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1.
Int Immunopharmacol ; 82: 106354, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32143008

RESUMO

The 5-hydroxytryptamine (5-HT) receptor is significant for the regulation of mood and memory. However, the role of 5-HT1AR in ß-Amyloid protein (Aß)-induced cognitive decline, neuroinflammation and the possible mechanism remains elusive. Thus, we aimed to evaluate the effects of 5-HT1AR on Aß-induced learning and memory decline and neuroinflammation in mice. Novel object recognition and Morris water maze tests were performed to observe learning and memory behavior in mice. Protein levels of Iba1, GFAP, MAP2, TNF-α, Tß4, C-fos, IKK-ß, IKB-α, NF-κBp65, phospho-NF-κBp65 in the hippocampus were examined by immunostaining or western blotting. Aß1-42-treatment inducing learning and memory decline was shown in novel object recognition and Morris water maze tests; neuroinflammation shown in immunostaining. Our study found out that 5-HT1AR inhibitor WAY100635 showed significant improvement in Aß-induced learning and memory decline. Moreover, WAY100635 decreases levels of Iba1, GFAP, and TNF-α in the hippocampus, which were related to neuroinflammation. While treatment with 5-HT1AR agonist 8-OH-DPAT or ERK inhibitor U0126 exerted no effects or even aggravated Aß-induced learning and memory decline. In addition, WAY100635 could downregulate phospho-NF-κB in the hippocampus of Aß1-42-injected mice. These results provide new insight into the mechanism, for 5-HT1AR in Aß-induced cognitive impairments through crosstalk with the NF-κB signaling pathway. Our data indicated that WAY100635 was involved in the protective effects against neuroinflammation and improvement of learning and memory in Alzheimer's disease.

2.
Neurobiol Learn Mem ; 168: 107154, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31904546

RESUMO

Cognitive impairment in Alzheimer's disease (AD) is characterized by being deficient at learning and memory. Aß1-42 oligomers have been shown to impair rodent cognitive function. We previously demonstrated that activation of α7nAChR, inhibition of p38 or JNK could alleviate Aß-induced memory deficits in Y maze test. In this study, we investigated whether the effects of α7nAChR and MAPKs on Y maze test is reproducible with a hippocampus-dependent spatial memory test such as Morris water maze. We also assessed the possible co-existence of hippocampus-independent recognition memory dysfunction using a novel object recognition test and an alternative and stress free hippocampus-dependent recognition memory test such as the novel place recognition. Besides, previous research from our lab has shown that MAPKs pathways regulate Aß internalization through mediating α7nAChR. In our study, whether MAPKs pathways exert their functions in cognition by modulating α7nAChR through regulating glutamate receptors and synaptic protein, remain little known. Our results showed that activation of α7nAChR restored spatial memory, novel place recognition memory, and short-term and long-term memory in novel object recognition. Inhibition of p38 restored spatial memory and short-term and long-term memory in novel object recognition. Inhibition of ERK restored short-term memory in novel object recognition and novel place recognition memory. Inhibition of JNK restored spatial memory, short-term memory in novel object recognition and novel place recognition memory. Beside this, the activation of α7nAChR, inhibition of p38 or JNK restored Aß-induced levels of NMDAR1, NMDAR2A, NMDAR2B, GluR1, GluR2 and PSD95 in Aß-injected mice without influencing synapsin 1. In addition, these treatments also recovered the expression of acetylcholinesterase (AChE). Finally, we found that the inhibition of p38 or JNK resulted in the upregulation of α7nAChR mRNA levels in the hippocampus. Our results indicated that inhibition of p38 or JNK MAPKs could alleviate Aß-induced spatial memory deficits through regulating activation of α7nAChR via recovering memory-related proteins. Moreover, p38, ERK and JNK MAPKs exert different functions in spatial and recognition memory.

