NO signaling and S-nitrosylation regulate PTEN inhibition in neurodegeneration

<p>Abstract</p> <p>Background</p> <p>The phosphatase PTEN governs the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway which is arguably the most important pro-survival pathway in neurons. Recently, PTEN has also been implicated in multiple important CNS functions such as neuronal differentiation, plasticity, injury and drug addiction. It has been reported that loss of PTEN protein, accompanied by Akt activation, occurs under excitotoxic conditions (stroke) as well as in Alzheimer's (AD) brains. However the molecular signals and mechanism underlying PTEN loss are unknown.</p> <p>Results</p> <p>In this study, we investigated redox regulation of PTEN, namely S-nitrosylation, a covalent modification of cysteine residues by nitric oxide (NO), and H₂O₂-mediated oxidation. We found that S-nitrosylation of PTEN was markedly elevated in brains in the early stages of AD (MCI). Surprisingly, there was no increase in the H₂O₂-mediated oxidation of PTEN, a modification common in cancer cell types, in the MCI/AD brains as compared to normal aged control. Using several cultured neuronal models, we further demonstrate that S-nitrosylation, in conjunction with NO-mediated enhanced ubiquitination, regulates both the lipid phosphatase activity and protein stability of PTEN. S-nitrosylation and oxidation occur on overlapping and distinct Cys residues of PTEN. The NO signal induces PTEN protein degradation via the ubiquitin-proteasome system (UPS) through NEDD4-1-mediated ubiquitination.</p> <p>Conclusion</p> <p>This study demonstrates for the first time that NO-mediated redox regulation is the mechanism of PTEN protein degradation, which is distinguished from the H₂O₂-mediated PTEN oxidation, known to only inactivate the enzyme. This novel regulatory mechanism likely accounts for the PTEN loss observed in neurodegeneration such as in AD, in which NO plays a critical pathophysiological role.</p

Brain Cytosolic Phospholipase A2α Mediates Angiotensin II-Induced Hypertension and Reactive Oxygen Species Production in Male Mice

Abstract BACKGROUND Recently, we reported that angiotensin II (Ang II)-induced hypertension is mediated by group IV cytosolic phospholipase A2α (cPLA2α) via production of prohypertensive eicosanoids. Since Ang II increases blood pressure (BP) via its action in the subfornical organ (SFO), it led us to investigate the expression and possible contribution of cPLA2α to oxidative stress and development of hypertension in this brain area. METHODS Adenovirus (Ad)-green fluorescence protein (GFP) cPLA2α short hairpin (sh) RNA (Ad-cPLA2α shRNA) and its control Ad-scrambled shRNA (Ad-Scr shRNA) or Ad-enhanced cyan fluorescence protein cPLA2α DNA (Ad-cPLA2α DNA) and its control Ad-GFP DNA were transduced