Sepsis Encephalopathy Is Partly Mediated by miR370-3p-Induced Mitochondrial Injury but Attenuated by BAM15 in Cecal Ligation and Puncture Sepsis Male Mice
BAM15 (a mitochondrial uncoupling agent) was tested on cecal ligation and puncture (CLP) sepsis mice with in vitro experiments. BAM15 attenuated sepsis as indicated by survival, organ histology (kidneys and livers), spleen apoptosis (activated caspase 3), brain injury (SHIRPA score, serum s100β, ser...
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MDPI AG
2022-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/10/5445 |
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| author | Pratsanee Hiengrach Peerapat Visitchanakun Pakteema Tongchairawewat Ponphisudti Tangsirisatian Thitiphat Jungteerapanich Patcharee Ritprajak Dhammika Leshan Wannigama Pattarin Tangtanatakul Asada Leelahavanichkul |
| author_facet | Pratsanee Hiengrach Peerapat Visitchanakun Pakteema Tongchairawewat Ponphisudti Tangsirisatian Thitiphat Jungteerapanich Patcharee Ritprajak Dhammika Leshan Wannigama Pattarin Tangtanatakul Asada Leelahavanichkul |
| author_sort | Pratsanee Hiengrach |
| collection | DOAJ |
| description | BAM15 (a mitochondrial uncoupling agent) was tested on cecal ligation and puncture (CLP) sepsis mice with in vitro experiments. BAM15 attenuated sepsis as indicated by survival, organ histology (kidneys and livers), spleen apoptosis (activated caspase 3), brain injury (SHIRPA score, serum s100β, serum miR370-3p, brain miR370-3p, brain TNF-α, and apoptosis), systemic inflammation (cytokines, cell-free DNA, endotoxemia, and bacteremia), and blood–brain barrier (BBB) damage (Evan’s blue dye and the presence of green fluorescent <i>E. coli</i> in brain after an oral administration). In parallel, brain miR arrays demonstrated miR370-3p at 24 h but not 120 h post-CLP, which was correlated with metabolic pathways. Either lipopolysaccharide (LPS) or TNF-α upregulated miR370-3p in PC12 (neuron cells). An activation by sepsis factors (LPS, TNF-α, or miR370-3p transfection) damaged mitochondria (fluorescent color staining) and reduced cell ATP, possibly through profound mitochondrial activity (extracellular flux analysis) that was attenuated by BAM15. In bone-marrow-derived macrophages, LPS caused mitochondrial injury, decreased cell ATP, enhanced glycolysis activity (extracellular flux analysis), and induced pro-inflammatory macrophages (<i>iNOS</i> and <i>IL-1β</i>) which were neutralized by BAM15. In conclusion, BAM15 attenuated sepsis through decreased mitochondrial damage, reduced neuronal miR370-3p upregulation, and induced anti-inflammatory macrophages. BAM15 is proposed to be used as an adjuvant therapy against sepsis hyperinflammation. |
| first_indexed | 2024-03-10T03:44:16Z |
| format | Article |
| id | doaj.art-3bd04317e4c94797ac09d925a8321c5e |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T03:44:16Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-3bd04317e4c94797ac09d925a8321c5e2023-11-23T11:22:49ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-05-012310544510.3390/ijms23105445Sepsis Encephalopathy Is Partly Mediated by miR370-3p-Induced Mitochondrial Injury but Attenuated by BAM15 in Cecal Ligation and Puncture Sepsis Male MicePratsanee Hiengrach0Peerapat Visitchanakun1Pakteema Tongchairawewat2Ponphisudti Tangsirisatian3Thitiphat Jungteerapanich4Patcharee Ritprajak5Dhammika Leshan Wannigama6Pattarin Tangtanatakul7Asada Leelahavanichkul8Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Chulalongkorn University, Bangkok 10330, ThailandCenter of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Chulalongkorn University, Bangkok 10330, ThailandChulalongkorn University International Medical Program, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, ThailandChulalongkorn University International Medical Program, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, ThailandChulalongkorn University International Medical