Cardiac-specific Traf2 overexpression enhances cardiac hypertrophy through activating AKT/GSK3β signaling

Tumor necrosis factor superfamily ligands provoke a dilated cardiac phenotype signal through a common scaffolding protein termed tumor necrosis factor receptor-associated factor 2 (Traf2); however, Traf2 signaling in the adult mammalian cardiac hypertrophy is not fully understood. This study was aimed to identify the effect of Traf2 on cardiac hypertrophy and the underlying mechanisms. A significant up-regulation of Traf2 expression was observed in mice failing hearts. To further investigate the role of Traf2 in cardiac hypertrophy, we used cultured neonatal rat cardiomyocytes with gain and loss of Traf2 function and cardiac-specific Traf2-overexpressing transgenic (TG) mice. In cultured cardiomyocytes, Traf2 positively regulated angiotensin II (Ang II)-mediated hypertrophic growth, as detected by [³H]-Leucine incorporation, cardiac myocyte area, and hypertrophic marker protein levels. Cardiac hypertrophy in vivo was produced by constriction of transverse aortic (TAC) in TG mice and their wild-type controls. The extent of cardiac hypertrophy was evaluated by echocardiography as well as by pathological and molecular analyses of heart samples. Traf2 overexpression in the heart remarkably enhanced cardiac hypertrophy, left ventricular dysfunction in mice in response to TAC. Further analysis of the signaling pathway in vitro and in vivo suggested that these adverse effects of Traf2 were associated with the activation of AKT/glycogen synthase kinase 3β (GSK3β). The present study demonstrates that Traf2 serves as a novel mediator that enhanced cardiac hypertrophy by activating AKT/GSK3β signaling.     

脑利钠肽后处理对兔急性心肌梗死的保护作用

目的：脑利钠肽后处理对兔急性心肌梗死的保护作用及可能机制。方法：30 只兔随机分为3 组,每组10 只,左冠状动脉的左 室支缺血30 分钟,再灌注120 分钟。AMI（急性心肌梗死）组：再灌注期间静脉滴注生理盐水;BNP（脑利钠肽）组：再灌注期间静脉 滴注rhBNP(重组人脑利钠肽);BNP+GLY（脑利钠肽+格列苯脲）组：再灌注期间静脉滴注rhBNP,同时舌下静脉注射GLY 。连续 监测心电变化,统计再灌注120 min 室性心动过速(VT)、心室颤动(VF)的发生率。心肌再灌注120 min 后,分别测定SOD(超氧化 物歧化酶)、MDA（丙二醛）、cTnI（肌钙蛋白I）、CK-MB（肌酸激酶同工酶）。各组随机抽取2 只兔,分别于再灌注1 小时和2 小时末 取心尖组织,HE 染色。结果：（1）再灌注心律失常：BNP 组与AMI组比较,VT 和VF发生率均明显升高（均为P<0.01）;BNP+GLY 组与BNP 组比较,VT 和VF 发生率均明显升高（均为P<0.01）。（2）SOD、MDA、cTnI 和CK-MB 水平：BNP 组与AMI 组比较, MDA、cTnI 和CK-MB 均明显降低（均为P<0.01）,而SOD 明显升高（P<0.01）;BNP+GLY 组与BNP 组比较,MDA、cTnI 和 CK-MB 均明显升高（分别为P<0.01,P<0.05和P<0.01）,而SOD明显降低（P<0.01）。（3）心肌HE 染色：AMI组和BNP+GLY 组心 肌损伤明显,BNP 组心肌损伤轻微。结论：脑利钠肽后处理对兔急性心肌梗死（缺血- 再灌注损伤）具有保护作用,可能与KATP 通道相关。     

痰热清注射液联合纳洛酮对老年慢性呼吸衰竭并发肺性脑病患者临床疗效的影响

目的:探讨痰热清注射液联合纳洛酮对老年慢性呼吸衰竭并发肺性脑病患者临床疗效的影响。方法:选取我院呼吸科收治的慢性呼吸衰竭并发肺性脑病患者60例,随机分为治疗组和对照组,每组30例。对照组给予加痰热清注射液治疗,治疗组在对照组治疗基础上联合纳洛酮注射液治疗。治疗结束后,比较治疗前后两组患者动脉血气分析结果、血清BNP(脑钠肽)、SOD(超氧化物歧化酶)、MDA(丙二醛)水平及临床疗效。结果:与治疗前相比,两组患者治疗后的血清BNP、MDA水平降低,SOD水平升高(P0.05),PaO_2水平升高,PaCO_2水平下降(P0.05);与对照组比较,治疗组总有效率较高,BNP、MDA水平较低,SOD水平较高(P0.05),PaO_2水平较高,PaCO_2水平较低(P0.05)。结论:痰热清注射液联合纳洛酮治疗老年慢性呼吸衰竭并发肺性脑病临床疗效好,推测其机制与降低血清BNP、MDA及升高血清SOD水平有关。     

