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1.
J Cardiovasc Dev Dis ; 11(7)2024 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-39057622

RESUMO

BACKGROUND: Amyloid light-chain (AL) amyloidosis is a multisystem disorder, with cardiac amyloid infiltration being a prevalent manifestation. This study aimed to explore the prognostic value of galectin-3 (Gal-3), a soluble marker associated with fibrosis, inflammation, heart failure, and kidney injury, in patients with cardiac AL amyloidosis. METHODS: A total of 60 patients who were diagnosed with cardiac AL amyloidosis from January 2015 to May 2018 were enrolled. The prognostic value of Gal-3 was assessed. Receiver operating characteristic (ROC) curves were used to evaluate the predictive accuracy of Gal-3. A Gal-3 cut-off value was identified to predict survival rates. RESULTS: The ROC curves demonstrated a moderate predictive accuracy of Gal-3 for 0.5- and 5-year survival, with area under the curve (AUC) values of 0.722 and 0.788, respectively. A Gal-3 cut-off value of 15.154 ng/mL was found to predict survival. Kaplan-Meier survival analysis revealed a significant difference in mean overall survival between patients with Gal-3 levels below and above the established cut-off (69.2 months versus 42.1 months, respectively; p = 0.036). Multivariate analysis confirmed that Gal-3 > 15.154 ng/mL remained an independent predictor of survival (HR 2.451, 95% CI 1.017-5.910, p = 0.046). CONCLUSIONS: This study suggests that Gal-3 holds independent prognostic value for survival in patients with cardiac AL amyloidosis. Gal-3 could potentially enhance the prognostic capabilities of the current soluble markers, thereby improving the management of cardiac AL amyloidosis. However, further validation in larger prospective studies is warranted.

2.
Heliyon ; 10(9): e30688, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38756560

RESUMO

In this study, the Ni/NiO catalyst was demonstrated to enhance the hydrogen storage performance of MgH2. The dehydrogenation of MgH2+10 wt% Ni/NiO started at approximately 180 °C, achieving 5.83 wt% of dehydrogenation within 10 min at 300 °C. Completely dehydrogenated, MgH2 began to rehydrogenate at about 50 °C, absorbing about 4.56 wt% of hydrogen in 10 min at 150 °C. In addition, the activation energies of dehydrogenation and rehydrogenation of MgH2+10 wt% Ni/NiO were 87.21 and 34.84 kJ/mol. During the dehydrogenation/rehydrogenation cycle, Mg2Ni/Mg2NiH4 could promote hydrogen diffusion, thus enhancing the hydrogen storage performance of Mg/MgH2.

3.
J Cardiothorac Surg ; 19(1): 50, 2024 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-38310296

RESUMO

BACKGROUND: Chylopericardium is a rare condition characterized by the accumulation of chyle in the pericardial space. It is most commonly caused by thoracic duct injury. Chylopericardium following esophagectomy is extremely rare but can cause life-threatening complications. This report presents a case of chylopericardium post-esophagectomy, resulting in cardiac tamponade and cardiac arrest. A systematic literature review was also conducted to facilitate the understanding of this rare condition. CASE PRESENTATION: A 41-year-old male was admitted to our hospital with intermediate to highly differentiated squamous cell carcinoma of the mid-thoracic esophagus (clinical T4NxM0). He underwent thoracoscopic-laparoscopic esophagectomy with cervical anastomosis. On postoperative day 1, patient had a cardiac arrest secondary to cardiac tamponade, requiring emergency ultrasound-guided drainage. The drained fluid was initially serous but became chylous after the administration of enteral nutritional emulsion. As a result of significant daily pericardial drainage, patient subsequently underwent thoracic duct ligation. The amount of drainage was substantially reduced post-thoracic duct ligation. Over a period of 2 years and 7 months, patient recovered well and tolerated full oral diet. A comprehensive literature review was conducted and 4 reported cases were identified. Among these cases, three patients developed pericardial tamponade secondary to chylopericardium post-esophagectomy. CONCLUSION: Chylopericardium is a rare but serious complication post-esophagectomy. Prompt echocardiography and thorough pericardial fluid analysis are crucial for diagnosis. Thoracic duct ligation has been shown to be an effective management approach for this condition.


