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OBJECTIVES: Carotid intima-media thickness (CIMT) is a noninvasive marker of atherosclerosis, a typical pathologic process underlying cardiovascular diseases (CVDs). It is essential to explore the relationships between weight loss and the reduction of CIMT. STUDY DESIGN: This was an updated systematic review and meta-analysis. METHODS: A systematic literature search was conducted to collect relevant clinical trials. The pooled results of meta-analyses were assessed by weighted mean difference (WMD) and the corresponding 95 % confidence interval (95% CI). RESULTS: Thirty-three articles involving 2273 participants were collected in this meta-analysis. Among all participants with obesity, the pooled mean of weight loss was -23.26 kg (95% CI: -27.71 to -18.81), and the pooled mean change of CIMT was -0.06 mm (95% CI: -0.08 to -0.04). Compared with Non-surgical interventions, Surgical ones could lead to much higher weight loss (Pbetween groups < 0.001). A more significant CIMT reduction was identified among Surgical intervention patients than among Non-surgical intervention participants (Pbetween groups < 0.001). CONCLUSIONS: Effective interventions, especially Surgical interventions, could reduce the weight of patients with obesity, followed by the decline of CIMT, which might further disturb atherosclerosis progression and lower CVD risk.
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Aterosclerose , Doenças Cardiovasculares , Humanos , Fatores de Risco , Espessura Intima-Media Carotídea , Obesidade/complicações , Redução de PesoRESUMO
Objective: To explore the metabolite profile and metabolic pathways of newly diagnosed multiple myeloma (MM). Methods: Gas chromatography-mass spectrometry (GC-MS) was employed for the high-throughput detection and identification of serum samples from 55 patients with MM and 37 healthy controls matched for age and sex from 2016 to 2017 collected at the First Affiliated Hospital of Soochow University. The relative standard deviation (RSD) of quality control (QC) samples was employed to validate the reproducibility of GC-MS approach. The differential metabolites between patients with MM and healthy controls were detected by partial least squares discrimination analysis (PLS-DA), and t-test with false discovery rate (FDR) correction. Metabolomics pathway analysis (MetPA) was employed to construct metabolic pathways. Results: There were 55 MM patients, including 34 males and 21 females. The median age was 60 years old (42-73 years old). There were 30 cases of IgG type, 9 cases of IgA type, 1 case of IgM type, 2 cases of non-secreted type, 1 case of double clone type and 12 cases of light chain type, including 3 cases of kappa light chain type and 9 cases of lambda light chain type. The result of QC sample test showed that the proportion of compounds with the RSD of the relative content of metabolites < 15% was 70.21% obtained by the reproducibility of GC-MS experimental data, which implied that the experimental data were reliable. A total of 17 metabolites were screened differently with the healthy control group, including myristic acid, hydroxyproline, cysteine, palmitic acid, L-leucine, stearic acid, methionine, phenylalanine, glycerin, serine, isoleucine, tyrosine, valine, citric acid, inositol, threonine, and oxalic acid (VIP>1, P<0.05). Metabolic pathway analysis suggested that metabolic disorders in MM patients comprised mainly phenylalanine metabolism, glyoxylic acid and dicarboxylic acid metabolism, phosphoinositide metabolism, cysteine and methionine metabolism, glycerolipid metabolism, glycine, serine, and threonine metabolism. Conclusion: Compared with normal people, patients with newly diagnosed MM have obvious differences in metabolic profiles and metabolic pathways.