Program, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, ThailandResearch Unit in Integrative Immuno-Microbial Biochemistry and Bioresponsive Nanomaterials, Department of Microbiology, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, ThailandAntimicrobial Resistance and Stewardship Research Unit, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, ThailandDepartment of Transfusion Medicine and Clinical Microbiology, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, ThailandCenter of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Chulalongkorn University, Bangkok 10330, ThailandBAM15 (a mitochondrial uncoupling agent) was tested on cecal ligation and puncture (CLP) sepsis mice with in vitro experiments. BAM15 attenuated sepsis as indicated by survival, organ histology (kidneys and livers), spleen apoptosis (activated caspase 3), brain injury (SHIRPA score, serum s100β, serum miR370-3p, brain miR370-3p, brain TNF-α, and apoptosis), systemic inflammation (cytokines, cell-free DNA, endotoxemia, and bacteremia), and blood–brain barrier (BBB) damage (Evan’s blue dye and the presence of green fluorescent <i>E. coli</i> in brain after an oral administration). In parallel, brain miR arrays demonstrated miR370-3p at 24 h but not 120 h post-CLP, which was correlated with metabolic pathways. Either lipopolysaccharide (LPS) or TNF-α upregulated miR370-3p in PC12 (neuron cells). An activation by sepsis factors (LPS, TNF-α, or miR370-3p transfection) damaged mitochondria (fluorescent color staining) and reduced cell ATP, possibly through profound mitochondrial activity (extracellular flux analysis) that was attenuated by BAM15. In bone-marrow-derived macrophages, LPS caused mitochondrial injury, decreased cell ATP, enhanced glycolysis activity (extracellular flux analysis), and induced pro-inflammatory macrophages (<i>iNOS</i> and <i>IL-1β</i>) which were neutralized by BAM15. In conclusion, BAM15 attenuated sepsis through decreased mitochondrial damage, reduced neuronal miR370-3p upregulation, and induced anti-inflammatory macrophages. BAM15 is proposed to be used as an adjuvant therapy against sepsis hyperinflammation.https://www.mdpi.com/1422-0067/23/10/5445sepsiscecal ligation and punctureBAM15uncoupling agentextracellular flux |
| spellingShingle | Pratsanee Hiengrach Peerapat Visitchanakun Pakteema Tongchairawewat Ponphisudti Tangsirisatian Thitiphat Jungteerapanich Patcharee Ritprajak Dhammika Leshan Wannigama Pattarin Tangtanatakul Asada Leelahavanichkul Sepsis Encephalopathy Is Partly Mediated by miR370-3p-Induced Mitochondrial Injury but Attenuated by BAM15 in Cecal Ligation and Puncture Sepsis Male Mice International Journal of Molecular Sciences sepsis cecal ligation and puncture BAM15 uncoupling agent extracellular flux |
| title | Sepsis Encephalopathy Is Partly Mediated by miR370-3p-Induced Mitochondrial Injury but Attenuated by BAM15 in Cecal Ligation and Puncture Sepsis Male Mice |
| title_full | Sepsis Encephalopathy Is Partly Mediated by miR370-3p-Induced Mitochondrial Injury but Attenuated by BAM15 in Cecal Ligation and Puncture Sepsis Male Mice |
| title_fullStr | Sepsis Encephalopathy Is Partly Mediated by miR370-3p-Induced Mitochondrial Injury but Attenuated by BAM15 in Cecal Ligation and Puncture Sepsis Male Mice |
| title_full_unstemmed | Sepsis Encephalopathy Is Partly Mediated by miR370-3p-Induced Mitochondrial Injury but Attenuated by BAM15 in Cecal Ligation and Puncture Sepsis Male Mice |
| title_short | Sepsis Encephalopathy Is Partly Mediated by miR370-3p-Induced Mitochondrial Injury but Attenuated by BAM15 in Cecal Ligation and Puncture Sepsis Male Mice |
| title_sort | sepsis encephalopathy is partly mediated by mir370 3p induced mitochondrial injury but attenuated by bam15 in cecal ligation and puncture sepsis male mice |
| topic | sepsis cecal ligation and puncture BAM15 uncoupling agent extracellular flux |
| url | https://www.mdpi.com/1422-0067/23/10/5445 |
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