Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 19 de 19
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Neuroinflammation ; 16(1): 214, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31722723

RESUMO

BACKGROUND: Neonatal hypoxic-ischemic brain damage (HIBD), a leading cause of neonatal mortality, has intractable sequela such as epilepsy that seriously affected the life quality of HIBD survivors. We have previously shown that ion channel dysfunction in the central nervous system played an important role in the process of HIBD-induced epilepsy. Therefore, we continued to validate the underlying mechanisms of TRPV1 as a potential target for epilepsy. METHODS: Neonatal hypoxic ischemia and oxygen-glucose deprivation (OGD) were used to simulate HIBD in vivo and in vitro. Primarily cultured astrocytes were used to assess the expression of TRPV1, glial fibrillary acidic protein (GFAP), cytoskeletal rearrangement, and inflammatory cytokines by using Western blot, q-PCR, and immunofluorescence. Furthermore, brain electrical activity in freely moving mice was recorded by electroencephalography (EEG). TRPV1 current and neuronal excitability were detected by whole-cell patch clamp. RESULTS: Astrocytic TRPV1 translocated to the membrane after OGD. Mechanistically, astrocytic TRPV1 activation increased the inflow of Ca2+, which promoted G-actin polymerized to F-actin, thus promoted astrocyte migration after OGD. Moreover, astrocytic TRPV1 deficiency decreased the production and release of pro-inflammatory cytokines (TNF, IL-6, IL-1ß, and iNOS) after OGD. It could also dramatically attenuate neuronal excitability after OGD and brain electrical activity in HIBD mice. Behavioral testing for seizures after HIBD revealed that TRPV1 knockout mice demonstrated prolonged onset latency, shortened duration, and decreased seizure severity when compared with wild-type mice. CONCLUSIONS: Collectively, TRPV1 promoted astrocyte migration thus helped the infiltration of pro-inflammatory cytokines (TNF, IL-1ß, IL-6, and iNOS) from astrocytes into the vicinity of neurons to promote epilepsy. Our study provides a strong rationale for astrocytic TRPV1 to be a therapeutic target for anti-epileptogenesis after HIBD.

2.
J Neuroinflammation ; 16(1): 114, 2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31142341

RESUMO

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is a serious birth complication with high incidence in both advanced and developing countries. Children surviving from HIE often have severe long-term sequela including cerebral palsy, epilepsy, and cognitive disabilities. The severity of HIE in infants is tightly associated with increased IL-1ß expression and astrocyte activation which was regulated by transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel in the TRP family. METHODS: Neonatal hypoxic ischemia (HI) and oxygen-glucose deprivation (OGD) were used to simulate HIE in vivo and in vitro. Primarily cultured astrocytes were used for investigating the expression of glial fibrillary acidic protein (GFAP), IL-1ß, Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), and activation of the nucleotide-binding, oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome by using Western blot, q-PCR, and immunofluorescence. Brain atrophy, infarct size, and neurobehavioral disorders were evaluated by Nissl staining, 2,3,5-triphenyltetrazolium chloride monohydrate (TTC) staining and neurobehavioral tests (geotaxis reflex, cliff aversion reaction, and grip test) individually. RESULTS: Astrocytes were overactivated after neonatal HI and OGD challenge. The number of activated astrocytes, the expression level of IL-1ß, brain atrophy, and shrinking infarct size were all downregulated in TRPV1 KO mice. TRPV1 deficiency in astrocytes attenuated the expression of GFAP and IL-1ß by reducing phosphorylation of JAK2 and STAT3. Meanwhile, IL-1ß release was significantly reduced in TRPV1 deficiency astrocytes by inhibiting activation of NLRP3 inflammasome. Additionally, neonatal HI-induced neurobehavioral disorders were significantly improved in the TRPV1 KO mice. CONCLUSIONS: TRPV1 promotes activation of astrocytes and release of astrocyte-derived IL-1ß mainly via JAK2-STAT3 signaling and activation of the NLRP3 inflammasome. Our findings provide mechanistic insights into TRPV1-mediated brain damage and neurobehavioral disorders caused by neonatal HI and potentially identify astrocytic TRPV1 as a novel therapeutic target for treating HIE in the subacute stages (24 h).


