for the treatment of osteoporosis after KP, zoledronate tends to reduce the development of new VCFs compared with other bisphosphonates, SERMs, or calcium.


Assuntos
Fraturas por Compressão , Cifoplastia , Osteoporose , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Vertebroplastia , Humanos , Cifoplastia/efeitos adversos , Cifoplastia/métodos , Fraturas por Compressão/complicações , Estudos Retrospectivos , Fraturas da Coluna Vertebral/cirurgia , Fraturas da Coluna Vertebral/complicações , Cálcio , Ácido Zoledrônico , Osteoporose/complicações , Osteoporose/tratamento farmacológico , Vertebroplastia/efeitos adversos , Vertebroplastia/métodos , Fatores de Risco , Resultado do Tratamento , Fraturas por Osteoporose/prevenção & controle , Fraturas por Osteoporose/complicações
5.
Int J Mol Sci ; 22(1)2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33401721

RESUMO

Mitochondrial dysfunction contributes to neurodegenerative diseases and developmental disorders such as Fragile X syndrome (FXS). The cross-talk between mitochondria and extracellular vesicles (EVs) suggests that EVs may transfer mitochondrial components as intermediators for intracellular communication under physiological and pathological conditions. In the present study, the ability of EVs to transfer mitochondrial components and their role in mitochondrial dysfunction in astrocytes were examined in the brains of Fmr1 knockout (KO) mice, a model of FXS. The amounts of mitochondrial transcription factor NRF-1, ATP synthases ATP5A and ATPB, and the mitochondrial membrane protein VDAC1 in EVs were reduced in cerebral cortex samples and astrocytes from Fmr1 KO mice. These reductions correspond to decreased mitochondrial biogenesis and transcriptional activities in Fmr1 KO brain, along with decreased mitochondrial membrane potential (MMP) with abnormal localization of vimentin intermediate filament (VIF) in Fmr1 KO astrocytes. Our results suggest that mitochondrial dysfunction in astrocytes is associated with the pathogenesis of FXS and can be monitored by depletion of components in EVs. These findings may improve the ability to diagnose developmental diseases associated with mitochondrial dysfunction, such as FXS and autism spectrum disorders (ASD).


Assuntos
Astrócitos/metabolismo , Vesículas Extracelulares/metabolismo , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Mitocôndrias/metabolismo , Animais , Células Cultivadas , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Vesículas Extracelulares/genética , Vesículas Extracelulares/ultraestrutura , Proteína do X Frágil da Deficiência Intelectual/genética , Imuno-Histoquímica , Masculino , Potencial da Membrana Mitocondrial/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Mitocôndrias/genética
6.
Neuron ; 101(3): 390-393, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30731064

RESUMO

Neuroscience research has become a national priority for the Korean government. Korean scholars have dedicated interest in the societal ramifications of neurotechnologies; neuroethics is an integral component of the Korea Brain Initiative and to the formation of its growing neuroscience community.


Assuntos
Códigos de Ética , Neurociências/ética , Humanos , Saúde Mental/ética , Neurociências/organização & administração , Neurociências/normas , República da Coreia
9.
Neuron ; 100(1): 19-36, 2018 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-30308169

RESUMO

Increasingly, national governments across the globe are prioritizing investments in neuroscience. Currently, seven active or in-development national-level brain research initiatives exist, spanning four continents. Engaging with the underlying values and ethical concerns that drive brain research across cultural and continental divides is critical to future research. Culture influences what kinds of science are supported and where science can be conducted through ethical frameworks and evaluations of risk. Neuroscientists and philosophers alike have found themselves together encountering perennial questions; these questions are engaged by the field of neuroethics, related to the nature of understanding the self and identity, the existence and meaning of free will, defining the role of reason in human behavior, and more. With this Perspective article, we aim to prioritize and advance to the foreground a list of neuroethics questions for neuroscientists operating in the context of these international brain initiatives.


Assuntos
Pesquisa Biomédica/ética , Encéfalo , Neurociências/ética , Humanos
10.
Elife ; 72018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29809138

RESUMO

In the central nervous system (CNS), myelin formation and repair are regulated by oligodendrocyte (OL) lineage cells, which sense and integrate signals from their environment, including from other glial cells and the extracellular matrix (ECM). The signaling pathways that coordinate this complex communication, however, remain poorly understood. The adhesion G protein-coupled receptor ADGRG1 (also known as GPR56) is an evolutionarily conserved regulator of OL development in humans, mice, and zebrafish, although its activating ligand for OL lineage cells is unknown. Here, we report that microglia-derived transglutaminase-2 (TG2) signals to ADGRG1 on OL precursor cells (OPCs) in the presence of the ECM protein laminin and that TG2/laminin-dependent activation of ADGRG1 promotes OPC proliferation. Signaling by TG2/laminin to ADGRG1 on OPCs additionally improves remyelination in two murine models of demyelination. These findings identify a novel glia-to-glia signaling pathway that promotes myelin formation and repair, and suggest new strategies to enhance remyelination.


