The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Pan Bing - One of the best experts on this subject based on the ideXlab platform.
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The compensatory enrichment of sphingosine -1- phosphate harbored on glycated high-density lipoprotein restores endothelial Protective Function in type 2 diabetes mellitus
'Springer Science and Business Media LLC', 2014Co-Authors: Tong Xunliang, Mathew Anna, Liu Donghui, Niu Chenguang, Wang Yan, Ji Liang, Li Jizhao, Fu Zhiwei, Pan BingAbstract:Abstract Background Glycation of high-density lipoprotein (HDL) decreases its ability to induce cyclooxygenase-2 (COX-2) expression and prostacyclin I-2 (PGI-2) release in endothelial cells. Whether lipid content of HDL, especially sphingosine-1-phosphate (S1P), plays any specific role in restoring the Protective Function of HDL in type 2 diabetes mellitus (T2DM) is still unknown. Methods and results Immunochemical techniques demonstrated that glycated HDL loses its Protective Function of regulating COX-2 expression compared with diabetic HDL. We proved that the lipid content, especially phospholipid content differed between diabetic HDL and glycated HDL. Levels of HDL-c-bound S1P were increased in T2DM compared with control subjects as detected by UPLC-MS/MS (HDL-c-bound S1P in control subjects vs. T2DM: 309.1 ± 13.71 pmol/mg vs. 382.1 ± 24.45 pmol/mg, P
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The compensatory enrichment of sphingosine-1-phosphate harbored on glycated high-density lipoprotein restores endothelial Protective Function in type 2 diabetes mellitus
cardiovascular diabetology, 2014Co-Authors: Tong Xunliang, Mathew Anna, Liu Donghui, Niu Chenguang, Wang Yan, Ji Liang, Li Jizhao, Fu Zhiwei, Pan BingAbstract:Background: Glycation of high-density lipoprotein (HDL) decreases its ability to induce cyclooxygenase-2 (COX-2) expression and prostacyclin I-2 (PGI-2) release in endothelial cells. Whether lipid content of HDL, especially sphingosine-1-phosphate (S1P), plays any specific role in restoring the Protective Function of HDL in type 2 diabetes mellitus (T2DM) is still unknown. Methods and results: Immunochemical techniques demonstrated that glycated HDL loses its Protective Function of regulating COX-2 expression compared with diabetic HDL. We proved that the lipid content, especially phospholipid content differed between diabetic HDL and glycated HDL. Levels of HDL-c-bound S1P were increased in T2DM compared with control subjects as detected by UPLC-MS/MS (HDL-c-bound S1P in control subjects vs. T2DM: 309.1 +/- 13.71 pmol/mg vs. 382.1 +/- 24.45 pmol/mg, P < 0.05). Additionally, mRNA levels of S1P lyase enzymes and S1P phosphatase 1/2 were decreased in peripheral blood by real-time PCR. Antagonist of S1P receptor 1 and 3 (S1PR1/3) diminished the Functional difference between apoHDL&PL (HDL containing the protein components and phospholipids) and diabetic apoHDL&PL (diabetic HDL containing the protein components and phospholipids). With different doses of S1P reconstituted on glycated HDL, its Function in inducing the COX-2 expression was restored to the same level as diabetic HDL. The mechanism of S1P reconstituted HDL (rHDL) in the process of regulating COX-2 expression involved the phosphorylation of ERK/MAPK-CREB signal pathway. Conclusion/Significance: S1P harbored on HDL is the main factor which restores its Protective Function in endothelial cells in T2DM. S1P and its receptors are potential therapeutic targets in ameliorating the vascular dysFunction in T2DM.Cardiac & Cardiovascular SystemsEndocrinology & MetabolismSCI(E)PubMed0ARTICLEzhengl@bjmu.edu.cn; ynhuang@sina.com821
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The compensatory enrichment of sphingosine-1-phosphate harbored on glycated high-density lipoprotein restores endothelial Protective Function in type 2 diabetes mellitus
