ABSTRACT
Follistatin (FST), a single-chain glycosylated protein, is expressed in various tissues. The essential biological function of FST is binding and neutralizing transforming growth factor ß (TGF-ß) superfamily, including activin, myostatin, and bone morphogenetic protein (BMP). Emerging evidence indicates that FST also serves as a stress responsive protein, which plays a protective role under a variety of stresses. In most cases, FST performs the protective function through its neutralization of TGF-ß superfamily. However, under certain circumstances, FST translocates into the nucleus to maintain cellular homeostasis independent of its extracellular antagonism activity. This review provides integrated insight into the most recent advances in understanding the role of FST under various stresses, and the clinical implications corresponding to these findings and discusses the mechanisms to be further studied.
Subject(s)
Follistatin/physiology , Stress, Physiological/physiology , Follistatin/genetics , Follistatin/metabolism , Humans , Protein Processing, Post-Translational , RNA Processing, Post-TranscriptionalABSTRACT
Follistatin (FST) plays a protective role during silica nanoparticle (SiO2 NP) exposure. SiO2 NP treatment induces FST transcription with an unknown mechanism. We herein reported that SIRT6, one of the sirtuin family members, induced epigenetic silencing of FST. The expression of FST was elevated after SIRT6 knockdown while reduced after SIRT6 overexpression. Chromatin immunoprecipitation revealed a direct interaction between SIRT6 with FST promoter. Knockdown of SIRT6 increased both Ac-H3K9 level and Ac-H3K56 level at FST promoter region. SiO2 NP treatment de-stabilized SIRT6 mRNA and reduced SIRT6 expression, leading to the activation of FST transcription. Finally, over-expression of SIRT6 increased SiO2 NP-induced apoptosis. Collectively, this study provided evidence that SIRT6 is a negative regulator of FST transcription and participates in the regulation of cell survival during silica nanoparticle exposure.
Subject(s)
Alveolar Epithelial Cells/drug effects , Apoptosis/drug effects , Epigenetic Repression/drug effects , Follistatin/antagonists & inhibitors , Nanoparticles/toxicity , Silicon Dioxide/toxicity , Sirtuins/metabolism , A549 Cells , Acetylation/drug effects , Alveolar Epithelial Cells/metabolism , Animals , Follistatin/agonists , Follistatin/genetics , Follistatin/metabolism , Gene Expression Regulation/drug effects , Genes, Reporter/drug effects , HEK293 Cells , Histones/metabolism , Humans , Mice , Oxidative Stress/drug effects , Promoter Regions, Genetic/drug effects , Protein Processing, Post-Translational/drug effects , RNA Interference , RNA Stability/drug effects , RNA, Messenger/chemistry , RNA, Messenger/metabolism , Sirtuins/antagonists & inhibitors , Sirtuins/chemistry , Sirtuins/geneticsABSTRACT
Silica nanoparticles (SiO2 NPs) cause oxidative stress in respiratory system. Meanwhile, human cells launch adaptive responses to overcome SiO2 NP toxicity. However, besides a few examples, the regulation of SiO2 NP-responsive proteins and their functions in SiO2 NP response remain largely unknown. In this study, we demonstrated that SiO2 NP induced the expression of follistatin (FST), a stress responsive gene, in mouse lung tissue as well as in human lung epithelial cells (A549). The levels of Ac-H3(K9/18) and H3K4me2, two active gene markers, at FST promoter region were significantly increased during SiO2 NP treatment. The induction of FST transcription was mediated by the nuclear factor erythroid 2-related factor 2 (Nrf2), as evidenced by the decreased FST expression in Nrf2-deficient cells and the direct binding of Nrf2 to FST promoter region. Down-regulation of FST promoted SiO2 NP-induced apoptosis both in cultured cells and in mouse lung tissue. Furthermore, knockdown of FST increased while overexpression of FST decreased the expression level of NADPH oxidase 1 (NOX1) and NOX5 as well as the production of cellular reactive oxygen species (ROS). Taken together, these findings demonstrated a protective role of FST in SiO2 NP-induced oxidative stress and shed light on the interaction between SiO2 NPs and biological systems.
Subject(s)
Alveolar Epithelial Cells/metabolism , Follistatin/genetics , NF-E2-Related Factor 2/metabolism , Nanoparticles , Oxidative Stress , Silicon Dioxide , Transcriptional Activation , Animals , Apoptosis/genetics , Cell Line , Gene Expression , Humans , Male , Membrane Proteins/genetics , Mice , NADPH Oxidase 1 , NADPH Oxidase 5 , NADPH Oxidases/genetics , Nanoparticles/adverse effects , Reactive Oxygen Species/metabolism , Silicon Dioxide/adverse effectsABSTRACT
OBJECTIVE: To assess the effects of 1-step method of changing the buccal position of the transported bone after distraction on early bone formation. METHODS: The custom-made bidirectional distraction devices were used. Total of 8 adult mongrel dogs were procured. The bilaterally mandible premolars were extracted. After 1 month, the complete osteotomy was performed and the devices were placed. The gradual distraction was started after 1 week latency at the rate of 1 mm per day, total 6 mm in height was achieved. The 1-step method of changing the buccal position of the transported bone was performed the day after the vertical distraction period in one side of the animals, and the other side as the controlled side. All animals were killed after a 7 days consolidation. The vascular system was stained post mortem carbon ink perfusion to assess possible damages. Quantitative evaluations of bone density were performed with dual-energy X-ray absorptiometry (DEXA), analysis of the ratio of vascular square was conducted in a computer. RESULTS: All animals tolerated the procedures well. After vertical distraction, the tested side can be moved 3 mm in buccal direction. DEXA examination showed that the density of the distracted bone was no statistical difference in both the tested and the controlled side. Vascular damage was not observed, and there was no statistical difference in the ratio of vascular square by analyzing the histological section in computer. CONCLUSION: In some extent, 1-step method of changing the buccal position of the transported bone after distraction can mold the regenerate bone to correct the axial displacement, without endangering early callus formation and vascularization.
Subject(s)
Osteogenesis, Distraction , Osteogenesis , Animals , Bone Density , Bone Regeneration , Bone and Bones , Dogs , MandibleABSTRACT
OBJECTIVE: To study the clinical effects, the merits and shortcomings of the hard palate flap in repairing postoperative defects of oral soft tissue. METHODS: The whole-palate flap pedicled with the unilateral greater palatine artery was used to repair 25 cases of oral soft tissue defects. RESULTS: Of the 25 cases, 22 flaps survived completely and 2 flaps survived partially. The postoperative appearance and functions were satisfactory. CONCLUSION: Compared with other flaps, the hard palate flap is easier to harvest and use. It has reliable blood supply and does not harm the patients' appearance and function. It is one of the most desirable methods for repairing the oral soft tissue defect.
