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1.
Front Pharmacol ; 12: 754387, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34867366

RESUMO

Atherosclerotic cardiovascular disease is a common and severe complication of diabetes. There is a large need to identify the effective and safety strategies on diabetic cardiovascular disease (DCVD). 9-PAHSA is a novel endogenous fatty acid, and has been reported to reduce blood glucose levels and attenuate inflammation. We aim to evaluate the effects of 9-PAHSA on DCVD and investigate the possible mechanisms underlying it. Firstly, serum 9-PAHSA levels in human were detected by HPLC-MS/MS analysis. Then 9-PAHSA was synthesized and purified. The synthesized 9-PAHSA was gavaged to db/db mice with 50 mg/kg for 4 weeks. The carotid arterial plaque and cardiac structure was assessed by ultrasound. Cardiac autophagy was tested by western blot analysis, electron microscope and iTRAQ. The results showed that 9-PAHSA, in patients with type 2 diabetes mellitus (T2DM), was significantly lower than that in non-diabetic subjects. Administration of 9-PAHSA for 2 weeks reduced blood glucose levels. Ultrasound observed that continue administration of 9-PAHSA for 4 weeks ameliorated carotid vascular calcification, and attenuated myocardial hypertrophy and dysfunction in db/db mice. Electron microscopy showed continue 9-PAHSA treatment significantly increased autolysosomes, while dramatically decreased greases in the myocardial cells of the db/db mice. Moreover, iTRAQ analysis exhibited that continue 9-PAHSA treatment upregulated BAG3 and HSPB8. Furthermore, western blot analysis confirmed that 9-PAHSA down-regulated Akt/mTOR and activated PI3KIII/BECN1 complex in diabetic myocardium. Thus, 9-PAHSA benefits DCVD in diabetic mice by ameliorating carotid vascular calcification, promoting autophagic flux and reducing myocardial hypertrophy.

2.
Metab Brain Dis ; 36(8): 2329-2341, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34665375

RESUMO

Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases among the elderly people. The T2DM increases the risk of cardio-cerebrovascular disease (CCD), and the main pathological change of the CCD is atherosclerosis (AS). Meanwhile, the carbonic anhydrases (CAs) are involved in the formation and progression of plaques in AS. However, the exact physiological mechanism of carbonic anhydrase III (CAIII) has not been clear yet, and there are also no correlation study between CAIII protein and T2DM with CCD. The 8-week old diabetic mice (db/db-/- mice) and wild-type mice (wt mice) were feed by a normal diet till 32 weeks, and detected the carotid artery vascular opening angle using the method of biomechanics; The changes of cerebral cortex and myocardium were watched by the ultrastructure, and the autophagy were observed by electron microscope; The tissue structure, inflammation and cell injury were observed by Hematoxylin and eosin (HE) staining; The apoptosis of cells were observed by TUNEL staining; The protein levels of CAIII, IL-17, p53 were detected by immunohistochemical and Western Blot, and the Beclin-1, LC3, NF-κB were detected by Western Blot. All statistical analysis is performed using PRISM software. Compared with wt mice, db/db-/- mice' carotid artery open angle increased significantly. Electron microscope results indicated that autophagy in db/db-/- mice cerebral cortex and heart tissue decreased and intracellular organelle ultrastructure were damaged. HE staining indicated that, db/db-/- mice' cerebral cortex and heart tissue stained lighter, inflammatory cells infiltration, cell edema were obvious, myocardial fibers were disorder, and myocardial cells showed different degrees of degeneration. Compared with wt mice, TUNEL staining showed that there was obviously increase in db/db-/- mice cortex and heart tissue cell apoptosis. The results of immunohistochemistry and Western Blot indicated that CAIII, Beclin-1 and LC3II/I expression levels conspicuously decreased in cortex and heart tissue of db/db-/- mice, and the expression level of IL-17, NF-κB and p53 obviously increased. The carotid artery' vascular stiffness was increased and which was probably related with formation of AS in diabetic mice. And the autophagy participated in the occurrence and development of diabetic CCD. CAIII protein might somehow be involved in the regulation of autophagy probably through affecting cell apoptosis and inflammation, but the underlying mechanism remains to be further studied.