Assuntos
Astrócitos/metabolismo , Encéfalo/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Interleucina-1beta/metabolismo , Canais de Cátion TRPV/deficiência , Animais , Astrócitos/patologia , Encéfalo/patologia , Células Cultivadas , Feminino , Hipóxia-Isquemia Encefálica/genética , Hipóxia-Isquemia Encefálica/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Canais de Cátion TRPV/genética
3.
J Neuroinflammation ; 15(1): 186, 2018 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-29925377

RESUMO

BACKGROUND: Neonatal hypoxic-ischemic brain damage, characterized by tissue loss and neurologic dysfunction, is a leading cause of mortality and a devastating disease of the central nervous system. We have previously shown that vitexin has been attributed various medicinal properties and has been demonstrated to have neuroprotective roles in neonatal brain injury models. In the present study, we continued to reinforce and validate the basic understanding of vitexin (45 mg/kg) as a potential treatment for epilepsy and explored its possible underlying mechanisms. METHODS: P7 Sprague-Dawley (SD) rats that underwent right common carotid artery ligation and rat brain microvascular endothelial cells (RBMECs) were used for the assessment of Na+-K+-Cl- co-transporter1 (NKCC1) expression, BBB permeability, cytokine expression, and neutrophil infiltration by western blot, q-PCR, flow cytometry (FCM), and immunofluorescence respectively. Furthermore, brain electrical activity in freely moving rats was recorded by electroencephalography (EEG). RESULTS: Our data showed that NKCC1 expression was attenuated in vitexin-treated rats compared to the expression in the HI group in vivo. Oxygen glucose deprivation/reoxygenation (OGD) was performed on RBMECs to explore the role of NKCC1 and F-actin in cytoskeleton formation with confocal microscopy, N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide, and FCM. Concomitantly, treatment with vitexin effectively alleviated OGD-induced NKCC1 expression, which downregulated F-actin expression in RBMECs. In addition, vitexin significantly ameliorated BBB leakage and rescued the expression of tight junction-related protein ZO-1. Furthermore, inflammatory cytokine and neutrophil infiltration were concurrently and progressively downregulated with decreasing BBB permeability in rats. Vitexin also significantly suppressed brain electrical activity in neonatal rats. CONCLUSIONS: Taken together, these results confirmed that vitexin effectively alleviates epilepsy susceptibility through inhibition of inflammation along with improved BBB integrity. Our study provides a strong rationale for the further development of vitexin as a promising therapeutic candidate treatment for epilepsy in the immature brain.


Assuntos
Anticonvulsivantes/uso terapêutico , Apigenina/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia/etiologia , Hipóxia-Isquemia Encefálica/complicações , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , Animais , Animais Recém-Nascidos , Hipóxia Celular/efeitos dos fármacos , Células Cultivadas , Cloretos/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/deficiência , Fator Estimulador de Colônias de Granulócitos/genética , Fator Estimulador de Colônias de Granulócitos/metabolismo , Interleucina-3/genética , Interleucina-3/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Membro 2 da Família 12 de Carreador de Soluto/genética , Proteína da Zônula de Oclusão-1/metabolismo
4.
CNS Neurosci Ther ; 24(10): 967-977, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29577640

RESUMO

AIM: Multiple sclerosis (MS) is a neurological autoimmune disorder characterized by mistaken attacks of inflammatory cells against the central nervous system (CNS), resulting in demyelination and axonal damage. Kv1.3 channel blockers can inhibit T-cell activation and have been designed for MS therapy. However, little is known about the effects of Kv1.3 blockers on protecting myelin sheaths/axons in MS. This study aimed at investigating the neuroprotection efficacy of a selective Kv1.3 channel blocker ImKTx88 (ImK) in MS animal model. METHODS: Experimental autoimmune encephalomyelitis (EAE) rat model was established. The neuroprotective effect of ImK was assessed by immunohistochemistry and transmission electron microscopy (TEM). In addition, the antiinflammatory effect of ImK by suppressing T-cell activation was assessed by flow cytometry and ELISA in vitro. RESULTS: Our results demonstrated that ImK administration ameliorated EAE clinical severity. Moreover, ImK increased oligodendrocytes survival, preserved axons, and myelin integrity and reduced the infiltration of activated T cells into the CNS. This protective effect of the peptide may be related to its suppression of autoantigen-specific T-cell activation via calcium influx inhibition. CONCLUSION: ImK prevents neurological damage by suppressing T-cell activation, suggesting the applicability of this peptide in MS therapy.