3.
Neurochem Int ; 133: 104610, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31778727

RESUMO

Our previous data indicated that tanshinone IIA (tan IIA) improves learning and memory in a mouse model of Alzheimer's disease (AD) induced by streptozotocin via restoring cholinergic function, attenuating oxidative stress and blocking p38 MAPK signal pathway activation. This study aims to estimate whether tan IIA inhibits endoplasmic reticulum (ER) stress-induced apoptosis to prevent cognitive decline in APP/PS1 transgenic mice. Tan IIA (10 mg/kg and 30 mg/kg) was intraperitoneally administered to the six-month-old APP/PS1 mice for 30 consecutive days. ß-amyloid (Aß) plaques were measured by immunohistochemisty and Thioflavin S staining, apoptotic cells were observed by TUNEL, ER stress markers and apoptosis signaling proteins were investigated by western blotting and RT-PCR. Our results showed that tan IIA significantly ameliorates cognitive deficits and improves spatial learning ability of APP/PS1 mice in the nest-building test, novel object recognition test and Morris water maze test. Furthermore, tan IIA significantly reduced the deposition of Aß plaques and neuronal apoptosis, and markedly prevented abnormal expression of glucose regulated protein 78 (GRP78), initiation factor 2α (eIF2α), inositol-requiring enzyme 1α (IRE1α), activating transcription factor 6 (ATF6), as well as suppressed the activation of C/EBP homologous protein (CHOP) and c-Jun N-terminal kinase (JNK) pathways in the parietal cortex and hippocampus. Moreover, tan IIA induced an up-regulation of the Bcl-2/Bax ratio and down-regulation of caspase-3 protein activity. Taken together, the above findings indicated that tan IIA improves learning and memory through attenuating Aß plaques deposition and inhibiting ER stress-induced apoptosis. These results suggested that tan IIA might become a promising therapeutic candidate drug against AD.

4.
World Neurosurg ; 133: e31-e61, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31415895

RESUMO

BACKGROUND: The association between matrix metalloproteinase 9 (MMP-9) gene -1562C/T (rs3918242) polymorphism and the susceptibility of ischemic stroke (IS) has been investigated. However, results were ambiguous and inconsistent. Therefore, we performed this study to better assess the potential relationship between rs3918242 polymorphism and susceptibility risk of IS. METHODS: We included case-control studies concerning the relationship between the rs3918242 polymorphism and IS, and odds ratios with corresponding 95% confidence intervals were used to describe the associations. Furthermore, meta-regression analyses, heterogeneity, cumulative analyses, sensitivity analyses, and publication bias were examined. RESULTS: A total of 19 studies were included for analysis. Significant associations with the risk of IS were detected for the rs3918242 polymorphism in overall population, Asians, and whites. When available data were stratified by gender, we found a significant correlation with the risk of IS in both males and females. Further subgroup analysis by the subtypes of IS showed that the rs3918242 polymorphism was significantly correlated with the risk of patients with large artery atherosclerosis. When stratified by age, we found that the rs3918242 polymorphism was significantly correlated with the risk of IS in patients both aged ≥65 years and >65 years. Both the diabetes and the nondiabetes subgroups reached significant results, and in an analysis stratified by smoking status, an increased risk of IS was associated with smoking. CONCLUSIONS: The rs3918242 polymorphism may be a susceptible predictor of susceptibility of IS. Further large-scale studies are needed to verify the results of our findings.


Assuntos
Isquemia Encefálica/genética , Metaloproteinase 9 da Matriz/genética , Polimorfismo de Nucleotídeo Único , Adulto , Distribuição por Idade , Idoso , Aterosclerose/epidemiologia , Isquemia Encefálica/enzimologia , Isquemia Encefálica/epidemiologia , Estudos de Casos e Controles , Fumar Cigarros/epidemiologia , Comorbidade , Intervalos de Confiança , Diabetes Mellitus/epidemiologia , Grupos Étnicos , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Embolia Intracraniana/epidemiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Distribuição por Sexo
5.
J Cell Physiol ; 2019 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-30779127

RESUMO

Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a microtubule-associated protein that plays a pivotal part in the formation of spindles. There is accumulating evidence that the expression of TPX2 is upregulated in many kinds of human cancers and that this protein is involved in the occurrence and progression of tumors. The purpose of this meta-analysis was to investigate the relationship between the overexpression of TPX2 and poor prognosis in cancer patients. A total of 18 eligible studies encompassing 3115 patients were included by searching relevant databases. Hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were pooled under random-/fixed-effect models. After calculation, the results showed that patients with increased TPX2 expression had a significantly shorter overall survival (HR = 2.21; 95% CI: 1.70-2.86), and disease-free survival (HR = 2.10; 95% CI: 1.67-2.64). In addition, it was found that increased TPX2 expression was significantly associated with TNM stage (OR = 2.17; 95% CI:1.42-3.32), lymph node metastasis (OR = 2.98; 95% CI: 2.28-3.89), distant metastasis (OR = 2.25; 95% CI:1.03-4.92), and vascular invasion (OR = 2.22; 95% CI:1.26-3.91). Nevertheless, there was no significant correlation between increased expression of TPX2 and either gender, tumor differentiation, or tumor size. Thus, we can come to the conclusion that the overexpression of TPX2 is related to poor clinical outcomes and can be used as a biomarker for the prognosis of patients with cancer.

