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1.
J Am Chem Soc ; 146(12): 8768-8779, 2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38483318

RESUMO

2'-Deoxynucleosides and analogues play a vital role in drug development, but their preparation remains a significant challenge. Previous studies have focused on ß-2'-deoxynucleosides with the natural ß-configuration. In fact, their isomeric α-2'-deoxynucleosides also exhibit diverse bioactivities and even better metabolic stability. Herein, we report that both α- and ß-2'-deoxynucleosides can be prepared with high yields and stereoselectivity using a remote directing diphenylphosphinoyl (DPP) group. It is particularly efficient to prepare α-2'-deoxynucleosides with an easily accessible 3,5-di-ODPP donor. Instead of acting as a H-bond acceptor on a 2-(diphenylphosphinoyl)acetyl (DPPA) group in our previous studies for syn-facial O-glycosylation, the phosphine oxide moiety here acts as a remote participating group to enable highly antifacial N-glycosylation. This proposed remote participation mechanism is supported by our first characterization of an important 1,5-briged P-heterobicyclic intermediate via variable-temperature NMR spectroscopy. Interestingly, antiproliferative assays led to a α-2'-deoxynucleoside with IC50 values in the low micromole range against central nervous system tumor cell lines SH-SY5Y and LN229, whereas its ß-anomer exhibited no inhibition at 100 µM. Furthermore, the DPP group significantly enhanced the antitumor activities by 10 times.


Assuntos
Neuroblastoma , Fosfinas , Humanos , Glicosilação
2.
Pak J Med Sci ; 40(1Part-I): 159-164, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38196488

RESUMO

Objective: To explore the prognostic value and correlation between the risk of lymph node metastasis (LNM) and Guanylate-binding Protein 1 (GBP1) in breast cancer (BC) patients. Methods: In this retrospective study, the clinical data of 150 patients with BC who were surgically resected in The Affiliated Qingdao Central Hospital of Qingdao University from January 2019 to December 2021 were included. Patients were divided into metastasis group (n=110) or non-metastasis group (n=40) according to whether there was LNM post-surgery. Logistic regression was used to analyze the risk factors for LNM in BC, and Kaplan-Meier was used to assess the risk of disease progression 12 months post-operation in both groups. Patients were divided into a GBP1 low expression-group (n=75) or a GBP1 high expression-group (n=75). The risk of disease progression, one-year post-surgery was analyzed, and the predictive value of GBP1 in BC tissue was assessed by the receiver operating characteristics (ROC) curve. Results: Independent risk factors for BC with LNM were GBP1, CEA and TNM stage (P<0.05). There is a linear relationship between GBP1 expression and LNM risk in BC (χ2=0.88, P<0.05). Patients with high expression of GBP1 had a higher risk of LNM (χ2=3.204, P<0.001) and early postoperative progression (χ2=7.412, P<0.05). The AUC of GBP1 in predicting the risk of LNM was 0.840. Conclusions: Patients with BC and a higher expression of GBP1 could be at an increased risk of LNM. Elevations in GBP1 expression can also suggest a poor prognosis for patients with BC.

3.
Angew Chem Int Ed Engl ; 63(2): e202313890, 2024 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-38059792

RESUMO

Room-temperature phosphorescent (RTP) materials have great potential for in vivo imaging because they can circumvent the autofluorescence of biological tissues. In this study, a class of organic-doped long-wavelength (≈600 nm) RTP materials with benzo[c][1,2,5] thiadiazole as a guest was constructed. Both host and guest molecules have simple structures and can be directly purchased commercially at a low cost. Owing to the long phosphorescence wavelength of the doping system, it exhibited good tissue penetration (10 mm). Notably, these RTP nanoparticles were successfully used to image atherosclerotic plaques, with a signal-to-background ratio (SBR) of 44.52. This study provides a new approach for constructing inexpensive red organic phosphorescent materials and a new method for imaging cardiovascular diseases using these materials.


