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1.
Acta Pharmacol Sin ; 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31165783

RESUMO

Obesity induces accumulation of adipose tissue macrophages (ATMs) and ATM-driven inflammatory responses that promote the development of glucose and lipid metabolism disorders. ClC-3 chloride channel/antiporter, encoded by the Clcn3, is critical for some basic cellular functions. Our previous work has shown significant alleviation of type 2 diabetes in Clcn3 knockout (Clcn3-/-) mice. In the present study we investigated the role of Clcn3 in high-fat diet (HFD)-induced obesity and ATM inflammation. To establish the mouse obesity model, both Clcn3-/- mice and wild-type mice were fed a HFD for 4 or 16 weeks. The metabolic parameters were assessed and the abdominal total adipose tissue was scanned using computed tomography. Their epididymal fat pad tissue and adipose tissue stromal vascular fraction (SVF) cells were isolated for analyses. We found that the HFD-fed Clcn3-/- mice displayed a significant decrease in obesity-induced body weight gain and abdominal visceral fat accumulation as well as an improvement of glucose and lipid metabolism as compared with HFD-fed wild-type mice. Furthermore, the Clcn3 deficiency significantly attenuated HFD-induced ATM accumulation, HFD-increased F4/80+ CD11c+ CD206- SVF cells as well as HFD-activated TLR-4/NF-κB signaling in epididymal fat tissue. In cultured human THP-1 macrophages, adenovirus-mediated transfer of Clcn3 specific shRNA inhibited, whereas adenovirus-mediated cDNA overexpression of Clcn3 enhanced lipopolysaccharide-induced activation of NF-κB and TLR-4. These results demonstrate a novel role for Clcn3 in HFD-induced obesity and ATM inflammation.

2.
Acta Pharmacol Sin ; 39(5): 875-884, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29595193

RESUMO

Xyloketal B (Xyl-B) is a novel marine compound isolated from mangrove fungus Xylaria sp. (No 2508). We previously showed that Xyl-B promoted endothelial NO release and protected against atherosclerosis through the Akt/eNOS pathway. Vascular NO production regulates vasoconstriction in central and peripheral arteries and plays an important role in blood pressure control. In this study, we examined whether Xyl-B exerted an antihypertensive effect in a hypertensive rat model, and further explored the possible mechanisms underlying its antihypertensive action. Administration of Xyl-B (20 mg·kg-1·d-1, ip, for 12 weeks) significantly decreased the systolic and diastolic blood pressure in a two-kidney, two-clip (2K2C) renovascular hypertensive rats. In endothelium-intact and endothelium-denuded thoracic aortic rings, pretreatment with Xyl-B (20 µmol/L) significantly suppressed phenylephrine (Phe)-induced contractions, suggesting that its vasorelaxant effect was attributed to both endothelial-dependent and endothelial-independent mechanisms. We used SNP, methylene blue (MB, guanylate cyclase inhibitor) and indomethacin (IMC, cyclooxygenase inhibitor) to examine which endothelial pathway was involved, and found that MB, but not IMC, reversed the inhibitory effects of Xyl-B on Phe-induced vasocontraction. Moreover, Xyl-B increased the endothelial NO bioactivity and smooth muscle cGMP level, revealing that the NO-sGC-cGMP pathway, rather than PGI2, mediated the anti-hypertensive effect of Xyl-B. We further showed that Xyl-B significantly attenuated KCl-induced Ca2+ entry in smooth muscle cells in vitro, which was supposed to be mediated by voltage-dependent Ca2+ channels (VDCCs), and reduced ryanodine-induced aortic contractions, which may be associated with store-operated Ca2+ entry (SOCE). Taken together, these findings demonstrate that Xyl-B exerts significant antihypertensive effects not only through the endothelial NO-sGC-cGMP pathway but also through smooth muscle calcium signaling, including VDCCs and SOCE.


Assuntos
Anti-Hipertensivos/uso terapêutico , Sinalização do Cálcio/efeitos dos fármacos , Hipertensão Renovascular/tratamento farmacológico , Piranos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Cálcio/metabolismo , GMP Cíclico/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Azul de Metileno/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos Sprague-Dawley , Guanilil Ciclase Solúvel/metabolismo , Vasodilatadores/uso terapêutico
3.
Biochem Biophys Res Commun ; 490(2): 91-97, 2017 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-28526415

