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1.
Aging (Albany NY) ; 122020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32091409

RESUMO

The data on the phenotypes associated with some rare germline mutations in Chinese breast cancer patients are limited. The difference in somatic mutation profiles in breast cancer patients with germline BRCA and non-BRCA mutations remains unexplored. We interrogated the germline and somatic mutational profile of 524 Chinese breast cancer patients with various stages unselected for predisposing factors using a panel consisting of 520 cancer-related genes including 62 cancer susceptibility genes. We divided the patients into three groups according to germline mutations: Germline-BRCA1/2, Germline-others (non-BRCA) and Others (non-carriers). A total of 58 patients (11.1%) carried 76 likely pathogenic or pathogenic (LP/P) germline variants in 15 cancer predisposition genes. Germline BRCA1/2 mutations were detected from 29 (5.53%) patients; with 11 (2.10%) BRCA1 carriers and 18 (3.44%) BRCA2 carriers. In addition, LP/P germline mutations were detected in other genes including MUTYH (n=4), PALB2 (n=4), ATM (n=3), BRIP1 (n=3), CDH1 (n=3), RAD51C (n=3), CHEK2 (n=2), FANCA (n=2), PMS2 (n=2), TP53 (n=2), FANCI (n=1), FANCL (n=1) and PTEN (n=1). At least one variant of uncertain significance (VUS) was identified in 490 (93.5%) patients. Young age (P=0.011), premenopausal status (P=0.013), and breast/ovarian cancer family history (P=0.001) were correlated with germline mutations. Germline-BRCA1/2 group was detected with more missense (P=0.02) and less copy-number amplification (P=0.04) than Germline-others group. Meanwhile, Germline-others group and Others group are very similar (P>0.05). The mutation rates of AKT1, CCND1, FGFR1, and PIK3CA were different among the three groups. By investigating all breast and ovarian cancer-related genes listed in the US genetic guidelines, we identified 15 cancer susceptibility genes frequently mutated in the germline of our population and must be included in cancer predisposition screening. Our study contributed a better understanding of the tumor characteristics of patients with LP/P germline mutations.

2.
Endocr Relat Cancer ; 27(3): 153-162, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31905165

RESUMO

HER2-positive breast cancer is a biologically and clinically heterogeneous disease. Based on the expression of hormone receptors (HR), breast tumors can be further categorized into HR positive and HR negative. Here, we elucidated the comprehensive somatic mutation profile of HR+ and HR- HER2-positive breast tumors to understand their molecular heterogeneity. In this study, 64 HR+/HER2+ and 43 HR-/HER2+ stage I-III breast cancer patients were included. Capture-based targeted sequencing was performed using a panel consisting of 520 cancer-related genes, spanning 1.64 megabases of the human genome. A total of 1119 mutations were detected among the 107 HER2-positive patients. TP53, CDK12 and PIK3CA were the most frequently mutated, with mutation rates of 76, 61 and 49, respectively. HR+/HER2+ tumors had more gene amplification, splice site and frameshift mutations and a smaller number of missense, nonsense and insertion-deletion mutations than HR-/HER2+ tumors. In KEGG analysis, HR+/HER2+ tumors had more mutations in genes involved in homologous recombination (P = 0.004), TGF-beta (P = 0.007) and WNT (P = 0.002) signaling pathways than HR-/HER2+ tumors. Moreover, comparative analysis of our cohort with datasets from The Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium revealed the distinct somatic mutation profile of Chinese HER2-positive breast cancer patients. Our study revealed the heterogeneity of somatic mutations between HR+/HER2+ and HR-/HER2+ in Chinese breast cancer patients. The distinct mutation profile and related pathways are potentially relevant in the development of optimal treatment strategies for this subset of patients.