Assuntos
Doenças Cardiovasculares , Nanopartículas , Placa Aterosclerótica , Humanos , Placa Aterosclerótica/diagnóstico por imagem , Temperatura , Diagnóstico por Imagem
4.
FASEB J ; 36(10): e22570, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36165217

RESUMO

The risk of high-grade gliomas is lower in young females, however, its incidence enhances after menopause, suggesting potential protective roles of female sex hormones. Hormone oscillations after menopause have received attention as a possible risk factor. Little is known about risk factors for adult gliomas. We examined the association of the aging brain after menopause, determining the risk of gliomas with proteomics and the MALDI-MSI experiment. Menopause caused low neurotransmitter levels such as GABA and ACH, high inflammatory factor levels like il-1ß, and increased lipid metabolism-related levels like triglycerides in the brain. Upregulated and downregulated proteins after menopause were correlated with differentially expressed glioma genes, such as ACTA2, CAMK2D, FNBPIL, ARL1, HEBP1, CAST, CLIC1, LPCAT4, MAST3, and DOCK9. Furthermore, differential gene expression analysis of monocytes showed that the downregulated gene LPCAT4 could be used as a marker to prevent menopausal gliomas in women. Our findings regarding the association of menopause with the risk of gliomas are consistent with several extensive cohort studies. In view of the available evidence, postmenopausal status is likely to represent a significant risk factor for gliomas.


Assuntos
Glioma , Menopausa , Adulto , Encéfalo , Canais de Cloreto , Progressão da Doença , Feminino , Glioma/genética , Hormônios Esteroides Gonadais , Hormônios , Humanos , Menopausa/genética , Triglicerídeos , Ácido gama-Aminobutírico
5.
FASEB J ; 36(2): e22079, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35028975

RESUMO

Atherosclerosis-related cardiovascular diseases are leading causes of mortality worldwide, characterized by the development of endothelial cell dysfunction, increased oxidized low-density lipoprotein uptake by macrophages, and the ensuing formation of atherosclerotic plaque. Local blood flow patterns cause uneven atherosclerotic lesion distribution, and endothelial dysfunction caused by disturbed flow is an early step in the development of atherosclerosis. The present research aims to elucidate the mechanism underlying the regulation of Neuropilin 2 (NRP2) under low shear stress (LSS) in the atheroprone phenotype of endothelial cells. We observed that NRP2 expression was significantly upregulated in LSS-stimulated human umbilical vein endothelial cells (HUVECs) and in mouse aortic endothelial cells. Knockdown of NRP2 in HUVECs significantly ameliorated cell apoptosis induced by LSS. Conversely, overexpression of NRP2 had the opposite effect on HUVEC apoptosis. Animal experiments suggest that NRP2 knockdown markedly mitigated the development of atherosclerosis in Apoe-/- mice. Mechanistically, NRP2 knockdown and overexpression regulated PARP1 protein expression in the condition of LSS, which in turn affected the expression of apoptosis-related genes. Moreover, the upstream transcription factor GATA2 was found to regulate NRP2 expression in the progression of atherosclerosis. These findings suggest that NRP2 plays an essential proatherosclerotic role through the regulation of cell apoptosis, and the results reveal that NRP2 is a promising therapeutic target for the treatment of atherosclerotic disorders.


Assuntos
Apoptose/fisiologia , Aterosclerose/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Neuropilina-2/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Animais , Apolipoproteínas E/metabolismo , Células Cultivadas , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Placa Aterosclerótica/metabolismo , Estresse Mecânico
6.
Sensors (Basel) ; 22(12)2022 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-35746190

RESUMO

In this paper, a novel ion-imprinted electrochemical sensor modified with magnetic nanomaterial Fe3O4@SiO2 was established for the high sensitivity and selectivity determination of UO22+ in the environment. Density functional theory (DFT) was employed to investigate the interaction between templates and binding ligands to screen out suitable functional binding ligand for the reasonable design of the ion imprinted sensors. The MIIP/MCPE (magnetic ion imprinted membrane/magnetic carbon paste electrode) modified with Fe3O4@SiO2 exhibited a strong response current and high sensitivity toward uranyl ion comparison with the bare carbon paste electrodes. Meanwhile, the MCPE was fabricated simultaneously under the action of strong magnetic adsorption, and the ion imprinted membrane can be adsorbed stably on the electrode surface, handling the problem that the imprinted membrane was easy to fall off during the process of experimental determination and elution. Based on the uranyl ion imprinting network, differential pulse voltammetry (DPV) was adopted for the detection technology to realize the electrochemical reduction of uranyl ions, which improved the selectivity of the sensor. Thereafter, uranyl ions were detected in the linear concentration range of 1.0 × 10-9 mol L-1 to 2.0 × 10-7 mol L-1, with the detection and quantification limit of 1.08 × 10-9 and 3.23 × 10-10 mol L-1, respectively. In addition, the sensor was successfully demonstrated for the determination of uranyl ions in uranium tailings soil samples and water samples with a recovery of 95% to 104%.


