Oleanolic acid derivatives act as newer protein tyrosine phosphatase 1B （PTP-1B） inhibitors for type 2 diabetes mellitus （T2DM）. In order to understand the structural requirement of PTP-1B inhibitors, 52 oleanolic...Oleanolic acid derivatives act as newer protein tyrosine phosphatase 1B （PTP-1B） inhibitors for type 2 diabetes mellitus （T2DM）. In order to understand the structural requirement of PTP-1B inhibitors, 52 oleanolic acid derivatives were divided into a training set （34 compounds） and a test set （18 compounds）. The highly reliable and predictive 3D-QSAR models were constructed by CoMFA, CoMSIA and topomer CoMFA methods, respectively. The results showed that the cross validated coefficient （q2） and non-cross-validated coefficient （R2） were 0.554 and 0.999 in the CoMFA model, 0.675 and 0.971 in the CoMSIA model, and 0.628 and 0.939 in the topomer CoMFA model, which suggests that three models are robust and have good exterior predictive capabilities. Furthermore, ten novel inhibitors with much higher inhibitory potency were designed. Our design strategy was that （i） the electronegative substituents （Cl, -CH2OH, OH and -CH2Cl） were introduced into the double bond of ring C, （ii） the hydrogen bond acceptor groups （C≡N and N atom）, electronegative groups （C≡N, N atom, -COOH and -COOCH3） and bulky substituents （C6H5N） were connected to the C-3 position, which would result in generating potent and selective PTP-1B inhibitors. We expect that the results in this paper have the potential to facilitate the process of design and to develop new potent PTP-1B inhibitors.展开更多
A DNA fragment encoding the intracellular part of tyrosine phosphatase RPTPα designated as RPTPα-2D gene was amplified by PCR from a human prostate cDNA library and cloned into the pT7 E. coli expression vector. The...A DNA fragment encoding the intracellular part of tyrosine phosphatase RPTPα designated as RPTPα-2D gene was amplified by PCR from a human prostate cDNA library and cloned into the pT7 E. coli expression vector. The resulting plasmid pT7-RPTPα-2D was used to transform Rosetta DE3 E. coli cells. RPTPα-2D was predominately expressed in the insoluble inclusion body and was effectively purified using preparative electrophoresis gels. Polyclonal antibodies were obtained after immunization of a rabbit with purified RPTPα-2D. The antibodies displayed a high titer and sensitivity. This study thus provided a valuable tool for further researches on RPTPα.展开更多
目的:检测肝再生磷酸酶3(PRL-3)mRNA在胃癌、癌旁正常组织及其转移灶中的表达,探讨其与胃癌发生发展以及侵袭转移的生物学行为之间的关系。方法:半定量PCR测定22例胃癌组织及其相对应的癌旁正常组织、6例远处转移灶PRL-3 mRNA相对表达水...目的:检测肝再生磷酸酶3(PRL-3)mRNA在胃癌、癌旁正常组织及其转移灶中的表达,探讨其与胃癌发生发展以及侵袭转移的生物学行为之间的关系。方法:半定量PCR测定22例胃癌组织及其相对应的癌旁正常组织、6例远处转移灶PRL-3 mRNA相对表达水平,并分析其表达水平与临床病理学指标的关系。结果:22例胃癌组织中PRL-3基因表达量较相应癌旁正常组织中高,但差异无统计学意义(0.95±0.24 vs 0.85±0.27,P>0.05)。6例转移灶PRL-3基因表达量(2.04±0.44)显著高于原发肿瘤(1.26±0.26)(P<0.05)。PRL-3基因表达水平与肿瘤远处转移有相关性(P<0.05),而与肿瘤大小、分化程度、浸润深度及性别无关(P>0.05)。结论:PRL-3基因在胃癌恶性进展中起重要作用,PRL-3可能成为判断胃癌转移高危因素的一个生物学标志物。展开更多
The protein tyrosine phosphatase 1B（PTP1B）is an important regulator of metabolism.The relationship between PTP1B and tumors is quite complex.The purpose of this study is to explore the expression pattern and role of...The protein tyrosine phosphatase 1B（PTP1B）is an important regulator of metabolism.The relationship between PTP1B and tumors is quite complex.The purpose of this study is to explore the expression pattern and role of PTP1B in breast cancer.The expression of PTP1B was detected in 67 samples of breast cancer tissue by Western blot.Cell growth assay,Transwell migration assay,and Scratch motility assay were used to examine the proliferation and migration of MCF-7 with and without PTP1B.The total levels and phosphorylated levels of signal transduction and activator of transcription 3（STAT3）and the expression of C-C motif chemokine ligand 5（CCL5）were also examined by Western blot.PTP1B was overexpressed in over 70%of breast cancer tissues,correlating with patients with estrogen receptor（ER）-negative,progesterone receptor（PR）-negative,and human epidermal growth factor receptor 2（HER2）-positive tumors.The data also showed that both tumor size and lymph node metastasis were significantly higher in patients with a higher level of PTP1B.The proliferation and migration of MCF-7 cells were found to be inhibited after knocking down the gene of PTP1B.Our data also showed that PTP1B could up-regulate the dephosphorylated level of STAT3,which could increase the expression of CCL5.These phenomena indicated that PTP1B may play a crucial role in the development of breast cancer.展开更多
Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibi...Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.展开更多
基金Supported by the Natural Science Foundation of Guangxi Province(Nos.2013GXNSFAA019019 and 2013GXNSFAA019041)
文摘Oleanolic acid derivatives act as newer protein tyrosine phosphatase 1B （PTP-1B） inhibitors for type 2 diabetes mellitus （T2DM）. In order to understand the structural requirement of PTP-1B inhibitors, 52 oleanolic acid derivatives were divided into a training set （34 compounds） and a test set （18 compounds）. The highly reliable and predictive 3D-QSAR models were constructed by CoMFA, CoMSIA and topomer CoMFA methods, respectively. The results showed that the cross validated coefficient （q2） and non-cross-validated coefficient （R2） were 0.554 and 0.999 in the CoMFA model, 0.675 and 0.971 in the CoMSIA model, and 0.628 and 0.939 in the topomer CoMFA model, which suggests that three models are robust and have good exterior predictive capabilities. Furthermore, ten novel inhibitors with much higher inhibitory potency were designed. Our design strategy was that （i） the electronegative substituents （Cl, -CH2OH, OH and -CH2Cl） were introduced into the double bond of ring C, （ii） the hydrogen bond acceptor groups （C≡N and N atom）, electronegative groups （C≡N, N atom, -COOH and -COOCH3） and bulky substituents （C6H5N） were connected to the C-3 position, which would result in generating potent and selective PTP-1B inhibitors. We expect that the results in this paper have the potential to facilitate the process of design and to develop new potent PTP-1B inhibitors.
基金the Scientific Innovation Foundation of Jilin University for Undergraduates(No.2007CX02)
文摘A DNA fragment encoding the intracellular part of tyrosine phosphatase RPTPα designated as RPTPα-2D gene was amplified by PCR from a human prostate cDNA library and cloned into the pT7 E. coli expression vector. The resulting plasmid pT7-RPTPα-2D was used to transform Rosetta DE3 E. coli cells. RPTPα-2D was predominately expressed in the insoluble inclusion body and was effectively purified using preparative electrophoresis gels. Polyclonal antibodies were obtained after immunization of a rabbit with purified RPTPα-2D. The antibodies displayed a high titer and sensitivity. This study thus provided a valuable tool for further researches on RPTPα.
文摘目的:检测肝再生磷酸酶3(PRL-3)mRNA在胃癌、癌旁正常组织及其转移灶中的表达,探讨其与胃癌发生发展以及侵袭转移的生物学行为之间的关系。方法:半定量PCR测定22例胃癌组织及其相对应的癌旁正常组织、6例远处转移灶PRL-3 mRNA相对表达水平,并分析其表达水平与临床病理学指标的关系。结果:22例胃癌组织中PRL-3基因表达量较相应癌旁正常组织中高,但差异无统计学意义(0.95±0.24 vs 0.85±0.27,P>0.05)。6例转移灶PRL-3基因表达量(2.04±0.44)显著高于原发肿瘤(1.26±0.26)(P<0.05)。PRL-3基因表达水平与肿瘤远处转移有相关性(P<0.05),而与肿瘤大小、分化程度、浸润深度及性别无关(P>0.05)。结论:PRL-3基因在胃癌恶性进展中起重要作用,PRL-3可能成为判断胃癌转移高危因素的一个生物学标志物。
基金supported by the Research Foundation of Public Health Bureau of Hubei Province(No.JX3A14),China
文摘The protein tyrosine phosphatase 1B（PTP1B）is an important regulator of metabolism.The relationship between PTP1B and tumors is quite complex.The purpose of this study is to explore the expression pattern and role of PTP1B in breast cancer.The expression of PTP1B was detected in 67 samples of breast cancer tissue by Western blot.Cell growth assay,Transwell migration assay,and Scratch motility assay were used to examine the proliferation and migration of MCF-7 with and without PTP1B.The total levels and phosphorylated levels of signal transduction and activator of transcription 3（STAT3）and the expression of C-C motif chemokine ligand 5（CCL5）were also examined by Western blot.PTP1B was overexpressed in over 70%of breast cancer tissues,correlating with patients with estrogen receptor（ER）-negative,progesterone receptor（PR）-negative,and human epidermal growth factor receptor 2（HER2）-positive tumors.The data also showed that both tumor size and lymph node metastasis were significantly higher in patients with a higher level of PTP1B.The proliferation and migration of MCF-7 cells were found to be inhibited after knocking down the gene of PTP1B.Our data also showed that PTP1B could up-regulate the dephosphorylated level of STAT3,which could increase the expression of CCL5.These phenomena indicated that PTP1B may play a crucial role in the development of breast cancer.
基金a Ph D fellowship by FCT-Fundacao para a Ciência Tecnologia (SFRH/BD/135868/2018)(to SSC)。
文摘Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.