3.
Oxid Med Cell Longev ; 2019: 5074367, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781339

RESUMO

Parkinson's disease (PD) is a common neurodegenerative disease accompanied by a loss of dopaminergic (DAergic) neurons. The development of therapies to prevent disease progression is the main goal of drug discovery. There is increasing evidence that oxidative stress and antioxidants may contribute to the pathogenesis and treatment of PD, respectively. In the present study, we investigated the antioxidative protective effects of the indole-derivative compound NC001-8 in DAergic neurons derived from SH-SY5Y cells and PD-specific induced pluripotent stem cells (PD-iPSCs) carrying a PARKIN ex5del mutation. In SH-SY5Y-differentiated DAergic neurons under 1-methyl-4-phenylpyridinium (MPP+) treatment, NC001-8 remarkably reduced the levels of reactive oxygen species (ROS) and cleaved caspase 3; upregulated nuclear factor erythroid 2-related factor 2 (NRF2) and NAD(P)H dehydrogenase, quinone 1 (NQO1); and promoted neuronal viability. In contrast, NRF2 knockdown abolished the effect of NC001-8 on the reduction of ROS and improvement of neuronal viability. In H2O2-treated DAergic neurons differentiated from PD-iPSCs, NC001-8 rescued the aberrant increase in ROS and cleaved caspase 3 by upregulating NRF2 and NQO1. Our results demonstrated the protective effect of NC001-8 in DAergic neurons via promoting the NRF2 antioxidative pathway and reducing ROS levels. We anticipate that our present in vitro assays may be a starting point for more sophisticated in vivo models or clinical trials that evaluate the potential of NC001-8 as a disease modifier for PD.

4.
Ann Transl Med ; 7(8): 179, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31168460

RESUMO

Background: The complexity of breast cancer at the clinical, morphological and genomic levels has been extensively studied in the western population. However, the mutational genomic profiles in Chinese breast cancer patients have not been explored in any detail. Methods: We performed targeted sequencing using a panel consisting of 33 breast cancer-related genes to investigate the genomic landscape of 304 consecutive treatment-naïve Chinese breast cancer patients at Guangdong Provincial People's Hospital (GDPH), and further compared the results to those in 453 of Caucasian breast cancer patients from The Cancer Genome Atlas (TCGA). Results: The most frequently mutated gene was TP53 (45%), followed by PIK3CA (44%), GATA3 (18%), MAP3K1 (10%), whereas the copy-number amplifications were frequently observed in genes of ERBB2 (24%), MYC (23%), FGFR1 (13%) and CCND1 (10%). Among the 8 most frequently mutated or amplified genes, at least one driver was identifiable in 87.5% (n=267) of our GDPH cohort, revealing the significant contribution of these known driver genes in the development of Chinese breast cancer. Compared to TCGA data, the median age at diagnosis in our cohort was significantly younger (48 vs. 58 years; P<0.001), while the distribution of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) statuses were similar. The largest difference occurred in HR+/HER2- subtype, where 8 of the 10 driver genes compared had statistically significant differences in their frequency, while there were differences in 2 of 10 driver genes among the TNBC and HR+/HER2+ group, but none in the HR-/HER2+ patients in our cohort compared to the TCGA data. Collectively, the most significant genomic difference was a significantly higher prevalence for TP53 and AKT1 in Chinese patients. Additionally, more than half of TP53-mutation HR+/HER2- Chinese patients (~60%) are likely to harbor more severe mutations in TP53, such as nonsense, indels, and splicing mutations. Conclusions: We elucidated the mutational landscape of cancer genes in Chinese breast cancer and further identified significant genomic differences between Asian and Caucasian patients. These results should improve our understanding of pathogenesis and/or metastatic behavior of breast cancer across races/ethnicities, including a better selection of targeted therapies.

5.
Nat Prod Res ; : 1-6, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30784312

RESUMO

A new pyrrolidine alkaloid, acanthophoraine A (1), along with six known alkaloids (2-7), had been isolated from the red alga Acanthophora spicifera. The structures of these compounds were identified by spectroscopic analyses. The absolute configuration of 1 was established by ECD calculation. Compound 1 represents the first example of N-isobutyl pyrrolidone with an urea arm. The antimicrobial activity of 1 was also evaluated.