Assuntos
Encefalomielite Autoimune Experimental/complicações , Canal de Potássio Kv1.3/metabolismo , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/etiologia , Bloqueadores dos Canais de Potássio/uso terapêutico , Linfócitos T/fisiologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Modelos Animais de Doenças , Feminino , Canal de Potássio Kv1.3/antagonistas & inibidores , Microscopia Eletrônica de Transmissão , Mycobacterium tuberculosis/patogenicidade , Proteína Básica da Mielina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Linfócitos T/efeitos dos fármacos , Linfócitos T/ultraestrutura
5.
Oncotarget ; 8(15): 25513-25524, 2017 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-28424420

RESUMO

Neonatal hypoxic-ischemic is a major cause of death and disability in neonates. In this study, we suggest for the first time that pretreatment with vitexin may suppress a pro-apoptotic signaling pathway in hypoxic-ischemic neuronal injury in neonates by inhibition of the phosphorylation of Ca2+/Calmodulin-dependent protein kinase II. Here we found that vitexin pretreatment reduced brain infarct volume in a dose-dependent manner. In addition, vitexin decreased the number of TUNEL-positive cells and brain atrophy. Furthermore, vitexin improved neurobehavioral outcomes. Vitexin also reduced oxygen glucose deprivation-induced neuronal injury and calcium entry. Vitexin pretreatment increased the Bcl-2/Bax protein ratio and decreased phosphorylation of Ca2+/Calmodulin-dependent protein kinase II and NF-κB, cleaved caspase-3 protein expression 24 hours after injury. Our data indicate that pretreatment with vitexin protects against neonatal hypoxic-ischemic brain injury and thus has potential as a treatment for hypoxic-ischemic brain injury.


Assuntos
Apigenina/farmacologia , Apoptose/efeitos dos fármacos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Atrofia , Infarto Encefálico/etiologia , Infarto Encefálico/metabolismo , Infarto Encefálico/patologia , Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Glucose/metabolismo , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Hipóxia-Isquemia Encefálica/patologia , Camundongos , NF-kappa B/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oxigênio/metabolismo
6.
Brain Res Bull ; 130: 188-199, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28161194

RESUMO

Hypoxia-ischemia brain damage (HIBD) is one of prevalent causes of neonatal mortality and morbidity. Our data demonstrated that hypoxia-ischemia (HI) induced Na+-K+-Cl--co-transporter 1 (NKCC1) increasing in hippocampus. Previous studies demonstrated that NKCC1 regulates various stages of neurogenesis. In this study, we studied the role of increased NKCC1 in regulating of HI-induced neurogenesis. HIBD model was established in 7days old Sprague-Dawley rat pup, and the expression of NKCC1 was detected by western blot and qPCR. Brain electrical activity in freely rats was monitored by electroencephalography (EEG) recordings. HI-induced neurogenesis was detected by immunofluorescence staining. Neurobehavioral test was to investigate the neuro-protective role of bumetanide, an inhibitor of NKCC1, on neonatal rats after HI. The results showed that bumetanide treatment significantly reduced brain electrical activity and the seizure stage of epilepsy induced by pentylenetetrazol (PTZ) in vivo after HI. In addition, bumetanide restored aberrant hippocampal neurogenesis and associated cognitive function. Our data demonstrated that bumetanide reduces the susceptibility of epilepsy induced by PTZ in rats suffering from HI injury during neonatal period via restoring the ectopic newborn neurons in dentate gyrus (DG) and cognitive function.