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Cisteína , Mieloma Múltiplo , Masculino , Feminino , Humanos , Pessoa de Meia-Idade , Adulto , Idoso , Mieloma Múltiplo/diagnóstico , Reprodutibilidade dos Testes , Metaboloma , Metabolômica/métodos , Redes e Vias Metabólicas , Metionina , Serina , Fenilalanina , Treonina , BiomarcadoresRESUMO
Gastric cancer (GC) is a kind of global malignancy. However, the expression pattern and clinical relevance of lamin B1 in GC remain to be elucidated. We endeavored to investigate how GC is influenced by lamin B1 and the related mechanisms. The lamin B1 expression in GC tissues from 71 patients was assessed by using immunohistochemistry (IHC). The expression of lamin B1 was connected with the clinical stage, depth of invasion, and poorer overall survival. Colony formation assays and methyl thiazolyl tetrazolium (MTT) were used to assess cell viability. The migration ability of GC cells was determined by cell scratch assay and Transwell invasion assay. Moreover, we used two cell lines of GC to explore the underlying mechanism of lamin B1 in boosting the GC cells proliferation and invasion in vitro by assessing the effects on related signal transduction pathways. Our data demonstrated that the expression level of lamin B1 was downregulated in GC tissues, and low expression level of lamin B1 was significantly correlated with higher clinical stage, depth of invasion, nodal stage, and poor prognosis. Moreover, in vitro experiments demonstrated that lamin B1 knockdown promoted, whereas lamin B1 overexpression inhibited, gastric cancer cell proliferation and migration. We also observed that lamin B1 knockdown could promote the activity of the PI3K/PTEN/Akt and MAPK/ERK pathway with a decrease in the p53/p21WAF1/CIP1 expression, whereas lamin B1 overexpression contributed to the opposite results. In conclusion, our studies indicate that lamin B1 deficiency is crucial in GC progression. Furthermore, the results elucidating the biological mechanisms of lamin B1 may potentially contribute to current GC treatment modalities.
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Lamina Tipo B/genética , Neoplasias Gástricas , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/genéticaRESUMO
We experimentally report the generation of wavelength-tunable blueshifting soliton in the visible spectral region through a gas-filled single-ring photonic crystal fiber (SR-PCF). In particular, in a He-filled SR-PCF, we observed a sharp narrow-band spectral peak at the first resonant spectral region of the SR-PCF, which results from phase-matched nonlinear processes. To the best of our knowledge, this is the first time investigating the influence of the core-cladding resonance on the blueshifting soliton. In addition, when Ar gas was filled into the SR-PCF, some interference fringes on the blueshifting soliton were observed at high pulse-energy levels due to plasma-induced pulse fission. These two experimental observations are confirmed by numerical simulations. Furthermore, through properly adjusting input pulse energy, we found that the blueshifting soliton can obtain a high conversion efficiency (â¼84%) and its wavelength can be tuned over hundreds of nanometers (â¼240 nm).
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Objective: To determine the clinical benefits of internal mammary sentinel lymph node biopsy (IM-SLNB) acquired by breast cancer patients with clinically positive axillary lymph node (ALN), and further optimize the IM-SLNB indications. Methods: All primary breast cancer patients with clinically positive ALN from February 2014 to September 2017 were prospectively recruited in this study. IM-SLNB was performed under the guidance of the modified injection technique. The success rate and visualization rate of IM-SLNB, metastatic rate of internal mammary sentinel lymph node (IMSLN) and its related factors were analyzed, and the clinical benefits were accessed according to the current guidelines. Results: Among 126 patients, all of 94 patients (74.6%) who showed internal mammary drainage successfully underwent IM-SLNB. The incidence of internal mammary artery bleeding and pleural lesion were 4.3%(4/94) and 9.6%(9/94), respectively. The metastatic rate of IMSLN was 38.3% (36/94), which was significantly associated with the number of positive ALN (P<0.001) and tumor size (P=0.024). The lymph node staging of 94 patients who underwent IM-SLNB was more accurate. Among them, 36 cases with positive IMSLN underwent internal mammary radiotherapy (IMRT), while the other 58 cases with negative IMSLN avoided radiotherapy. Conclusions: IM-SLNB should be routinely performed in patients with positive ALN. IM-SLNB can provide more accurate staging and guide tailored IMRT to benefit more breast cancer patients.
