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Dai J.,Shanghai JiaoTong University | Kuang Y.,Shanghai Research Center for Model Organisms | Fang B.,Shanghai JiaoTong University | Gong H.,Shanghai Research Center for Model Organisms | And 12 more authors.
Biomaterials | Year: 2013

Craniofacial skeleton mainly originate from the cranial neural crest stem cells (CNCCs), which is a subpopulation of neural crest stem cells (NCCs). Dlx2, a member of the homeodomain family of transcription factors, plays crucial roles in the development of the CNCCs derived craniofacial skeleton. Previous reports reveal that Dlx2-targeted null mutation resulted in anomalies in the skeletal derivatives of CNCCs in mice. Dlx2 overexpression in ova disturbed the migration and differentiation of affected CNCCs and induced the development of ectopic skeleton elements. However, whether Dlx2 overexpression can impair the morphogenesis of CNCCs derived craniofacial skeleton in vivo has not been explored. Here, we generated a transgenic mouse overexpressing Dlx2 in NCCs (Wnt1Cre::iZEG-Dlx2). The Wnt1Cre::iZEG-Dlx2 embryos showed decreased cell proliferation, increased cell apoptosis, abnormal chondrogenesis and impaired osteogenesis within the CNCCs population, resulting in obvious craniofacial defects that ranged from a cleft lip and midfacial clefts to neural tube defects and exencephaly. Adult Wnt1Cre::iZEG-Dlx2 mice showed nasal and premaxillary hypoplasia and spinal deformities. These findings reveal that Dlx2 overexpression in NCCs may be a new pathogenesis of facial cleft and spinal kyphosis in mammals, and may offer us a useful model organism to find suitable therapy methods for these genetic defects that may be different from the traumatic defect and resected defect. © 2012 Elsevier Ltd. Source


Ruan C.-C.,Shanghai JiaoTong University | Zhu D.-L.,State Key Laboratory of Medical Genomics | Chen Q.-Z.,Shanghai JiaoTong University | Chen J.,Shanghai JiaoTong University | And 3 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2010

Objective- To examine the role of perivascular adipose tissue (PVAT)-derived factors in the regulation of adventitial fibroblast (AF) function in vitro and in vivo. Methods and Results- PVAT is an active component of blood vessels. Bioactive substances released from PVAT play regulatory roles in vascular function. However, their effects on vascular AFs remain unclear. PVAT-conditioned medium stimulated AF migration using a transwell technique, and differentiation was evaluated by α-smooth muscle-actin induction. We identified the secretome of PVAT by liquid chromatography-tandem mass spectrometry. One of the major secretory proteins in PVAT is complement 3 (C3). The C3 antagonist and neutralizing antibody attenuated PVAT-conditioned medium-induced AF migration and differentiation. Similar to PVAT-conditioned medium, C3 recombinant protein stimulated AF migration and differentiation. We demonstrated that the effects of PVAT-derived C3 were mediated by the c-Jun N-terminal kinase pathway. Moreover, we found morphological changes in perivascular adipocytes and increased expression of C3 in PVAT that was tightly associated with adventitial thickening and myofibroblast clustering around PVAT in deoxycorticosterone acetate-salt hypertensive rats. Conclusion- PVAT-derived C3 stimulated AF migration and differentiation via the c-Jun N-terminal kinase pathway. PVAT-derived C3 may contribute to adventitial remodeling in a deoxycorticosterone acetate-salt hypertensive model. © 2010 American Heart Association. All rights reserved. Source


Mou L.,Shanghai JiaoTong University | Mou L.,Tongji University | Mou L.,University of Chinese Academy of Sciences | Xu J.-Y.,Shanghai JiaoTong University | And 13 more authors.
Investigative Ophthalmology and Visual Science | Year: 2010

PURPOSE. To explore the target genes of HSF4, especially those involved in lens developmental processes and cataract formation. METHODS. A slit lamp biomicroscopy examination was performed on Hsf4tm1Xyk-knockout mice and wild-type mice. Two-dimensional electrophoresis combined with mass spectrometry was used to identify differentially expressed lens proteins between wild-type and Hsf4tm1Xyk-knockout mice and further confirmed by Western blot and immunohistochemistry. Histologic analysis was used to analyze the denucleation process of lens fiber cells. Moreover, an electrophoretic mobility shift assay (EMSA), luciferase assay, and chromatin immunoprecipitation (ChIP) assay were used to validate the effects of HSF4 on vimentin expression. RESULTS. Hsf4tm1Xyk-knockout mice had abnormal lenses and developed cataract. The downregulated proteins were major structural proteins including α- and β-crystallins, whereas the upregulated proteins were mainly enzymes and an intermediate filament protein, vimentin. The upregulated vimentin expression level was further confirmed by Western blot, Q-PCR, and immunofluorescence. EMSA, luciferase assay, and ChIP assay validated that HSF4 had DNA-binding ability to vimentin promoter and repressed vimentin expression. CONCLUSIONS. These findings indicate that HSF4 represses vimentin gene expression via the HSE-like element. The loss of HSF4 function results in an increase in vimentin expression in Hsf4tm1Xyk-knockout mice and affects lens differentiation, particularly impairing the denucleation of lens fiber cells. These events appear to implicate a molecular mechanism in abnormal lens development and cataract formation in Hsf4tm1Xyk-knockout mice. The HSF4-vimentin axis appears to be a new target for developing anti-cataract drugs, especially for those cataracts resulting from aberrations in HSF4 expression. © Association for Research in Vision and Ophthalmology. Source