Assuntos
Anticonvulsivantes/administração & dosagem , Bumetanida/administração & dosagem , Hipocampo/fisiopatologia , Hipóxia-Isquemia Encefálica/complicações , Neurogênese/efeitos dos fármacos , Convulsões/fisiopatologia , Animais , Animais Recém-Nascidos , Movimento Celular/efeitos dos fármacos , Proliferação de Células , Eletroencefalografia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Memória/efeitos dos fármacos , Pentilenotetrazol/administração & dosagem , Ratos Sprague-Dawley , Convulsões/induzido quimicamente , Convulsões/complicações , Convulsões/metabolismo , Membro 2 da Família 12 de Carreador de Soluto/metabolismo
7.
Neuropharmacology ; 99: 38-50, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26187393

RESUMO

Previous studies have demonstrated that the early suppression of HIF-1α after hypoxia-ischemia (HI) injury provides neuroprotection. Vitexin (5, 7, 4-trihydroxyflavone-8-glucoside), an HIF-1α inhibitor, is a c-glycosylated flavone that has been identified in medicinal plants. Therefore, we hypothesized that treatment with vitexin would protect against HI brain injury. Newborn rat pups were subjected to unilateral carotid artery ligation followed by 2.5 h of hypoxia (8% O2 at 37 °C). Vitexin (30, 45 or 60 mg/kg) was administered intraperitoneally at 5 min or 3 h after HI. Vitexin, administered 5 min after HI, was neuroprotective as seen by decreased infarct volume evaluated at 48 h post-HI. This neuroprotection was removed when vitexin was administered 3 h after HI. Neuronal cell death, blood-brain barrier (BBB) integrity, brain edema, HIF-1α and VEGF protein levels were evaluated using a combination of Nissl staining, IgG staining, brain water content, immunohistochemistry and Western blot at 24 and 48 h after HI. The long-term effects of vitexin were evaluated by brain atrophy measurement, Nissl staining and neurobehavioral tests. Vitexin (45 mg/kg) ameliorated brain edema, BBB disruption and neuronal cell death; Upregulation of HIF-1α by dimethyloxalylglycine (DMOG) increased the BBB permeability and brain edema compared to HI alone. Vitexin attenuated the increase in HIF-1α and VEGF. Vitexin also had long-term effects of protecting against the loss of ipsilateral brain and improveing neurobehavioral outcomes. In conclusion, our data indicate early HIF-1α inhibition with vitexin provides both acute and long-term neuroprotection in the developing brain after neonatal HI injury.


Assuntos
Apigenina/farmacologia , Encéfalo/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Animais , Animais Recém-Nascidos , Apigenina/química , Atrofia/tratamento farmacológico , Atrofia/fisiopatologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/fisiopatologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Edema Encefálico/tratamento farmacológico , Edema Encefálico/patologia , Edema Encefálico/fisiopatologia , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade Capilar/fisiologia , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Hipóxia-Isquemia Encefálica/fisiopatologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/fisiologia , Fármacos Neuroprotetores/química , Distribuição Aleatória , Ratos Sprague-Dawley , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/metabolismo
8.
Brain Behav Immun ; 48: 68-77, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25801060

RESUMO

Febrile seizure (FS) is the most common seizure disorder in children, and children with FS are regarded as a high risk for the eventual development of epilepsy. Brain inflammation may be implicated in the mechanism of FS. Transient receptor potential vanilloid 1 (TRPV1) is believed to act as a monitor and regulator of body temperature. The role of inflammation in synaptic plasticity mediation indicates that TRPV1 is relevant to several nervous system diseases, such as epilepsy. Here, we report a critical role for TRPV1 in a febrile seizure mouse model and reveal increased levels of pro-inflammatory factors in the immature brain. Animals were subjected to hyperthermia for 30 min, which generates seizures lasting approximately 20 min, and then were used for experiments. To invoke frequently repetitive febrile seizures, mice are exposed to hyperthermia for three times daily at an interval of 4h between every time induced seizure, and a total of 4 days to induce. Behavioral testing for febrile seizures revealed that a TRPV1 knock-out mouse model demonstrated a prolonged onset latency and a shortened duration and seizure grade of febrile seizure when compared with wild type (WT) mice. The expression levels of both TRPV1 mRNA and protein increased after a hyperthermia-induced febrile seizure in WT mice. Notably, TRPV1 activation resulted in a significant elevation in the expression of pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α and HMGB1) in the hippocampus and cortex. These data indicate that the reduction of TRPV1 expression parallels a decreased susceptibility to febrile seizures. Thus, preventative strategies might be developed for use during febrile seizures.