Assuntos
Tamponamento Cardíaco , Parada Cardíaca , Derrame Pericárdico , Masculino , Humanos , Adulto , Derrame Pericárdico/diagnóstico , Derrame Pericárdico/etiologia , Derrame Pericárdico/cirurgia , Tamponamento Cardíaco/diagnóstico , Tamponamento Cardíaco/etiologia , Tamponamento Cardíaco/cirurgia , Esofagectomia/efeitos adversos , Mediastino , Ducto Torácico/cirurgia , Ligadura/efeitos adversos , Parada Cardíaca/cirurgia
4.
Curr Vasc Pharmacol ; 22(3): 203-217, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38141195

RESUMO

INTRODUCTION: Myocardial ischaemia reperfusion injury (MIRI) determines infarct size and long-term outcomes after acute myocardial infarction (AMI). Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, alleviates MIRI in animal models. METHOD: We investigated the potential mechanisms underlying the cardioprotective effect of dapagliflozin against MIRI, focusing on mitochondrial injury and mitophagy. MIRI mouse and H9C2 cell models were established. RESULTS: 2,3,5-Triphenyltetrazolium chloride (TTC) staining showed a significant alleviation of MIRI after pre-treatment of dapagliflozin compared to the model group (14.91 ± 1.76 vs. 40.47 ± 3.69%). Data from the pre-treatment dapagliflozin group showed a significant decrease in left ventricular ejection fraction (LVEF) (44.8 ± 2.7 vs. 28.5 ± 5.3%, P<0.01), left ventricular end-diastolic volume (LVEDV) (70.6 ± 9.5 vs. 93.5 ± 13.8 ul, P<0.05), and left ventricular end-systolic volume (LVESV) (39.0 ± 8.3 vs. 67.9 ± 13.7 ul, P<0.05) compared to the model group. Dapagliflozin also reduced the levels of reactive oxygen species (ROS) and fragmented mitochondrial DNA, reversed the decrease in mitochondrial membrane potential, and suppressed apoptosis. Further study showed that dapagliflozin could protect against mitochondrial injury by rapidly clearing damaged mitochondria via mitophagy in a phosphatase and tensin homologue (PTEN)-induced putative kinase 1 (PINK1)/parkindependent manner. Dapagliflozin regulated mitophagy in cardiomyocytes by suppressing the adenosine 5'monophosphate-activated protein kinase (AMPK)-PINK1/parkin signalling pathway, resulting in attenuated MIRI. CONCLUSION: Dapagliflozin alleviated MIRI by activating mitophagy via the AMPK-PINK1/parkin signalling pathway.


Assuntos
Proteínas Quinases Ativadas por AMP , Compostos Benzidrílicos , Modelos Animais de Doenças , Glucosídeos , Camundongos Endogâmicos C57BL , Mitofagia , Traumatismo por Reperfusão Miocárdica , Miócitos Cardíacos , Proteínas Quinases , Transdução de Sinais , Ubiquitina-Proteína Ligases , Função Ventricular Esquerda , Animais , Glucosídeos/farmacologia , Mitofagia/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases/metabolismo , Compostos Benzidrílicos/farmacologia , Ubiquitina-Proteína Ligases/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Masculino , Função Ventricular Esquerda/efeitos dos fármacos , Linhagem Celular , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/patologia , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/enzimologia , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Camundongos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos
5.
Oxf Med Case Reports ; 2023(10): omad112, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37881267

RESUMO

Boerhaave syndrome is a rare but potentially life-threatening condition that involves a full-thickness tear of the oesophagus. It accounts for around 15% of all cases of oesophageal perforations and is associated with up to 40% of mortality. Vomiting has been found to be associated with the development of Boerhaave syndrome. However, the aetiology of vomiting varies broadly in the available literatures from alcohol indulgence to marathon running, and from panic attack to radiotherapy for cancer. We present here an unusual case of Boerhaave syndrome where the patient developed spontaneous oesophageal perforation in the setting of renal colic.

