RESUMO
OBJECTIVES: To investigate the effect of glucagon-like peptide-1 (GLP-1) receptor and glucose dependent insulinotrophic polypeptide (GIP) receptor dual agonist DA-JC4 on alleviating Parkinson's disease (PD) and unveil related cellular mechanisms. METHODS: Rotenone was injected to generate a rat PD model, on which the effect of DA-JC4 on motor functions was evaluated by rotational behavioral assay and open field test. The survival of dopaminergic neurons was analyzed, in addition to assays for mitochondrial stress and quantification of neurotransmitter levels using high performance liquid chromatography (HPLC). In cultured hippocampal neurons, the effect of DA-JC4 on mitochondrial stress and related cellular mechanism was analyzed by Flow cytometry, western blotting and reactive oxygen species (ROS). RESULTS: DA-JC4 significantly improved motor functions in PD rats, and elevated levels of major neurotransmitters. By histological analysis, DA-JC4 protected dopaminergic neurons from rotenone-induced cell death, which was associated with reduced mitochondrial stress. Experiments in cultured rat hippocampal neurons validated the neuroprotective role of DA-JC4 against cell apoptosis and mitochondrial stress induced by rotenone. The protective effect of DA-JC4 was later found to be dependent on AKT/JNK signal pathway, as treatment using AKT inhibitor or JNK activator abolished such effects. CONCLUSION: Our results showed that the dual agonist of GLP-1/GIP receptor could ameliorate motor dysfunctions of PD by protecting dopaminergic neurons which was mediated by relieved mitochondrial stress and apoptosis via AKT/JNK signal pathway.
Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Fármacos Neuroprotetores/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Receptores dos Hormônios Gastrointestinais/agonistas , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Neurônios Dopaminérgicos/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Transtornos Parkinsonianos/fisiopatologia , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Rotenona/toxicidadeRESUMO
BACKGROUND: This study is conducted to investigate the protective role of elevated microRNA-375 (miR-375) in dopaminergic neurons in Parkinson's disease through down-regulating transcription factor specificity protein 1 (SP1). RESULTS: The successfully modeled rats with Parkinson's disease showed aggregated neurobehavioral change, increased neuroinflammatory response and oxidative stress, and lowered dopamine content. Parkinson's disease rats treated with overexpressed miR-375 displayed improved neurobehavioral change, ameliorated neuroinflammatory response and oxidative stress, heightened dopamine content and abated neuronal apoptosis by down-regulating SP1. Up-regulation of SP1 reversed the protective effect of upregulated miR-375 on Parkinson's disease. CONCLUSION: Up-regulation of miR-375 ameliorated the damage of dopaminergic neurons, reduced oxidative stress and inflammation in Parkinson's disease by inhibiting SP1. METHODS: Parkinson's disease rat model was established by targeted injection of 6-hydroxydopamine to damage the substantia nigra striatum. The successfully modeled Parkinson's disease rats were intracerebroventricularly injected with miR-375 mimics or pcDNA3.1-SP1. The functions of miR-375 and SP1 in neurobehavioral change, neuroinflammatory response, oxidative stress, dopamine content and expression of apoptosis-related proteins in the substantia nigra of Parkinson's disease rats were evaluated. The target relation of miR-375 and SP1 was confirmed by bioinformatics analysis and dual luciferase reporter gene assay.
Assuntos
Neurônios Dopaminérgicos/metabolismo , Regulação da Expressão Gênica , Estresse Oxidativo/genética , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Fator de Transcrição Sp1/metabolismo , Animais , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Modelos Animais de Doenças , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Ratos , Substância Negra/metabolismoRESUMO
Hepatic artery aneurysm rupture is a rare cause of massive hemobilia, which is potentially life-threatening, cause of upper gastrointestinal hemorrhage. Cases of mycotic hepatic artery aneurysm associated with streptococcal endocarditis have rarely been reported. In the present study, we report a case of massive hemobilia that was caused by ruptured mycotic hepatic artery aneurysm in a patient who was infected with streptococcal endocarditis 3 months previously. Transarterial embolization in the patient failed, possibly due to vascular variations. However, surgical treatment was successfully performed, and the patient completely recovered. In conclusion, surgical treatment may be useful in treating massive hemobilia under life-threatening conditions, even in cases of vascular variations and failure of transarterial embolization.