Multi-Omics and Network-Based Drug Repurposing for Septic Cardiomyopathy
Background/Objectives: Septic cardiomyopathy (SCM) is a severe cardiac complication of sepsis, characterized by cardiac dysfunction with limited effective treatments. This study aimed to identify repurposable drugs for SCM by integrated multi-omics and network analyses. Methods: We generated a mouse...
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2025-01-01
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| author | Pei-Pei Liu Xin-Yue Yu Qing-Qing Pan Jia-Jun Ren Yu-Xuan Han Kai Zhang Yan Wang Yin Huang Tao Ban |
| author_facet | Pei-Pei Liu Xin-Yue Yu Qing-Qing Pan Jia-Jun Ren Yu-Xuan Han Kai Zhang Yan Wang Yin Huang Tao Ban |
| author_sort | Pei-Pei Liu |
| collection | DOAJ |
| description | Background/Objectives: Septic cardiomyopathy (SCM) is a severe cardiac complication of sepsis, characterized by cardiac dysfunction with limited effective treatments. This study aimed to identify repurposable drugs for SCM by integrated multi-omics and network analyses. Methods: We generated a mouse model of SCM induced by lipopolysaccharide (LPS) and then obtained comprehensive metabolic and genetic data from SCM mouse hearts using ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) and RNA sequencing (RNA-seq). Using network proximity analysis, we screened for FDA-approved drugs that interact with SCM-associated pathways. Additionally, we tested the cardioprotective effects of two drug candidates in the SCM mouse model and explored their mechanism-of-action in H9c2 cells. Results: Network analysis identified 129 drugs associated with SCM, which were refined to 14 drug candidates based on strong network predictions, proven anti-infective effects, suitability for ICU use, and minimal side effects. Among them, acetaminophen and pyridoxal phosphate significantly improved cardiac function in SCM moues, as demonstrated by the increased ejection fraction (EF) and fractional shortening (FS), and the reduced levels of cardiac injury biomarkers: B-type natriuretic peptide (BNP) and cardiac troponin I (cTn-I). In vitro assays revealed that acetaminophen inhibited prostaglandin synthesis, reducing inflammation, while pyridoxal phosphate restored amino acid balance, supporting cellular function. These findings suggest that both drugs possess protective effects against SCM. Conclusions: This study provides a robust platform for drug repurposing in SCM, identifying acetaminophen and pyridoxal phosphate as promising candidates for clinical translation, with the potential to improve treatment outcomes in septic patients with cardiac complications. |
| format | Article |
| id | doaj-art-c4f7300a2acd459dbb998ba84ced078c |
| institution | Kabale University |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj-art-c4f7300a2acd459dbb998ba84ced078c2025-01-24T13:45:08ZengMDPI AGPharmaceuticals1424-82472025-01-011814310.3390/ph18010043Multi-Omics and Network-Based Drug Repurposing for Septic CardiomyopathyPei-Pei Liu0Xin-Yue Yu1Qing-Qing Pan2Jia-Jun Ren3Yu-Xuan Han4Kai Zhang5Yan Wang6Yin Huang7Tao Ban8Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, ChinaKey Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, ChinaDepartment of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, ChinaDepartment of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, ChinaDepartment of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, ChinaDepartment of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, ChinaDepartment of Critical Care Medicine, Nanjing Drum Tower Hospital, Clinical College, Nanjing Medical University, Nanjing 210008, ChinaKey Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, ChinaDepartment of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, ChinaBackground/Objectives: Septic cardiomyopathy (SCM) is a severe cardiac complication of sepsis, characterized by cardiac dysfunction with limited effective treatments. This study aimed to identify repurposable drugs for SCM by integrated multi-omics and network analyses. Methods: We generated a mouse model of SCM induced by lipopolysaccharide (LPS) and then obtained comprehensive metabolic and genetic data from SCM mouse hearts using ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) and RNA sequencing (RNA-seq). Using network proximity analysis, we screened for FDA-approved drugs that interact with SCM-associated pathways. Additionally, we tested the cardioprotective effects of two drug candidates in the SCM mouse model and explored their mechanism-of-action in H9c2 cells. Results: Network analysis identified 129 drugs associated with SCM, which were refined to 14 drug candidates based on strong network predictions, proven anti-infective effects, suitability for ICU use, and minimal side effects. Among them, acetaminophen and pyridoxal phosphate significantly improved cardiac function in SCM moues, as demonstrated by the increased ejection fraction (EF) and fractional shortening (FS), and the reduced levels of cardiac injury biomarkers: B-type natriuretic peptide (BNP) and cardiac troponin I (cTn-I). In vitro assays revealed that acetaminophen inhibited prostaglandin synthesis, reducing inflammation, while pyridoxal phosphate restored amino acid balance, supporting cellular function. These findings suggest that both drugs possess protective effects against SCM. Conclusions: This study provides a robust platform for drug repurposing in SCM, identifying acetaminophen and pyridoxal phosphate as promising candidates for clinical translation, with the potential to improve treatment outcomes in septic patients with cardiac complications.https://www.mdpi.com/1424-8247/18/1/43metabolomicstranscriptomicsnetwork medicineacetaminophenLC-MS |
| spellingShingle | Pei-Pei Liu Xin-Yue Yu Qing-Qing Pan Jia-Jun Ren Yu-Xuan Han Kai Zhang Yan Wang Yin Huang Tao Ban Multi-Omics and Network-Based Drug Repurposing for Septic Cardiomyopathy Pharmaceuticals metabolomics transcriptomics network medicine acetaminophen LC-MS |
| title | Multi-Omics and Network-Based Drug Repurposing for Septic Cardiomyopathy |
| title_full | Multi-Omics and Network-Based Drug Repurposing for Septic Cardiomyopathy |
| title_fullStr | Multi-Omics and Network-Based Drug Repurposing for Septic Cardiomyopathy |
| title_full_unstemmed | Multi-Omics and Network-Based Drug Repurposing for Septic Cardiomyopathy |
| title_short | Multi-Omics and Network-Based Drug Repurposing for Septic Cardiomyopathy |
| title_sort | multi omics and network based drug repurposing for septic cardiomyopathy |
| topic | metabolomics transcriptomics network medicine acetaminophen LC-MS |
| url | https://www.mdpi.com/1424-8247/18/1/43 |
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