Scar formation after spinal cord injury is regarded as an obstacle to axonal regeneration and functional recovery.Epothilone B provides moderate microtubule stabilization and is mainly used for anti-tumor therapy.It a...Scar formation after spinal cord injury is regarded as an obstacle to axonal regeneration and functional recovery.Epothilone B provides moderate microtubule stabilization and is mainly used for anti-tumor therapy.It also reduces scar tissue formation and promotes axonal regeneration after spinal cord injury.The aim of the present study was to investigate the effect and mechanism of the microtubule-stabilizing reagent epothilone B in decreasing fibrotic scarring through its action on pericytes after spinal cord injury.A rat model of spinal cord injury was established via dorsal complete transection at the T10 vertebra.The rats received an intraperitoneal injection of epothilone B(0.75 mg/kg) at 1 and 15 days post-injury in the epothilone B group or normal saline in the vehicle group.Neuron-glial antigen 2,platelet-derived growth factor receptor β,and fibronectin protein expression were dramatically lower in the epothilone B group than in the vehicle group,but β-tubulin protein expression was greater.Glial fibrillary acidic protein at the injury site was not affected by epothilone B treatment.The Basso,Beattie,and Bresnahan locomotor scores were significantly higher in the epothilone B group than in the vehicle group.The results of this study demonstrated that epothilone B reduced the number of pericytes,inhibited extracellular matrix formation,and suppressed scar formation after spinal cord injury.展开更多
The abnormal activation of HER family kinase activity is closely related to the development of human malignancies.In this study,we used HER kinases as targets for the treatment of nasopharyngeal carcinoma(NPC)and expl...The abnormal activation of HER family kinase activity is closely related to the development of human malignancies.In this study,we used HER kinases as targets for the treatment of nasopharyngeal carcinoma(NPC)and explored the anti-tumor effects of the novel pan-HER inhibitor HM781-36B,alone or in combination with cisplatin.We found that HER family proteins were positively expressed in tumor tissues of some NPC patients,and the high levels of those proteins were significantly related to poor prognosis.HM781-36B inhibited NPC in vitro and in vivo.HM781-36B exerted synergistic effects with cisplatin on inhibiting proliferation and promoting apoptosis of NPC cells.In NPC xenograft models in nude mice,HM781-36B and cisplatin synergistically inhibited tumor growth.Downregulating the activity of HER family proteins and their downstream signaling pathways and regulating tumor microenvironment may explain the synergistic anti-tumor effects of HM781-36B and cisplatin.In conclusion,our study provides evidence for HER family proteins as prognostic biomarkers and potential therapeutic targets for NPC.The pan-HER inhibitor HM781-36B alone or in combination with cisplatin represents promising therapeutic effects for the treatment of NPC patients,which provides a new idea for the comprehensive treatment of NPC.展开更多
Background:Recent advances in surgical and neuroprotective strategies could effectively manage the pathophysiological progression of subarachnoid hemorrhage(SAH).However,pulmonary dysfunction frequently occurs in SAH ...Background:Recent advances in surgical and neuroprotective strategies could effectively manage the pathophysiological progression of subarachnoid hemorrhage(SAH).However,pulmonary dysfunction frequently occurs in SAH patients with an increased risk of unsatisfactory outcomes.Based on the similar microvascular structures in the blood-air barrier and blood-brain barrier and possible brain-lung crosstalks,we believe that pericytes may be involved in both neurological and pulmonary dysfunction after SAH.Methods:In our experiments,platelet-derived growth factor B(PDGF-B)retention motif knockout(PDGF-Bret/ret)mice and adeno-associated virus PDGF-B were employed to show the involvement of pericyte deficiency and PDGF-B expression.Neurological score,SAH grade,hematoxylin-eosin staining,and PaO2/FiO2 ratio analysis were performed to evaluate the neurological deficits and pulmonary functions in endovascular perforation SAH models at 24 h after surgery,as well as western blotting and immunofluorescence staining for underlying molecular expressions.Results:We found that neonatal PDGF-Bret/ret mice exhibited pulmonary atelectasis 12 h after birth.Further investigation showed a decrease in PaO2/FiO2 and lung-specific surfactant proteins in adult PDGF-Bret/ret mice.These dysfunctions were much worse than those in wild-type mice at 24 h after SAH.PDGF-B overexpression alleviated pulmonary dysfunction after SAH.Conclusions:These results suggested pulmonary dysfunction after SAH and the pivotal role of PDGF-B signaling for the pathophysiological process and future therapeutic targets of pulmonary injury treatment after SAH.Further studies are needed for pathophysiological investigations and translational studies on pulmonary injuries after SAH.展开更多
