α‐Ketoglutarate Improves Ovarian Reserve Function in Primary Ovarian Insufficiency by Inhibiting NLRP3‐Mediated Pyroptosis of Granulosa Cells
Scope Premature ovarian insufficiency (POI) is a common female infertility problem, with its pathogenesis remains unknown. The NOD‐like receptor family pyrin domain‐containing 3 (NLRP3)‐mediated pyroptosis has been proposed as a possible mechanism in POI. This study investigates the therapeutic effe...
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| Veröffentlicht in: | Molecular nutrition & food research 2024-03, Vol.68 (5), p.e2300784-n/a |
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| creator | Liu, Ke Wu, Yafei Yang, Wenqin Li, Tianlong Wang, Zhongxu Xiao, Shu Peng, Zhenghua Li, Meng Xiong, Wenhao Li, Meixiang Chen, Xi Zhang, Shun Lei, Xiaocan |
| description | Scope
Premature ovarian insufficiency (POI) is a common female infertility problem, with its pathogenesis remains unknown. The NOD‐like receptor family pyrin domain‐containing 3 (NLRP3)‐mediated pyroptosis has been proposed as a possible mechanism in POI. This study investigates the therapeutic effect of α‐ketoglutarate (AKG) on ovarian reserve function in POI rats and further explores the potential molecular mechanisms.
Methods and results
POI rats are caused by administration of cyclophosphamide (CTX) to determine whether AKG has a protective effect. AKG treatment increases the ovarian index, maintains both serum hormone levels and follicle number, and improves the ovarian reserve function in POI rats, as evidence by increased the level of lactate and the expression of rate‐limiting enzymes of glycolysis in the ovaries, additionally reduced the expression of NLRP3, Gasdermin D (GSDMD), Caspase‐1, Interleukin‐18 (IL‐18), and Interleukin‐1 beta (IL‐1β). In vitro, KGN cells are treated with LPS and nigericin to mimic pyroptosis, then treated with AKG and MCC950. AKG inhibits inflammatory and pyroptosis factors such as NLRP3, restores the glycolysis process in vitro, meanwhile inhibition of NLRP3 has the same effect.
Conclusion
AKG ameliorates CTX‐induced POI by inhibiting NLRP3‐mediated pyroptosis, which provides a new therapeutic strategy and drug target for clinical POI patients.
AKG protects against CTX‐induced POI by inhibiting NLRP3‐mediated pyroptosis of granulosa cells, restoring the glycolysis and improving ovarian reserve function.(Created with BioRender.com). |
| doi_str_mv | 10.1002/mnfr.202300784 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2922952382</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2973326007</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3230-7a24f0d4773ba2a027b646d60d0448545997d901e5145efa9246c0c76fa735e83</originalsourceid><addsrcrecordid>eNqFkUuOEzEQhi0EYh6wZYkssWGTYLvcDy9RNJmJyMxEEaxb7u7y4FG3HezuoN5xBMRNuAiH4CR4lCELNqyqVPrqr8dPyCvO5pwx8a53JswFE8BYUcon5JTnHGaSAzw95iI7IWcx3jMGXEh4Tk6gBC4VqFPy49fP39--f8DB33XjoIMekK76XfB7jPR2r4PVjm4xYtgjXY6uGax31Dq6CbbXYToyKxdHY2xj0TUTradU-GxrO1h3R2_W2w2kMdfY2jSgpZsp-N3go43UG3oZtBs7HzVdYNfFF-SZ0V3El4_xnHxaXnxcXM3Wt5erxfv1rIF07qzQQhrWyqKAWgvNRFHnMm9z1jIpy0xmShWtYhwzLjM0WgmZN6wpcqMLyLCEc_L2oJuu_TJiHKrexiZtoB36MVZCCaEyAaVI6Jt_0Hs_Bpe2S1QBIPL0_kTND1QTfIwBTbU7PKnirHpwq3pwqzq6lRpeP8qOdY_tEf9rTwLkAfhqO5z-I1dd3yy3MlcM_gDnI6Om</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2973326007</pqid></control><display><type>article</type><title>α‐Ketoglutarate Improves Ovarian Reserve Function in Primary Ovarian Insufficiency by