Buyang huanwu decoction inhibits the activation of the RhoA/Rock2 signaling pathway through the phenylalanine metabolism pathway, thereby reducing neuronal apoptosis following cerebral ischemia-reperfusion injury
Buyang Huanwu Decoction (BYHWD) exerts its anti-cerebral ischemia effects through multiple pathways and targets, although its specific mechanisms remain unclear. Ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF-MS) metabolomics and other methods w...
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| creator | Li, Yanling Hu, Zhongji Xie, Linli Xiong, Tingting Zhang, Yanyan Bai, Yang Ding, Huang Huang, Xiaoping Liu, Xiaodan Deng, Changqing |
| description | Buyang Huanwu Decoction (BYHWD) exerts its anti-cerebral ischemia effects through multiple pathways and targets, although its specific mechanisms remain unclear.
Ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF-MS) metabolomics and other methods were employed to investigate the role of BYHWD in inhibiting neuronal apoptosis following cerebral ischemia-reperfusion by modulating the RhoA/Rock2 pathway.
A rat model of exhaustion swimming combined with middle cerebral artery occlusion (ES + I/R) was established to evaluate the intervention effects of Buyang Huanwu Decoction on cerebral ischemia-reperfusion. This was assessed using neurological function scores, Qi deficiency and blood stasis syndrome scores, HE staining, Nissl staining and TT staining. Differential metabolites and metabolic pathways associated with cerebral ischemia-reperfusion were identified using UPLC-QTOF-MS metabolomics, with key differential metabolites validated through ELISA. Molecular docking techniques were employed to predict interactions between the key differential metabolite, hippuric acid, and its primary downstream pathways. Finally, the levels of neurocellular apoptosis, as well as key molecules in the RhoA/Rock2 signaling pathway and the mitochondrial apoptosis pathway, were measured.
The results indicated that the primary differential metabolites associated with BYHWD's protective effects against ischemia-reperfusion injury were hippuric acid, lysophosphatidic acid, and lysophosphatidylethanolamine, with the main metabolic pathway being phenylalanine metabolism. Molecular docking studies demonstrated that malonic acid exhibited a strong affinity for proteins related to the RhoA/Rock2 signaling pathway and the mitochondrial apoptosis pathway.Furthermore, we found that BYHWD treatment significantly decreased the apoptosis rate of cells following cerebral ischemia-reperfusion and inhibited the expression of key molecules in both the RhoA/Rock2 signaling pathway and the mitochondrial apoptosis pathway in brain tissue.
BYHWD ameliorated brain tissue injury after cerebral ischemia/reperfusion in rats with qi deficiency and blood stasis. The underlying mechanism may involve BYHWD's inhibition of the RhoA/Rock2 signaling pathway activation through modulation of the phenylalanine metabolism pathway, thereby reducing neuronal apoptosis mediated by the mitochondrial apoptosis pathway.
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•This study employs a rat exhaus |
| doi_str_mv | 10.1016/j.jep.2024.119246 |
| format | Article |
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Ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF-MS) metabolomics and other methods were employed to investigate the role of BYHWD in inhibiting neuronal apoptosis following cerebral ischemia-reperfusion by modulating the RhoA/Rock2 pathway.
A rat model of exhaustion swimming combined with middle cerebral artery occlusion (ES + I/R) was established to evaluate the intervention effects of Buyang Huanwu Decoction on cerebral ischemia-reperfusion. This was assessed using neurological function scores, Qi deficiency and blood stasis syndrome scores, HE staining, Nissl staining and TT staining. Differential metabolites and metabolic pathways associated with cerebral ischemia-reperfusion were identified using UPLC-QTOF-MS metabolomics, with key differential metabolites validated through ELISA. Molecular docking techniques were employed to predict interactions between the key differential metabolite, hippuric acid, and its primary downstream pathways. Finally, the levels of neurocellular apoptosis, as well as key molecules in the RhoA/Rock2 signaling pathway and the mitochondrial apoptosis pathway, were measured.