'Springer Science and Business Media LLC', 2014Co-Authors: Tong Xunliang, Mathew Anna, Liu Donghui, Niu Chenguang, Wang Yan, Ji Liang, Li Jizhao, Fu Zhiwei, Pan BingAbstract:National S&T Major Project of China [2008ZX09312-017, 2010CB912504, 2011CB503900]; National Natural Science Foundation of China [81370235, 81170101]; Natural Science Foundation of Beijing [7122106]; PUHSC-University of Michigan JIBackground: Glycation of high-density lipoprotein (HDL) decreases its ability to induce cyclooxygenase-2 (COX-2) expression and prostacyclin I-2 (PGI-2) release in endothelial cells. Whether lipid content of HDL, especially sphingosine-1-phosphate (S1P), plays any specific role in restoring the Protective Function of HDL in type 2 diabetes mellitus (T2DM) is still unknown. Methods and results: Immunochemical techniques demonstrated that glycated HDL loses its Protective Function of regulating COX-2 expression compared with diabetic HDL. We proved that the lipid content, especially phospholipid content differed between diabetic HDL and glycated HDL. Levels of HDL-c-bound S1P were increased in T2DM compared with control subjects as detected by UPLC-MS/MS (HDL-c-bound S1P in control subjects vs. T2DM: 309.1 +/- 13.71 pmol/mg vs. 382.1 +/- 24.45 pmol/mg, P < 0.05). Additionally, mRNA levels of S1P lyase enzymes and S1P phosphatase 1/2 were decreased in peripheral blood by real-time PCR. Antagonist of S1P receptor 1 and 3 (S1PR1/3) diminished the Functional difference between apoHDL&PL (HDL containing the protein components and phospholipids) and diabetic apoHDL&PL (diabetic HDL containing the protein components and phospholipids). With different doses of S1P reconstituted on glycated HDL, its Function in inducing the COX-2 expression was restored to the same level as diabetic HDL. The mechanism of S1P reconstituted HDL (rHDL) in the process of regulating COX-2 expression involved the phosphorylation of ERK/MAPK-CREB signal pathway. Conclusion/Significance: S1P harbored on HDL is the main factor which restores its Protective Function in endothelial cells in T2DM. S1P and its receptors are potential therapeutic targets in ameliorating the vascular dysFunction in T2DM
Geert Berx - One of the best experts on this subject based on the ideXlab platform.
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transforming growth factor beta and mutant p53 conspire to induce metastasis by antagonizing p63 a ternary complex affair
Breast Cancer Research, 2009Co-Authors: Jeanchristophe Marine, Geert BerxAbstract:How and when a tumor acquires metastatic properties remain largely unknown. Recent work has uncovered an intricate new mechanism through which transforming growth factor-beta (TGFβ) acts in concert with oncogenic Ras to antagonize p63-metastasis Protective Function. p63 inhibition requires the combined action of Ras-activated mutant p53 and TGFβ-induced Smads. Mechanistically, it involves the formation of a p63-Smads-mutant p53 ternary complex. Remarkably, just two of the key downstream targets of p63 turn out to be sufficient as a prognostic tool for breast cancer metastasis. Moreover, the molecular mechanism of this inhibition points to novel therapeutic possibilities.
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viewpoint transforming growth factor beta and mutant p53 conspire to induce metastasis by antagonizing p63 a ternary complex
2009Co-Authors: Geert BerxAbstract:How and when a tumor acquires metastatic properties remain largely unknown. Recent work has uncovered an intricate new mechanism through which transforming growth factor-beta (TGFβ) acts in concert with oncogenic Ras to antagonize p63-metastasis Protective Function. p63 inhibition requires the combined action of Ras-activated mutant p53 and TGFβ-induced Smads. Mechanistically, it involves the formation of a p63-Smads-mutant p53 ternary complex. Remarkably, just two of the key downstream targets of p63 turn out to be sufficient as a prognostic tool for breast cancer metastasis. Moreover, the molecular mechanism of this inhibition points to novel therapeutic possibilities.
Olga Pletnikova - One of the best experts on this subject based on the ideXlab platform.