Assuntos
Doenças Desmielinizantes/genética , Proteínas de Ligação ao GTP/genética , Microglia/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Oligodendroglia/metabolismo , Receptores Acoplados a Proteínas G/genética , Transglutaminases/genética , Animais , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Diferenciação Celular , Linhagem da Célula/genética , Cerebelo/citologia , Cerebelo/metabolismo , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Feminino , Proteínas de Ligação ao GTP/deficiência , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Laminina/genética , Laminina/metabolismo , Masculino , Camundongos , Camundongos Knockout , Microglia/citologia , Neurogênese/genética , Células Precursoras de Oligodendrócitos/citologia , Oligodendroglia/citologia , Prosencéfalo/citologia , Prosencéfalo/metabolismo , Proteína 2 Glutamina gama-Glutamiltransferase , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Remielinização/genética , Transdução de Sinais , Transglutaminases/deficiência
11.
Neuron ; 92(3): 607-611, 2016 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-27810002

RESUMO

This article introduces the history and the long-term goals of the Korea Brain Initiative, which is centered on deciphering the brain functions and mechanisms that mediate the integration and control of brain functions that underlie decision-making. The goal of this initiative is the mapping of a functional connectome with searchable, multi-dimensional, and information-integrated features. The project also includes the development of novel technologies and neuro-tools for integrated brain mapping. Beyond the scientific goals this grand endeavor will ultimately have socioeconomic ramifications that not only facilitate global collaboration in the neuroscience community, but also develop various brain science-related industrial and medical innovations.


Assuntos
Encéfalo/fisiologia , Tomada de Decisões/fisiologia , Neurociências/organização & administração , Mapeamento Encefálico , Conectoma , Humanos , Cooperação Internacional , Parcerias Público-Privadas , República da Coreia
13.
Sci Rep ; 6: 18631, 2016 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-26750588

RESUMO

Understanding the structural organization of organs and organisms at the cellular level is a fundamental challenge in biology. This task has been approached by reconstructing three-dimensional structure from images taken from serially sectioned tissues, which is not only labor-intensive and time-consuming but also error-prone. Recent advances in tissue clearing techniques allow visualization of cellular structures and neural networks inside of unsectioned whole tissues or the entire body. However, currently available protocols require long process times. Here, we present the rapid and highly reproducible ACT-PRESTO (active clarity technique-pressure related efficient and stable transfer of macromolecules into organs) method that clears tissues or the whole body within 1 day while preserving tissue architecture and protein-based signals derived from endogenous fluorescent proteins. Moreover, ACT-PRESTO is compatible with conventional immunolabeling methods and expedites antibody penetration into thick specimens by applying pressure. The speed and consistency of this method will allow high-content mapping and analysis of normal and pathological features in intact organs and bodies.


Assuntos
Acrilamida/química , Encéfalo/ultraestrutura , Fixadores/química , Formaldeído/química , Técnicas de Preparação Histocitológica , Polímeros/química , Animais , Encéfalo/anatomia & histologia , Encéfalo/fisiologia , Difusão , Eletroforese , Humanos , Hidrogéis/química , Imageamento Tridimensional , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Pressão , Coelhos , Ratos , Ratos Sprague-Dawley , Fixação de Tecidos/métodos , Xenopus , Peixe-Zebra
14.
Neuron ; 85(4): 755-69, 2015 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-25695270

RESUMO

Myelin ensheathes axons to allow rapid propagation of action potentials and proper nervous system function. In the peripheral nervous system, Schwann cells (SCs) radially sort axons into a 1:1 relationship before wrapping an axonal segment to form myelin. SC myelination requires the adhesion G protein-coupled receptor GPR126, which undergoes autoproteolytic cleavage into an N-terminal fragment (NTF) and a seven-transmembrane-containing C-terminal fragment (CTF). Here we show that GPR126 has domain-specific functions in SC development whereby the NTF is necessary and sufficient for axon sorting, whereas the CTF promotes wrapping through cAMP elevation. These biphasic roles of GPR126 are governed by interactions with Laminin-211, which we define as a novel ligand for GPR126 that modulates receptor signaling via a tethered agonist. Our work suggests a model in which Laminin-211 mediates GPR126-induced cAMP levels to control early and late stages of SC development.


