Intermittent hypoxia-induced enhancement of sociability and working memory associates with CNTNAP2 upregulation

IntroductionHypoxia is an environmental risk factor for many disorders throughout life. Perinatal hypoxia contributes to autism spectrum disorder (ASD), while hypoxic conditions in the elderly facilitate memory deficits. However, the effects of hypoxia on adolescence remains elusive. CNTNAP2 is a critical molecule in ASD pathogenesis with undefined mechanisms. We investigate hypoxia’s impact on adolescence and the underlying mechanism related to CNTNAP2.MethodsThree-chamber social approach test, Y maze, Morris Water Maze and Open Field Test were applied to evaluate behavioral alterations. Immunoblotting, 5′- RACE and dual-luciferase reporter assay were performed to examine CNTNAP2 protein expression, transcription start site (TSS) of human CNTNAP2 gene and CNTNAP2 promoter activity, respectively.ResultsIntermittent hypoxia treatment improved social behaviors and working memory in adolescent mice. CNTNAP2 was increased in the brains of hypoxia-treated mice. The sequencing results identified the TSS at 518 bp upstream of the translation start site ATG. Hypoxia upregulated CNTNAP2 by interacting with functional hypoxia response elements in CNTNAP2 promoter.ConclusionIntermittent hypoxia enhanced sociability and working memory associated with CNTNAP2 upregulation. Our study provides novel insights into intermittent hypoxia’s impact on development and the interaction between genetic and environmental risk factors in ASD pathogenesis

CLDN6 promotes chemoresistance through GSTP1 in human breast cancer

Abstract Background Claudin-6 (CLDN6), a member of CLDN family and a key component of tight junction, has been reported to function as a tumor suppressor in breast cancer. However, whether CLDN6 plays any role in breast cancer chemoresistance remains unclear. In this study, we investigated the role of CLDN6 in the acquisition of chemoresistance in breast cancer cells. Methods We manipulated the expression of CLDN6 in MCF-7 and MCF-7/MDR cells with lv-CLDN6 and CLDN6-shRNA and investigated whether CLDN6 manipulation lead to different susceptibilities to several chemotherapeutic agents in these cells. The cytotoxicity of adriamycin (ADM), 5-fluorouracil (5-FU), and cisplatin (DDP) was tested by cck-8 assay. Cell death was determined by DAPI nuclear staining. The enzyme activity of glutanthione S-transferase-p1 (GSTP1) was detected by a GST activity kit. Then lv-GSTP1 and GSTP1-shRNA plasmids were constructed to investigate the potential of GSTP1 in regulating chemoresistance of breast cancer. The TP53-shRNA was adopted to explore the regulation mechanism of GSTP1. Finally, immunohistochemistry was used to explore the relationship between CLDN6 and GSTP1 expression in breast cancer tissues. Results Silencing CLDN6 increased the cytotoxicity of ADM, 5-FU, and DDP in MCF-7/MDR cells. Whereas overexpression of CLDN6 in MCF-7, the parental cell line of MCF-7/MDR expressing low level of CLDN6, increased the resistance to the above drugs. GSTP1 was upregulated in CLDN6-overexpressed MCF-7 cells. RNAi –mediated silencing of CLDN6 downregulated both GSTP1 expression and GST enzyme activity in MCF-7/MDR cells. Overexpresssion of GSTP1 in CLDN6 silenced MCF-7/MDR cells restored chemoresistance, whereas silencing GSTP1 reduced the chemoresistance due to ectopic overexpressed of CLDN6 in MCF-7 cells. These observations were also repeated in TNBC cells Hs578t. We further confirmed that CLDN6 interacted with p53 and promoted translocation of p53 from nucleus to cytoplasm, and both the expression and enzyme activity of GSTP1 were regulated by p53. Clinicopathologic analysis revealed that GSTP1 expression was positively associated with CLDN6 in human breast cancer samples. Conclusion High expression of CLDN6 confers chemoresistance on breast cancer which is mediated by GSTP1, the activity of which is regulated by p53. Our findings provide a new insight into mechanisms and strategies to overcome chemoresistance in breast cancer

The Sources and Transport Dynamics of Eolian Sediments in the NE Tibetan Plateau Since 6.7 Ma