Assuntos
Anidrase Carbônica III , Transtornos Cerebrovasculares , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Animais , Autofagia , Camundongos
3.
Foods ; 10(7)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34359488

RESUMO

In order to make HPI have a wide application prospect in the food industry, we used EGCG to modify HPI. In this study, we prepared different concentrations (1, 2, 3, 4, and 5 mM) of (-)-epigallocatechin gallate (EGCG) covalently linked to HPI and use methods such as particle size analysis, circular dichroism (CD), and three-dimensional fluorescence spectroscopy to study the changes in the structure and functional properties of HPI after being covalently combined with EGCG. The particle size data indicated that the covalent HPI-EGCG complex was larger than native HPI, and the particle size was mainly distributed at about 200 µm. CD and three-dimensional fluorescence spectroscopy analyses showed that the conformation of the protein was changed by conjugation with EGCG. The ß-sheet content decreased from 82.79% to 66.67% after EGCG bound to the protein, and the hydrophobic groups inside the protein were exposed, which increased the hydrophobicity of the protein and changed its conformation. After HPI and 1 mM of EGCG were covalently bonded, the solubility and emulsifying properties of the covalent complex were improved compared with native HPI. These results indicated that HPI-EGCG conjugates can be added in some foods.

4.
CNS Neurosci Ther ; 27(4): 484-496, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33459523

RESUMO

AIMS: Type 2 diabetes mellitus (T2DM) can lead to brain dysfunction and a series of neurological complications. Previous research demonstrated that a novel palmitic acid (5-PAHSA) exerts effect on glucose tolerance and chronic inflammation. Autophagy was important in diabetic-related neurodegeneration. The aim of the present study was to investigate whether 5-PAHSA has specific therapeutic effects on neurological dysfunction in diabetics, particularly with regard to autophagy. METHODS: 5-PAHSA was successfully synthesized according to a previously described protocol. We then carried out a series of in vitro and in vivo experiments using PC12 cells under diabetic conditions, and DB/DB mice, respectively. PC12 cells were treated with 5-PAHSA for 24 h, while mice were administered with 5-PAHSA for 30 days. At the end of each experiment, we analyzed glucolipid metabolism, autophagy, apoptosis, oxidative stress, cognition, and a range of inflammatory factors. RESULTS: Although there was no significant improvement in glucose metabolism in mice administered with 5-PAHSA, ox-LDL decreased significantly following the administration of 5-PAHSA in serum of DB/DB mice (p < 0.0001). We also found that the phosphorylation of m-TOR and ULK-1 was suppressed in both PC12 cells and DB/DB mice following the administration of 5-PAHSA (p < 0.05 and p < 0.01), although increased levels of autophagy were only observed in vitro (p < 0.05). Following the administration of 5-PAHSA, the concentration of ROS decreased in PC12 cells and the levels of CRP increased in high-dose group of 5-PAHSA (p < 0.01). There were no significant changes in terms of apoptosis, other inflammatory factors, or cognition in DB/DB mice following the administration of 5-PAHSA. CONCLUSION: We found that 5-PAHSA can enhance autophagy in PC12 cells under diabetic conditions. Our data demonstrated that 5-PAHSA inhibits phosphorylation of the m-TOR-ULK1 pathway and suppressed oxidative stress in PC12 cells, and exerted influence on lipid metabolism in DB/DB mice.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/antagonistas & inibidores , Autofagia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ácido Palmítico/farmacologia , Ácidos Esteáricos/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Autofagia/fisiologia , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/uso terapêutico , Células PC12 , Ácido Palmítico/uso terapêutico , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Ácidos Esteáricos/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo
6.
Biochem Biophys Res Commun ; 524(3): 525-532, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32014256

RESUMO

Diabetes mellitus (DM) is currently a major global health problem, which is associated with the development of cognitive dysfunction. However, although numerous clinical drugs for hyperglycemia have been used at present, safer and more effective therapeutic intervention strategies for diabetic cognitive impairments are still a huge challenge. Recently, several studies have indicated that a novel class of branched palmitic acid esters of hydroxyl stearic acids (PAHSAs) may have anti-diabetes and anti-inflammatory effects in insulin-resistant mice. Herein, whether the 9-PAHSA that one of the PAHSAs can attenuates DM-associated cognitive impairment in a mouse model of type 2 diabetes has been investigated. Our results showed that 9-PAHSA mildly prevented deficits of spatial working memory in Y-maze test while reversed the preference bias toward novel mice in Social choice test. Furthermore, the effect of REST on cognitive impairment of diabetes was explored for the first time. It was found that the expression of REST in diabetic mice increased, and the expression of target protein BDNF (Brain-derived neurotrophic factor) was decreased. After administration of 9-PAHSA, the situation was reversed. In summary, we conclude that exogenous supplement of 9-PAHSA can improve DM-related cognitive impairment to some extent, and the protective effect may be associated with decreased REST/NRSF (repressor element-1 silencing transcription factor/neuron-restrictive silence factor) and upregulated BDNF expression in frontal cortex.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/fisiopatologia , Ácido Palmítico/uso terapêutico , Ácidos Esteáricos/uso terapêutico , Envelhecimento/sangue , Envelhecimento/patologia , Animais , Comportamento Animal , Glicemia/metabolismo , Peso Corporal , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/sangue , Diabetes Mellitus Experimental/sangue , Comportamento Exploratório , Masculino , Transtornos da Memória/sangue , Transtornos da Memória/complicações , Transtornos da Memória/fisiopatologia , Camundongos , Proteínas Repressoras/metabolismo , Comportamento Social , Memória Espacial
7.
Metab Brain Dis ; 33(6): 1887-1897, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30187180