Inhibiting NLRP3‐Mediated Pyroptosis of Granulosa Cells</title><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><creator>Liu, Ke ; Wu, Yafei ; Yang, Wenqin ; Li, Tianlong ; Wang, Zhongxu ; Xiao, Shu ; Peng, Zhenghua ; Li, Meng ; Xiong, Wenhao ; Li, Meixiang ; Chen, Xi ; Zhang, Shun ; Lei, Xiaocan</creator><creatorcontrib>Liu, Ke ; Wu, Yafei ; Yang, Wenqin ; Li, Tianlong ; Wang, Zhongxu ; Xiao, Shu ; Peng, Zhenghua ; Li, Meng ; Xiong, Wenhao ; Li, Meixiang ; Chen, Xi ; Zhang, Shun ; Lei, Xiaocan</creatorcontrib><description>Scope
Premature ovarian insufficiency (POI) is a common female infertility problem, with its pathogenesis remains unknown. The NOD‐like receptor family pyrin domain‐containing 3 (NLRP3)‐mediated pyroptosis has been proposed as a possible mechanism in POI. This study investigates the therapeutic effect of α‐ketoglutarate (AKG) on ovarian reserve function in POI rats and further explores the potential molecular mechanisms.
Methods and results
POI rats are caused by administration of cyclophosphamide (CTX) to determine whether AKG has a protective effect. AKG treatment increases the ovarian index, maintains both serum hormone levels and follicle number, and improves the ovarian reserve function in POI rats, as evidence by increased the level of lactate and the expression of rate‐limiting enzymes of glycolysis in the ovaries, additionally reduced the expression of NLRP3, Gasdermin D (GSDMD), Caspase‐1, Interleukin‐18 (IL‐18), and Interleukin‐1 beta (IL‐1β). In vitro, KGN cells are treated with LPS and nigericin to mimic pyroptosis, then treated with AKG and MCC950. AKG inhibits inflammatory and pyroptosis factors such as NLRP3, restores the glycolysis process in vitro, meanwhile inhibition of NLRP3 has the same effect.
Conclusion
AKG ameliorates CTX‐induced POI by inhibiting NLRP3‐mediated pyroptosis, which provides a new therapeutic strategy and drug target for clinical POI patients.
AKG protects against CTX‐induced POI by inhibiting NLRP3‐mediated pyroptosis of granulosa cells, restoring the glycolysis and improving ovarian reserve function.(Created with BioRender.com).</description><identifier>ISSN: 1613-4125</identifier><identifier>EISSN: 1613-4133</identifier><identifier>DOI: 10.1002/mnfr.202300784</identifier><identifier>PMID: 38314939</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>alpha‐ketoglutarate ; Animals ; Caspase ; Cyclophosphamide ; Cytokines ; Female ; Glycolysis ; granulosa cell ; Granulosa cells ; Granulosa Cells - metabolism ; Humans ; Infertility ; Inflammasomes - metabolism ; Inflammation ; Interleukins ; Ketoglutaric Acids - pharmacology ; Molecular modelling ; Nigericin ; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism ; Ovarian Reserve ; Ovaries ; Pathogenesis ; premature ovarian insufficiency ; Primary Ovarian Insufficiency - chemically induced ; Primary Ovarian Insufficiency - drug therapy ; Pyrin protein ; Pyroptosis ; Rats ; Therapeutic targets</subject><ispartof>Molecular nutrition & food research, 2024-03, Vol.68 (5), p.e2300784-n/a</ispartof><rights>2024 Wiley‐VCH GmbH</rights><rights>2024 Wiley‐VCH GmbH.