Assuntos
Impressão Molecular , Carbono , Computadores , Técnicas Eletroquímicas , Eletrodos , Íons , Limite de Detecção , Fenômenos Magnéticos , Polímeros , Dióxido de Silício
7.
J Cell Mol Med ; 24(8): 4716-4725, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32163656

RESUMO

Vascular dysfunction resulting from diabetes is an important factor in arteriosclerosis. Previous studies have shown that during hyperglycaemia and diabetes, AKAP150 promotes vascular tone enhancement by intensifying the remodelling of the BK channel. However, the interaction between AKAP150 and the BK channel remains open to discussion. In this study, we investigated the regulation of impaired BK channel-mediated vascular dysfunction in diabetes mellitus. Using AKAP150 null mice (AKAP150-/- ) and wild-type (WT) control mice (C57BL/6J), diabetes was induced by intraperitoneal injection of streptozotocin. We found that knockout of AKAP150 reversed vascular remodelling and fibrosis in mice with diabetes and in AKAP150-/- diabetic mice. Impaired Akt/GSK3ß signalling contributed to decreased BK-ß1 expression in aortas from diabetic mice, and the silencing of AKAP150 increased Akt phosphorylation and BK-ß1 expression in MOVAS cells treated with HG medium. The inhibition of Akt activity caused a decrease in BK-ß1 expression, and treatment with AKAP150 siRNA suppressed GSK3ß expression in the nuclei of MOVAS cells treated with HG. Knockout of AKAP150 reverses impaired BK channel-mediated vascular dysfunction through the Akt/GSK3ß signalling pathway in diabetes mellitus.


Assuntos
Proteínas de Ancoragem à Quinase A/genética , Complicações do Diabetes/genética , Diabetes Mellitus Experimental/genética , Glicogênio Sintase Quinase 3 beta/genética , Subunidades beta do Canal de Potássio Ativado por Cálcio de Condutância Alta/genética , Animais , Arteriosclerose/complicações , Arteriosclerose/genética , Arteriosclerose/patologia , Arteriosclerose/terapia , Complicações do Diabetes/patologia , Complicações do Diabetes/terapia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/terapia , Modelos Animais de Doenças , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Humanos , Hiperglicemia/complicações , Hiperglicemia/genética , Hiperglicemia/patologia , Hiperglicemia/terapia , Canais de Potássio Ativados por Cálcio de Condutância Alta/genética , Camundongos , Camundongos Knockout , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia
8.
FASEB J ; 33(6): 7202-7212, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30860864

RESUMO

Low shear stress (LSS) increases degradation of the endothelial glycocalyx, leading to production of endothelial inflammation and atherosclerosis. However, the underlying mechanisms of how LSS diminishes the endothelial glycocalyx remain unclear. We showed that LSS inactivated AMPK, enhanced Na+-H+ exchanger (NHE)1 activity, and induced glycocalyx degradation. Activation of AMPK prevented LSS-induced NHE1 activity and endothelial glycocalyx impairment. We further identified hyaluronidase 2 (HYAL2) as a mediator of endothelial glycocalyx impairment in HUVECs exposed to LSS. Inactivation of AMPK by LSS up-regulates the activity of HYAL2, which acts downstream of NHE1. We characterized a left common carotid artery partial ligation (PL) model of LSS in C57BL/6 mice. The results showed decreased expression of hyaluronan (HA) in the endothelial glycocalyx and decreased thickness of the endothelial glycocalyx in PL mice. Pharmacological activation of AMPK by ampkinone not only attenuated glycocalyx impairment due to HA degradation but also blocked vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 expression increase and macrophage recruitment in the endothelia of PL mice. Our results revealed that AMPK dephosphorylation induced by LSS activates NHE1 and HYAL2 to promote HA degradation and glycocalyx injury, which may contribute to endothelial inflammatory reaction and macrophage recruitment.-Zhang, J., Kong, X., Wang, Z., Gao, X., Ge, Z., Gu, Y., Ye, P., Chao, Y., Zhu, L., Li, X., Chen, S. AMP-activated protein kinase regulates glycocalyx impairment and macrophage recruitment in response to low shear stress.