RESUMO

LNK (SH2B3) is an intracellular adaptor protein that negatively regulates cellular proliferation or self-renewal of hematopoietic stem cells and some other progenitor cells. LNK is also recognized as a key regulator of insulin resistance and inflammatory responses in several tissues and organs. The function of LNK in adipose tissue is unknown. We previously demonstrated that type 2 diabetes mellitus (T2DM) mouse model had elevated serum free fatty acids (FFAs) levels and increased preadipocyte apoptosis in visceral fat tissue, showing the occurrence of lipotoxicity. Herein, when compared to control mice, the protein expression of LNK decreased in epididymal fat tissue from the high-sucrose/fat diet, low-dose streptozotocin induced T2DM mouse model. We thus investigated whether LNK could regulate palmitate-induced preadipocyte apoptosis in an in vitro apoptotic model in 3T3-L1 preadipocytes. LNK specific siRNA exacerbated palmitate-induced apoptosis and increased pro-apoptotic protein levels of cleaved caspase-3, Bax and cytochrome C; while overexpression of LNK cDNA exhibited significant anti-apoptotic effects. Consistently, LNK specific siRNA further decreased the Akt Ser-473 phosphorylation reduced by palmitate and located on upstream of Bax and cytochrome C. The siRNA-mediated LNK knockdown exacerbated mitochondrial membrane depolarization and mitochondrial-derived reactive oxygen species production induced by palmitate, whereas overexpression of LNK attenuated that. These results indicated that LNK plays a regulatory role in the palmitate-related preadipocyte apoptosis and might be involved in adipose tissue dysfunction.


Assuntos
Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Palmitatos/farmacologia , Adipócitos/metabolismo , Animais , Diabetes Mellitus Tipo 2/induzido quimicamente , Dieta Hiperlipídica , Sacarose na Dieta , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estreptozocina
4.
BMC Cancer ; 14: 744, 2014 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-25280428

RESUMO

BACKGROUND: Peripheral blood monocyte count is an easily assessable parameter of systemic inflammatory response. The aim of this study was to determine whether monocyte count was prognostic in hepatocellular carcinoma (HCC) following hepatic resection. METHODS: We retrospectively reviewed 351 patients with HCC treated with hepatic resection from 2006 to 2009. Preoperative absolute peripheral monocyte count, demographics, and clinical and pathological data were analyzed. RESULTS: On univariate and multivariate analysis, elevated monocyte counts (≥ 545/mm(3)), tumor size ≥ 5 cm, non-capsulation, and multiple tumors were associated with poor disease-free survival (DFS) and overall survival (OS). The 1-, 3- and 5-year DFS rates were 58%, 41% and 35%, respectively, for patients with monocyte counts <545/mm(3), and 36%, 23% and 21% for patients with monocyte counts ≥ 545/mm(3). Correspondingly, the 1-, 3- and 5-year OS rates were 79%, 53% and 46% for monocyte counts <545/mm(3), and 64%, 36% and 29% for monocyte counts ≥ 545/mm(3). Subgroup analysis indicated that DFS after hepatic resection in hepatitis B virus (HBV)-infected patients was significantly better in those with a peripheral blood monocyte counts <545/mm(3), but it did not differ between patients without HBV infection. In addition, DFS was significantly better for patients with a peripheral blood monocyte count <545/mm(3), whether or not cirrhosis was present. Patients with elevated monocyte counts tended to have larger tumors. CONCLUSIONS: Elevated preoperative monocyte count is an independent predictor of worse prognosis for patients with HCC after hepatic resection, especially for those with HBV infection. Postoperative adjuvant treatment might be considered for patients with elevated preoperative monocyte counts.


Assuntos
Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/patologia , Monócitos/fisiologia , Adulto , Idoso , Carcinoma Hepatocelular/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Contagem de Leucócitos , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Adulto Jovem
5.
Cardiovasc Pathol ; 22(5): 401-7, 2013 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23375582

RESUMO

Vascular fibrosis, characterized by reduced lumen diameter and arterial wall thickening attributable to excessive deposition of extracellular matrix (ECM), links with many clinical diseases and pathological progresses including atherosclerosis. It involves proliferation of vascular smooth muscle cell (VSMC), accumulation of ECM and inhibition of matrix degradation. The risk factors associated with cardiovascular disease, including hypertension, hyperglycemia, dyslipidemia and hyperhomocysteinemia (HHcy), are also suggested as initiation and progression factors of vascular fibrosis. Vascular fibrosis has been found to relate to renin-angiotensin-aldosterone system (RAAS), oxidative stress, inflammatory factors, growth factors and imbalance of endothelium-derived cytokine secretion. Angiotensin II (Ang II) and aldosterone, the circulating effector hormones of RAAS, are recognized as responsible for the pathophysiology of vascular fibrosis. Transforming growth factor-beta (TGF-beta) plays a critical role in ECM accumulation and vascular remodeling via up-regulating the production of several agents including connective tissue growth factor (CTGF) and fibroblast growth factor. An imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) results in collagen accumulation and adverse matrix remodeling. Aberrant expression or function of peroxisome proliferator-activated receptor gamma (PPAR gamma) is also associated with, and very likely contributes to, the progression of pathological fibrosis and vascular remodeling. In this review, we discuss the pathogenesis of vascular fibrosis in atherosclerosis with focus on the networking among main responsible mediators. The main pathophysiologic factors leading to vascular fibrosis will also be discussed.