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c3230-7a24f0d4773ba2a027b646d60d0448545997d901e5145efa9246c0c76fa735e83</cites><orcidid>0000-0001-6733-4046</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fmnfr.202300784$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fmnfr.202300784$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38314939$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Ke</creatorcontrib><creatorcontrib>Wu, Yafei</creatorcontrib><creatorcontrib>Yang, Wenqin</creatorcontrib><creatorcontrib>Li, Tianlong</creatorcontrib><creatorcontrib>Wang, Zhongxu</creatorcontrib><creatorcontrib>Xiao, Shu</creatorcontrib><creatorcontrib>Peng, Zhenghua</creatorcontrib><creatorcontrib>Li, Meng</creatorcontrib><creatorcontrib>Xiong, Wenhao</creatorcontrib><creatorcontrib>Li, Meixiang</creatorcontrib><creatorcontrib>Chen, Xi</creatorcontrib><creatorcontrib>Zhang, Shun</creatorcontrib><creatorcontrib>Lei, Xiaocan</creatorcontrib><title>α‐Ketoglutarate Improves Ovarian Reserve Function in Primary Ovarian Insufficiency by Inhibiting NLRP3‐Mediated Pyroptosis of Granulosa Cells</title><title>Molecular nutrition & food research</title><addtitle>Mol Nutr Food Res</addtitle><description>Scope
Premature ovarian insufficiency (POI) is a common female infertility problem, with its pathogenesis remains unknown. The NOD‐like receptor family pyrin domain‐containing 3 (NLRP3)‐mediated pyroptosis has been proposed as a possible mechanism in POI. This study investigates the therapeutic effect of α‐ketoglutarate (AKG) on ovarian reserve function in POI rats and further explores the potential molecular mechanisms.
Methods and results
POI rats are caused by administration of cyclophosphamide (CTX) to determine whether AKG has a protective effect. AKG treatment increases the ovarian index, maintains both serum hormone levels and follicle number, and improves the ovarian reserve function in POI rats, as evidence by increased the level of lactate and the expression of rate‐limiting enzymes of glycolysis in the ovaries, additionally reduced the expression of NLRP3, Gasdermin D (GSDMD), Caspase‐1, Interleukin‐18 (IL‐18), and Interleukin‐1 beta (IL‐1β). In vitro, KGN cells are treated with LPS and nigericin to mimic pyroptosis, then treated with AKG and MCC950. AKG inhibits inflammatory and pyroptosis factors such as NLRP3, restores the glycolysis process in vitro, meanwhile inhibition of NLRP3 has the same effect.
Conclusion
AKG ameliorates CTX‐induced POI by inhibiting NLRP3‐mediated pyroptosis, which provides a new therapeutic strategy and drug target for clinical POI patients.
AKG protects against CTX‐induced POI by inhibiting NLRP3‐mediated pyroptosis of granulosa cells, restoring the glycolysis and improving ovarian reserve function.(Created with BioRender.com).</description><subject>alpha‐ketoglutarate</subject><subject>Animals</subject><subject>Caspase</subject><subject>Cyclophosphamide</subject><subject>Cytokines</subject><subject>Female</subject><subject>Glycolysis</subject><subject>granulosa cell</subject><subject>Granulosa cells</subject><subject>Granulosa Cells - metabolism</subject><subject>Humans</subject><subject>Infertility</subject><subject>Inflammasomes - metabolism</subject><subject>Inflammation</subject><subject>Interleukins</subject><subject>Ketoglutaric Acids - pharmacology</subject><subject>Molecular modelling</subject><subject>Nigericin</subject><subject>NLR Family, Pyrin Domain-Containing 3 Protein - metabolism</subject><subject>Ovarian Reserve</subject><subject>Ovaries</subject><subject>Pathogenesis</subject><subject>premature ovarian insufficiency</subject><subject>Primary Ovarian Insufficiency - chemically induced</subject><subject>Primary Ovarian Insufficiency - drug therapy</subject><subject>Pyrin