into SFO of cPLA2α+/+ and cPLA2α−/− male mice, respectively. Ang II (700 ng/kg/min) was infused for 14 days in these mice, and BP was measured by tail-cuff and radio telemetry. cPLA2 activity, reactive oxygen species production, and endoplasmic reticulum stress were measured in the SFO. RESULTS Transduction of SFO with Ad-cPLA2α shRNA, but not Ad-Scr shRNA in cPLA2α+/+ mice, minimized expression of cPLA2α, Ang II-induced cPLA2α activity and oxidative stress in the SFO, BP, and cardiac and renal fibrosis. In contrast, Ad-cPLA2α DNA, but not its control Ad-GFP DNA in cPLA2α−/− mice, restored the expression of cPLA2α, and Ang II-induced increase in cPLA2 activity and oxidative stress in the SFO, BP, cardiac, and renal fibrosis. CONCLUSIONS These data suggest that cPLA2α in the SFO is crucial in mediating Ang II-induced hypertension and associated pathogenesis. Therefore, development of selective cPLA2α inhibitors could be useful in treating hypertension and its pathogenesis

Food Frontiers : An academically sponsored new journal

n/

Search for a light CP -odd Higgs boson in radiative decays of J /&#968;

none406siWe search for a light Higgs boson A0 in the fully reconstructed decay chain of J/ψ→γA0, A0→μ+μ- using (225.0±2.8)×106 J/ψ events collected by the BESIII experiment. The A0 is a hypothetical CP-odd light Higgs boson predicted by many extensions of the Standard Model including two spin-0 doublets plus an extra singlet. We find no evidence for A0 production and set 90% confidence-level upper limits on the product branching fraction B(J/ψ→γA0)×B(A0→μ+μ-) in the range of (2.8-495.3)×10-8 for 0.212≤mA0≤3.0 GeV/c2. The new limits are five times below our previous results, and the nature of the A0 is constrained to be mostly singlet.noneAblikim, M.; Achasov, M.N.; Ai, X.C.; Albayrak, O.; Albrecht, M.; Ambrose, D.J.; Amoroso, A.; An, F.F.; An, Q.; Bai, J.Z.; Baldini Ferroli, R.; Ban, Y.; Bennett, D.W.; Bennett, J.V.; Bertani, M.; Bettoni, D.; Bian, J.M.; Bianchi, F.; Boger, E.; Boyko, I.; Briere, R.A.; Cai, H.; Cai, X.; Cakir, O.; Calcaterra, A.; Cao, G.F.; Cetin, S.A.; Chang, J.F.; Chelkov, G.; Chen, G.; Chen, H.S.; Chen, H.Y.; Chen, J.C.; Chen, M.L.; Chen, S.J.; Chen, X.; Chen, X.R.; Chen, Y.B.; Cheng, H.P.; Chu, X.K.; Cibinetto, G.; Dai, H.L.; Dai, J.P.; Dbeyssi, A.; Dedovich, D.; Deng, Z.Y.; Denig, A.; Denysenko, I.; Destefanis, M.; De Mori, F.; Ding, Y.; Dong, C.; Dong, J.; Dong, L.Y.; Dong, M.Y.; Dou, Z.L.; Du, S.X.; Duan, P.F.; Fan, J.Z.; Fang, J.; Fang, S.S.; Fang, X.; Fang, Y.; Fava, L.; Feldbauer, F.; Felici, G.; Feng, C.Q.; Fioravanti, E.; Fritsch, M.; Fu, C.D.; Gao, Q.; Gao, X.L.; Gao, X.Y.; Gao, Y.; Gao, Z.; Garzia, I.; Goetzen, K.; Gong, W.X.; Gradl, W.; Greco, M.; Gu, M.H.; Gu, Y.T.; Guan, Y.H.; Guo, A.Q.; Guo, L.B.; Guo, Y.; Guo, Y.P.; Haddadi, Z.; Hafner, A.; Han, S.; Harris, F.A.; He, K.L.; Held, T.; Heng, Y.K.; Hou, Z.L.; Hu, C.; Hu, H.M.; Hu, J.F.; Hu, T.; Hu, Y.; Huang, G.M.; Huang, G.S.; Huang, J.S.; Huang, X.T.; Huang, Y.; Hussain, T.; Ji, Q.; Ji, Q.P.; Ji, X.B.; Ji, X.L.; Jiang, L.W.; Jiang, X.S.; Jiang, X.Y.; Jiao, J.B.; Jiao, Z.; Jin, D.P.; Jin, S.; Johansson, T.; Julin, A.; Kalantar-Nayestanaki, N.; Kang, X.L.; Kang, X.S.; Kavatsyuk, M.; Ke, B.C.; Kiese, P.; Kliemt, R.; Kloss, B.; Kolcu, O.B.; Kopf, B.; Kornicer, M.; Kühn, W.; Kupsc, A.; Lange, J.S.; Lara, M.; Larin, P.; Leng, C.; Li, C.; Li, Cheng; Li, D.M.; Li, F.; Li, F.Y.; Li, G.; Li, H.B.; Li, J.C.; Li, Jin; Li, K.; Li, K.; Li, Lei; Li, P.R.; Li, T.; Li, W.D.; Li, W.G.; Li, X.L.; Li, X.M.; Li, X.N.; Li, X.Q.; Li, Z.B.; Liang, H.; Liang, Y.F.; Liang, Y.T.; Liao, G.R.; Lin, D.X.; Liu, B.J.; Liu, C.X.; Liu, D.; Liu, F.H.; Liu, Fang; Liu, Feng; Liu, H.B.; Liu, H.H.; Liu, H.H.; Liu, H.M.; Liu, J.; Liu, J.B.; Liu, J.P.; Liu, J.Y.; Liu, K.; Liu, K.Y.; Liu, L.D.; Liu, P.L.; Liu, Q.; Liu, S.B.; Liu, X.; Liu, Y.B.; Liu, Z.A.; Liu, Zhiqing; Loehner, H.; Lou, X.C.; Lu, H.J.; Lu, J.G.; Lu, Y.; Lu, Y.P.; Luo, C.L.; Luo, M.X.; Luo, T.; Luo, X.L.; Lyu, X.R.; Ma, F.C.; Ma, H.L.; Ma, L.L.; Ma, Q.M.; Ma, T.; Ma, X.N.; Ma, X.Y.; Maas, F.E.; Maggiora, M.; Mao, Y.J.; Mao, Z.P.; Marcello, S.; Messchendorp, J.G.; Min, J.; Mitchell, R.E.; Mo, X.H.; Mo, Y.J.; Morales Morales, C.; Muchnoi, N. Yu.; Muramatsu, H.; Nefedov, Y.; Nerling, F.; Nikolaev, I.B.; Ning, Z.; Nisar, S.; Niu, S.L.; Niu, X.Y.; Olsen, S.L.; Ouyang, Q.; Pacetti, S.; Pan, Y.; Patteri, P.; Pelizaeus, M.; Peng, H.P.; Peters, K.; Pettersson, J.; Ping, J.L.; Ping, R.G.; Poling, R.; Prasad, V.; Qi, M.; Qian, S.; Qiao, C.F.; Qin, L.Q.; Qin, N.; Qin, X.S.; Qin, Z.H.; Qiu, J.F.; Rashid, K.H.; Redmer, C.F.; Ripka, M.; Rong, G.; Rosner, Ch.; Ruan, X.D.; Santoro, V.; Sarantsev, A.; Savrié, M.; Schoenning, K.; Schumann, S.; Shan, W.; Shao, M.; Shen, C.P.; Shen, P.X.; Shen, X.Y.; Sheng, H.Y.; Song, W.M.; Song, X.Y.; Sosio, S.; Spataro, S.; Sun, G.X.; Sun, J.F.; Sun, S.S.; Sun, Y.J.; Sun, Y.Z.; Sun, Z.J.; Sun, Z.T.; Tang, C.J.; Tang, X.; Tapan, I.; Thorndike, E.H.; Tiemens, M.; Ullrich, M.; Uman, I.; Varner, G.S.; Wang, B.; Wang, B.L.; Wang, D.; Wang, D.Y.; Wang, K.; Wang, L.L.; Wang, L.S.; Wang, M.; Wang, P.; Wang, P.L.; Wang, S.G.; Wang, W.; Wang, W.P.; Wang, X.F.; Wang, Y.D.; Wang, Y.F.; Wang, Y.Q.; Wang, Z.; Wang, Z.G.; Wang, Z.H.; Wang, Z.Y.; Weber, T.; Wei, D.H.; Wei, J.B.; Weidenkaff, P.; Wen, S.P.; Wiedner, U.; Wolke, M.; Wu, L.H.; Wu, Z.; Xia, L.; Xia, L.G.; Xia, Y.; Xiao, D.; Xiao, H.; Xiao, Z.J.; Xie, Y.G.; Xiu, Q.L.; Xu, G.F.; Xu, L.; Xu, Q.J.; Xu, X.P.; Yan, L.; Yan, W.B.; Yan, W.C.; Yan, Y.H.; Yang, H.J.; Yang, H.X.; Yang, L.; Yang, Y.; Yang, Y.Y.; Ye, M.; Ye, M.H.; Yin, J.H.; Yu, B.X.; Yu, C.X.; Yu, J.S.; Yuan, C.Z.; Yuan, W.L.; Yuan, Y.; Yuncu, A.; Zafar, A.A.; Zallo, A.; Zeng, Y.; Zeng, Z.; Zhang, B.X.; Zhang, B.Y.; Zhang, C.; Zhang, C.C.; Zhang, D.H.; Zhang, H.H.; Zhang, H.Y.; Zhang, J.J.; Zhang, J.L.; Zhang, J.Q.; Zhang, J.W.; Zhang, J.Y.; Zhang, J.Z.; Zhang, K.; Zhang, L.; Zhang, X.Y.; Zhang, Y.; Zhang, Y.H.; Zhang, Y.N.; Zhang, Y.T.; Zhang, Yu; Zhang, Z.H.; Zhang, Z.P.; Zhang, Z.Y.; Zhao, G.; Zhao, J.W.; Zhao, J.Y.; Zhao, J.Z.; Zhao, Lei; Zhao, Ling; Zhao, M.G.; Zhao, Q.; Zhao, Q.W.; Zhao, S.J.; Zhao, T.C.; Zhao, Y.B.; Zhao, Z.G.; Zhemchugov, A.; Zheng, B.; Zheng, J.P.; Zheng, W.J.; Zheng, Y.H.; Zhong, B.; Zhou, L.; Zhou, X.; Zhou, X.K.; Zhou, X.R.; Zhou, X.Y.; Zhu, K.; Zhu, K.J.; Zhu, S.; Zhu, S.H.; Zhu, X.L.; Zhu, Y.C.; Zhu, Y.S.; Zhu, Z.A.; Zhuang, J.; Zotti, L.; Zou, B.S.; Zou, J.H.Ablikim, M.; Achasov, M. N.; Ai, X. C.; Albayrak, O.; Albrecht, M.; Ambrose, D. J.; Amoroso, A.; An, F. F.; An, Q.; Bai, J. Z.; Baldini Ferroli, R.; Ban, Y.; Bennett, D. W.; Bennett, J. V.; Bertani, M.; Bettoni, D.; Bian, J. M.; Bianchi, F.; Boger, E.; Boyko, I.; Briere, R. A.; Cai, H.; Cai, X.; Cakir, O.; Calcaterra, A.; Cao, G. F.; Cetin, S. A.; Chang, J. F.; Chelkov, G.; Chen, G.; Chen, H. S.; Chen, H. Y.; Chen, J. C.; Chen, M. L.; Chen, S. J.; Chen, X.; Chen, X. R.; Chen, Y. B.; Cheng, H. P.; Chu, X. K.; Cibinetto, G.; Dai, H. L.; Dai, J. P.; Dbeyssi, A.; Dedovich, D.; Deng, Z. Y.; Denig, A.; Denysenko, I.; Destefanis, M.; De Mori, F.; Ding, Y.; Dong, C.; Dong, J.; Dong, L. Y.; Dong, M. Y.; Dou, Z. L.; Du, S. X.; Duan, P. F.; Fan, J. Z.; Fang, J.; Fang, S. S.; Fang, X.; Fang, Y.; Fava, L.; Feldbauer, F.; Felici, G.; Feng, C. Q.; Fioravanti, E.; Fritsch, M.; Fu, C. D.; Gao, Q.; Gao, X. L.; Gao, X. Y.; Gao, Y.; Gao, Z.; Garzia, I.; Goetzen, K.; Gong, W. X.; Gradl, W.; Greco, M.; Gu, M. H.; Gu, Y. T.; Guan, Y. H.; Guo, A. Q.; Guo, L. B.; Guo, Y.; Guo, Y. P.; Haddadi, Z.; Hafner, A.; Han, S.; Harris, F. A.; He, K. L.; Held, T.; Heng, Y. K.; Hou, Z. L.; Hu, C.; Hu, H. M.; Hu, J. F.; Hu, T.; Hu, Y.; Huang, G. M.; Huang, G. S.; Huang, J. S.; Huang, X. T.; Huang, Y.; Hussain, T.; Ji, Q.; Ji, Q. P.; Ji, X. B.; Ji, X. L.; Jiang, L. W.; Jiang, X. S.; Jiang, X. Y.; Jiao, J. B.; Jiao, Z.; Jin, D. P.; Jin, S.; Johansson, T.; Julin, A.; Kalantar Nayestanaki, N.; Kang, X. L.; Kang, X. S.; Kavatsyuk, M.; Ke, B. C.; Kiese, P.; Kliemt, R.; Kloss, B.; Kolcu, O. B.; Kopf, B.; Kornicer, M.; Kühn, W.; Kupsc, A.; Lange, J. S.; Lara, M.; Larin, P.; Leng, C.; Li, C.; Li, Cheng; Li, D. M.; Li, F.; Li, F. Y.; Li, G.; Li, H. B.; Li, J. C.; Li, Jin; Li, K.; Li, K.; Li, Lei; Li, P. R.; Li, T.; Li, W. D.; Li, W. G.; Li, X. L.; Li, X. M.; Li, X. N.; Li, X. Q.; Li, Z. B.; Liang, H.; Liang, Y. F.; Liang, Y. T.; Liao, G. R.; Lin, D. X.; Liu, B. J.; Liu, C. X.; Liu, D.; Liu, F. H.; Liu, Fang; Liu, Feng; Liu, H. B.; Liu, H. H.; Liu, H. H.; Liu, H. M.; Liu, J.; Liu, J. B.; Liu, J. P.; Liu, J. Y.; Liu, K.; Liu, K. Y.; Liu, L. D.; Liu, P. L.; Liu, Q.; Liu, S. B.; Liu, X.; Liu, Y. B.; Liu, Z. A.; Liu, Zhiqing; Loehner, H.; Lou, X. C.; Lu, H. J.; Lu, J. G.; Lu, Y.; Lu, Y. P.; Luo, C. L.; Luo, M. X.; Luo, T.; Luo, X. L.; Lyu, X. R.; Ma, F. C.; Ma, H. L.; Ma, L. L.; Ma, Q. M.; Ma, T.; Ma, X. N.; Ma, X. Y.; Maas, F. E.; Maggiora, M.; Mao, Y. J.; Mao, Z. P.; Marcello, S.; Messchendorp, J. G.; Min, J.; Mitchell, R. E.; Mo, X. H.; Mo, Y. J.; Morales Morales, C.; Muchnoi, N. Y. u.; Muramatsu, H.; Nefedov, Y.; Nerling, F.; Nikolaev, I. B.; Ning, Z.; Nisar, S.; Niu, S. L.; Niu, X. Y.; Olsen, S. L.; Ouyang, Q.; Pacetti, S.; Pan, Y.; Patteri, P.; Pelizaeus, M.; Peng, H. P.; Peters, K.; Pettersson, J.; Ping, J. L.; Ping, R. G.; Poling, R.; Prasad, V.; Qi, M.; Qian, S.; Qiao, C. F.; Qin, L. Q.; Qin, N.; Qin, X. S.; Qin, Z. H.; Qiu, J. F.; Rashid, K. H.; Redmer, C. F.; Ripka, M.; Rong, G.; Rosner, C. h.; Ruan, X. D.; Santoro, V.; Sarantsev, A.; Savrie', Mauro; Schoenning, K.; Schumann, S.; Shan, W.; Shao, M.; Shen, C. P.; Shen, P. X.; Shen, X. Y.; Sheng, H. Y.; Song, W. M.; Song, X. Y.; Sosio, S.; Spataro, S.; Sun, G. X.; Sun, J. F.; Sun, S. S.; Sun, Y. J.; Sun, Y. Z.; Sun, Z. J.; Sun, Z. T.; Tang, C. J.; Tang, X.; Tapan, I.; Thorndike, E. H.; Tiemens, M.; Ullrich, M.; Uman, I.; Varner, G. S.; Wang, B.; Wang, B. L.; Wang, D.; Wang, D. Y.; Wang, K.; Wang, L. L.; Wang, L. S.; Wang, M.; Wang, P.; Wang, P. L.; Wang, S. G.; Wang, W.; Wang, W. P.; Wang, X. F.; Wang, Y. D.; Wang, Y. F.; Wang, Y. Q.; Wang, Z.; Wang, Z. G.; Wang, Z. H.; Wang, Z. Y.; Weber, T.; Wei, D. H.; Wei, J. B.; Weidenkaff, P.; Wen, S. P.; Wiedner, U.; Wolke, M.; Wu, L. H.; Wu, Z.; Xia, L.; Xia, L. G.; Xia, Y.; Xiao, D.; Xiao, H.; Xiao, Z. J.; Xie, Y. G.; Xiu, Q. L.; Xu, G. F.; Xu, L.; Xu, Q. J.; Xu, X. P.; Yan, L.; Yan, W. B.; Yan, W. C.; Yan, Y. H.; Yang, H. J.; Yang, H. X.; Yang, L.; Yang, Y.; Yang, Y. Y.; Ye, M.; Ye, M. H.; Yin, J. H.; Yu, B. X.; Yu, C. X.; Yu, J. S.; Yuan, C. Z.; Yuan, W. L.; Yuan, Y.; Yuncu, A.; Zafar, A. A.; Zallo, A.; Zeng, Y.; Zeng, Z.; Zhang, B. X.; Zhang, B. Y.; Zhang, C.; Zhang, C. C.; Zhang, D. H.; Zhang, H. H.; Zhang, H. Y.; Zhang, J. J.; Zhang, J. L.; Zhang, J. Q.; Zhang, J. W.; Zhang, J. Y.; Zhang, J. Z.; Zhang, K.; Zhang, L.; Zhang, X. Y.; Zhang, Y.; Zhang, Y. H.; Zhang, Y. N.; Zhang, Y. T.; Zhang, Yu; Zhang, Z. H.; Zhang, Z. P.; Zhang, Z. Y.; Zhao, G.; Zhao, J. W.; Zhao, J. Y.; Zhao, J. Z.; Zhao, Lei; Zhao, Ling; Zhao, M. G.; Zhao, Q.; Zhao, Q. W.; Zhao, S. J.; Zhao, T. C.; Zhao, Y. B.; Zhao, Z. G.; Zhemchugov, A.; Zheng, B.; Zheng, J. P.; Zheng, W. J.; Zheng, Y. H.; Zhong, B.; Zhou, L.; Zhou, X.; Zhou, X. K.; Zhou, X. R.; Zhou, X. Y.; Zhu, K.; Zhu, K. J.; Zhu, S.; Zhu, S. H.; Zhu, X. L.; Zhu, Y. C.; Zhu, Y. S.; Zhu, Z. A.; Zhuang, J.; Zotti, L.; Zou, B. S.; Zou, J. H