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A Nuclear Attack on Traumatic Brain Injury: Sequestration of Cell Death in the Nucleus
Summary Background Exportin 1 (XPO1/CRM1) plays prominent roles in the regulation of nuclear protein export. Selective inhibitors of nuclear export (SINE) are small orally bioavailable molecules that serve as drug‐like inhibitors of XPO1, with potent anti‐cancer properties. Traumatic brain injury (T...
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| Published in: | CNS neuroscience & therapeutics 2016-04, Vol.22 (4), p.306-315 |
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| container_issue | 4 |
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| container_title | CNS neuroscience & therapeutics |
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| creator | Tajiri, Naoki De La Peña, Ike Acosta, Sandra A. Kaneko, Yuji Tamir, Sharon Landesman, Yosef Carlson, Robert Shacham, Sharon Borlongan, Cesar V. |
| description | Summary
Background
Exportin 1 (XPO1/CRM1) plays prominent roles in the regulation of nuclear protein export. Selective inhibitors of nuclear export (SINE) are small orally bioavailable molecules that serve as drug‐like inhibitors of XPO1, with potent anti‐cancer properties. Traumatic brain injury (TBI) presents with a secondary cell death characterized by neuroinflammation that is putatively regulated by nuclear receptors.
Aims and Results
Here, we report that the SINE compounds (KPT‐350 or KPT‐335) sequestered TBI‐induced neuroinflammation‐related proteins (NF‐kB, AKT, FOXP1) within the nucleus of cultured primary rat cortical neurons, which coincided with protection against TNF‐α (20 ng/mL)‐induced neurotoxicity as shown by at least 50% and 100% increments in preservation of cell viability and cellular enzymatic activity, respectively, compared to non‐treated neuronal cells (P's |
| doi_str_mv | 10.1111/cns.12501 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5067638</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3992230971</sourcerecordid><originalsourceid>FETCH-LOGICAL-c6121-288e6db180556b23e2e3d683df9006d9057444ffe6e974d5f35b41f69e24f44b3</originalsourceid><addsrcrecordid>eNp1kctKxDAUhoMo3he-gATc6GI0SXNpXAjjeAXRhZdtSNsTp2On1aRV5u2NVgcVzOYEzsfHf_gR2qJkn8Z3kNdhnzJB6AJapUqIgdBcL87_CVlBayFMCJEs1ekyWmEy5UxytYoehvi6yyuwHg_b1uZPuKnxnbfd1LZljo-9LWt8WU86PzvEt_DSQWh9XEWqcXgEVYVPwLZjHLF2DL2sCxtoydkqwObXXEf3Z6d3o4vB1c355Wh4NcglZXTA0hRkkdGUCCEzlgCDpJBpUjgdwxaaCMU5dw4kaMUL4RKRceqkBsYd51myjo5673OXTaHIoY7pKvPsy6n1M9PY0vze1OXYPDavRhCpZJJGwe6XwDefx5lpGfJ4lq2h6YKhKmZjhGkd0Z0_6KTpfB3Pi5TiUgmieKT2eir3TQge3DwMJeajLRPbMp9tRXb7Z_o5-V1PBA564K2sYPa_yYyub3vlO-3KnW0</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1774675074</pqid></control><display><type>article</type><title>A Nuclear Attack on Traumatic Brain Injury: Sequestration of Cell Death in the Nucleus</title><source>Wiley Open Access</source><source>PubMed Central</source><creator>Tajiri, Naoki ; De La Peña, Ike ; Acosta, Sandra A. ; Kaneko, Yuji ; Tamir, Sharon ; Landesman, Yosef ; Carlson, Robert ; Shacham, Sharon ; Borlongan, Cesar V.</creator><creatorcontrib>Tajiri, Naoki ; De La Peña, Ike ; Acosta, Sandra A. ; Kaneko, Yuji ; Tamir, Sharon ; Landesman, Yosef ; Carlson, Robert ; Shacham, Sharon ; Borlongan, Cesar V.</creatorcontrib><description>Summary
Background
Exportin 1 (XPO1/CRM1) plays prominent roles in the regulation of nuclear protein export. Selective inhibitors of nuclear export (SINE) are small orally bioavailable molecules that serve as drug‐like inhibitors of XPO1, with potent anti‐cancer properties. Traumatic brain injury (TBI) presents with a secondary cell death characterized by neuroinflammation that is putatively regulated by nuclear receptors.