基金supported by a grant from the Science and Technology Developing Program of Shandong Provincial Government of China,No.2010GSF10254a grant from the Medical and Health Science and Technology Plan Project of Shandong Province of China,No.2015WS0504
文摘Scar formation after spinal cord injury is regarded as an obstacle to axonal regeneration and functional recovery.Epothilone B provides moderate microtubule stabilization and is mainly used for anti-tumor therapy.It also reduces scar tissue formation and promotes axonal regeneration after spinal cord injury.The aim of the present study was to investigate the effect and mechanism of the microtubule-stabilizing reagent epothilone B in decreasing fibrotic scarring through its action on pericytes after spinal cord injury.A rat model of spinal cord injury was established via dorsal complete transection at the T10 vertebra.The rats received an intraperitoneal injection of epothilone B(0.75 mg/kg) at 1 and 15 days post-injury in the epothilone B group or normal saline in the vehicle group.Neuron-glial antigen 2,platelet-derived growth factor receptor β,and fibronectin protein expression were dramatically lower in the epothilone B group than in the vehicle group,but β-tubulin protein expression was greater.Glial fibrillary acidic protein at the injury site was not affected by epothilone B treatment.The Basso,Beattie,and Bresnahan locomotor scores were significantly higher in the epothilone B group than in the vehicle group.The results of this study demonstrated that epothilone B reduced the number of pericytes,inhibited extracellular matrix formation,and suppressed scar formation after spinal cord injury.
基金supported by the National Science Foundation for Excellent Young Scholars(No.32122052)National Natural Science Regional Innovation and Development Foundation(No.U19A2003).
文摘The abnormal activation of HER family kinase activity is closely related to the development of human malignancies.In this study,we used HER kinases as targets for the treatment of nasopharyngeal carcinoma(NPC)and explored the anti-tumor effects of the novel pan-HER inhibitor HM781-36B,alone or in combination with cisplatin.We found that HER family proteins were positively expressed in tumor tissues of some NPC patients,and the high levels of those proteins were significantly related to poor prognosis.HM781-36B inhibited NPC in vitro and in vivo.HM781-36B exerted synergistic effects with cisplatin on inhibiting proliferation and promoting apoptosis of NPC cells.In NPC xenograft models in nude mice,HM781-36B and cisplatin synergistically inhibited tumor growth.Downregulating the activity of HER family proteins and their downstream signaling pathways and regulating tumor microenvironment may explain the synergistic anti-tumor effects of HM781-36B and cisplatin.In conclusion,our study provides evidence for HER family proteins as prognostic biomarkers and potential therapeutic targets for NPC.The pan-HER inhibitor HM781-36B alone or in combination with cisplatin represents promising therapeutic effects for the treatment of NPC patients,which provides a new idea for the comprehensive treatment of NPC.
基金This study was supported by the Top-notch Talent Cultivation Plan of Southwest Hospital(SWH2018BJKJ-05)Natural Science Foundation of Liaoning Province(20180550504)the Major Innovation Project of Southwest Hospital(SWH2016ZDCX1011).
文摘Background:Recent advances in surgical and neuroprotective strategies could effectively manage the pathophysiological progression of subarachnoid hemorrhage(SAH).However,pulmonary dysfunction frequently occurs in SAH patients with an increased risk of unsatisfactory outcomes.Based on the similar microvascular structures in the blood-air barrier and blood-brain barrier and possible brain-lung crosstalks,we believe that pericytes may be involved in both neurological and pulmonary dysfunction after SAH.Methods:In our experiments,platelet-derived growth factor B(PDGF-B)retention motif knockout(PDGF-Bret/ret)mice and adeno-associated virus PDGF-B were employed to show the involvement of pericyte deficiency and PDGF-B expression.Neurological score,SAH grade,hematoxylin-eosin staining,and PaO2/FiO2 ratio analysis were performed to evaluate the neurological deficits and pulmonary functions in endovascular perforation SAH models at 24 h after surgery,as well as western blotting and immunofluorescence staining for underlying molecular expressions.Results:We found that neonatal PDGF-Bret/ret mice exhibited pulmonary atelectasis 12 h after birth.Further investigation showed a decrease in PaO2/FiO2 and lung-specific surfactant proteins in adult PDGF-Bret/ret mice.These dysfunctions were much worse than those in wild-type mice at 24 h after SAH.PDGF-B overexpression alleviated pulmonary dysfunction after SAH.Conclusions:These results suggested pulmonary dysfunction after SAH and the pivotal role of PDGF-B signaling for the pathophysiological process and future therapeutic targets of pulmonary injury treatment after SAH.Further studies are needed for pathophysiological investigations and translational studies on pulmonary injuries after SAH.