Pulmonary emphysema is characterized by loss of alveolar structure. Bone marrow mesenchymal stem cells (MSCs) have been shown to differentiate into alveolar epithelial cells. However, the effect of MSCs transplantation on pulmonary emphysema is unknown. To address this question, cultured bone marrow MSCs from male donor rats were infused into female recipients treated with irradiation and instillation of papain. We found that the emphysematous changes in rats received MSCs transplantation were ameliorated when compared with the rats without MSCs transplantation. Y chromosome fluorescent in situ hybridization (FISH) and immunohistochemical staining for SP-C, confirmed that MSCs engrafted in recipient lungs and differentiated into type II alveolar epithelial cells. Additionally, MSCs transplantation reduced the extent of irradiation and papain-induced alveolar cell apoptosis, likely due to the up-regulation of the expression of Bcl-2 and Bax gene. We conclude that MSCs transplantation protects against the irradiation and papain-induced pulmonary emphysema. The mechanisms of protection may involve the engraftment of MSCs in the lungs, differentiation of MSCs into type II alveolar epithelial cells and suppression of alveolar cell apoptosis.
Asthma is characterized by airway inflammation, mucus overproduction, airway hyperreactivity, and peribronchial fibrosis. Intelectin has been shown to be increased in airway epithelium of asthmatics. However, the role of intelectin in the pathogenesis of asthma is unknown. Airway epithelial cells can secrete chemokines such as monocyte chemotactic protein (MCP)-1 and -3 that play crucial roles in asthmatic airway inflammation. We hypothesized that intelectin plays a role in allergic airway inflammation by regulating chemokine expression. In a mouse allergic asthma model, we found that mRNA expression of intelectin-2 as well as MCP-1 and -3 in mouse lung was increased very early (within 2 h) after allergen challenge. Expression of intelectin protein was localized to mucous cells in airway epithelium. Treatment of MLE12 mouse lung epithelial cells with interleukin IL-13, a critical mediator of allergic airway disease, induced expression of intelectin-1 and -2 as well as MCP-1 and -3. When IL-13-induced intelectin-1 and -2 expression was inhibited by RNA interference, IL-13-induced extracellular signal-regulated kinase 1/2 phosphorylation and MCP-1 and -3 production by MLE12 cells was inhibited. Furthermore, inhibition of intelectin expression by airway transfection with shRNA targeting intelectin-1 and -2 attenuated allergen-induced airway inflammation. We conclude that intelectin, a molecule expressed by airway epithelial cells and upregulated in asthma, is required for IL-13-induced MCP-1 and -3 production in mouse lung epithelial cells and contributes to allergic airway inflammation.
Objective: This study was conducted to elucidate the long non-coding RNA FOXD2-AS1 (lncRNA FOXD2-AS1) expression in glioma and its mechanism on the biological features of glioma cells and the drug resistance of temozolomide (TMZ).Results: Highly expressed FOXD2-AS1 was found in glioma. There was more powerful chemotherapeutic resistance of TMZ resistant cell lines than that of the parent cell lines. Silence of FOXD2-AS1 suppressed proliferation and drug resistance and promoted apoptosis of drug-resistant glioma cells. Overexpressed FOXD2-AS1 presented an opposite trend. FOXD2-AS1 could be used as a competing endogenous RNA to adsorb miR-98-5p, thereby up-regulating CPEB4.Conclusion: Our study suggests that down-regulated FOXD2-AS1 repressed invasion, proliferation, migration and drug resistance of drug-resistant glioma cells while stimulating their apoptosis via increasing miR-98-5p and inhibiting CPEB4 expression.Methods: FOXD2-AS1, microRNA-98-5p (miR-98-5p) and cytoplasmic polyadenylation element binding (CPEB4) expression in glioma tissues were tested. Expression of E-cadherin, N-cadherin and Vimentin in glioma cells were explored. A series of assays were conducted to detect the function of FOXD2-AS1 in migration, proliferation, apoptosis, and invasion of glioma cells. Changes in drug-resistance of cells under TMZ treatment were examined, and tumor formation in nude mice was performed to test the changes of drug resistance in vivo.