Assuntos
Aterosclerose/patologia , Aterosclerose/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Dislipidemias/complicações , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Fibrose , Humanos , Hiperglicemia/complicações , Hiper-Homocisteinemia/complicações , Hipertensão/complicações , Metaloproteinases da Matriz/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , PPAR gama/metabolismo , Sistema Renina-Angiotensina , Fatores de Risco , Fator de Crescimento Transformador beta/metabolismo
6.
PLoS One ; 7(11): e49758, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23185428

RESUMO

Endothelial injury related to oxidative stress is a key event in cardiovascular diseases, such as hypertension and atherosclerosis. The activation of the redox-sensitive Kv1.5 potassium channel mediates mitochondrial reactive oxygen species (ROS)-induced apoptosis in vascular smooth muscle cells and some cancer cells. Kv1.5 channel is therefore taken as a new potential therapeutic target for pulmonary hypertension and cancers. Although Kv1.5 is abundantly expressed in vascular endothelium, there is little knowledge of its role in endothelial injury related to oxidative stress. We found that DPO-1, a specific inhibitor of Kv1.5, attenuated H(2)O(2)-evoked endothelial cell apoptosis in an in vivo rat carotid arterial model. In human umbilical vein endothelial cells (HUVECs) and human pulmonary arterial endothelial cells (HPAECs), angiotensin II and oxLDL time- or concentration-dependently enhanced Kv1.5 protein expression in parallel with the production of intracellular ROS and endothelial cell injury. Moreover, siRNA-mediated knockdown of Kv1.5 attenuated, whereas adenovirus-mediated Kv1.5 cDNA overexpression enhanced oxLDL-induced cellular damage, NADPH oxidase and mitochondria-derived ROS production and restored the decrease in protein expression of mitochondria uncoupling protein 2 (UCP2). Collectively, these data suggest that Kv1.5 may play an important role in oxidative vascular endothelial injury.


Assuntos
Apoptose , Células Endoteliais/citologia , Canal de Potássio Kv1.5/metabolismo , Adenoviridae/genética , Adenoviridae/metabolismo , Animais , Artérias Carótidas/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Peróxido de Hidrogênio/química , Canais Iônicos/metabolismo , Lipoproteínas LDL/metabolismo , Masculino , Proteínas Mitocondriais/metabolismo , Estresse Oxidativo , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio , Proteína Desacopladora 2
7.
Zhonghua Wei Chang Wai Ke Za Zhi ; 13(11): 814-7, 2010 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-21108056

RESUMO

OBJECTIVE: To investigate the effects of oral intake of glucose solution before surgery on the pH at the lower esophagus, perioperative blood glucose level, and plasmic protein in patients undergoing radical resection for colorectal cancer. METHODS: Between January 2008 and December 2008, 60 patients undergoing radical surgery for colorectal cancer were enrolled and randomized into three groups using the table of random digits. Four patients were withdrawn from the study. Patients in group A (n=19) were given 800 ml of 12.5% glucose solution for oral intake the night before surgery, and 200 ml two hours before surgery. Patients in group B (n=19) were given distilled water instead of glucose. Patients in group C (n=18) were asked to fast for 8-12 hours before operation. Combined general and epidural anesthesia was used. pH at the lower esophagus was monitored during intubation and extubation. Albumin, transferrin, prealbumin, insulin, and fasting blood glucose were measured before surgery and at postoperative day 1, 3, and 7. RESULTS: pH at the lower esophagus was 8.05±0.43 in group A, 7.98±0.41 in group B, and 7.94±0.41 in group C. There were no perioperative acid regurgitations (P>0.05). Serum insulin in group A at postoperative day 1 was (16.32±16.11) µU/L, which was significantly lower than that in group B (30.65±41.74) µU/L and group C (34.01±52.91) µU/L. Log HOMA-IR in group A at postoperative day 1 was significantly lower than that in group B and group C (0.49±0.35 vs. 0.59±0.56 and 0.60±0.63, P<0.05). Transferrin in group C at postoperative day 3 and 7 was significantly lower than that in the other two groups, as was albumin at postoperative day 3 (P<0.05). CONCLUSION: Oral liquid intake 2 hours before surgery is not associated with increased risk of regurgitation or aspiration during intubation and extubation, and may glucose solution intake reduce insulin resistance and protein degradation after colorectal surgery.


