Matches in SemOpenAlex for { <https://semopenalex.org/work/W4313407005> ?p ?o ?g. }
Showing items 1 to 66 of
66
with 100 items per page.
- W4313407005 endingPage "111.15" @default.
- W4313407005 startingPage "111.15" @default.
- W4313407005 abstract "Abstract Background Severe and chronic infections, such as sepsis and Tuberculosis, result in macrophage immune tolerance in order to prevent pathologic inflammation. Immune tolerance is believed to be a result of metabolic dysregulation, especially of the TCA cycle. Metabolites play a critical role in regulating epigenetic mechanism, but many aspects remain poorly understood. Methods An in-vitro LPS tolerance model was used to evaluate if manipulating the TCA cycle could mitigate immune tolerance. Intracellular signaling, DNA methylation, and nuclear localization were measured using RPPA, Illumina EPIC, and confocal microscopy, respectively. Results Metabolic inhibitors of glycolysis (metformin), the TCA cycle (BAY 1436032), and mTOR (rapamycin and everolimus) blocked LPS-induced immune tolerance. LPS treatment changed the methylome with hypermethylation of key genes of the TCA cycle including PDP2, NDUFS8, TRAP1 and PDK2 and lead to increased nuclear localization of the TCA enzymes, which could be ameliorated with inhibitors. Increased levels of key mediators of the TCA by LPS treatment including p-mTOR, pAKT, LDHA, IDH1, LC3A and epigenetic regulator p300 was significantly downregulated by pre-treatment with metformin, everolimus and BAY 1436032. BAY 1436032 also significantly reduced the LPS induced upregulation of epigenetic enzymes including histone deacetylases (HDAC) 3,4, and EZH2. Conclusion Previous studies demonstrated that LPS induces epigenetic-mediated immune tolerance. Here we show this can be mitigated by inhibiting glycolysis, mTOR pathway and TCA cycle. This could have clinical implications in treatment of sepsis and Tuberculosis among other diseases. Supported by NIAID K23 AI141681-02" @default.
- W4313407005 created "2023-01-06" @default.
- W4313407005 creator A5042948892 @default.
- W4313407005 creator A5075567572 @default.
- W4313407005 creator A5075869267 @default.
- W4313407005 creator A5082486147 @default.
- W4313407005 creator A5087113710 @default.
- W4313407005 creator A5078936329 @default.
- W4313407005 date "2022-05-01" @default.
- W4313407005 modified "2023-09-25" @default.
- W4313407005 title "Targeting TCA cycle metabolites by small molecule inhibitors ameliorate LPS induced immune tolerance in Macrophages through epigenetic mechanisms" @default.
- W4313407005 doi "https://doi.org/10.4049/jimmunol.208.supp.111.15" @default.
- W4313407005 hasPublicationYear "2022" @default.
- W4313407005 type Work @default.
- W4313407005 citedByCount "0" @default.
- W4313407005 crossrefType "journal-article" @default.
- W4313407005 hasAuthorship W4313407005A5042948892 @default.
- W4313407005 hasAuthorship W4313407005A5075567572 @default.
- W4313407005 hasAuthorship W4313407005A5075869267 @default.
- W4313407005 hasAuthorship W4313407005A5078936329 @default.
- W4313407005 hasAuthorship W4313407005A5082486147 @default.
- W4313407005 hasAuthorship W4313407005A5087113710 @default.
- W4313407005 hasConcept C104317684 @default.
- W4313407005 hasConcept C165135838 @default.
- W4313407005 hasConcept C181199279 @default.
- W4313407005 hasConcept C203014093 @default.
- W4313407005 hasConcept C41091548 @default.
- W4313407005 hasConcept C502942594 @default.
- W4313407005 hasConcept C55493867 @default.
- W4313407005 hasConcept C62478195 @default.
- W4313407005 hasConcept C86554907 @default.
- W4313407005 hasConcept C86803240 @default.
- W4313407005 hasConcept C8891405 @default.
- W4313407005 hasConcept C95444343 @default.
- W4313407005 hasConceptScore W4313407005C104317684 @default.
- W4313407005 hasConceptScore W4313407005C165135838 @default.
- W4313407005 hasConceptScore W4313407005C181199279 @default.
- W4313407005 hasConceptScore W4313407005C203014093 @default.
- W4313407005 hasConceptScore W4313407005C41091548 @default.
- W4313407005 hasConceptScore W4313407005C502942594 @default.
- W4313407005 hasConceptScore W4313407005C55493867 @default.
- W4313407005 hasConceptScore W4313407005C62478195 @default.
- W4313407005 hasConceptScore W4313407005C86554907 @default.
- W4313407005 hasConceptScore W4313407005C86803240 @default.
- W4313407005 hasConceptScore W4313407005C8891405 @default.
- W4313407005 hasConceptScore W4313407005C95444343 @default.
- W4313407005 hasIssue "1_Supplement" @default.
- W4313407005 hasLocation W43134070051 @default.
- W4313407005 hasOpenAccess W4313407005 @default.
- W4313407005 hasPrimaryLocation W43134070051 @default.
- W4313407005 hasRelatedWork W2044401234 @default.
- W4313407005 hasRelatedWork W2051740108 @default.
- W4313407005 hasRelatedWork W2769292253 @default.
- W4313407005 hasRelatedWork W3007075535 @default.
- W4313407005 hasRelatedWork W3011142704 @default.
- W4313407005 hasRelatedWork W3023464363 @default.
- W4313407005 hasRelatedWork W3106075474 @default.
- W4313407005 hasRelatedWork W3121877887 @default.
- W4313407005 hasRelatedWork W4241494942 @default.
- W4313407005 hasRelatedWork W4310701073 @default.
- W4313407005 hasVolume "208" @default.
- W4313407005 isParatext "false" @default.
- W4313407005 isRetracted "false" @default.
- W4313407005 workType "article" @default.