Assuntos
Adenilato Quinase/fisiologia , Células Endoteliais/enzimologia , Glicocálix/metabolismo , Hemorreologia , Macrófagos/fisiologia , Animais , Artéria Carótida Primitiva , Estenose das Carótidas/metabolismo , Estenose das Carótidas/patologia , Moléculas de Adesão Celular/biossíntese , Moléculas de Adesão Celular/genética , Ativação Enzimática , Proteínas Ligadas por GPI/biossíntese , Proteínas Ligadas por GPI/genética , Glicocálix/ultraestrutura , Células Endoteliais da Veia Umbilical Humana , Humanos , Ácido Hialurônico/metabolismo , Hialuronoglucosaminidase/biossíntese , Hialuronoglucosaminidase/genética , Ligadura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Recombinantes/metabolismo , Trocador 1 de Sódio-Hidrogênio/fisiologia , Estresse Mecânico
9.
Mol Cell Biochem ; 450(1-2): 25-34, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29790114

RESUMO

This study aimed to investigate the effects and molecular mechanisms of ivabradine in preventing cardiac hypertrophy in an established transverse aortic constriction (TAC) mouse model. A total of 56 male C57BL/6 mice were randomly assigned into the following seven groups (8 mice per group): sham, TAC model, Iva-10 (10 mg/kg/day ivabradine), Iva-20 (20 mg/kg/day ivabradine), Iva-40 (40 mg/kg/day ivabradine), Iva-80 (80 mg/kg/day ivabradine), and Rap (rapamycin, a positive control). Echocardiography and left ventricular hemodynamics were performed. Hematoxylin-eosin (H&E), Masson's trichome staining, and TUNEL assays were conducted to evaluate cardiac hypertrophy, fibrosis, and apoptosis, respectively. Western blotting was performed to detect the expression of proteins related to the PI3K/Akt/mTOR/p70S6K pathway. Ivabradine could effectively improve left ventricular dysfunction and hypertrophy induced by TAC in a dose-independent manner. Moreover, no obvious change in heart rate (HR) was observed in the TAC and Rap groups, whereas a significant decrease in HR was found after ivabradine treatment (P < 0.05). Cardiac hypertrophy, fibrosis, and apoptosis induced by TAC were notably suppressed after either rapamycin or ivabradine treatment (P < 0.05). Ivabradine and rapamycin also decreased the expression of PI3K/Akt and mTOR induced by TAC. Ivabradine improved cardiac hypertrophy and fibrosis as well as reduced cardiomyocyte apoptosis via the PI3K/Akt/mTOR/p70S6K pathway in TAC model mice.


Assuntos
Doenças da Aorta/fisiopatologia , Apoptose , Constrição Patológica/fisiopatologia , Modelos Animais de Doenças , Hipertrofia Ventricular Esquerda/prevenção & controle , Ivabradina/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Disfunção Ventricular Esquerda/prevenção & controle , Animais , Fármacos Cardiovasculares/farmacologia , Hipertrofia Ventricular Esquerda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/patologia , Pressão , Disfunção Ventricular Esquerda/patologia
10.
Mediators Inflamm ; 2019: 7162976, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31316302

RESUMO

BACKGROUND: Oscillatory shear stress (OSS) disrupts endothelial homeostasis and promotes oxidative stress, which can lead to atherosclerosis. In atherosclerotic lesions, Toll-like receptor 4 (TLR4) is highly expressed. However, the molecular mechanism by which TLR4 modulates oxidative changes and the cell signaling transudation upon OSS is yet to be determined. METHODS AND RESULTS: Carotid artery constriction (CAC) surgery and a parallel-plate flow chamber were used to modulate shear stress. The results showed that OSS significantly increased the oxidative burden, and this was partly due to TLR4 activation. OSS activated NOX2 and had no significant influence to NOX1 or NOX4 in endothelial cells (ECs). OSS phosphorylated caveolin-1, promoted its binding with endothelial nitric oxide synthase (eNOS), and resulted in deactivation of eNOS. TLR4 inhibition restored levels of nitric oxide (NO) and superoxide dismutase (SOD) in OSS-exposed cells. CONCLUSION: TLR4 modulates OSS-induced oxidative stress by activating NOX2 and suppressing eNOS.


