Glioma is one of the most common types of primary brain tumors. Ivermectin (IVM), a broad-spectrum antiparasitic drug, has been identified as a novel anticancer agent due to its inhibitory effects on the proliferation of glioma cells in vitro and in vivo. However, the ability of IVM to induce autophagy and its role in glioma cell death remains unclear. The main objective of the present study was to explore autophagy induced by IVM in glioma U251 and C6 cells, and the deep underlying molecular mechanisms. In addition, we examined the effects of autophagy on apoptosis in glioma cells. In the present study, transmission electron microscopy (TEM), immunofluorescence, Western blot and immunohistochemistry were used to evaluate autophagy activated by IVM. Cell viability was measured by 3-(4,5-dimethylthiazol2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and colony formation assay. The apoptosis rate was detected by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Meanwhile, autophagy inhibition was achieved by using chloroquine (CQ). U251-derived xenografts were established for examination of IVM-induced autophagy on glioma in vivo. Taken together, the results of the present study showed that autophagy induced by IVM has a protective effect on cell apoptosis in vitro and in vivo. Mechanistically, IVM induced autophagy through AKT/mTOR signaling and induced energy impairment. Our findings show that IVM is a promising anticancer agent and may be a potential effective treatment for glioma cancers.
Cancer Science. 2020;111:1555-1566. | 1555 wileyonlinelibrary.com/journal/cas | INTRODUC TI ONRenal cell carcinoma is a highly malignant tumor that is common in the urinary system. It has the characteristics of radiotherapy and chemotherapy tolerance. 1,2 Regarding the pathological types of RCC, approximately 75%-80% of cases are clear cell renal cell carcinoma (ccRCC). Although surgical treatment is available, the recurrence rate after radical nephrectomy is still as high as 20%-40%, and the 5-year survival rate of ccRCC after surgical resection is only approximately 20%. 3 Therefore, revealing the molecular mechanism of renal cancer radiotherapy and chemotherapy tolerance is critical. 4The bone morphogenetic protein (BMP) ligand family plays an important role in embryonic development, morphogenesis, differentiation, proliferation and apoptosis of various types of cells throughout the body. BMP are found to be members of the transforming growth factor-beta (TGF-β) family, including activin in This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractThere is increasing evidence that bone morphogenetic proteins (BMP) are involved in the proliferation and drug tolerance of kidney cancer. However, the molecular mechanism of BMP8A in renal cell proliferation and drug tolerance is not clear. Here we showed that BMP8A was highly expressed in renal cell carcinoma, which suggests a poor prognosis of ccRCC. Promotion of cell proliferation and inhibition of apoptosis were detected by CCK-8 assay, Trypan Blue staining, flow cytometry and bioluminescence. BMP8A promoted resistance of As 2 O 3 by regulating Nrf2 and Wnt pathways in vitro and in vivo. Mechanistically, BMP8A enhanced phosphorylation of Nrf2, which, in turn, inhibited Keap1-mediated Nrf2 ubiquitination and, ultimately, promoted nuclear translocation and transcriptional activity of Nrf2. Nrf2 regulates the transcription of TRIM24 detected by ChIP-qPCR. BMP8A was highly expressed in ccRCC, which suggests a poor prognosis. BMP8A was expected to be an independent prognostic molecule for ccRCC. On the one hand, activated Nrf2 regulated reactive oxygen balance, and on the other hand, by regulating the transcription level of TRIM24, it was involved in the regulation of the Wnt pathway to promote the proliferation, invasion and metastasis of ccRCC and the resistance of As 2 O 3 . Taken together, our findings describe a regulatory axis where BMP8A promotes Nrf2 phosphorylation and activates TRIM24 to promote survival and drug resistance in ccRCC. K E Y W O R D S As 2 O 3 , BMP8A, Nrf2, TRIM24, Wnt pathway
AIM:To investigate the safety of combined cranioplasty (CP) and ventriculoperitoneal shunt (VPS) placement. Furthermore, we investigated whether the sequence of these procedures affects the postoperative complication rates associated with staged CP and VPS placement. MATERIAL and METHODS:We retrospectively investigated patients who developed communicating hydrocephalus after decompressive craniectomy and subsequently underwent VPS placement and CP at the hospital at which this study was performed between January 2009 and December 2019. Patients were categorized into group 1 (simultaneous CP and VPS placement) and group 2 (CP and VPS placement performed separately). Group 2 was subcategorized into subgroup 2a (CP performed before VPS placement) and subgroup 2b (VPS placement performed before CP). The Student's t and Chi square tests were used to analyze intergroup differences. RESULTS:This study included 86 patients; 22 in group 1 and 64 in group 2 (24 patients in subgroup 2a and 40 patients in subgroup 2b). No statistically significant difference was observed in the overall complication rates between groups 1 and 2 (36.4% vs. 28.1%, P=0.591). However, the incidence of infections was significantly higher in group 1 than in group 2 (22.7% vs. 4.7%, P=0.024). Subgroup analysis showed that the overall complication rate was significantly lower in subgroup 2a than in subgroup 2b (12.5% vs. 37.5%, P=0.031). CONCLUSION:Simultaneous CP and VPS placement is associated with a high incidence of infections. Moreover, compared with initial CP, initial VPS placement is associated with a significantly higher risk of overall complications in patients who undergo a staged procedure.