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phosphorylation by the c abl protein tyrosine kinase inhibits parkin s ubiquitination and Protective Function
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Han Seok Ko, Olga Pletnikova, Juan C Troncoso, Valina L Dawson, Senthilkumar S. Karuppagounder, Joo Ho Shin, Bharathi S Gadad, Anthony J Koleske, Ted M DawsonAbstract:Mutations in PARK2/Parkin, which encodes a ubiquitin E3 ligase, cause autosomal recessive Parkinson disease (PD). Here we show that the nonreceptor tyrosine kinase c-Abl phosphorylates tyrosine 143 of parkin, inhibiting parkin's ubiquitin E3 ligase activity and Protective Function. c-Abl is activated by dopaminergic stress and by dopaminergic neurotoxins, 1-methyl-4-phenylpyridinium (MPP+) in vitro and in vivo by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), leading to parkin inactivation, accumulation of the parkin substrates aminoacyl-tRNA synthetase-interacting multiFunctional protein type 2 (AIMP2) (p38/JTV-1) and fuse-binding protein 1 (FBP1), and cell death. STI-571, a c-Abl-family kinase inhibitor, prevents the phosphorylation of parkin, maintaining parkin in a catalytically active and Protective state. STI-571’s Protective effects require parkin, as shRNA knockdown of parkin prevents STI-571 protection. Conditional knockout of c-Abl in the nervous system also prevents the phosphorylation of parkin, the accumulation of its substrates, and subsequent neurotoxicity in response to MPTP intoxication. In human postmortem PD brain, c-Abl is active, parkin is tyrosine-phosphorylated, and AIMP2 and FBP1 accumulate in the substantia nigra and striatum. Thus, tyrosine phosphorylation of parkin by c-Abl is a major posttranslational modification that inhibits parkin Function, possibly contributing to pathogenesis of sporadic PD. Moreover, inhibition of c-Abl may be a neuroProtective approach in the treatment of PD.
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Stress-induced alterations in parkin solubility promote parkin aggregation and compromise parkin's Protective Function
Human molecular genetics, 2005Co-Authors: Cheng Wang, Bobby Thomas, Fai Tsang, Katherine C. M. Chew, Shiam Peng Tay, Tit Meng Lim, Tuck Wah Soong, Olga PletnikovaAbstract:Mutations in parkin are currently recognized as the most common cause of familial Parkinsonism. Emerging evidence also suggests that parkin expression variability may confer a risk for the development of the more common, sporadic form of Parkinson’s disease (PD). Supporting this, we have recently demonstrated that parkin solubility in the human brain becomes altered with age. As parkin apparently Functions as a broadspectrum neuroprotectant, the resulting decrease in the availability of soluble parkin with age may underlie the progressive susceptibility of the brain to stress. Interestingly, we also observed that many familial-PD mutations of parkin alter its solubility in a manner that is highly reminiscent of our observations with the aged brain. The converging effects on parkin brought about by aging and PD-causing mutations are probably not trivial and suggest that environmental modulators affecting parkin solubility would increase an individual’s risk of developing PD. Using both cell culture and in vivo models, we demonstrate here that several PDlinked stressors, including neurotoxins (MPP1, rotenone, 6-hydroxydopamine), paraquat, NO, dopamine and iron, induce alterations in parkin solubility and result in its intracellular aggregation. Furthermore, the depletion of soluble, Functional forms of parkin is associated with reduced proteasomal activities and increased cell death. Our results suggest that exogenously introduced stress as well as endogenous dopamine could affect the native structure of parkin, promote its misfolding, and concomitantly compromise its Protective Functions. Mechanistically, our results provide a link between the influence of environmental and intrinsic factors and genetic susceptibilities in PD pathogenesis.
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s nitrosylation of parkin regulates ubiquitination and compromises parkin s Protective Function
Science, 2004Co-Authors: Kenny K K Chung, Olga Pletnikova, Juan C Troncoso, Valina L Dawson, Bobby Thomas, Laura Marsh, Ted M DawsonAbstract:Parkin is an E3 ubiquitin ligase involved in the ubiquitination of proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). We show that parkin is S-nitrosylated in vitro, as well as in vivo in a mouse model of PD and in brains of patients with PD and diffuse Lewy body disease. Moreover, S-nitrosylation inhibits parkin's ubiquitin E3 ligase activity and its Protective Function. The inhibition of parkin's ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in these disorders by impairing the ubiquitination of parkin substrates.
Ted M Dawson - One of the best experts on this subject based on the ideXlab platform.
