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:探讨Bruton酪氨酸激酶(Bruton's tyrosine kinase,BTK)抑制剂ibrutinib抑制弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)细胞生存的作用及其相关机制。方法:用不同浓度的ibrutinib处理DLBCL细胞系SUDHL-10、HBL-1...目的:探讨Bruton酪氨酸激酶(Bruton's tyrosine kinase,BTK)抑制剂ibrutinib抑制弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)细胞生存的作用及其相关机制。方法:用不同浓度的ibrutinib处理DLBCL细胞系SUDHL-10、HBL-1和患者原代细胞,以MTT法检测细胞的增殖抑制情况;以Annexin V/PI流式细胞术和DAPI染色法检测细胞的凋亡情况;应用Western blot法检测细胞表达磷酸化BTK、AKT、ERK的变化。DLBCL细胞与MSC共培养后,体外克隆形成实验和NOD/SCID肿瘤模型小鼠检测ibrutinib在肿瘤微环境里对DLBCL细胞的抑制作用。结果:2.5μmol/L及更高浓度的ibrutinib对DLBCL细胞的增殖有明显的抑制作用,且呈剂量依赖性。1.0、2.5μmol/L ibrutinib作用于SUDHL-10细胞24 h,细胞凋亡率分别为(21.73±3.64)%和(34.71±2.36)%,高于对照组(3.55±1.89)%(P<0.05)。5、10μmol/L ibrutinib处理24 h后,DLBCL细胞系均出现核皱缩(5μmol/L)、碎裂(10μmol/L)。ibrutinib处理细胞后磷酸化BTK、AKT、ERK的表达均明显降低。ibrutinib抑制共培养时DLBCL细胞的体外克隆形成(P<0.01)及DLBCL细胞在体内的增殖生长,差异均具有统计学意义(P<0.05)。结论:ibrutinib可抑制细胞系SUDHL-10和HBL-1的增殖,诱导凋亡,其机制可能通过阻断AKT、ERK信号途径而实现;在肿瘤微环境中ibrutinib同样对DLBCL细胞具有较强的抑制生存的作用,该药物有望为DLBCL的治疗带来希望。展开更多
Ibrutinib is a first-line treatment drug for B-cell malignancies.However,resistance to ibrutinib has been reported due to BTKC481Smutation.Although PROTAC strategy is expected to overcome this clinical resistance,it h...Ibrutinib is a first-line treatment drug for B-cell malignancies.However,resistance to ibrutinib has been reported due to BTKC481Smutation.Although PROTAC strategy is expected to overcome this clinical resistance,it has limitations such as large molecular weight and moderate bioactivity,which restrict its potential clinical application.Herein,we report a new type of potent BTKC481S-targeting PROTAC degrader.Through design,computer-assisted optimization and SAR studies,we have developed a representative BTKC481Sdegrader L6 with a much smaller molecular weight and improved solubility.Notably,L6 demonstrates better BTK degrading activity and lower IC50value in ibrutinib-resistant cell line than the first-generation BTK degrader P13I.Optimization strategy of L6 provides a general approach in the development of PROTACs targeting BTK and other proteins for future study.展开更多
BACKGROUND Wells’ syndrome(eosinophilic cellulitis) is an uncommon eosinophilic dermatosis of uncertain pathogenesis,characterized by clinical polymorphism and suggestive but nonspecific histopathologic traits.Its co...BACKGROUND Wells’ syndrome(eosinophilic cellulitis) is an uncommon eosinophilic dermatosis of uncertain pathogenesis,characterized by clinical polymorphism and suggestive but nonspecific histopathologic traits.Its course is recurrent,and response to therapy is unpredictable.In a case in which the patient has a number of potential triggers for the manifestation of Wells’ syndrome skin rash,the treating physician must decide or must make an assumption in order to establish the most likely clinical scenario.This is important for the patient’s future treatment plans.CASE SUMMARY We describe the clinical case of a 46-year-old female with chronic lymphocytic leukemia who had already received treatment for several months with ibrutinib.She was diagnosed with Wells’ syndrome 10 d after an influenza vaccination containing thimerosal.Based on the literature,the patient was treated with a course of oral steroids.Resolution of clinical symptoms and rash were observed in response to the treatment.Ibrutinib was not discontinued.CONCLUSION The etiology of Wells’ syndrome remains unknown.Clinically,it resembles bacterial cellulitis.Lack of response to antibiotic treatment should lead the physician to consider a diagnosis of Wells’ syndrome.Treating the underlying condition is important and may lead to resolution of the syndrome.However,the most common and effective treatment to limit the course of the disease are systemic steroids.展开更多
