Danlian-Tongmai formula improves diabetic vascular calcification by regulating CCN3/NOTCH signal axis to inhibit inflammatory reaction
BackgroundVascular calcification (VC) commonly occurs in diabetes and is associated with cardiovascular disease incidence and mortality. Currently, there is no drug treatment for VC. The Danlian-Tongmai formula (DLTM) is a traditional Chinese medicine (TCM) prescription used for diabetic VC (DVC), b...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1510030/full |
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| author | Wenting Wang Yiwen Li Mengmeng Zhu Qian Xu Jing Cui Yanfei Liu Yanfei Liu Yue Liu |
| author_facet | Wenting Wang Yiwen Li Mengmeng Zhu Qian Xu Jing Cui Yanfei Liu Yanfei Liu Yue Liu |
| author_sort | Wenting Wang |
| collection | DOAJ |
| description | BackgroundVascular calcification (VC) commonly occurs in diabetes and is associated with cardiovascular disease incidence and mortality. Currently, there is no drug treatment for VC. The Danlian-Tongmai formula (DLTM) is a traditional Chinese medicine (TCM) prescription used for diabetic VC (DVC), but its mechanisms of action remain unclear. This study aims to elucidate the effects of DLTM on DVC and explore the underlying mechanisms of action.MethodsUltra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) was used to identify the metabolites of DLTM. A DVC rat model was established using streptozotocin (STZ) combined with vitamin D3 (VitD3). The effects of DLTM on DVC were evaluated through alizarin red staining, calcium deposition, and changes in osteogenic and contractile markers. The specific molecular mechanism of DLTM in treating diabetic VC was comprehensively analyzed by transcriptomics, molecular docking and in vivo experimental verification.ResultsWe identified 108 major metabolites of DLTM. In vivo, high-dose DLTM significantly alleviated VC in diabetic rats. Transcriptomic analysis showed that DLTM treatment markedly altered the transcriptomic profile of rat aortas, which was associated with regulating the CCN3/NOTCH signaling pathway, promoting vascular smooth muscle contraction, and inhibiting the inflammatory responses. Molecular docking and molecular dynamics simulation demonstrated strong binding interactions between DLTM metabolites and key molecules within the CCN3/NOTCH pathway, including NOTCH1, DLL1, DLL4, hes1, and hey1. In vivo experiments confirmed that DLTM could upregulate CCN3, inhibit the activation of NOTCH signaling ligands DLL1 and downstream transcription factors hes1 and hey1, and reduce the release of inflammatory cytokines IL6, IL1β, and TNFα.ConclusionDLTM alleviates DVC by regulating the CCN3/NOTCH signaling axis to inhibit inflammatory responses. Our research provides experimental basis for clinical treatment and drug transformation of diabetic VC. |
| format | Article |
| id | doaj-art-4fae90e92ab44fbbb0b3a9430a6b93cc |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-4fae90e92ab44fbbb0b3a9430a6b93cc2025-01-06T06:59:06ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-01-011510.3389/fphar.2024.15100301510030Danlian-Tongmai formula improves diabetic vascular calcification by regulating CCN3/NOTCH signal axis to inhibit inflammatory reactionWenting Wang0Yiwen Li1Mengmeng Zhu2Qian Xu3Jing Cui4Yanfei Liu5Yanfei Liu6Yue Liu7National Clinical Research Center for TCM Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, ChinaBeijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, ChinaNational Clinical Research Center for TCM Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, ChinaNational Clinical Research Center for TCM Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, ChinaNational Clinical Research Center for TCM Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, ChinaNational Clinical Research Center for TCM Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, ChinaThe Second Department of Geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, ChinaNational Clinical Research Center for TCM Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, ChinaBackgroundVascular calcification (VC) commonly occurs in diabetes and is associated with cardiovascular disease incidence and mortality. Currently, there is no drug treatment for VC. The Danlian-Tongmai formula (DLTM) is a traditional Chinese medicine (TCM) prescription used for diabetic VC (DVC), but its mechanisms of action remain unclear. This study aims to elucidate the effects of DLTM on DVC and explore the underlying mechanisms of action.MethodsUltra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) was used to identify the metabolites of DLTM. A DVC rat model was established using streptozotocin (STZ) combined with vitamin D3 (VitD3). The effects of DLTM on DVC were evaluated through alizarin red staining, calcium deposition, and changes in osteogenic and contractile markers. The specific molecular mechanism of DLTM in treating diabetic VC was comprehensively analyzed by transcriptomics, molecular docking and in vivo experimental verification.ResultsWe identified 108 major metabolites of DLTM. In vivo, high-dose DLTM significantly alleviated VC in diabetic rats. Transcriptomic analysis showed that DLTM treatment markedly altered the transcriptomic profile of rat aortas, which was associated with regulating the CCN3/NOTCH signaling pathway, promoting vascular smooth muscle contraction, and inhibiting the inflammatory responses. Molecular docking and molecular dynamics simulation demonstrated strong binding interactions between DLTM metabolites and key molecules within the CCN3/NOTCH pathway, including NOTCH1, DLL1, DLL4, hes1, and hey1. In vivo experiments confirmed that DLTM could upregulate CCN3, inhibit the activation of NOTCH signaling ligands DLL1 and downstream transcription factors hes1 and hey1, and reduce the release of inflammatory cytokines IL6, IL1β, and TNFα.ConclusionDLTM alleviates DVC by regulating the CCN3/NOTCH signaling axis to inhibit inflammatory responses. Our research provides experimental basis for clinical treatment and drug transformation of diabetic VC.https://www.frontiersin.org/articles/10.3389/fphar.2024.1510030/fullvascular calcificationDanlian-Tongmai formulaUHPLC-MSCCN3notch signaling |
| spellingShingle | Wenting Wang Yiwen Li Mengmeng Zhu Qian Xu Jing Cui Yanfei Liu Yanfei Liu Yue Liu Danlian-Tongmai formula improves diabetic vascular calcification by regulating CCN3/NOTCH signal axis to inhibit inflammatory reaction Frontiers in Pharmacology vascular calcification Danlian-Tongmai formula UHPLC-MS CCN3 notch signaling |
| title | Danlian-Tongmai formula improves diabetic vascular calcification by regulating CCN3/NOTCH signal axis to inhibit inflammatory reaction |
| title_full | Danlian-Tongmai formula improves diabetic vascular calcification by regulating CCN3/NOTCH signal axis to inhibit inflammatory reaction |
| title_fullStr | Danlian-Tongmai formula improves diabetic vascular calcification by regulating CCN3/NOTCH signal axis to inhibit inflammatory reaction |
| title_full_unstemmed | Danlian-Tongmai formula improves diabetic vascular calcification by regulating CCN3/NOTCH signal axis to inhibit inflammatory reaction |
| title_short | Danlian-Tongmai formula improves diabetic vascular calcification by regulating CCN3/NOTCH signal axis to inhibit inflammatory reaction |
| title_sort | danlian tongmai formula improves diabetic vascular calcification by regulating ccn3 notch signal axis to inhibit inflammatory reaction |
| topic | vascular calcification Danlian-Tongmai formula UHPLC-MS CCN3 notch signaling |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1510030/full |
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