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61.
DCA is hepatocarcinogenic in rodents. At carcinogenic doses, DCA causes a large accumulation of liver glycogen. Thus, we studied the effects of DCA treatment on insulin levels and expression of insulin-controlled signaling proteins in the liver. DCA treatment (0.2-2.0 g/l in drinking water for 2 weeks) reduced serum insulin levels. The decrease persisted for at least 8 weeks. In livers of mice treated with DCA for 2-, 10-, and 52-week periods, insulin receptor (IR) protein levels were significantly depressed. Additionally, protein kinase B (PKBalpha) expression decreased significantly with DCA treatment. In normal liver, glycogen levels were increased as early as at 1 week, and this effect preceded changes in insulin and IR and PKBalpha. In contrast to normal liver, IR protein was elevated in DCA-induced liver tumors relative to that in liver tissue of untreated animals and to an even greater extent when compared to adjacent normal liver in the treated animal. Mitogen-activated protein kinase (MAP kinase) phosphorylation was also increased in tumor tissue relative to normal liver tissue and tissue from untreated controls. These data suggest that normal hepatocytes down-regulate insulin-signaling proteins in response to the accumulation of liver glycogen caused by DCA. Furthermore, these results suggest that the initiated cell population, which does not accumulate glycogen and is promoted by DCA treatment, responds differently from normal hepatocytes to the insulin-like effects of this chemical. The differential sensitivity of the 2 cell populations may contribute to the tumorigenic effects of DCA in the liver.  相似文献   
62.
The PTEN gene is often mutated in primary human tumors and cell lines, but the low rate of somatic PTEN mutation in human breast cancer has led to debate over the role of this tumor suppressor in this disease. The involvement of PTEN in human mammary oncogenesis has been implicated from studies showing that germline PTEN mutation in Cowden disease predisposes to breast cancer, the frequent loss of heterozygosity at the PTEN locus, and reduced PTEN protein levels in sporadic breast cancers. To assay the potential contribution of PTEN loss in breast tumor promotion, Li et al. [1] crossed Pten heterozygous mice with mouse mammary tumor virus-Wnt-1 transgenic (Wnt-1 TG, Pten+/-) mice. Mammary ductal carcinoma developed earlier in Wnt-1 TG, Pten+/- mice than in mice bearing either genetic change alone, and showed frequent loss of the remaining wild-type PTEN allele. These data indicate a role for PTEN in breast tumorigenesis in an in vivo model.  相似文献   
63.
Objective To explore the role of RAS/PI3K pathway in the impairment of long-term potentiation(LTP) induced by acute aluminum(Al) treatment in rats in vivo. Methods First, different dosages of aluminum-maltolate complex [Al(mal)_3] were given to rats via acute intracerebroventricular(i.c.v.) injection. Following Al exposure, the RAS activity of rat hippocampus were detected by ELISA assay after the hippocampal LTP recording by field potentiation technique in vivo. Second, the antagonism on the aluminum-induced suppression of hippocampal LTP was observed after the treatment of the RAS activator epidermal growth factor(EGF). Finally, the antagonism on the downstream molecules(PKB activity and the phosphorylation of Glu R1 S831 and S845) were tested by ELISA and West-blot assays at the same time. Results With the increasing aluminum dosage, a gradually decreasing in RAS activity of the rat hippocampus was produced after a gradually suppressing on LTP. The aluminum-induced early suppression of hippocampal LTP was antagonized by the RAS activator epidermal growth factor(EGF). And the EGF treatment produced changes similar to those observed for LTP between the groups on PKB activity as well as the phosphorylation of Glu R1 S831 and S845. Conclusion The RAS→PI3K/PKB→GluR 1 S831 and S845 signal transduction pathway may be involved in the inhibition of hippocampal LTP by aluminum exposure in rats. However, the mechanisms underlying this observation need further investigation.  相似文献   
64.