6.
Mol Neurobiol ; 56(6): 3972-3983, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30238389

RESUMO

Alzheimer's disease (AD), probably caused by abnormal accumulation of ß-amyloid (Aß) and aberrant phosphorylation of tau, is the most common cause of dementia among older people. Generation of patient-specific neurons by induced pluripotent stem cell (iPSC) technology facilitates exploration of the disease features in live human neurons from AD patients. In this study, we generated iPSCs from two familial AD patients carrying a heterozygous D678H mutation in the APP gene (AD-iPSCs). The neurons derived from our AD-iPSCs demonstrated aberrant accumulation of intracellular and secreted Aß42 and Aß40, reduction of serine 9 phosphorylation in glycogen synthase kinase 3ß (GSK3ß) hyperphosphorylation of threonine 181 and serine 396 in tau protein, impaired neurite outgrowth, downregulation of synaptophysin, and increased caspase 1 activity. The comparison between neurons derived from a sibling pair of wild-type and mutated iPSCs successfully recapitulated these AD phenotypes. Treatment with indole compound NC009-1 (3-((1H-Indole-3-yl)methyl)-4-(2-nitrophenyl)but-3-en-2-one), a potential Aß aggregation reducer, normalized the Aß levels and GSK3ß and tau phosphorylation, attenuated caspase 1 activity, and improved neurite outgrowth in AD-iPSC-derived neurons. Thus, APP D678H iPSCs-derived neurons recapitulate the cellular characteristics relevant to AD and enable exploration of the underlying pathogenesis and therapeutic strategies for AD.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Modelos Biológicos , Mutação/genética , Adulto , Animais , Sequência de Bases , Diferenciação Celular/efeitos dos fármacos , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Indóis/farmacologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Masculino , Camundongos , Pessoa de Meia-Idade , Neuritos/efeitos dos fármacos , Neuritos/metabolismo , Linhagem , Fenótipo , Fosforilação/efeitos dos fármacos , Proteínas tau/metabolismo
7.
Shock ; 51(1): 105-113, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29424796

RESUMO

BACKGROUND: Global cerebral ischemic/reperfusion (I/R) injury after cardiac arrest (CA) is a major cause of mortality and morbidity in survivors of resuscitation. We utilized a rat model of asphyxia CA to explore the functional effects and mechanisms of Sigma-1 receptor (Sig-1R) activation in cerebral protection using the Sig-1R agonist cutamesine (SA-4503). METHODS: After resuscitation, the surviving rats were randomly divided into three groups (n = 18 each): the cardiopulmonary resuscitation (CPR) group (0.9% saline at 1 mL/kg); the SA4503 low-dose group (1 mg/kg SA4503); and the SA4503 high-dose group (2.5 mg/kg SA4503). The neurological deficit scores were recorded, and the cerebral cortex was harvested for western blotting. Mitochondrial transmembrane potential, adenosine triphosphate (ATP) concentrations, calcium homeostasis, and mitochondrial ultrastructure were also studied. RESULTS: The SA4503 treatment groups exhibited improved neurological outcomes compared with the CPR group. The protein levels of caspase-3 and the endoplasmic reticulum stress markers C/EBP homologous protein and caspase-12 were lower in the SA4503 treatment groups compared with the CPR group. SA4503 treatment also normalized mitochondrial membrane potential, tissue ATP concentrations, intracellular Ca overload, and upregulated Sig-1R protein level compared with the CPR group. The SA4503 high dose treatment showed significant cerebral protective effects compared with the SA4503 low dose treatment. The therapeutic effect of SA4503 was dose-dependent. CONCLUSIONS: CA downregulated Sig-1R protein expression. Activating Sig-1R using SA4503 protected against global cerebral I/R injury in a rat model of asphyxia CA by alleviating endoplasmic reticulum stress and mitochondrial dysfunction and eventually inhibiting neuronal apoptosis.

8.
Mater Sci Eng C Mater Biol Appl ; 82: 354-362, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29025669

RESUMO

A new type of wound healing agent was developed using two marine biomaterials (squid ink polysaccharide and chitosan) as carriers and calcium chloride as an initiator for coagulation. Based on central composite design-response surface methodology, comprehensive evaluation of appearance quality for composite sponges and water absorbency were used as evaluation indices to identify the optimized preparation conditions and further evaluate the performance of the squid ink polysaccharide-chitosan sponge (SIP-CS). The optimized formulation of SIP-CS was as follows: chitosan concentration, 2.29%; squid ink polysaccharide concentration, 0.55%; and calcium chloride concentration, 2.82%, at a volume ratio of 15:5:2. SIP-CS was conducive to sticking on the wound, characterized by the spongy property, strong absorptivity, and tackiness. Rabbit ear arterial, hepatic, and femoral artery hemorrhage experiments indicated that, compared with chitosan dressings and absorbable gelatin, the hemostatic times were shorter and the bleeding volume was smaller. Furthermore, SIP-CS absorbed a large amount of hemocytes, leading to rapid hemostasis. The healing areas and wound pathological sections in scalded New Zealand rabbits indicated that SIP-CS promoted wound healing more rapidly than chitosan and better than commercially available burn cream. Thus, SIP-CS is a good wound healing agent for rapid hemostasis, promoting burn/scalded skin healing, and protecting from wound infection.