Ibrutinib,a targeted therapy for B-cell malignancies,has shown remarkable efficacy in treating various hematologic cancers.However,its clinical use has raised concerns regarding cardiovascular complications,notably at...Ibrutinib,a targeted therapy for B-cell malignancies,has shown remarkable efficacy in treating various hematologic cancers.However,its clinical use has raised concerns regarding cardiovascular complications,notably atrial fibrillation(AF).This comprehensive review critically evaluates the association between ibrutinib and AF by examining incidence,risk factors,mechanistic links,and management strategies.Through an extensive analysis of original research articles,this review elucidates the complex interplay between ibrutinib’s therapeutic benefits and cardiovascular risks.Moreover,it highlights the need for personalized treatment approaches,vigilant monitoring,and interdisciplinary collaboration to optimize patient outcomes and safety in the context of ibrutinib therapy.The review provides a valuable resource for healthcare professionals aiming to navigate the intricacies of ibrutinib’s therapeutic landscape while prioritizing patient well-being.展开更多
<strong>Objective:</strong> Therapeutic results of relapsed/refractory mantle cell lymphoma (R/R MCL) are very disappointing at present, and there is no standard effective treatment regimen. Ibrutinib has ...<strong>Objective:</strong> Therapeutic results of relapsed/refractory mantle cell lymphoma (R/R MCL) are very disappointing at present, and there is no standard effective treatment regimen. Ibrutinib has been proved to be effective for R/R MCL, however, the sample size of these individual clinical studies was relatively small. Hence, current clinical experience in its usage is still limited. It is necessary to systematically analyze the efficacy and adverse reactions of ibrutinib in the treatment of R/R MCL. <strong>Methods:</strong> The PubMed, Cochrane Library, and Embase databases were searched using English search terms, mantle cell lymphoma, MCL, and ibrutinib;the VIP, Wanfang, and China National Knowledge Infrastructure (CNKI) databases were searched using the Chinese search terms, ibrutinib and mantle cell lymphoma. The extracted data were subjected to meta-analysis using R software to deduce the effective rate and occurrence rate of serious adverse reactions. <strong>Results:</strong> A total of 12 cohort studies were included in this analysis. The results demonstrated that ibrutinib could be an efficient therapy regimen for R/R MCL patients and the effect of combination therapy was better than that of single-drug therapy. During the treatment with ibrutinib, the adverse reactions mainly included hematological toxicity, infection, atrial fibrillation, and bleeding. <strong>Discussion:</strong> Our analysis showed ibrutinib is an optimal second-line treatment for R/R MCL, and the combination therapy is more effective than monotherapy as it was well-tolerated by the patients. Therefore, the combination of other drugs for R/R MCL should be considered for patients with poor efficacy of ibrutinib alone or relapse after treatment.展开更多
Background:Ibrutinib is a first-line drug that targets Bruton's tyrosine kinase for the treatment of B cell cancer.However,cardiotoxicity induced by ibrutinib is a major side effect that limits its clinical use.Th...Background:Ibrutinib is a first-line drug that targets Bruton's tyrosine kinase for the treatment of B cell cancer.However,cardiotoxicity induced by ibrutinib is a major side effect that limits its clinical use.This study aimed to investigate themechanism of ibrutinib-induced cardiotoxicity and evaluate the protective role of metformin.Methods:The study utilized male C57BL/6 J mice,which were administered ibrutinib at a dosage of 30 mg/kg/day via oralgavage for 4 weeks to induce cardiotoxicity.Metformin was administered orally at 200 mg/kg/day for 5 weeks,starting 1 weekbefore ibrutinib treatment.Cardiac function was assessed using echocardiography and electrophysiological studies,includingsurface electrocardiography and epicardial electrical mapping.Blood pressure was measured using a tail-cuff system.Westernblot analysis was conducted to evaluate the activity of the PI3K-AKT and AMPK pathways,along with apoptosis markers.Results:C57BL/6 J mice were treated with ibrutinib for 4 weeks to assess its effect on cardiac function.We observed thatibrutinib induced ventricular arrhythmia and abnormal conduction while reducing the left ventricular ejection fraction.Furthermore,pretreatment with metformin reversed ibrutinib-induced cardiotoxicity.Mechanistically,ibrutinib decreased PI3K-AKT activity,resulting in apoptosis of cardiomyocytes.Administration of metformin upregulated AMPK and PI3K-AKTactivity,which contributed to the improvement of cardiac function.Conclusion:The study concludes that metformin effectively mitigates ibrutinib-induced cardiotoxicity,including ventriculararrhythmia and cardiac dysfunction,by enhancing AMPK and PI3K-AKT pathway activity.These findings suggest that metformin holds potential as a therapeutic strategy to protect against the adverse cardiac effects associated with ibrutinib treatment,offering a promising approach for improving the cardiovascular safety of patients undergoing therapy for B cell cancers.展开更多