Assuntos
Células Endoteliais/citologia , NADPH Oxidase 2/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , Receptor 4 Toll-Like/metabolismo , Animais , Artérias Carótidas/patologia , Caveolina 1/metabolismo , Vasos Coronários/metabolismo , Modelos Animais de Doenças , Homeostase , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , NADPH Oxidase 1/metabolismo , NADPH Oxidase 4/metabolismo , Óxido Nítrico , Ratos , Resistência ao Cisalhamento , Transdução de Sinais , Estresse Mecânico , Superóxido Dismutase-1/metabolismo
11.
Regul Toxicol Pharmacol ; 104: 50-55, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30826316

RESUMO

Di (2-ethylhexyl) adipate (DEHA) is a potential plasticizer alternative for di-2-ethylhexyl phthalate (DEHP). Toxicity of DEHA has been studied mostly via oral exposure but not assessed after repeated intravenous exposure. The present study shows the toxicity effects after intravenous administration for 28 consecutive days and the reversibility of the effects following a 14-day recovery period. The study was conducted under GLP conditions. Four groups of rats (15/sex/group) each received either vehicle or DEHA in vehicle (100, 200, or 450 mg/kg/day). Criteria for evaluation included clinical observations, body weight, food consumption, clinical pathology (hematology, serum chemistry, coagulation, urinalyses), gross (necropsy) evaluation, organ weight and histopathological evaluation. There were no DEHA-related changes in all the endpoints evaluated at 100 or 200 mg/kg/day. There were no test article-related changes in clinical pathology or gross necropsy observation at 450 mg/kg/day. At the high-dose, DEHA-related findings included clinical observations, decreased body weight gain and food consumption, increased liver weight in females associated with minimal hepatocellular hypertrophy, and decreased thymus weight in males and females without histopathology findings. All these findings were completely reversible within a 14-day recovery period. Therefore, the 200 mg/kg/day dose is considered to be the No-Observed-Effect Level (NOEL).


Assuntos
Adipatos/administração & dosagem , Adipatos/toxicidade , Peso Corporal/efeitos dos fármacos , Ingestão de Energia/efeitos dos fármacos , Fígado/efeitos dos fármacos , Timo/efeitos dos fármacos , Administração Intravenosa , Animais , Relação Dose-Resposta a Droga , Feminino , Masculino , Ratos , Ratos Sprague-Dawley
12.
Int Heart J ; 60(3): 546-553, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31105152

RESUMO

Antithrombotic strategies for patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) remain challenging. This study aims to explore the best antithrombotic strategy for AF patients after PCI based on a network meta-analysis. This study was registered in PROSPERO (CRD42018093928). The PubMed, Cochrane, and EMBASE databases were searched to identify clinical trials concerning antithrombotic therapy for AF patients with PCI from inception to April 2018. Pairwise and network meta-analysis were conducted to compare clinical outcomes of different antithrombotic therapy. The primary endpoint was major bleeding. Fifteen studies including 16,382 patients were identified with follow-up ranging from 3 to 12 months. Non-vitamin K oral anticoagulants (NOAC) plus P2Y12 inhibitor ranked first with a reduced risk of major bleeding compared with vitamin K antagonist (VKA) plus dual antiplatelet therapy (OR: 0.57, 95% CI: 0.43-0.75) but with no significant difference compared with VKA plus single platelet therapy (OR: 0.85, 95% CI: 0.62-1.16). Similar thrombotic events were evident among these groups. Subgroup analysis showed that VKA plus aspirin exhibited a similar risk of major bleeding compared with VKA plus clopidogrel (OR: 0.94, 95% CI: 0.73-1.23) but was associated with increased risks of ischaemic stroke (OR: 2.10, 95% CI: 1.33-3.32) and all-cause death (OR: 1.77, 95% CI: 1.15-2.74) versus VKA plus clopidogrel. In AF patients undergoing PCI, NOAC plus P2Y12 inhibitor and VKA plus clopidogrel, but not VKA plus aspirin, were associated with reduced risk of major bleeding compared with the recommended VKA-based triple therapy, while thrombotic events were similar among these treatments.