6.
BMC Cardiovasc Disord ; 23(1): 220, 2023 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-37118659

RESUMO

BACKGROUND: Acute coronary syndrome(ACS) is the leading cause of mortality and disability worldwide. Immune response has been confirmed to play a vital role in the occurrence and development of ACS. The objective of this prospective, multicenter, observational study is to define immune response and their relationship to the occurrence and progressive of ACS. METHODS: This is a multicenter, prospective, observational longitudinal cohort study. The primary outcome is the incidence of major adverse cardiovascular events (MACE) including in-stent restenosis, severe ventricular arrhythmia, heart failure, recurrent angina pectoris, and sudden cardiac death, and stroke one year later after ACS. Demographic characteristics, clinical data, treatments, and outcomes are collected by local investigators. Furthermore, freshly processed samples will be stained and assessed by flow cytometry. The expression of S100A4, CD47, SIRPα and Tim-3 on monocytes, macrophages and T cells in ACS patients were collected. FOLLOW-UP: during hospitalization, 3, 6 and 12 months after discharge. DISCUSSION: It is expected that this study will reveal the possible targets to improve the prognosis or prevent from occurrence of MACE in ACS patients. Since it's a multicenter study, the enrollment rate of participants will be accelerated and it can ensure that the collected data are more symbolic and improve the richness and credibility of the test basis. ETHICS AND DISSEMINATION: This study has been registered in Chinese Clinical Trial Registry Center. Ethical approval was obtained from the Affiliated Hospital of Guizhou Medical University. The dissemination will occur through the publication of articles in international peer-reviewed journals. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2200066382.


Assuntos
Síndrome Coronariana Aguda , Humanos , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/terapia , Síndrome Coronariana Aguda/epidemiologia , Estudos Prospectivos , Prognóstico , Monócitos , Estudos Longitudinais , Linfócitos T , Estudos de Coortes , Macrófagos , Estudos Observacionais como Assunto , Estudos Multicêntricos como Assunto
7.
Hepatology ; 76(5): 1466-1481, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35102596

RESUMO

BACKGROUND AND AIMS: NASH is associated with high levels of cholesterol and triglyceride (TG) in the liver; however, there is still no approved pharmacological therapy. Synthesis of cholesterol and TG is controlled by sterol regulatory element-binding protein (SREBP), which is found to be abnormally activated in NASH patients. We aim to discover small molecules for treating NASH by inhibiting the SREBP pathway. APPROACH AND RESULTS: Here, we identify a potent SREBP inhibitor, 25-hydroxylanosterol (25-HL). 25-HL binds to insulin-induced gene (INSIG) proteins, stimulates the interaction between INSIG and SCAP, and retains them in the endoplasmic reticulum, thereby suppressing SREBP activation and inhibiting lipogenesis. In NASH mouse models, 25-HL lowers levels of cholesterol and TG in serum and the liver, enhances energy expenditure to prevent obesity, and improves insulin sensitivity. 25-HL dramatically ameliorates hepatic steatosis, inflammation, ballooning, and fibrosis through down-regulating the expression of lipogenic genes. Furthermore, 25-HL exhibits both prophylactic and therapeutic efficacies of alleviating NASH and atherosclerosis in amylin liver NASH model diet-treated Ldlr-/- mice, and reduces the formation of cholesterol crystals and associated crown-like structures of Kupffer cells. Notably, 25-HL lowers lipid contents in serum and the liver to a greater extent than lovastatin or obeticholic acid. 25-HL shows a good safety and pharmacokinetics profile. CONCLUSIONS: This study provides the proof of concept that inhibiting SREBP activation by targeting INSIG to lower lipids could be a promising strategy for treating NASH. It suggests the translational potential of 25-HL in human NASH and demonstrates the critical role of SREBP-controlled lipogenesis in the progression of NASH by pharmacological inhibition.


Assuntos
Insulinas , Hepatopatia Gordurosa não Alcoólica , Humanos , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Lipogênese/fisiologia , Proteínas de Ligação a Elemento Regulador de Esterol , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Fígado/metabolismo , Triglicerídeos/metabolismo , Colesterol/metabolismo , Lovastatina/metabolismo , Insulinas/metabolismo , Camundongos Endogâmicos C57BL
8.
BMC Nephrol ; 21(1): 159, 2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32366263