Background:Ibrutinib,a potent Bruton’s tyrosine kinase inhibitor with marked efficacy against hematological malignancies,is associated with the heightened risk of atrial fibrillation(AF).Although ibrutinib-induced AF...Background:Ibrutinib,a potent Bruton’s tyrosine kinase inhibitor with marked efficacy against hematological malignancies,is associated with the heightened risk of atrial fibrillation(AF).Although ibrutinib-induced AF is linked to enhanced oxidative stress,the underlying mechanisms remain unclear.Objective:This research aimed to explore the molecular mechanism and regulatory target in ibrutinib-induced AF.Methods:We performed in vivo electrophysiology studies using ibrutinib-treated mice,and then employed proteomic and single-cell transcriptomic analyses to identify the underlying targets and mechanisms.The effects of A-kinase anchoring protein 1(AKAP1)depletion on mitochondrial quality surveillance(MQS)were evaluated using both in vivo and ex vivo AKAP1 overexpression models.Results:Atrial AKAP1 expression was significantly reduced in ibrutinib-treated mice,leading to inducible AF,atrial fibrosis,and mitochondrial fragmentation.These pathological changes were effectively mitigated in an overexpression model of ibrutinib-treated mice injected with an adeno-associated virus carrying Akap1.In ibrutinib-treated atrial myocytes,AKAP1 down-regulation promoted dynamin-related protein 1(DRP1)translocation into mitochondria by facilitating DRP1 dephosphorylation at Ser637,thereby mediating excessive mitochondrial fission.Impaired MQS was also suggested by defective mitochondrial respiration,mitochondrial metabolic reprogramming,and suppressed mitochondrial biogenesis,accompanied by excessive oxidative stress and inflammatory activation.The ibrutinib-mediated MQS disturbance can be markedly improved with the inducible expression of the AKAP1 lentiviral system.Conclusions:Our findings emphasize the key role of AKAP1-mediated MQS disruption in ibrutinib-induced AF,which explains the previously observed reactive oxygen species overproduction.Hence,AKAP1 activation can be employed to prevent and treat ibrutinib-induced AF.展开更多
Objective To improve the knowledge and experience of ibrutinib combined with CAR-T cells in the treatment of high-risk chronic lymphoblastic leukemia(CLL)patients or small lymphocytic lymphoma(SLL)with TP53 gene aberr...Objective To improve the knowledge and experience of ibrutinib combined with CAR-T cells in the treatment of high-risk chronic lymphoblastic leukemia(CLL)patients or small lymphocytic lymphoma(SLL)with TP53 gene aberration.Methods One case of del(17 p)CLL patients with BCL-2 inhibitor resistance was treated with ibrutinib combined with CAR-T cells,successfully bridged to allogeneic hematopoietic stem cell transplantation(allo-HSCT),and the relative literatures were reviewed.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.
基金supported by the National Natural Science Foundation of China(Nos.82125034,81773567)National Major Scientific and Technological Project(Nos.2020YFE0202200,2021YFA1300200 and 2021YFA1302100)Shuimu Tsinghua Scholar。
文摘Ibrutinib is a first-line treatment drug for B-cell malignancies.However,resistance to ibrutinib has been reported due to BTKC481Smutation.Although PROTAC strategy is expected to overcome this clinical resistance,it has limitations such as large molecular weight and moderate bioactivity,which restrict its potential clinical application.Herein,we report a new type of potent BTKC481S-targeting PROTAC degrader.Through design,computer-assisted optimization and SAR studies,we have developed a representative BTKC481Sdegrader L6 with a much smaller molecular weight and improved solubility.Notably,L6 demonstrates better BTK degrading activity and lower IC50value in ibrutinib-resistant cell line than the first-generation BTK degrader P13I.Optimization strategy of L6 provides a general approach in the development of PROTACs targeting BTK and other proteins for future study.