Assuntos
Laminina/metabolismo , Bainha de Mielina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Células de Schwann/metabolismo , Animais , Animais Geneticamente Modificados , Animais Recém-Nascidos , Células COS , Células Cultivadas , Chlorocebus aethiops , Embrião de Mamíferos , Embrião não Mamífero , Gânglios Espinais/citologia , Humanos , Técnicas In Vitro , Laminina/genética , Larva , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Morfolinos/farmacologia , Bainha de Mielina/ultraestrutura , Neuroglia/metabolismo , Neuroglia/ultraestrutura , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Células de Schwann/ultraestrutura , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
15.
Nat Commun ; 6: 6121, 2015 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-25607655

RESUMO

Mutations in GPR56, a member of the adhesion G protein-coupled receptor family, cause a human brain malformation called bilateral frontoparietal polymicrogyria (BFPP). Magnetic resonance imaging (MRI) of BFPP brains reveals myelination defects in addition to brain malformation. However, the cellular role of GPR56 in oligodendrocyte development remains unknown. Here, we demonstrate that loss of Gpr56 leads to hypomyelination of the central nervous system in mice. GPR56 levels are abundant throughout early stages of oligodendrocyte development, but are downregulated in myelinating oligodendrocytes. Gpr56-knockout mice manifest with decreased oligodendrocyte precursor cell (OPC) proliferation and diminished levels of active RhoA, leading to fewer mature oligodendrocytes and a reduced number of myelinated axons in the corpus callosum and optic nerves. Conditional ablation of Gpr56 in OPCs leads to a reduced number of mature oligodendrocytes as seen in constitutive knockout of Gpr56. Together, our data define GPR56 as a cell-autonomous regulator of oligodendrocyte development.


Assuntos
Regulação da Expressão Gênica , Oligodendroglia/citologia , Receptores Acoplados a Proteínas G/metabolismo , Animais , Axônios/metabolismo , Encéfalo/metabolismo , Linhagem da Célula , Proliferação de Células , Sobrevivência Celular , Sistema Nervoso Central/embriologia , Sistema Nervoso Central/metabolismo , Corpo Caloso/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Malformações do Desenvolvimento Cortical/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Mutação , Bainha de Mielina/química , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Nervo Óptico/metabolismo , Transdução de Sinais , Tamoxifeno/química , Proteínas rho de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP
16.
PLoS One ; 9(6): e100043, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24949629

RESUMO

GPR56 is a member of the adhesion G protein-coupled receptor (GPCR) family. Despite the importance of GPR56 in brain development, where mutations cause a devastating human brain malformation called bilateral frontoparietal polymicrogyria (BFPP), the signaling mechanism(s) remain largely unknown. Like many other adhesion GPCRs, GPR56 is cleaved via a GPCR autoproteolysis-inducing (GAIN) domain into N- and C-terminal fragments (GPR56N and GPR56C); however, the biological significance of this cleavage is elusive. Taking advantage of the recent identification of a GPR56 ligand and the presence of BFPP-associated mutations, we investigated the molecular mechanism of GPR56 signaling. We demonstrate that ligand binding releases GPR56N from the membrane-bound GPR56C and triggers the association of GPR56C with lipid rafts and RhoA activation. Furthermore, one of the BFPP-associated mutations, L640R, does not affect collagen III-induced lipid raft association of GPR56. Instead, it specifically abolishes collagen III-mediated RhoA activation. Together, these findings reveal a novel signaling mechanism that may apply to other members of the adhesion GPCR family.


Assuntos
Colágeno Tipo III/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Sequência de Aminoácidos , Animais , Sequência Conservada , Ativação Enzimática/efeitos dos fármacos , Evolução Molecular , Células HEK293 , Humanos , Ligantes , Malformações do Desenvolvimento Cortical/genética , Microdomínios da Membrana/efeitos dos fármacos , Microdomínios da Membrana/metabolismo , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Estrutura Secundária de Proteína , Transporte Proteico/efeitos dos fármacos , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais/efeitos dos fármacos
17.
PLoS One ; 8(7): e68781, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23874761

RESUMO

Loss of function mutations in GPR56, which encodes a G protein-coupled receptor, cause a specific human brain malformation called bilateral frontoparietal polymicrogyria (BFPP). Studies from BFPP postmortem brain tissue and Gpr56 knockout mice have previously showed that GPR56 deletion leads to breaches in the pial basement membrane (BM) and neuronal ectopias during cerebral cortical development. Since α3ß1 integrin also plays a role in pial BM assembly and maintenance, we evaluated whether it functions together with GPR56 in regulating the same developmental process. We reveal that loss of α3 integrin enhances the cortical phenotype associated with Gpr56 deletion, and that neuronal overmigration through a breached pial BM occurs earlier in double knockout than in Gpr56 single knockout mice. These observations provide compelling evidence of the synergism of GPR56 and α3ß1 integrin in regulating the development of cerebral cortex.