RESUMO

To assess whether EGb761 could protect elderly diabetic mice with cognitive disorders and explore the role of beclin-1-mediated autophagy in these protective effects. Two-month-old male db/db-/- mice and wild-type C57/BL6 mice were randomly divided into six groups: db/db-/- control, db/db-/- 50 mg, db/db-/- 100 mg, wild-type (WT) control, WT 50 mg, and WT 100 mg. EGb761 (50 mg/kg or 100 mg/kg of bodyweight) was given by gavage once a day for 1 month from the age of 6 months. Y-maze and social choice tests were performed at 8th months. The blood pressure was measured. The imaging changes in the brain were measured using magnetic resonance imaging (MRI). The expression and distribution of beclin-1, LC3, and NF-κB were detected using immunohistochemistry staining and western blotting. Ultrastructure alterations in the hippocampus were observed using transmission electron microscopy. Compared with WT mice, the learning ability, memory and overall cognitive function of db/db-/- mice decreased (P < 0.05), and EGb761 could significantly improve the learning and memory function of db/db-/- mice (P < 0.05). EGb761 significantly improved systolic blood pressure in db/db-/- mice (P < 0.01). In addition, fMRI-bold showed a decline in the hippocampus of mice in the db/db-/- group compared with WT. EGb761 could improve these above changes. Immunohistochemistry staining and western blotting confirmed that EGb761 significantly increased beclin-1 and reduced LC3-II/I levels in the brains of db/db-/- mice (P < 0.05). NF-κB levels were obviously higher in the db/db-/- group than that in the WT group, and EGb761 significantly reduced NF-κB levels in db/db-/- mice (P < 0.05). There was a trend of increased autophagosomes in db/db-/- mice, but EGb761 did not change obviously the number of autophagosomes. Compared with normal aged WT mice, aging db/db-/- mice had more common complications of cerebral small vessel disease and cognitive dysfunction. EGb761 could significantly improve the cognitive function of aging db/db-/- mice via a mechanism that may involve the regulation of beclin-1, LC3, and NF-κB.


Assuntos
Envelhecimento/metabolismo , Proteína Beclina-1/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , NF-kappa B/metabolismo , Extratos Vegetais/uso terapêutico , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Animais , Proteína Beclina-1/agonistas , Disfunção Cognitiva/genética , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Relação Dose-Resposta a Droga , Ginkgo biloba , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/antagonistas & inibidores , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
8.
Acta Pharmacol Sin ; 39(10): 1582-1589, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29795362

RESUMO

Both in vivo and in vitro studies have shown the beneficial effects of the delta-opioid receptor (DOR) on neurodegeneration in hypoxia/ischemia. We previously reported that DOR stimulation with [(D-Ala2, D-Leu5) enkephalin] (DADLE), a potent DOR agonist, for both a short (minutes) and long (days) time has notable protective effects against sodium azide (NaN3)-induced cell injury in primary cultured rat cortical neurons. We further demonstrated that short-term DADLE stimulation increased neuronal survival through the PKC-mitochondrial ERK pathway. However, the mechanisms underlying long-term neuroprotection by DADLE remain unclear. Here, we showed that DOR stimulation with DADLE (0.1 µmol/L) for 2 d selectively activates the PI3K/Akt/NF-κB pathway in NaN3-treated neurons; this activation increased Bcl-2 expression, attenuated Cyto c release and promoted neuronal survival. Further investigation revealed that sustained DADLE stimulation increased Bcl-2 expression by enhancing NF-κB binding to the Bcl-2 promoter and upregulating the histone acetylation levels of the Bcl-2 promoter. Our results demonstrate that prolonged DADLE exposure epigenetically promotes Bcl-2 expression and elicits neuroprotective effects in the NaN3 model via the PI3K/Akt/NF-κB pathway.