6.
Int J Biochem Cell Biol ; 107: 82-91, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30578955

RESUMO

Endoplasmic reticulum (ER) stress caused by ß-amyloid protein (Aß) may play an important role in the pathogenesis of Alzheimer disease (AD). Our previous data have indicated that tanshinone IIA (tan IIA) protected primary neurons from Aß induced neurotoxicity. To further explore the neuroprotection of tan IIA, here we study the effects of tan IIA on the ER stress response in oligomeric Aß1-42 (oAß1-42)-induced SH-SY5Y cell injury. Our data showed that tan IIA pretreatment could increase cell viability and inhibit apoptosis caused by oAß1-42. Furthermore, tan IIA markedly suppressed ER dilation and prevented oAß1-42-induced abnormal expression of glucose regulated protein 78 (GRP78), initiation factor 2α (eIF2α), activating transcription factor 6 (ATF6), as well as inhibited the activation of C/EBP homologous protein (CHOP) and c-Jun N-terminal kinase (JNK) pathways. Moreover, tan IIA ameliorated oAß1-42-induced Bcl-2/Bax ratio reduction, prevented cytochrome c translocation into cytosol from mitochondria, reduced oAß1-42-induced cleavage of caspase-9 and caspase-3, suppressed caspase-3/7 activity, and increased mitochondrial membrane potential (MMP) and ATP content. Meanwhile, oAß1-42-induced cell apoptosis and activation of ER stress can also be attenuated by the inhibitor of ER stress 4-phenylbutyric acid (4-PBA). Taken together, these data indicated that tan IIA protects SH-SY5Y cells against oAß1-42-induced apoptosis through attenuating ER stress, modulating CHOP and JNK pathways, decreasing the expression of cytochrome c, cleaved caspase-9 and cleaved caspase-3, as well as increasing the ratio of Bcl-2/Bax, MMP and ATP content. Our results strongly suggested that tan IIA may be effective in treating AD associated with ER stress.


Assuntos
/farmacologia , Peptídeos beta-Amiloides/toxicidade , Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fragmentos de Peptídeos/toxicidade , Linhagem Celular Tumoral , Citoproteção/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Resposta a Proteínas não Dobradas/efeitos dos fármacos
7.
Front Immunol ; 10: 2886, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31921149

RESUMO

A successful pregnancy depends on not only the tolerance of the fetal immune system by the mother but also resistance against the threat of hazardous microorganisms. Infection with pathogenic microorganisms during pregnancy may lead to premature delivery, miscarriage, growth restriction, neonatal morbidity, and other adverse outcomes. Moreover, the host also has an intact immune system to avoid these adverse outcomes. It is important to note the presence of normal bacteria in the maternal reproductive tract and the principal role of the maternal-placental-fetal interaction in antimicrobial immunity. Previous studies mainly focused on maternal infection during pregnancy. However, this review summarizes the new views on the study of the maternal microbiome and expounds the innate immune defense mechanism of the maternal vagina and decidua as well as how cytotrophoblasts and syncytiotrophoblasts recognize and kill bacteria in the placenta. Fetal immune systems, thought to be weak, also exhibit an immune defense function that is indispensable for maintaining the safety of the fetus. The skin, lungs, and intestines of the fetus during pregnancy constitute the main immune barriers. These findings will provide a new understanding of the effects of normal microbial flora and how the host resists harmful microbes during pregnancy. We believe that it may also contribute to the reference on the clinical prevention and treatment of gestational infection to avoid adverse pregnancy outcomes.

8.
Neurochem Int ; 120: 238-250, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30217465

RESUMO

Amyloid ß peptide 1-42 (Aß1-42) could induce cognitive deficits through oxidative stress, inflammation, and neuron death in Alzheimer's disease (AD). MAPK pathways have been thought to mediate Aß1-42-induced neuroinflammation responses, neuron death and cognitive decline in AD. The α7 nicotinic acetylcholine receptor (α7nAChR) exerts a neuroprotective effect. However, whether α7nAChR alleviates Aß1-42-induced neurotoxicity through MAPKs (p38, ERK, JNK) in vivo remains unclear. In our study, memory was assessed in C57BL/6 mice using a Y-maze test. Cell death was assessed by Nissl and Hoechst staining and Bax, Bcl-2, Caspase 3, and Cytochrome C levels using Western blotting. Oxidative stress was assayed by superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) levels. Inflammation was examined with GFAP and Iba1 using immunohistochemistry. The Aß degrading enzymes insulin degrading enzyme (IDE) and neprilysin (NEP) were tested using Western blotting. We found that activating α7nAChR or inhibiting p38 or JNK pathway alleviated Aß1-42-induced cognitive deficits and neuron loss and death by reducing oxidative stress. In addition, activating α7nAChR or inhibiting p38 or JNK pathway also reduced inflammation, which was observed as reduced GFAP and Iba1 levels with different effects on Aß degrading enzymes. Finally, we found that the activation of α7nAChR led to the downregulation of pp38 and pJNK levels. Conversely, the inhibition of p38 or JNK resulted in the upregulation of α7nAChR levels in the hippocampus and cortex. Our data indicate that the activation of α7nAChR alleviates Aß1-42-induced neurotoxicity, and this protective effect might act through the downregulation of p38 and JNK MAPKs.


