Discovery of Novel Pterostilbene Derivatives That Might Treat Sepsis by Attenuating Oxidative Stress and Inflammation through Modulation of MAPKs/NF-κB Signaling Pathways
Sepsis remains one of the most common life-threatening illnesses that is characterized by a systemic inflammatory response syndrome (SIRS) and usually arises following severe trauma and various septic infections. It is still in urgent need of new effective therapeutic agents, and chances are great t...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-08-01
|
| Series: | Antioxidants |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3921/10/9/1333 |
| _version_ | 1797520481194082304 |
|---|---|
| author | Mengyuan Fang Tingfeng Zou Xiaoxiao Yang Zhen Zhang Peichang Cao Jihong Han Yajun Duan Ban-Feng Ruan Qing-Shan Li |
| author_facet | Mengyuan Fang Tingfeng Zou Xiaoxiao Yang Zhen Zhang Peichang Cao Jihong Han Yajun Duan Ban-Feng Ruan Qing-Shan Li |
| author_sort | Mengyuan Fang |
| collection | DOAJ |
| description | Sepsis remains one of the most common life-threatening illnesses that is characterized by a systemic inflammatory response syndrome (SIRS) and usually arises following severe trauma and various septic infections. It is still in urgent need of new effective therapeutic agents, and chances are great that some candidates can be identified that can attenuate oxidative stress and inflammatory responses. Pterostilbene, which exerts attractive anti-oxidative and anti-inflammatory activities, is a homologue of natural polyphenolic derivative of resveratrol. Starting from it, we have made several rounds of rational optimizations. Firstly, based on the strategy of pharmacophore combination, indanone moiety was introduced onto the pterostilbene skeleton to generate a novel series of pterostilbene derivatives (<b>PIF_1</b>–<b>PIF_16</b>) which could possess both anti-oxidative and anti-inflammatory activities for sepsis treatment. Then, all target compounds were subjected to their structure–activity relationships (SAR) screening of anti-inflammatory activity in mouse mononuclear macrophage RAW264.7 cell line, and their cytotoxicities were determined after. Finally, an optimal compound, <b>PIF_9</b>, was identified. It decreased the mRNA levels of lipopolysaccharide (LPS)-induced interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX2). We also found that the anti-inflammatory effects might be contributed by its suppression on the nuclear factor-κB (NF-κB) and MAPKs signaling pathway. Moreover, <b>PIF_9</b> also demonstrated potent anti-oxidative activity in RAW264.7 macrophages and the sepsis mouse model. Not surprisingly, with the benefits mentioned above, it ameliorated LPS-induced sepsis in C57BL/6J mice and reduced multi-organ toxicity. Taken together, <b>PIF_9</b> was identified as a potential sepsis solution, targeting inflammation and oxidative stress through modulating MAPKs/NF-κB. |
| first_indexed | 2024-03-10T07:57:21Z |
| format | Article |
| id | doaj.art-accf39da9dc1493192bddcdb8410e5c3 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T07:57:21Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-accf39da9dc1493192bddcdb8410e5c32023-11-22T11:47:07ZengMDPI AGAntioxidants2076-39212021-08-01109133310.3390/antiox10091333Discovery of Novel Pterostilbene Derivatives That Might Treat Sepsis by Attenuating Oxidative Stress and Inflammation through Modulation of MAPKs/NF-κB Signaling PathwaysMengyuan Fang0Tingfeng Zou1Xiaoxiao Yang2Zhen Zhang3Peichang Cao4Jihong Han5Yajun Duan6Ban-Feng Ruan7Qing-Shan Li8Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, ChinaKey Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, ChinaKey Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, ChinaKey Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, ChinaKey Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, ChinaKey Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, ChinaKey Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, ChinaKey Lab of Biofabrication of Anhui Higher Education Institution Centre for Advanced Biofabrication, Hefei University, Hefei 230601, ChinaKey Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, ChinaSepsis remains one of the most common life-threatening illnesses that is characterized by a systemic inflammatory response syndrome (SIRS) and usually arises following severe trauma and various septic infections. It is still in urgent need of new effective therapeutic agents, and chances are great that some candidates can be identified that can attenuate oxidative stress and inflammatory responses. Pterostilbene, which exerts attractive anti-oxidative and anti-inflammatory activities, is