Assuntos
Leucina Encefalina-2-Alanina/farmacologia , Epigênese Genética/efeitos dos fármacos , Neuroproteção/fisiologia , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Transdução de Sinais/efeitos dos fármacos , Animais , Células Cultivadas , Citocromos c/metabolismo , NF-kappa B/metabolismo , Neurônios/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Receptores Opioides delta/agonistas , Regulação para Cima
9.
CNS Neurosci Ther ; 23(6): 462-474, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28374506

RESUMO

AIMS: Although cognitive dysfunction is a common neurological complication in elderly patients with diabetes, the mechanisms underlying this relationship remain unclear, and effective preventive interventions have yet to be developed. Thus, this study investigated the preventive effects and mechanisms of action associated with granulocyte colony-stimulating factor (G-CSF) on cognitive dysfunction in elderly diabetic mice with cerebral small vessel disease. METHODS: This study included 40 male db/db diabetic and wild-type (WT) mice that were categorized into the following four groups at the age of 3 weeks: db/db group (DG), db/db+G-CSF group (DGG), WT group (WG), and WT+G-CSF group (WGG). The mice were fed normal diets for 4 months and then given G-CSF (75 µg/kg) via intraperitoneal injections for 1 month. At 7.5 months of age, the cognitive abilities of the mice were assessed with the Y-maze test and the Social Choice Test; body weight, blood pressure (BP), and blood glucose measurements were obtained throughout the study. Brain imaging and blood oxygen level-dependent (BOLD) contrast imaging analyses were performed with a small animal magnetic resonance imaging (MRI) system, autophagosome levels were detected with a transmission electron microscope (TEM), hippocampal neurons were assessed with hematoxylin and eosin (HE) staining, and protein expressions and distributions were evaluated using immunohistochemistry and Western blot analyses. RESULTS: (i) The body weight and blood glucose levels of the DG and DGG mice were significantly higher than those of the WG and WGG mice; (ii) social choice and spatial memory capabilities were significantly reduced in DG mice but were recovered by G-CSF in DGG mice; (iii) the MRI scans revealed multiple lacunar lesions and apparent hippocampal atrophy in the brains of DG mice, but G-CSF reduced the number of lacunar lesions and ameliorated hippocampal atrophy; (iv) the MRI-BOLD scans showed a downward trend in whole-brain activity and reductions in the connectivities of the hippocampus and amygdala with subcortical structures in DG mice, but G-CSF clearly improved the altered brain activity as well as the connectivity of the hippocampus in DGG mice; (v) HE staining revealed fewer neurons in the hippocampus in DG mice; (vi) TEM analyses revealed significantly fewer autophagosomes in the hippocampi of DG mice, but G-CSF did not increase these numbers; (vii) there were significant reductions in mechanistic target of rapamycin (mTOR) and LC3-phosphatidylethanolamine conjugate (LC3)-II/I levels in the hippocampi of DG mice, whereas p62 was upregulated, and G-CSF significantly enhanced the levels of Beclin1, mTOR, and LC-II/I in DGG mice; and (viii) G-CSF significantly reversed increases in nuclear factor κB (NF-κB) protein levels in DG but not in WG mice. CONCLUSIONS: In this study, aged diabetic mice were prone to cognitive dysfunction and cerebral small vessel disease. However, administration of G-CSF significantly improved cognitive function in elderly db/db diabetic mice, and this change was likely related to the regulation of autophagy and NF-κB signaling pathways.


Assuntos
Envelhecimento , Doenças de Pequenos Vasos Cerebrais/complicações , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/prevenção & controle , Diabetes Mellitus Experimental/complicações , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Animais , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/ultraestrutura , Doenças de Pequenos Vasos Cerebrais/sangue , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Comportamento de Escolha , Transtornos Cognitivos/sangue , Transtornos Cognitivos/diagnóstico por imagem , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/diagnóstico por imagem , Diabetes Mellitus Experimental/genética , Fator Estimulador de Colônias de Granulócitos/farmacologia , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Oxigênio/sangue , Ratos , Comportamento Social , Serina-Treonina Quinases TOR/metabolismo
10.
Transl Neurodegener ; 5: 22, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27999666

