RESUMO
Unlike the 1p36 microdeletion syndrome, which has been extensively described, 1p36.3 microduplications have rarely been reported. We report the two siblings of familial 1p36.3 microduplication, presenting with a severe global developmental delay, epilepsy, and a few dysmorphic features. They were referred to moderate-to-severe developmental delay (DD) and intellectual disability (ID). Both were considered eyelid myoclonus with absence of epilepsy (Jeavons syndrome). The EEG is characterized by widespread 2.5-3.5 Hz spikes and spike slow complex wave, eye closure sensitivity, and photosensitivity. The children has same dysmorphic features, including mild bitemporal narrowing and sloping forehead, sparse eyebrows, hypertelorism, ptosis, strabismus, infraorbital creases, wide nasal bridge with bulbous nasal tip, dystaxia, hallux valgus, and flat feet. Family exome sequencing revealed a maternally inherited 3.2-Mb microduplication of chromosomal band 1p36.3p36.2. However, DNA purified from blood samples of either parent did not find evidence for a microduplication of 1p36 in somatic tissue, indicating that such a mutation might be carried in the germline of the parents as gonadal mosaicism. No other family members of the affected siblings' parents were reported to be affected by the symptoms found.
Assuntos
Epilepsia , Deficiência Intelectual , Criança , Humanos , Deficiência Intelectual/genética , Mutação , Epilepsia/genética , Deficiências do Desenvolvimento/genéticaRESUMO
The current study aimed to investigate the effects of LACC1 on cognitive disorder due to stroke, as well as its underlying mechanism. LACC1 promoted inflammation and aggravated cognitive impairment in a mouse model of stroke. In an in vitro model of stroke, inhibition of LACC1 reduced inflammation and ROSinduced oxidative stress by activating AMPactivated protein kinase (AMPK) expression and suppressing NLPR3 expression. Furthermore, our studies revealed that inhibition of AMPK activity reduced the effects of siLACC1 on cognitive disorder in mice after stroke via the AMPK/NLPR3 pathway. AMPK activation also reduced the effects of LACC1 on inflammation and ROSinduced oxidative stress via the NLPR3 pathway in the in vitro model that we evaluated. Our study suggests that LACC1aggravated inflammation causes cognitive impairment after stroke via the AMPK/NLRP3 pathway, which may provide a new therapeutic target for stroke and other neurological diseases and their associated complications. In sum, we identified an important role and regulatory mechanism for LACC1 in maintaining strokeinduced cognitive disorder via the AMPK/NLRP3 pathway.
Assuntos
Proteínas Quinases Ativadas por AMP , Transtornos Cognitivos , Inflamação , Peptídeos e Proteínas de Sinalização Intracelular , Proteína 3 que Contém Domínio de Pirina da Família NLR , Acidente Vascular Cerebral , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Cognição/fisiologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/genética , Transtornos Cognitivos/metabolismo , Inflamação/genética , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismoRESUMO
BACKGROUND/AIM: This study aimed to investigate the effect and mechanism of lupeol on cerebral ischemia-reperfusion injury in rats. METHODS: The effects of lupeol on cerebral infarction, cerebral water content, neurological symptoms and cerebral blood flow in rats were evaluated. Nissl staining was carried out to assess the neuronal damage of ischemic brain after I/R in rats. Apoptosis of ischemic brain neurons after I/R was detected by TUNEL staining. Western blotting was carried out to detect the effects of lupeol on the expression of p-PDK1, p-Akt, pc-Raf, p-BAD, cleaved caspase-3 and p-PTEN. RESULTS: Lupeol significantly increased cerebral blood flow after I/R in rats, reduced brain water content and infarct volume, and decreased neurological function scores. It significantly reduced neuronal damage after I/R in rats, and significantly reduced neuronal cell loss. PI3K inhibitor (LY294002) can eliminate the effect of lupeol on I/R in rats. In addition, lupeol significantly increased the protein expression of p-PDK1, p-Akt, pc-Raf, p-BAD, and down-regulated the expression of cleaved caspase-3. LY294002 reversed the effects of lupeol on the expression of PI3K/Akt signaling pathway-related proteins and cleaved caspase-3 after I/R in rats. CONCLUSION: Lupeol had significant neuroprotective effects on brain I/R injury and neuronal apoptosis, and its mechanism may be related to the activation of PI3K/Akt signaling pathway.