Chk1 signaling pathways that mediated G(2)M checkpoint in relation to the cellular resistance to the novel topoisomerase I poison BNP1350

A novel karenitecin, BNP1350, is a topoisomerase I-targeting anticancer agent with significant antitumor activity in vitro and in vivo. A BNP1350-resistant human head and neck carcinoma A253 cell line, denoted A253/BNPR, was developed. The A253/BNPR cell line was approximately 9-fold resistant to BNP1350 and 4-fold cross-resistant to another topoisomerase I inhibitor SN-38, the active metabolite of irinotecan. After drug treatment with equimolar concentrations of BNP1350 (0.7 microM) for 2h, activation of the DNA double-strand break repair protein complexes was similar in the two cell lines, suggesting that DNA dsb repair is not attributable to resistance to BNP1350 in the A253/BNPR cells. Cell cycle analysis indicates that the A253 cell line accumulated primarily in S phase, but G(2) phase accumulation was observed in the A253/BNPR cell line at 48 h after drug removal. Elevated chk1 phosphorylation at Ser(345) following DNA damage induced by BNP1350 was accompanied by G(2) accumulation in the A253/BNPR cell line, while exposure to equimolar concentrations of BNP1350 (0.7 microM) induced S-phase arrest and no increased phosphorylation of chk1 at Ser(345) in the A253 cell line. Under the same conditions, increased chk1 activity was observed in the A253/BNPR cell line, but not in the A253 cell line. Moreover, stimulated binding of 14-3-3 proteins to chk1 was observed in BNP1350-treated A253/BNPR cells. To confirm relationship between chk1 expression/phosphorylation and drug resistance to topo I poisons, we examined the effects of chk1 or chk2 antisense oligonucleotides on the cellular growth inhibition. Chk1 antisense oligonucleotide can sensitize the A253/BNPR cells to killing by topo I inhibitor BNP1350, but no significant sensitization of BNP1350-induced growth inhibition was observed in the drug-sensitive cell line. Chk2 antisense oligonucleotide has only a small sensitization effect on BNP1350-induced growth inhibition in both cell lines. The data indicate that the chk1 signaling pathways that mediate cell cycle checkpoint are associated with cellular resistance to BNP1350 in the A253/BNPR cell line.     

rt-PA静脉溶栓治疗急性大脑中动脉脑梗死的临床疗效

目的:探讨rt-PA静脉溶栓治疗在急性大脑中动脉脑梗死的临床疗效及安全性。方法:选取我院急性大脑中动脉脑梗死患者70例,随机分为实验组和对照组,每组35例。对照组给予保护神经、清除自由基及抗血小板抑制等治疗,实验组在对照组基础上联合阿替普酶静脉滴注。观察并比较治疗前后两组患者血清BNP,CRP及NSE水平的变化情况,以及临床疗效和并发症的发生率。结果:与治疗前相比,治疗后两组患者血清BNP,CRP及NSE水平均降低,差异具有统计学意义(P0.05);与对照组比较,实验组患者治疗后血清BNP,CRP及NSE水平较低,差异具有统计学意义(P0.05);实验组总有效率(85.71%)明显高于对照组(65.71%),差异具有统计学意义(P0.05)。两组患者颅内出血、再灌注损伤、血管再闭塞等并发症的发生率比较,差异无统计学意义(P0.05)。结论:rt-PA静脉溶栓治疗急性大脑中动脉脑梗死的临床疗效显著,能够降低患者血清BNP,CRP及NSE水平。     