Assuntos
Encéfalo/metabolismo , Citocinas/metabolismo , Hipertermia Induzida , Convulsões Febris/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Encéfalo/imunologia , Linhagem Celular , Modelos Animais de Doenças , Hipocampo/imunologia , Hipocampo/metabolismo , Camundongos , Camundongos Knockout , Convulsões Febris/imunologia , Canais de Cátion TRPV/genética
9.
Neurosci Bull ; 30(6): 985-998, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25370443

RESUMO

Gamma-amino-butyric acid (GABA)-containing interneurons are crucial to both development and function of the brain. Down-regulation of GABAergic inhibition may result in the generation of epileptiform activity. Loss, axonal sprouting, and dysfunction of interneurons are regarded as mechanisms involved in epileptogenesis. Recent evidence suggests that network connectivity and the properties of interneurons are responsible for excitatory-inhibitory neuronal circuits. The balance between excitation and inhibition in CA1 neuronal circuitry is considerably altered during epileptic changes. This review discusses interneuron diversity, the causes of interneuron dysfunction in epilepsy, and the possibility of using GABAergic neuronal progenitors for the treatment of epilepsy.


Assuntos
Epilepsia/fisiopatologia , Neurônios GABAérgicos/fisiologia , Hipocampo/fisiopatologia , Interneurônios/fisiologia , Animais , Humanos , Rede Nervosa/fisiologia , Inibição Neural/fisiologia
12.
Toxicon ; 71: 66-75, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23732125

RESUMO

The transient receptor potential vanilloid 1(TRPV1) channels are members of the transient receptor potential (TRP) superfamily. Members of this family are expressed in primary sensory neurons and are best known for their role in nociception and sensory transmission. Multiple painful stimuli can activate these channels. In this review, we discussed the mechanisms of different types of venoms that target TRPV1, such as scorpion venom, botulinum neurotoxin, spider toxin, ciguatera fish poisoning (CFP) and neurotoxic shellfish poisoning (NSP). Some of these toxins activate TRPV1; however, some do not. Regardless of TRPV1 inhibition or activation, they occur through different pathways. For example, BoNT/A decreases TRPV1 expression levels by blocking TRPV1 trafficking to the plasma membrane, although the exact mechanism is still under debate. Vanillotoxins from tarantula (Psalmopoeus cambridgei) are proposed to activate TRPV1 via interaction with a region of TRPV1 that is homologous to voltage-dependent ion channels. Here, we offer a description of the present state of knowledge for this complex subject.


Assuntos
Dor/patologia , Canais de Cátion TRPV/metabolismo , Toxinas Biológicas/toxicidade , Animais , Toxinas Botulínicas/toxicidade , Humanos , Dor/induzido quimicamente , Venenos de Escorpião/toxicidade , Venenos de Aranha/toxicidade , Relação Estrutura-Atividade , Canais de Cátion TRPV/genética
13.
Sci China Life Sci ; 56(1): 51-8, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23314867

RESUMO

To design a releasable PEGylated TNF-α (rPEG-TNF-α), a cathepsin B-sensitive dipeptide (Val-Cit moiety) was inserted into conventional PEG-modified TNF-α (PEG-TNF-α), facilitating its clinical use for anti-tumor therapy. Comparative pharmacokinetic and pharmacodynamic studies showed that the half-lives of both PEGylated forms of TNF-α were ∼60-fold greater than that of unmodified TNF-α. In addition, the in vitro bioactivity of rPEG-TNF-α was greater than that of PEG-TNF-α with the same degree of PEG modification. Release of TNF-α from rPEG-TNF-α in vitro was dependent on the presence of cathepsin B and was inhibited by a cathepsin B inhibitor. Despite the potent cytotoxicity of unmodified TNF-α against normal cells, its PEGylated forms at higher TNF-α concentrations showed low cytotoxic activity against these cells. In contrast, both forms of PEGylated TNF-α showed potent cytotoxic activity against the B16 and L929 cell lines, with rPEG-TNF-α being 5- and 9-fold more potent, respectively, than PEG-TNF-α. Moreover, rPEG-TNF-α was a more potent in vivo antitumor agent than PEG-TNF-α.


