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1.
Clin Exp Pharmacol Physiol ; 47(1): 60-66, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31454428

RESUMO

To examine the effect of chronic intermittent hypobaric hypoxia (CIHH) on heart rate variability (HRV), male adult Sprague Dawley rats were exposed to hypoxia (oxygen 11.1%) in a hypobaric chamber for 42 days, 6 hours each day, simulating an altitude of 5000 m. The body weight and blood pressure of rats were recorded once a week, electrocardiograms were analyzed continuously using biotelemetry, before, during and after CIHH treatment each day, and HRV was evaluated using spectrum analysis. No significant difference of body weight and blood pressure was found between CIHH and control rats. After 4 weeks of CIHH treatment, total power (TP) and very low-frequency component (VLF) were lower in CIHH rats than in control rats under hypobaric hypoxia condition. During CIHH treatment, low frequency (LF) was higher in 1 week and lower in 5-6 weeks in CIHH rats than control rats under hypobaric hypoxia, but not normoxic conditions. The high-frequency component (HF) was not changed during CIHH treatment, so LF/HF increased initially, and then recovered under the hypobaric hypoxia condition following 3 weeks of CIHH treatment. In addition, the HR was increased in CIHH rats after 4 weeks of CIHH treatment compared with control rats. Furthermore, HRV was altered significantly in control rats, but not in CIHH rats exposed to acute normobaric hypoxia. These data suggest that CIHH treatment modulates cardiac autonomic activity adaptively and inhibits the acute normobaric hypoxia-induced changes in HRV.

2.
Front Cell Neurosci ; 13: 415, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31616252

RESUMO

Hyperpolarization-activated cyclic nucleotide-gated ion channels (HCN channels) are widely expressed in the central and peripheral nervous systems and organs, while their functions are not well elucidated especially in the sympathetic nerve. The present study aimed to investigate the roles of HCN channel isoforms in the differentiation of sympathetic neurons using PC12 cell as a model. PC12 cells derived from rat pheochromocytoma were cultured and induced by nerve growth factor (NGF) (25 ng/ml) to differentiate to sympathetic neuron-like cells. Sympathetic directional differentiation of PC12 cells were evaluated by expressions of growth-associated protein 43 (GAP-43) (a growth cone marker), tyrosine hydroxylase (TH) (a sympathetic neuron marker) and neurite outgrowth. Results show that the HCN channel isoforms (HCN1-4) were all expressed in PC12 cells; blocking HCN channels with ivabradine suppressed NGF-induced GAP-43 expression and neurite outgrowth; silencing the expression of HCN2 and HCN4 using silenced using small interfering RNAs (siRNA), rather than HCN1 and HCN3, restrained GAP-43 expression and neurite outgrowth, while overexpression of HCN2 and HCN4 channels with gene transfer promoted GAP-43 expression and neurite outgrowth. Patch clamp experiments show that PC12 cells exhibited resting potentials (RP) of about -65 to -70 mV, and also presented inward HCN channel currents and outward (K+) currents, but no inward voltage-gated Na+ current was induced; NGF did not significantly affect the RP but promoted the establishment of excitability as indicated by the increased ability to depolarize and repolarize in the evoked suspicious action potentials (AP). We conclude that HCN2 and HCN4 channel isoforms, but not HCN1 and HCN3, promote the differentiation of PC12 cells toward sympathetic neurons. NGF potentiates the establishment of excitability during PC12 cell differentiation.

3.
J Cell Mol Med ; 23(9): 6085-6097, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31270949

RESUMO

The surged systemic vascular inflammation after acute myocardial infarction (AMI) aggravates the atherosclerotic endothelial injury. To explore roles of miR-499 released from cardiomyocytes during AMI in endothelial injury. Using qPCR and ELISA, we discovered that patients with AMI had significantly increased plasma miR-499, which was directly correlated with serum thrombomodulin, a marker for endothelial injury. Plasma of AMI patients, when incubated with human umbilical vein endothelial cells (HUVECs), significantly increased the expression of endothelial injury markers, which could be abrogated by antagomiR-499. In vitro, neonatal rat cardiomyocytes subjected to hypoxia/reoxygenation (HX/R) released miR-499 that could be internalized into rat pulmonary microvascular endothelial cells (RPMECs), worsening the high glucose-induced injury. In silico analysis demonstrated that CHRNA7 encoding α7-nAchR is a target of miR-499, which was validated in cell lines expressing endogenous α7-nAchR. In high glucose-induced RPMECs injury model, miR-499 aggravated, whereas forced CHRNA7 expression ameliorated the injury. Moreover, the perfusate from Langendorff perfused rat heart subjected to HX/R contained higher level of miR-499 that significantly impaired the Bradykinin-mediated endothelium-dependent relaxation in both conduit and resistance arteries, which could be partially abrogated by antagomiR-499. Finally, the correlation between plasma miR-499 and endothelial injury was further confirmed in another cohort of AMI patients. We conclude that miR-499 released from injured cardiomyocytes contributes to the endothelial injury by targeting α7-nAchR. This study implies that miR-499 may serve as a potential target for the treatment of the surged vascular inflammation post-AMI.