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Neoplasias da Mama/patologia , Biópsia de Linfonodo Sentinela , Axila , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Metástase Linfática , Estadiamento de Neoplasias , Medicina de Precisão , Estudos Prospectivos , Linfonodo Sentinela/patologia , Biópsia de Linfonodo Sentinela/efeitos adversos , Biópsia de Linfonodo Sentinela/estatística & dados numéricosRESUMO
Objectives: This study aimed to assess the efficacy and safety of bendamustine in combination with rituximab (BR regimen) for the treatment of newly diagnosed indolent B-cell non-Hodgkin's lymphoma (B-iNHL) and elderly mantle cell lymphoma (eMCL) . Methods: From December 1, 2020 to September 10, 2022, a multi-center prospective study was conducted across ten Grade A tertiary hospitals in Shandong Province, China. The BR regimen was administered to evaluate its efficacy and safety in newly diagnosed B-iNHL and eMCL patients, and all completed at least four cycles of induction therapy. Results: The 72 enrolled patients with B-iNHL or MCL were aged 24-74 years, with a median age of 55 years. Eastern Cooperative Oncology Group (ECOG) performance status scores of 0-1 were observed in 76.4% of patients, while 23.6% had scores of 2. Disease distribution included follicular lymphoma (FL) (51.4% ), marginal zone lymphoma (MZL) (33.3% ), eMCL (11.1% ), and the unknown subtype (4.2% ). According to the Ann Arbor staging system, 16.7% and 65.3% of patients were diagnosed with stage â ¢ and stage â £ lymphomas, respectively. Following four cycles of BR induction therapy, the overall response rate was 98.6%, with a complete response (CR) rate of 83.3% and a partial response (PR) rate of 15.3%. Only one eMCL patient experienced disease progression during treatment, and only one FL patient experienced a relapse. Even when evaluated using CT alone, the CR rate was 63.9%, considering the differences between PET/CT and CT assessments. The median follow-up duration was 11 months (range: 4-22), with a PFS rate of 96.8% and an OS rate of 100.0%. The main hematologic adverse reactions included grade 3-4 leukopenia (27.8%, with febrile neutropenia observed in 8.3% of patients), grade 3-4 lymphopenia (23.6% ), grade 3-4 anemia (5.6% ), and grade 3-4 thrombocytopenia (4.2% ). The main non-hematologic adverse reactions such as fatigue, nausea/vomiting, rash, and infections occurred in less than 20.0% of patients. Conclusion: Within the scope of this clinical trial conducted in China, the BR regimen demonstrated efficacy and safety in treating newly diagnosed B-iNHL and eMCL patients.
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Leucopenia , Linfoma Folicular , Linfoma de Célula do Manto , Idoso , Humanos , Adulto , Pessoa de Meia-Idade , Rituximab/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Estudos Prospectivos , Cloridrato de Bendamustina/uso terapêutico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Recidiva Local de Neoplasia , ChinaRESUMO
Gynogenesis was induced by using UV-irradiated spermatozoa of blunt snout bream Megalobrama amblycephala to activate eggs of common carp Cyprinus carpio. The maternal genome was then duplicated by cold shock in 0 to 4° C cold water to retain the second polar body. Two kinds of fry, normal fry and abnormal tortuous fry, were hatched. Their DNA content was measured by flow cytometry. The normal fry were identified as diploid, representing the successful gynogenesis in C. carpio whereas the abnormal tortuous fry were haploid. Ten microsatellite loci were used to study the genetic diversity among C. carpio, diploid gynogenetic C. carpio and unduplicated haploid tortuous fry. The results indicated that the genetic homozygosity of gynogenetic C. carpio was significantly higher than that of C. carpio. The genetic homozygosity of the haploid C. carpio was intermediate between that of gynogenetic C. carpio and C. carpio. It might be easier for the allogenetic DNA fragments to be integrated into the haploid genome than into diploid gynogenetic genome.
