Bioactive compound C498-0670 alleviates LPS-induced sepsis via JAK/STAT and NFκB signaling pathways
The JAK/STAT and NFκB signaling pathways are two major inflammatory signaling pathways that are usually activated simultaneously in the body’s inflammatory response to bacterial or viral infections. Hyperactivation of these two prominent signaling pathways is associated with various immune-related d...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-04-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1132265/full |
| _version_ | 1797847223304716288 |
|---|---|
| author | Jing Xu Jing Xu Xinxin Zhang Mingming Zhou Peizhe Lu Yuting Xu Lihong Wu Qianyue Zhang Zhihua Wu Xiaoyu Xu Pengfei Shi Qingda Wei Xiaoyu Li Qiaoling Song Qiaoling Song |
| author_facet | Jing Xu Jing Xu Xinxin Zhang Mingming Zhou Peizhe Lu Yuting Xu Lihong Wu Qianyue Zhang Zhihua Wu Xiaoyu Xu Pengfei Shi Qingda Wei Xiaoyu Li Qiaoling Song Qiaoling Song |
| author_sort | Jing Xu |
| collection | DOAJ |
| description | The JAK/STAT and NFκB signaling pathways are two major inflammatory signaling pathways that are usually activated simultaneously in the body’s inflammatory response to bacterial or viral infections. Hyperactivation of these two prominent signaling pathways is associated with various immune-related diseases and mortality, pointing to an urgent need for drug development targeting JAK/STAT and/or NFκB signaling. In this study, we screened 18,840 compounds using our well-established dual STAT-NFκB driven luciferase reporter based high-throughput screening system and identified a bioactive compound C498-0670, which inhibits both JAK/STAT and NFκB signaling. C498-0670 inhibits the activation of STATs and p-IKKα/β in both the immortalized cell lines and primary peritoneal macrophages, while suppressing the expression of LPS-induced inflammatory mediators in vitro. In addition, the overall anti-inflammatory effects of C498-0670 were investigated using transcriptome sequencing and bioinformatics approaches. C498-0670 was predicted to alleviate sepsis/septic shock by disease/function analysis using IPA software, which was further verified in the LPS-induced mouse sepsis model in vivo. C498 reduced LPS-induced liver and kidney damage, myeloid cell infiltration, and pro-inflammatory cytokine and chemokine production in vivo. Furthermore, the SPR-HPLC-MS-based target fishing approach was used to identify the putative drug targets, and the high affinities of JAK2 (JAK/STAT signaling), NFKBIA (NFκB signaling), and IL-1β, NLRP1b (inflammasome signaling) for C498-0670 were verified by molecular docking approach. These results suggest that C498-0670 can be used as a dual-target inhibitor of JAK/STAT and NFκB signaling pathways for the treatment of various inflammatory diseases, especially septic shock. |
| first_indexed | 2024-04-09T18:07:51Z |
| format | Article |
| id | doaj.art-5b0522e60d4f41a2b8baf95da3bed194 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-09T18:07:51Z |
| publishDate | 2023-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-5b0522e60d4f41a2b8baf95da3bed1942023-04-14T04:55:24ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-04-011410.3389/fimmu.2023.11322651132265Bioactive compound C498-0670 alleviates LPS-induced sepsis via JAK/STAT and NFκB signaling pathwaysJing Xu0Jing Xu1Xinxin Zhang2Mingming Zhou3Peizhe Lu4Yuting Xu5Lihong Wu6Qianyue Zhang7Zhihua Wu8Xiaoyu Xu9Pengfei Shi10Qingda Wei11Xiaoyu Li12Qiaoling Song13Qiaoling Song14Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, ChinaInnovation Platform of Marine Drug Screening & Evaluation, Qingdao Pilot National Laboratory for Marine Science and Technology, Qingdao, Shandong, ChinaInnovation Platform of Marine Drug Screening & Evaluation, Qingdao Pilot National Laboratory for Marine Science and Technology, Qingdao, Shandong, ChinaInnovation Platform of Marine Drug Screening & Evaluation, Qingdao Pilot National Laboratory for Marine Science and Technology, Qingdao, Shandong, ChinaDepartment of Neuroscience, University of Michigan, Ann Arbor, MI, United StatesKey Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, ChinaKey Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, ChinaKey Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, ChinaInnovation Platform of Marine Drug Screening & Evaluation, Qingdao Pilot National Laboratory for Marine Science and Technology, Qingdao, Shandong, ChinaCollege of Marine Life Sciences, Ocean University of China, Qingdao, ChinaInnovation Platform of Marine Drug Screening & Evaluation, Qingdao Pilot National Laboratory for Marine Science and Technology, Qingdao, Shandong, ChinaSchool of Medicine, Zhengzhou University, Zhengzhou, ChinaDepartment of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, ChinaInnovation Platform of Marine Drug Screening & Evaluation, Qingdao