MIcroglia/macrophage-mediated erythrophagocytosis plays a crucial role in hematoma clearance after intracerebral hemorrhage.Dynamic cytoskeletal changes accompany phagocytosis.However,whether and how these changes are...MIcroglia/macrophage-mediated erythrophagocytosis plays a crucial role in hematoma clearance after intracerebral hemorrhage.Dynamic cytoskeletal changes accompany phagocytosis.However,whether and how these changes are associated with microglia/macrophage-mediated erythrophagocytosis remain unclear.In this study,we investigated the function of acetylatedα-tubulin,a stabilized microtubule form,in microglia/macrophage erythrophagocytosis after intracerebral hemorrhage both in vitro and in vivo.We first assessed the function of acetylatedα-tubulin in erythrophagocytosis using primary DiO GFP-labeled red blood cells co-cultured with the BV2 microglia or RAW264.7 macrophage cell lines.Acetylatedα-tubulin expression was significantly decreased in BV2 and RAW264.7 cells during erythrophagocytosis.Moreover,silencingα-tubulin acetyltransferase 1(ATAT1),a newly discoveredα-tubulin acetyltransferase,decreased Ac-α-tub levels and enhanced the erythrophagocytosis by BV2 and RAW264.7 cells.Consistent with these findings,in ATAT1-/-mice,we observed increased ionized calcium binding adapter molecule 1(Iba1)and Perls-positive microglia/macrophage phagocytes of red blood cells in peri-hematoma and reduced hematoma volume in mice with intracerebral hemorrhage.Additionally,knocking out ATAT1 alleviated neuronal apoptosis and pro-inflammatory cytokines and increased anti-inflammatory cytokines around the hematoma,ultimately improving neurological recovery of mice after intracerebral hemorrhage.These findings suggest that ATAT1 deficiency accelerates erythrophagocytosis by microglia/macrophages and hematoma absorption after intracerebral hemorrhage.These results provide novel insights into the mechanisms of hematoma clearance and suggest ATAT1 as a potential target for the treatment of intracerebral hemorrhage.展开更多
Objective: To investigate whether Naoxueshu Oral Liquid(NXS) could promote hematoma absorption in post-craniotomy hematoma(PCH) patients. Methods: This is an open-label, multicenter, and randomized controlled trial co...Objective: To investigate whether Naoxueshu Oral Liquid(NXS) could promote hematoma absorption in post-craniotomy hematoma(PCH) patients. Methods: This is an open-label, multicenter, and randomized controlled trial conducted at 9 hospitals in China. Patients aged 18–80 years with post-craniotomy supratentorial hematoma volume ranging from 10 to 30 mL or post-craniotomy infratentorial hematoma volume less than 10 mL, or intraventricular hemorrhage following cranial surgery were enrolled. They were randomly assigned at a 1:1 ratio to the NXS(10 m L thrice daily for 15 days) or control groups using a randomization code table. Standard medical care was administered in both groups. The primary outcome was the percentage reduction in hematoma volume from day 1 to day 15. The secondary outcomes included the percentage reduction in hematoma volume from day 1 to day 7, the absolute reduction in hematoma volume from day 1 to day 7 and 15, and the change in neurological function from day 1 to day 7 and 15. The safety was closely monitored throughout the study. Moreover, subgroup analysis was performed based on age, gender, history of diabetes, and etiology of intracerebral hemorrhage(ICH). Results: A total of 120 patients were enrolled and randomly assigned between March 30, 2018 and April 15, 2020. One patient was lost to follow-up in the control group. Finally, there were 119 patients(60 in the NXS group and 59 in the control group) included in the analysis. In the full analysis set(FAS) analysis, the NXS group had a greater percentage reduction in hematoma volume from day 1 to day 15 than the control group [median(Q1, Q3): 85%(71%, 97%) vs. 76%(53%, 93%), P<0.05]. The secondary outcomes showed no statistical significance between two groups, either in FAS or per-protocol set(P>0.05). Furthermore, no adverse events were reported during the study. In the FAS analysis, the NXS group exhibited a higher percentage reduction in hematoma volume on day 15 in the following subgroups: male patients, patients younger than 65 years, patients without diabetes, or those with initial cranial surgery due to ICH(all P<0.05). Conclusions: The administration of NXS demonstrated the potential to promote the percentage reduction in hematoma volume from day 1 to day 15. This intervention was found to be safe and feasible. The response to NXS may be influenced by patient characteristics.展开更多