RESUMO

BACKGROUND: Mesoamerican nephropathy (MeN) is a pattern of chronic kidney disease (CKD) prevalent among Central American men who work in agriculture, and its underlying cause has not been elucidated. Currently, experts hypothesize that MeN is related to repeated episodes of occupational heat stress leading to water loss and hence it is also called dehydration-associated CKD. CASE PRESENTATION: We report a case of a 40-year-old man, whose first admission to Peking Union Medical College Hospital was due to acute kidney injury (AKI). The clinical and pathological processes were consistent with acute tubular necrosis (ATN). However, after full recovery, CKD developed 1 year later. The second renal biopsy showed characteristics of ischemic renal disease but there was no evidence of vascular disease. It is worth noting that the patient had been taking part in long-distance running without drinking adequate water for years, which would have markedly decrease his renal blood flow. Thus, this patient may have developed chronic dehydration-associated kidney disease sharing the similar etiology of MeN. CONCLUSIONS: We report here a case of dehydration-associated CKD in a Chinese patient which shared similar etiology to MeN. Even in non-agricultural areas, this etiology of CKD should be noted to obtain a relevant history and prompt diagnosis.


Assuntos
Injúria Renal Aguda/etiologia , Desidratação/complicações , Insuficiência Renal Crônica/etiologia , Injúria Renal Aguda/patologia , Adulto , China , Ingestão de Líquidos , Humanos , Masculino , Insuficiência Renal Crônica/patologia , Corrida , Água/administração & dosagem
9.
BMJ Open ; 9(9): e030721, 2019 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-31501126

RESUMO

INTRODUCTION: Accelerated atherosclerosis is a major complication of systemic lupus erythematosus (SLE), and it leads to increased cardiovascular morbidity and mortality in patients with SLE. This study aimed to investigate the natural progression of carotid intima-media thickness (CIMT), and to examine the risk factors for progression of CIMT and atherosclerotic plaques based on a Chinese SLE cohort. METHODS AND ANALYSIS: Participants were continuously enrolled as outpatients of the Department of Rheumatology in Peking Union Medical College Hospital (PUMCH) from October 2013 to December 2016. Inclusion criteria were as follows: (1) age ≥18 years, (2) fulfilment of clinical classification criteria of SLE and (3) provision of signed written informed consent. Patients with clinically overt coronary artery disease, a history of cardiovascular disease (previous stroke, heart failure, myocardial infarction, angina or symptomatic peripheral artery disease) and malignancy, and pregnant/lactating women were excluded. The primary outcome is progression of CIMT from baseline. A total of 440 patients with SLE will be enrolled. Participants will receive follow-up surveys ~5 years after their baseline visit. A standard structural survey form, including demographic data, medical history, clinical and laboratory assessments and CIMT measurement, is planned for data collection at baseline and follow-up. The risk prediction model for progression of CIMT will be created by using a mixed effect model. ETHICS AND DISSEMINATION: The study protocol was approved by the institutional review board of PUMCH (S-599). Informed consent was obtained from all participants according to the Declaration of Helsinki on Biomedical Research Involving Human Studies. All data will be managed confidentially according to guidelines and legislation. Dissemination will include publication of scientific papers and/or presentations of the study findings at international conferences.


Assuntos
Artérias , Aterosclerose , Espessura Intima-Media Carotídea , Lúpus Eritematoso Sistêmico/complicações , Adulto , Artérias/diagnóstico por imagem , Artérias/fisiopatologia , Aterosclerose/diagnóstico , Aterosclerose/etiologia , China/epidemiologia , Progressão da Doença , Feminino , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Masculino , Estudos Observacionais como Assunto , Prognóstico , Estudos Prospectivos , Fatores de Risco , Rigidez Vascular
10.
Exp Mol Pathol ; 110: 104282, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31301305

