Chronic myeloid leukemia （CML） is a clonal myeloprolif- erative disorder characterized by a chromosome translocation that generates the Bcr-Abl oncogene en- coding a constitutive kinase activity. Despite remarkable ...Chronic myeloid leukemia （CML） is a clonal myeloprolif- erative disorder characterized by a chromosome translocation that generates the Bcr-Abl oncogene en- coding a constitutive kinase activity. Despite remarkable success in controlling CML at chronic phase by Bcr-Abl tyrosine kinase inhibitors （TKIs）, a significant proportion of CML patients treated with TKIs develop drug resis- tance due to the inability of TKIs to kill leukemia stem cells （LSCs） that are responsible for initiation, drug re- sistance, and relapse of CML. Therefore, there is an ur- gent need for more potent and safer therapies against leukemia stem cells for curing CML. A number of LSC- associated targets and corresponding signaling path- ways, including CaMKII-y, a critical molecular switch for co-activating mu｜tipte LSC-associated signaling path- ways, have been identified over the past decades and various small inhibitors targeting LSC are also under development. Increasing evidence shows that leukemia stem cells are the root of CML and targeting LSC may offer a curable treatment option for CML patients. This review summarizes the molecular biology of LSC and its- associated targets, and the potential clinical application in chronic myeloid leukemia.展开更多
Dysregulation of neurotransmitter metabolism in the central nervous system contributes to mood disorders such as depression, anxiety, and post–traumatic stress disorder. Monoamines and amino acids are important types...Dysregulation of neurotransmitter metabolism in the central nervous system contributes to mood disorders such as depression, anxiety, and post–traumatic stress disorder. Monoamines and amino acids are important types of neurotransmitters. Our previous results have shown that disco-interacting protein 2 homolog A(Dip2a) knockout mice exhibit brain development disorders and abnormal amino acid metabolism in serum. This suggests that DIP2A is involved in the metabolism of amino acid–associated neurotransmitters. Therefore, we performed targeted neurotransmitter metabolomics analysis and found that Dip2a deficiency caused abnormal metabolism of tryptophan and thyroxine in the basolateral amygdala and medial prefrontal cortex. In addition, acute restraint stress induced a decrease in 5-hydroxytryptamine in the basolateral amygdala. Additionally, Dip2a was abundantly expressed in excitatory neurons of the basolateral amygdala, and deletion of Dip2a in these neurons resulted in hopelessness-like behavior in the tail suspension test. Altogether, these findings demonstrate that DIP2A in the basolateral amygdala may be involved in the regulation of stress susceptibility. This provides critical evidence implicating a role of DIP2A in affective disorders.展开更多
目的:研究柴胡疏肝汤对氯化锂-匹罗卡品所致的慢性颞叶癫痫模型大鼠NMDA(N-methylD-aspartate)受体亚单位NR2B和钙调蛋白依赖性蛋白激酶Ⅱ(Calcium/Calmodulin-dependent Protein KinaseⅡ,CaMKII)表达及行为学的影响。方法:将50只制备...目的:研究柴胡疏肝汤对氯化锂-匹罗卡品所致的慢性颞叶癫痫模型大鼠NMDA(N-methylD-aspartate)受体亚单位NR2B和钙调蛋白依赖性蛋白激酶Ⅱ(Calcium/Calmodulin-dependent Protein KinaseⅡ,CaMKII)表达及行为学的影响。方法:将50只制备成功的Wistar慢性颞叶癫痫大鼠(B)随机分为5组(B_(1-5)),艾芬地尔组(B_2)予艾芬地尔(ifenprodil)10 mg·kg^(-1)腹腔注射,柴胡疏肝汤低、中、高剂量组(B_(3-5))分别予柴胡疏肝汤2.5,5,10 g·kg^(-1)灌胃,空白对照组(A)和生理盐水组(B_1)均予等容积生理盐水腹腔注射,各组连续干预8周,同时进行行为学视频监测,8周后运用免疫组织化学和western blot检测各组大鼠海马、颞叶皮层NR2B和CaMKII的表达情况。结果:艾芬地尔组和柴胡疏肝汤高剂量组大鼠的发作次数较模型组明显降低(P<0.05);在大鼠海马、颞叶皮层,与空白对照组相比,模型组NR2B和CaMKII的表达水平明显增高(P<0.05);与模型组相比,艾芬地尔组及柴胡疏肝汤高剂量组NR2B和CaMKII的表达水平降低(P<0.05);艾芬地尔组与柴胡疏肝汤高剂量组的表达无明显差异(P>0.05)。结论:柴胡疏肝汤高剂量可减少慢性颞叶癫痫大鼠痫性发作次数,且具有抑制NR2B及CaMKII的作用,这可能是柴胡疏肝汤发挥其抗癫痫作用的机制之一。展开更多
基金We apologize to the scientists who made contributions to the field, but have not been cited due to the space limitations. This work was sup- ported in part by the National Natural Science Foundation of China （Grant Nos. 81270601, 81328016, and 81470306） and Leukemia Research Innovative Team of Zhejiang Province （2011 R50015）.
文摘Chronic myeloid leukemia （CML） is a clonal myeloprolif- erative disorder characterized by a chromosome translocation that generates the Bcr-Abl oncogene en- coding a constitutive kinase activity. Despite remarkable success in controlling CML at chronic phase by Bcr-Abl tyrosine kinase inhibitors （TKIs）, a significant proportion of CML patients treated with TKIs develop drug resis- tance due to the inability of TKIs to kill leukemia stem cells （LSCs） that are responsible for initiation, drug re- sistance, and relapse of CML. Therefore, there is an ur- gent need for more potent and safer therapies against leukemia stem cells for curing CML. A number of LSC- associated targets and corresponding signaling path- ways, including CaMKII-y, a critical molecular switch for co-activating mu｜tipte LSC-associated signaling path- ways, have been identified over the past decades and various small inhibitors targeting LSC are also under development. Increasing evidence shows that leukemia stem cells are the root of CML and targeting LSC may offer a curable treatment option for CML patients. This review summarizes the molecular biology of LSC and its- associated targets, and the potential clinical application in chronic myeloid leukemia.
基金supported by the STI 2030—Major Projects 2021ZD0204000,No.2021ZD0204003 (to XZ)the National Natural Science Foundation of China,Nos.32170973 (to XZ),32071018 (to ZH)。
文摘Dysregulation of neurotransmitter metabolism in the central nervous system contributes to mood disorders such as depression, anxiety, and post–traumatic stress disorder. Monoamines and amino acids are important types of neurotransmitters. Our previous results have shown that disco-interacting protein 2 homolog A(Dip2a) knockout mice exhibit brain development disorders and abnormal amino acid metabolism in serum. This suggests that DIP2A is involved in the metabolism of amino acid–associated neurotransmitters. Therefore, we performed targeted neurotransmitter metabolomics analysis and found that Dip2a deficiency caused abnormal metabolism of tryptophan and thyroxine in the basolateral amygdala and medial prefrontal cortex. In addition, acute restraint stress induced a decrease in 5-hydroxytryptamine in the basolateral amygdala. Additionally, Dip2a was abundantly expressed in excitatory neurons of the basolateral amygdala, and deletion of Dip2a in these neurons resulted in hopelessness-like behavior in the tail suspension test. Altogether, these findings demonstrate that DIP2A in the basolateral amygdala may be involved in the regulation of stress susceptibility. This provides critical evidence implicating a role of DIP2A in affective disorders.