Pilot National Laboratory for Marine Science and Technology, Qingdao, Shandong, ChinaKey Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, ChinaThe JAK/STAT and NFκB signaling pathways are two major inflammatory signaling pathways that are usually activated simultaneously in the body’s inflammatory response to bacterial or viral infections. Hyperactivation of these two prominent signaling pathways is associated with various immune-related diseases and mortality, pointing to an urgent need for drug development targeting JAK/STAT and/or NFκB signaling. In this study, we screened 18,840 compounds using our well-established dual STAT-NFκB driven luciferase reporter based high-throughput screening system and identified a bioactive compound C498-0670, which inhibits both JAK/STAT and NFκB signaling. C498-0670 inhibits the activation of STATs and p-IKKα/β in both the immortalized cell lines and primary peritoneal macrophages, while suppressing the expression of LPS-induced inflammatory mediators in vitro. In addition, the overall anti-inflammatory effects of C498-0670 were investigated using transcriptome sequencing and bioinformatics approaches. C498-0670 was predicted to alleviate sepsis/septic shock by disease/function analysis using IPA software, which was further verified in the LPS-induced mouse sepsis model in vivo. C498 reduced LPS-induced liver and kidney damage, myeloid cell infiltration, and pro-inflammatory cytokine and chemokine production in vivo. Furthermore, the SPR-HPLC-MS-based target fishing approach was used to identify the putative drug targets, and the high affinities of JAK2 (JAK/STAT signaling), NFKBIA (NFκB signaling), and IL-1β, NLRP1b (inflammasome signaling) for C498-0670 were verified by molecular docking approach. These results suggest that C498-0670 can be used as a dual-target inhibitor of JAK/STAT and NFκB signaling pathways for the treatment of various inflammatory diseases, especially septic shock.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1132265/fullanti-inflammatoryJAK/STATNFκBLPStranscriptome sequencingseptic shock |
| spellingShingle | Jing Xu Jing Xu Xinxin Zhang Mingming Zhou Peizhe Lu Yuting Xu Lihong Wu Qianyue Zhang Zhihua Wu Xiaoyu Xu Pengfei Shi Qingda Wei Xiaoyu Li Qiaoling Song Qiaoling Song Bioactive compound C498-0670 alleviates LPS-induced sepsis via JAK/STAT and NFκB signaling pathways Frontiers in Immunology anti-inflammatory JAK/STAT NFκB LPS transcriptome sequencing septic shock |
| title | Bioactive compound C498-0670 alleviates LPS-induced sepsis via JAK/STAT and NFκB signaling pathways |
| title_full | Bioactive compound C498-0670 alleviates LPS-induced sepsis via JAK/STAT and NFκB signaling pathways |
| title_fullStr | Bioactive compound C498-0670 alleviates LPS-induced sepsis via JAK/STAT and NFκB signaling pathways |
| title_full_unstemmed | Bioactive compound C498-0670 alleviates LPS-induced sepsis via JAK/STAT and NFκB signaling pathways |
| title_short | Bioactive compound C498-0670 alleviates LPS-induced sepsis via JAK/STAT and NFκB signaling pathways |
| title_sort | bioactive compound c498 0670 alleviates lps induced sepsis via jak stat and nfκb signaling pathways |
| topic | anti-inflammatory JAK/STAT NFκB LPS transcriptome sequencing septic shock |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1132265/full |
| work_keys_str_mv | AT jingxu bioactivecompoundc4980670alleviateslpsinducedsepsisviajakstatandnfkbsignalingpathways AT jingxu bioactivecompoundc4980670alleviateslpsinducedsepsisviajakstatandnfkbsignalingpathways AT xinxinzhang bioactivecompoundc4980670alleviateslpsinducedsepsisviajakstatandnfkbsignalingpathways AT mingmingzhou bioactivecompoundc4980670alleviateslpsinducedsepsisviajakstatandnfkbsignalingpathways AT peizhelu bioactivecompoundc4980670alleviateslpsinducedsepsisviajakstatandnfkbsignalingpathways AT yutingxu bioactivecompoundc4980670alleviateslpsinducedsepsisviajakstatandnfkbsignalingpathways AT lihongwu bioactivecompoundc4980670alleviateslpsinducedsepsisviajakstatandnfkbsignalingpathways AT qianyuezhang bioactivecompoundc4980670alleviateslpsinducedsepsisviajakstatandnfkbsignalingpathways AT zhihuawu bioactivecompoundc4980670alleviateslpsinducedsepsisviajakstatandnfkbsignalingpathways AT xiaoyuxu bioactivecompoundc4980670alleviateslpsinducedsepsisviajakstatandnfkbsignalingpathways AT pengfeishi bioactivecompoundc4980670alleviateslpsinducedsepsisviajakstatandnfkbsignalingpathways AT qingdawei bioactivecompoundc4980670alleviateslpsinducedsepsisviajakstatandnfkbsignalingpathways AT xiaoyuli bioactivecompoundc4980670alleviateslpsinducedsepsisviajakstatandnfkbsignalingpathways AT qiaolingsong bioactivecompoundc4980670alleviateslpsinducedsepsisviajakstatandnfkbsignalingpathways AT qiaolingsong bioactivecompoundc4980670alleviateslpsinducedsepsisviajakstatandnfkbsignalingpathways |