文摘BACKGROUND Wells’ syndrome(eosinophilic cellulitis) is an uncommon eosinophilic dermatosis of uncertain pathogenesis,characterized by clinical polymorphism and suggestive but nonspecific histopathologic traits.Its course is recurrent,and response to therapy is unpredictable.In a case in which the patient has a number of potential triggers for the manifestation of Wells’ syndrome skin rash,the treating physician must decide or must make an assumption in order to establish the most likely clinical scenario.This is important for the patient’s future treatment plans.CASE SUMMARY We describe the clinical case of a 46-year-old female with chronic lymphocytic leukemia who had already received treatment for several months with ibrutinib.She was diagnosed with Wells’ syndrome 10 d after an influenza vaccination containing thimerosal.Based on the literature,the patient was treated with a course of oral steroids.Resolution of clinical symptoms and rash were observed in response to the treatment.Ibrutinib was not discontinued.CONCLUSION The etiology of Wells’ syndrome remains unknown.Clinically,it resembles bacterial cellulitis.Lack of response to antibiotic treatment should lead the physician to consider a diagnosis of Wells’ syndrome.Treating the underlying condition is important and may lead to resolution of the syndrome.However,the most common and effective treatment to limit the course of the disease are systemic steroids.
文摘Ibrutinib,a targeted therapy for B-cell malignancies,has shown remarkable efficacy in treating various hematologic cancers.However,its clinical use has raised concerns regarding cardiovascular complications,notably atrial fibrillation(AF).This comprehensive review critically evaluates the association between ibrutinib and AF by examining incidence,risk factors,mechanistic links,and management strategies.Through an extensive analysis of original research articles,this review elucidates the complex interplay between ibrutinib’s therapeutic benefits and cardiovascular risks.Moreover,it highlights the need for personalized treatment approaches,vigilant monitoring,and interdisciplinary collaboration to optimize patient outcomes and safety in the context of ibrutinib therapy.The review provides a valuable resource for healthcare professionals aiming to navigate the intricacies of ibrutinib’s therapeutic landscape while prioritizing patient well-being.
文摘<strong>Objective:</strong> Therapeutic results of relapsed/refractory mantle cell lymphoma (R/R MCL) are very disappointing at present, and there is no standard effective treatment regimen. Ibrutinib has been proved to be effective for R/R MCL, however, the sample size of these individual clinical studies was relatively small. Hence, current clinical experience in its usage is still limited. It is necessary to systematically analyze the efficacy and adverse reactions of ibrutinib in the treatment of R/R MCL. <strong>Methods:</strong> The PubMed, Cochrane Library, and Embase databases were searched using English search terms, mantle cell lymphoma, MCL, and ibrutinib;the VIP, Wanfang, and China National Knowledge Infrastructure (CNKI) databases were searched using the Chinese search terms, ibrutinib and mantle cell lymphoma. The extracted data were subjected to meta-analysis using R software to deduce the effective rate and occurrence rate of serious adverse reactions. <strong>Results:</strong> A total of 12 cohort studies were included in this analysis. The results demonstrated that ibrutinib could be an efficient therapy regimen for R/R MCL patients and the effect of combination therapy was better than that of single-drug therapy. During the treatment with ibrutinib, the adverse reactions mainly included hematological toxicity, infection, atrial fibrillation, and bleeding. <strong>Discussion:</strong> Our analysis showed ibrutinib is an optimal second-line treatment for R/R MCL, and the combination therapy is more effective than monotherapy as it was well-tolerated by the patients. Therefore, the combination of other drugs for R/R MCL should be considered for patients with poor efficacy of ibrutinib alone or relapse after treatment.
基金National Natural Science Foundation of China(Grants:82170327,82200344,82370332)Tianjin Key Medical Discipline(Specialty)Construction Project(Grant:TJYXZDXK-029A)Tianjin Natural Science Foundation(Grants:20JCZDJC00340,20JCZXJC00130).