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phosphorylation by the c abl protein tyrosine kinase inhibits parkin s ubiquitination and Protective Function
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Han Seok Ko, Olga Pletnikova, Juan C Troncoso, Valina L Dawson, Senthilkumar S. Karuppagounder, Joo Ho Shin, Bharathi S Gadad, Anthony J Koleske, Ted M DawsonAbstract:Mutations in PARK2/Parkin, which encodes a ubiquitin E3 ligase, cause autosomal recessive Parkinson disease (PD). Here we show that the nonreceptor tyrosine kinase c-Abl phosphorylates tyrosine 143 of parkin, inhibiting parkin's ubiquitin E3 ligase activity and Protective Function. c-Abl is activated by dopaminergic stress and by dopaminergic neurotoxins, 1-methyl-4-phenylpyridinium (MPP+) in vitro and in vivo by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), leading to parkin inactivation, accumulation of the parkin substrates aminoacyl-tRNA synthetase-interacting multiFunctional protein type 2 (AIMP2) (p38/JTV-1) and fuse-binding protein 1 (FBP1), and cell death. STI-571, a c-Abl-family kinase inhibitor, prevents the phosphorylation of parkin, maintaining parkin in a catalytically active and Protective state. STI-571’s Protective effects require parkin, as shRNA knockdown of parkin prevents STI-571 protection. Conditional knockout of c-Abl in the nervous system also prevents the phosphorylation of parkin, the accumulation of its substrates, and subsequent neurotoxicity in response to MPTP intoxication. In human postmortem PD brain, c-Abl is active, parkin is tyrosine-phosphorylated, and AIMP2 and FBP1 accumulate in the substantia nigra and striatum. Thus, tyrosine phosphorylation of parkin by c-Abl is a major posttranslational modification that inhibits parkin Function, possibly contributing to pathogenesis of sporadic PD. Moreover, inhibition of c-Abl may be a neuroProtective approach in the treatment of PD.
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s nitrosylation of parkin regulates ubiquitination and compromises parkin s Protective Function
Science, 2004Co-Authors: Kenny K K Chung, Olga Pletnikova, Juan C Troncoso, Valina L Dawson, Bobby Thomas, Laura Marsh, Ted M DawsonAbstract:Parkin is an E3 ubiquitin ligase involved in the ubiquitination of proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). We show that parkin is S-nitrosylated in vitro, as well as in vivo in a mouse model of PD and in brains of patients with PD and diffuse Lewy body disease. Moreover, S-nitrosylation inhibits parkin's ubiquitin E3 ligase activity and its Protective Function. The inhibition of parkin's ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in these disorders by impairing the ubiquitination of parkin substrates.
Tong Xunliang - One of the best experts on this subject based on the ideXlab platform.
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The compensatory enrichment of sphingosine -1- phosphate harbored on glycated high-density lipoprotein restores endothelial Protective Function in type 2 diabetes mellitus
'Springer Science and Business Media LLC', 2014Co-Authors: Tong Xunliang, Mathew Anna, Liu Donghui, Niu Chenguang, Wang Yan, Ji Liang, Li Jizhao, Fu Zhiwei, Pan BingAbstract:Abstract Background Glycation of high-density lipoprotein (HDL) decreases its ability to induce cyclooxygenase-2 (COX-2) expression and prostacyclin I-2 (PGI-2) release in endothelial cells. Whether lipid content of HDL, especially sphingosine-1-phosphate (S1P), plays any specific role in restoring the Protective Function of HDL in type 2 diabetes mellitus (T2DM) is still unknown. Methods and results Immunochemical techniques demonstrated that glycated HDL loses its Protective Function of regulating COX-2 expression compared with diabetic HDL. We proved that the lipid content, especially phospholipid content differed between diabetic HDL and glycated HDL. Levels of HDL-c-bound S1P were increased in T2DM compared with control subjects as detected by UPLC-MS/MS (HDL-c-bound S1P in control subjects vs. T2DM: 309.1 ± 13.71 pmol/mg vs. 382.1 ± 24.45 pmol/mg, P
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The compensatory enrichment of sphingosine-1-phosphate harbored on glycated high-density lipoprotein restores endothelial Protective Function in type 2 diabetes mellitus