The results indicated that the primary differential metabolites associated with BYHWD's protective effects against ischemia-reperfusion injury were hippuric acid, lysophosphatidic acid, and lysophosphatidylethanolamine, with the main metabolic pathway being phenylalanine metabolism. Molecular docking studies demonstrated that malonic acid exhibited a strong affinity for proteins related to the RhoA/Rock2 signaling pathway and the mitochondrial apoptosis pathway.Furthermore, we found that BYHWD treatment significantly decreased the apoptosis rate of cells following cerebral ischemia-reperfusion and inhibited the expression of key molecules in both the RhoA/Rock2 signaling pathway and the mitochondrial apoptosis pathway in brain tissue.
BYHWD ameliorated brain tissue injury after cerebral ischemia/reperfusion in rats with qi deficiency and blood stasis. The underlying mechanism may involve BYHWD's inhibition of the RhoA/Rock2 signaling pathway activation through modulation of the phenylalanine metabolism pathway, thereby reducing neuronal apoptosis mediated by the mitochondrial apoptosis pathway.
[Display omitted]
•This study employs a rat exhaustion swimming + MCAO/R combined disease model to investigate the mechanism of action of BYHWD.•The downstream pathways of differential metabolites were validated using a combination of metabolomics and molecular docking.•BYHWD protects neurons from apoptosis by regulating phenylalanine metabolism.</description><identifier>ISSN: 0378-8741</identifier><identifier>ISSN: 1872-7573</identifier><identifier>EISSN: 1872-7573</identifier><identifier>DOI: 10.1016/j.jep.2024.119246</identifier><identifier>PMID: 39681201</identifier><language>eng</language><publisher>Ireland: Elsevier B.V</publisher><subject>Animals ; Apoptosis ; Apoptosis - drug effects ; Brain Ischemia - drug therapy ; Brain Ischemia - metabolism ; BYHWD ; Cerebral ischemia-reperfusion injury ; Disease Models, Animal ; Drugs, Chinese Herbal - pharmacology ; Infarction, Middle Cerebral Artery - drug therapy ; Infarction, Middle Cerebral Artery - metabolism ; Infarction, Middle Cerebral Artery - pathology ; Male ; Metabolomics ; Molecular Docking Simulation ; Neurons - drug effects ; Neurons - metabolism ; Neurons - pathology ; Neuroprotective Agents - pharmacology ; Phenylalanine - analogs & derivatives ; Phenylalanine - pharmacology ; Phenylalanine metabolic pathway ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury - drug therapy ; Reperfusion Injury - metabolism ; rho GTP-Binding Proteins - metabolism ; rho-Associated Kinases - metabolism ; RhoA/Rock2 signalling pathway ; Signal Transduction - drug effects</subject><ispartof>Journal of ethnopharmacology, 2025-01, Vol.340, p.119246, Article 119246</ispartof><rights>2024 Elsevier B.V.</rights><rights>Copyright © 2024 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c235t-383e0ed84f6bd84cc4a7d98d0fdf90e1e64802bfd1cd6ed1460d224def332b863</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0378874124015459$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39681201$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Yanling</creatorcontrib><creatorcontrib>Hu, Zhongji</creatorcontrib><creatorcontrib>Xie, Linli</creatorcontrib><creatorcontrib>Xiong, Tingting</creatorcontrib><creatorcontrib>Zhang, Yanyan</creatorcontrib><creatorcontrib>Bai, Yang</creatorcontrib><creatorcontrib>Ding, Huang</creatorcontrib><creatorcontrib>Huang, Xiaoping</creatorcontrib><creatorcontrib>Liu, Xiaodan</creatorcontrib><creatorcontrib>Deng, Changqing</creatorcontrib><title>Buyang huanwu decoction inhibits the activation of the RhoA/Rock2 signaling pathway through the phenylalanine metabolism pathway, thereby reducing neuronal apoptosis following cerebral ischemia-reperfusion injury</title><title>Journal of ethnopharmacology</title><addtitle>J Ethnopharmacol</addtitle><description>Buyang Huanwu Decoction (BYHWD) exerts its anti-cerebral ischemia effects through multiple pathways and targets, although its specific mechanisms remain unclear.
Ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF-MS) metabolomics and other methods were employed to investigate the role of BYHWD in inhibiting neuronal apoptosis following cerebral ischemia-reperfusion by modulating the RhoA/Rock2 pathway.