BackgroundArsenic trioxide (As2O3) has a dramatic therapeutic effect on acute promyelocytic leukemia (APL) patients. It can also cause apoptosis in various tumor cells. This study investigated whether As2O3 has an antitumor effect on glioma and explored the underlying mechanism.ResultsMTT and trypan blue assays showed that As2O3 remarkably inhibited growth of C6 and 9 L glioma cells. Cell viability decreased in glioma cells to a greater extent than in normal glia cells. The annexin V-FITC/PI and Hoechest/PI staining assays revealed a significant increase in apoptosis that correlated with the duration of As2O3 treatment and occurred in glioma cells to a greater extent than in normal glial cells. As2O3 treatment induced reactive oxygen species (ROS) production in C6 and 9 L cells in a time-dependent manner. Cells pretreated with the antioxidant N-acetylcysteine (NAC) showed significantly lower As2O3-induced ROS generation. As2O3 significantly inhibited the expression of the anti-apoptotic gene Bcl-2, and upregulated the proapoptotic gene Bax in both C6 and 9 L glioma cells in a time-dependent manner.ConclusionsAs2O3 can significantly inhibit the growth of glioma cells and it can induce cell apoptosis in a time- and concentration-dependent manner. ROS were found to be responsible for apoptosis in glioma cells induced by As2O3. These results suggest As2O3 is a promising agent for the treatment of glioma.
Background/Aims: Alcohol consumption has been shown to cause neuroinflammation and increase a variety of immune-related signaling processes. Microglia are a crucial part of alcohol-induced neuroinflammation and undergo apoptosis. Even though the importance of these inflammatory processes in the effects of alcohol-related neurodegeneration have been established, the mechanism of alcohol-induced microglia apoptosis is unknown. In prior research, we discovered that alcohol increases expression of salt-inducible kinase 1 (SIK1) in rodent brain tissue. In this study, we sought to determine what role SIK1 expression plays in alcohol-induced neuroinflammation as well as whether and by what mechanism it regulates microglia apoptosis. Methods: Adult C57BL/6 mice were divided into four groups and for 3 weeks treated with either 0%, 5%, 10%, or 15% alcohol during 3 hour periods. The mice were sacrificed and their brains excised for analysis. Additionally, primary microglia were isolated from neonatal mice. SIK1 expression in alcohol-treated brain tissue and microglia was analyzed via RT-PCR and western blotting. TUNEL staining, caspase-3, and caspase-9 activity assays were performed to evaluate microglial apoptosis. Cell fluorescence staining and NF-κB luciferase activity assays were used to evaluate the effects of SIK1 expression on the NF-κB signaling pathway. Results: SIK1 expression was increased in the brains of mice that consumed alcohol, and this effect was seen in mouse primary microglia. SIK1 knockdown in microglia increased alcohol-induced apoptosis in these cells. Furthermore, SIK1 reduced NF-κB signaling pathway factors, and SIK1 knockdown in microglia promoted alcohol-induced NF-κB activity. TUNEL staining, caspase-3, and caspase-9 activity assays consistently revealed that alcohol-induced microglial apoptosis was inhibited by depletion of p65. Finally, we determined that NF-κB signaling is required for alcohol-induced, SIK1-mediated apoptosis in microglia. Conclusion: This study establishes for the first time not only that SIK1 is crucial to regulating alcohol-induced microglial apoptosis, but also that the NF-κB signaling pathway is required for its activity. Overall, our results help elucidate mechanisms of alcohol-induced neuroinflammation.
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