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1.
Neurobiol Dis ; 132: 104590, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31470106

RESUMO

While Brain-derived Neurotrophic Factor (BDNF) has long been implicated in treating neurological diseases, recombinant BDNF protein has failed in multiple clinical trials. In addition to its unstable and adhesive nature, BDNF can activate p75NTR, a receptor mediating cellular functions opposite to those of TrkB. We have now identified TrkB agonistic antibodies (TrkB-agoAbs) with several properties superior to BDNF: They exhibit blood half-life of days instead of hours, diffuse centimeters in neural tissues instead millimeters, and bind and activate TrkB, but not p75NTR. In addition, TrkB-agoAbs elicit much longer TrkB activation, reduced TrkB internalization and less intracellular degradation, compared with BDNF. More importantly, some of these TrkB-agoAbs bind TrkB epitopes distinct from that by BDNF, and work cooperatively with endogenous BDNF. Unlike BDNF, the TrkB-agoAbs exhibit a half-life of days/weeks and diffused readily in nerve tissues. We tested one of TrkB-agoAbs further and showed that it enhanced motoneuron survival in the spinal-root avulsion model for motoneuron degeneration in vivo. Thus, TrkB-agoAbs are promising drug candidates for the treatment of neural injury.


Assuntos
Anticorpos Monoclonais/farmacologia , Neurônios Motores/efeitos dos fármacos , Degeneração Neural/patologia , Fármacos Neuroprotetores/farmacologia , Receptor trkB/agonistas , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Humanos , Neurônios Motores/patologia
2.
Eur J Clin Pharmacol ; 75(8): 1059-1068, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31081522

RESUMO

PURPOSE: High on-treatment platelet reactivity (HTPR) after clopidogrel administration in patients with acute coronary syndrome (ACS) has been associated with an increased risk of adverse events. Our previous studies reported that half-dose ticagrelor provides a similar inhibitory effect on adenosine diphosphate (ADP)-induced platelet aggregation as standard-dose ticagrelor, but half-dose of ticagrelor has not been studied in Chinese ACS patients with HTPR. This study aimed to compare the antiplatelet action of half-dose ticagrelor with high-dose clopidogrel in ACS patients with HTPR. METHODS: In this single-center randomized controlled trial, 80 (of 418 screened, 19.13%) ACS patients with HTPR while on clopidogrel were randomized to either half-dose ticagrelor (90 mg LD, then 45 mg twice daily) or high-dose clopidogrel (150 mg once daily). Platelet function was assessed by thromboelastography (TEG) and light transmission aggregometry (LTA), and adverse events were monitored throughout the study for 30 days. RESULTS: The ADP-induced platelet inhibition rate (IR) as measured by TEG was significantly higher for half-dose ticagrelor compared with high-dose clopidogrel (70.40% [61.10%-91.70%] vs. 44.25% [34.67%-79.07%], p = 0.001). The repeated HTPR rate was dramatically higher for high-dose clopidogrel compared with half-dose ticagrelor (6 of 32, 18.75% vs. 1 of 35, 2.85%; p = 0.04). No patients in either treatment group exhibited a major bleeding event or other adverse events. CONCLUSIONS: In ACS patients with HTPR, half-dose ticagrelor is more effective than high-dose clopidogrel in reducing platelet reactivity (NCT03062462).


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Clopidogrel/administração & dosagem , Inibidores da Agregação Plaquetária/administração & dosagem , Ticagrelor/administração & dosagem , Síndrome Coronariana Aguda/sangue , Idoso , Povo Asiático , Clopidogrel/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/efeitos adversos , Testes de Função Plaquetária , Ticagrelor/efeitos adversos , Resultado do Tratamento
3.
JACC Basic Transl Sci ; 9(2): 244-256, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38510719

RESUMO

This study assesses the feasibility, safety, and effectiveness of noninvasive stereotactic body radiotherapy (SBRT) as an approach for pulmonary artery denervation in canine models. SBRT with CyberKnife resulted in reduced mean pulmonary artery pressure, pulmonary capillary wedge pressure, and pulmonary vascular resistance, and insignificantly increased cardiac output. In comparison to the control group, serum norepinephrine levels at 1 month and 6 months were significantly lower in the CyberKnife group. Computed tomography, pulmonary angiography, and histology analysis revealed that SBRT was associated with minimal collateral damage.