Assuntos
Dipeptídeos/química , Neoplasias Experimentais/tratamento farmacológico , Polietilenoglicóis/química , Fator de Necrose Tumoral alfa/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Catepsina B/antagonistas & inibidores , Catepsina B/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Composição de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Glicopeptídeos/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Leucina/análogos & derivados , Leucina/farmacologia , Lisossomos/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Pepstatinas/farmacologia , Inibidores de Proteases/farmacologia , Ratos , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos , Fator de Necrose Tumoral alfa/química , Fator de Necrose Tumoral alfa/farmacocinética
14.
Acta Virol ; 56(4): 283-91, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23237084

RESUMO

One of the most fascinating findings in retrovirology is the construction of viral vectors based on foamy viruses (FVs) for gene therapy. The envelope glycoprotein (Env), one of the structural proteins of FV, is an important antigen in the immunoassays, as it is highly specific. To compare the characteristics of all 15 available FV Envs, the phylogenesis, hydrophobicity, modifications, and conserved motifs were analyzed based on the Env sequences. Meanwhile, the secondary structures of transmembrane (TM) domains of FV Envs were predicted. The results of phylogenetic analyses based on Envs indicated that the foamy viruses from different hosts could form three groups. The hydrophobicity analysis revealed that FV Envs had two prominent hydrophobic regions, which was similar to other retroviruses. Though the glycosylation, ubiquitination, and the secondary structures of TM domains of FV Envs were in line with other retroviruses, the roles were distinctly different. Interestingly, the analyses of conserved motifs suggested that FV Envs possessed several specific functional motifs.


Assuntos
Infecções por Retroviridae/veterinária , Infecções por Retroviridae/virologia , Spumavirus/genética , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/genética , Sequência de Aminoácidos , Animais , Humanos , Dados de Sequência Molecular , Filogenia , Conformação Proteica , Alinhamento de Sequência , Spumavirus/química , Spumavirus/classificação , Proteínas do Envelope Viral/metabolismo
15.
J Biol Chem ; 287(35): 29479-94, 2012 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-22761436

RESUMO

The voltage-gated Kv1.3 K(+) channel in effector memory T cells serves as a new therapeutic target for multiple sclerosis. In our previous studies, the novel peptide ADWX-1 was designed and synthesized as a specific Kv1.3 blocker. However, it is unclear if and how ADWX-1 alleviates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. In this study, the administration of ADWX-1 significantly ameliorated the rat experimental autoimmune encephalomyelitis model by selectively inhibiting CD4(+)CCR7(-) phenotype effector memory T cell activation. In contrast, the Kv1.3-specific peptide had little effect on CD4(+)CCR7(+) cells, thereby limiting side effects. Furthermore, we determined that ADWX-1 is involved in the regulation of NF-κB signaling through upstream protein kinase C-θ (PKCθ) in the IL-2 pathway of CD4(+)CCR7(-) cells. The elevated expression of Kv1.3 mRNA and protein in activated CD4(+)CCR7(-) cells was reduced by ADWX-1 engagement; however, an apparent alteration in CD4(+)CCR7(+) cells was not observed. Moreover, the selective regulation of the Kv1.3 channel gene expression pattern by ADWX-1 provided a further and sustained inhibition of the CD4(+)CCR7(-) phenotype, which depends on the activity of Kv1.3 to modulate its activation signal. In addition, ADWX-1 mediated the activation of differentiated Th17 cells through the CCR7(-) phenotype. The efficacy of ADWX-1 is supported by multiple functions, which are based on a Kv1.3(high) CD4(+)CCR7(-) T cell selectivity through two different pathways, including the classic channel activity-associated IL-2 pathway and the new Kv1.3 channel gene expression pathway.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Memória Imunológica/efeitos dos fármacos , Canal de Potássio Kv1.3/antagonistas & inibidores , Esclerose Múltipla/tratamento farmacológico , Peptídeos/farmacologia , Receptores CCR7 , Animais , Encefalomielite Autoimune Experimental/imunologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Interleucina-2/imunologia , Células Jurkat , Canal de Potássio Kv1.3/imunologia , Esclerose Múltipla/imunologia , RNA Mensageiro/imunologia , Ratos , Ratos Sprague-Dawley
16.
Bing Du Xue Bao ; 28(3): 285-90, 2012 May.
Artigo em Chinês | MEDLINE | ID: mdl-22764533