Assuntos
Materiais Biocompatíveis/química , Quitosana/química , Decapodiformes/metabolismo , Tinta , Polissacarídeos/química , Adsorção , Animais , Artérias/lesões , Bandagens , Materiais Biocompatíveis/farmacologia , Células Sanguíneas/citologia , Células Sanguíneas/efeitos dos fármacos , Células Sanguíneas/metabolismo , Hemorragia/prevenção & controle , Microscopia Eletrônica de Varredura , Coelhos , Cicatrização/efeitos dos fármacos
9.
Shock ; 50(6): 706-713, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29283979

RESUMO

Lung injury is a common complication after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR), and Rho kinase (ROCK) may be involved in the process of this injury. In this study, we aimed to study the effects of ROCK inhibition by fasudil on lung injury induced by asphyxial CA and CPR in rats. A total of 130 rats were randomized into three groups: Sham, Control, and Fasudil intervention group. Animals in the Fasudil intervention group were intraperitoneally administered with 10 mg/kg of the drug, 1 h before inducing CA. Rats in the Control group received equivalent volume of saline and were subjected to the same experimental procedures with as the Fasudil group. Blood was collected and lungs were harvested at 3, 6, 12, 24, and 48 h after return of spontaneous circulation (ROSC) for blood gas and biochemical analysis. Fasudil significantly increased the partial pressure of oxygen and pH in arterial blood, as well as attenuated lung histological injury and lung edema after ROSC. Additionally, it significantly decreased lung inflammatory response (decreased levels of tumor necrosis factor-α and interleukin-6, and myeloperoxidase activity) and oxidative stress (decreased malonaldehyde level and increased superoxide dismutase activity) after ROSC. Using western blot analysis, we found that fasudil inhibited both isoforms ROCK1 and ROCK2, and intercellular adhesion molecule-1; nevertheless, it increased vascular endothelial cadherin protein expression after ROSC. Our study suggested that the Rho kinase signaling pathway is critical for CA-induced lung injury and fasudil has protective effects on lung injury after CA and CPR.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Lesão Pulmonar Aguda/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Isquemia/tratamento farmacológico , Quinases Associadas a rho/metabolismo , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Lesão Pulmonar Aguda/sangue , Animais , Western Blotting , Citocinas/metabolismo , Parada Cardíaca , Inflamação/sangue , Inflamação/tratamento farmacológico , Isquemia/sangue , Masculino , Malondialdeído/sangue , Estresse Oxidativo/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/sangue
10.
Shock ; 49(6): 704-711, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-28846566

RESUMO

No pharmacological interventions are currently available to provide neuroprotection for patients suffering from cardiac arrest. Dichloroacetate (DCA) is a pyruvate dehydrogenase kinase inhibitor, which activates pyruvate dehydrogenase (PDH), and increases cell adenosine triphosphate (ATP) production by promoting influx of pyruvate into the Krebs cycle. In this study, we investigated the effects of DCA on post-resuscitation neurological injury in an asphyxial cardiac arrest rat model. Asphyxial cardiac arrest was established by endotracheal tube clamping. A total of 111 rats were randomized into three groups: Sham group, Control group, and DCA intervention group. Animals in DCA intervention group were intraperitoneally administered DCA with a loading dose of 80 mg/kg at 15 min after return of spontaneous circulation (ROSC), whereas rats in the Control group received equivalent volume of saline. DCA treatment increased 3-day survival time, and reduced neurologic deficit scores at 24, 48, and 72 h after ROSC. It also attenuated cellular apoptosis and neuronal damage in the hippocampal cornuammonis one region by hematoxylin-eosin staining and TdT-mediated dUTP nick-end labeling assay. In addition, DCA reduced the messenger RNA expression of tumor necrosis factor α and interleukin 1ß in brain hippocampus and cortex after ROSC. Furthermore, DCA treatment significantly increased ATP production, PDH activity, and decreased blood glucose, lactate, and brain pyruvate levels after ROSC. Our results suggested that DCA has neuroprotective effects on brain injury after cardiac arrest, and its salutary effects were associated with an increase of mitochondrial energy metabolism in the brain through activation of PDH activity.