Du Y.,Shanghai JiaoTong University | Xia Y.,Shanghai JiaoTong University | Xia Y.,University of Chinese Academy of Sciences | Pan X.,Shanghai JiaoTong University | And 8 more authors.
Antioxidants and Redox Signaling | Year: 2014

Aims: We have recently shown that fenretinide preferentially targets CD34+ cells of acute myeloid leukemia (AML), and here, we test whether this agent exerts the effect on CD34+ cells of chronic myeloid leukemia (CML), which are refractory to imatinib. Results: As tested by colony-forming cell assays using clinical specimens, both number and size of total colonies derived from CD34+ CML cells were significantly reduced by fenretinide, and by combining fenretinide with imatinib. In particular, colonies derived from erythroid progenitors and more primitive pluripotent/multipotent progenitors were highly sensitive to fenretinide/fenretinide plus imatinib. Accordantly, fenretinide appeared to induce apoptosis in CD34+ CML cells, particularly with regard to the cells in the subpopulation of CD34+CD38-. Through cell quiescent assays, including Ki-67 negativity test, we added evidence that nonproliferative CD34+ CML cells were largely eliminated by fenretinide. Transcriptome and molecular data further showed that mechanisms underlying the apoptosis in CD34+ CML cells were highly complex, involving multiple events of oxidative stress responses. Innovation and Conclusion: As compared with CD34+ AML cells, the apoptotic effects of fenretinide on CD34+ CML cells were more prominent whereas less varied among the samples of different patients, and also various stress-responsive events appeared to be more robust in fenretinide-treated CD34+ CML cells. Thus, the combination of fenretinide with imatinib may represent a more sophisticated strategy for CML treatment, in which imatinib mainly targets leukemic blast cells through the intrinsic pathway of apopotosis, whereas fenretinide primarily targets CML stem/progenitor cells through the oxidative/endoplasmic reticulum stress-mediated pathway. Antioxid. Redox Signal. 20, 1866-1880. © Copyright 2014, Mary Ann Liebert, Inc. 2014. Source


Wang R.-Y.,State Key Laboratory of Medical Genomics | Wang R.-Y.,CAS Shanghai Institutes for Biological Sciences | Wang R.-Y.,Shanghai JiaoTong University | Lin X.-J.,Shanghai JiaoTong University | And 5 more authors.
Neuroscience | Year: 2014

Hirulog-like peptide (HLP) and low-molecular-weight heparin (LMWH) are thrombin inhibitor peptides. Our previous study demonstrated that HLP could reduce vascular neointimal formation or restenosis in animals undergoing balloon catheter injury in the carotid artery. However, the function of HLP during ischemic stroke is largely unknown. The present study investigated the effect of HLP on brain injury, which was induced by suture of middle cerebral artery occlusion in mice. Mice were divided into four groups, which included a sham group and three treatment groups. Ischemia was induced by transient suture insertion into the middle cerebral artery for 90. min, and mice were either treated with saline, HLP or LMWH. Infarct volume, neurologic deficits and apoptotic factors were measured following 1-14. days of ischemia. We demonstrated that HLP intravenous injection alleviated brain infarct volume and improved neurologic outcomes (p<. 0.05). HLP decreased levels of protease-activated receptor-1 (PAR-1), caspase-3, malondialdehyde (MDA) and Bcl-2-associated X protein (Bax), increased the activities of catalase and B cell lymphoma-2 (Bcl-2), and improved the ratio of Bcl-2/Bax compared with the control (p<. 0.05). This study indicates that HLP and LMWH reduced infarct volume and improved neurobehavioral outcomes induced by transient middle cerebral artery occlusion (tMCAO). In addition, HLP had a beneficial effect on the regulation of the thrombin receptor and key apoptosis regulators in the mouse brain. These results suggest that HLP may be a potential alternative therapy for arterial occlusion-induced cerebral ischemia. © 2014. Source

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