Acute pancreatitis is an inflammation of the pancreas that may lead to systemic inflammatory response syndrome and death due to multiple organ failure. Acinar cells, together with leukocytes, trigger the inflammatory ...Acute pancreatitis is an inflammation of the pancreas that may lead to systemic inflammatory response syndrome and death due to multiple organ failure. Acinar cells, together with leukocytes, trigger the inflammatory cascade in response to local damage of the pancreas. Amplification of the inflammatory cascade requires up-regulation of proinflammatory cytokines and this process is mediated not only by nuclear factor κB but also by chromatinmodifying complexes and chromatin remodeling. Among the different families of histone acetyltransferases, the p300/CBP family seems to be particularly associated with the inflammatory process. cAMP activates gene expression via the cAMP-responsive element (CRE) and the transcription factor CRE-binding protein (CREB). CREB can be phosphorylated and activated by different kinases, such as protein kinase A and MAPK, and then it recruits the histone acetyltransferase co-activator CREB-binding protein (CBP) and its homologue p300. The recruitment of CBP/p300 and changes in the level of histone acetylation are required for transcription activation. Transcriptional repression is also a dynamic and essential mechanism of down-regulation of genes for resolution of inflammation, which seems to be mediated mainly by protein phosphatases (PP1, PP2A and MKP1) and histone deacetylases(HDACs) .Class HDACs are key transcriptional regulators whose activities are controlled via phosphorylationdependent nucleo/cytoplasmic shuttling. PP2A is responsible for dephosphorylation of class HDACs, triggeringnuclear localization and repression of target genes, whereas phosphorylation triggers cytoplasmic localization leading to activation of target genes. The potential benefit from treatment with phosphodiesterase inhibitors and histone deacetylase inhibitors is discussed.展开更多
Reversible phosphorylation and dephosphorylation play important roles in cell function and cell signal transduction. PPP2R5A (protein phosphatase 2 regulatory subunit B’ alpha) is responsible for specifically regulat...Reversible phosphorylation and dephosphorylation play important roles in cell function and cell signal transduction. PPP2R5A (protein phosphatase 2 regulatory subunit B’ alpha) is responsible for specifically regulating the catalytic function, substrate specificity and intracellular localization of the tumor suppressor phosphatase PP2A (serine/threonine protein phosphatase 2A). Therefore, the abnormal expression and function of PPP2R5A may be related to canceration. The aim of this study was to reveal its role in the occurrence and development of hepatocellular carcinoma (HCC). It is hoped that the results of this study can provide guidance for the prevention and treatment of HCC. The results showed that PPP2R5A inhibited the proliferation and metastasis of HCC cells, and acted as a tumor suppressor in HCC cells, but it had no significant effect on cell cycle. Further research found that PPP2R5A exerted tumor suppressor efficacy by inhibiting the MAPK/AKT/WNT signaling pathway. Combined with analysis of clinical tissue samples and TCGA database, it was found that the expression of PPP2R5A in tumor tissues of Chinese HCC patients was down-regulated and significantly correlated with the progression-free survival (PFS) of HCC patients. On the contrary, PPP2R5A showed an up-regulation trend in HCC cases in TCGA database although its effect on PFS was the same with that in Chinese HCC patients. Hepatitis B virus (HBV) infection is the main pathogenic factor of HCC in China. It was found that HBV infection reduced the content of PPP2R5A in cells. It was concluded that HBV inhibited the initiation of the protective mechanism mediated by PPP2R5A, making the occurrence and progress of HCC more “unimpeded”. This conclusion will further reveal the role of PPP2R5A in HBV-induced and HBV-unrelated HCC, therefore, providing clues for the prevention and treatment of the two types of HCC, respectively.展开更多
