OBJECTIVE Previous studies have demonstrated a close association between an altered immune system and major depressive disorders,and inhibition of neuroinflammation may represent an alternative mechanism to treat depr...OBJECTIVE Previous studies have demonstrated a close association between an altered immune system and major depressive disorders,and inhibition of neuroinflammation may represent an alternative mechanism to treat depression.Recently,the anti-inflammatory activ⁃ity of ibrutinib has been reported.However,the effect of ibrutinib on neuroinflammation-induced depression and its underlying mechanism has not been comprehensively studied.Therefore,we aimed to elucidate the potential anti-depres⁃sive role and mechanism of ibrutinib against neu⁃roinflammation-induced depression and synaptic defects.METHODS AND RESULTS Ibrutinib treatment significantly reduced lipopolysaccha⁃ride(LPS)-induced depressive-like behaviors and neuroinflammation via inhibiting NF-κB acti⁃vation,decreasing proinflammatory cytokine levels,and normalizing redox signaling and its downstream components,including Nrf2,HO-1,and SOD2,as well as glial cell activation mark⁃ers,such as Iba-1 and GFAP.Further,ibrutinib treatment inhibited LPS-activated inflammasome activation by targeting NLRP3/P38/caspase-1 signaling.Interestingly,LPS reduced the number of dendritic spines and expression of BDNF,and synaptic-related markers,including PSD95,snap25,and synaptophysin,were improved by ibrutinib treatment in the hippocampal area of the mouse brain.CONCLUSION Ibrutinib can allevi⁃ate neuroinflammation and synaptic defects,sug⁃gesting it has antidepressant potential against LPS-induced neuroinflammation and depression.展开更多
目的近年来发现依鲁替尼是B细胞恶性肿瘤的新型靶向药物,利妥昔单抗联合新药依鲁替尼对弥漫性大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)的研究逐步展开,本研究探讨利妥昔单抗与依鲁替尼对DLBCL细胞系Farage增殖及凋亡影响的...目的近年来发现依鲁替尼是B细胞恶性肿瘤的新型靶向药物,利妥昔单抗联合新药依鲁替尼对弥漫性大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)的研究逐步展开,本研究探讨利妥昔单抗与依鲁替尼对DLBCL细胞系Farage增殖及凋亡影响的协同作用。方法不同浓度的单药利妥昔单抗和单药依鲁替尼处理Farage细胞24、48和72h后,采用CCK8法检测细胞增殖抑制率。15μmol/L依鲁替尼处理Farage细胞48h后,采用RT-PCR法检测凋亡相关因子mRNA的表达变化。含人补体的培养条件下,1μg/mL利妥昔单抗联合10μmol/L依鲁替尼同时处理Farage细胞48h后,采用CCK8法检测增殖抑制率,采用流式细胞术检测凋亡率。结果利妥昔单抗在不含人补体的培养基中对Farage细胞增殖抑制作用不明显,在含人补体的培养基中有明显增殖抑制作用,并呈浓度和时间依赖性。依鲁替尼在含或不含人补体的培养条件下对Farage细胞均有明显增殖抑制作用,呈浓度和时间依赖性,2种条件下的增殖抑制率差异无统计学意义(F=0.978,P=0.329),15μmol/L依鲁替尼作用Farage细胞48h时,Fas(1.63±0.09)、Caspase-8(1.90±0.11)和Caspase-3(2.20±0.11)mRNA相对表达量均高于空白组(1.00±0.00)。在含人补体的培养基中,1μg/mL利妥昔单抗联合10μmol/L依鲁替尼同时处理Farage细胞48h后,联合组增殖抑制率为(57.06±1.48)%,高于依鲁替尼单药组(33.83±3.39)%和利妥昔单抗单药组(26.92±2.74)%,差异有统计学意义,F=87.403,P<0.001。联合组的凋亡和坏死率(44.30±2.20)%高于利妥昔单抗单药组(21.73±2.00)%和依鲁替尼单药组(17.44±1.60)%,且利妥昔单抗单药组和依鲁替尼单药组均高于空白组(2.32±0.21)%,差异均有统计学意义,F=327.205,P<0.001。结论利妥昔单抗可通过CDC效应引起DLBCL细胞凋亡坏死及增殖抑制,依鲁替尼可能通过上调Fas、Caspase-3和Caspase-8基因的表达,促使DLBCL细胞凋亡和增殖抑制,利妥昔单抗联展开更多
