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1.
Ann Transl Med ; 7(16): 383, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31555697

RESUMO

Background: Familial focal segmental glomerulosclerosis (fFSGS) is difficult to treat, and stem cell transplantation is one of the most promising approaches for treating this condition. According to the novel mutation site found in our FSGS family, we established a novel animal model of FSGS to explore the application of stem cell therapy in FSGS. Methods: The animal model used in this experiment was p.Gly1617Valfs X15 (C57BL/6) mutant mice. This mutation was first found in a focal segmental glomerulosclerosis (FSGS) family undergoing renal biopsy in our department. The mouse model was then constructed via CRISPR/Cas9 genomic editing technology. Then, the animals were injected with human umbilical cord mesenchymal stem cells (UCMSC) through the tail vein and regularly followed up to determine phenotypic changes in urine protein quantities, serum creatinine and histological outcomes. Results: Compared with the positive control group, the levels of urinary protein and serum creatine were decreased significantly after UCMSC transplantation. HE staining images revealed a delay in glomerular sclerosis. Moreover, the secretion of the type IV collagen α3 chain was significantly increased compared with the positive control group, as shown by using immunofluorescence microscopic observation, and electron microscopy proved that the podocytes and basement membrane recovered well from the damage. The intervention also resulted in enhanced IL-22 expression. Conclusions: UCMSC transplantation may be a potential treatment for FSGS, and IL-22 may play an important role in this process. Further studies are needed to reveal the underlying mechanism.

2.
J Pharmacol Exp Ther ; 371(2): 250-259, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31488603

RESUMO

Recent imaging studies of amyloid and tau in cognitively normal elderly subjects imply that Alzheimer's pathology can be tolerated by the brain to some extent due to compensatory mechanisms operating at the cellular and synaptic levels. The present study investigated the effects of an allosteric inhibitor of phosphodiesterase-4D (PDE4D), known as BPN14770 (2-(4-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)acetic Acid), on impairment of memory, dendritic structure, and synaptic proteins induced by bilateral microinjection of oligomeric amyloid beta (Aß 1-42 into the hippocampus of humanized PDE4D (hPDE4D) mice. The hPDE4D mice provide a unique and powerful genetic tool for assessing PDE4D target engagement. Behavioral studies showed that treatment with BPN14770 significantly improved memory acquisition and retrieval in the Morris water maze test and the percentage of alternations in the Y-maze test in the model of Aß impairment. Microinjection of oligomeric Aß 1-42 caused decreases in the number of dendrites, dendritic length, and spine density of pyramid neurons in the hippocampus. These changes were prevented by BPN14770 in a dose-dependent manner. Furthermore, molecular studies showed that BPN14770 prevented Aß-induced decreases in synaptophysin, postsynaptic density protein 95, phosphorylated cAMP-response element binding protein (CREB)/CREB, brain-derived neurotrophic factor, and nerve growth factor inducible protein levels in the hippocampus. The protective effects of BPN14770 against Aß-induced memory deficits, synaptic damage, and the alteration in the cAMP-meditated cell signaling cascade were blocked by H-89 (N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride), an inhibitor of protein kinase A. These results suggest that BPN14770 may activate compensatory mechanisms that support synaptic health even with the onset of amyloid pathology in Alzheimer's disease. SIGNIFICANCE STATEMENT: This study demonstrates that a phosphodiesterase-4D allosteric inhibitor, BPN14770, protects against memory loss and neuronal atrophy induced by oligomeric Aß 1-42. The study provides useful insight into the potential role of compensatory mechanisms in Alzheimer's disease in a model of oligomeric Aß 1-42 neurotoxicity.

3.
Neuropsychopharmacology ; 43(11): 2299-2309, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30131563

RESUMO

Inhibitors of phosphodiesterase-4 (PDE4) have beneficial effects on memory in preclinical and clinical studies. Development of these drugs has stalled due to dose-limiting side effects of nausea and emesis. While use of subtype-selective inhibitors (i.e., for PDE4A, B, or D) could overcome this issue, conservation of the catalytic region, to which classical inhibitors bind, limits this approach. The present study examined the effects of BPN14770, an allosteric inhibitor of PDE4D, which binds to a primate-specific, N-terminal region. In mice engineered to express PDE4D with this primate-specific sequence, BPN14770 was 100-fold more potent for improving memory than in wild-type mice; meanwhile, it exhibited low potency in a mouse surrogate model for emesis. BPN14770 also antagonized the amnesic effects of scopolamine, increased cAMP signaling in brain, and increased BDNF and markers of neuronal plasticity associated with memory. These data establish a relationship between PDE4D target engagement and effects on memory for BPN14770 and suggest clinical potential for PDE4D-selective inhibitors.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Memória/efeitos dos fármacos , Inibidores da Fosfodiesterase 4/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibidores da Fosfodiesterase 4/química , Ligação Proteica/fisiologia
4.
Clin J Am Soc Nephrol ; 13(9): 1330-1338, 2018 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-30042224

RESUMO

BACKGROUND AND OBJECTIVES: At least 20 susceptibility loci of IgA nephropathy have been identified by genome-wide association studies to date. Whether these loci were associated with disease progression is unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We enrolled 613 adult patients with IgA nephropathy for a follow-up of ≥12 months. All 20 IgA nephropathy susceptibility loci were selected and their tag single nucleotide polymorphisms (SNPs) were genotyped. After strict quality control, 16 SNPs and 517 patients with IgA nephropathy were eligible for subsequent analysis. Progression was defined as ESKD or 50% decrease in eGFR. A stepwise Cox regression analysis of all SNPs on Akaike information criterion was performed to select the best model. RESULTS: A four-SNP model, rs11150612 (ITGAM-ITGAX), rs7634389 (ST6GAL1), rs2412971 (HORMAD2), and rs2856717 (HLA-DQ/DR), was selected as the best predictive model. The genetic risk score calculated on the basis of the four SNPs was independently associated with disease progression before (hazard ratio [HR], 1.65; 95% confidence interval [95% CI], 1.29 to 2.12) and after adjustment by a recently reported clinical model (HR, 1.29; 95% CI, 1.03 to 1.62) or clinical-pathologic model (HR, 1.35; 95% CI, 1.03 to 1.77). Compared with low genetic risk, patients with middle genetic risk had a 2.12-fold (95% CI, 1.33 to 3.40) increase of progression risk, whereas patients with high genetic risk had 3.61-fold (95% CI, 2.00 to 6.52) progression risk increase. In addition, incorporation of genetic risk score could potentially increase discrimination of the clinical model (c-statistic increase from 0.83 to 0.86) or the clinical-pathologic model (c-statistic increase from 0.82 to 0.85) in predicting 5-year progression risk. CONCLUSIONS: The four-SNP genetic risk score was independently associated with IgA nephropathy progression and could enhance the performance of clinical and clinical-pathologic risk models.


Assuntos
Loci Gênicos/genética , Predisposição Genética para Doença , Glomerulonefrite por IGA/genética , Polimorfismo de Nucleotídeo Único , Adulto , Progressão da Doença , Feminino , Humanos , Masculino , Estudos Retrospectivos
5.
Neuropharmacology ; 133: 181-188, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29373817

RESUMO

trans-Resveratrol, a natural polyphenol enriched in grape seed and skin, has been extensively investigated for its antioxidant, anti-inflammatory and anti-psychiatric properties. The present study examined the effects of trans-resveratrol on ameliorating anxiety-like behaviors and fear memory deficits induced by time-dependent sensitization (TDS) procedure, which is a classical animal model for mimicking posttraumatic stress disorder (PTSD). The results suggested that trans-resveratrol at doses of 10, 20 and 40 mg/kg (via gavage, i.g.) reversed TDS-induced decreases in the percentage of time spent in the center of arena, the open arm entries and time spent in the open arms in the open field and elevated plus maze tests. It also decreased the percentage of freezing time in the contextual fear paradigm that was increased in TDS treated rats. Further study suggested that TDS-induced abnormality in the limbic hypothalamus-pituitary-adrenal gland (L-HPA) axis was reversed by trans-resveratrol, i.e. it reversed increased adrenal gland index and corticotropin-releasing factor (CRF) levels, and rescued the differential expression of glucocorticoid receptor (GR) in the hypothalamus, hippocampus and amygdala. Neurobiological studies suggested that trans-resveratrol increased phosphorylation of cAMP response element binding protein (pCREB) and brain derived neurotrophic factor (BDNF) levels, which were decreased in rats subjected to TDS. These results provide compelling evidence that trans-resveratrol protects neurons against PTSD-like stress insults by regulation of L-HPA axis function and activation of downstream neuroprotective molecules, such as pCREB and BDNF expression.