Assuntos
Fibrilação Atrial/cirurgia , Fibrinolíticos/efeitos adversos , Hemorragia/epidemiologia , Aspirina/efeitos adversos , Clopidogrel/efeitos adversos , Hemorragia/induzido quimicamente , Humanos , Estudos Observacionais como Assunto , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Vitamina K/antagonistas & inibidores
13.
Molecules ; 24(3)2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30736379

RESUMO

A group of nitrate derivatives of naturally occurring sauropunol A and B were designed and synthesized. Nitric oxide (NO) releasing capacity and vasodilatory capacity studies were performed to explore the structure-activity relationship of resulted nitrates. Biological evaluation of these compounds revealed that most of the synthesized mononitrate derivatives demonstrated superior releasing capacity than isosorbide mononitrate (ISMN), and 2MNS-6 even demonstrated stronger NO releasing capacity than isosorbide dinitrate (ISDN). Two dinitrates, DNS-1 and DNS-2, showed higher NO releasing capacity than ISDN. Evaluation of inhibitory activities to the contractions in mesenteric artery rings revealed that 2MNS-8 and DNS-2 showed stronger vasorelaxation activities than ISDN. High level of NO and soluble guanylyl cyclase (sGC) may be essential for the potent vasodilatory effect of DNS-2. The vasodilatory effects of DNS-2 may result from cellular signal transduction of NO-sGC-cGMP. DNS-2 was found to be the most potent sauropunol-derived nitrate vasodilatory agent for further pharmaceutical investigation against cardiovascular diseases.


Assuntos
Desenho de Fármacos , Nitratos/química , Nitratos/farmacologia , Vasodilatadores/química , Vasodilatadores/farmacologia , Animais , Técnicas de Química Sintética , Técnicas In Vitro , Artérias Mesentéricas/efeitos dos fármacos , Estrutura Molecular , Nitratos/síntese química , Óxido Nítrico/química , Ratos , Relação Estrutura-Atividade , Vasodilatadores/síntese química
14.
BMC Cardiovasc Disord ; 18(1): 103, 2018 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-29793432

RESUMO

BACKGROUND: The relationship between platelet reactivity and long-term clinical outcomes remains controversial. The present prospective study was designed to explore the association between high platelet reactivity (HPR) on clopidogrel and long-term clinical outcomes following implantation of drug eluting stents (DES). METHODS: A total of 1769 consecutive patients assessed by Aggrestar (PL-11) were enrolled at our center from February 2011 to December 2017. The primary end point was major adverse cardiovascular and cerebrovascular events (MACCE), defined as definite or probable stent thrombosis, spontaneous myocardial infarction, all cause death, clinically driven target vessel revascularization (TVR), or ischemic stroke. Bleeding served as the safety endpoint. Propensity score matching (PSM) analysis was performed to adjust for baseline differences in the overall cohort. RESULTS: Finally, 409 patients (23.1%) were identified with HPR on clopidogrel. At a median follow-up of 4.1 years (interquartile range, 1.8 years), the occurrence of MACCE was significantly higher in HPR on clopidogrel group than normal platelet reactivity (NPR) on clopidogrel group (15.6% vs. 5.4%, p < 0.001). After PSM, 395 paired patients were matched, and the difference in MACCE between HPR (15.7%) versus NPR (9.4%) on clopidogrel groups remained significant (P < 0.001), mainly driven by increased all cause death (5.3% vs. 1.8%, p < 0.001), and clinically driven TVR (8.1% vs. 6.3%, p = 0.019) in the HPR group. The risk of bleeding between two groups was similar. CONCLUSIONS: This prospective study confirms the relationship between HPR on clopidogrel and long-term adverse cardiovascular events after coronary stenting.