文摘OBJECTIVE Previous studies have demonstrated a close association between an altered immune system and major depressive disorders,and inhibition of neuroinflammation may represent an alternative mechanism to treat depression.Recently,the anti-inflammatory activ⁃ity of ibrutinib has been reported.However,the effect of ibrutinib on neuroinflammation-induced depression and its underlying mechanism has not been comprehensively studied.Therefore,we aimed to elucidate the potential anti-depres⁃sive role and mechanism of ibrutinib against neu⁃roinflammation-induced depression and synaptic defects.METHODS AND RESULTS Ibrutinib treatment significantly reduced lipopolysaccha⁃ride(LPS)-induced depressive-like behaviors and neuroinflammation via inhibiting NF-κB acti⁃vation,decreasing proinflammatory cytokine levels,and normalizing redox signaling and its downstream components,including Nrf2,HO-1,and SOD2,as well as glial cell activation mark⁃ers,such as Iba-1 and GFAP.Further,ibrutinib treatment inhibited LPS-activated inflammasome activation by targeting NLRP3/P38/caspase-1 signaling.Interestingly,LPS reduced the number of dendritic spines and expression of BDNF,and synaptic-related markers,including PSD95,snap25,and synaptophysin,were improved by ibrutinib treatment in the hippocampal area of the mouse brain.CONCLUSION Ibrutinib can allevi⁃ate neuroinflammation and synaptic defects,sug⁃gesting it has antidepressant potential against LPS-induced neuroinflammation and depression.
文摘目的近年来发现依鲁替尼是B细胞恶性肿瘤的新型靶向药物,利妥昔单抗联合新药依鲁替尼对弥漫性大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)的研究逐步展开,本研究探讨利妥昔单抗与依鲁替尼对DLBCL细胞系Farage增殖及凋亡影响的协同作用。方法不同浓度的单药利妥昔单抗和单药依鲁替尼处理Farage细胞24、48和72h后,采用CCK8法检测细胞增殖抑制率。15μmol/L依鲁替尼处理Farage细胞48h后,采用RT-PCR法检测凋亡相关因子mRNA的表达变化。含人补体的培养条件下,1μg/mL利妥昔单抗联合10μmol/L依鲁替尼同时处理Farage细胞48h后,采用CCK8法检测增殖抑制率,采用流式细胞术检测凋亡率。结果利妥昔单抗在不含人补体的培养基中对Farage细胞增殖抑制作用不明显,在含人补体的培养基中有明显增殖抑制作用,并呈浓度和时间依赖性。依鲁替尼在含或不含人补体的培养条件下对Farage细胞均有明显增殖抑制作用,呈浓度和时间依赖性,2种条件下的增殖抑制率差异无统计学意义(F=0.978,P=0.329),15μmol/L依鲁替尼作用Farage细胞48h时,Fas(1.63±0.09)、Caspase-8(1.90±0.11)和Caspase-3(2.20±0.11)mRNA相对表达量均高于空白组(1.00±0.00)。在含人补体的培养基中,1μg/mL利妥昔单抗联合10μmol/L依鲁替尼同时处理Farage细胞48h后,联合组增殖抑制率为(57.06±1.48)%,高于依鲁替尼单药组(33.83±3.39)%和利妥昔单抗单药组(26.92±2.74)%,差异有统计学意义,F=87.403,P<0.001。联合组的凋亡和坏死率(44.30±2.20)%高于利妥昔单抗单药组(21.73±2.00)%和依鲁替尼单药组(17.44±1.60)%,且利妥昔单抗单药组和依鲁替尼单药组均高于空白组(2.32±0.21)%,差异均有统计学意义,F=327.205,P<0.001。结论利妥昔单抗可通过CDC效应引起DLBCL细胞凋亡坏死及增殖抑制,依鲁替尼可能通过上调Fas、Caspase-3和Caspase-8基因的表达,促使DLBCL细胞凋亡和增殖抑制,利妥昔单抗联