4.
Clin Nucl Med ; 44(6): 431-438, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30985422

RESUMO

AIM: Combined Ga-PSMA-617 PET imaging and Lu-PSMA-617 therapy is a precise targeted theranostic approach for patients with metastatic castration-resistant prostate cancer (mCRPC). The purpose of this study was to determine whether pretherapeutic standard uptake value (SUV) in Ga-PSMA-617 PET could indicate the effective dose in the main organs and absorbed dose in tumor lesions. METHODS: After institutional review board approval and informed consent, 9 patients with mCRPC were recruited and underwent Ga-PSMA-617 PET/CT scans. Five patients received Lu-PSMA-617 (1.30-1.42 GBq, 35-38.4 mCi) and then underwent serial whole-body planar imaging and SPECT/CT imaging of both thoracic and abdominal regions at 0.5-, 2-, 24-, 48-, and 72-hour time points. The other 4 patients received Lu-EB-PSMA-617 (0.80-1.1 GBq, 21.5-30 mCi) and then underwent the same imaging procedures at 2-, 24-, 72-, 120-, and 168-hour time points. The effective dose in the main organs and the absorbed dose in tumor lesions were calculated. Detailed correlations between the pretherapeutic SUV in Ga-PSMA-617 PET and effective dose in the main organs as well as absorbed dose in the tumor lesions were analyzed. RESULTS: SUV of Ga-PSMA-617 PET was moderately correlated with effective dose in main organs (r = 0.610 for Lu-PSMA-617, r = 0.743 for Lu-EB-PSMA-617, both P < 0.001). SUV of tumor lesions in Ga-PSMA-617 PET had high correlation with those in Lu-PSMA-617 (r = 0.915, P < 0.001) and moderate correlation with those in Lu-EB-PSMA-617 (r = 0.611, P = 0.002). CONCLUSIONS: Pretherapeutic Ga-PSMA-617 PET may indicate the dosimetry of Lu-PSMA-617 and Lu-EB-PSMA-617. Both the effective dose in main organs and absorbed dose in tumor lesions correlate with SUV of Ga-PSMA-617 PET. This relationship may help select appropriate candidates for peptide receptor radionuclide therapy. Further investigations of larger cohorts are needed to confirm these initial findings.


Assuntos
Dipeptídeos/administração & dosagem , Dipeptídeos/farmacocinética , Compostos Heterocíclicos com 1 Anel/administração & dosagem , Compostos Heterocíclicos com 1 Anel/farmacocinética , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Neoplasias de Próstata Resistentes à Castração/radioterapia , Compostos Radiofarmacêuticos/administração & dosagem , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Radiometria , Compostos Radiofarmacêuticos/farmacocinética , Dosagem Radioterapêutica , Estudos Retrospectivos , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único/métodos , Imagem Corporal Total
5.
Phytother Res ; 33(4): 1191-1198, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30768745

RESUMO

The purpose of this study was to investigate the renal protective effect of celastrol on diabetic rats. Furthermore, the mechanism of its action was discussed whether it was related to MAPK/NF-κB signaling pathway. There were a total of 36 rats. Six rats were randomly chosen as the control group. The remaining 30 rats were given 1% streptozotocin intraperitoneal injection (50 mg/kg) and were randomly divided into five groups: the model control group, the low-dose celastrol group, the high-dose celastrol group, the Tripterygium wilfordii polyglycosides group, and the MAPK/NF-κB inhibitor group. After 4 weeks of continuous administration, 24-hr urine volume, urinary protein, blood urea nitrogen, and serum creatinine content were observed, and hematoxylin-eosin (HE) staining of the kidney and liver were evaluated. p38MAPK was designated by immunohistochemical method, and NF-κB p65 in renal tissue was detected by western blotting. Our results showed that celastrol could not only reduce contents of creatinine and urea nitrogen in blood but also reduce excretion of urinary protein in diabetic rats, improve renal pathological injury, and down-regulate the expression of p38MAPK and NF-κB p65. In conclusion, celastrol could protect kidney of diabetic rats by regulating the signal pathway of MAPK/NF-κB, inhibiting inflammation and delaying renal injury.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Rim/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , Tripterygium/química , Triterpenos/uso terapêutico , Animais , Diabetes Mellitus Experimental/metabolismo , Rim/patologia , Masculino , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Transcrição RelA/metabolismo , Triterpenos/farmacologia
6.
Pathol Oncol Res ; 25(4): 1497-1503, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30421088

