Exosomes secreted by FNDC5-BMMSCs protect myocardial infarction by anti-inflammation and macrophage polarization via NF-κB signaling pathway and Nrf2/HO-1 axis.

BACKGROUND: Exosomes are considered a substitute for stem cell-based therapy for myocardial infarction (MI). FNDC5, a transmembrane protein located in the cytoplasm, plays a crucial role in inflammation diseases and MI repair. Furthermore, our previous study found that FNDC5 pre-conditioning bone marrow-derived mesenchymal stem cells (BMMSCs) could secrete more exosomes, but little was known on MI repair. METHODS: Exosomes isolated from BMMSCs with or without FNDC5-OV were injected into infarcted hearts. Then, cardiomyocytes apoptosis and inflammation responses were detected. Furthermore, exosomes were administrated to RAW264.7 macrophage with LPS treatment to investigate its effect on inflammation and macrophage polarization. RESULTS: Compared with MSCs-Exo, FNDC5-MSCs-Exo had superior therapeutic effects on anti-inflammation and anti-apoptosis, as well as polarizing M2 macrophage in vivo. Meanwhile, the in vitro results also showed that FNDC5-MSCs-Exo decreased pro-inflammatory secretion and increased anti-inflammatory secretion under LPS stimulation, which partly depressed NF-κB signaling pathway and upregulated Nrf2/HO-1 Axis. CONCLUSIONS: FNDC5-BMMSCs-derived exosomes play anti-inflammation effects and promote M2 macrophage polarization via NF-κB signaling pathway and Nrf2/HO-1 Axis, which may develop a promising cell-free therapy for MI.

Irisin ameliorates high glucose-induced cardiomyocytes injury via AMPK/mTOR signal pathway.

High glucose (HG)-induced cardiomyocytes (CMs) injury is a leading cause of diabetic cardiomyopathy with little treatment options. Irisin, a new myokine, which is cleaved from its precursor fibronectin type III domain-containing protein 5 (FNDC5), has aroused great attention as an essential cardioprotective factor and glucose metabolism regulator but little was known on diabetic cardiomyopathy yet. Here, we aim to clarify the role of irisin in the HG-induced CMs injury. Neonatal Sprague-Dawley rat CMs were cultured in a normal or HG medium for 12, 24, and 48 hr, respectively before exposing to irisin. The apoptosis level was determined by terminal-deoxynucleotidyl transferase-mediated-dUTP nick end-labeling assay. Cell viability was measured with the conventional methyl thiazolyl tetrazolium assay. Moreover, reactive oxygen species production was evaluated by dihydroethidium staining. Inflammatory factors, namely tumor necrosis factor-α, interleukin-6, interleukin-1ß were determined by enzyme-linked immunosorbent assay kits. Furthermore, protein and messenger RNA (mRNA) expressions were measured by western blot and quantitative real-time polymerase chain reaction, respectively. HG increases the apoptosis of CMs and activated the inflammatory responses and oxidative stress in CMs. Meanwhile, the mRNA and protein expressions of FNDC5 are decreased after HG exposure. Nevertheless, the increased apoptosis is alleviated by irisin treatment. Notably, irisin suppresses the inflammatory responses and oxidative stress in injured CMs. Mechanically, after the administration of Compound C, AMP-activated protein kinase (AMPK) inhibitor, these cardioprotective effects resulting from irisin are reversed. Irisin plays a significant role in antiapoptosis, anti-inflammation, antioxidative stress in HG-induced CMs via AMPK/mammalian target of the rapamycin signaling pathway.

ß-arrestin1 inhibits hypoxic injury-induced autophagy in human pulmonary artery endothelial cells via the Akt/mTOR signaling pathway.

Autophagy has been greatly implicated in injured endothelial cells during pulmonary arterial hypertension (PAH). ß-arrestin1, a multifunctional cytoplasmic protein, has attracted considerable attention as an essential protective factor in PAH. However, its role in autophagy of injured pulmonary arterial endothelial cells (PAECs) remains to be determined. Here, we investigated the potential effects of ß-arrestin1 on autophagy and apoptosis in human PAECs (hPAECs) under hypoxic stress. Hypoxic stimuli increases autophagy and decreases the level of ß-arrestin1 in hPAECs. Furthermore, pathologic changes, namely increased proliferation, migration, and apoptosis resistance, are observed after hypoxia exposure. These are reversed after ß-arrestin1 overexpression (ß-arrestin1-OV) or treatment with 3-MA, an autophagy inhibitor. Finally, ß-arrestin1 suppresses the increase in autophagy and apoptosis resistance of hypoxic hPAECs. Mechanistically, ß-arrestin1 upregulates the activity of the Akt/mTOR signaling pathway and downregulates the expression of BNIP3 and Nix after hypoxic stress. Collectively, we have demonstrated, for the first time, that ß-arrestin1 reduces excessive autophagy and apoptosis resistance by activating the Akt/mTOR axis in hypoxic hPAECs. This knowledge suggests a promising therapeutic target for PAH.