Assuntos
Proteínas Sanguíneas/metabolismo , Neoplasias Colorretais/metabolismo , Glucose/uso terapêutico , Resistência à Insulina , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/cirurgia , Feminino , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Período Intraoperatório , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios , Adulto Jovem
8.
Zhonghua Yi Xue Za Zhi ; 88(17): 1163-7, 2008 Apr 29.
Artigo em Chinês | MEDLINE | ID: mdl-18844108

RESUMO

OBJECTIVE: To observe the hemodynamic changes, recovery profiles, and side effects of propofol and remifentanil anesthesia by target controlled infusion (TCI). At different neurosurgical stages in patients undergoing neurosurgical operations. METHODS: 230 patients were scheduled for elective craniotomy in five hospitals in Beijing, Changsha, and Guangzhou. During the general anesthesia the plasma target-concentration of propofol remained unchangeable and the dose of remifentanil changed at different stages before skin incision, during skull opening, during intracranial procedure, and at skull closing. The hemodynamics changes and anesthetic recovery profiles were recorded. RESULTS: The plasma target-concentrations of remifentanil were set to 3.0, 3.5, 3.6 and 3.4 ng/ml respectively. The time of consciousness loss during induction was (2.0 +/- 0.9) min. The mean arterial pressure (MAP) and heart rate (HR) decreased after induction (both P < 0.05) and increased after intubation. The hemodynamic changes were stable at different surgical stages and the HR was significantly lower than the baseline value (P < 0.01). MAP and HR increased gradually when the spontaneous breathing was recovered. 80, 41, 9, and 12 patients received nicardipine, atropine, esmolol, and ephedrine respectively during the operation. The times of recovery of spontaneous breathing, eye opening, extubation, and orientation were (12 +/- 9) min, (13 +/- 7) min, (16 +/- 8) min, and (21 +/- 8) min respectively. CONCLUSION: When combined with 3 microg/ml propofol, the plasma target-concentrations of remifentanil, 3.0, 3.5, 3.6, and 3.4 ng/ml before skin incision, during skull opening, during intracranial procedure, and at skull closing respectively, can provide rapid induction, faster emergence , and better hemodynamic stability.


Assuntos
Anestésicos Intravenosos/administração & dosagem , Procedimentos Neurocirúrgicos/métodos , Piperidinas/administração & dosagem , Adolescente , Adulto , Idoso , Anestesia Intravenosa , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Propofol/administração & dosagem , Remifentanil , Fatores de Tempo , Adulto Jovem
9.
World J Gastroenterol ; 12(6): 935-9, 2006 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-16521223

RESUMO

AIM: To investigate the effect of low central venous pressure (LCVP) on blood loss during hepatectomy for hepatocellular carcinoma (HCC). METHODS: By the method of sealed envelope, 50 HCC patients were randomized into LCVP group (n=25) and control group (n=25). In LCVP group, CVP was maintained at 2-4 mmHg and systolic blood pressure (SBP) above 90 mmHg by manipulation of the patient's posture and administration of drugs during hepatectomy, while in control group hepatectomy was performed routinely without lowering CVP. The patients' preoperative conditions, volume of blood loss during hepatectomy, volume of blood transfusion, length of hospital stay, changes in hepatic and renal functions were compared between the two groups. RESULTS: There were no significant differences in patients' preoperative conditions, maximal tumor dimension, pattern of hepatectomy, duration of vascular occlusion, operation time, weight of resected liver tissues, incidence of post-operative complications, hepatic and renal functions between the two groups. LCVP group had a markedly lower volume of total intraoperative blood loss and blood loss during hepatectomy than the control group, being 903.9+/-180.8 mL vs 2 329.4+/-2 538.4 (W=495.5, P<0.01) and 672.4+/-429.9 mL vs 1 662.6+/-1 932.1 (W=543.5, P<0.01). There were no remarkable differences in the pre-resection and post-resection blood losses between the two groups. The length of hospital stay was significantly shortened in LCVP group as compared with the control group, being 16.3+/-6.8 d vs 21.5+/-8.6 d (W=532.5, P<0.05). CONCLUSION: LCVP is easily achievable in technique. Maintenance of CVP

Assuntos
Perda Sanguínea Cirúrgica/fisiopatologia , Hemostasia Cirúrgica/métodos , Hepatectomia/efeitos adversos , Hipotensão/fisiopatologia , Adulto , Carcinoma Hepatocelular/cirurgia , Feminino , Humanos , Cuidados Intraoperatórios , Testes de Função Hepática , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
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