Assuntos
Peptídeos beta-Amiloides/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Regulação para Baixo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
9.
Onco Targets Ther ; 11: 743-749, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29445289

RESUMO

Objective: Nemo-like kinase (NLK) has been reported to play different roles in tumors. However, the role of NLK in cervical squamous cell carcinoma (CSCC) remains unknown. In this study, we explored the clinical significance including survival of NLK protein expression in CSCCs. Patients and methods: Immunohistochemical method was performed using tissues from 130 patients with CSCC. The associations between NLK expression and the clinicopathological factors and prognosis of CSCCs were evaluated. Statistical analyses were performed using the chi-square test, the multivariate Cox proportional hazard model, and the Kaplan-Meier method. Results: Immunohistochemical staining analysis showed that NLK was localized predominately in the nucleus of the tumor cells, and increased NLK expression was detected in 71 (54.6%) of 130 patients. NLK overexpression significantly correlated with higher histological grade (P=0.001), vascular/lymphatic invasion (P=0.010), lymph node metastasis (P=0.012), and recurrence (P=0.022). Patients with elevated NLK expression had poorer overall survival (OS) and disease-free survival (DFS) (P=0.006 and P=0.004, respectively) compared with patients with decreased NLK expression. Multivariate Cox analysis demonstrated that NLK overexpression was an independent factor for OS and DFS (P=0.034 and P=0.025, respectively). Conclusion: NLK may be a valuable biomarker for predicting the prognosis of CSCC patients and may serve as a potential target for cancer therapy.

10.
Infect Drug Resist ; 11: 45-54, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29386908

RESUMO

Objectives: To provide information about the genetic relationships and mechanism underlying carbapenem resistance in Pseudomonas aeruginosa clinical isolates of a hospital in China. Materials and methods: One hundred and sixty P. aeruginosa strains were isolated from a hospital in China. Susceptibility to 14 antimicrobial agents was determined by antimicrobial susceptibility testing. Multilocus sequence typing was used to characterize the genetic backgrounds of these clinical isolates. Forty-five strains were randomly selected for further evaluation of their carbapenem resistance mechanism. Their oprD gene was compared with the PAO1 sequence. Results: Multilocus sequence typing analysis demonstrated that these isolates were highly diverse; 68 sequence types were identified, of which 28 were novel sequence types. Polygenic and eBURST analysis demonstrated genetically similar clones with dissimilar resistance profiles. Among the 45 randomly selected strains associated with carbapenem resistance, 2 were metallo ß-lactamase producers; all the 45 strains were not AmpC overproducers. Sequence analysis revealed a high diversity in the oprD sequences among isolates. Strains susceptible to imipenem and meropenem with shortened L7 and L8 loops in oprD were the major strain types observed in this hospital. Conclusion: This study indicated that oprD provided the main mechanism for carbapenem resistance. The shortened L7 and L8 loops are responsible for carbapenem susceptibility.

11.
Brain Res Bull ; 137: 41-52, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29128415

RESUMO

Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders. Intracellular ß-amyloid protein (Aß) is an early event in AD. It induces the formation of amyloid plaques and neuron damage. The α7 nicotinic acetylcholine receptor (α7nAChR) has been suggested to play an important role in Aß caused cognition. It has high affinity with Aß and could mediate Aß internalization in vitro. However, whether in mouse brain the p38 MAPK signaling pathway is involved in the regulation of the α7nAChR mediated Aß internalization and their role in mitochondria remains little known. Therefore, in this study, we revealed that Aß is internalized by cholinergic and GABAergic neurons. The internalized Aß were found deposits in lysosomes/endosomes and mitochondria. Aß could form Aß-α7nAChR complex with α7nAChR, activates the p38 mitogen activated protein kinase (MAPK). And the increasing of α7nAChR could in return mediate Aß internalization in the cortex and hippocampus. In addition, by using the α7nAChR agonist PNU282987, the p38 phosphorylation level decreases, rescues the biochemical changes which are tightly associated with Aß-induced apoptosis, such as Bcl2/Bax level, cytochrome c (Cyt c) release. Collectively, the p38 MAPK signaling pathway could regulate the α7nAChR-mediated internalization of Aß. The activation of α7nAChR or the inhibition of p38 MAPK signaling pathway may be a beneficial therapy to AD.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Neurônios Colinérgicos/metabolismo , Neurônios GABAérgicos/metabolismo , Fragmentos de Peptídeos/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Benzamidas/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Compostos Bicíclicos com Pontes/farmacologia , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/patologia , Endossomos/efeitos dos fármacos , Endossomos/metabolismo , Endossomos/patologia , Feminino , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/patologia , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Lisossomos/patologia , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Agonistas Nicotínicos/farmacologia , Fosforilação , Distribuição Aleatória , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores
12.
Brain Res ; 1663: 151-160, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28274609