A rat model of exhaustion swimming combined with middle cerebral artery occlusion (ES + I/R) was established to evaluate the intervention effects of Buyang Huanwu Decoction on cerebral ischemia-reperfusion. This was assessed using neurological function scores, Qi deficiency and blood stasis syndrome scores, HE staining, Nissl staining and TT staining. Differential metabolites and metabolic pathways associated with cerebral ischemia-reperfusion were identified using UPLC-QTOF-MS metabolomics, with key differential metabolites validated through ELISA. Molecular docking techniques were employed to predict interactions between the key differential metabolite, hippuric acid, and its primary downstream pathways. Finally, the levels of neurocellular apoptosis, as well as key molecules in the RhoA/Rock2 signaling pathway and the mitochondrial apoptosis pathway, were measured.
The results indicated that the primary differential metabolites associated with BYHWD's protective effects against ischemia-reperfusion injury were hippuric acid, lysophosphatidic acid, and lysophosphatidylethanolamine, with the main metabolic pathway being phenylalanine metabolism. Molecular docking studies demonstrated that malonic acid exhibited a strong affinity for proteins related to the RhoA/Rock2 signaling pathway and the mitochondrial apoptosis pathway.Furthermore, we found that BYHWD treatment significantly decreased the apoptosis rate of cells following cerebral ischemia-reperfusion and inhibited the expression of key molecules in both the RhoA/Rock2 signaling pathway and the mitochondrial apoptosis pathway in brain tissue.
BYHWD ameliorated brain tissue injury after cerebral ischemia/reperfusion in rats with qi deficiency and blood stasis. The underlying mechanism may involve BYHWD's inhibition of the RhoA/Rock2 signaling pathway activation through modulation of the phenylalanine metabolism pathway, thereby reducing neuronal apoptosis mediated by the mitochondrial apoptosis pathway.
[Display omitted]
•This study employs a rat exhaustion swimming + MCAO/R combined disease model to investigate the mechanism of action of BYHWD.•The downstream pathways of differential metabolites were validated using a combination of metabolomics and molecular docking.•BYHWD protects neurons from apoptosis by regulating phenylalanine metabolism.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Brain Ischemia - drug therapy</subject><subject>Brain Ischemia - metabolism</subject><subject>BYHWD</subject><subject>Cerebral ischemia-reperfusion injury</subject><subject>Disease Models, Animal</subject><subject>Drugs, Chinese Herbal - pharmacology</subject><subject>Infarction, Middle Cerebral Artery - drug therapy</subject><subject>Infarction, Middle Cerebral Artery - metabolism</subject><subject>Infarction, Middle Cerebral Artery - pathology</subject><subject>Male</subject><subject>Metabolomics</subject><subject>Molecular Docking Simulation</subject><subject>Neurons - drug effects</subject><subject>Neurons - metabolism</subject><subject>Neurons - pathology</subject><subject>Neuroprotective Agents - pharmacology</subject><subject>Phenylalanine - analogs & derivatives</subject><subject>Phenylalanine - pharmacology</subject><subject>Phenylalanine metabolic pathway</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Reperfusion Injury - drug therapy</subject><subject>Reperfusion Injury - metabolism</subject><subject>rho GTP-Binding Proteins - metabolism</subject><subject>rho-Associated Kinases - metabolism</subject><subject>RhoA/Rock2 signalling pathway</subject><subject>Signal Transduction - drug