RESUMO

The aim of the study was to perform a meta-analysis to compare the therapeutic effects and adverse events (AEs) of sorafenib in second-line treatments of metastatic renal cell carcinoma (mRCC). We searched online electronic databases: Pubmed, Embase, Cochrane library updated on November 2017.Trials of the effectiveness of sorafenib in second-line treatments of advanced RCC were included, of which the main outcomes were objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and grade 3/4 AE. Other TAs significantly reduced the risk of PFS compared to sorafenib with respect to second-line treatment (HR = 0.74; 95% CI, 0.65-0.83; p < 0.00001). No significant differences were, however, found in patients in terms of the ORR (HR = 1.82; 95% CI, 0.98-3.35; p = 0.06). Frequencies of the most common toxicities were overall similar and adverse events differed only in sensitivity analysis in rash with exclusion of other TAs (HR = 0.16; 95% CI, 0.05-0.52; p = 0.002). Overall survival was not debated between groups. In patients with mRCC, second-line sorafenib is associated with similar ORR as other target agents. While, sorafenib did not demonstrate a PFS advantage compared with other target agents, suggests sorafenib may not benefit patients with mRCC. Tolerability due to toxicities is similar compared sorafenib with other target agents. Further characterization of the RCC oncogenic pathway, and the ongoing clinical trials should help optimize the treatment option for second-line therapy of advanced renal cell carcinoma.

7.
Eur J Nucl Med Mol Imaging ; 46(1): 148-158, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30090965

RESUMO

PURPOSE: This translational study is designed to assess the safety, dosimetry and therapeutic response to a single, low-dose of 177Lu-EB-PSMA-617 in comparison to 177Lu-PSMA-617 in patients with mCRPC. METHODS: Following institutional review board approval and informed consent, nine patients with mCRPC were recruited. Four patients accepted intravenous injection of 0.80-1.1 GBq (21.5-30 mCi) of 177Lu-EB-PSMA-617, then underwent serial whole-body planar and SPECT/CT imaging at 2, 24, 72, 120 and 168 h. The other five patients accepted intravenous injection of 1.30-1.42 GBq (35-38.4 mCi) 177Lu-PSMA-617, then underwent the same imaging procedures at 0.5, 2, 24, 48, and 72 h. All patients were evaluated by 68Ga-PSMA-617 PET/CT before and one month after the treatment. Dosimetry evaluation was compared in both patient groups. RESULTS: When the bone metastasis tumors with comparable baseline SUVmax in the range of 10.0-15.0 were selected from the two groups for comparison, the accumulated radioactivity of 177Lu-EB-PSMA-617 was about 3.02-fold higher than that of 177Lu-PSMA-617. Imaging dose of 177Lu-EB-PSMA-617 treatment showed significant decrease of 68Ga-PSMA-617 uptake within a month, which was not observed in patients imaged with 177Lu-PSMA-617 (SUV change: -32.43 ± 0.14% vs. 0.21 ± 0.37%; P = 0.002). 177Lu-EB-PSMA-617 also had higher absorbed doses in the red bone marrow and kidneys than 177Lu-PSMA-617 (0.0547 ± 0.0062 vs. 0.0084 ± 0.0057 mSv/MBq for red bone marrow, P < 0.01; 2.39 ± 0.69 vs. 0.39 ± 0.06 mSv/MBq for kidneys, P < 0.01). CONCLUSION: This first-in-human study demonstrated that 177Lu-EB-PSMA-617 had higher accumulation in mCRPC and that low imaging dose appears to be effective in treating tumors with high 68Ga-PSMA-617 uptakes. Elevated uptakes of 177Lu-EB-PSMA-617 in kidneys and red bone marrow were well tolerated at the administered low dose. Further investigations with increased dose and frequency of administration are warranted.


Assuntos
Dipeptídeos/farmacocinética , Compostos Heterocíclicos com 1 Anel/farmacocinética , Neoplasias de Próstata Resistentes à Castração/radioterapia , Compostos Radiofarmacêuticos/farmacocinética , Idoso , Idoso de 80 Anos ou mais , Dipeptídeos/efeitos adversos , Dipeptídeos/uso terapêutico , Azul Evans , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/patologia , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/uso terapêutico , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único
8.
Med Sci Monit ; 24: 8459-8468, 2018 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-30468686

