ABSTRACT
Spinal cord injury (SCI) is a devastating disease characterized by neuronal apoptosis. Gli-similar 3 (GLIS3), a transcriptional factor, was involved in cell apoptosis and associated with the transcription of downstream target genes related to neuronal function. However, the function of GLIS3 in SCI remains unknown. Therefore, we used the mouse model of SCI to explore the role of GLIS3 in SCI. The results showed that GLIS3 expression was significantly increased in spinal cord tissues of SCI mice, and GLIS3 overexpression promoted the functional recovery, reserved histological changes, and inhibited neuronal apoptosis after SCI. Through online tools, the potential target genes of GLIS3 were analyzed and we found that Mps one binder kinase activator 1b (Mob1b) had a strong association with SCI among these genes. MOB1b is a core component of Hippo signaling pathway, which was reported to inhibit cell apoptosis. MOB1b expression was significantly increased in mice at 7 days post-SCI and GLIS3 overexpression further increased its expression. Dual-luciferase reporter assay revealed that GLIS3 bound to the promoter of Mob1b and promoted its transcription. In conclusion, our findings reveal that the compensatory increase of GLIS3 promotes functional recovery after SCI through inhibiting neuronal apoptosis by transcriptionally regulating MOB1b. Our study provides a novel target for functional recovery after SCI.
Subject(s)
Apoptosis , Spinal Cord Injuries , Mice , Animals , Apoptosis/genetics , Spinal Cord Injuries/genetics , Spinal Cord Injuries/pathology , Neurons/pathology , Spinal Cord/metabolism , Recovery of Function/physiology , Adaptor Proteins, Signal Transducing/metabolismABSTRACT
Introduction: Osteoporosis affects approximately 10% of the population worldwide. ß-sitosterol (BSS), a major phytosterol in plants, has been claimed for centuries to have numerous medical benefits, including bone strengthening. This study aimed to find the benefit of BSS in treating osteoporosis according to traditional methods and to investigate the protective effect of BSS on glucocorticoid-induced osteoporosis in rats. Design: Wistar rats were randomly assigned to one of four groups: the control group, the dexamethasone (DEX) group and one of two BSS-treated osteoporosis groups (100 and 200 mg/kg). Blood samples and femur bones were collected for histopathology, immunohistochemistry, biochemical and mRNA expression analysis. Results: The results indicated that BSS (100 and 200 mg/kg) increased bone length, bone weight and bone mineral density (BMD) and suppressed DEX-induced reduction in body weight, dose-dependently. Mechanistically, BSS (100 and 200 mg/kg) treatment alleviated the increase of bone resorption markers and the decline of osteogenic markers, which might be partially mediated by regulation of nuclear factor kappa-ß ligand/osteoprotegerin (RANKL/OPG) and RunX2 pathways. The immunohistochemical inducible nitric oxide synthase (iNOS) results of the rats' distal femur were negative in all groups. However, except in the DEX group, the endothelial nitric oxide synthase (eNOS) color reaction in osteoblasts was strongly positive in the other 3 groups. These results suggest that BSS showed promising effects in protection against glucocorticoid-induced osteoporosis by protecting osteoblasts and suppressing osteoclastogenesis.
Subject(s)
Osteoporosis , Osteoprotegerin , Animals , Bone Density , Core Binding Factor Alpha 1 Subunit/metabolism , Core Binding Factor Alpha 1 Subunit/pharmacology , Dexamethasone , Glucocorticoids , Ligands , Nitric Oxide Synthase Type II/metabolism , Nitric Oxide Synthase Type II/pharmacology , Nitric Oxide Synthase Type III/metabolism , Nitric Oxide Synthase Type III/pharmacology , Osteoporosis/chemically induced , Osteoporosis/drug therapy , Osteoporosis/prevention & control , Osteoprotegerin/genetics , Osteoprotegerin/metabolism , RANK Ligand/metabolism , RNA, Messenger/pharmacology , Rats , Rats, Wistar , SitosterolsABSTRACT
Cisplatin resistance has been long considered an obstacle to the efficacy of chemotherapy in non-small-cell lung cancer (NSCLC). Long non-coding RNAs (lncRNAs) have been widely reported to participate in the various biological process including cancer. In the present study, we aim to explore the functions of Linc00221 and miR-519a in the sensitivity and the resistance of NSCLC to cisplatin. The levels of Linc00221, miR-519a, and zinc finger and BTB domain-containing five (ZBTB5) in NSCLC tissues were detected by qRT-PCR and Western blot. Colony formation and MTT assays were applied to detect the viability of cells after cisplatin treatment. Dual luciferase reporter assays were used to detect the inhibitory effect of miR-519a on ZBTB5 and Linc00221, and pull down experiments were employed to determine the direct interaction between Linc00221 and miR-519a. Our results showed that Linc00221 was highly expressed in cisplatin-resistant NSCLC tissues and cells and closely associated with poor prognosis. Linc00221 promoted the cisplatin resistance of NSCLC and miR-519a was a direct target of Linc00221. In addition, miR-519a could promote cisplatin sensitivity in NSCLC cells by targeting ZBTB5. Linc00221 could mediate the cisplatin sensitivity in NSCLC by adsorbing miR-519a to prevent its down-regulation of ZBTB5. In conclusion, Linc00221 promotes cisplatin resistance in NSCLC through the downstream miR-519a/ZBTB5 signaling axis, which could be used as a potential diagnostic and therapeutic target for clinical cisplatin-resistant NSCLC patients.