Assuntos
Córtex Cerebral/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Membrana Basal/metabolismo , Membrana Basal/patologia , Movimento Celular/genética , Córtex Cerebral/embriologia , Córtex Cerebral/patologia , Colágeno Tipo III/metabolismo , Deleção de Genes , Integrina alfa3beta1/genética , Integrina alfa3beta1/metabolismo , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Fenótipo , Ligação Proteica , Receptores Acoplados a Proteínas G/genética
18.
Mol Neurobiol ; 47(1): 186-96, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23001883

RESUMO

GPR56, a member of the adhesion G protein-coupled receptor (GPCR) family, is integral to the development of the cortex, as mutations in GPR56 cause bilateral frontoparietal polymicrogyria (BFPP). BFPP is a cobblestone-like cortical malformation, characterized by overmigrating neurons and the formation of neuronal ectopias on the surface of the brain. Since its original cloning a decade ago, GPR56 has emerged from an orphaned and uncharacterized protein to an increasingly well-understood receptor, both in terms of its signaling and function. Collagen III is the ligand of GPR56 in the developing brain. Upon binding to collagen III, GPR56 activates RhoA via coupling to Gα(12/13). This pathway appears to be particularly critical in the preplate neurons, which are the earliest born neurons in the cortex, as the expression pattern of GPR56 in these neurons mimics the anterior to posterior gradient of malformation associated with loss of GPR56 in both humans and mice. Further characterizing the role of GPR56 in the preplate will shed light on the mechanism of cortical development and patterning.


Assuntos
Movimento Celular , Córtex Cerebral/crescimento & desenvolvimento , Matriz Extracelular/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Córtex Cerebral/anormalidades , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Humanos , Receptores Acoplados a Proteínas G/química , Transdução de Sinais
19.
J Neurooncol ; 110(3): 359-68, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23096132

RESUMO

Glioblastoma multiforme (GBM) modulates the immune system to engance its malignant potential. Signal transducer and activator of transcription 3 (STAT3) activation is a regulatory node in modulating the immune microenvironment in several human tumors, including GBM. To investigate whether STAT3 inhibition might enhance anti-tumor responses, we inhibited STAT3 signaling using small interfering RNA against STAT3. We tested the human GBM cell lines U87, U251, and HS683, which are known to constitutively express high levels of phospho-STAT3. STAT3 inhibition resulted in enhanced expression of several pro-inflammatory cytokines and chemokines and supernatants from STAT3-silenced human GBM cell lines increased lipopolysaccharide-induced dendritic cell activation in vitro. We obtained comparable results when STAT3 activity was suppressed with specific small molecule inhibitors. Our results support the hypothesis that activated STAT3 contributes to the immunosuppressive microenvironment in GBM and support previous studies implicating STAT3 as a potential target for immunotherapy.


Assuntos
Neoplasias Encefálicas/imunologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Células Dendríticas/citologia , Glioblastoma/imunologia , Fator de Transcrição STAT3/metabolismo , Ácidos Aminossalicílicos/farmacologia , Benzenossulfonatos/farmacologia , Western Blotting , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Humanos , Lipopolissacarídeos/farmacologia , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Transdução de Sinais , Células Tumorais Cultivadas
20.
J Comp Neurol ; 520(13): 2930-40, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22351047

RESUMO

GPR56, one of the adhesion G-protein-coupled receptors (GPCRs), plays an important role in the development of the cerebral cortex. Mutations in GPR56 cause a severe human cortical malformation called bilateral frontoparietal polymicrogyria (BFPP), characterized by a global malformation of the cerebral cortex that most severely affects the frontal and parietal regions. To characterize the expression pattern of GPR56 in the developing cerebral cortex, we developed a mouse monoclonal antibody against mouse GPR56. We revealed that GPR56 is expressed in multiple cell types in the preplate, marginal zone, subventricular zone (SVZ), and ventricular zone (VZ). Most interestingly, the expression of GPR56 in preplate neurons showed an anterior-to-posterior gradient at embryonic day (E) 10.5-11.5. In contrast, the expression pattern of the GPR56 ligand, collagen III, revealed no visible gradient pattern. With the widespread expression of GPR56 in the developing cortex, it is difficult to draw a specific conclusion as to which of the GPR56-expressing cells are critical for human brain development. However, the correlation between GPR56 expression in neurons at E10.5-E11.5 and the anatomic distribution of the cortical malformation in both humans and mice suggests that its function in preplate neurons is indispensible.


Assuntos
Neocórtex/embriologia , Neocórtex/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Receptores Acoplados a Proteínas G/biossíntese , Animais , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Células-Tronco Neurais/metabolismo
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