We investigated the effects of cisplatin (cisPt) on matrix metalloproteinase-2 (MMP-2) gelatinolitic activity in transformed PC E1Araf rat thyroid cells. Cells incubated with increasing cisPt concentrations showed dose- and time-dependent decrease of the MMP-2 protein and activity. CisPt provoked the translocation from the cytosol to the plasma membrane of atypical protein kinase C-zeta (PKC-ζ) and the activation of PKB/AKT. The effect of cisPt on MMP-2 was dependent on PKC-ζ activation since it was potentiated by a myristoylated PKC-ζ pseudo substrate peptide or by PKC-ζ down-regulation by siRNA. Moreover, MMP-2 activity modulation by cisPt was also dependent on PKB/AKT activation since it was decreased by PKB/AKT down-regulation by siRNA or by pharmacological inhibition of PI3K, thus indicating the importance of the balance of PKB/AKT and PKC-ζ in regulating the cisPt effect on MMP-2 activity. The PC E1Araf cells displayed a migratory capacity that was blocked by MMP-2 down-regulation using siRNA or pharmacological inhibition. The inhibition of cell migration was also obtained with cisPt; in cisPt-treated cells the administration of MMP-2 active protein was able to restore cell migration capacity. In conclusion, the decrease of MMP-2 secretion after cisPt was allowed by PKB/AKT and counteracted by PKC-ζ; the cisPt-provoked inhibition of MMP-2 secretion ended in reduction of cell migration.  相似文献   
65.
Akt/PKB is a critical regulator of cardiac function and morphology, and its activity is governed by dual phosphorylation at active loop (Thr308) by phosphoinositide-dependent protein kinase-1 (PDK1) and at carboxyl-terminal hydrophobic motif (Ser473) by a putative PDK2. P21-activated kinase-1 (Pak1) is a serine/threonine protein kinase implicated in the regulation of cardiac hypertrophy and contractility and was shown previously to activate Akt through an undefined mechanism. Here we report Pak1 as a potential PDK2 that is essential for Akt activity in cardiomyocytes. Both Pak1 and Akt can be activated by multiple hypertrophic stimuli or growth factors in a phosphatidylinositol-3-kinase (PI3K)-dependent manner. Pak1 overexpression induces Akt phosphorylation at both Ser473 and Thr308 in cardiomyocytes. Conversely, silencing or inactivating Pak1 gene diminishes Akt phosphorylation in vitro and in vivo. Purified Pak1 can directly phosphorylate Akt only at Ser473, suggesting that Pak1 may be a relevant PDK2 responsible for AKT Ser473 phosphorylation in cardiomyocytes. In addition, Pak1 protects cardiomyocytes from cell death, which is blocked by Akt inhibition. Our results connect two important regulators of cellular physiological functions and provide a potential mechanism for Pak1 signaling in cardiomyocytes.  相似文献   
66.
目的 观察高糖高脂联合低剂量链脲佐菌素(Streptozocin,STZ)对版纳微型猪糖、脂代谢紊乱、肝组织病理改变及其蛋白激酶B(Protein Kinase B,PKB)磷酸化的影响,并探讨其机制。方法 高糖高脂联合低剂量STZ诱导云南版纳微型猪2型糖尿病模型,每月末测定血糖、血脂、胰岛素,HE、PAS和苏丹Ⅳ染色观察肝脏显微结构。12个月末处死动物,real time-PCR和western blotting 检测肝组织 PKBmRNA和总蛋白表达及PKB丝氨酸473(PKB-Ser473)的磷酸化水平。结果 喂养12月后,与正常对照组比较,模型组显示高血糖、血脂障碍及胰岛素缺乏(P<0.05)。肝脏脂肪病变,肝糖原合成显著减少;PKBmRNA及蛋白表达增高(P<0.05),但PKB磷酸化降低(P<0.05)。结论 高糖高脂联合STZ可诱导版纳微型猪发生胰岛素抵抗、糖尿病,促进肝脏脂质蓄积,抑制糖原合成,可能与信号分子PKB抑制有关。  相似文献   
67.
目的构建靶向蛋白激酶B基因的短发夹环RNA表达载体,观察其对血管平滑肌细胞增殖活性的影响。方法设计多个针对大鼠蛋白激酶B基因的短发夹环RNA序列,化学合成方法合成并经pGEM-T载体克隆后双酶切,将cDNA序列插入逆转录病毒载体pLXIN,包装后获得蛋白激酶B的逆转录表达载体,感染血管平滑肌细胞,Northern blot和Western blot法检测蛋白激酶B及其下游底物的表达变化,流式细胞仪检测细胞周期变化,MTT法检测血管平滑肌细胞增殖活性的改变。结果成功构建蛋白激酶B基因的逆转录病毒载体并包装,感染血管平滑肌细胞,证实其能显著抑制蛋白激酶B的mRNA和蛋白产物表达,下游的p70s6k表达相应减少;被感染血管平滑肌细胞的分裂、增殖过程受阻,更多细胞停滞在G0/G1期。结论成功构建蛋白激酶B基因逆转录病毒RNA干扰表达载体,感染血管平滑肌细胞能够明显抑制其分裂、分化和增殖。  相似文献   
68.
目的观察酰化ghrelin和非酰化ghrelin分别对胰岛素抵抗(insulinresistance,IR)骨骼肌细胞的胰岛素受体后信号通路关键因子P13Kp85α、Akt/PKB及GLUT4的影响。方法大鼠L6成肌细胞经棕榈酸诱导分化,建立IR模型成功后入选实验,分为酰化ghrelin组(AG组)、非酰化ghrelin组(UAG组)、P13K抑制剂(LY)+酰化ghrelin组(LY+AG组)、LY+非酰化ghrelin组(LY+UAG组)和对照组(IR—CO组)。各组经处理因素干预24h后,激光共聚焦和流式细胞术检测各组骨骼肌细胞在胰岛素刺激下对荧光葡萄糖的摄取能力,免疫印迹法检测骨骼肌组织的磷酸化/总P13Kp85α、磷酸化/总Akt、细胞膜/总GLUT4的蛋白表达,实时荧光定量PCR法检测骨骼肌组织P13Kp85α、Akt、GLUT4mRNA的表达。结果L6成肌细胞诱导分化及IR模型建立成功;AG组和UAG组的细胞在胰岛素刺激下的葡萄糖摄取分别是IR—CO组的1.25和1.28倍,磷酸形总P13Kp85α相对蛋白表达量分别是IR-CO组的1.78和1.89倍,磷酸化/总Akt、细胞膜/总GLUT4的蛋白表达是IR—CO组的1.84和1.80倍,细胞P13Kp85α、Akt/PKB、GLUT4的mRNA表达均较对照组显著升高,LY+AG组和LY+UAG组细胞的上述指标较单独使用酰化ghrelin或非酰化ghrelin作用时显著下降。结论酰化ghrelin和非酰化ghrelin均能改善骨骼肌细胞的IR,增加骨骼肌细胞在胰岛素刺激下的葡萄糖摄取;能够上调骨骼肌细胞的磷酸化P13Kp85α、磷酸化Akt/PKB、细胞膜GLUT4的相对蛋白表达和3者的mRNA表达,PI3K抑制剂LY294002能够抑制酰化和非酰化ghrelin的上述改善作用。  相似文献   
69.