Assuntos
Lesões Encefálicas , Ácido Dicloroacético/farmacologia , Parada Cardíaca , Fármacos Neuroprotetores/farmacologia , Complexo Piruvato Desidrogenase/metabolismo , Animais , Lesões Encefálicas/enzimologia , Lesões Encefálicas/patologia , Lesões Encefálicas/prevenção & controle , Metabolismo Energético/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Parada Cardíaca/tratamento farmacológico , Parada Cardíaca/enzimologia , Parada Cardíaca/patologia , Masculino , Oxirredução/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ressuscitação
11.
Biomed Res Int ; 2017: 1948070, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29445732

RESUMO

Mitochondria change their morphology dynamically by continual fusion and fission processes to fulfill their function. However, little is known about the effect of cardiac arrest on mitochondrial dynamics. This study aimed to investigate time-dependent change of the mitochondrial dynamics after brain ischemic injury in rats of cardiac arrest. After resuscitation, obvious neuronal injury, reduced adenosine triphosphate (ATP) levels, excessive reactive oxygen species (ROS) generation, decreased mitochondrial membrane potential (MMP), and increased release of mitochondrial cytochrome c were observed at 12 h and 24 h after cardiac arrest. Moreover, we found that elongation of mitochondria was observed at 4 h after cardiac arrest, whereas fragmented mitochondria were significantly increased, along with concomitant increase in the fission proteins Drp1 and Fis1 and a reduction in the fusion proteins Mfn1 and Mfn2 at 12 h and 24 h after cardiac arrest. Taken together, these findings suggest that imbalance in mitochondrial dynamics probably contributes to brain injury after cardiac arrest.


Assuntos
Lesões Encefálicas/metabolismo , Parada Cardíaca/metabolismo , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Trifosfato de Adenosina/metabolismo , Animais , Lesões Encefálicas/complicações , Lesões Encefálicas/genética , Lesões Encefálicas/patologia , Dinaminas/genética , Parada Cardíaca/complicações , Parada Cardíaca/genética , Parada Cardíaca/fisiopatologia , Humanos , Masculino , Potencial da Membrana Mitocondrial/genética , Dinâmica Mitocondrial/genética , Neurônios/metabolismo , Neurônios/patologia , Ratos , Espécies Reativas de Oxigênio/metabolismo
12.
Biomed Res Int ; 2016: 1253842, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27648441

RESUMO

Objective. We investigated whether and how diazoxide can attenuate brain injury after cardiopulmonary resuscitation (CPR) by selective opening of mitochondrial ATP-sensitive potassium (mitoKATP) channels. Methods. Adult male Sprague-Dawley rats with induced cerebral ischemia (n = 10 per group) received an intraperitoneal injection of 0.1% dimethyl sulfoxide (1 mL; vehicle group), diazoxide (10 mg/kg; DZ group), or diazoxide (10 mg/kg) plus 5-hydroxydecanoate (5 mg/kg; DZ + 5-HD group) 30 min after CPR. The control group (sham group, n = 5) underwent sham operation, without cardiac arrest. Mitochondrial respiratory control rate (RCR) was determined. Brain cell apoptosis was assessed using TUNEL staining. Expression of Bcl-2, Bax, and protein kinase C epsilon (PKCε) in the cerebral cortex was determined by Western blotting and immunohistochemistry. Results. The neurological deficit scores (NDS) in the vehicle group decreased significantly at 24 h and 48 h after CPR. Diazoxide significantly improved NDS and mitochondrial RCR after CPR at both time points; 5-HD cotreatment abolished these effects. Diazoxide decreased TUNEL-positive cells following CPR, upregulated Bcl-2 and PKCε, downregulated Bax, and increased the Bcl-2/Bax ratio; 5-HD cotreatment reversed these effects. Conclusions. Diazoxide attenuates postresuscitation brain injury, protects mitochondrial function, inhibits brain cell apoptosis, and activates the PKC pathway by opening mitoKATP channels.


Assuntos
Asfixia/terapia , Lesões Encefálicas , Diazóxido/farmacologia , Parada Cardíaca/terapia , Proteínas do Tecido Nervoso/metabolismo , Canais de Potássio/metabolismo , Ressuscitação/efeitos adversos , Animais , Asfixia/enzimologia , Lesões Encefálicas/enzimologia , Lesões Encefálicas/etiologia , Lesões Encefálicas/prevenção & controle , Córtex Cerebral/enzimologia , Modelos Animais de Doenças , Parada Cardíaca/enzimologia , Masculino , Ratos , Ratos Sprague-Dawley
13.
Brain Res ; 1648(Pt A): 345-355, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27495984