RESUMO

BACKGROUND: Diabetes is the most common metabolic disease with many chronic complications, and cognitive disorders are one of the common complications in patients with diabetes. Previous studies have showed that autophagy played important roles in the progression of metabolic syndrome, diabetes and other diseases. So we investigated whether aged diabetic mice are prone to be associated with the cognitive and affective disorders and whether Beclin-1-mediated autophagy might be involved in thepahological process. METHODS: High-fat diet/streptozotocin (STZ) injection-induced diabetic C57 mice were adopted in this study. Cognitive disorders were detected by Morris water maze and fear conditional test. Affective disorders were detected by tail suspension test and forced swimming test. Magnetic resonance imaging was applied to observe changes of morphology and metabolism in the brain. The 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) was used to assess metabolism changes in the brain of aged diabetic mice. Autophagy were evaluated by Beclin- 1, LC3II/I and P62, which were detected by western blot analysis and observed by electron microscopy. RESULTS: 1. Compared with control group, diabetes mice showed significantly decreasing abilities in spatial memory and conditioned fear memory (all P < 0.05), and increasing tendency of depression (P < 0.05). 2. MRI showed that the majority of elderly diabetic mice were associated with multiple cerebral small vessel disease. Some even showed hippocampal atrophy, ventricular dilatation and leukoaraiosis. 3. FDG-PET-CT discovered that the glucose metabolism in the amygdala and hippocampus was significantly decreased compared with normal aged mice (P < 0.05). 4. Electron microscopy found that, although autophagy bodies was not widespread, and there was no significant difference between the two groups, yet compared with normal aged mice, apparent cell edema, myelinated tow reduction and intracellular lipofuscin augmentation existed in elderly diabetic mice brain. 5. The level of p62 was increased in the STZ-induced diabetic mice hippocampus and striatum, and beclin1 protein expression were significantly decreased in diabetic mice hippocampus compared with normal aged mice (P < 0.05). There was a upward trend of the ratio of LC3II/I in hippocampus, cortex and striatum, but no statistically difference between the two groups. CONCLUSION: Compared with normal aged mice, diabetic aged mice were apt to cerebral small vessel disease and associated with cognitive and affective disorders, which may be related to the significantly reduced glucose metabolism in hippocampus and amygdala. Beclin1 mediated autophagy in hippocampus probably played an important role in cognitive and affective disorders of STZ-induced aged diabetic mice.

11.
CNS Neurosci Ther ; 21(12): 926-35, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26255634

RESUMO

AIM: Hypoxic-ischemic encephalopathy (HIE) is a common neurological disease in infants with persistent neurobehavioral impairments. Studies found that neural stem cell (NSC) therapy benefits HIE rats; however, the mechanisms underlying are still unclear. The current study investigated the efficacy and molecular events of human embryonic neural stem cells (hNSCs) in neonatal hypoxic-ischemic (HI) rats. METHODS: PKH-26-labeled hNSCs were intranasally delivered to P7 Sprague Dawley rats 24 h after HI. Neurobehavioral tests were performed at the indicated time after delivery: righting reflex and gait testing at D1, 3, 5, and 7; grid walking at D7 and 14; social choice test (SCT) at D28; and Morris water maze from D35 to 40. Protein expression was determined by Western blot analysis. Brain damage was assessed by cresyl violet staining and MBP staining. hNSC distribution and differentiation were observed by in vivo bioluminescence imaging and immunofluorescence staining. RESULTS: (1) hNSCs migrated extensively into brain areas within 24 h after the delivery, survived even at D42 with the majority in ipsi-hemisphere, and could be co-labeled with NeuN or GFAP. (2) hNSCs reduced the upregulation in cytosolic IL-1ß, p-IκBα, and NF-κB p65 levels, whereas enhanced nuclear p65 expression in HI rats at D3 after the delivery. (3) hNSCs decreased HI-induced brain tissue loss and white matter injury at D42 after the delivery. (4) hNSCs improved neurological outcomes in HI rats in the tests of righting reflex (within 3 days), gait (D5), grid (D7), SCT (D28), and water maze (D42). CONCLUSION: Intranasal delivery of hNSCs could prevent HI-induced brain injury and improve neurobehavioral outcomes in neonatal HI rats, which is possibly related to the modulation of NF-κB signaling.


Assuntos
Encéfalo/fisiopatologia , Células-Tronco Embrionárias/transplante , Hipóxia-Isquemia Encefálica/terapia , NF-kappa B/metabolismo , Células-Tronco Neurais/transplante , Animais , Animais Recém-Nascidos , Encéfalo/patologia , Movimento Celular , Sobrevivência Celular , Comportamento de Escolha/fisiologia , Modelos Animais de Doenças , Células-Tronco Embrionárias/patologia , Células-Tronco Embrionárias/fisiologia , Marcha/fisiologia , Humanos , Hipóxia-Isquemia Encefálica/patologia , Hipóxia-Isquemia Encefálica/fisiopatologia , Interleucina-1beta/metabolismo , Aprendizagem em Labirinto/fisiologia , Atividade Motora/fisiologia , Células-Tronco Neurais/patologia , Células-Tronco Neurais/fisiologia , Nariz , Ratos Sprague-Dawley , Reflexo/fisiologia , Comportamento Social
12.
Sheng Li Xue Bao ; 66(6): 691-701, 2014 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-25516518