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Carpas/genética , Repetições de Microssatélites , Ploidias , Animais , Carpas/anatomia & histologia , DNA/análise , Feminino , Masculino , Ovário/anatomia & histologia , PartenogêneseRESUMO
Objective: To observe hippocampal damage and cognitive impairment of offspring exposed to prenatal maternal seizure induced by amygdala kindling, and to explore the underlying mechanism by the detection of pathological changes of placenta. Method: Adult female SD rats were randomly divided into three groups: control group(8 rats), kindling group(12 rats) and sham group(8 rats). All the rats were allowed to mate after one week's fully kindling. The pregnant rats in kindling group received electric stimulation every 48 h. Dams were allowed to deliver naturally. Effects of maternal seizure on the number of offspring, the survival rate and body weight of pups were observed. HE staining was used to visualize histopathological changes of placenta. Morris water maze test was used to assess the cognitive function and Nissal's staining to detect hippocampal morphology of the offspring. One-way ANOVA analysis and χ2 test were used. Result: Compared with the sham group (95%(78/82)) and the control group (95%(82/86)), the survival rate of pups in kindling group(81%(66/82))was much lower (χ2=13.817, P=0.001). There were no significant differences in the number of pups per litter and pups birth-weight between kindling group and sham group or control group(F=0.312 and 0.257, P=0.736 and 0.776). HE staining showed that placental tissues from control and sham groups were normal whereas the histologic abnormalities of placentas from kindling group were characterized by thickening of the villus vascular walls, luminal stenosis, trophoblasts hyperplasia, abnormalities of trophoblasts with nuclear pyknosis and karyorrhexis and accumulation of inflammatory lymphocytes in labyrinthine zone. Nissl staining showed that neurons in hippocampus of P0(0 d after birth) and P84(84 d after birth) offspring from control and sham groups were normal, but neuronal damages were obvious in hippocampus of P0 and P84 offspring from kindling groups, and the damages in P0 pups were severe with a marked loss of neuron, shrinkage of cells and nuclear pyknosis and karyorrhexis. In the Morris water maze, compared with the sham group ((29±8), (19±9), (10±4)s) and the control group ((25±6), (17±5), (14±4)s) rats in the kindling group ((36±8), (29±8), (30±11)s) exhibited significantly longer escape latency from the 3rd, 4th, and 5th days (F=6.276, 7.518, 18.422, P=0.030, 0.003, 0.000), significant less time in the target quadrant ((27±8) vs.(58±11)and(68±13)s, F=35.993, P=0.000) and reduced number of crossing the platform ((4.4±1.7) vs. (7.2±1.6) and (8.5±1.3)times, F=18.377, P=0.000). In addition, there was no significant difference between control and sham groups(P all >0.05). Conclusion: The prenatal maternal seizures induced significant pathological damages to hippocampus and cognitive impairment of offspring. Hypoxia-ischemia of placenta might play an important role in this process.
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Cognição , Hipocampo/patologia , Convulsões/complicações , Animais , Feminino , Excitação Neurológica , Masculino , Neurônios , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Sprague-DawleyRESUMO
Autoantibodies to cardiac beta1-adrenoceptors and M2-muscarinic receptors have mainly been found in the sera of patients with idiopathic dilated cardiomyopathy (DCM). In order to elucidate the pathological significance of these autoantibodies in DCM, it is necessary to understand their characteristic distribution in a healthy population of different genders and ages. The peptides corresponding to the sequences of the second extracellular loops of the human beta1-adrenoceptor and M2-muscarinic receptors were therefore used as antigens to screen the sera of 408 healthy subjects of different ages (ranging from 0.5 to 85 years). Of 408 sera, 41 (10.0%) and 46 (11.3%) recognized the beta1-adrenoceptor and M2-muscarinic receptor peptides respectively. Of the positive sera for beta1-adrenoceptors and M2-muscarinic receptors, up to 63.4% and 56.5% had both anti-beta1-adrenoceptor and anti-M2-muscarinic receptor autoantibodies respectively. The antibody titres of the positive sera of healthy subjects were all of a low level, with a geometric mean titre of 1:42+/-1.9 for anti-beta1-adrenoceptor antibodies and 1:51+/-1.7 for anti-M2-muscarinic receptor antibodies. The frequency of occurrence of autoantibodies to both receptors in the sera of healthy subjects increased significantly with age. In conclusion, the autoantibodies to beta1-adrenoceptors and M2-muscarinic receptors in the sera of healthy subjects are characterized by a low frequency of occurrence and low titre, with the frequency of occurrence increasing with age.