Objective

Insulin resistance plays an important role in the pathogenesis of diabetic cardiomyopathy. Berberine (BBR) is a plant alkaloid which promotes hypoglycemia via increasing insulin sensitivity in peripheral tissues. Little is known of BBR’s role in regulating glucose metabolism in heart.

Materials/methods

We examined the effect and mechanism of BBR on glucose consumption and glucose uptake in insulin sensitive or insulin resistant rat H9c2 cardiomyocyte cells. H9c2 myoblast cells were differentiated into cardiomyocytes and incubated with insulin for 24 h to induce insulin resistance.

Results

BBR-treatment of H9c2 cells increased glucose consumption and glucose uptake compared to controls. In addition, BBR-treatment attenuated the reduction in glucose consumption and glucose uptake in insulin resistant H9c2 cells. Compound C, an inhibitor of AMP-activated protein kinase (AMPK), abolished the enhancement of glucose consumption and glucose uptake mediated by BBR in both insulin sensitive and insulin resistant H9c2 cells compared to controls.

Conclusion

BBR significantly increased AMPK activity, but had little effect on the activity of protein kinase B (AKT) in insulin resistant H9c2 cells, suggesting that berberine improves insulin resistance in H9c2 cardiomyocytes at least in part via stimulation of AMPK activity.  相似文献   
70.
Aims/hypothesis Diabetes mellitus is a strong risk factor for the development of heart failure, and left ventricular (LV) hypertrophy has been detected in a significant proportion of diabetic patients. Because several studies have suggested that the Na+/H+ exchanger (NHE1) plays a part in the molecular mechanisms involved in cardiac hypertrophy, we investigated its activity and its role in LV myocytes from the Goto–Kakizaki (GK) rat model of type 2 diabetes. Materials and methods Fluorometric measurements were used to assess sarcolemmal NHE1 activity in isolated myocytes. NHE1 levels and the possible molecular pathways driving and/or related to NHE1 activity were investigated in relation to the diabetic LV phenotype. Results Enhanced NHE1 activity was associated with LV myocyte hypertrophy. This occurred in the absence of any change in NHE1 protein levels; however, activation of several molecular pathways related to NHE1 activity was demonstrated. Thus, phosphorylation of the extracellular signal-regulated protein kinase (Erk), of the protein kinase Akt (also known as protein kinase B) and of the Ca2+/calmodulin-dependent kinase II was increased in GK LV myocytes. Intracellular Ca2+ levels were also increased. Chronic treatment (10–12 weeks) with the NHE1 inhibitor cariporide normalised NHE1 activity, decreased levels and reduced LV myocyte hypertrophy. Moreover, among the various activated pathways, cariporide treatment markedly reduced Akt activity only. Conclusions/interpretation These findings indicate that activation of the Akt pathway represents a likely mechanism mediating the hypertrophic effect of increased NHE1 activity in the GK model of type 2 diabetes.  相似文献   
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