Panax notoginseng Saponins Protect Brain Microvascular Endothelial Cells against Oxygen-Glucose Deprivation/Resupply-Induced Necroptosis via Suppression of RIP1-RIP3-MLKL Signaling Pathway
Recently, necroptosis has emerged as one of the important mechanisms of ischemia stroke. Necroptosis can be rapidly activated in endothelial cells to cause vascular damage and neuroinflammation. Panax notoginseng saponins (PNS), an ingredient extracted from the root of Panax notoginseng (Burk.) F.H....
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| Veröffentlicht in: | Neurochemical research 2022-11, Vol.47 (11), p.3261-3271 |
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| creator | Hu, Yanhong Lei, Hongtao Zhang, Sai Ma, Jiabao Kang, Soyeon Wan, Liangqin Li, Fanghe Zhang, Fan Sun, Tianshi Zhang, Chujun Li, Weihong |
| description | Recently, necroptosis has emerged as one of the important mechanisms of ischemia stroke. Necroptosis can be rapidly activated in endothelial cells to cause vascular damage and neuroinflammation.
Panax notoginseng
saponins (PNS), an ingredient extracted from the root of
Panax notoginseng
(Burk.) F.H. Chen, was commonly used for ischemic stroke, while its molecular mechanism and targets have not been fully clarified. Our study aimed to clarify the anti-necroptosis effect of PNS by regulating RIP1-RIP3-MLKL signaling pathway in brain microvascular endothelial cells (BMECs) subjected to transient oxygen-glucose deprivation (OGD/resupply [R]). In vitro, the necroptosis model of rat BMECs was established by testing the effect of OGD/R in the presence of the pan-caspase inhibitor z-VAD-FMK. After administration of PNS and Nec-1, cell viability, cell death modality, the expression of RIP1-RIP3-MLKL pathway and mitochondrial membrane potential (Δψm) level were investigated in BMECs upon OGD/R injury. The results showed that PNS significantly enhanced cell viability of BMECs determined by CCK-8 analysis, and protected BMECs from necroptosis by Flow cytometry and TEM. In addition, PNS inhibited the phosphorylation of RIP1, RIP3, MLKL and the downstream expression of PGAM5 and Drp1, while similar results were observed in Nec-1 intervention. We further investigated whether PNS prevented the Δψm depolarization. Our current findings showed that PNS effectively reduced the occurrence of necroptosis in BMECs exposed to OGD/R by inhibition of the RIP1-RIP3-MLK signaling pathway and mitigation of mitochondrial damage. This study provided a novel insight of PNS application in clinics. |
| doi_str_mv | 10.1007/s11064-022-03675-0 |
| format | Article |
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Panax notoginseng
saponins (PNS), an ingredient extracted from the root of
Panax notoginseng
(Burk.) F.H. Chen, was commonly used for ischemic stroke, while its molecular mechanism and targets have not been fully clarified. Our study aimed to clarify the anti-necroptosis effect of PNS by regulating RIP1-RIP3-MLKL signaling pathway in brain microvascular endothelial cells (BMECs) subjected to transient oxygen-glucose deprivation (OGD/resupply [R]). In vitro, the necroptosis model of rat BMECs was established by testing the effect of OGD/R in the presence of the pan-caspase inhibitor z-VAD-FMK. After administration of PNS and Nec-1, cell viability, cell death modality, the expression of RIP1-RIP3-MLKL pathway and mitochondrial membrane potential (Δψm) level were investigated in BMECs upon OGD/R injury. The results showed that PNS significantly enhanced cell viability of BMECs determined by CCK-8 analysis, and protected BMECs from necroptosis by Flow cytometry and TEM. In addition, PNS inhibited the phosphorylation of RIP1, RIP3, MLKL and the downstream expression of PGAM5 and Drp1, while similar results were observed in Nec-1 intervention. We further investigated whether PNS prevented the Δψm depolarization. Our current findings showed that PNS effectively reduced the occurrence of necroptosis in BMECs exposed to OGD/R by inhibition of the RIP1-RIP3-MLK signaling pathway and mitigation of mitochondrial damage. This study provided a novel insight of PNS application in clinics.