protein</subject><subject>Pyroptosis</subject><subject>Rats</subject><subject>Therapeutic targets</subject><issn>1613-4125</issn><issn>1613-4133</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUuOEzEQhi0EYh6wZYkssWGTYLvcDy9RNJmJyMxEEaxb7u7y4FG3HezuoN5xBMRNuAiH4CR4lCELNqyqVPrqr8dPyCvO5pwx8a53JswFE8BYUcon5JTnHGaSAzw95iI7IWcx3jMGXEh4Tk6gBC4VqFPy49fP39--f8DB33XjoIMekK76XfB7jPR2r4PVjm4xYtgjXY6uGax31Dq6CbbXYToyKxdHY2xj0TUTradU-GxrO1h3R2_W2w2kMdfY2jSgpZsp-N3go43UG3oZtBs7HzVdYNfFF-SZ0V3El4_xnHxaXnxcXM3Wt5erxfv1rIF07qzQQhrWyqKAWgvNRFHnMm9z1jIpy0xmShWtYhwzLjM0WgmZN6wpcqMLyLCEc_L2oJuu_TJiHKrexiZtoB36MVZCCaEyAaVI6Jt_0Hs_Bpe2S1QBIPL0_kTND1QTfIwBTbU7PKnirHpwq3pwqzq6lRpeP8qOdY_tEf9rTwLkAfhqO5z-I1dd3yy3MlcM_gDnI6Om</recordid><startdate>202403</startdate><enddate>202403</enddate><creator>Liu, Ke</creator><creator>Wu, Yafei</creator><creator>Yang, Wenqin</creator><creator>Li, Tianlong</creator><creator>Wang, Zhongxu</creator><creator>Xiao, Shu</creator><creator>Peng, Zhenghua</creator><creator>Li, Meng</creator><creator>Xiong, Wenhao</creator><creator>Li, Meixiang</creator><creator>Chen, Xi</creator><creator>Zhang, Shun</creator><creator>Lei, Xiaocan</creator><general>Wiley Subscription Services, Inc</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>7QO</scope><scope>7QP</scope><scope>7T5</scope><scope>7T7</scope><scope>7TK</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-6733-4046</orcidid></search><sort><creationdate>202403</creationdate><title>α‐Ketoglutarate Improves Ovarian Reserve Function in Primary Ovarian Insufficiency by Inhibiting NLRP3‐Mediated Pyroptosis of Granulosa Cells</title><author>Liu, Ke ; Wu, Yafei ; Yang, Wenqin ; Li, Tianlong ; Wang, Zhongxu ; Xiao, Shu ; Peng, Zhenghua ; Li, Meng ; Xiong, Wenhao ; Li, Meixiang ; Chen, Xi ; Zhang, Shun ; Lei, Xiaocan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3230-7a24f0d4773ba2a027b646d60d0448545997d901e5145efa9246c0c76fa735e83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>alpha‐ketoglutarate</topic><topic>Animals</topic><topic>Caspase</topic><topic>Cyclophosphamide</topic><topic>Cytokines</topic><topic>Female</topic><topic>Glycolysis</topic><topic>granulosa cell</topic><topic>Granulosa cells</topic><topic>Granulosa Cells - metabolism</topic><topic>Humans</topic><topic>Infertility</topic><topic>Inflammasomes - metabolism</topic><topic>Inflammation</topic><topic>Interleukins</topic><topic>Ketoglutaric Acids - pharmacology</topic><topic>Molecular modelling</topic><topic>Nigericin</topic><topic>NLR Family, Pyrin Domain-Containing 3 Protein - metabolism</topic><topic>Ovarian Reserve</topic><topic>Ovaries</topic><topic>Pathogenesis</topic><topic>premature ovarian insufficiency</topic><topic>Primary Ovarian Insufficiency - chemically induced</topic><topic>Primary Ovarian Insufficiency - drug therapy</topic><topic>Pyrin protein</topic><topic>Pyroptosis</topic><topic>Rats</topic><topic>Therapeutic targets</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Ke</creatorcontrib><creatorcontrib>Wu, Yafei</creatorcontrib><creatorcontrib>Yang, Wenqin</creatorcontrib><creatorcontrib>Li, Tianlong</creatorcontrib><creatorcontrib>Wang, Zhongxu</creatorcontrib><creatorcontrib>Xiao, Shu</creatorcontrib><creatorcontrib>Peng, Zhenghua</creatorcontrib><creatorcontrib>Li, Meng</creatorcontrib><creatorcontrib>Xiong, Wenhao</creatorcontrib><creatorcontrib>Li, Meixiang</creatorcontrib><creatorcontrib>Chen, Xi</creatorcontrib><creatorcontrib>Zhang, Shun</creatorcontrib><creatorcontrib>Lei, Xiaocan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular nutrition & food research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Ke</au><au>Wu, Yafei</au><au>Yang, Wenqin</au><au>Li, Tianlong</au><au>Wang, Zhongxu</au><au>Xiao, Shu</au><au>Peng, Zhenghua</au><au>Li, Meng</au><au>Xiong, Wenhao</au><au>Li, Meixiang</au><au>Chen, Xi</au><au>Zhang, Shun</au><au>Lei, Xiaocan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>α‐Ketoglutarate Improves Ovarian Reserve Function in Primary Ovarian Insufficiency by Inhibiting NLRP3‐Mediated Pyroptosis of Granulosa Cells</atitle><jtitle>Molecular nutrition & food research</jtitle><addtitle>Mol Nutr Food Res</addtitle><date>2024-03</date><risdate>2024</risdate><volume>68</volume><issue>5</issue><spage>e2300784</spage><epage>n/a</epage><pages>e2300784-n/a</pages><issn>1613-4125</issn><eissn>1613-4133</eissn><abstract>Scope
Premature ovarian insufficiency (POI) is a common female infertility problem, with its pathogenesis remains unknown. The NOD‐like receptor family pyrin domain‐containing 3 (NLRP3)‐mediated pyroptosis has been proposed as a possible mechanism in POI. This study investigates the therapeutic effect of α‐ketoglutarate (AKG) on ovarian reserve function in POI rats and further explores the potential molecular mechanisms.
Methods and results
POI rats are caused by administration of cyclophosphamide (CTX) to determine whether AKG has a protective effect. AKG treatment increases the ovarian index, maintains both serum hormone levels and follicle number, and improves the ovarian reserve function in POI rats, as evidence by increased the level of lactate and the expression of rate‐limiting enzymes of glycolysis in the ovaries, additionally reduced the expression of NLRP3, Gasdermin D (GSDMD), Caspase‐1, Interleukin‐18 (IL‐18), and Interleukin‐1 beta (IL‐1β). In vitro, KGN cells are treated with LPS and nigericin to mimic pyroptosis, then treated with AKG and MCC950. AKG inhibits inflammatory and pyroptosis factors such as NLRP3, restores the glycolysis process in vitro, meanwhile inhibition of NLRP3 has the same effect.
Conclusion
AKG ameliorates CTX‐induced POI by inhibiting NLRP3‐mediated pyroptosis, which provides a new therapeutic strategy and drug target for clinical POI patients.
AKG protects against CTX‐induced POI by inhibiting NLRP3‐mediated pyroptosis of granulosa cells, restoring the glycolysis and improving ovarian reserve function.(Created with BioRender.com).</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>38314939</pmid><doi>10.1002/mnfr.202300784</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0001-6733-4046</orcidid></addata></record> |
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| subjects | alpha‐ketoglutarate Animals Caspase Cyclophosphamide Cytokines Female Glycolysis granulosa cell Granulosa cells Granulosa Cells - metabolism Humans Infertility Inflammasomes - metabolism Inflammation Interleukins Ketoglutaric Acids - pharmacology Molecular modelling Nigericin NLR Family, Pyrin Domain-Containing 3 Protein - metabolism Ovarian Reserve Ovaries Pathogenesis premature ovarian insufficiency Primary Ovarian Insufficiency - chemically induced Primary Ovarian Insufficiency - drug therapy Pyrin protein Pyroptosis Rats Therapeutic targets |
| title | α‐Ketoglutarate Improves Ovarian Reserve Function in Primary Ovarian Insufficiency by Inhibiting NLRP3‐Mediated Pyroptosis of Granulosa Cells |
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