Aims and Results
Here, we report that the SINE compounds (KPT‐350 or KPT‐335) sequestered TBI‐induced neuroinflammation‐related proteins (NF‐kB, AKT, FOXP1) within the nucleus of cultured primary rat cortical neurons, which coincided with protection against TNF‐α (20 ng/mL)‐induced neurotoxicity as shown by at least 50% and 100% increments in preservation of cell viability and cellular enzymatic activity, respectively, compared to non‐treated neuronal cells (P's < 0.05). In parallel, using an in vivo controlled cortical impact (CCI) model of TBI, we demonstrate that adult Sprague‐Dawley rats treated post‐injury with SINE compounds exhibited significant reductions in TBI‐induced behavioral and histological deficits. Animals that received KPT‐350 orally starting at 2 h post‐TBI and once a day thereafter over the next 4 days exhibited significantly better motor coordination, and balance in the rotorod test and motor asymmetry test by 100–200% improvements, as early as 4 h after initial SINE compound injection that was sustained during subsequent KPT‐350 dosing, and throughout the 18‐day post‐TBI study period compared to vehicle treatment (P's < 0.05). Moreover, KPT‐350 reduced cortical core impact area and peri‐impact cell death compared to vehicle treatment (P's < 0.05).
Conclusions
Both in vitro and in vivo experiments revealed that KPT‐350 increased XPO1, AKT, and FOXP1 nuclear expression and relegated NF‐kB expression within the neuronal nuclei. Altogether, these findings advance the utility of SINE compounds to stop trafficking of cell death proteins within the nucleus as an efficacious treatment for TBI.</description><identifier>ISSN: 1755-5930</identifier><identifier>EISSN: 1755-5949</identifier><identifier>DOI: 10.1111/cns.12501</identifier><identifier>PMID: 26842647</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>Acrylamides - pharmacology ; Active Transport, Cell Nucleus - drug effects ; Active Transport, Cell Nucleus - physiology ; Animals ; Brain - drug effects ; Brain - pathology ; Brain - physiopathology ; Brain Injuries, Traumatic - drug therapy ; Brain Injuries, Traumatic - pathology ; Brain Injuries, Traumatic - physiopathology ; Cell Death - drug effects ; Cell Death - physiology ; Cell death protein trafficking ; Cell Nucleus - drug effects ; Cell Nucleus - metabolism ; Cell Nucleus - pathology ; Cell Survival - drug effects ; Cell Survival - physiology ; Cells, Cultured ; Disease Models, Animal ; Forkhead Transcription Factors - metabolism ; Hydrazines - pharmacology ; Male ; Motor Activity - drug effects ; Motor Activity - physiology ; Neuroimmunomodulation - drug effects ; Neuroimmunomodulation - physiology ; Neuroinflammation ; Neuroprotective Agents - pharmacology ; NF-kappa B - metabolism ; Nuclear export inhibitor ; Original ; Proto-Oncogene Proteins c-akt - metabolism ; Rats, Sprague-Dawley ; Recovery of Function - drug effects ; Recovery of Function - physiology ; Repressor Proteins - metabolism ; Secondary cell death ; Tumor Necrosis Factor-alpha - metabolism</subject><ispartof>CNS neuroscience & therapeutics, 2016-04, Vol.22 (4), p.306-315</ispartof><rights>2016 The Authors. published by John Wiley & Sons Ltd.</rights><rights>2016 John Wiley & Sons Ltd.</rights><rights>Copyright © 2016 John Wiley & Sons Ltd</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6121-288e6db180556b23e2e3d683df9006d9057444ffe6e974d5f35b41f69e24f44b3</citedby><cites>FETCH-LOGICAL-c6121-288e6db180556b23e2e3d683df9006d9057444ffe6e974d5f35b41f69e24f44b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067638/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067638/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,11561,27923,27924,46051,46475,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26842647$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tajiri, Naoki</creatorcontrib><creatorcontrib>De La Peña, Ike</creatorcontrib><creatorcontrib>Acosta, Sandra A.</creatorcontrib><creatorcontrib>Kaneko, Yuji</creatorcontrib><creatorcontrib>Tamir, Sharon</creatorcontrib><creatorcontrib>Landesman, Yosef</creatorcontrib><creatorcontrib>Carlson, Robert</creatorcontrib><creatorcontrib>Shacham, Sharon</creatorcontrib><creatorcontrib>Borlongan, Cesar V.</creatorcontrib><title>A Nuclear Attack on Traumatic Brain Injury: Sequestration of Cell Death in the Nucleus</title><title>CNS neuroscience & therapeutics</title><addtitle>CNS Neurosci Ther</addtitle><description>Summary
Background
Exportin 1 (XPO1/CRM1) plays prominent roles in the regulation of nuclear protein export. Selective inhibitors of nuclear export (SINE) are small orally bioavailable molecules that serve as drug‐like inhibitors of XPO1, with potent anti‐cancer properties. Traumatic brain injury (TBI) presents with a secondary cell death characterized by neuroinflammation that is putatively regulated by nuclear receptors.
