Triptolide alleviates cerebral ischemia/reperfusion injury via regulating the Fractalkine/CX3CR1 signaling pathway
Purpose: To evaluate the potential efficacy of Triptolide (TP) on cerebral ischemia/reperfusion injury (CIRI) and to uncover the underlying mechanism through which TP regulates CIRI. Methods: We constructed a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model to simulate CIRI, and est...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-06-01
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| Series: | Brain Research Bulletin |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0361923024000728 |
| _version_ | 1827274365318725632 |
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| author | Jiajun Zhou Wei Ye Ling Chen Junheng Li Yijun Zhou Chunfeng Bai Lian Luo |
| author_facet | Jiajun Zhou Wei Ye Ling Chen Junheng Li Yijun Zhou Chunfeng Bai Lian Luo |
| author_sort | Jiajun Zhou |
| collection | DOAJ |
| description | Purpose: To evaluate the potential efficacy of Triptolide (TP) on cerebral ischemia/reperfusion injury (CIRI) and to uncover the underlying mechanism through which TP regulates CIRI. Methods: We constructed a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model to simulate CIRI, and established a lipopolysaccharide (LPS)-stimulated BV-2 cell model to mimic the inflammatory state during CIRI. The neurological deficits score (NS) of mice were measured for assessment of neurologic functions. Both the severity of cerebral infarction and the apoptosis level in mouse brain tissues or cells were respectively evaluated using corresponding techniques. The expression levels of Ionized calcium binding adapter molecule 1 (IBA-1), Inductible Nitric Oxide Synthase (iNOS), Arginase 1 (Arg-1), Tumor necrosis factor-α (TNF-α), Interleukin 1β (IL-1β), Cysteine histoproteinase S (CTSS), Fractalkine, chemokine C-X3-C motif receptor 1 (CX3CR1), BCL-2-associated X protein (BAX), and antiapoptotic proteins (Bcl-2) were detected using immunofluorescence, qRT-PCR as well as Western blot, respectively. Results: Relative to the Sham group, treatment with TP attenuated the increased NS, infarct area and apoptosis levels observed in MCAO/R mice. Upregulated expression levels of IBA-1, iNOS, Arg-1, TNF-α and IL-1β were found in MCAO/R mice, while TP suppressed iNOS, TNF-α and IL-1β expression, and enhanced Arg-1 expression in both MCAO/R mice and LPS-stimulated BV-2 cells. Besides, TP inhibited the CTSS/Fractalkine/CX3CR1 pathway activation in both MCAO/R mice and LPS-induced BV-2 cells, while overexpression of CTSS reversed such effect. Co-culturing HT-22 cells with TP+LPS-treated BV-2 cells led to enhanced cell viability and decreased apoptosis levels. However, overexpression of CTSS further aggravated HT-22 cell injury. Conclusion: TP inhibits not only microglia polarization towards the M1 phenotype by suppressing the CTSS/Fractalkine/CX3CR1 pathway activation, but also HT-22 apoptosis by crosstalk with BV-2 cells, thereby ameliorating CIRI. These findings reveal a novel mechanism of TP in improving CIRI, and offer potential implications for addressing the preventive and therapeutic strategies of CIRI. |
| first_indexed | 2024-04-24T13:11:50Z |
| format | Article |
| id | doaj.art-8115e6af3ce249eca86c26982fc0dcd0 |
| institution | Directory Open Access Journal |
| issn | 1873-2747 |
| language | English |
| last_indexed | 2025-03-22T06:23:51Z |
| publishDate | 2024-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Brain Research Bulletin |
| spelling | doaj.art-8115e6af3ce249eca86c26982fc0dcd02024-04-26T04:58:14ZengElsevierBrain Research Bulletin1873-27472024-06-01211110939Triptolide alleviates cerebral ischemia/reperfusion injury via regulating the Fractalkine/CX3CR1 signaling pathwayJiajun Zhou0Wei Ye1Ling Chen2Junheng Li3Yijun Zhou4Chunfeng Bai5Lian Luo6Department of Neurology, Affiliated Hangzhou Xixi Hospital Zhejiang University of Medicine, Hangzhou, Zhejiang, ChinaDepartment of Neurology, Affiliated Hangzhou Xixi Hospital Zhejiang University of Medicine, Hangzhou, Zhejiang, ChinaDepartment of Neurology, Affiliated Hangzhou Xixi Hospital Zhejiang University of