BNP/NPR-A/BKCa信号通路在大鼠神经痛形成中的作用及机制研究

摘要 目的：探讨BNP/NPR-A/BKCa信号通路在大鼠神经痛形成中的作用及机制研究。方法：选取SPF级大鼠作为研究对象,并构建神经痛病理性疼痛大鼠模型。并分为空白对照组、假手术组、A组（20 ng/mL BNP梢内注射）、B组（50 ng/mL BNP梢内注射）和C组（100 ng/mL BNP梢内注射）。采用qRT-PCR和Western blot检测NPR-A和BKCa的mRNA和蛋白表达水平。采用ELISA法检查炎症因子。全细胞膜片钳技术检测痛觉神经元BKCa通道电流;对大鼠进行机械性痛觉过敏测试和温度性痛觉敏感测试。结果：与空白组相比,模型组、A、B和C组PWT和PWL明显更低（P＜0.05）;与模型组相比,A、B和C组PWT和PWL明显更高,且C组大于B和A组,B组大于A组（P＜0.05）。与空白组相比,模型组NPR-A的蛋白和mRAN水平明显更高,而BKCa-α明显更低（P＜0.05）;与模型组相比,A、B和C组NPR-A和BKCa-α的蛋白和mRNA明显更高,且C组大于B和A组,B组大于A组（P＜0.05）。各电压水平,与空白组相比,模型组、A、B和C组BKCa-α电流水平明显更低（P＜0.05）;与模型组相比,A、B和C组BKCa-α电流水平明显更高,且C组大于B和A组,B组大于A组（P＜0.05）。与空白组相比,模型组、A、B和C组TNF-α、IL-6和IL-18水平明显更高（P＜0.05）;与模型组相比,A、B和C组TNF-α、IL-6和IL-18水平明显更低,且C组小于B和A组,B组小于A组（P＜0.05）。结论：靶向上调BNP的表达水平可增加BKCa的表达及BKCa电流,同时BNP的表达上调还有助于抑制炎症因子水平,从而达到多途径缓解疼痛的目的。     

Central and peripheral forms of C-type natriuretic peptide (CNP): evidence for differential regulation in plasma and cerebrospinal fluid

Aminoterminal proCNP (NTproCNP), a stable product of CNP gene expression and readily measured in human plasma, provides a new approach to studies of CNP which is rapidly degraded at source. CNP is detectable in human CSF but the presence and proportions of NTproCNP in CSF are unknown. Since CNP is widely expressed throughout the CNS, we hypothesized that the ratio of NTproCNP to CNP in CSF is greatly increased when compared to plasma and that CSF CNP peptides may contribute to their concentrations in the systemic circulation. Concurrent plasma and CSF concentrations of CNP forms were measured in 51 subjects undergoing spinal anesthesia for arranged orthopedic procedures. Elevated concentrations of NTproCNP (1045 ± 359 pmol/L), characterized by HPLC-RIA, were found in CSF and greatly exceeded those of CNP (7.9 ± 3.2 pmol/L). The ratio of NTproCNP to CNP in CSF (145 ± 55) was much higher than in plasma (31 ± 27). A significant inverse relation was found between plasma and CSF CNP concentrations (r = −0.29, p < 0.05). cGMP and neprilysin were unrelated to CNP levels in CSF. We conclude that CNP is differentially regulated across the brain in normal health. Despite markedly elevated levels of NTproCNP in CSF, it is unlikely that these contribute to systemic levels in healthy adults. Identifying NTproCNP as the dominant CNP form in CSF opens up the possibility of its use in future studies exploring CNP regulation within the CNS and possible applications in the diagnosis and monitoring of subjects with central neural disorders.     

前列腺素E1注射液治疗冠心病心力衰竭的临床观察

目的：观察前列腺素EI（PGE1）治疗冠心病心力衰竭的I盛床效果。方法：病人随机分为PGE1治疗组（40例）和对照组（40例）。治疗组用PGE1loug加入5％葡萄糖溶液250ml静滴,每日1次,10d为一疗程。对照组除不用PGE1外,其他治疗与PGE1治疗组相同。治疗后测定血BNP、无创血流动力学监测心输出量（CO）、心脏指数（CI）、肺动脉楔压（PCWP）以及测定血小板数值。结果：PGE1治疗组血BNP水平较对照组明显下降（P〈0．05）;无创性心功能监测CI、CO较对照组明显增加,PCWP较对照组下降（P〈0．05）;血小板较对照组明显减少（P〈0．05）结论：PGE1能改善冠心病心衰患者心功能,其疗效肯定。