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Autoanticorpos/sangue , Miocárdio/imunologia , Receptores Adrenérgicos beta 1/imunologia , Receptores Muscarínicos/imunologia , Adolescente , Adulto , Fatores Etários , Idoso , Cardiomiopatia Dilatada/etiologia , Cardiomiopatia Dilatada/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Receptor Muscarínico M2 , Fatores SexuaisRESUMO
This study evaluated the coronary dopamine receptors by using the dopamine D1 receptor agonist fenoldopam, dopamine D2 receptor agonist propylbutyldopamine, and their selective antagonists SCH23390 and domperidone. Left circumflex coronary flow (CF), coronary perfusion pressure at constant flow, left ventricular hemodynamics, and total peripheral vascular resistance (TPR) were measured in pentobarbital-anesthetized dogs at constant arterial pressures. At doses of 200, 500 and 5000 nM, both fenoldopam and propylbutyldopamine induced dose-related inotropic effects, as evidenced by maximal dp/dt and cardiac output, an increase in CF, decrease in coronary vascular resistance and a decrease in TPR. Fenoldopam was more potent in its cardiac and coronary effects while propylbutyldopamine was more potent peripherally. On the basis of dosage used, the positive inotropic effects of fenoldopam and propylbutyldopamine were much weaker than dopamine. After beta-receptor blockade, the inotropic and coronary effects of fenoldopam and propylbutyldopamine were extremely attenuated. Domperidone could largely antagonize the propylbutyldopamine-induced inotropic and coronary effects while SCH23390 showed no significant effect. In addition, under our experimental conditions, the fenoldopam- and propylbutyldopamine-induced decreases in TPR were markedly reduced by SCH23390 and domperidone, respectively. The results indicate that the coronary effects of fenoldopam and propylbutyldopamine result not from a primary coronary vasodilating action, but from vasodilation secondary to positive inotropic effects. Both dopamine D1 and dopamine D2 receptors are involved in the peripheral vascular hemodynamics.
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Circulação Coronária/efeitos dos fármacos , Dopaminérgicos/farmacologia , Receptores Dopaminérgicos/efeitos dos fármacos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Animais , Benzazepinas/farmacologia , Fármacos Cardiovasculares/farmacologia , Cães , Domperidona/farmacologia , Dopamina/análogos & derivados , Dopamina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Coração/efeitos dos fármacos , Técnicas In Vitro , Masculino , Resistência Vascular/efeitos dos fármacosRESUMO
Previous studies of myocardium have shown that ischemic preconditioning could be mimicked by nitroglycerin through stimulating the release of calcitonin gene-related peptide (CGRP). The present study examined whether nitroglycerin could also provide a preconditioning stimulus in the peripheral vascular bed (the anse intestinalis of rat), and whether endogenous CGRP is involved in this process. The model of in situ perfusion was prepared with rat small intestine. One hour of ischemia and 15 min of reperfusion caused a significant impairment of intestinal morphology and an increase in the release of both lactate dehydrogenase and malondialdehyde. Pretreatment with nitroglycerin, 10(-7), 3 x 10(-7), 10(-6) M for 5 min produced a significant improvement of intestinal tissue morphology and a decrease in the release of both lactate dehydrogenase and malondialdehyde. However, the protection afforded by nitroglycerin was abolished by CGRP-(8-37), a selective CGRP acceptor antagonist. Pretreatment with capsaicin, which specifically depletes the transmitter content of sensory nerves, also abolished the protection by nitroglycerin. In addition, the content of CGRP-like immunoreactivity in the effluent was increased during nitroglycerin perfusion. On the other hand, the results from the in vivo experiment showed that nitroglycerin (i.v. 0.13 mg/kg) injected 5 min before prolonged ischemia could provide significant protection against the injury caused by 30-min ischemia and 1-h reperfusion in the rat small intestine, but would also cause a significant increase in the levels of CGRP in the plasma. All these findings suggest that nitroglycerin-induced preconditioning is related to stimulation of CGRP release in the rat small intestine.