RESUMO

BACKGROUND This study investigated the effect and the possible mechanism of trimetazidine in atherosclerosis. MATERIAL AND METHODS We established an atherosclerotic rat model by high-fat diet and vitamin D injection. Rats were separated into 3 different groups: control, atherosclerosis, and trimetazidine (n=10). The aortic artery was isolated and its morphological features were examined by hematoxylin and eosin (HE) staining. Serum low-density lipoprotein cholesterol (LDL-c), total cholesterol (TC), and triglycerides (TG) were analyzed using an automatic biochemical analyzer. Human aortic smooth muscle cells (HASMCs) were cultured and divided into 5 groups: no treatment, H2O2 treatment only, trimetazidine preincubation before H2O2 treatment, oxidized low-density lipoprotein (oxLDL) treatment only, and trimetazidine preincubation before oxLDL treatment. HASMCs proliferation was tested using the Cell Counting Kit-8. Reactive oxygen species (ROS) and malondialdehyde (MDA) levels, superoxide dismutase (SOD) activity of the aortic artery, and HASMCs were measured using commercially available kits. RESULTS HE staining assay showed that trimetazidine suppressed the progression of atherosclerosis and reduced foam cell formation in the aortic artery without affecting serum lipid levels. HASMCs proliferation assay revealed that trimetazidine alleviated the inhibitory effect of H2O2 on HASMCs proliferation and inhibited oxLDL-induced proliferation of HASMCs. Moreover, trimetazidine ameliorated ROS up-regulation elicited by H2O2 or oxLDL in HASMCs. Additionally, trimetazidine restored SOD activity and reduced MDA content of HASMCs. CONCLUSIONS Trimetazidine suppressed the progression of atherosclerosis by enhancing energy value, decreasing ROS level of aortic artery, modulating HASMCs proliferation, and reducing oxidative stress in HASMCs.


Assuntos
Aterosclerose/tratamento farmacológico , Trimetazidina/farmacologia , Animais , Aorta/citologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , China , Dieta Hiperlipídica , Modelos Animais de Doenças , Humanos , Lipoproteínas LDL , Masculino , Malondialdeído/metabolismo , Miócitos de Músculo Liso/citologia , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio , Superóxido Dismutase/metabolismo , Triglicerídeos/sangue
9.
Artigo em Inglês | MEDLINE | ID: mdl-30046340

RESUMO

Benign prostatic hyperplasia (BPH) is a common disease in the current ageing male population. This research aims to study the effects of Kelong-Capsules (KLC) on testosterone-induced BPH. Thirty rats were randomly divided into normal group, model group, and three treatment groups. Three treatment groups were given KLC (3.6 g/kg), KLC (7.2 g/kg), and finasteride (0.9 mg/kg), respectively, for 28 days after establishing the animal model. The BPH rat models were evaluated by Traditional Chinese Medicine (TCM) symptoms and prostate index (PI). Results indicated that three treatment groups all alleviated the pathological changes of prostate and kidney at different levels. Compared with the model group, the PI of the groups treated with KLC (7.2 g/kg) and finasteride decreased significantly. The expressions of NF-E2 related factor 2 (Nrf-2) and quinine oxidoreductase (NQO1) in the group treated with KLC (3.6 g/kg) increased markedly (p < 0.01). The cyclooxygenase-2 (COX-2) protein expression of the group treated with KLC (7.2 g/kg) was increased (p < 0.01). In conclusion, KLC could obviously inhibit the growth of prostate, and KLC (3.6 g/kg) could promote the expressions of Nrf2 and NQO1.

10.
J Nucl Med ; 59(6): 922-928, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29123014

RESUMO

This study was designed to analyze the safety, biodistribution, and radiation dosimetry of a gastrin-releasing peptide receptor (GRPR) antagonist PET tracer, 68Ga-RM26; to assess its clinical diagnostic value in prostate cancer patients; and to perform a direct comparison between GRPR antagonist 68Ga-RM26 and agonist 68Ga-BBN. Methods: Five healthy volunteers were enrolled to validate the safety of 68Ga-RM26 and calculate dosimetry. A total of 28 patients with prostate cancer (17 newly diagnosed and 11 posttherapy) were recruited and provided written informed consent. All the cancer patients underwent PET/CT at 15-30 min after intravenous injection of 1.85 MBq (0.05 mCi) per kilogram of body weight of 68Ga-RM26. Among them, 22 patients (11 newly diagnosed and 11 posttherapy) underwent 68Ga-BBN PET/CT for comparison within 1 wk. 99mTc-MDP (methylene diphosphonate) bone scans were obtained within 2 wk for comparison. GRPR immunohistochemical staining of tumor samples was performed. Results: The administration of 68Ga-M26 was well tolerated by all subjects, with no adverse symptoms being noticed or reported during the procedure and at 2-wk follow-up. The total effective dose equivalent and effective dose were 0.0912 ± 0.0140 and 0.0657 ± 0.0124 mSv/MBq, respectively. In the 17 patients with newly diagnosed prostate cancer, 68Ga-RM26 PET/CT showed positive prostate-confined findings in 15 tumors with an SUVmax of 6.49 ± 2.37. In the 11 patients who underwent prostatectomy or brachytherapy with or without androgen deprivation therapy, 68Ga-RM26 PET/CT detected 8 metastatic lymph nodes in 3 patients with an SUVmax of 4.28 ± 1.25 and 21 bone lesions in 8 patients with an SUVmax of 3.90 ± 3.07. Compared with 68Ga-RM26 PET/CT, GRPR agonist 68Ga-BBN PET/CT detected fewer primary lesions and lymph node metastases as well as demonstrated lower tracer accumulation. There was a significant positive correlation between SUV derived from 68Ga-RM26 PET and the expression level of GRPR (P < 0.001). Conclusion: This study indicates the safety and significant efficiency of GRPR antagonist 68Ga-RM26. 68Ga-RM26 PET/CT would have remarkable value in detecting both primary prostate cancer and metastasis. 68Ga-RM26 is also expected to be better than GRPR agonist as an imaging marker to evaluate GRPR expression in prostate cancer.