cardiovascular diabetology, 2014Co-Authors: Tong Xunliang, Mathew Anna, Liu Donghui, Niu Chenguang, Wang Yan, Ji Liang, Li Jizhao, Fu Zhiwei, Pan BingAbstract:Background: Glycation of high-density lipoprotein (HDL) decreases its ability to induce cyclooxygenase-2 (COX-2) expression and prostacyclin I-2 (PGI-2) release in endothelial cells. Whether lipid content of HDL, especially sphingosine-1-phosphate (S1P), plays any specific role in restoring the Protective Function of HDL in type 2 diabetes mellitus (T2DM) is still unknown. Methods and results: Immunochemical techniques demonstrated that glycated HDL loses its Protective Function of regulating COX-2 expression compared with diabetic HDL. We proved that the lipid content, especially phospholipid content differed between diabetic HDL and glycated HDL. Levels of HDL-c-bound S1P were increased in T2DM compared with control subjects as detected by UPLC-MS/MS (HDL-c-bound S1P in control subjects vs. T2DM: 309.1 +/- 13.71 pmol/mg vs. 382.1 +/- 24.45 pmol/mg, P < 0.05). Additionally, mRNA levels of S1P lyase enzymes and S1P phosphatase 1/2 were decreased in peripheral blood by real-time PCR. Antagonist of S1P receptor 1 and 3 (S1PR1/3) diminished the Functional difference between apoHDL&PL (HDL containing the protein components and phospholipids) and diabetic apoHDL&PL (diabetic HDL containing the protein components and phospholipids). With different doses of S1P reconstituted on glycated HDL, its Function in inducing the COX-2 expression was restored to the same level as diabetic HDL. The mechanism of S1P reconstituted HDL (rHDL) in the process of regulating COX-2 expression involved the phosphorylation of ERK/MAPK-CREB signal pathway. Conclusion/Significance: S1P harbored on HDL is the main factor which restores its Protective Function in endothelial cells in T2DM. S1P and its receptors are potential therapeutic targets in ameliorating the vascular dysFunction in T2DM.Cardiac & Cardiovascular SystemsEndocrinology & MetabolismSCI(E)PubMed0ARTICLEzhengl@bjmu.edu.cn; ynhuang@sina.com821
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The compensatory enrichment of sphingosine-1-phosphate harbored on glycated high-density lipoprotein restores endothelial Protective Function in type 2 diabetes mellitus
'Springer Science and Business Media LLC', 2014Co-Authors: Tong Xunliang, Mathew Anna, Liu Donghui, Niu Chenguang, Wang Yan, Ji Liang, Li Jizhao, Fu Zhiwei, Pan BingAbstract:National S&T Major Project of China [2008ZX09312-017, 2010CB912504, 2011CB503900]; National Natural Science Foundation of China [81370235, 81170101]; Natural Science Foundation of Beijing [7122106]; PUHSC-University of Michigan JIBackground: Glycation of high-density lipoprotein (HDL) decreases its ability to induce cyclooxygenase-2 (COX-2) expression and prostacyclin I-2 (PGI-2) release in endothelial cells. Whether lipid content of HDL, especially sphingosine-1-phosphate (S1P), plays any specific role in restoring the Protective Function of HDL in type 2 diabetes mellitus (T2DM) is still unknown. Methods and results: Immunochemical techniques demonstrated that glycated HDL loses its Protective Function of regulating COX-2 expression compared with diabetic HDL. We proved that the lipid content, especially phospholipid content differed between diabetic HDL and glycated HDL. Levels of HDL-c-bound S1P were increased in T2DM compared with control subjects as detected by UPLC-MS/MS (HDL-c-bound S1P in control subjects vs. T2DM: 309.1 +/- 13.71 pmol/mg vs. 382.1 +/- 24.45 pmol/mg, P < 0.05). Additionally, mRNA levels of S1P lyase enzymes and S1P phosphatase 1/2 were decreased in peripheral blood by real-time PCR. Antagonist of S1P receptor 1 and 3 (S1PR1/3) diminished the Functional difference between apoHDL&PL (HDL containing the protein components and phospholipids) and diabetic apoHDL&PL (diabetic HDL containing the protein components and phospholipids). With different doses of S1P reconstituted on glycated HDL, its Function in inducing the COX-2 expression was restored to the same level as diabetic HDL. The mechanism of S1P reconstituted HDL (rHDL) in the process of regulating COX-2 expression involved the phosphorylation of ERK/MAPK-CREB signal pathway. Conclusion/Significance: S1P harbored on HDL is the main factor which restores its Protective Function in endothelial cells in T2DM. S1P and its receptors are potential therapeutic targets in ameliorating the vascular dysFunction in T2DM