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Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Intestino Delgado/efeitos dos fármacos , Precondicionamento Isquêmico , Nitroglicerina/farmacologia , Vasodilatadores/farmacologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/sangue , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Capsaicina/farmacologia , Relação Dose-Resposta a Droga , Hemorragia Gastrointestinal/prevenção & controle , Enteropatias/prevenção & controle , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Intestino Delgado/irrigação sanguínea , Intestino Delgado/fisiopatologia , L-Lactato Desidrogenase/efeitos dos fármacos , L-Lactato Desidrogenase/metabolismo , Masculino , Malondialdeído/metabolismo , Fragmentos de Peptídeos/farmacologia , Perfusão , Ratos , Ratos Wistar , Índice de Gravidade de Doença , Fatores de TempoRESUMO
By using radioreceptor binding techniques and [3H]SCH23390 as a ligand, a comparative study was performed on the pharmacological properties and the density of dopamine-1 (D1) receptors in different vascular systems. [3H]SCH23390 was specifically bound to membranes from rabbit renal, mesenteric and pulmonary, but not femoral, arteries. The binding was saturable and in a manner consistent with the labeling of D1 receptors. The Kd value and Hill coefficient (nH) were similar in all three arteries with no statistically significant differences (p > 0.05) among them, indicating a homogenous binding site with a single class of high affinity. In competitive binding tests, the selective D1 antagonist and agonist inhibited the binding much more potently than the D2 antagonist, indicating a pharmacological characteristic of D1 receptors. The Bmax values, however, differed considerably among these arteries, with the value being the largest in the renal artery and smallest in the pulmonary artery. These findings are indicative of the existence of D1 receptor sites with identical properties but diverse density in different vascular beds, which underlies the relative functional importance of the receptors in regulating local blood flow in distinct vessels.
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Benzazepinas/metabolismo , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Receptores de Dopamina D1/metabolismo , Animais , Ligação Competitiva , Domperidona/farmacologia , Relação Dose-Resposta a Droga , Feminino , Fenoldopam/farmacologia , Técnicas In Vitro , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Coelhos , Ensaio Radioligante , Receptores de Dopamina D1/efeitos dos fármacos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Artéria Renal/efeitos dos fármacos , Artéria Renal/metabolismo , Trítio/metabolismoRESUMO
The effects of insulin-like growth factor I (IGF-I) on cardiomyocyte apoptosis induced by hypoxia in cultured neonatal rat cardiomyocyte were investigated. Primary neonatal rat cardiomyocytes were cultured in 95% N2-5% CO2 to imitate the in vivo hypoxic condition. Electron microscopic observation revealed a series of typical morphological changes characteristic of apoptosis in cardiomyocytes under the hypoxic condition. DNA gel electrophoresis showed DNA laddering in an ischemic duration-dependent manner. The hypoxia-induced cardiomyocyte apoptosis was also evidenced by flow cytometry and TUNEL assay. DNA gel electrophoresis showed that IGF-I in a dose range of 10(-9)-10(-7) mol/l could significantly prevent the hypoxia-induced cardiomyocyte apoptosis. The protective effects of IGF-I against hypoxia-induced apoptosis could also be verified by flow cytometry and TUNEL assay. A tyrosine kinase inhibitor (genistein), a MAPK inhibitor (PD-098059) and a P13 kinase inhibitor (wortmannin) could also suppress the antiapoptotic effects of IGF-I. These results suggest that IGF-I can directly alleviate the hypoxia-induced cardiomyocyte apoptosis and that the three kinase routes mentioned above may be involved in its signaling pathways.