RESUMO

ß-Amyloid (Aß) accumulation in the brain is the major pathophysiology of Alzheimer disease (AD). Hypertension is a risk factor for AD by promoting Aß deposition. Traditional Chinese medicinal compound tongxinluo (TXL) can improve blood circulation and endothelium-dependent vasodilation. This study investigates the effects of TXL on cognition and Aß using spontaneously hypertensive rats (SHRs). TXL was intragastrically administered to SHRs at low-dose, mid-dose and high-dose for 15, 30 or 60days. Cognition was evaluated with a Morris Water Maze (MWM). Aß in the brain was detected by western blot, ELISA and Thioflavin-S staining. Western blot and RT-PCR were employed to exam the expression of receptor for advanced glycation end products (RAGE), low-density lipoprotein receptor-related protein-1 (LRP-1) and amyloid precursor protein (APP). After TXL treatment for 60days, compared with the vehicle, the number of crossed platform and the time spent in the target quadrant increased in parallel with the increasing length of treatment in MWM. Moreover, the Aß in the hippocampus significantly decreased compared to the vehicle group, both in western blot and ELISA. Additionally, TXL reduced RAGE expression in a dose- and time-depended manner, but LRP-1 expression had no difference between TXL groups and vehicle groups. Furthermore, the ß-secretase expression was significantly decreased compared to the vehicle group, but APP expression had no difference. In conclusion, TXL improved cognition and decreased Aß in SHRs in a dose- and time-dependent manner, the underlying mechanism may involved in inhibiting RAGE and ß-secretase expression.


Assuntos
Peptídeos beta-Amiloides/efeitos dos fármacos , Cognição/efeitos dos fármacos , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Doença de Alzheimer/fisiopatologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/fisiologia , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Hipocampo/metabolismo , Hipertensão/etiologia , Hipertensão/terapia , Masculino , Medicina Tradicional Chinesa , Ratos , Ratos Endogâmicos SHR , Ratos Wistar
13.
Int J Biochem Cell Biol ; 76: 75-86, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27163530

RESUMO

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Recently, increasing evidence suggests that intracellular ß-amyloid protein (Aß) alone plays a pivotal role in the progression of AD. Therefore, understanding the signaling pathway and proteins that control Aß internalization may provide new insight for regulating Aß levels. In the present study, the regulation of Aß internalization by p38 mitogen-activated protein kinases (MAPK) through low-density lipoprotein receptor-related protein 1 (LRP1) was analyzed in vivo. The data derived from this investigation revealed that Aß1-42 were internalized by neurons and astrocytes in mouse brain, and were largely deposited in mitochondria and lysosomes, with some also being found in the endoplasmic reticulum. Aß1-42-LRP1 complex was formed during Aß1-42 internalization, and the p38 MAPK signaling pathway was activated by Aß1-42 via LRP1. Aß1-42 and LRP1 were co- localized in the cells of parietal cortex and hippocampus. Furthermore, the level of LRP1-mRNA and LRP1 protein involved in Aß1-42 internalization in mouse brain. The results of this investigation demonstrated that Aß1-42 induced an LRP1-dependent pathway that related to the activation of p38 MAPK resulting in internalization of Aß1-42. These results provide evidence supporting a key role for the p38 MAPK signaling pathway which is involved in the regulation of Aß1-42 internalization in the parietal cortex and hippocampus of mouse through LRP1 in vivo.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Astrócitos/metabolismo , Hipocampo/metabolismo , Sistema de Sinalização das MAP Quinases , Neurônios/metabolismo , Lobo Parietal/metabolismo , Fragmentos de Peptídeos/metabolismo , Receptores de LDL/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Feminino , Hipocampo/patologia , Camundongos , Lobo Parietal/patologia , Fragmentos de Peptídeos/genética , RNA Mensageiro/metabolismo , Receptores de LDL/genética , Proteínas Supressoras de Tumor/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética
14.
Brain Res ; 1631: 137-46, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26656068