BACKGROUND It is well known that nonalcoholic fatty liver disease(NAFLD)is associated with insulin resistance(IR).LB100,a serine/threonine protein phosphatase 2A(PP2A)inhibitor,is closely related to IR.However,there i...BACKGROUND It is well known that nonalcoholic fatty liver disease(NAFLD)is associated with insulin resistance(IR).LB100,a serine/threonine protein phosphatase 2A(PP2A)inhibitor,is closely related to IR.However,there is little data regarding its direct influence on NAFLD.AIM To elucidate the effect and underlying mechanism of LB100 in NAFLD.METHODS After 10 wk of high fat diet(HFD)feeding,male C57BL/6 mice were injected intraperitoneally with vehicle or LB100 for an additional 6 wk(three times a week).The L02 cell line was treated with LB100 and free fatty acids(FFAs)for 24 h.Hematoxylin and eosin and oil red O staining were performed for histological examination.Western blot analysis was used to detect the protein expression of Sirtuin 1(Sirt1),total and phosphorylated AMP-activated protein kinaseα(AMPKα),and the proteins involved in lipogenesis and fatty acid oxidation.The mRNA levels were determined by qPCR.Pharmacological inhibition of AMPK was performed to further examine the exact mechanism of LB100 in NAFLD.RESULTS LB100 significantly ameliorated HFD-induced obesity,hepatic lipid accumulation and hepatic injury in mice.In addition,LB100 significantly downregulated the protein levels of acetyl-CoA carboxylase,sterol regulatory element-binding protein 1 and its lipogenesis target genes,including stearoyl-CoA desaturase-1 and fatty acid synthase,and upregulated the levels of proteins involved in fatty acidβ-oxidation,such as peroxisome proliferator-activated receptorα(PPARα),peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α),carnitine palmitoyltransferase 1α,acyl-CoA oxidase 1 and uncoupling protein 2,as well as the upstream mediators Sirt1 and AMPKαin the livers of HFD-fed mice.In vitro,LB100 alleviated FFA-induced lipid accumulation in L02 cells through the AMPK/Sirt1 signaling pathway.Further studies showed that the curative effect of LB100 on lipid accumulation was abolished by inhibiting AMPKαin L02 cells.CONCLUSION PP2A inhibition by LB100 significantly ameliorates hepatic steatosis by regulating hepatic lipogenesis and fatty acid oxidation via the AMPK/Sirt1 pathway.LB100 may be a potential therapeutic agent for NAFLD.展开更多
基金Supported by Grants SAF2006-06963, SAF2009-09500 and Consolider CSD-2007-00020 to Sastre J BFU2007-63120 and CSD2006-49 to López-Rodas G
文摘Acute pancreatitis is an inflammation of the pancreas that may lead to systemic inflammatory response syndrome and death due to multiple organ failure. Acinar cells, together with leukocytes, trigger the inflammatory cascade in response to local damage of the pancreas. Amplification of the inflammatory cascade requires up-regulation of proinflammatory cytokines and this process is mediated not only by nuclear factor κB but also by chromatinmodifying complexes and chromatin remodeling. Among the different families of histone acetyltransferases, the p300/CBP family seems to be particularly associated with the inflammatory process. cAMP activates gene expression via the cAMP-responsive element (CRE) and the transcription factor CRE-binding protein (CREB). CREB can be phosphorylated and activated by different kinases, such as protein kinase A and MAPK, and then it recruits the histone acetyltransferase co-activator CREB-binding protein (CBP) and its homologue p300. The recruitment of CBP/p300 and changes in the level of histone acetylation are required for transcription activation. Transcriptional repression is also a dynamic and essential mechanism of down-regulation of genes for resolution of inflammation, which seems to be mediated mainly by protein phosphatases (PP1, PP2A and MKP1) and histone deacetylases(HDACs) .Class HDACs are key transcriptional regulators whose activities are controlled via phosphorylationdependent nucleo/cytoplasmic shuttling. PP2A is responsible for dephosphorylation of class HDACs, triggeringnuclear localization and repression of target genes, whereas phosphorylation triggers cytoplasmic localization leading to activation of target genes. The potential benefit from treatment with phosphodiesterase inhibitors and histone deacetylase inhibitors is discussed.