RESUMO

Foamy virus can establish lifelong persistent infection in mammal hosts without inducing diseases. Such special characteristic stimulates the interests of researchers. As reported, the accessory protein Bet of foamy virus could regulate the gene expression and infection cycle of foamy virus and take part in the generation of chronic viral infection. And also, Bet might prevent the host cellular defense factor APO-BEC3 from interfering the replication of virus and play a role in maintaining viral persistent infection. In order to elucidate the roles of Bet in the foamy virus replication and infection, this review summarized the research progress of Bet protein reported in recent years.


Assuntos
Infecções por Retroviridae/virologia , Proteínas dos Retroviridae/metabolismo , Spumavirus/metabolismo , Animais , Regulação Viral da Expressão Gênica , Humanos , Infecções por Retroviridae/imunologia , Proteínas dos Retroviridae/genética , Spumavirus/genética
17.
Neurosci Bull ; 28(3): 301-8, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22622830

RESUMO

Febrile seizures (FSs) are the most common convulsions in childhood. Studies have demonstrated a significant relationship between a history of prolonged FSs during early childhood and temporal sclerosis, which is responsible for intractable mesial temporal lobe epilepsy. It has been shown that interleukin-1ß (IL-1ß) is intrinsically involved in the febrile response in children and in the generation of FSs. We summarize the gene polymorphisms, changes of IL-1ß levels and the putative role of IL-1ß in the generation of FSs. IL-1ß could play a role either in enhancing or in reducing neural excitability. If the enhancing and reducing effects are balanced, an FS does not occur. When the enhancing effect plays the leading role, an FS is generated. A mild imbalance can cause simple FSs while a severe imbalance can cause complex FSs and febrile status epilepticus. Therefore, anti-IL-1ß therapy may help to treat FSs.


Assuntos
Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Convulsões Febris/genética , Convulsões Febris/metabolismo , Humanos , Polimorfismo Genético
19.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 26(2): 121-4, 2010 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-20230669

RESUMO

AIM: To construct replication-defective HFV-IL24 virus vector and to investigate its inhibitive effect on cancer cells after infected or transfected by this vector. METHODS: pDeltaphi-IL24 was constructed and was co-transfected with helper-plasmids into HEK 293T cells. Recombinant HFV-IL24 vector was extracted to infect HeLa cells and the inhibitive effect of IL-24 on cancer cells was examined by RT-PCR, MTT, cell counting and FCM methods. RESULTS: pDeltaphi-IL24 plasmid and HFV-IL24 particles were successfully constructed. HeLa cells exhibited obvious growth inhibition, cell cycle variation and visible apoptosis (mortality) after infected or transfected by HFV-IL24 or pDeltaphi-IL24. CONCLUSION: The results of the study provide some evidence for human foamy virus used as an effective gene transfer tool and for cancer gene therapy with HFV-IL24.


Assuntos
Terapia Genética , Interleucinas/genética , Neoplasias/terapia , Vírus Espumoso dos Símios/genética , Ciclo Celular , Proliferação de Células , Sobrevivência Celular , Vetores Genéticos/genética , Células HeLa , Humanos , Neoplasias/patologia , Plasmídeos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA