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1.
Bioorg Med Chem ; 26(16): 4687-4692, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30119994

RESUMO

MBRI-001 was demonstrated preliminary better pharmacokinetics and antitumor effects than that of plinabulin in vivo. In this approach, we further carried out systematic pharmacokinetic and pharmacodynamic study of MBRI-001 in vitro and in vivo. MBRI-001 was tested stable in rat plasma and more stable in liver microsomes than plinabulin in vitro. In vivo, MBRI-001 could be distributed rapidly and widely in various tissues, especially the concentration of MBRI-001 in lung was remarkably higher than other tissues. Excretion study indicated that MBRI-001 might been decomposed and excreted as metabolites. Additionally, the combination treatment of MBRI-001 and gefitinib revealed better antitumor inhibition rate than monotherapy in vivo. Therefore, we suggest that MBRI-001 could be developed as a promising anti-cancer agent in near future.

2.
Bioorg Med Chem ; 26(8): 2061-2072, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29571653

RESUMO

Based on the co-crystal structures of tubulin with plinabulin and Compound 1 (a derivative of plinabulin), a total of 18 novel plinabulin derivatives were designed and synthesized. Their biological activities were evaluated against human pancreatic cancer BxPC-3 cell lines. Two novel Compounds 13d and 13e exhibited potent activities with IC50 at 1.56 and 1.72 nM, respectively. The tubulin polymerization assay indicated that these derivatives could inhibit microtubule polymerization. Furthermore, the interaction between tubulin and these compounds were elucidated by molecular docking. The binding modes of Compounds 13d and 13e were similar to the co-crystal structure of Compound 1. H-π interaction was observed between the aromatic hydrogen of thiophene moiety with Phe20, which could enhance their binding affinities.


Assuntos
Antineoplásicos/síntese química , Dicetopiperazinas/química , Desenho de Drogas , Moduladores de Tubulina/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Dicetopiperazinas/metabolismo , Dicetopiperazinas/farmacologia , Humanos , Simulação de Acoplamento Molecular , Neoplasias Pancreáticas/patologia , Estrutura Terciária de Proteína , Solubilidade , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/metabolismo , Moduladores de Tubulina/farmacologia
3.
Medicine (Baltimore) ; 97(1): e9112, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29505509

RESUMO

RATIONALE: Stevens-Johnson syndrome (SJS) is an acute blistering disease of the skin and mucous membranes. SJS in children is not common but potentially serious disease. But the epidemiology of SJS in China is not well defined. PATIENT CONCERNS: A 6-year-old boy was initially diagnosed as pneumonia admitted to hospital after admission, and the body appears red rash with blisters, skin damage, lip debaucjed, repeated high fever, and rapid progression. DIAGNOSES: SJS often results from an allergy reaction response to a range of drugs. It is a clinical diagnosis suggested by fever and malaise followed by an extensive painful, nonblanching, macular rash that commonly progresses to blistering or sloughing, and mucositis. INTERVENTIONS: The boy was treated with continuous renal replacement therapy, anti-infection therapy, high-dose glucocorticoid treatment, and symptomatic treatment. OUTCOMES: The patient was recovered after 33 days of treatment. LESSONS: The current treatment is mainly symptomatic treatment, and for the patient, it is important to make skin care related well, included early out blisters at effusion, reducing skin ulceration of the mucosa area, keeping skin clean, removing mucosa secretion and blood clots, doing eye care related, preventing the complications, ensuring adequate intake of nutrition and warm and so on.


Assuntos
Antibacterianos/efeitos adversos , Azitromicina/efeitos adversos , Higiene da Pele/enfermagem , Síndrome de Stevens-Johnson/enfermagem , Criança , Humanos , Masculino , Pneumonia/tratamento farmacológico , Síndrome de Stevens-Johnson/etiologia
4.
Cancer Chemother Pharmacol ; 81(5): 853-862, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29532153

RESUMO

PURPOSE: MBRI-001 is a novel synthetic derivative of plinabulin. In this study, our purpose is to investigate the inhibition effects of MBRI-001 on human hepatocellular carcinoma as monotherapy or in combination with sorafenib. METHODS: HCCLM3 and Bel-7402 cell lines were used for activity evaluation in vitro. The anti-proliferative activity of MBRI-001 was assessed by MTT assay. The morphological change of microtubules was determined by immunofluorescence assay. The cell cycle was measured by flow cytometer. The expression of cyclin B1 (CCNB1) was analyzed by RT-qPCR and western blotting assays. The antitumor activities in vivo were evaluated with human HCC xenograft mice model. RESULTS: Our data demonstrated that MBRI-001 had better anti-proliferative activities than that of plinabulin against HCCLM3 and Bel-7402 cell lines. MBRI-001 inhibited the formation of microtubules and induced G2/M arrest with the downregulation of CCNB1. In vivo orthotopic mice model demonstrated that MBRI-001 significantly inhibited the growth of HCCLM3 with the apoptosis and necrosis observed in tumor. The combination treatment of MBRI-001 with sorafenib in subcutaneous mice model exhibited a higher antitumor inhibition rate at 72.0%, in comparison with MBRI-001 or sorafenib as monotherapy at 40.7% or 47.7%, respectively. CONCLUSION: MBRI-001 had better inhibition effects on microtubules and human hepatocellular carcinoma than that of plinabulin. The combination treatment of MBRI-001 and sorafenib exhibited a higher antitumor effect, which could provide a new strategy to treat HCC in the future.