The prognosis for patients who experience intracerebral hemorrhage is poor because of a lack of effective treatments.Tumor necrosis factor-α-stimulated gene 6(TSG6)is a secreted glycoprotein that exerts anti-inflamma...The prognosis for patients who experience intracerebral hemorrhage is poor because of a lack of effective treatments.Tumor necrosis factor-α-stimulated gene 6(TSG6)is a secreted glycoprotein that exerts anti-inflammatory effects in various inflammatory diseases.We previously showed that adipose-derived stem cells can inhibit inflammation by upregulating TSG6 secretion in an in vitro model of intracerebral hemorrhage.However,the direct effects of TSG6 on hematoma clearance in vivo remain largely unknown.The aim of this study was to determine how TSG6 affects hematoma absorption in mice subjected to intracerebral hemorrhage and to explore the potential underlying mechanisms.We first analyzed the gene profiles of patients with intracerebral hemorrhage from the GEO database and examined changes in TSG6 expression in the brain tissues of mice subjected to intracerebral hemorrhage.We found that TSG6 expression exhibited a transient increase following intracerebral hemorrhage,and that there was a negative correlation between the initial hematoma volume and TSG6 levels.Immunofluorescence analysis showed that TSG6 was primarily expressed in microglia and macrophages.Furthermore,we found that TSG6 promoted functional recovery in mice subjected to intracerebral hemorrhage by accelerating hematoma clearance,reducing the number of apoptotic cells and degenerated neurons,increasing the proportion of phagocytic microglia/macrophages,and decreasing iron deposition.Western blotting and immunofluorescence analysis indicated that TSG6 promoted M2 polarization of microglia/macrophages.In vitro phagocytosis experiments confirmed that TSG6 enhanced the ability of microglia to phagocytize red blood cells.Finally,we identified the signal transducer and activator of transcription 6/growth arrest-specific protein 6 signaling pathway as playing a critical role in TSG6-mediated hematoma absorption.In summary,our results demonstrate an essential role for TSG6 in promoting hematoma absorption in a mouse model of intracerebral hemorrhage.These findings suggest that TSG6 accelerates hematoma clearance and improves neurological function by promoting microglia/macrophage polarization to the M2 phenotype,activating the STAT6/GAS6 signaling pathway,and increasing phagocytic receptor expression on the surface of phagocytes,thereby enhancing their ability to phagocytize red blood cells.展开更多
基金supported by Science and Technology Innovation Enhancement Project of Army Medical University(to LX).
文摘MIcroglia/macrophage-mediated erythrophagocytosis plays a crucial role in hematoma clearance after intracerebral hemorrhage.Dynamic cytoskeletal changes accompany phagocytosis.However,whether and how these changes are associated with microglia/macrophage-mediated erythrophagocytosis remain unclear.In this study,we investigated the function of acetylatedα-tubulin,a stabilized microtubule form,in microglia/macrophage erythrophagocytosis after intracerebral hemorrhage both in vitro and in vivo.We first assessed the function of acetylatedα-tubulin in erythrophagocytosis using primary DiO GFP-labeled red blood cells co-cultured with the BV2 microglia or RAW264.7 macrophage cell lines.Acetylatedα-tubulin expression was significantly decreased in BV2 and RAW264.7 cells during erythrophagocytosis.Moreover,silencingα-tubulin acetyltransferase 1(ATAT1),a newly discoveredα-tubulin acetyltransferase,decreased Ac-α-tub levels and enhanced the erythrophagocytosis by BV2 and RAW264.7 cells.Consistent with these findings,in ATAT1-/-mice,we observed increased ionized calcium binding adapter molecule 1(Iba1)and Perls-positive microglia/macrophage phagocytes of red blood cells in peri-hematoma and reduced hematoma volume in mice with intracerebral hemorrhage.Additionally,knocking out ATAT1 alleviated neuronal apoptosis and pro-inflammatory cytokines and increased anti-inflammatory cytokines around the hematoma,ultimately improving neurological recovery of mice after intracerebral hemorrhage.These findings suggest that ATAT1 deficiency accelerates erythrophagocytosis by microglia/macrophages and hematoma absorption after intracerebral hemorrhage.These results provide novel insights into the mechanisms of hematoma clearance and suggest ATAT1 as a potential target for the treatment of intracerebral hemorrhage.