RESUMO

BACKGROUND: Postmenopausal osteoporosis (PMO), as a frequent disease in postmenopausal women, is mainly caused by the lack of estrogen. MiR-320a has been found to abate osteoblast function and induce oxidative stress before osteoporosis. However, studies on the downstream target gene and related signaling pathway of miR-320a in PMO are still obscure. This study aims to deal with these problems. METHODS: The expression levels of miR-320a and microtubule-associated protein 9 (MAP9) in patients with osteoporosis were analyzed on the basis of the GEO database. The cells viability was determined by methylthiazolyl tetrazolium bromide (MTT). Flow cytometry and western blot were used to detect the cells apoptosis and the expression of apoptosis-related proteins, respectively. The cells differentiation-related proteins were detected by qRT-PCR and western blot. The interaction between miR-320a and MAP9 was predicted by biological software and verified by dual luciferase reporter assay and rescue assay. The expression levels of PI3K, p-PI3K, AKT and p-AKT in MC3T3-E1 cells were assessed by western blot. RESULTS: We observed that miR-320a was over-expressed in PMO patients and exhibited inhibitory effects on MC3T3-E1 cells activity and differentiation, as well as promoting effects on MC3T3-E1 cells apoptosis. MAP9 was verified as a target gene of miR-320a and was negatively regulated by miR-320a. Based on the GEO database, MAP9 was found to be lower expressed in PMO patients. Rescue assay demonstrated that down-regulation of MAP9 could alleviate the promoting effects of miR-320a inhibitor on MC3T3-E1 cells activity and differentiation and the inhibitory effects of miR-320a inhibitor on MC3T3-E1 cells apoptosis. Mechanically, miR-320a/MAP9 possibly took part in MC3T3-E1 cells viability, differentiation and apoptosis via mediating PI3K/AKT signaling pathway. CONCLUSIONS: Our outcomes demonstrated that miR-320a promoted MC3T3-E1 cells apoptosis, suppressed MC3T3-E1 cells viability and differentiation through targeting MAP9 and modulating PI3K/AKT signaling pathway, which provided theoretical support for miR-320a/MAP9 as promising targets for the treatment and prevention of PMO.


Assuntos
MicroRNAs/genética , Proteínas Associadas aos Microtúbulos/genética , Osteoporose Pós-Menopausa/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Animais , Apoptose/genética , Diferenciação Celular/genética , Linhagem Celular , Sobrevivência Celular/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Osteoporose Pós-Menopausa/metabolismo
12.
Rheumatol Int ; 38(3): 481-487, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29230494

RESUMO

The aim of this study is to investigate the association of the polymorphisms in tumor necrosis factor (TNF) and granulin (GRN) with ankylosing spondylitis (AS) in a Chinese Han population. Five single nucleotide polymorphisms (SNPs) covering TNF and six SNPs covering GRN were investigated in 861 Chinese Han AS patients and 864 healthy controls. For rs1799964, the C allele was linked to reduced risk of AS (p < 0.0001, OR = 0.60, 95% CI = 0.50-0.71). The carriers of the C/C homozygote showed a significantly lower risk of AS compared with the TT homozygote and the C/T heterozygote under the recessive model (p < 0.0001, OR = 0.23, 95% CI = 0.12-0.45). For rs1800629, the A allele was also linked to reduced risk of AS (p < 0.0001, OR = 0.54, 95% CI = 0.39-0.74). For rs1800630, the A allele was also linked to reduced risk of AS (p < 0.0001, OR = 0.59, 95% CI = 0.48-0.72). The carriers of the A/A homozygote showed a significantly lower risk of AS compared with the C/C homozygote and the A/C heterozygote under the recessive model (p < 0.0001, OR = 0.18, 95% CI = 0.07-0.47). For rs769178, the T allele was linked to increased risk of AS (p < 0.0001, OR = 2.59, 95% CI = 2.18-3.09). The carriers of the T/T homozygote showed a significantly higher risk of AS compared with the GG homozygote and the G/T heterozygote under the recessive model (p < 0.0001, OR = 3.34, 95 %CI = 1.95-5.72). There was no significant difference between the AS patients and the controls in the genotype or allele frequencies of rs361525. For GRN, there was no significant difference between the AS patients and the controls in the genotype or allele frequencies of rs25646, rs3760365, rs3785817, rs4792939, rs5848, rs850713 (p > 0.05). This study indicates that polymorphisms in TNF are related to AS, but polymorphisms in GRN are not related to AS susceptibility in a Chinese Han population.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/genética , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante/genética , Fator de Necrose Tumoral alfa/genética , Adulto , Povo Asiático/genética , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , China/epidemiologia , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Heterozigoto , Homozigoto , Humanos , Desequilíbrio de Ligação , Masculino , Razão de Chances , Fenótipo , Progranulinas , Fatores de Risco , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/etnologia , Adulto Jovem
13.
J Med Chem ; 60(19): 7965-7983, 2017 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-28885834