文摘Reversible phosphorylation and dephosphorylation play important roles in cell function and cell signal transduction. PPP2R5A (protein phosphatase 2 regulatory subunit B’ alpha) is responsible for specifically regulating the catalytic function, substrate specificity and intracellular localization of the tumor suppressor phosphatase PP2A (serine/threonine protein phosphatase 2A). Therefore, the abnormal expression and function of PPP2R5A may be related to canceration. The aim of this study was to reveal its role in the occurrence and development of hepatocellular carcinoma (HCC). It is hoped that the results of this study can provide guidance for the prevention and treatment of HCC. The results showed that PPP2R5A inhibited the proliferation and metastasis of HCC cells, and acted as a tumor suppressor in HCC cells, but it had no significant effect on cell cycle. Further research found that PPP2R5A exerted tumor suppressor efficacy by inhibiting the MAPK/AKT/WNT signaling pathway. Combined with analysis of clinical tissue samples and TCGA database, it was found that the expression of PPP2R5A in tumor tissues of Chinese HCC patients was down-regulated and significantly correlated with the progression-free survival (PFS) of HCC patients. On the contrary, PPP2R5A showed an up-regulation trend in HCC cases in TCGA database although its effect on PFS was the same with that in Chinese HCC patients. Hepatitis B virus (HBV) infection is the main pathogenic factor of HCC in China. It was found that HBV infection reduced the content of PPP2R5A in cells. It was concluded that HBV inhibited the initiation of the protective mechanism mediated by PPP2R5A, making the occurrence and progress of HCC more “unimpeded”. This conclusion will further reveal the role of PPP2R5A in HBV-induced and HBV-unrelated HCC, therefore, providing clues for the prevention and treatment of the two types of HCC, respectively.
文摘BACKGROUND It is well known that nonalcoholic fatty liver disease(NAFLD)is associated with insulin resistance(IR).LB100,a serine/threonine protein phosphatase 2A(PP2A)inhibitor,is closely related to IR.However,there is little data regarding its direct influence on NAFLD.AIM To elucidate the effect and underlying mechanism of LB100 in NAFLD.METHODS After 10 wk of high fat diet(HFD)feeding,male C57BL/6 mice were injected intraperitoneally with vehicle or LB100 for an additional 6 wk(three times a week).The L02 cell line was treated with LB100 and free fatty acids(FFAs)for 24 h.Hematoxylin and eosin and oil red O staining were performed for histological examination.Western blot analysis was used to detect the protein expression of Sirtuin 1(Sirt1),total and phosphorylated AMP-activated protein kinaseα(AMPKα),and the proteins involved in lipogenesis and fatty acid oxidation.The mRNA levels were determined by qPCR.Pharmacological inhibition of AMPK was performed to further examine the exact mechanism of LB100 in NAFLD.RESULTS LB100 significantly ameliorated HFD-induced obesity,hepatic lipid accumulation and hepatic injury in mice.In addition,LB100 significantly downregulated the protein levels of acetyl-CoA carboxylase,sterol regulatory element-binding protein 1 and its lipogenesis target genes,including stearoyl-CoA desaturase-1 and fatty acid synthase,and upregulated the levels of proteins involved in fatty acidβ-oxidation,such as peroxisome proliferator-activated receptorα(PPARα),peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α),carnitine palmitoyltransferase 1α,acyl-CoA oxidase 1 and uncoupling protein 2,as well as the upstream mediators Sirt1 and AMPKαin the livers of HFD-fed mice.In vitro,LB100 alleviated FFA-induced lipid accumulation in L02 cells through the AMPK/Sirt1 signaling pathway.Further studies showed that the curative effect of LB100 on lipid accumulation was abolished by inhibiting AMPKαin L02 cells.CONCLUSION PP2A inhibition by LB100 significantly ameliorates hepatic steatosis by regulating hepatic lipogenesis and fatty acid oxidation via the AMPK/Sirt1 pathway.LB100 may be a potential therapeutic agent for NAFLD.