Assuntos
Acetatos/química , Acetatos/farmacologia , Radioisótopos de Gálio , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Próstata/diagnóstico por imagem , Receptores da Bombesina/antagonistas & inibidores , Acetatos/efeitos adversos , Acetatos/farmacocinética , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Radiometria , Recidiva , Segurança , Distribuição Tecidual
11.
J Huazhong Univ Sci Technolog Med Sci ; 37(5): 761-765, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29058292

RESUMO

Danshen, an efficacious agent for cardiovascular diseases, has been found to play an essential role in kidney injury. In the present study, the effect of Danshen on cisplatin-induced renal dysfunction was investigated in a mouse model. Danshen was administered to mice at a dose of 3 g/kg 4 days before and 3 days after cisplatin treatment. A single intraperitoneal injection of 20 mg/kg cisplatin was used to induce nephrotoxicity. The mice were sacrificed 72 h after cisplatin intoxication. Biochemical parameters including serum creatinine and blood urea nitrogen were analyzed. Histopathological changes of kidney tissues were detected using HE staining. Antioxidant enzymes (GSH-Px and SOD) and peroxidative product (MDA) were detected. Protein expressions of Nrf2 and its target genes including HO-1 and NQO1 were measured by Western blotting. The results showed that pretreatment with Danshen significantly reduced serum creatinine and blood urea nitrogen in the cisplatin-treated mice. Histopathological examination showed that Danshen mitigated the renal damage induced by cisplatin. Moreover, Danshen restored the activities of antioxidant enzymes (GSH-Px and SOD) and normalized the MDA contents in renal tissues. Western blotting revealed that Danshen enhanced the expressions of Nrf2 and its target genes in cisplatin-exposed mice. It was suggested that Danshen protects against the cisplatin-induced renal impairment in the mice, which is potentially associated with the upregulation of Nrf2-mediated signaling pathway.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/tratamento farmacológico , Cisplatino/efeitos adversos , Medicamentos de Ervas Chinesas/administração & dosagem , Fator 2 Relacionado a NF-E2/metabolismo , Lesão Renal Aguda/metabolismo , Animais , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Regulação da Expressão Gênica , Masculino , Camundongos , Transdução de Sinais/efeitos dos fármacos
12.
Sci Rep ; 7(1): 2717, 2017 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-28578429

RESUMO

Epidemiological studies have shown a strong correlation between tumor and AF. However, the molecular link between tumor and AF remains unknown. ECRG4, a tumor suppressor gene that is expressed in the A-V node and in sporadic ventricular myocytes, inhibits tumorigenesis and monitors tissue homeostasis by functioning as a 'sentinel' molecule gauging inflammatory and cell proliferative responses. To explore the potential physiological function of Ecrg4 in heart, we evaluated its distribution in heart, analyzed its expression in patients with persistent AF and in a canine AF model, and dissected the molecular events downstream of Ecrg4. The results showed that the level of Ecrg4 expression is homogenously high in atria and the conduction systems and in sporadic ventricular myocytes. Importantly, the expression of Ecrg4 was significantly decreased in atrial appendages of AF patients than patients with SR. Moreover, in rapid pacing canine AF models, the expression of ECRG4 in atria was significantly decreased compared to that of the controls. Mechanistically, knockdown ECRG4 in atrial myocytes significantly shortened the APDs, inhibited the expression of Gja1, and activated pro-inflammatory cascades and genes involved in cardiac remodeling. These results suggest that Ecrg4 may play a critical role in the pathogenesis of AF.