基金Supported by the Technology Platform Construction Project of Fujian Province (No. 2021Y2001 and 2020Y2003)。
文摘Objective: To investigate whether Naoxueshu Oral Liquid(NXS) could promote hematoma absorption in post-craniotomy hematoma(PCH) patients. Methods: This is an open-label, multicenter, and randomized controlled trial conducted at 9 hospitals in China. Patients aged 18–80 years with post-craniotomy supratentorial hematoma volume ranging from 10 to 30 mL or post-craniotomy infratentorial hematoma volume less than 10 mL, or intraventricular hemorrhage following cranial surgery were enrolled. They were randomly assigned at a 1:1 ratio to the NXS(10 m L thrice daily for 15 days) or control groups using a randomization code table. Standard medical care was administered in both groups. The primary outcome was the percentage reduction in hematoma volume from day 1 to day 15. The secondary outcomes included the percentage reduction in hematoma volume from day 1 to day 7, the absolute reduction in hematoma volume from day 1 to day 7 and 15, and the change in neurological function from day 1 to day 7 and 15. The safety was closely monitored throughout the study. Moreover, subgroup analysis was performed based on age, gender, history of diabetes, and etiology of intracerebral hemorrhage(ICH). Results: A total of 120 patients were enrolled and randomly assigned between March 30, 2018 and April 15, 2020. One patient was lost to follow-up in the control group. Finally, there were 119 patients(60 in the NXS group and 59 in the control group) included in the analysis. In the full analysis set(FAS) analysis, the NXS group had a greater percentage reduction in hematoma volume from day 1 to day 15 than the control group [median(Q1, Q3): 85%(71%, 97%) vs. 76%(53%, 93%), P<0.05]. The secondary outcomes showed no statistical significance between two groups, either in FAS or per-protocol set(P>0.05). Furthermore, no adverse events were reported during the study. In the FAS analysis, the NXS group exhibited a higher percentage reduction in hematoma volume on day 15 in the following subgroups: male patients, patients younger than 65 years, patients without diabetes, or those with initial cranial surgery due to ICH(all P<0.05). Conclusions: The administration of NXS demonstrated the potential to promote the percentage reduction in hematoma volume from day 1 to day 15. This intervention was found to be safe and feasible. The response to NXS may be influenced by patient characteristics.
基金supported by the National Natural Science Foundation of China,Nos.92148206,82071330(both to ZT),82201474(to GL)a grant from Tongji Hospital,No.2022ZHFY01(to ZT).
文摘The prognosis for patients who experience intracerebral hemorrhage is poor because of a lack of effective treatments.Tumor necrosis factor-α-stimulated gene 6(TSG6)is a secreted glycoprotein that exerts anti-inflammatory effects in various inflammatory diseases.We previously showed that adipose-derived stem cells can inhibit inflammation by upregulating TSG6 secretion in an in vitro model of intracerebral hemorrhage.However,the direct effects of TSG6 on hematoma clearance in vivo remain largely unknown.The aim of this study was to determine how TSG6 affects hematoma absorption in mice subjected to intracerebral hemorrhage and to explore the potential underlying mechanisms.We first analyzed the gene profiles of patients with intracerebral hemorrhage from the GEO database and examined changes in TSG6 expression in the brain tissues of mice subjected to intracerebral hemorrhage.We found that TSG6 expression exhibited a transient increase following intracerebral hemorrhage,and that there was a negative correlation between the initial hematoma volume and TSG6 levels.Immunofluorescence analysis showed that TSG6 was primarily expressed in microglia and macrophages.Furthermore,we found that TSG6 promoted functional recovery in mice subjected to intracerebral hemorrhage by accelerating hematoma clearance,reducing the number of apoptotic cells and degenerated neurons,increasing the proportion of phagocytic microglia/macrophages,and decreasing iron deposition.Western blotting and immunofluorescence analysis indicated that TSG6 promoted M2 polarization of microglia/macrophages.In vitro phagocytosis experiments confirmed that TSG6 enhanced the ability of microglia to phagocytize red blood cells.Finally,we identified the signal transducer and activator of transcription 6/growth arrest-specific protein 6 signaling pathway as playing a critical role in TSG6-mediated hematoma absorption.In summary,our results demonstrate an essential role for TSG6 in promoting hematoma absorption in a mouse model of intracerebral hemorrhage.These findings suggest that TSG6 accelerates hematoma clearance and improves neurological function by promoting microglia/macrophage polarization to the M2 phenotype,activating the STAT6/GAS6 signaling pathway,and increasing phagocytic receptor expression on the surface of phagocytes,thereby enhancing their ability to phagocytize red blood cells.