microRNA-33a (miR-33a) belongs to the miR-33 family that is implicated in the progression of various types of cancers. Aberrant expression of miR-33a has been detected in several human cancers, and has been shown to regulate the migration and invasion as well as proliferation and apoptosis of tumor cells. However, the clinical significance and precise mechanisms underlying the dysfunction of miR-33a in glioma have not been well investigated in previous studies. In this study, overexpression of miR-33a was observed in clinical glioma specimens and cell lines. Clinicopathological detection revealed that miR-33a highly expressing patients showed large tumor sized and advanced World Health Organization (WHO) grade as well as reduced overall survival. Furthermore, the results of in vitro experiments confirmed that loss of miR-33a resulted in reduced proliferation and enhanced apoptosis in U251 cells, while miR-33a restoration showed opposite effects in U87 cells. Further studies indicated that miR-33a knockdown restrained tumor growth of glioma in vivo. miR-33a negatively regulated the expression of sirtuin 6 (SIRT6) at both mRNA and protein levels via targeting the 3'UTR of SIRT6 mRNA. SIRT6 was underexpressed and inversely correlated with miR-33a expression in the glioma tissues. Mechanistically, SIRT6 overexpression increased the levels of lactate dehydrogenase (LDH) and reactive oxygen species (ROS) while it reduced cell survival under H2O2 treatment. In addition, SIRT6 restoration led to apoptosis with alterative expression of Bax, Bcl-2, cleaved caspase-8, and inhibition of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway in glioma. Thus, our studies demonstrated that the deregulation of miR-33a may promote tumor development in human glioma by regulating the expression of its target gene, SIRT6.
Malignant gliomas are the most common tumor in central nervous system with poor prognosis. Due to the limitation of histological classification in earlier diagnosis and individualized medicine, it is necessary to combine the molecular signatures and the pathological characteristics of gliomas. Lots of microRNAs presented abnormal expression in gliomas and modulated gliomas development.Exploration the miRNAs profile is helpful for the diagnosis, therapy and prognosis of gliomas. It has been demonstrated that miR-144 plays important roles in solid tumors. However, the detail mechanisms remained unrevealed. In this study, we have demonstrated the level of miR-144 decreased in glioma tissues from patients, especially in gliomas with higher grades. MiR-144 was also validated have lower expression in glioma cell lines compared with cortical neuron cell by using qRT-PCR. The in vitro functional experiment indicated miR-144 improved gliomas progression through repressing proliferation, sensitizing to chemotherapeutics and inhibiting metastasis. We further identified fibroblast growth factor 7 (FGF7) and Caveolin 2 (CAV2) were target genes of miR-144 by luciferase reporter assay and western blotting. The mechanisms study suggested forced FGF7 expression elevated Akt activation and decreased reactive oxygen species (ROS) generation. The MTT and cell cycle assay indicated miR-144 suppressed glioma cells proliferation through modulating FGF mediated Akt signaling pathway. Meanwhile, miR-144 promoted Temozolomide (TMZ) induced apoptosis in glioma cells via increasing ROS production by using FACS. On the other hand, CAV2, as another target of miR-144, accelerated glioma cells migration and invasion via promoting glioma cells EMT progress. Retrieved expression of FGF7 or CAV2 rescued the proliferation and migration function mediated by miR-144. Furthermore, the in vivo experiments in PDX models displayed the anti-tumor function of miR-144, which could be retrieved by overexpression of FGF7 and CAV2. Taken together, these findings indicated miR-144 acted as a potential target against gliomas progression and uncovered a novel regulatory mechanism, which may provide a new therapeutic strategy and prognostic indicator for gliomas.
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