</description><identifier>ISSN: 0364-3190</identifier><identifier>EISSN: 1573-6903</identifier><identifier>DOI: 10.1007/s11064-022-03675-0</identifier><identifier>PMID: 35904697</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Animals ; Biochemistry ; Biomedical and Life Sciences ; Biomedicine ; Brain ; Brain - metabolism ; Caspase ; Caspase inhibitors ; Caspases - metabolism ; Caspases - pharmacology ; Cell Biology ; Cell death ; Cell viability ; Cholecystokinin ; Damage ; Depolarization ; Deprivation ; Endothelial cells ; Endothelial Cells - metabolism ; Flow cytometry ; Glucose ; Glucose - metabolism ; Inflammation ; Ischemia ; Kinases ; Membrane potential ; Microvasculature ; Mitochondria ; Necroptosis ; Neurochemistry ; Neurology ; Neurosciences ; Original Paper ; Oxygen ; Oxygen - metabolism ; Panax notoginseng ; Panax notoginseng - chemistry ; Phosphorylation ; Protein Kinases - metabolism ; Rats ; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism ; Saponins ; Saponins - pharmacology ; Signal Transduction ; Signaling ; Stroke</subject><ispartof>Neurochemical research, 2022-11, Vol.47 (11), p.3261-3271</ispartof><rights>The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022</rights><rights>2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.</rights><rights>The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-f3fd61b7ad6929ef6ea4de1b7e19b8b831cf39da15d19b5ae1144604951bae003</citedby><cites>FETCH-LOGICAL-c375t-f3fd61b7ad6929ef6ea4de1b7e19b8b831cf39da15d19b5ae1144604951bae003</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s11064-022-03675-0$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11064-022-03675-0$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35904697$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hu, Yanhong</creatorcontrib><creatorcontrib>Lei, Hongtao</creatorcontrib><creatorcontrib>Zhang, Sai</creatorcontrib><creatorcontrib>Ma, Jiabao</creatorcontrib><creatorcontrib>Kang, Soyeon</creatorcontrib><creatorcontrib>Wan, Liangqin</creatorcontrib><creatorcontrib>Li, Fanghe</creatorcontrib><creatorcontrib>Zhang, Fan</creatorcontrib><creatorcontrib>Sun, Tianshi</creatorcontrib><creatorcontrib>Zhang, Chujun</creatorcontrib><creatorcontrib>Li, Weihong</creatorcontrib><title>Panax notoginseng Saponins Protect Brain Microvascular Endothelial Cells against Oxygen-Glucose Deprivation/Resupply-Induced Necroptosis via Suppression of RIP1-RIP3-MLKL Signaling Pathway</title><title>Neurochemical research</title><addtitle>Neurochem Res</addtitle><addtitle>Neurochem Res</addtitle><description>Recently, necroptosis has emerged as one of the important mechanisms of ischemia stroke. Necroptosis can be rapidly activated in endothelial cells to cause vascular damage and neuroinflammation.
Panax notoginseng
saponins (PNS), an ingredient extracted from the root of
Panax notoginseng
(Burk.) F.H. Chen, was commonly used for ischemic stroke, while its molecular mechanism and targets have not been fully clarified. Our study aimed to clarify the anti-necroptosis effect of PNS by regulating RIP1-RIP3-MLKL signaling pathway in brain microvascular endothelial cells (BMECs) subjected to transient oxygen-glucose deprivation (OGD/resupply [R]). In vitro, the necroptosis model of rat BMECs was established by testing the effect of OGD/R in the presence of the pan-caspase inhibitor z-VAD-FMK. After administration of PNS and Nec-1, cell viability, cell death modality, the expression of RIP1-RIP3-MLKL pathway and mitochondrial membrane potential (Δψm) level were investigated in BMECs upon OGD/R injury. The results showed that PNS significantly enhanced cell viability of BMECs determined by CCK-8 analysis, and protected BMECs from necroptosis by Flow cytometry and TEM. In addition, PNS inhibited the phosphorylation of RIP1, RIP3, MLKL and the downstream expression of PGAM5 and Drp1, while similar results were observed in Nec-1 intervention. We further investigated whether PNS prevented the Δψm depolarization. Our current findings showed that PNS effectively reduced the occurrence of necroptosis in BMECs exposed to OGD/R by inhibition of the RIP1-RIP3-MLK signaling pathway and mitigation of mitochondrial damage. This study provided a novel insight of PNS application in clinics.</description><subject>Animals</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Brain</subject><subject>Brain - metabolism</subject><subject>Caspase</subject><subject>Caspase inhibitors</subject><subject>Caspases - metabolism</subject><subject>Caspases - pharmacology</subject><subject>Cell Biology</subject><subject>Cell death</subject><subject>Cell viability</subject><subject>Cholecystokinin</subject><subject>Damage</subject><subject>Depolarization</subject><subject>Deprivation</subject><subject>Endothelial cells</subject><subject>Endothelial Cells - metabolism</subject><subject>Flow cytometry</subject><subject>Glucose</subject><subject>Glucose - metabolism</subject><subject>Inflammation</subject><subject>Ischemia</subject><subject>Kinases</subject><subject>Membrane potential</subject><subject>Microvasculature</subject><subject>Mitochondria</subject><subject>Necroptosis</subject><subject>Neurochemistry</subject><subject>Neurology</subject><subject>Neurosciences</subject><subject>Original Paper</subject><subject>Oxygen</subject><subject>Oxygen - metabolism</subject><subject>Panax notoginseng</subject><subject>Panax notoginseng - chemistry</subject><subject>Phosphorylation</subject><subject>Protein Kinases - metabolism</subject><subject>Rats</subject><subject>Receptor-Interacting Protein Serine-Threonine Kinases - metabolism</subject><subject>Saponins</subject><subject>Saponins - pharmacology</subject><subject>Signal Transduction</subject><subject>Signaling</subject><subject>Stroke</subject><issn>0364-3190</issn><issn>1573-6903</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kcFu1DAQhi0EokvhBTggS1y4mNpx4qyPsJSyYktXXThHk2SSusraqe0s3Xfj4fCyBSQOXGxr5pt_ZvwT8lLwt4Lz8iwIwVXOeJYxLlVZMP6IzERRSqY0l4_JLEVzJoXmJ-RZCLecp7JMPCUnstA8V7qckR9rsHBPrYuuNzag7ekGRmfTm669i9hE-t6DsfTSNN7tIDTTAJ6e29bFGxwMDHSBwxAo9IkKkV7d73u07GKYGheQfsDRmx1E4-zZNYZpHIc9W9p2arClXzBpjtEFE-jOAN2ktMcQEkxdR6-Xa8HSIdnl6vOKbkxvYTBpxDXEm--wf06edDAEfPFwn5JvH8-_Lj6x1dXFcvFuxRpZFpF1smuVqEtolc40dgohbzEFUOh6Xs-laDqpWxBFmwIFoBB5rniuC1EDci5PyZuj7ujd3YQhVlsTmrQ1WHRTqDKl1byY6yJL6Ot_0Fs3-TR2ososU7zU6iCYHam0fggeuyp90hb8vhK8OnhbHb2tkrfVL2-rQ9GrB-mp3mL7p-S3mQmQRyCklO3R_-39H9mf3KeyqQ</recordid><startdate>20221101</startdate><enddate>20221101</enddate><creator>Hu, Yanhong</creator><creator>Lei, Hongtao</creator><creator>Zhang, Sai</creator><creator>Ma, Jiabao</creator><creator>Kang, Soyeon</creator><creator>Wan, Liangqin</creator><creator>Li, Fanghe</creator><creator>Zhang, Fan</creator><creator>Sun, Tianshi</creator><creator>Zhang, Chujun</creator><creator>Li, Weihong</creator><general>Springer US</general><general>Springer Nature B.V</general><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>3V.</scope><scope>7QR</scope><scope>7TK</scope><scope>7U7</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>20221101</creationdate><title>Panax notoginseng Saponins Protect Brain Microvascular Endothelial Cells against Oxygen-Glucose Deprivation/Resupply-Induced Necroptosis via Suppression of RIP1-RIP3-MLKL Signaling Pathway</title><author>Hu, Yanhong ; Lei, Hongtao ; Zhang, Sai ; Ma, Jiabao ; Kang, Soyeon ; Wan, Liangqin ; Li, Fanghe ; Zhang, Fan ; Sun, Tianshi ; Zhang, Chujun ; Li, Weihong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-f3fd61b7ad6929ef6ea4de1b7e19b8b831cf39da15d19b5ae1144604951bae003</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Brain</topic><topic>Brain - metabolism</topic><topic>Caspase</topic><topic>Caspase inhibitors</topic><topic>Caspases - metabolism</topic><topic>Caspases - pharmacology</topic><topic>Cell Biology</topic><topic>Cell death</topic><topic>Cell viability</topic><topic>Cholecystokinin</topic><topic>Damage</topic><topic>Depolarization</topic><topic>Deprivation</topic><topic>Endothelial cells</topic><topic>Endothelial Cells - metabolism</topic><topic>Flow cytometry</topic><topic>Glucose</topic><topic>Glucose - metabolism</topic><topic>Inflammation</topic><topic>Ischemia</topic><topic>Kinases</topic><topic>Membrane potential</topic><topic>Microvasculature</topic><topic>Mitochondria</topic><topic>Necroptosis</topic><topic>Neurochemistry</topic><topic>Neurology</topic><topic>Neurosciences</topic><topic>Original Paper</topic><topic>Oxygen</topic><topic>Oxygen - metabolism</topic><topic>Panax notoginseng</topic><topic>Panax notoginseng - chemistry</topic><topic>Phosphorylation</topic><topic>Protein Kinases - metabolism</topic><topic>Rats</topic><topic>Receptor-Interacting Protein Serine-Threonine Kinases - metabolism</topic><topic>Saponins</topic><topic>Saponins - pharmacology</topic><topic>Signal