RESUMO

The purpose of this study is to explore the fate and effect of human embryonic neural stem cells (hNSCs) after transplantation into ipsilateral lateral ventricle of stroke rats. Adult rats were exposed to one-hour transient middle cerebral artery occlusion (MCAO), and then hNSCs were transplanted into ipsilateral lateral ventricle 7 days after reperfusion. Infarct volume was calculated by cresyl violet staining. The improvements of neural functions were assessed by behavioral tests. Immunofluorescence staining was performed to observe the migration and differentiation of transplanted hNSCs. The results showed that transplanted hNSCs significantly reduced ischemia-induced infarction in MCAO rats, and improved neural functional restoration when assessed by rotarod, footfault and corner-turn tests. The grafted cells migrated predominantly to several specific brain regions, such as corpus callosum and peri-infarct area. Furthermore, these cells differentiated into oligodendrocytes and astrocytes in corpus callosum, and neurons in peri-infarct parenchyma. These results suggest that transplanted hNSCs through lateral ventricle of the ischemic side may exert effective therapeutic effects on stroke rats via migration and differentiation in specific brain regions.


Assuntos
Infarto da Artéria Cerebral Média/terapia , Células-Tronco Neurais/transplante , Animais , Astrócitos/citologia , Encéfalo/citologia , Encéfalo/patologia , Diferenciação Celular , Movimento Celular , Humanos , Ventrículos Laterais , Neurônios/citologia , Oligodendroglia/citologia , Ratos , Ratos Sprague-Dawley
13.
Opt Lett ; 38(8): 1209-11, 2013 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-23595433

RESUMO

We demonstrate an ultrasensitive temperature sensor based on an isopropanol-sealed optical microfiber taper (OMT) in a capillary. The OMT is highly sensitive to ambient refractive index (RI) with a maximum sensitivity of 18989 nm/RI unit in the range of 1.3955-1.4008. The thermo-optic effect of isopropanol and the thermal expansions of the sealant and sealed liquid turn the OMT into an ultrasensitive temperature sensor with the maximum sensitivity of -3.88 nm/°C in the range of 20°C-50°C. The temperature sensitivity contributions from different mechanisms are also investigated theoretically and experimentally.

14.
Langmuir ; 28(23): 8814-21, 2012 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-22594626

RESUMO

We present novel nanoporous TiO(2)/polyion thin-film-coated long-period fiber grating (LPFG) sensors for the direct measurement of low-molecular-weight chemicals by monitoring the resonance wavelength shift. The hybrid overlay films are prepared by a simple layer-by-layer deposition approach, which is mainly based on the electrostatic interaction of TiO(2) nanoparticles and polyions. By the alternate immersion of LPFG into dispersions of TiO(2) nanoparticles and polyions, respectively, the so-formed TiO(2)/polyion thin film exhibits a unique nanoporous internal structure and has a relative higher refractive index than LPFG cladding. In particular, the porosity of the thin film reduces the diffusion coefficient and enhances the permeability retention of low-molecular-weight analytes within the porous film. The increases in the refractive index of the LPFG overlay results in a distinguished modulation of the resonance wavelength. Therefore, the detection sensitivity of LPFG sensors has been greatly improved, according to theoretical simulation. After the structure of the TiO(2)/polyion thin film was optimized, glucose solutions as an example with a low concentration of 10(-7) M was easily detected and monitored at room temperature.


Assuntos
Glucose/análise , Nanoestruturas/química , Titânio/química , Peso Molecular , Porosidade , Refratometria , Soluções , Eletricidade Estática , Ressonância de Plasmônio de Superfície , Água
15.
Brain Res ; 1347: 132-41, 2010 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-20513368

RESUMO

Microtubule-associated proteins (MAPs) play a critical role in maintaining normal cytoskeletal architecture and functions. In the present study, we aim to explore the effects of the emotional stressor, chronic restraint stress, on the expression levels and localization of tau and MAP2. We found that after chronic restraint stress, soluble hyperphosphorylated tau was greatly increased, whereas MAP2 was decreased. Moreover, immunohistochemistry analysis demonstrated that phosphorylated tau and MAP2 displayed the similar subcellular distribution pattern after chronic restraint stress. Robust hyperphosphorylated tau immunolabeling was observed both in cortex and hippocampus of stressed animals and mainly located to perikaryal/dendritic elements. After stress, the MAP2 was mainly distributed in the perikaryal compartments, discontinuous dendrites and neuropil. Moreover, the distribution pattern of MAP2 in hippocampus significantly changed. Immunofluorescence double labeling indicated that hyperphosphorylated tau increased in the regions where there displayed an decrease of MAP2. These results suggest that the involvement of repeated restraint stress may not only induce phosphorylation state of tau and distribution of phosphorylated tau, but also alter the content and neuronal distribution of MAP2. Tau and MAP2 are most important MAPs for neuronal cells, the subcellular distribution change of them might be link to functional change of neurons after emotional stress.