Assuntos
Fibrilação Atrial/genética , Predisposição Genética para Doença , Proteínas de Neoplasias/genética , Potenciais de Ação , Adulto , Animais , Apêndice Atrial/metabolismo , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Remodelamento Atrial , Cães , Eletrocardiografia , Expressão Gênica , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Átrios do Coração/metabolismo , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Miócitos Cardíacos/metabolismo , Proteínas de Neoplasias/metabolismo , Ratos , Proteínas Supressoras de Tumor
13.
Artigo em Inglês | MEDLINE | ID: mdl-28286534

RESUMO

In the past few decades, the incidence of liver cancer has been rapidly rising across the world. Rosemary is known to possess antioxidant activity and is used as natural antioxidant food preservative. It is proposed to have anticancer activity in treating different tumor models. In this study, we try to explore the impact of rosemary extracts on upregulating the level of Nrf2 and Nrf2-regulatory proteins, Sestrin2 and MRP2 in HepG2 cells, and to speculate its potential mechanism. The anticancer activity of rosemary extract, including its polyphenolic diterpenes carnosic acid and carnosol, was evaluated to understand the potential effect on HepG2 cells. Rosemary extract, carnosic acid, and carnosol induced the expression of Sestrin2 and MRP2 associate with enhancement of Nrf2 protein level in HepG2 cells, in which carnosic acid showed most obvious effect. Although the activation pathway of Nrf2/ARE was not exactly assessed, it can be assumed that the enhancement of expression of Sestrin2 and MRP2 may result from upregulation of Nrf2.

14.
Pharmacology ; 99(5-6): 226-235, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28132058

RESUMO

AIMS: To investigate the effects of ketamine on human hyperpolarization-activated cyclic nucleotide-gated (hHCN) 1, 2, 4 channel currents expressed in Xenopus oocytes and spontaneous action potentials (APs) of rabbit sinoatrial node (SAN). METHODS: The 2-electrode voltage clamp and standard microelectrode techniques were respectively applied to record hHCN channels currents expressed in Xenopus oocytes and APs of SAN separated from rabbit heart. RESULTS: Ketamine (1-625 µmol/L) blocked hHCN1, 2, and 4 currents with IC50 of 67.0, 89.1, and 84.0 µmol/L, respectively, in a concentration-dependent manner. The currents were rapidly blocked by ketamine and partially recovered after washout. The steady-state activation curves of hHCN1, 2, and 4 currents demonstrated a concentration-dependent shift to the left and the rates of activation were significantly decelerated. But ketamine blocked hHCN channels in a voltage-independence and non-use-dependent manner, and did not modify the voltage dependence of activation and reversal potentials. Furthermore, ketamine suppressed phase-4 spontaneous depolarization rate in isolated rabbit SAN and decreased the beat rates in a concentration-dependent manner. CONCLUSION: Ketamine could inhibit hHCN channels expressed in Xenopus oocytes in a concentration-dependent manner as a close-state blocker and decrease beat rates of isolated rabbit SAN. This study may provide novel insights into other unexplained actions of ketamine.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/antagonistas & inibidores , Ketamina/farmacologia , Nó Sinoatrial/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Humanos , Oócitos , Coelhos , Nó Sinoatrial/metabolismo , Transfecção , Xenopus laevis
15.
J Nucl Med ; 58(2): 228-234, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27493267

RESUMO

This study aimed to document the first-in-human application of a 68Ga-labeled heterodimeric peptide BBN-RGD (bombesin-RGD) that targets both integrin αvß3 and gastrin-releasing peptide receptor (GRPR). We evaluated the safety and assessed the clinical diagnostic value of 68Ga-BBN-RGD PET/CT in prostate cancer patients in comparison with 68Ga-BBN. METHODS: Five healthy volunteers (4 men and 1 woman; age range, 28-53 y) were enrolled to validate the safety of 68Ga-BBN-RGD. Dosimetry was calculated using the OLINDA/EXM software. Thirteen patients with prostate cancer (4 newly diagnosed and 9 posttherapy) were enrolled. All the patients underwent PET/CT scans 15-30 min after intravenous injection of 1.85 MBq (0.05 mCi) per kilogram of body weight of 68Ga-BBN-RGD and also accepted 68Ga-BBN PET/CT within 2 wk for comparison. RESULTS: With a mean injected dose of 107.3 ± 14.8 MBq per patient, no side effect was found during the whole procedure and 2 wk follow-up, demonstrating the safety of 68Ga-BBN-RGD. A patient would be exposed to a radiation dose of 2.90 mSv with an injected dose of 129.5 MBq (3.5 mCi), which is much lower than the dose limit set by the Food and Drug Administration. In 13 patients with prostate cancer diagnosed by biopsy, 68Ga-BBN-RGD PET/CT detected 3 of 4 primary tumors, 14 metastatic lymph nodes, and 20 bone lesions with an SUVmax of 4.46 ± 0.50, 6.26 ± 2.95, and 4.84 ± 1.57, respectively. Only 2 of 4 primary tumors, 5 lymph nodes, and 12 bone lesions were positive on 68Ga-BBN PET/CT, with the SUVmax of 2.98 ± 1.24, 4.17 ± 1.89, and 3.61 ± 1.85, respectively. CONCLUSION: This study indicates the safety and efficiency of a new type of dual integrin αvß3- and GRPR-targeting PET radiotracer in prostate cancer diagnosis and staging.