文摘Background:Ibrutinib is a first-line drug that targets Bruton's tyrosine kinase for the treatment of B cell cancer.However,cardiotoxicity induced by ibrutinib is a major side effect that limits its clinical use.This study aimed to investigate themechanism of ibrutinib-induced cardiotoxicity and evaluate the protective role of metformin.Methods:The study utilized male C57BL/6 J mice,which were administered ibrutinib at a dosage of 30 mg/kg/day via oralgavage for 4 weeks to induce cardiotoxicity.Metformin was administered orally at 200 mg/kg/day for 5 weeks,starting 1 weekbefore ibrutinib treatment.Cardiac function was assessed using echocardiography and electrophysiological studies,includingsurface electrocardiography and epicardial electrical mapping.Blood pressure was measured using a tail-cuff system.Westernblot analysis was conducted to evaluate the activity of the PI3K-AKT and AMPK pathways,along with apoptosis markers.Results:C57BL/6 J mice were treated with ibrutinib for 4 weeks to assess its effect on cardiac function.We observed thatibrutinib induced ventricular arrhythmia and abnormal conduction while reducing the left ventricular ejection fraction.Furthermore,pretreatment with metformin reversed ibrutinib-induced cardiotoxicity.Mechanistically,ibrutinib decreased PI3K-AKT activity,resulting in apoptosis of cardiomyocytes.Administration of metformin upregulated AMPK and PI3K-AKTactivity,which contributed to the improvement of cardiac function.Conclusion:The study concludes that metformin effectively mitigates ibrutinib-induced cardiotoxicity,including ventriculararrhythmia and cardiac dysfunction,by enhancing AMPK and PI3K-AKT pathway activity.These findings suggest that metformin holds potential as a therapeutic strategy to protect against the adverse cardiac effects associated with ibrutinib treatment,offering a promising approach for improving the cardiovascular safety of patients undergoing therapy for B cell cancers.
基金supported by the National Natural Science Foundation of China(Grant Nos.82170318,81870243,82170310,and 82300315)the Guangdong Province Basic and Applied Basic Research Fund Project(No.2024A1515012174).
文摘Background:Ibrutinib,a potent Bruton’s tyrosine kinase inhibitor with marked efficacy against hematological malignancies,is associated with the heightened risk of atrial fibrillation(AF).Although ibrutinib-induced AF is linked to enhanced oxidative stress,the underlying mechanisms remain unclear.Objective:This research aimed to explore the molecular mechanism and regulatory target in ibrutinib-induced AF.Methods:We performed in vivo electrophysiology studies using ibrutinib-treated mice,and then employed proteomic and single-cell transcriptomic analyses to identify the underlying targets and mechanisms.The effects of A-kinase anchoring protein 1(AKAP1)depletion on mitochondrial quality surveillance(MQS)were evaluated using both in vivo and ex vivo AKAP1 overexpression models.Results:Atrial AKAP1 expression was significantly reduced in ibrutinib-treated mice,leading to inducible AF,atrial fibrosis,and mitochondrial fragmentation.These pathological changes were effectively mitigated in an overexpression model of ibrutinib-treated mice injected with an adeno-associated virus carrying Akap1.In ibrutinib-treated atrial myocytes,AKAP1 down-regulation promoted dynamin-related protein 1(DRP1)translocation into mitochondria by facilitating DRP1 dephosphorylation at Ser637,thereby mediating excessive mitochondrial fission.Impaired MQS was also suggested by defective mitochondrial respiration,mitochondrial metabolic reprogramming,and suppressed mitochondrial biogenesis,accompanied by excessive oxidative stress and inflammatory activation.The ibrutinib-mediated MQS disturbance can be markedly improved with the inducible expression of the AKAP1 lentiviral system.Conclusions:Our findings emphasize the key role of AKAP1-mediated MQS disruption in ibrutinib-induced AF,which explains the previously observed reactive oxygen species overproduction.Hence,AKAP1 activation can be employed to prevent and treat ibrutinib-induced AF.
文摘Objective To improve the knowledge and experience of ibrutinib combined with CAR-T cells in the treatment of high-risk chronic lymphoblastic leukemia(CLL)patients or small lymphocytic lymphoma(SLL)with TP53 gene aberration.Methods One case of del(17 p)CLL patients with BCL-2 inhibitor resistance was treated with ibrutinib combined with CAR-T cells,successfully bridged to allogeneic hematopoietic stem cell transplantation(allo-HSCT),and the relative literatures were reviewed.