RESUMO

Our previous studies demonstrated that tanshinone IIA (tan IIA) has significant protective effects against the neurotoxicity induced by ß-amyloid protein (Aß) in cultured cortical neurons and PC12 cells. This study was designed to investigate the protective effects of tan IIA against memory deficits induced by streptozotocin (STZ) in a model of sporadic Alzheimer's disease (AD). STZ was injected twice intracerebroventrically (3mg/kg ICV) on alternate days (day 1 and day 3) in mice. Daily treatment with tan IIA (20, 40, and 80mg/kg, i.g.) starting from the first dose of STZ for 28 days showed a dose dependent improvement in STZ induced memory deficits as assessed by Morris water maze (MWM) test. Nissl staining results confirmed the protective effects of tan IIA on cerebral cortical and hippocampal neurons damage induced by STZ. In addition, tan IIA markedly reduced STZ induced elevation in acetylcholinesterase (AChE) activity and malondialdehyde (MDA) level, and significantly inhibited STZ induced reduction in superoxide dismutases (SOD) and glutathione peroxidase (GSH-Px) activities in the parietal cortex and hippocampus. Moreover, tan IIA attenuated p38 mitogen activated protein kinase (MAPK) phosphorylation in the parietal cortex and hippocampus. These findings demonstrate that tan IIA prevents STZ induced memory deficits may be attributed to ameliorating neuronal damage, restoring cholinergic function, attenuating oxidative stress and blocking p38 MAPK signal pathway activation. Based on our previous studies, the present study provides further support for the potential use of tan IIA in the treatment of AD.


Assuntos
/farmacologia , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Acetilcolinesterase/metabolismo , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Córtex Cerebral/metabolismo , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Hipocampo/metabolismo , Infusões Intraventriculares , Masculino , Malondialdeído/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Lobo Parietal/efeitos dos fármacos , Lobo Parietal/enzimologia , Lobo Parietal/metabolismo , Distribuição Aleatória , Estreptozocina/administração & dosagem , Superóxido Dismutase/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
Neurotoxicology ; 51: 166-71, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26511841

RESUMO

Puerarin (PUE), an isoflavone purified from the root of Pueraria lobata (Chinese herb), has been reported to attenuate learning and memory impairments in the transgenic mouse model of Alzheimer's disease (AD). In the present study, we tested PUE in a sporadic AD (SAD) mouse model which was induced by the intracerebroventricular injection of streptozotocin (STZ). The mice were administrated PUE (25, 50, or 100mg/kg/d) for 28 days. Learning and memory abilities were assessed by the Morris water maze test. After behavioral test, the biochemical parameters of oxidative stress (glutathione peroxidase (GSH-Px), superoxide dismutases (SOD), and malondialdehyde (MDA)) were measured in the cerebral cortex and hippocampus. The SAD mice exhibited significantly decreased learning and memory ability, while PUE attenuated these impairments. The activities of GSH-Px and SOD were decreased while MDA was increased in the SAD animals. After PUE treatment, the activities of GSH-Px and SOD were elevated, and the level of MDA was decreased. The middle dose PUE was more effective than others. These results indicate that PUE attenuates learning and memory impairments and inhibits oxidative stress in STZ-induced SAD mice. PUE may be a promising therapeutic agent for SAD.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Isoflavonas/administração & dosagem , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Doença de Alzheimer/induzido quimicamente , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Feminino , Glutationa Peroxidase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Malondialdeído/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Estreptozocina , Superóxido Dismutase/metabolismo
16.
Int J Biochem Cell Biol ; 64: 252-64, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25936756

RESUMO

Mounting evidence suggests that the pathological hallmarks of Alzheimer's disease (AD) are caused by the intraneuronal accumulation of beta-amyloid protein (Aß). Reuptake of extracellular Aß is believed to contribute significantly to the intraneuronal Aß pool in the early stages of AD. Published reports have claimed that the low-density lipoprotein receptor-related protein 1 (LRP1) mediates Aß1-42 uptake and lysosomal trafficking in GT1-7 neuronal cells and mouse embryonic fibroblast non-neuronal cells. However, there is no direct evidence supporting the role of LRP1 in Aß internalization in primary neurons. Our recent study indicated that p38 MAPK and ERK1/2 signaling pathways are involved in regulating α7 nicotinic acetylcholine receptor (α7nAChR)-mediated Aß1-42 uptake in SH-SY5Y cells. This study was designed to explore the regulation of MAPK signaling pathways on LRP1-mediated Aß internalization in neurons. We found that extracellular Aß1-42 oligomers could be internalized into endosomes/lysosomes and mitochondria in cortical neurons. Aß1-42 and LRP1 were also found co-localized in neurons during Aß1-42 internalization, and they could form Aß1-42-LRP1 complex. Knockdown of LRP1 expression significantly decreased neuronal Aß1-42 internalization. Finally, we identified that p38 MAPK and ERK1/2 signaling pathways regulated the internalization of Aß1-42 via LRP1. Therefore, these results demonstrated that LRP1, p38 MAPK and ERK1/2 mediated the internalization of Aß1-42 in neurons and provided evidence that blockade of LRP1 or inhibitions of MAPK signaling pathways might be a potential approach to lowering brain Aß levels and served a potential therapeutic target for AD.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Sistema de Sinalização das MAP Quinases , Fragmentos de Peptídeos/metabolismo , Receptores de LDL/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Linhagem Celular Tumoral , Células Cultivadas , Córtex Cerebral/citologia , Endossomos/metabolismo , Humanos , Lisossomos/metabolismo , Camundongos , Mitocôndrias/metabolismo , Neurônios , Cultura Primária de Células , Transporte Proteico
17.
Sheng Li Xue Bao ; 67(1): 103-9, 2015 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-25672633