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Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Coração/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Transdução de Sinais/efeitos dos fármacos , Androstadienos/farmacologia , Animais , Células Cultivadas , Fragmentação do DNA/efeitos dos fármacos , Eletroforese em Gel Bidimensional , Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Citometria de Fluxo , Genisteína/farmacologia , Coração/fisiologia , Hipóxia/fisiopatologia , Marcação In Situ das Extremidades Cortadas , Microscopia Eletrônica , Miocárdio/citologia , Miocárdio/ultraestrutura , Ratos , Transdução de Sinais/fisiologia , WortmaninaRESUMO
To further evaluate the functional significance of dopamine (DA) receptors in different vasculature, in this study we compared the effects of D1- and D2-receptor agonists on canine coronary and renal arteries by measuring adenylate cyclase (AC) activity as a biomedical index of DA receptor function. It was found that both the selective D1-receptor agonist, fenoldopam, and the D2-receptor agonist, propyl-butyl-dopamine (PBDA), induced a dose-related increases in cAMP formation in coronary and renal arteries; however, the magnitude of increase in the renal artery was remarkably greater than that in the coronary artery. The stimulatory effect on AC activity of fenoldopam was significantly more potent than that of PBDA. The selective D1-receptor antagonist, SCH23390, blocked fenoldopam- and PBDA-induced cAMP production, while the selective D2-receptor antagonist, domperidone, was without effect on the increase of cAMP elicited by PBDA. After beta-adrenergic blockade with propranolol, fenoldopam still increased the cAMP level significantly but to a much lesser degree. The existence of postsynaptic D2-receptor associated with inhibition of cAMP formation could not be demonstrated in this study. These data suggest the presence of D1-receptors associated with stimulation of AC activity in both renal and coronary arteries. However, there are much fewer receptor sites in the coronary artery than in the renal artery, suggesting less physiological importance of such receptors in the coronary artery than in the renal artery.
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Vasos Coronários/metabolismo , AMP Cíclico/biossíntese , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia , Artéria Renal/metabolismo , Animais , Benzazepinas/farmacologia , Vasos Coronários/efeitos dos fármacos , Cães , Dopamina/análogos & derivados , Dopamina/farmacologia , Feminino , Fenoldopam/farmacologia , Técnicas In Vitro , Masculino , Propranolol/farmacologia , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , Artéria Renal/efeitos dos fármacosRESUMO
The mechanisms responsible for the cardiac positive inotropic effects of dopexamine hydrochloride, a combined dopamine receptor agonist at both D1-receptors and beta 2-adrenoceptors, were studied. The calcium channel currents were recorded using whole-cell patch clamp technique in isolated guinea pig ventricular myocytes. At a holding potential of -40 mV, cells were depolarized to 0 mV for 400 ms at a frequency of 0.2 Hz. Dopexamine hydrochloride at doses of 5, 50 and 100 microM increased the verapamil-sensitive Ca2+ inward current by 109, 147 and 194%, respectively. The effects of dopexamine hydrochloride on Ca2+ current reached its maximum at 5 min and partially recovered after washout of the drugs. The increased Ca2+ current induced by dopexamine hydrochloride was completely inhibited by 20 microM propranolol, a beta-adrenoceptor antagonist, and was not antagonized by 20 microM of SCH23390, a highly selective D1-receptor antagonist. These results suggest that the cardiac positive inotropic effects of dopexamine hydrochloride are brought about by the increase of Ca2+ current via stimulation of beta 2-adrenoceptors.