Assuntos
Córtex Cerebral/metabolismo , Regulação da Expressão Gênica/fisiologia , Hipocampo/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Estresse Psicológico/patologia , Proteínas tau/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Fosforilação/fisiologia , Ratos , Ratos Sprague-Dawley , Restrição Física/métodos , Estresse Psicológico/etiologia
16.
Biochem Biophys Res Commun ; 390(4): 1294-8, 2009 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-19878659

RESUMO

Huntington's disease (HD) and other polyglutamine (polyQ) neurodegenerative diseases are characterized by neuronal accumulation of the disease protein, suggesting that the cellular ability to handle abnormal proteins is compromised. As a multi-subunit protein localized in the mitochondria of eukaryotic cells, the F(0)F(1)-ATP synthase alpha belongs to the family of stress proteins HSP60. Currently, mounting evidences indicate F(0)F(1)-ATP synthase alpha may play a role in neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Recently, ATP synthase alpha was reported to have protective and therapeutic roles in primary cardiacmyocytes of iron-overloaded rats by lowering ROS production. However, little is understood about the role of ATP synthase alpha in cell death and neurodegeneration. Here, we demonstrate that overexpression of ATP synthase alpha suppresses huntingtin (htt) polyQ aggregation and toxicity in transfected SH-SY5Y cell lines. Overexpression of ATP synthase alpha is able to protect cell death caused by polyglutamine-expanded htt. Transient overexpression of ATP synthase alpha suppresses the aggregate formation by estimation of polyQ aggregation, Western blot analysis, and filter trap assay (FTA) in transfected SH-SY5Y cells. These results indicated that ATP synthase alpha has a strong inhibitory effect on polyglutamine aggregate formation and toxicity in vitro, and suggest a novel neuroprotective role of ATP synthase alpha.


Assuntos
Doença de Huntington/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , ATPases Translocadoras de Prótons/biossíntese , Animais , Apoptose , Linhagem Celular Tumoral , Humanos , Proteína Huntingtina , Camundongos , Peptídeos/farmacologia , Ratos
17.
Neurosci Lett ; 465(3): 276-81, 2009 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-19766167

RESUMO

The biological function of full-length amyloid-beta protein precursor (APP), the precursor of Abeta, is not fully understood. Mounting studies reported that antibody binding to cell surface APP causes neuronal injury. However, the mechanism of cell surface APP mediating neuronal injury remains to be determined. Colocalization of APP with integrin on cell surface leads us to suppose that focal adhesion (FA) related mechanism is involved in surface APP-mediated neuronal injury. In the present study, results demonstrated that primary cultured neurons treated with antibody against APP-N-terminal not only caused neuronal injury and aberrant morphologic changes of neurite, but also induced reaction of FA proteins appearing an acute increase then decrease pattern. Moreover, the elevation of tyrosine phosphorylation of FA proteins including paxillin and focal adhesion kinase (FAK), and down-regulated expression of protein tyrosine phosphatase (PTP1B) induced by APP antibody were prevented by inhibitor of Src protein kinases 4-amino-5-(4-chlorophenyl)-7(t-butyl) pyrazol (3,4-D) pyramide (PP2) and G protein inhibitor pertussis toxin (PTX), implying that Src family kinase and G protein play roles in APP-induced FA signals. In addition, pretreatment with PTX and PP2 was able to suppress APP-antibody induced neuronal injury. Taken together, the results suggest a novel mechanism for APP mediating neuronal injury through deregulating FA signals.


Assuntos
Precursor de Proteína beta-Amiloide/imunologia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Proteína-Tirosina Quinases de Adesão Focal/imunologia , Neurônios/imunologia , Neurônios/patologia , Transdução de Sinais/imunologia , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Neurônios/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/imunologia , Ratos , Transdução de Sinais/efeitos dos fármacos
18.
Brain Res ; 1252: 183-91, 2009 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-19056363