RESUMO

The aim of the present study was to observe the effect of trypsin digestion on the purity of in vitro cultured astrocytes and optimize the culture methods. The cerebral cortical tissue from newborn Sprague Dawley (SD) rats was isolated and digested with 0.25% trypsin for 20, 30, or 40 min. The obtained single cell suspension was then cultured. Once reaching confluence, the cells were shaken at a constant temperature. Then, each of 20 and 30 min groups was subdivided into two groups, the control group with normal digestion and two-time-digestion group, and the cells were passaged and purified. Through inverted phase contrast microscope and MTT assay, cell growth and proliferation were observed, respectively. Immunofluorescence for glial fibrillary acidic protein (GFAP) was used to observe the morphology of astrocytes and to assess their purity in different stages. Flow cytometric analysis was used to detect the apoptotic rates of purified astrocytes. The results showed that, the cells being digested for 20 min usually reached confluence at 9 d after seeding. When the digestion time was extended to 30 min, the cells grew faster and reached confluence at 7 d after seeding, meanwhile the morphology of astrocytes was normal, GFAP positive rate (70.2 ± 4.0)% being much higher than that of the 20 min group (P < 0.05). Compared with 20 min group, 40 min group showed higher GFAP positive rate, whereas the cell proliferation was slower, and cell injury was more obvious. After shaking at constant temperature, two times of trypsin digestion could decrease the number of contaminated cells after passage. The GFAP positive rates of two-time-digestion groups in passage 1 (P1) were higher than those of corresponding control groups, and the GFAP positive rate of 30 min + two-time-digestion group in P1 reached (98.1 ± 1.7)%, which was equivalent to that of the 20 min + control group in P3. However, the apoptotic rate showed no significant difference between these two groups. Based on above mentioned results, we conclude that 30 min + two-time of trypsin digestion effectively improves the purity of astrocytes and shortens the time of primary culture and purification, suggesting that it is a rapid and effective method to obtain astrocytes with high purity in vitro.


Assuntos
Astrócitos/citologia , Técnicas de Cultura de Células , Tripsina , Animais , Proliferação de Células , Separação Celular/métodos , Proteína Glial Fibrilar Ácida/metabolismo , Ratos , Ratos Sprague-Dawley
18.
Brain Res Bull ; 109: 46-53, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25290208

RESUMO

Perindopril, an angiotensin converting enzyme inhibitor, has been reported to improve learning and memory in a mouse or rat model of Alzheimer's disease (AD) induced by injection of beta-amyloid protein. However, the exact mechanism of perindopril on the cognitive deficits is not fully understood. Our previous data have indicated that perindopril improves learning and memory in a mouse model of AD induced by D-galactose (D-gal) and aluminum trichloride (AlCl3) via inhibition of acetylcholinesterase activity and oxidative stress. Whether perindopril also inhibit apoptosis to prevent cognitive decline remains unknown in mice. Therefore, the present study explored the protective effects of perindopril in the hippocampus of mice further. Perindopril (0.5 mg/kg/day) was administered intragastrically for 60 days after the mice were given a D-gal (150 mg/kg/day) and AlCl3 (10 mg/kg/day) intraperitoneally for 90 days. Then the expression of Bcl-2, Bax, Fas, FasL, caspase-3, caspase-8 and caspase-9 were analyzed by RT-PCR and western blotting in the hippocampus. Perindopril significantly decreased caspase-3 and caspase-9 activities, and elevated Bcl-2/Bax ratio in the hippocampus. However, the expression of Fas, FasL and caspase-8 did not change in the hippocampus whether treatment with d-gal and AlCl3 or perindopril. Taken together, the above findings indicated that perindopril inhibited apoptosis in the hippocampus may be another mechanism by which perindopril improves learning and memory functions in d-gal and AlCl3 treated mice.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Apoptose/efeitos dos fármacos , Hipocampo/patologia , Mitocôndrias/efeitos dos fármacos , Perindopril/farmacologia , Cloreto de Alumínio , Compostos de Alumínio/toxicidade , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Caspase 8/metabolismo , Cloretos/toxicidade , Modelos Animais de Doenças , Interações de Medicamentos , Proteína Ligante Fas/genética , Proteína Ligante Fas/metabolismo , Proteína de Domínio de Morte Associada a Fas/genética , Proteína de Domínio de Morte Associada a Fas/metabolismo , Galactose/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/ultraestrutura , Masculino , Camundongos , Mitocôndrias/metabolismo , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Perindopril/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
19.
Vaccine ; 32(35): 4450-6, 2014 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-24962758

