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10.1016/j.ebiom.2021.103672 http://scihub22266oqcxt.onion/10.1016/j.ebiom.2021.103672 34740102!8579134!34740102     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=34740102&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       EBioMedicine 2021 ; 73 (ä): 103672 Nephropedia Template TP {{tp|p=34740102|t=2021. alpha-Ketoglutarate Inhibits Thrombosis and Inflammation by Prolyl Hydroxylase-2 Mediated Inactivation of Phospho-Akt |pdf=|usr=}}{{34740102}} gab.com Text alpha-Ketoglutarate Inhibits Thrombosis and Inflammation by Prolyl Hydroxylase-2 Mediated Inactivation of Phospho-Akt JO: EBioMedicine http://www.kidney.de/pget.php?&tw=1&pmid=34740102 #FOAvip BACKGROUND: Phospho-Akt1 (pAkt1) undergoes prolyl hydroxylation at Pro125 and Pro313 by the prolyl hydroxylase-2 (PHD2) in a reaction decarboxylating alpha-ketoglutarate (alphaKG). We investigated whether the alphaKG supplementation could inhibit Akt-mediated activation of platelets and monocytes, in vitro as well as in vivo, by augmenting PHD2 activity. METHODS: We treated platelets or monocytes isolated from healthy individuals with alphaKG in presence of agonists in vitro and assessed the signalling molecules including pAkt1. We supplemented mice with dietary alphaKG and estimated the functional responses of platelets and monocytes ex vivo. Further, we investigated the impact of dietary alphaKG on inflammation and thrombosis in lungs of mice either treated with thrombosis-inducing agent carrageenan or infected with SARS-CoV-2. FINDINGS: Octyl alphaKG supplementation to platelets promoted PHD2 activity through elevated intracellular alphaKG to succinate ratio, and reduced aggregation in vitro by suppressing pAkt1(Thr308). Augmented PHD2 activity was confirmed by increased hydroxylated-proline and enhanced binding of PHD2 to pAkt in alphaKG-treated platelets. Contrastingly, inhibitors of PHD2 significantly increased pAkt1 in platelets. Octyl-alphaKG followed similar mechanism in monocytes to inhibit cytokine secretion in vitro. Our data also describe a suppressed pAkt1 and reduced activation of platelets and leukocytes ex vivo from mice supplemented with dietary alphaKG, unaccompanied by alteration in their number. Dietary alphaKG significantly reduced clot formation and leukocyte accumulation in various organs including lungs of mice treated with thrombosis-inducing agent carrageenan. Importantly, in SARS-CoV-2 infected hamsters, we observed a significant rescue effect of dietary alphaKG on inflamed lungs with significantly reduced leukocyte accumulation, clot formation and viral load alongside down-modulation of pAkt in the lung of the infected animals. INTERPRETATION: Our study suggests that dietary alphaKG supplementation prevents Akt-driven maladies such as thrombosis and inflammation and rescues pathology of COVID19-infected lungs. FUNDING: Study was funded by the Department of Biotechnology (DBT), Govt. of India (grants: BT/PR22881 and BT/PR22985); and the Science and Engineering Research Board, Govt. of India (CRG/000092). Twit Text FOAVip alpha-Ketoglutarate Inhibits Thrombosis and Inflammation by Prolyl Hydroxylase-2 Mediated Inactivation of Phospho-Akt ????EBioMedicine http://www.kidney.de/pget.php?&tw=1&pmid=34740102 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=34740102 #FOAvip English Wikipedia <ref>{{Cite pmid|34740102}}</ref> alpha-Ketoglutarate Inhibits Thrombosis and Inflammation by Prolyl Hydroxylase-2 Mediated Inactivation of Phospho-Akt #MMPMID34740102 Shrimali NM; Agarwal S; Kaur S; Bhattacharya S; Bhattacharyya S; Prchal JT; Guchhait P EBioMedicine 2021[Nov]; 73 (ä): 103672 PMID34740102show ga BACKGROUND: Phospho-Akt1 (pAkt1) undergoes prolyl hydroxylation at Pro125 and Pro313 by the prolyl hydroxylase-2 (PHD2) in a reaction decarboxylating alpha-ketoglutarate (alphaKG). We investigated whether the alphaKG supplementation could inhibit Akt-mediated activation of platelets and monocytes, in vitro as well as in vivo, by augmenting PHD2 activity. METHODS: We treated platelets or monocytes isolated from healthy individuals with alphaKG in presence of agonists in vitro and assessed the signalling molecules including pAkt1. We supplemented mice with dietary alphaKG and estimated the functional responses of platelets and monocytes ex vivo. Further, we investigated the impact of dietary alphaKG on inflammation and thrombosis in lungs of mice either treated with thrombosis-inducing agent carrageenan or infected with SARS-CoV-2. FINDINGS: Octyl alphaKG supplementation to platelets promoted PHD2 activity through elevated intracellular alphaKG to succinate ratio, and reduced aggregation in vitro by suppressing pAkt1(Thr308). Augmented PHD2 activity was confirmed by increased hydroxylated-proline and enhanced binding of PHD2 to pAkt in alphaKG-treated platelets. Contrastingly, inhibitors of PHD2 significantly increased pAkt1 in platelets. Octyl-alphaKG followed similar mechanism in monocytes to inhibit cytokine secretion in vitro. Our data also describe a suppressed pAkt1 and reduced activation of platelets and leukocytes ex vivo from mice supplemented with dietary alphaKG, unaccompanied by alteration in their number. Dietary alphaKG significantly reduced clot formation and leukocyte accumulation in various organs including lungs of mice treated with thrombosis-inducing agent carrageenan. Importantly, in SARS-CoV-2 infected hamsters, we observed a significant rescue effect of dietary alphaKG on inflamed lungs with significantly reduced leukocyte accumulation, clot formation and viral load alongside down-modulation of pAkt in the lung of the infected animals. INTERPRETATION: Our study suggests that dietary alphaKG supplementation prevents Akt-driven maladies such as thrombosis and inflammation and rescues pathology of COVID19-infected lungs. FUNDING: Study was funded by the Department of Biotechnology (DBT), Govt. of India (grants: BT/PR22881 and BT/PR22985); and the Science and Engineering Research Board, Govt. of India (CRG/000092). |Animals[MESH] |Blood Platelets/cytology/drug effects/metabolism[MESH] |COVID-19/pathology/prevention & control/veterinary/virology[MESH] |Cricetinae[MESH] |Dietary Supplements[MESH] |Down-Regulation/drug effects[MESH] |Humans[MESH] |Ketoglutaric Acids/pharmacology/*therapeutic use[MESH] |Lung/metabolism/pathology[MESH] |Mesocricetus[MESH] |Mice[MESH] |Mice, Inbred BALB C[MESH] |Monocytes/cytology/drug effects/metabolism[MESH] |Phosphorylation[MESH] |Platelet Aggregation/drug effects[MESH] |Prolyl Hydroxylases/*metabolism[MESH] |Protein Isoforms/genetics/metabolism[MESH] |Proto-Oncogene Proteins c-akt/genetics/*metabolism[MESH] |SARS-CoV-2/isolation & purification/physiology[MESH]alpha-Ketoglutarate Inhibits Thrombosis and Inflammation by Prolyl Hyd(epmc).pdf DeepDyve Pubget Overpricing