RESUMO

Cancer metabolism and epigenetics are among the most intensely pursued research areas in anticancer drug discovery. Here we report the first small molecules that simultaneously inhibit nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylase (HDAC), two important targets of cancer metabolism and epigenetics, respectively. Through iterative structure-based drug design, chemical synthesis, and biological assays, a highly potent dual NAMPT and HDAC inhibitor was successfully identified. Compound 35 possessed excellent and balanced activities against both NAMPT (IC50 = 31 nM) and HDAC1 (IC50 = 55 nM). It could effectively induce cell apoptosis and autophagy and ultimately led to cell death. Importantly, compound 35 showed excellent in vivo antitumor efficacy in the HCT116 xenograft model. This proof-of-concept study demonstrates the feasibility of discovering an inhibitor targeting cancer metabolism and epigenetics and provides an efficient strategy for multitarget antitumor drug discovery.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Epigênese Genética/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Neoplasias/genética , Neoplasias/metabolismo , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Descoberta de Drogas , Inibidores de Histona Desacetilases/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Neoplasias/tratamento farmacológico , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Bioorg Med Chem ; 25(17): 4553-4559, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28716641

RESUMO

Osimertinib has been identified as a promising therapeutic drug targeting for EGFR T790M mutant non-small cell lung cancer (NSCLC). A new series of N-oxidized and fluorinated osimertinib derivatives were designed and synthesized. The cellular anti-proliferative activity, kinase inhibitory activity and the activation of EGFR signaling pathways of 1-6 in vitro were determined against L858R/T790M and wild-type EGFR, the antitumor efficacy in NCI-H1975 xenografts in vivo were further studied. Compound 2, the newly synthesized N-oxide metabolite in N,N,N'-trimethylethylenediamine side chain of osimertinib, showed a comparable kinase selectivity in vitro and a slightly better antitumor efficacy in vivo to osimertinib, making it valuable and suitable for the potential lung cancer therapy.


Assuntos
Acrilamidas/síntese química , Receptores ErbB/antagonistas & inibidores , Fenilenodiaminas/síntese química , Piperazinas/química , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/síntese química , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Compostos de Anilina , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Camundongos , Camundongos Nus , Mutação , Neoplasias/tratamento farmacológico , Fenilenodiaminas/farmacologia , Fenilenodiaminas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transplante Heterólogo
15.
Mod Rheumatol ; 25(1): 67-71, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24754275

RESUMO

OBJECTIVES: To investigate the association of the polymorphisms in SPARC and NLRP2 with rheumatoid arthritis (RA) in a Chinese Han population. METHODS: Four single nucleotide polymorphisms (SNPs) covering SPARC and three SNPs covering NLRP2 were investigated in 624 Chinese Han RA patients and 1920 healthy controls. RESULTS: The A allele at SPARC rs3210714, SPARC rs11950384, NLRP2 rs2217659, and NLRP2 rs703468 were linked to reduced risk of RA (p = 0.0016, p = 0.0051, p < 0.0001, and p = 0.0033, respectively). Under the recessive model, the A/A genotype of rs3210714, rs11950384, rs2217659, and rs703468 were relevant with RA (p = 0.0071, p = 0.017, p < 0.0001 and p = 0.0066, respectively). Haplotype analysis identified the SPARC GGCG haplotype, AAAA haplotype were associated with the risk for RA (p < 0.0001 and p = 0.0015, respectively), while the risk of RA was lower for carriers of the GAAA haplotype (p < 0.0001), AACG haplotype (p < 0.0001), and the AGCG haplotype (p < 0.0001). The NLRP2 GG haplotype was a risk factor (p < 0.0001), while the GA haplotype and the AG haplotype were associated with lower risk of RA (p < 0.0001 and p = 0.0017, respectively). There was no significant difference between the RA patients and the controls in polymorphisms of rs7719521, rs1978707, and rs269913. CONCLUSION: This study indicates that polymorphisms in SPARC and NLRP2 are related to RA susceptibility in a Chinese Han population.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Artrite Reumatoide/genética , Predisposição Genética para Doença , Osteonectina/genética , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Proteínas Reguladoras de Apoptose , Povo Asiático/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade
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