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
背景:肿瘤干细胞与肿瘤的复发、转移以及耐药等之间存在十分密切的联系。目的:探讨CD44^+CD24^(-/low)乳腺癌干细胞活性与多药耐药的相关性。方法:运用免疫磁珠法从多药耐药乳腺癌细胞株MCF-7/ADR中分选出CD44^+CD24^(-/low)乳腺癌干细...背景:肿瘤干细胞与肿瘤的复发、转移以及耐药等之间存在十分密切的联系。目的:探讨CD44^+CD24^(-/low)乳腺癌干细胞活性与多药耐药的相关性。方法:运用免疫磁珠法从多药耐药乳腺癌细胞株MCF-7/ADR中分选出CD44^+CD24^(-/low)乳腺癌干细胞。流式细胞仪测定分选后CD44^+CD24^(-/low)乳腺癌干细胞亚群比例和细胞膜P-gp荧光强度,RT-PCR法检测多药耐药基因MDR m RNA表达水平。结果与结论:(1)获得的CD44^+CD24^(-/low)乳腺癌干细胞比例在90%以上;(2)CD44^+CD24^(-/low)细胞亚群成球比例明显强于non-CD44^+CD24^(-/low)细胞亚群;(3)CD44^+CD24^(-/low)细胞亚群的细胞膜P-gp荧光强度显著高于MFC-7/ADR细胞株(P<0.05);(4)CD44^+CD24^(-/low)细胞亚群的MDR mRNA表达水平显著高于MFC-7/ADR细胞株(P<0.05);(5)结果表明,分选得到的CD44^+CD24^(-/low)乳腺癌干细胞具有很强的体外成球能力,高表达P-gp蛋白和MDR mRNA可能是导致多药耐药的原因之一。展开更多
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.
文摘背景:肿瘤干细胞与肿瘤的复发、转移以及耐药等之间存在十分密切的联系。目的:探讨CD44^+CD24^(-/low)乳腺癌干细胞活性与多药耐药的相关性。方法:运用免疫磁珠法从多药耐药乳腺癌细胞株MCF-7/ADR中分选出CD44^+CD24^(-/low)乳腺癌干细胞。流式细胞仪测定分选后CD44^+CD24^(-/low)乳腺癌干细胞亚群比例和细胞膜P-gp荧光强度,RT-PCR法检测多药耐药基因MDR m RNA表达水平。结果与结论:(1)获得的CD44^+CD24^(-/low)乳腺癌干细胞比例在90%以上;(2)CD44^+CD24^(-/low)细胞亚群成球比例明显强于non-CD44^+CD24^(-/low)细胞亚群;(3)CD44^+CD24^(-/low)细胞亚群的细胞膜P-gp荧光强度显著高于MFC-7/ADR细胞株(P<0.05);(4)CD44^+CD24^(-/low)细胞亚群的MDR mRNA表达水平显著高于MFC-7/ADR细胞株(P<0.05);(5)结果表明,分选得到的CD44^+CD24^(-/low)乳腺癌干细胞具有很强的体外成球能力,高表达P-gp蛋白和MDR mRNA可能是导致多药耐药的原因之一。