Assuntos
Bombesina/farmacocinética , Integrina alfaVbeta3/metabolismo , Oligopeptídeos/farmacocinética , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/metabolismo , Receptores da Bombesina/metabolismo , Adulto , Idoso , Feminino , Radioisótopos de Gálio/farmacocinética , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Imagem Molecular , Especificidade de Órgãos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Distribuição Tecidual
16.
Acta Pharmacol Sin ; 37(11): 1432-1441, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27569391

RESUMO

AIM: The augmentation of late sodium current (INa.L) not only causes intracellular Na+ accumulation, which results in intracellular Ca2+ overload via the reverse mode of the Na+/Ca2+ exchange current (reverse-INCX), but also prolongs APD and induces early afterdepolarizations (EAD), which can lead to arrhythmia and cardiac dysfunction. Thus, the inhibition of INa.L is considered to be a potential way for therapeutic intervention in ischemia and heart failure. In this study we investigated the effects of tolterodine (Tol), a competitive muscarinic receptor antagonist, on normal and veratridine (Ver)-augmented INa.L, reverse-INCX and APD in isolated rabbit ventricular myocytes, which might contribute to its cardioprotective activity. METHODS: Rabbit ventricular myocytes were prepared. The INa.L and reverse-INCX were recorded in voltage clamp mode, whereas action potentials and Ver-induced early afterdepolarizations (EADs) were recorded in current clamp mode. Drugs were applied via superfusion. RESULTS: Tol (3-120 nmol/L) concentration-dependently inhibited the normal and Ver-augmented INa.L with IC50 values of 32.08 nmol/L and 42.47 nmol/L, respectively. Atropine (100 µmol/L) did not affect the inhibitory effects of Tol (30 nmol/L) on Ver-augmented INa.L. In contrast, much high concentrations of Tol was needed to inhibit the transient sodium current (INa.T) with an IC50 value of 183.03 µmol/L. In addition, Tol (30 nmol/L) significantly shifted the inactivation curve of INa.T toward a more depolarizing membrane potential without affecting its activation characteristics. Moreover, Tol (30 nmol/L) significantly decreased Ver-augmented reverse-INCX. Tol (30 nmol/L) increased the action potential duration (APD) by 16% under the basal conditions. Ver (20 µmol/L) considerably extended the APD and evoked EADs in 18/24 cells (75%). In the presence of Ver, Tol (30 nmol/L) markedly decreased the APD and eliminated EADs (0/24 cells). CONCLUSION: Tol inhibits normal and Ver-augmented INaL and decreases Ver-augmented reverse-INCX. In addition, Tol reverses the prolongation of the APD and eliminates the EADs induced by Ver, thus prevents Ver-induced arrhythmia.


Assuntos
Antiarrítmicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/fisiologia , Trocador de Sódio e Cálcio/metabolismo , Tartarato de Tolterodina/farmacologia , Veratridina/farmacologia , Potenciais de Ação , Animais , Feminino , Ventrículos do Coração/citologia , Técnicas In Vitro , Masculino , Miócitos Cardíacos/fisiologia , Técnicas de Patch-Clamp , Coelhos
17.
J Pharmacol Sci ; 132(4): 235-243, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27107824

RESUMO

Acehytisine, a multi-ion channel blocker, can markedly inhibit INa, ICa, IKur, If at various concentrations and effectively terminate and prevent atrial fibrillation (AF) in patients and animal models, but the molecular mechanism underlying its blockage remains elusive. In this study, we investigated the effects of acehytisine on action potentials and sodium channels of atrial and ventricular myocytes isolated from rabbit, using whole-cell recording system. We found that acehytisine exerted stronger blocking effects on sodium channels in atria than in ventricles, especially at depolarization (IC50: 48.48 ± 7.75 µmol/L in atria vs. 560.17 ± 63.98 µmol/L in ventricles). It also significantly shifted steady state inactivation curves toward negative potentials in atrial myocytes, without affecting the recovery kinetics from inactivation of sodium channels in the same cells. In addition, acehytisine inhibited INa in a use-dependent manner and regulated slow inactivation kinetics by different gating configurations. These findings indicate that acehytisine selectively blocks atrial sodium channels and possesses affinity to sodium channel in certain states, which provides additional evidence for the anti-AF of acehytisine.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Bloqueadores dos Canais de Sódio/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/metabolismo , Átrios do Coração/citologia , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Ventrículos do Coração/citologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Técnicas de Patch-Clamp , Coelhos
18.
Mol Med Rep ; 13(2): 1725-31, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26707917