effects</subject><issn>0378-8741</issn><issn>1872-7573</issn><issn>1872-7573</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1u1TAQhS0EoreFB2CDsmRBbv2T5kes2goKUiWkCtaWY49vHBI72HGv8p48EM5Ny5KNLc1852hmDkLvCN4TTMrLft_DtKeYFntCGlqUL9CO1BXNq6uKvUQ7zKo6r6uCnKHzEHqMcUUK_BqdsaasCcVkh_7cxEXYQ9ZFYY8xUyCdnI2zmbGdac0csrmDTKTaozjVnT5VHjp3ffng5C-aBXOwYjDJZBJzdxRLAryLh-4ETh3YZRCDsMZCNsIsWjeYMD7DH1fKQ7tkHlSUq42F6F2yzMTkptkFEzLthsEd16ZcYZ-aJsgORiNyDxN4HcM2dR_98ga90mII8Pbpv0A_v3z-cfs1v_9-9-32-j6XlF3NOasZYFB1ocs2vVIWolJNrbBWusFAoCxqTFutiFQlKFKUWFFaKNCM0bYu2QX6sPlO3v2OEGY-pqlgSMuCi4GzJGnSxXGVULKh0rsQPGg-eTMKv3CC-Rom73kKk69h8i3MpHn_ZB_bEdQ_xXN6Cfi0AZCWfDTgeZAGrARlPMiZK2f-Y_8X5F63Yg</recordid><startdate>20250131</startdate><enddate>20250131</enddate><creator>Li, Yanling</creator><creator>Hu, Zhongji</creator><creator>Xie, Linli</creator><creator>Xiong, Tingting</creator><creator>Zhang, Yanyan</creator><creator>Bai, Yang</creator><creator>Ding, Huang</creator><creator>Huang, Xiaoping</creator><creator>Liu, Xiaodan</creator><creator>Deng, Changqing</creator><general>Elsevier 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>7X8</scope></search><sort><creationdate>20250131</creationdate><title>Buyang huanwu decoction inhibits the activation of the RhoA/Rock2 signaling pathway through the phenylalanine metabolism pathway, thereby reducing neuronal apoptosis following cerebral ischemia-reperfusion injury</title><author>Li, Yanling ; Hu, Zhongji ; Xie, Linli ; Xiong, Tingting ; Zhang, Yanyan ; Bai, Yang ; Ding, Huang ; Huang, Xiaoping ; Liu, Xiaodan ; Deng, Changqing</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c235t-383e0ed84f6bd84cc4a7d98d0fdf90e1e64802bfd1cd6ed1460d224def332b863</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Brain Ischemia - drug therapy</topic><topic>Brain Ischemia - metabolism</topic><topic>BYHWD</topic><topic>Cerebral ischemia-reperfusion injury</topic><topic>Disease Models, Animal</topic><topic>Drugs, Chinese Herbal - pharmacology</topic><topic>Infarction, Middle Cerebral Artery - drug therapy</topic><topic>Infarction, Middle Cerebral Artery - metabolism</topic><topic>Infarction, Middle Cerebral Artery - pathology</topic><topic>Male</topic><topic>Metabolomics</topic><topic>Molecular Docking Simulation</topic><topic>Neurons - drug effects</topic><topic>Neurons - metabolism</topic><topic>Neurons - pathology</topic><topic>Neuroprotective Agents - pharmacology</topic><topic>Phenylalanine - analogs & derivatives</topic><topic>Phenylalanine - pharmacology</topic><topic>Phenylalanine metabolic pathway</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Reperfusion Injury - drug therapy</topic><topic>Reperfusion Injury - metabolism</topic><topic>rho GTP-Binding Proteins - metabolism</topic><topic>rho-Associated Kinases - metabolism</topic><topic>RhoA/Rock2 signalling pathway</topic><topic>Signal Transduction - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Yanling</creatorcontrib><creatorcontrib>Hu, Zhongji</creatorcontrib><creatorcontrib>Xie, Linli</creatorcontrib><creatorcontrib>Xiong, Tingting</creatorcontrib><creatorcontrib>Zhang, Yanyan</creatorcontrib><creatorcontrib>Bai, Yang</creatorcontrib><creatorcontrib>Ding, Huang</creatorcontrib><creatorcontrib>Huang, Xiaoping</creatorcontrib><creatorcontrib>Liu, Xiaodan</creatorcontrib><creatorcontrib>Deng, Changqing</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of ethnopharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Yanling</au><au>Hu, Zhongji</au><au>Xie, Linli</au><au>Xiong, Tingting</au><au>Zhang, Yanyan</au><au>Bai, Yang</au><au>Ding, Huang</au><au>Huang, Xiaoping</au><au>Liu, Xiaodan</au><au>Deng, Changqing</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Buyang huanwu decoction inhibits the activation of the RhoA/Rock2 signaling pathway through the phenylalanine metabolism pathway, thereby reducing neuronal apoptosis following cerebral ischemia-reperfusion injury</atitle><jtitle>Journal of ethnopharmacology</jtitle><addtitle>J Ethnopharmacol</addtitle><date>2025-01-31</date><risdate>2025</risdate><volume>340</volume><spage>119246</spage><pages>119246-</pages><artnum>119246</artnum><issn>0378-8741</issn><issn>1872-7573</issn><eissn>1872-7573</eissn><abstract>Buyang Huanwu Decoction (BYHWD) exerts its anti-cerebral ischemia effects through multiple pathways and targets, although its specific mechanisms remain unclear.
Ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF-MS) metabolomics and other methods were employed to investigate the role of BYHWD in inhibiting neuronal apoptosis following cerebral ischemia-reperfusion by modulating the RhoA/Rock2 pathway.
A rat model of exhaustion swimming combined with middle cerebral artery occlusion (ES + I/R) was established to evaluate the intervention effects of Buyang Huanwu Decoction on cerebral ischemia-reperfusion. This was assessed using neurological function scores, Qi deficiency and blood stasis syndrome scores, HE staining, Nissl staining and TT staining. Differential metabolites and metabolic pathways associated with cerebral ischemia-reperfusion were identified using UPLC-QTOF-MS metabolomics, with key differential metabolites validated through ELISA. Molecular docking techniques were employed to predict interactions between the key differential metabolite, hippuric acid, and its primary downstream pathways. Finally, the levels of neurocellular apoptosis, as well as key molecules in the RhoA/Rock2 signaling pathway and the mitochondrial apoptosis pathway, were measured.
The results indicated that the primary differential metabolites associated with BYHWD's protective effects against ischemia-reperfusion injury were hippuric acid, lysophosphatidic acid, and lysophosphatidylethanolamine, with the main metabolic pathway being phenylalanine metabolism. Molecular docking studies demonstrated that malonic acid exhibited a strong affinity for proteins related to the RhoA/Rock2 signaling pathway and the mitochondrial apoptosis pathway.Furthermore, we found that BYHWD treatment significantly decreased the apoptosis rate of cells following cerebral ischemia-reperfusion and inhibited the expression of key molecules in both the RhoA/Rock2 signaling pathway and the mitochondrial apoptosis pathway in brain tissue.
BYHWD ameliorated brain tissue injury after cerebral ischemia/reperfusion in rats with qi deficiency and blood stasis. The underlying mechanism may involve BYHWD's inhibition of the RhoA/Rock2 signaling pathway activation through modulation of the phenylalanine metabolism pathway, thereby reducing neuronal apoptosis mediated by the mitochondrial apoptosis pathway.
[Display omitted]
•This study employs a rat exhaustion swimming + MCAO/R combined disease model to investigate the mechanism of action of BYHWD.•The downstream pathways of differential metabolites were validated using a combination of metabolomics and molecular docking.•BYHWD protects neurons from apoptosis by regulating phenylalanine metabolism.</abstract><cop>Ireland</cop><pub>Elsevier B.V</pub><pmid>39681201</pmid><doi>10.1016/j.jep.2024.119246</doi></addata></record> |
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| subjects | Animals Apoptosis Apoptosis - drug effects Brain Ischemia - drug therapy Brain Ischemia - metabolism BYHWD Cerebral ischemia-reperfusion injury Disease Models, Animal Drugs, Chinese Herbal - pharmacology Infarction, Middle Cerebral Artery - drug therapy Infarction, Middle Cerebral Artery - metabolism Infarction, Middle Cerebral Artery - pathology Male Metabolomics Molecular Docking Simulation Neurons - drug effects Neurons - metabolism Neurons - pathology Neuroprotective Agents - pharmacology Phenylalanine - analogs & derivatives Phenylalanine - pharmacology Phenylalanine metabolic pathway Rats Rats, Sprague-Dawley Reperfusion Injury - drug therapy Reperfusion Injury - metabolism rho GTP-Binding Proteins - metabolism rho-Associated Kinases - metabolism RhoA/Rock2 signalling pathway Signal Transduction - drug effects |
| title | Buyang huanwu decoction inhibits the activation of the RhoA/Rock2 signaling pathway through the phenylalanine metabolism pathway, thereby reducing neuronal apoptosis following cerebral ischemia-reperfusion injury |
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