Aims and Results
Here, we report that the SINE compounds (KPT‐350 or KPT‐335) sequestered TBI‐induced neuroinflammation‐related proteins (NF‐kB, AKT, FOXP1) within the nucleus of cultured primary rat cortical neurons, which coincided with protection against TNF‐α (20 ng/mL)‐induced neurotoxicity as shown by at least 50% and 100% increments in preservation of cell viability and cellular enzymatic activity, respectively, compared to non‐treated neuronal cells (P's < 0.05). In parallel, using an in vivo controlled cortical impact (CCI) model of TBI, we demonstrate that adult Sprague‐Dawley rats treated post‐injury with SINE compounds exhibited significant reductions in TBI‐induced behavioral and histological deficits. Animals that received KPT‐350 orally starting at 2 h post‐TBI and once a day thereafter over the next 4 days exhibited significantly better motor coordination, and balance in the rotorod test and motor asymmetry test by 100–200% improvements, as early as 4 h after initial SINE compound injection that was sustained during subsequent KPT‐350 dosing, and throughout the 18‐day post‐TBI study period compared to vehicle treatment (P's < 0.05). Moreover, KPT‐350 reduced cortical core impact area and peri‐impact cell death compared to vehicle treatment (P's < 0.05).
Conclusions
Both in vitro and in vivo experiments revealed that KPT‐350 increased XPO1, AKT, and FOXP1 nuclear expression and relegated NF‐kB expression within the neuronal nuclei. Altogether, these findings advance the utility of SINE compounds to stop trafficking of cell death proteins within the nucleus as an efficacious treatment for TBI.</description><subject>Acrylamides - pharmacology</subject><subject>Active Transport, Cell Nucleus - drug effects</subject><subject>Active Transport, Cell Nucleus - physiology</subject><subject>Animals</subject><subject>Brain - drug effects</subject><subject>Brain - pathology</subject><subject>Brain - physiopathology</subject><subject>Brain Injuries, Traumatic - drug therapy</subject><subject>Brain Injuries, Traumatic - pathology</subject><subject>Brain Injuries, Traumatic - physiopathology</subject><subject>Cell Death - drug effects</subject><subject>Cell Death - physiology</subject><subject>Cell death protein trafficking</subject><subject>Cell Nucleus - drug effects</subject><subject>Cell Nucleus - metabolism</subject><subject>Cell Nucleus - pathology</subject><subject>Cell Survival - drug effects</subject><subject>Cell Survival - physiology</subject><subject>Cells, Cultured</subject><subject>Disease Models, Animal</subject><subject>Forkhead Transcription Factors - metabolism</subject><subject>Hydrazines - pharmacology</subject><subject>Male</subject><subject>Motor Activity - drug effects</subject><subject>Motor Activity - physiology</subject><subject>Neuroimmunomodulation - drug effects</subject><subject>Neuroimmunomodulation - physiology</subject><subject>Neuroinflammation</subject><subject>Neuroprotective Agents - pharmacology</subject><subject>NF-kappa B - metabolism</subject><subject>Nuclear export inhibitor</subject><subject>Original</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Rats, Sprague-Dawley</subject><subject>Recovery of Function - drug effects</subject><subject>Recovery of Function - physiology</subject><subject>Repressor Proteins - metabolism</subject><subject>Secondary cell death</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><issn>1755-5930</issn><issn>1755-5949</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><recordid>eNp1kctKxDAUhoMo3he-gATc6GI0SXNpXAjjeAXRhZdtSNsTp2On1aRV5u2NVgcVzOYEzsfHf_gR2qJkn8Z3kNdhnzJB6AJapUqIgdBcL87_CVlBayFMCJEs1ekyWmEy5UxytYoehvi6yyuwHg_b1uZPuKnxnbfd1LZljo-9LWt8WU86PzvEt_DSQWh9XEWqcXgEVYVPwLZjHLF2DL2sCxtoydkqwObXXEf3Z6d3o4vB1c355Wh4NcglZXTA0hRkkdGUCCEzlgCDpJBpUjgdwxaaCMU5dw4kaMUL4RKRceqkBsYd51myjo5673OXTaHIoY7pKvPsy6n1M9PY0vze1OXYPDavRhCpZJJGwe6XwDefx5lpGfJ4lq2h6YKhKmZjhGkd0Z0_6KTpfB3Pi5TiUgmieKT2eir3TQge3DwMJeajLRPbMp9tRXb7Z_o5-V1PBA564K2sYPa_yYyub3vlO-3KnW0</recordid><startdate>201604</startdate><enddate>201604</enddate><creator>Tajiri, Naoki</creator><creator>De La Peña, Ike</creator><creator>Acosta, Sandra A.