Assuntos
Antioxidantes/uso terapêutico , Ansiedade/tratamento farmacológico , Medo/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Estilbenos/uso terapêutico , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/patologia , Análise de Variância , Animais , Ansiedade/etiologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação a CREB/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/etiologia , Ratos , Ratos Sprague-Dawley , Resveratrol , Transtornos de Estresse Pós-Traumáticos/complicações , Transtornos de Estresse Pós-Traumáticos/patologia
6.
ScientificWorldJournal ; 2014: 602875, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25101319

RESUMO

Due to limited resources in wireless sensor nodes, energy efficiency is considered as one of the primary constraints in the design of the topology of wireless sensor networks (WSNs). Since data that are collected by wireless sensor nodes exhibit the characteristics of temporal association, data fusion has also become a very important means of reducing network traffic as well as eliminating data redundancy as far as data transmission is concerned. Another reason for data fusion is that, in many applications, only some of the data that are collected can meet the requirements of the sink node. In this paper, we propose a method to calculate the number of cluster heads or data aggregators during data fusion based on the rate-distortion function. In our discussion, we will first establish an energy consumption model and then describe a method for calculating the number of cluster heads from the point of view of reducing energy consumption. We will also show through theoretical analysis and experimentation that the network topology design based on the rate-distortion function is indeed more energy-efficient.


Assuntos
Redes de Comunicação de Computadores , Tecnologia sem Fio , Análise por Conglomerados , Modelos Teóricos
7.
Artigo em Chinês | MEDLINE | ID: mdl-19452713

RESUMO

OBJECTIVE: To investigate the value of the endoscopy in the operation of microvascular decompression (MVD) for the hemifacial spasm by approach of postauricular suboccipital to the cerebellopontine angle (CPA) with posterior auricular small incision. METHOD: Two hundred and eighty-six cases of hemifacial spasm had received the operation of MVD with endoscopy by approach of postauricular suboccipital to the CPA. RESULT: Responsible blood vessels were found in 285 cases (99.7 percent), including 264 cases of anterior inferior cerebellar artery, 21 cases of basilar artery. The root entry zone of the facial nerve were completely decompressed with Teflon. There is no responsible blood vessels but adhesion in 1 cases (0.3 percent). After surgery, hemifacial spasm immediately disappeared. House-Brackmann(1985) grading system was used to evaluated the recovery of facial nerve function. After 1 week of operation 196 cases' facial nerve function are stage 1/6, 62 cases' are stage 2/6, 23 cases' are stage 3/6, 4 cases' are stage 4/6, 1 cases' is stage 5/6. And after Six months of operation, 274 cases' are stage 1/6, 10 cases' are stage 2/6, 2 cases' are stage 3/6. After 1 month of operation there is no significant change of hearing in 238,there are 35 cases of hearing loss less than 20 dB, 10 cases of hearing loss more than 20 dB, but less than 50 dB,3 cases of hearing loss more than 50 dB. Ear-nose cerebrospinal fluid leakage occurred in 2 cases are cured. During 1 year to 4 years following-up, only 3 (1.0 percent) preliminary suffered relapse,among which 1 case was cured by the secondary operation. The long term cure rate was 99.3 percent without occurrence of serious complications such as death. CONCLUSION: The microneurosurgery of MVD for the treatment of hemifacial spasm is an ideally functional and etiotropic operation. It is useful not only to discover the responsible blood vessels which are regarded as those pressing the root entry zone of facial nerve,but also to protect the function of the brain tissue and nerves as well. It is a safe, minimally invasive and efficient operation. To avoid the complications, enough knowledge of the craniotopography and skilled technique of endoscopic operation are primary.


Assuntos
Descompressão Cirúrgica/métodos , Espasmo Hemifacial/cirurgia , Adulto , Idoso , Ângulo Cerebelopontino/cirurgia , Endoscopia , Nervo Facial/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
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