RESUMO

In this study, we investigated the effects of remote ischemic preconditioning on post resuscitation cerebral function in a rat model of cardiac arrest and resuscitation. The animals were randomized into six groups: 1) sham operation, 2) lateral ventricle injection and sham operation, 3) cardiac arrest induced by ventricular fibrillation, 4) lateral ventricle injection and cardiac arrest, 5) remote ischemic preconditioning initiated 90min before induction of ventricular fibrillation, and 6) lateral ventricle injection and remote ischemic preconditioning before cardiac arrest. Reagent of Lateral ventricle injection is neuroglobin antisense oligodeoxynucleotides which initiated 24h before sham operation, cardiac arrest or remote ischemic preconditioning. Remote ischemic preconditioning was induced by four cycles of 5min of limb ischemia, followed by 5min of reperfusion. Ventricular fibrillation was induced by current and lasted for 6min. Defibrillation was attempted after 6min of cardiopulmonary resuscitation. The animals were then monitored for 2h and observed for an additionally maximum 70h. Post resuscitation cerebral function was evaluated by neurologic deficit score at 72h after return of spontaneous circulation. Results showed that remote ischemic preconditioning increased neurologic deficit scores. To investigate the neuroprotective effects of remote ischemic preconditioning, we observed neuronal injury at 48 and 72h after return of spontaneous circulation and found that remote ischemic preconditioning significantly decreased the occurrence of neuronal apoptosis and necrosis. To further comprehend mechanism of neuroprotection induced by remote ischemic preconditioning, we found expression of neuroglobin at 24h after return of spontaneous circulation was enhanced. Furthermore, administration of neuroglobin antisense oligodeoxynucleotides before induction of remote ischemic preconditioning showed that the level of neuroglobin was decreased then partly abrogated neuroprotection of remote ischemic preconditioning. These date suggested that neuroglobin involved in neuroprotective effect of remote ischemic preconditioning. In conclusion, remote ischemic preconditioning attenuated post resuscitation cerebral dysfunction and the neuroprotection was mediated partly by high level of neuroglobin in a rat model of cardiac arrest and resuscitation.


Assuntos
Encéfalo/fisiopatologia , Reanimação Cardiopulmonar , Globinas/metabolismo , Parada Cardíaca/prevenção & controle , Precondicionamento Isquêmico/métodos , Proteínas do Tecido Nervoso/metabolismo , Animais , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/patologia , Morte Celular , Modelos Animais de Doenças , Parada Cardíaca/complicações , Masculino , Neuroglobina , Ratos , Ratos Sprague-Dawley
14.
Parkinsonism Relat Disord ; 24: 81-8, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26797011

RESUMO

BACKGROUND: Parkinson's disease (PD) is associated with the progressive degeneration of dopaminergic neurons with abnormal accumulation of α-synuclein mainly in the ventral midbrain. However, the lack of live human neurons from PD patients and their heterogeneous pathogenic nature limit mechanistic studies and therefore the development of drugs to modify the disease progression of PD. The evolution of induced pluripotent stem cell (iPSC) technology makes it possible to generate patient-specific neurons to explore the pathogenesis in individual PD patients. METHODS: We generated PD-iPSCs from a sporadic early onset PD patient carrying a heterozygous deletion of exon 5 (Ex5del) in PARK2. The expression of α-synuclein and proteasome and anti-oxidative functions were examined in differentiated iPSC-derived neurons. RESULTS: The neurons derived from our PD-iPSCs demonstrated abnormal α-synuclein accumulation and down-regulation of the proteasome and anti-oxidative pathways. Environmental triggers such as proteasome inhibitor MG132 and H2O2 markedly induced cell death, while the proteasome enhancer benzamil and anti-oxidative compound genipin significantly rescued these increased susceptibilities. CONCLUSIONS: These results demonstrate that unique genetic-environmental interactions are involved in neuronal death in PD patients. Our findings also provide a new model to identify potential disease-modifying strategies and an insight into personalized medicine for patients with PD.


Assuntos
Regulação para Baixo/fisiologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Estresse Oxidativo/genética , Doença de Parkinson/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Adulto , Diferenciação Celular , Células Cultivadas , Neurônios Dopaminérgicos/metabolismo , Feminino , Humanos , Cariotipagem , Proteína Homeobox Nanog/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Transdução de Sinais/fisiologia , Tirosina 3-Mono-Oxigenase/metabolismo
15.
Int J Mol Sci ; 16(9): 20595-608, 2015 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-26334271