</creator><creator>Kaneko, Yuji</creator><creator>Tamir, Sharon</creator><creator>Landesman, Yosef</creator><creator>Carlson, Robert</creator><creator>Shacham, Sharon</creator><creator>Borlongan, Cesar V.</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>K9.</scope><scope>5PM</scope></search><sort><creationdate>201604</creationdate><title>A Nuclear Attack on Traumatic Brain Injury: Sequestration of Cell Death in the Nucleus</title><author>Tajiri, Naoki ; De La Peña, Ike ; Acosta, Sandra A. ; Kaneko, Yuji ; Tamir, Sharon ; Landesman, Yosef ; Carlson, Robert ; Shacham, Sharon ; Borlongan, Cesar V.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c6121-288e6db180556b23e2e3d683df9006d9057444ffe6e974d5f35b41f69e24f44b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Acrylamides - pharmacology</topic><topic>Active Transport, Cell Nucleus - drug effects</topic><topic>Active Transport, Cell Nucleus - physiology</topic><topic>Animals</topic><topic>Brain - drug effects</topic><topic>Brain - pathology</topic><topic>Brain - physiopathology</topic><topic>Brain Injuries, Traumatic - drug therapy</topic><topic>Brain Injuries, Traumatic - pathology</topic><topic>Brain Injuries, Traumatic - physiopathology</topic><topic>Cell Death - drug effects</topic><topic>Cell Death - physiology</topic><topic>Cell death protein trafficking</topic><topic>Cell Nucleus - drug effects</topic><topic>Cell Nucleus - metabolism</topic><topic>Cell Nucleus - pathology</topic><topic>Cell Survival - drug effects</topic><topic>Cell Survival - physiology</topic><topic>Cells, Cultured</topic><topic>Disease Models, Animal</topic><topic>Forkhead Transcription Factors - metabolism</topic><topic>Hydrazines - pharmacology</topic><topic>Male</topic><topic>Motor Activity - drug effects</topic><topic>Motor Activity - physiology</topic><topic>Neuroimmunomodulation - drug effects</topic><topic>Neuroimmunomodulation - physiology</topic><topic>Neuroinflammation</topic><topic>Neuroprotective Agents - pharmacology</topic><topic>NF-kappa B - metabolism</topic><topic>Nuclear export inhibitor</topic><topic>Original</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Rats, Sprague-Dawley</topic><topic>Recovery of Function - drug effects</topic><topic>Recovery of Function - physiology</topic><topic>Repressor Proteins - metabolism</topic><topic>Secondary cell death</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tajiri, Naoki</creatorcontrib><creatorcontrib>De La Peña, Ike</creatorcontrib><creatorcontrib>Acosta, Sandra A.</creatorcontrib><creatorcontrib>Kaneko, Yuji</creatorcontrib><creatorcontrib>Tamir, Sharon</creatorcontrib><creatorcontrib>Landesman, Yosef</creatorcontrib><creatorcontrib>Carlson, Robert</creatorcontrib><creatorcontrib>Shacham, Sharon</creatorcontrib><creatorcontrib>Borlongan, Cesar V.</creatorcontrib><collection>Wiley Open Access</collection><collection>Wiley Online Library Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>CNS neuroscience & therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tajiri, Naoki</au><au>De La Peña, Ike</au><au>Acosta, Sandra A.</au><au>Kaneko, Yuji</au><au>Tamir, Sharon</au><au>Landesman, Yosef</au><au>Carlson, Robert</au><au>Shacham, Sharon</au><au>Borlongan, Cesar V.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Nuclear Attack on Traumatic Brain Injury: Sequestration of Cell Death in the Nucleus</atitle><jtitle>CNS neuroscience & therapeutics</jtitle><addtitle>CNS Neurosci Ther</addtitle><date>2016-04</date><risdate>2016</risdate><volume>22</volume><issue>4</issue><spage>306</spage><epage>315</epage><pages>306-315</pages><issn>1755-5930</issn><eissn>1755-5949</eissn><abstract>Summary
Background
Exportin 1 (XPO1/CRM1) plays prominent roles in the regulation of nuclear protein export. Selective inhibitors of nuclear export (SINE) are small orally bioavailable molecules that serve as drug‐like inhibitors of XPO1, with potent anti‐cancer properties. Traumatic brain injury (TBI) presents with a secondary cell death characterized by neuroinflammation that is putatively regulated by nuclear receptors.