[Corrigendum] CENPE promotes lung adenocarcinoma proliferation and is directly regulated by FOXM1.

Subsequently to the publication of this article, the authors have realized that the order of the corresponding authors in the author list should have been reversed: Wenshu Chai was listed as the penultimate author on the paper, whereas Xianbao Shi should have been featured before Wenshu Chai. Therefore, the authors and affiliations for this paper should have appeared as follows: LINA SHAN1, MINJIE ZHAO1, YA LU1, HONGJUAN NING1, SHUMAN YANG2, YONGGUI SONG3, XIANBAO SHI1 and WENSHU CHAI1 1Department of Respiratory, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121001; 2School of Public Health, Jilin University, Changchun, Jilin 130021; 3School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330006, P.R. China Correspondence to: Professor Xianbao Shi or Professor Wenshu Cai, Department of Respiratory, The First Affiliated Hospital of Jinzhou Medical University, 5 Renmin Street, Guta, Jinzhou, Liaoning 121001, P.R. China The authors regret that this error was not corrected prior to the publication of the above article, and apologize to the readership for any inconvenience caused. [the original article was published in International Journal of Oncology 55: 257­266, 2019; DOI: 10.3892/ijo.2019.4805].

Inositol pyrophosphates mediated the apoptosis induced by hypoxic injury in bone marrow-derived mesenchymal stem cells by autophagy.

OBJECTIVE: To investigate the potential effect of IP7 on the autophagy and apoptosis of bone marrow mesenchymal stem cells (BM-MSCs) caused by hypoxia. METHODS: BM-MSCs isolated from adult male C57BL/6 mice were exposed to normoxic condition and hypoxic stress for 6 h, 12 h, and 24 h, respectively. Then, flow cytometry detected the characteristics of BM-MSCs. Furthermore, N6-(p-nitrobenzyl) purine (TNP) was administrated to inhibit inositol pyrophosphates (IP7). TUNEL assay determined the apoptosis in BM-MSCs with hypoxia. Meanwhile, RFP-GFP-LC3 plasmid transfection and transmission microscope was used for measuring autophagy. In addition, Western blotting assay evaluated protein expressions. RESULTS: Hypoxic injury increased the autophagy and apoptosis of BM-MSCs. At the same time, hypoxic injury enhanced the production of IP7. Moreover, hypoxia decreased the activation of Akt/mTOR signaling pathway. At last, TNP (inhibitor of IP7) repressed the increased autophagy and apoptosis of BM-MSCs under hypoxia. CONCLUSION: The present study indicated that hypoxia increased autophagy and apoptosis via IP7-mediated Akt/mTOR signaling pathway of BM-MSCs. It may provide a new potential therapy target for myocardial infarction (MI).

CENPE promotes lung adenocarcinoma proliferation and is directly regulated by FOXM1.

Lung cancer is the most common and most lethal type of cancer. A sustained proliferative capacity is one of the hallmarks of cancer, and microtubules serve an important role in maintaining a sustained cell cycle. Therefore, understanding the regulation of microtubule proteins in the cell cycle is important for tumor prevention and treatment. Centromere protein E (CENPE) is a human kinetochore protein that is highly expressed in the G2/M phase of the cell cycle. The present study identified that CENPE is highly expressed in lung adenocarcinoma (LUAD) tissues. Following knockdown of CENPE expression, the proliferation of lung cancer cells was inhibited. In addition, it was revealed that forkhead box M1 (FOXM1) is significantly correlated with CENE expression. Following FOXM1­knockdown, the expression level of CENPE was decreased and the proliferation of lung cancer cells was inhibited. Overexpression of FOXM1 promoted the expression of CENPE and the proliferation of lung cancer cells. A chromatin immunoprecipitation assay identified that FOXM1 binds directly to the promoter region of CENPE. Therefore, the present data demonstrated that CENPE can promote the proliferation of LUAD cells and is directly regulated by FOXM1.