RESUMO

Carbon monoxide (CO) has shown various physiological effects including anti-inflammatory activity in several diseases, whereas the therapeutic efficacy of CO on sepsis-induced acute kidney injury (AKI) has not been reported as of yet. The purpose of the present study was to explore the effects of exogenous CO on sepsis-induced AKI and nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation in rats. Male rats were subjected to cecal ligation and puncture (CLP) to induce sepsis and AKI. Exogenous CO delivered from CO-releasing molecule 2 (CORM-2) was used intraperitoneally as intervention after CLP surgery. Therapeutic effects of CORM-2 on sepsis-induced AKI were assessed by measuring serum creatinine (Scr) and blood urea nitrogen (BUN), kidney histology scores, apoptotic cell scores, oxidative stress, levels of cytokines TNF-α and IL-1ß, and NLRP3 inflammasome expression. CORM-2 treatment protected against the sepsis-induced AKI as evidenced by reducing serum Scr/BUN levels, apoptotic cells scores, increasing survival rates, and decreasing renal histology scores. Furthermore, treatment with CORM-2 significantly reduced TNF-α and IL-1ß levels and oxidative stress. Moreover, CORM-2 treatment significantly decreased NLRP3 inflammasome protein expressions. Our study provided evidence that CORM-2 treatment protected against sepsis-induced AKI and inhibited NLRP3 inflammasome activation, and suggested that CORM-2 could be a potential therapeutic candidate for treating sepsis-induced AKI.


Assuntos
Lesão Renal Aguda/etiologia , Lesão Renal Aguda/metabolismo , Monóxido de Carbono/administração & dosagem , Proteínas de Transporte/metabolismo , Inflamassomos/metabolismo , Sepse/complicações , Lesão Renal Aguda/mortalidade , Lesão Renal Aguda/patologia , Lesão Renal Aguda/terapia , Animais , Apoptose , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Citocinas/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR , Estresse Oxidativo , Ratos
16.
Yi Chuan ; 34(10): 1291-7, 2012 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-23099785

RESUMO

The Hedgehog (Hh) signaling pathway inhibits fat accumulation, which is conserved in a wide variety of organisms from Drosophila to vertebrates, but few reports about its effect on pigs are available. In this study, pig Gli1 gene was cloned for the first time by rapid amplification of cDNA ends (RACE) and RT-PCR. Pig Gli1 expression profiles were then studied in different tissues and in different developmental stages of the adipose tissue of pigs using real-time PCR. Finally, the eukaryotic expression vector and the adipose tissue specific expression vector were constructed. The results showed that the full pig Gli1 cDNA length was 3 576 bp, the genomic sequence contained 10 715 bp with 12 exons, and 1 106 amino acids were encoded. Pig Gli1 was predicted as an unstable hydrophilic protein without a tans-membrane structure or a signal peptide. The C2H2 zinc finger domain and a nuclear localization sequence were found in pig Gli1. A homology analysis of the Gli1 amino acids and the genomic sequences among seven species showed that the identities were all greater than 80%, which indicates that Gli1 is highly conserved among different species. Tissue expression profile analysis showed that pig Gli1 was only expressed in the tone tissue of adult pigs. Analysis of the pig adipose tissue developmental process showed that Gli1 was detected in the adipose tissue of one-week-old pigs, but not in one-month-old and three-month-old pigs. Finally, a pig Gli1 eukaryotic expression vector was constructed and properly expressed with cell transfection. An adipose tissue specific expression vector was constructed for transgenic animal studies.


Assuntos
Tecido Adiposo/metabolismo , Proteínas Oncogênicas/genética , Suínos/genética , Transativadores/genética , Animais , Clonagem Molecular , DNA Complementar/química , Perfilação da Expressão Gênica , Vetores Genéticos , Proteína GLI1 em Dedos de Zinco
17.
J Phys Chem A ; 115(3): 274-9, 2011 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-21166400

RESUMO

Alkoxy radicals are important intermediates in the formation of tropospheric ozone. The spectroscopic identification and characterization of these species are important for understanding their chemistry in the atmosphere. In this work, we report the observation of the laser induced fluorescence (LIF) excitation spectrum of cycloheptoxy radical. The spectrum was assigned preliminary to the lowest energy twist-chair conformer (TC-i) of cycloheptoxy. The whole picture of the interconversions at ground state between different conformers of cycloheptoxy radicals was described by density functional theory calculations. The results revealed that despite the ring strain, the seven-membered ring alkoxy radical could exist in the supersonic jet-cooled condition. The decomposition and the low energy barrier pseudorotation between twist-chair conformers might be the reason of the much quieter spectrum of cycloheptoxy compared with the LIF spectrum of cyclohexoxy.