Abstract The red clay and loess‐paleosol sediments of the Xiaoshuizi and Halagu planation surfaces of the northeastern Tibetan Plateau (TP) provide insights into the response of paleo‐atmospheric circulation and surface processes to TP uplift and global climate changes. We present silicate Sr‐Nd isotope compositions and bulk sediment grain‐size parameters of the red clay and loess‐paleosol sequences, with the aim of reconstructing changes in the transporting wind systems and sediment source regions. The results indicate that the red clay on the planation surface was transported mainly by the westerlies from the Tarim Basin and the Qilian Mountains, while the loess‐paleosol sediments were transported mainly by the East Asian winter monsoon (EAWM) from the Badain Jaran Desert, Tengger Desert, and Qaidam Basin. These shifts in transport mechanism and source were likely related to major changes in the topography of the TP and the expansion of Northern Hemisphere glaciation since the Middle Pliocene. In addition, we reconstructed the evolution of the paleo‐atmospheric circulation from the Late Miocene to the Middle Pliocene. During the Late Miocene, both the paleo‐EAWM and East Asian summer monsoon (EASM) were weak, and westerly winds dominated the climate of the study area. During the Early Pliocene, both the paleo‐EAWM and EASM exerted an increasing influence on the study area. We ascribe the slight enhancement of the paleo‐EAWM to the gradual growth of the northern TP and the significant enhancement of the paleo‐EASM to global climate changes

OCT4 maintains self-renewal and reverses senescence in human hair follicle mesenchymal stem cells through the downregulation of p21 by DNA methyltransferases

Abstract Background Self-renewal is dependent on an intrinsic gene regulatory network centered on OCT4 and on an atypical cell cycle G1/S transition, which is also regulated by OCT4. p21, a gene negatively associated with self-renewal and a senescence marker, is a member of the universal cyclin-dependent kinase inhibitors (CDKIs) and plays critical roles in the regulation of the G1/S transition. The expression of p21 can be regulated by OCT4-targeted DNA methyltransferases (DNMTs), which play distinct roles in gene regulation and maintaining pluripotency properties. The aim of this study was to determine the role of OCT4 in the regulation of self-renewal and senescence in human hair follicle mesenchymal stem cells (hHFMSCs) and to characterize the molecular mechanisms involved. Methods A lentiviral vector was used to ectopically express OCT4. The influences of OCT4 on the self-renewal and senescence of hHFMSCs were investigated. Next-generation sequencing (NGS) was performed to identify the downstream genes of OCT4 in this process. Methylation-specific PCR (MSP) analysis was performed to measure the methylation level of the p21 promoter region. p21 was overexpressed in hHFMSCsOCT4 to test its downstream effect on OCT4. The regulatory effect of OCT4 on DNMTs was examined by ChIP assay. 5-aza-dC/zebularine was used to inhibit the expression of DNMTs, and then self-renewal properties and senescence in hHFMSCs were detected. Results The overexpression of OCT4 promoted proliferation, cell cycle progression, and osteogenic differentiation capacity of hHFMSCs. The cell senescence of hHFMSCs was markedly suppressed due to the ectopic expression of OCT4. Through NGS, we identified 2466 differentially expressed genes (DEGs) between hHFMSCsOCT4 and hHFMSCsEGFP, including p21, which was downregulated. The overexpression of p21 abrogated the proliferation and osteogenic differentiation capacity of hHFMSCsOCT4 and promoted cell senescence. OCT4 enhanced the transcription of DNMT genes, leading to an elevation in the methylation of the p21 promoter. The inhibition of DNMTs reversed the OCT4-induced p21 reduction, depleted the self-renewal of hHFMSCsOCT4, and triggered cell senescence. Conclusions OCT4 maintains the self-renewal ability of hHFMSCs and reverses senescence by suppressing the expression of p21 through the upregulation of DNMTs

La Charente

22 juillet 18931893/07/22 (A22,N10115)-1893/07/22.Appartient à l’ensemble documentaire : PoitouCh

Additional file 6: Figure S6. of CLDN6 promotes chemoresistance through GSTP1 in human breast cancer

P-gp expression when CLDN6 overexpression in MCF-7 cells. **P < 0.01. (PDF 29 kb

Additional file 1: Figure S1. of CLDN6 promotes chemoresistance through GSTP1 in human breast cancer

Flow cytometric analysis of cell apoptosis in CLDN6 knockdown MCF-7/MDR cells when treated with DDP. *, P < 0.05; **, P < 0.01. (PDF 435 kb