a homologue of natural polyphenolic derivative of resveratrol. Starting from it, we have made several rounds of rational optimizations. Firstly, based on the strategy of pharmacophore combination, indanone moiety was introduced onto the pterostilbene skeleton to generate a novel series of pterostilbene derivatives (<b>PIF_1</b>–<b>PIF_16</b>) which could possess both anti-oxidative and anti-inflammatory activities for sepsis treatment. Then, all target compounds were subjected to their structure–activity relationships (SAR) screening of anti-inflammatory activity in mouse mononuclear macrophage RAW264.7 cell line, and their cytotoxicities were determined after. Finally, an optimal compound, <b>PIF_9</b>, was identified. It decreased the mRNA levels of lipopolysaccharide (LPS)-induced interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX2). We also found that the anti-inflammatory effects might be contributed by its suppression on the nuclear factor-κB (NF-κB) and MAPKs signaling pathway. Moreover, <b>PIF_9</b> also demonstrated potent anti-oxidative activity in RAW264.7 macrophages and the sepsis mouse model. Not surprisingly, with the benefits mentioned above, it ameliorated LPS-induced sepsis in C57BL/6J mice and reduced multi-organ toxicity. Taken together, <b>PIF_9</b> was identified as a potential sepsis solution, targeting inflammation and oxidative stress through modulating MAPKs/NF-κB.https://www.mdpi.com/2076-3921/10/9/1333antioxidantsanti-inflammatory agentsindanonepterostilbenesepsis |
| spellingShingle | Mengyuan Fang Tingfeng Zou Xiaoxiao Yang Zhen Zhang Peichang Cao Jihong Han Yajun Duan Ban-Feng Ruan Qing-Shan Li Discovery of Novel Pterostilbene Derivatives That Might Treat Sepsis by Attenuating Oxidative Stress and Inflammation through Modulation of MAPKs/NF-κB Signaling Pathways Antioxidants antioxidants anti-inflammatory agents indanone pterostilbene sepsis |
| title | Discovery of Novel Pterostilbene Derivatives That Might Treat Sepsis by Attenuating Oxidative Stress and Inflammation through Modulation of MAPKs/NF-κB Signaling Pathways |
| title_full | Discovery of Novel Pterostilbene Derivatives That Might Treat Sepsis by Attenuating Oxidative Stress and Inflammation through Modulation of MAPKs/NF-κB Signaling Pathways |
| title_fullStr | Discovery of Novel Pterostilbene Derivatives That Might Treat Sepsis by Attenuating Oxidative Stress and Inflammation through Modulation of MAPKs/NF-κB Signaling Pathways |
| title_full_unstemmed | Discovery of Novel Pterostilbene Derivatives That Might Treat Sepsis by Attenuating Oxidative Stress and Inflammation through Modulation of MAPKs/NF-κB Signaling Pathways |
| title_short | Discovery of Novel Pterostilbene Derivatives That Might Treat Sepsis by Attenuating Oxidative Stress and Inflammation through Modulation of MAPKs/NF-κB Signaling Pathways |
| title_sort | discovery of novel pterostilbene derivatives that might treat sepsis by attenuating oxidative stress and inflammation through modulation of mapks nf κb signaling pathways |
| topic | antioxidants anti-inflammatory agents indanone pterostilbene sepsis |
| url | https://www.mdpi.com/2076-3921/10/9/1333 |
| work_keys_str_mv | AT mengyuanfang discoveryofnovelpterostilbenederivativesthatmighttreatsepsisbyattenuatingoxidativestressandinflammationthroughmodulationofmapksnfkbsignalingpathways AT tingfengzou discoveryofnovelpterostilbenederivativesthatmighttreatsepsisbyattenuatingoxidativestressandinflammationthroughmodulationofmapksnfkbsignalingpathways AT xiaoxiaoyang discoveryofnovelpterostilbenederivativesthatmighttreatsepsisbyattenuatingoxidativestressandinflammationthroughmodulationofmapksnfkbsignalingpathways AT zhenzhang discoveryofnovelpterostilbenederivativesthatmighttreatsepsisbyattenuatingoxidativestressandinflammationthroughmodulationofmapksnfkbsignalingpathways AT peichangcao discoveryofnovelpterostilbenederivativesthatmighttreatsepsisbyattenuatingoxidativestressandinflammationthroughmodulationofmapksnfkbsignalingpathways AT jihonghan discoveryofnovelpterostilbenederivativesthatmighttreatsepsisbyattenuatingoxidativestressandinflammationthroughmodulationofmapksnfkbsignalingpathways AT yajunduan discoveryofnovelpterostilbenederivativesthatmighttreatsepsisbyattenuatingoxidativestressandinflammationthroughmodulationofmapksnfkbsignalingpathways AT banfengruan discoveryofnovelpterostilbenederivativesthatmighttreatsepsisbyattenuatingoxidativestressandinflammationthroughmodulationofmapksnfkbsignalingpathways AT qingshanli discoveryofnovelpterostilbenederivativesthatmighttreatsepsisbyattenuatingoxidativestressandinflammationthroughmodulationofmapksnfkbsignalingpathways |