Medicine, Hangzhou, Zhejiang, ChinaDepartment of Neurology, Affiliated Hangzhou Xixi Hospital Zhejiang University of Medicine, Hangzhou, Zhejiang, ChinaDepartment of Liver Diseases, Affiliated Hangzhou Xixi Hospital Zhejiang University of Medicine, Hangzhou, Zhejiang, ChinaDepartment of Neurology, Affiliated Hangzhou Xixi Hospital Zhejiang University of Medicine, Hangzhou, Zhejiang, ChinaDepartment of Neurology, Affiliated Hangzhou Xixi Hospital Zhejiang University of Medicine, Hangzhou, Zhejiang, China; Corresponding author.Purpose: To evaluate the potential efficacy of Triptolide (TP) on cerebral ischemia/reperfusion injury (CIRI) and to uncover the underlying mechanism through which TP regulates CIRI. Methods: We constructed a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model to simulate CIRI, and established a lipopolysaccharide (LPS)-stimulated BV-2 cell model to mimic the inflammatory state during CIRI. The neurological deficits score (NS) of mice were measured for assessment of neurologic functions. Both the severity of cerebral infarction and the apoptosis level in mouse brain tissues or cells were respectively evaluated using corresponding techniques. The expression levels of Ionized calcium binding adapter molecule 1 (IBA-1), Inductible Nitric Oxide Synthase (iNOS), Arginase 1 (Arg-1), Tumor necrosis factor-α (TNF-α), Interleukin 1β (IL-1β), Cysteine histoproteinase S (CTSS), Fractalkine, chemokine C-X3-C motif receptor 1 (CX3CR1), BCL-2-associated X protein (BAX), and antiapoptotic proteins (Bcl-2) were detected using immunofluorescence, qRT-PCR as well as Western blot, respectively. Results: Relative to the Sham group, treatment with TP attenuated the increased NS, infarct area and apoptosis levels observed in MCAO/R mice. Upregulated expression levels of IBA-1, iNOS, Arg-1, TNF-α and IL-1β were found in MCAO/R mice, while TP suppressed iNOS, TNF-α and IL-1β expression, and enhanced Arg-1 expression in both MCAO/R mice and LPS-stimulated BV-2 cells. Besides, TP inhibited the CTSS/Fractalkine/CX3CR1 pathway activation in both MCAO/R mice and LPS-induced BV-2 cells, while overexpression of CTSS reversed such effect. Co-culturing HT-22 cells with TP+LPS-treated BV-2 cells led to enhanced cell viability and decreased apoptosis levels. However, overexpression of CTSS further aggravated HT-22 cell injury. Conclusion: TP inhibits not only microglia polarization towards the M1 phenotype by suppressing the CTSS/Fractalkine/CX3CR1 pathway activation, but also HT-22 apoptosis by crosstalk with BV-2 cells, thereby ameliorating CIRI. These findings reveal a novel mechanism of TP in improving CIRI, and offer potential implications for addressing the preventive and therapeutic strategies of CIRI.http://www.sciencedirect.com/science/article/pii/S0361923024000728Cerebral ischemia/reperfusion injuryTriptolideCTSSFractalkineCX3CR1 |
| spellingShingle | Jiajun Zhou Wei Ye Ling Chen Junheng Li Yijun Zhou Chunfeng Bai Lian Luo Triptolide alleviates cerebral ischemia/reperfusion injury via regulating the Fractalkine/CX3CR1 signaling pathway Brain Research Bulletin Cerebral ischemia/reperfusion injury Triptolide CTSS Fractalkine CX3CR1 |
| title | Triptolide alleviates cerebral ischemia/reperfusion injury via regulating the Fractalkine/CX3CR1 signaling pathway |
| title_full | Triptolide alleviates cerebral ischemia/reperfusion injury via regulating the Fractalkine/CX3CR1 signaling pathway |
| title_fullStr | Triptolide alleviates cerebral ischemia/reperfusion injury via regulating the Fractalkine/CX3CR1 signaling pathway |
| title_full_unstemmed | Triptolide alleviates cerebral ischemia/reperfusion injury via regulating the Fractalkine/CX3CR1 signaling pathway |
| title_short | Triptolide alleviates cerebral ischemia/reperfusion injury via regulating the Fractalkine/CX3CR1 signaling pathway |
| title_sort | triptolide alleviates cerebral ischemia reperfusion injury via regulating the fractalkine cx3cr1 signaling pathway |
| topic | Cerebral ischemia/reperfusion injury Triptolide CTSS Fractalkine CX3CR1 |
| url | http://www.sciencedirect.com/science/article/pii/S0361923024000728 |
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