Transduction</topic><topic>Signaling</topic><topic>Stroke</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hu, Yanhong</creatorcontrib><creatorcontrib>Lei, Hongtao</creatorcontrib><creatorcontrib>Zhang, Sai</creatorcontrib><creatorcontrib>Ma, Jiabao</creatorcontrib><creatorcontrib>Kang, Soyeon</creatorcontrib><creatorcontrib>Wan, Liangqin</creatorcontrib><creatorcontrib>Li, Fanghe</creatorcontrib><creatorcontrib>Zhang, Fan</creatorcontrib><creatorcontrib>Sun, Tianshi</creatorcontrib><creatorcontrib>Zhang, Chujun</creatorcontrib><creatorcontrib>Li, Weihong</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Neurochemical research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hu, Yanhong</au><au>Lei, Hongtao</au><au>Zhang, Sai</au><au>Ma, Jiabao</au><au>Kang, Soyeon</au><au>Wan, Liangqin</au><au>Li, Fanghe</au><au>Zhang, Fan</au><au>Sun, Tianshi</au><au>Zhang, Chujun</au><au>Li, Weihong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Panax notoginseng Saponins Protect Brain Microvascular Endothelial Cells against Oxygen-Glucose Deprivation/Resupply-Induced Necroptosis via Suppression of RIP1-RIP3-MLKL Signaling Pathway</atitle><jtitle>Neurochemical research</jtitle><stitle>Neurochem Res</stitle><addtitle>Neurochem Res</addtitle><date>2022-11-01</date><risdate>2022</risdate><volume>47</volume><issue>11</issue><spage>3261</spage><epage>3271</epage><pages>3261-3271</pages><issn>0364-3190</issn><eissn>1573-6903</eissn><abstract>Recently, necroptosis has emerged as one of the important mechanisms of ischemia stroke. Necroptosis can be rapidly activated in endothelial cells to cause vascular damage and neuroinflammation.
Panax notoginseng
saponins (PNS), an ingredient extracted from the root of
Panax notoginseng
(Burk.) F.H. Chen, was commonly used for ischemic stroke, while its molecular mechanism and targets have not been fully clarified. Our study aimed to clarify the anti-necroptosis effect of PNS by regulating RIP1-RIP3-MLKL signaling pathway in brain microvascular endothelial cells (BMECs) subjected to transient oxygen-glucose deprivation (OGD/resupply [R]). In vitro, the necroptosis model of rat BMECs was established by testing the effect of OGD/R in the presence of the pan-caspase inhibitor z-VAD-FMK. After administration of PNS and Nec-1, cell viability, cell death modality, the expression of RIP1-RIP3-MLKL pathway and mitochondrial membrane potential (Δψm) level were investigated in BMECs upon OGD/R injury. The results showed that PNS significantly enhanced cell viability of BMECs determined by CCK-8 analysis, and protected BMECs from necroptosis by Flow cytometry and TEM. In addition, PNS inhibited the phosphorylation of RIP1, RIP3, MLKL and the downstream expression of PGAM5 and Drp1, while similar results were observed in Nec-1 intervention. We further investigated whether PNS prevented the Δψm depolarization. Our current findings showed that PNS effectively reduced the occurrence of necroptosis in BMECs exposed to OGD/R by inhibition of the RIP1-RIP3-MLK signaling pathway and mitigation of mitochondrial damage. This study provided a novel insight of PNS application in clinics.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>35904697</pmid><doi>10.1007/s11064-022-03675-0</doi><tpages>11</tpages></addata></record> |
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| subjects | Animals Biochemistry Biomedical and Life Sciences Biomedicine Brain Brain - metabolism Caspase Caspase inhibitors Caspases - metabolism Caspases - pharmacology Cell Biology Cell death Cell viability Cholecystokinin Damage Depolarization Deprivation Endothelial cells Endothelial Cells - metabolism Flow cytometry Glucose Glucose - metabolism Inflammation Ischemia Kinases Membrane potential Microvasculature Mitochondria Necroptosis Neurochemistry Neurology Neurosciences Original Paper Oxygen Oxygen - metabolism Panax notoginseng Panax notoginseng - chemistry Phosphorylation Protein Kinases - metabolism Rats Receptor-Interacting Protein Serine-Threonine Kinases - metabolism Saponins Saponins - pharmacology Signal Transduction Signaling Stroke |
| title | Panax notoginseng Saponins Protect Brain Microvascular Endothelial Cells against Oxygen-Glucose Deprivation/Resupply-Induced Necroptosis via Suppression of RIP1-RIP3-MLKL Signaling Pathway |
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