RESUMO

It is recognized in recent years that activation of delta-opioid receptor (DOR) elicits neuroprotection against hypoxia and ischemia. However, the underlying mechanisms are not well understood yet. Mitochondrial dysfunction plays a key role in hypoxic neuronal injury, but the effect of DOR activation on neurons with a mitochondrial respiratory chain deficiency is poorly elucidated. In this study we tested the effects of DOR activation and inhibition on cultured cortical neurons after inhibiting mitochondrial respiratory chain with sodium azide (NaN(3)) in days 8 cultures. Neuronal injury was assessed by lactate dehydrogenase release. Changes in DOR proteins were investigated using an antibody against the N-terminus of the DOR, which recognizes the 60, 48, and 32 kDa proteins. Our main findings are that 1) delta- but not mu-opioid receptor activation reduces NaN(3)-induced neuronal damage, and this neuroprotective effect is abolished by DOR antagonist (naltrindole, NTI); 2) prolonged DOR inhibition with NTI further increases NaN(3)-induced neuronal damage; 3) NaN(3) treatment down-regulates DOR protein levels in neurons, and the 60 and 32 kDa proteins are particularly sensitive; 4) DADLE, besides activating DOR directly, also reverses the decrease of neuronal DOR protein levels induced by NaN(3), which may contribute greatly to its neuroprotective effect; 5) NTI reverses NaN(3)-induced down-regulation of DOR proteins as well, the effect of NTI amplifying NaN(3)-induced neuronal damage therefore is probably due to its inhibition on DOR activity only. In conclusion, these data suggest that DOR activation plays an important role in neuroprotection against mitochondrial respiratory chain injury.


Assuntos
Mitocôndrias/metabolismo , Neurônios/metabolismo , Receptores Opioides delta/metabolismo , Animais , Western Blotting , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Transporte de Elétrons/efeitos dos fármacos , Eletroforese em Gel de Poliacrilamida , Leucina Encefalina-2-Alanina/farmacologia , Imunoprecipitação , L-Lactato Desidrogenase/metabolismo , Mitocôndrias/efeitos dos fármacos , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Ratos , Ratos Sprague-Dawley , Receptores Opioides delta/agonistas , Receptores Opioides mu/metabolismo , Azida Sódica/farmacologia
19.
Sheng Li Xue Bao ; 60(4): 475-84, 2008 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-18690389

RESUMO

This work was performed to determine the role of delta-opioid receptor (DOR) in protection against acute ischemia/reperfusion injury. Transient (1 h) focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO). DOR agonist TAN-67 (30 nmol, 60 nmol, 200 nmol), DOR antagonist naltrindole (20 nmol, 50 nmol, 100 nmol) or artificial cerebral spinal fluid (aCSF) was injected respectively into the lateral cerebroventricle of the rat 30 min before the induction of brain ischemia. Neurological deficits were assessed by the five-grade system (Longa's methods). The brain infarct was measured by cresyl violet (CV) staining and infarct volume was analyzed by an image processing and analysis system. The expression of DOR was detected by Western blot. The results showed that 60 nmol TAN-67 significantly reduced the infarct volume (P<0.05), attenuated neurological deficits (P<0.05) and tended to increase the expression of about 60 kDa DOR protein (P>0.05), while 100 nmol naltrindole aggravated ischemic damage and decreased about 60 kDa DOR protein expression (P<0.05). These results suggest that DOR activation protects the brain against acute ischemia/reperfusion injury in rat.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Naltrexona/análogos & derivados , Quinolinas/farmacologia , Receptores Opioides delta/agonistas , Animais , Encéfalo/patologia , Infarto da Artéria Cerebral Média , Injeções Intraventriculares , Naltrexona/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão
20.
Zhong Xi Yi Jie He Xue Bao ; 6(6): 632-8, 2008 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-18559244

RESUMO

OBJECTIVE: To explore the effect of delta-opioid receptor (DOR) in electroacupuncture (EA) protecting the brain against acute ischemic injury. METHODS: Fifty-one rats were randomly divided into sham ischemia group, ischemia group, sham EA group, EA group, and EA+DOR antagonist (naltrindole) group. Transient focal cerebral ischemia (1 hour) was induced in rat brain by middle cerebral artery occlusion (MCAO) method. EA was applied on Shuigou (GV 26) and Neiguan (PC 6) for 30 min, starting immediately after the onset of reperfusion. Neurological deficit scores and volume of cerebral infarction were detected after 24-hour reperfusion. Other 12 rats were randomly divided into sham ischemia group, ischemia group, EA group and EA + naltrindole group. DOR protein expressions were assessed by Western blotting after 24-hour reperfusion. RESULTS: In comparison with the ischemia group and sham EA group, EA significantly reduced ischemic infarction and neurological deficits (P<0.05); EA significantly increased the expression of 60 kD DOR protein (P<0.05) and tended to increase that of 36 kD DOR protein (P>0.05). When naltrindole was combined with EA, the naltrindole completely abolished the EA-induced protection in ischemic infarction and neurological deficits, and also arrested the expression of DOR. CONCLUSION: EA can up-regulate DOR expression and protect the brain from ischemia-reperfusion injury.


Assuntos
Eletroacupuntura , Infarto da Artéria Cerebral Média/terapia , Receptores Opioides delta/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Animais , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Regulação para Cima
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