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Agonistas Adrenérgicos beta/farmacologia , Canais de Cálcio/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Dopamina/análogos & derivados , Ventrículos do Coração/efeitos dos fármacos , Miocárdio/citologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Benzazepinas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Cobaias , Contração Miocárdica/efeitos dos fármacos , Técnicas de Patch-Clamp , Propranolol/farmacologia , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Verapamil/farmacologiaRESUMO
Previous studies have shown that ischemia and reperfusion are potent stimuli for eliciting cardiomyocyte apoptosis, and that polymorphonuclear leukocytes (PMNs) are involved in the development of myocardial injury induced by ischemia and reperfusion. The present study examined whether PMN could directly induce cardiomyocyte apoptosis and, if so, it possible signal transduction pathways. In addition, we also investigated the effects of carvedilol, a potent antioxidant, on PMN-induced apoptosis. Cultured primary neonatal rat cardiomyocytes were exposed to PAF-activated PMNs at concentrations of 10(5), 3 x 10(5) and 10(6) cells/well for 48 h. Multiple detecting techniques, including electron microscopy, DNA gel electrophoresis. TUNEL assay and flow cytometry were used to identify myocyte apoptosis. All of these techniques demonstrated that activated PMNs directly induced cardiomyocyte apoptosis in a concentration-dependent manner, while unactivated PMNs showed no such effect. Activated PMN-induced apoptosis was partially inhibited by SB203580, a specific inhibitor of the p38-MAPK signaling system. Carvedilol (at a dose range of 1-10 mumol/l) significantly prevented activated PMN-induced cardiomyocyte apoptosis. These results suggest that PMNs, when activated, directly induce cardiomyocyte apoptosis and that the p38-MAPK signaling pathway might be involved in this process. Carvedilol may prevent PMN-induced apoptosis possibly because of its antioxidant properties.
Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Carbazóis/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Fator de Ativação de Plaquetas/farmacologia , Propanolaminas/farmacologia , Animais , Animais Recém-Nascidos , Carvedilol , Células Cultivadas , Fragmentação do DNA , Inibidores Enzimáticos/farmacologia , Citometria de Fluxo/métodos , Imidazóis/farmacologia , Marcação In Situ das Extremidades Cortadas/métodos , Microscopia Eletrônica , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Neutrófilos/ultraestrutura , Piridinas/farmacologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
The coronary flow (CF) at constant perfusion pressure and other hemodynamic variables were measured in anesthetized open-chest dogs. At the same doses of 20, 100, 500 and 2000 nM, the dopamine-1 receptor agonist, fenoldopam, was much more potent than dopamine-2 receptor agonist, N-n-propyl-N-n-butyl dopamine (PBDA), in increasing CF. Under conditions of constant systemic arterial pressure, fenoldopam produced a dose-related increase in maximal +dp/dt (dp/dt) and CF. After adrenergic blockade (combined alpha- and beta-adrenoceptor blockade), however, both cardiac and coronary effects of fenoldopam were greatly attenuated. The coronary effects of both dopamine agonists under uncontrolled arterial pressure were apparently greater than those under constant arterial pressure. Under conditions of uncontrolled arterial pressure and after adrenergic blockade, fenoldopam induced a dose-related decrease in mean arterial pressure (MAP) and corresponding increase in CF. SCH23390 and domperidone markedly inhibited the coronary effects of fenoldopam and PBDA, respectively. Our data suggest that the coronary effects of fenoldopam are predominantly secondary to the fenoldopam-induced decrease in total peripheral resistance (TPR) at small doses and to its positive inotropic action at large doses, while the primary dopaminergic coronary vasodilation plays only a minor role and therefore cannot be of physiological importance in regulating CF.