18.
J Cereb Blood Flow Metab ; 30(6): 1121-36, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20051973

RESUMO

Transient compression of rat somatosensory cortex has been reported to affect cerebral microvasculature and sensory function simultaneously. However, the effects of long-term cortical compression remain unknown. Here, we investigated whether and to what extent sustained but moderate epidural compression of rat somatosensory cortex impairs somatic sensation and/or cortical microvasculature. Electrophysiological and behavioral tests revealed that sustained compression caused only short-term sensory deficit, particularly at 1 day after injury. Although the diameter of cortical microvessels was coincidentally reduced, no ischemic insult was observed. By measuring Evans Blue and immunoglobulin G extravasation, the blood-brain barrier (BBB) permeability was found to dramatically increase during 1 to 3 days, but this did not lead to brain edema. Furthermore, immunoblotting showed that the BBB component proteins occludin, claudin-5, type IV collagen, and glial fibrillary acidic protein were markedly upregulated in the injured cortex during 1 to 2 weeks when BBB regained integrity. Conversely, treatment of ascorbic acid prevented compression-induced BBB disruption and sensory impairment. Together, these data suggest that sustained compression of the somatosensory cortex compromises BBB integrity and somatic sensation only in the early period. Ascorbic acid may be used therapeutically to modulate cortical compression and/or BBB dysfunction.


Assuntos
Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Barreira Hematoencefálica/metabolismo , Encefalopatias/prevenção & controle , Transtornos das Sensações/prevenção & controle , Córtex Somatossensorial/metabolismo , Animais , Barreira Hematoencefálica/patologia , Encefalopatias/metabolismo , Claudina-5 , Colágeno Tipo IV/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Ocludina , Ratos , Ratos Sprague-Dawley , Transtornos das Sensações/metabolismo , Córtex Somatossensorial/patologia , Regulação para Cima/efeitos dos fármacos
19.
Exp Neurol ; 216(2): 499-510, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19320008

RESUMO

Reconnection of interrupted peripheral nerve by microsurgical suture is a common clinical practice. However, the extent to which peripheral neurorrhaphy improves nerve regeneration and functional recovery remains unsatisfactory. Here, we used anatomical and electrophysiological techniques to investigate the temporal correlation between the expressions of oxidative stress-related biomarkers such as neuronal nitric oxide synthase (nNOS) and the facial axonal regeneration after an immediate facial nerve repair in adult rats since peripheral nerve lesion is well known to induce a dramatic increase of NOS expression in the affected neuronal cell bodies. We found that compared to nerve cut without suture, facial nerve repair not only caused the facial axonal regeneration but also consistently prevented the fluctuations of expressions of oxidative stress-related biomarkers in 10 weeks postlesion. To further elucidate the role of nitric oxide (NO) in the axonal degeneration/regeneration, four different NOS inhibitors were applied to additional rats after facial nerve cut or repair. Both of facial nerve cut+NOS inhibition and facial nerve repair+NOS inhibition were seen to prevent the alterations of expressions of the biomarkers, no matter which NOS inhibitor was used. Moreover, we found that facial nerve repair+NOS inhibition promoted earlier and better axonal regeneration than facial nerve repair, demonstrated by labeling of neuromuscular junctions, retrograde tracing, and electromyography. These results provide direct evidence that peripheral nerve suture and/or treatment of NOS inhibitors can maintain the homeostasis of oxidative stress-related biomarkers, especially nNOS in neuronal cell bodies. These actions may thus facilitate the axonal regeneration.


Assuntos
Traumatismos do Nervo Facial/fisiopatologia , Regeneração Nervosa/fisiologia , Óxido Nítrico Sintase/metabolismo , Aminoácidos , Análise de Variância , Animais , Axônios/efeitos dos fármacos , Axônios/fisiologia , Biofísica , Calcineurina/metabolismo , Catalase/metabolismo , DNA de Cadeia Simples/metabolismo , Estimulação Elétrica/métodos , Inibidores Enzimáticos/administração & dosagem , Nervo Facial/efeitos dos fármacos , Nervo Facial/fisiopatologia , Traumatismos do Nervo Facial/tratamento farmacológico , Traumatismos do Nervo Facial/enzimologia , Traumatismos do Nervo Facial/cirurgia , Masculino , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/patologia , Músculo Esquelético/inervação , Músculo Esquelético/fisiopatologia , Regeneração Nervosa/efeitos dos fármacos , Condução Nervosa/efeitos dos fármacos , Condução Nervosa/fisiologia , Procedimentos Neurocirúrgicos/métodos , Óxido Nítrico Sintase/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Ubiquitina Tiolesterase/metabolismo
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