Assuntos
Plaquetas/efeitos dos fármacos , Clopidogrel/uso terapêutico , Doença da Artéria Coronariana/cirurgia , Stents Farmacológicos , Intervenção Coronária Percutânea/instrumentação , Inibidores da Agregação Plaquetária/uso terapêutico , Idoso , Plaquetas/metabolismo , Clopidogrel/efeitos adversos , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/mortalidade , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Inibidores da Agregação Plaquetária/efeitos adversos , Pontuação de Propensão , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
15.
Bioorg Chem ; 81: 35-43, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30092385

RESUMO

Four sesquiterpenoid-chalcone hybrids (nardochalaristolones A-D, 1-4), a pair of epimeric sesquiterpenoid-flavonone hybrids ((2'S)- and (2'R)-nardoflavaristolone A, 5 and 6), and a sesquiterpenoid dimer (dinardokanshone F, 7), all sharing a kanshone C-derived sesquiterpenoid unit, were isolated from the underground parts of Nardostachys jatamansi (D.Don) DC. Their structures were elucidated by analysis of the extensive spectroscopic data, and the absolute configurations were established by analysis of 2D NMR spectroscopic data including NOESY data, combined with comparisons of experimental and calculated electronic circular dichroism spectra. Further, the plausible biosynthetic pathways for these compounds were proposed. And the results of SERT activity assay revealed that nardochalaristolones C-D (3 and 4) and nardoflavaristolone A (5 and 6) significantly enhanced SERT activity, while other compounds didn't show any SERT regulatory activities.


Assuntos
Chalcona/isolamento & purificação , Nardostachys/química , Sesquiterpenos/isolamento & purificação , Chalcona/química , Estrutura Molecular , Sesquiterpenos/química
16.
Bioconjug Chem ; 28(4): 1305-1323, 2017 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-28276682

RESUMO

A novel class of platinum(IV) complexes comprising a monoaminophosphonate ester moiety, which can not only act as a bone-targeting group but also inhibit matrix metalloproteinases (MMPs), were designed and synthesized. Biological assay of these compounds showed that they had potent antitumor activities against the tested cancer cell lines compared with cisplatin and oxaliplatin and indicated low cytotoxicity to human normal liver cells. Particularly, the platinum(IV) complexes were very sensitive to cisplatin resistant cancer cell lines. The corresponding structure-activity relationships were studied and discussed. Related mechanism study revealed that the typical complex 11 caused cell cycle arrest at S phase and induced apoptosis in Bel-7404 cells via a mitochondrial-dependent apoptosis pathway. Moreover, complex 11 had potent ability to inhibit the tumor growth in the NCI-H460 xenograft model comparable to cisplatin.


Assuntos
Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Inibidores de Metaloproteinases de Matriz/farmacologia , Compostos Organoplatínicos/administração & dosagem , Platina/uso terapêutico , Pró-Fármacos/química , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino , Humanos , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Compostos Organoplatínicos/farmacologia , Pró-Fármacos/síntese química , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Bioorg Med Chem ; 25(17): 4686-4700, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28728896

RESUMO

Pt(IV) complexes comprising a phenstatin analogue, as dual-targeting Pt(IV) prodrug, were designed and synthesized. They were found not only to carry the DNA binding platinum warhead into the tumor cells, but also to have a small molecular unit to inhibit tubulin polymerization. In vitro evaluation results revealed that Pt(IV) complexes showed better and more potent activity against the test human cancer cells including cisplatin resistant cell lines than their corresponding Pt(II) counterparts. In addition, the Pt(IV) derivative of cisplatin, complex 10, exhibited highly selective inhibition in human cancer cells and displayed no obvious toxicity to two human normal cell lines, respectively. Mechanism study suggested that complex 10 induced cell-cycle arrest at the G2/M phase and caused apoptotic cell death of human lung cancer NCI-H460 cells through the mitochondrial mediated pathway. Moreover, complex 10 effectively inhibited the tumor growth in the NCI-H460 xenograft model.