RESUMO

ß-Amyloid peptide (Aß) immunization is regarded as a promising therapy to Alzheimer's disease. The full length Aß as antigen might induce meningoencephalitis adverse effect since the middle and C-terminal fragments of Aß contain T cell epitopes. While N-terminal fragment of Aß, containing B cell epitope, has weak or no immunogenicity. To improve the immunogenicity, in the previous study, we used HBv core antigen as carrier to make fusion protein containing 2 Aß1-15. The fusion protein could form virus-like particles (VLPs) and had strong immunogenicity. The antisera prevented Aß fiber formation and protected the PC12 cells against toxicity of Aß. In the present study, we immunized 12-month old AD transgenic mice, PDAPP mice, to observe the therapeutic effect of immunization on behaviour and pathology. During immunization, the titer of anti-Aß antibody reached to nearly 1:10(6) after 4th inoculation, and then maintained that level to the end of the experiment. After 6-month immunization, the behavioral changes of mice were tested by Morris Water Maze (MWM). The escape latency of immunized mice was shorter than control, and these mice entered platform quadrant more times. Immunohistochemistry results showed that Aß-HBc VLPs immunized mice had less amyloid deposit with less microglia in cortex and hippocampus. In conclusion, Aß-HBc VLPs ameliorated the learning and memory and reduced cerebral Aß deposit in PDAPP mice.


Assuntos
Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/imunologia , Imunoterapia/métodos , Aprendizagem/fisiologia , Memória/fisiologia , Vacinas de Subunidades/imunologia , Vacinas de Partículas Semelhantes a Vírus/imunologia , Doença de Alzheimer/imunologia , Doença de Alzheimer/patologia , Animais , Comportamento Animal , Córtex Cerebral/patologia , Modelos Animais de Doenças , Feminino , Hipocampo/patologia , Imuno-Histoquímica , Masculino , Camundongos Transgênicos , Resultado do Tratamento , Vacinas de Subunidades/administração & dosagem , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem
20.
Neurol Res ; 36(7): 651-8, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24620968

RESUMO

OBJECTIVES: Valsartan has been reported to reduce brain beta-amyloid protein levels and improve spatial learning in the Tg2576 transgenic mouse model of Alzheimer's disease (AD). However, the exact mechanism of neuroprotective effects of valsartan has not been properly studied especially in cholinergic function and oxidative damage, the essential factors that undergo impairment in AD. Therefore, the present study examined the effects of valsartan on memory impairment, cholinergic dysfunction, and oxidative stress in aluminum trichloride (AlCl3) and d-galactose (d-gal)-induced experimental sporadic dementia of Alzheimer's type. METHODS: Valsartan was administered intragastrically (i.g.) (20 mg/kg/day) for 60 days after mice were given AlCl3 (10 mg/kg/day) and d-gal (150 mg/kg/day) intraperitoneally (i.p.) once daily for 90 days. Then, memory function was evaluated by Morris water maze test. Acetylcholinesterase (AChE), superoxide dismutases (SOD) and glutathione peroxidase (GSH-Px) activities and malondialdehyde (MDA) level in cortex and hippocampus were also assessed with biochemical technique. RESULTS: Chronic administration of valsartan not only improved learning and memory but also restored the elevation of AChE activity induced by AlCl3 and d-gal in cortex and hippocampus. In addition, valsartan significantly restored SOD and GSH-Px activities and reduced MDA level in cortex and hippocampus indicating attenuation of oxidative stress. DISCUSSION: Our results indicate that valsartan prevents AlCl3- and d-gal-induced cognitive decline partly to restore cholinergic function and attenuate oxidative damage. These findings further support the potential of valsartan to be used in AD treatment.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Nootrópicos/farmacologia , Tetrazóis/farmacologia , Valina/análogos & derivados , Acetilcolinesterase/metabolismo , Cloreto de Alumínio , Compostos de Alumínio , Animais , Córtex Cerebral/fisiopatologia , Cloretos , Transtornos Cognitivos/fisiopatologia , Demência , Modelos Animais de Doenças , Galactose , Glutationa Peroxidase/metabolismo , Hipocampo/fisiopatologia , Malondialdeído/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/fisiopatologia , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Distribuição Aleatória , Superóxido Dismutase/metabolismo , Valina/farmacologia , Valsartana
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