Aims and Results
Here, we report that the SINE compounds (KPT‐350 or KPT‐335) sequestered TBI‐induced neuroinflammation‐related proteins (NF‐kB, AKT, FOXP1) within the nucleus of cultured primary rat cortical neurons, which coincided with protection against TNF‐α (20 ng/mL)‐induced neurotoxicity as shown by at least 50% and 100% increments in preservation of cell viability and cellular enzymatic activity, respectively, compared to non‐treated neuronal cells (P's < 0.05). In parallel, using an in vivo controlled cortical impact (CCI) model of TBI, we demonstrate that adult Sprague‐Dawley rats treated post‐injury with SINE compounds exhibited significant reductions in TBI‐induced behavioral and histological deficits. Animals that received KPT‐350 orally starting at 2 h post‐TBI and once a day thereafter over the next 4 days exhibited significantly better motor coordination, and balance in the rotorod test and motor asymmetry test by 100–200% improvements, as early as 4 h after initial SINE compound injection that was sustained during subsequent KPT‐350 dosing, and throughout the 18‐day post‐TBI study period compared to vehicle treatment (P's < 0.05). Moreover, KPT‐350 reduced cortical core impact area and peri‐impact cell death compared to vehicle treatment (P's < 0.05).
Conclusions
Both in vitro and in vivo experiments revealed that KPT‐350 increased XPO1, AKT, and FOXP1 nuclear expression and relegated NF‐kB expression within the neuronal nuclei. Altogether, these findings advance the utility of SINE compounds to stop trafficking of cell death proteins within the nucleus as an efficacious treatment for TBI.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>26842647</pmid><doi>10.1111/cns.12501</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | CNS neuroscience & therapeutics, 2016-04, Vol.22 (4), p.306-315 |
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| language | eng |
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| source | Wiley Open Access; PubMed Central |
| subjects | Acrylamides - pharmacology Active Transport, Cell Nucleus - drug effects Active Transport, Cell Nucleus - physiology Animals Brain - drug effects Brain - pathology Brain - physiopathology Brain Injuries, Traumatic - drug therapy Brain Injuries, Traumatic - pathology Brain Injuries, Traumatic - physiopathology Cell Death - drug effects Cell Death - physiology Cell death protein trafficking Cell Nucleus - drug effects Cell Nucleus - metabolism Cell Nucleus - pathology Cell Survival - drug effects Cell Survival - physiology Cells, Cultured Disease Models, Animal Forkhead Transcription Factors - metabolism Hydrazines - pharmacology Male Motor Activity - drug effects Motor Activity - physiology Neuroimmunomodulation - drug effects Neuroimmunomodulation - physiology Neuroinflammation Neuroprotective Agents - pharmacology NF-kappa B - metabolism Nuclear export inhibitor Original Proto-Oncogene Proteins c-akt - metabolism Rats, Sprague-Dawley Recovery of Function - drug effects Recovery of Function - physiology Repressor Proteins - metabolism Secondary cell death Tumor Necrosis Factor-alpha - metabolism |
| title | A Nuclear Attack on Traumatic Brain Injury: Sequestration of Cell Death in the Nucleus |
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