5.
BMC Pediatr ; 18(1): 8, 2018 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-29347924

RESUMO

BACKGROUND: In China, the majority (77%) of urban children die in hospitals. Hospital-based review could provide insight leading to improvements in clinical practice and increase the survival of critically ill children. The aim of the present study is to identify the trends of immediate causes and chronic underlying diseases associated with deaths of children at one of the largest teaching hospitals in China over a period of 10 years (2006-2015). METHODS: A retrospective analysis of data of all children aged 1 month to 11 years who died at Xinhua Hospital between 2006 and 2015. Demographic details, main causes of deaths, and chronic underlying diseases were reviewed. RESULTS: Case fatality rate was 0.55% (510/93,443) and it represented 0.41-0.80% deaths per year. Overall, the most common immediate causes of deaths in hospitalized children were pneumonia (36.7%), sepsis (13.5%), tumour (11.4%), followed by nontraumatic intracranial or gastrointestinal hemorrhage (10.6%) and cardiac shock (9.6%). Over 70% of the deaths in children were complicated with chronic underlying diseases. Congenital abnormality was the most frequent chronic underlying disease observed in infants (60.3%) and tumour was the main chronic underlying disease in toddlers (31.1%) and older children (44%). CONCLUSIONS: Infectious diseases, especially pneumonia, were the major immediate causes of deaths, and the mortality in the study population decreased with age. Tumour and other noninfectious disease accounted for more deaths in older children. Chronic underlying diseases were found in most deaths of children.


Assuntos
Causas de Morte/tendências , Mortalidade Hospitalar/tendências , Criança , Pré-Escolar , China/epidemiologia , Doença Crônica , Estado Terminal , Feminino , Hospitalização , Humanos , Lactente , Masculino , Estudos Retrospectivos
6.
Medicine (Baltimore) ; 96(21): e6952, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28538388

RESUMO

RAIONALE: Myxedema coma (MC) is extremely rare but lethal in pediatric patients with hypothyroidism leading to altered mental status and hypothermia. But there is no clinical guideline for such cases. PATIENT CONCERNS: A 6-year-old Chinese girl presented with coma and hypothermia preceded by pneumonia. Her lab results were: free thyroxin (T4) 4.18 pmol/L and thyroid-stimulating hormone (TSH) > 150 µIU/mL with extremely elevated anti-thyroid peroxidase (TPO-Ab) and anti-thyroglobulin. Pneumonia, mild pleural, and pericardial effusion were seen on computed tomographic (CT) scan. DIAGNOSES: MC, autoimmune hypothyroidism, pneumonia and sepsis were diagnosed. INTERVENTION: Gastric levothyroxine, intravenous dexamethasone and antibiotics were administered. OUTCOME: Her consciousness was restored and temperature returned to normal 2 days after starting levothyroxine. She was discharged two weeks later. CONCLUSION: MC is rare but may be the initial presentation in pediatric patients with prolonged untreated hypothyroidism. Autoimmune thyroiditis could cause hypothyroidism in children. MC should be suspected in pediatric patients with altered mental status, hypothermia and cardiovascular instability. Treatment with 100 mg/m of gastric levothyroxine is an option for pediatric patients with MC.

7.
J Biol Chem ; 289(18): 12922-30, 2014 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-24644294

RESUMO

Reelin is a secreted glycoprotein that plays essential roles in the brain. Reelin is specifically cleaved at two distinct sites, called N-t and C-t, with the former being the major one. N-t cleavage can occur both in the extracellular space and in the endosomes, although the physiological importance of endosomal N-t cleavage has not been investigated. In this study, we first determined the exact N-t cleavage site catalyzed by a protease secreted by cerebral cortical neurons. Cleavage occurred between Pro-1244 and Ala-1245 within Reelin repeat 3. A Reelin mutant in which Pro-1244 was replaced with aspartate (Reelin-PD) was resistant to a protease secreted by cultured cerebral cortical neurons, and its biological activity stayed active longer than that of wild-type Reelin. Interestingly, Reelin-PD remained in the intracellular compartments longer than wild-type Reelin and persistently activated downstream signaling. Therefore, N-t cleavage of Reelin is required for halting the signaling machinery in the extracellular space as well as within endosomes of target neurons. We established a monoclonal antibody specific to uncleaved Reelin protein and found that it is localized in the vicinity of Reelin-producing cells, whereas the N-terminal fragment diffuses, or is transported, to distant regions. These data demonstrate that N-t cleavage of Reelin plays critical roles in regulating the duration and range of Reelin functions both in the extracellular milieu and in the intracellular compartments.


Assuntos
Ácido Aspártico/genética , Moléculas de Adesão Celular Neuronais/genética , Proteínas da Matriz Extracelular/genética , Mutação , Proteínas do Tecido Nervoso/genética , Prolina/genética , Serina Endopeptidases/genética , Transdução de Sinais/genética , Sequência de Aminoácidos , Animais , Ácido Aspártico/metabolismo , Sítios de Ligação/genética , Western Blotting , Moléculas de Adesão Celular Neuronais/metabolismo , Células Cultivadas , Endossomos/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Espaço Extracelular/metabolismo , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Peptídeo Hidrolases/metabolismo , Prolina/metabolismo , Proteólise , Homologia de Sequência de Aminoácidos , Serina Endopeptidases/metabolismo
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