4.
J Geriatr Cardiol ; 21(8): 791-798, 2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-39308500

RESUMO

BACKGROUND: The prevention of coronary artery disease (CAD) faces dual challenges: the aspirin-induced gastrointestinal injury, and the residual cardiovascular risk after statin treatment. Geraniol acetate (Gefarnate) is an anti-ulcer drug. It was reported that geraniol might participate in lipid metabolism through a variety of pathways. The aim of this study was to assess the lipid-lowering effects of gefarnate in statin-treated CAD patients with residual hypertriglyceridemia. METHODS: In this prospective, open-label, randomized, controlled trial, 69 statin-treated CAD patients with residual hypertriglyceridemia were randomly assigned to gefarnate group and control group, received gefarnate (100 mg/3 times a day) combined with statin and statin alone, respectively. At baseline and after one-month treatment, the levels of plasma triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and total cholesterol were tested. RESULTS: After one-month gefarnate treatment, triglyceride level was significantly lowered from 2.64 mmol/L to 2.12 mmol/L (P = 0.0018), LDL-C level lowered from 2.7 mmol/L to 2.37 mmol/L (P = 0.0004), HDL-C level increased from 0.97 mmol/L to 1.17 mmol/L (P = 0.0228). Based on statin therapy, gefarnate could significantly reduce the plasma triglyceride level (P = 0.0148) and increase the plasma HDL-C level (P = 0.0307). Although the LDL-C and total cholesterol levels tended to decrease, there was no statistically significant difference. CONCLUSIONS: The addition of gefarnate to statin reduced triglyceride level and increased HDL-C level to a significant extent compared to statin alone in CAD patients with residual hypertriglyceridemia. This suggested that gefarnate might provide the dual benefits of preventing gastrointestinal injury and lipid lowering in CAD patients.

5.
J Geriatr Cardiol ; 20(4): 309-313, 2023 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-37122988

RESUMO

The main management principle for patients with coronary thrombus should be "more removal and less implantation". Routine thrombus aspiration (TA) is ineffective for intracoronary thrombus or high residual thrombus burden after TA and may result in a refractory coronary thrombus. It is unwise to implant a stent in the vessel with high residual thrombus, which is associated with no-reflow, impaired microvascular perfusion, and consequently worse clinical outcomes. Therefore, increasing the efficiency of TA during percutaneous coronary intervention procedures, especially under some conditions of refractory coronary thrombus, is very important to restore myocardial reperfusion and improve microvascular dysfunction early. In the present work, we aimed to demonstrate the factors that may affect TA efficiency and introduce several highly effective approaches to treat refractory coronary thrombus.

6.
Cells ; 8(8)2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31430955

RESUMO

Receptor tyrosine kinases are believed to be activated through ligand-induced dimerization. We now demonstrate that in cultured neurons, a substantial amount of endogenous TrkB, the receptor for brain-derived neurotrophic factor (BDNF), exists as an inactive preformed dimer, and the application of BDNF activates the pre-existing dimer. Deletion of the extracellular juxtamembrane motif (EJM) of TrkB increased the amount of preformed dimer, suggesting an inhibitory role of EJM on dimer formation. Further, binding of an agonistic antibody (MM12) specific to human TrkB-EJM activated the full-length TrkB and unexpectedly also truncated TrkB lacking ECD (TrkBdelECD365), suggesting that TrkB is activated by attenuating the inhibitory effect of EJM through MM12 binding-induced conformational changes. Finally, in cells co-expressing rat and human TrkB, MM12 could only activate TrkB human-human dimer but not TrkB human-rat TrkB dimer, indicating that MM12 binding to two TrkB monomers is required for activation. Our results support a model that TrkB preforms as an inactive dimer and BDNF induces TrkB conformation changes leading to its activation.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Glicoproteínas de Membrana/química , Neurônios/metabolismo , Receptor trkB/química , Motivos de Aminoácidos , Animais , Células CHO , Membrana Celular/metabolismo , Cricetulus , Neurônios/citologia , Células PC12 , Multimerização Proteica , Ratos
8.
Chin Med J (Engl) ; 129(17): 2074-8, 2016 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-27569234

RESUMO

BACKGROUND: Previous studies revealed that culprit vessels of ST-segment elevation myocardial infarction (STEMI) were often related to mild or moderate stenosis. However, recent studies suggested that severe stenosis was primarily found in culprit lesions. The objective of this study was to analyze the stenosis severity of culprit lesions in STEMI patients and to clarify the paradoxical results. METHODS: A total of 489 consecutive STEMI patients who underwent primary percutaneous coronary intervention were retrospectively studied from January 2012 to December 2014. The patients were divided into three groups based on stenosis severity using quantitative coronary analysis: Group A, 314 cases, stenosis ≥70%; Group B, 127 cases, stenosis 50-70%; and Group C, 48 cases, stenosis ≤50%. The clinical, demographic, and angiographic data of all groups were analyzed. RESULTS: Patients in Group A exhibited a significantly higher prevalence of history of angina pectoris (95.9% vs. 62.5%, P< 0.001), multivessel disease (73.2% vs. 54.2%, P = 0.007), and lower cardiac ejection fraction (53.3 ± 8.6 vs. 56.8 ± 8.4, P= 0.009) than those in Group C. Multivariable analysis revealed that history of angina pectoris (odds ratio [OR]: 13.89, 95% confidence interval [CI]: 6.21-31.11) and multivessel disease (OR: 2.32, 95% CI: 1.25-4.31) were correlated with severe stenosis of the culprit lesion in Group A. CONCLUSIONS: Most culprit lesions in STEMI patients were severe stenosis. These patients exhibited a higher prevalence of angina history and multivessel diseases.


Assuntos
Trombose Coronária/diagnóstico , Trombose Coronária/terapia , Infarto do Miocárdio/complicações , Infarto do Miocárdio/terapia , Idoso , Angiografia Coronária , Trombose Coronária/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Infarto do Miocárdio/patologia , Intervenção Coronária Percutânea , Estudos Retrospectivos
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