RESUMO

Myricetin (Myr) is a flavonoid that exerts anti-arrhythmic effects. However, its potential effects on ion channels have remained elusive. The aim of the present study was to investigate the effects of Myr on Kv1.5 channels in HEK293 cells. The current of Kv1.5 channels (Ikur) in HEK293 cells was recorded using the whole-cell patch-clamp technique and the expression of the Kv1.5 protein was measured using western blot analysis 24 h after treatment with Myr. The results showed that 5 µM Myr significantly reduced Ikur from 215.04 ± 40.59 to 77.72 ± 17.94 pA/pF (P<0.05; n=5). Myr increased the current suppression from 0 to 0.31 ± 0.12 and 0.55 ± 0.11 over 5 or 20 min, respectively. In addition, Ikur decreased from 376.23 ± 1.30 to 270.19 ± 4.28 pA/pF when the frequency was increased from 0.5 to 4 Hz in HEK293 cells treated with 10 µM Myr for 5 min. Furthermore, Myr reduced hKv1.5 protein expression in a dose-dependent manner. These results demonstrated that Myr inhibited Ikur and the expression of hKv1.5 in HEK293 cells in a dose-, time- and frequency-dependent manner. These observations partly explained the mechanisms by which Myr exerts anti-arrhythmic effect.


Assuntos
Flavonoides/toxicidade , Canal de Potássio Kv1.5/antagonistas & inibidores , Relação Dose-Resposta a Droga , Flavonoides/química , Células HEK293 , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Canal de Potássio Kv1.5/metabolismo , Fatores de Tempo
19.
Zhongguo Zhong Xi Yi Jie He Za Zhi ; 35(8): 1011-4, 2015 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-26485920

RESUMO

The essence of endogenous turbidity in Chinese medicine (CM) is different from cream, fat, phlegm, retention, damp, toxicity, and stasis. Along with the development of modern scientific technologies and biology, researches on the essence of endogenous turbidity should keep pace with the time. Its material bases should be defined and new connotation endowed at the microscopic level. The essence of turbidity lies in abnormal functions of zang-fu organs. Sugar, fat, protein, and other nutrient substances cannot be properly decomposed, but into semi-finished products or intermediate metabolites. They are inactive and cannot participate in normal material syntheses and decomposition. They cannot be transformed to energy metabolism, but also cannot be synthesized as executive functioning of active proteins. If they cannot be degraded by autophagy-lysosome or ubiquitin-prosome into glucose, fatty acids, amino acids, and other basic nutrients to be used again, they will accumulate inside the human body and become endogenous turbidity. Therefore, endogenous turbidity is different from final metabolites such as urea, carbon dioxide, etc., which can transform vital qi. How to improve the function of zang-fu organs, enhance its degradation by autophagy-lysosome or ubiquitin-prosome is of great significance in normal operating of zang-fu organs and preventing the emergence and progress of related diseases.


Assuntos
Medicina Tradicional Chinesa , Autofagia , Humanos , Complexo de Endopeptidases do Proteassoma
20.
Med Sci Monit ; 21: 1207-13, 2015 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-25918274

RESUMO

BACKGROUND: The incidence of atrial fibrillation (AF) in rheumatic heart diseases (RHD) is very high and increases with age. Occurrence and maintenance of AF are very complicated process accompanied by many different mechanisms. Ion-channel remodeling, including the voltage-gated potassium channel Kv1.5, plays an important role in the pathophysiology of AF. However, the changes of Kv1.5 channel expression in Han Chinese patients with RHD and AF remain poorly understood. The aim of the present study was to investigate whether the Kv1.5 channels of the right atria may be altered with RHD, age, and sex to contribute to AF. MATERIAL/METHODS: Right atrial appendages were obtained from 20 patients with normal cardiac functions who had undergone surgery, and 26 patients with AF. Subjects were picked from 4 groups: adult and aged patients in normal sinus rhythm (SR) and AF. Patients were divided into non-RHD and RHD groups or men and women groups in normal SR and AF, respectively. The expression of Kv1.5 protein and messenger RNA (mRNA) were measured using Western blotting and polymerase chain reaction (PCR) method, respectively. RESULTS: Compared with the SR group, the expression of Kv1.5 protein decreased significantly in the AF group. However, neither Kv1.5 protein nor KCNA5 mRNA had significant differences in adult and aged groups, non-RHD and RHD group, and men and women group of AF. CONCLUSIONS: The expression of Kv1.5 channel protein changes with AF but not with age, RHD, and sex in AF.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Canal de Potássio Kv1.5/genética , Canal de Potássio Kv1.5/metabolismo , Adolescente , Adulto , Fatores Etários , Fibrilação Atrial/etiologia , Estudos de Casos e Controles , Feminino , Átrios do Coração/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Cardiopatia Reumática/complicações , Cardiopatia Reumática/genética , Cardiopatia Reumática/metabolismo , Fatores Sexuais , Adulto Jovem
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