Assuntos
Benzofenonas/química , Complexos de Coordenação/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Platina/química , Moduladores de Tubulina/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Cisplatino/toxicidade , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Estrutura Terciária de Proteína , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transplante Heterólogo , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/uso terapêutico
18.
Bioconjug Chem ; 27(9): 2132-48, 2016 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-27494235

RESUMO

Three new Pt(IV) complexes comprising a combretastatin A-4 analogue were designed and synthesized. The resulting antitumor Pt(IV) complexes could significantly improve the antiproliferative activity and overcome the drug resistance of cisplatin in vitro. Interestingly, these novel compounds not only can carry the DNA binding Pt(II) warhead into the cancer cells but also have a small molecule fragment that can inhibit tubulin polymerization. Among them, complex 13, which was attached to an inhibitor of tubulin at one axial position of Pt(IV) octahedral coordination sphere, could effectively enter cancer cells, arrest the cell cycle in HepG-2 cancer cells at G2/M phases, and induce activation of caspases triggering apoptotic signaling via the mitochondrial-dependent apoptosis pathways. Moreover, complex 13 has the ability to effectively inhibit the tumor growth in the HepG-2 xenograft model without causing significant loss of animal body weight in comparison with cisplatin.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Bibenzilas/química , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Transporte Biológico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Modelos Moleculares , Compostos Organoplatínicos/metabolismo , Pró-Fármacos/metabolismo , Multimerização Proteica/efeitos dos fármacos , Estrutura Quaternária de Proteína , Espécies Reativas de Oxigênio/metabolismo , Tubulina (Proteína)/química , Moduladores de Tubulina/metabolismo
19.
J Cardiovasc Pharmacol ; 68(6): 441-451, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27560458

RESUMO

Pressure overload-induced cardiac remodeling and dysfunction progress to heart failure, which is mainly due to excessive oxidative stress. Hence, our study aimed to illustrate whether cardamonin, a kind of chalcone, could attenuate maladaptive cardiac changes and ameliorate cardiac insufficiency through its antioxidant mechanism. In vivo, our study revealed that cardamonin treatment could attenuate transverse aortic contraction-induced cardiac remodeling and dysfunction. Histological observations have suggested that cardamonin inhibited the occurrence of excessive cardiac oxidative stress and apoptosis. In vitro, we found that 3 treatments with angiotensin II (Ang II), hydrogen peroxide, and Nox4 overexpression in H9C2 cells markedly augmented intracellular oxidative stress as measured by superoxide dismutase, L-glutathione, and malonaldehyde. Conversely, cardamonin treatment notably alleviated oxidative stress induced by the 3 above-mentioned treatments. Furthermore, all 3 treatments resulted in increased apoptotic cell death, whereas cardamonin treatment reduced apoptosis in H9C2 cells. Moreover, cardamonin significantly abrogated the expression of Bax, apoptosis inducing factor, cytochrome c, and caspase-3 and caspase-9 and enhanced the expression of Bcl-2 and Bcl-xl. In conclusion, these findings provide a new possibility for cardamonin to alleviate pressure overload-induced heart failure.


Assuntos
Chalconas/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Zingiberaceae , Animais , Células Cultivadas , Chalconas/farmacologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/fisiologia , Remodelação Ventricular/fisiologia
20.
Inorg Chem ; 55(9): 4519-28, 2016 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-27074104

RESUMO

A series of platinum(II) complexes, with N-monosubstituted 1R,2R-diaminocyclohexane bearing methoxy-substituted benzyl groups as carrier ligands, were designed and synthesized. The newly prepared compounds, with chloride anions as leaving groups, were found to be very active against the tested cancer cell lines, including a cisplatin-resistant cell line. Despite their efficacy against tumor cells, they also showed low toxicity to a human normal liver cell line. Among them, complex 1 had superior cytotoxic activity against A549, HCT-116, MCF-7, SGC7901, and SGC7901/CDDP cancer cell lines. The DNA binding assay is of further special interest, as an unusual monofunctional binding mode was found, due to the introduction of a rigid substituted aromatic ring in the 1R,2R-diaminocyclohexane framework as steric hindrance. The linkage of complex 1 with DNA was stable and insensitive to nucleophilic attack. Moreover, studies including cellular uptake, gel electrophoresis, apoptosis and cell cycle, and Western blot analysis have provided insight into the high potency of this compound.


Assuntos
Antineoplásicos/farmacologia , Compostos Organoplatínicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/farmacologia , DNA/química , Adutos de DNA/química , Estabilidade de Medicamentos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Glutationa/química , Guanosina Monofosfato/química , Humanos , Ligantes , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Oxaliplatina , Solubilidade , Relação Estrutura-Atividade
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