查看更多>>摘要：The regulation of various types of cell death may help to restore the normal physiological function of cells and play a protective role in sepsis.In the current study,we explore the role of programmed cell necrosis in sepsis and the underlying mechanisms.The septic rat model is established by Cecal-ligation and perforation(CLP),and the in vitro model is established by LPS in IEC-6 cells.Our results demonstrate that receptor-interacting protein 1(RIP1)is significantly upregulated in the ileum of septic rats and LPS-treated IEC-6 cells at both the mRNA and protein levels.Nec-1,an inhibitor of RIP1,reduces the protein levels of RIP1,p-RIP3,and phosphorylated mixed-lineage kinase domain-like(MLKL)(serine 358)and relieves intestinal injury in CLP-induced septic rats with decreased IL-6 and TNF-α levels.The in vitro experiments further reveal that LPS induces the colocalization of RIP1 and RIP3,resulting in the phosphorylation and translocation of MLKL to the plasma membrane in IEC-6 cells.LPS also facilitates ROS production in IEC-6 cells,but this effect is further reversed by Nec-1,si-RIP1 and si-RIP3.Furthermore,LPS-induced necrosis in IEC-6 cells is counteracted by NAC.Thus,we conclude that RIP1/RIP3-dependent programmed cell necrosis participates in intestinal injury in sepsis and may be associated with RIP1/RIP3-mediated ROS.
查看更多>>摘要：Triple-negative breast cancer(TNBC)is a subtype of breast cancer,and its mechanisms of occurrence and devel-opment remain unclear.In this study,we aim to investigate the role and molecular mechanisms of the demethylase FTO(fat mass and obesity-associated protein)in TNBC.Through analysis of public databases,we identify that FTO may regulate the maturation of miR-17-5p and subsequently influence the expression of zinc finger and BTB domain-containing protein 4(ZBTB4),thereby affecting the occurrence and progression of TNBC.We screen for relevant miRNAs and mRNAs from the GEO and TCGA databases and find that the FTO gene may play a crucial role in TNBC.In vitro cell experiments demonstrate that overexpression of FTO can suppress the proliferation,migra-tion,and invasion ability of TNBC cells and can regulate the maturation of miR-17-5p through an m6A-dependent mechanism.Furthermore,we establish a xenograft nude mouse model and collect clinical samples to further confirm the role and impact of the FTO/miR-17-5p/ZBTB4 regulatory axis in TNBC.Our findings unveil the potential role of FTO and its underlying molecular mechanisms in TNBC,providing new perspectives and strategies for the research and treatment of TNBC.
查看更多>>摘要：Esophageal squamous cell carcinoma(ESCC)commonly has aggressive properties and a poor prognosis.In-vestigating the molecular mechanisms underlying the progression of ESCC is crucial for developing effective therapeutic strategies.Here,by performing transcriptome sequencing in ESCC and adjacent normal tissues,we find that E74-like transcription factor 4(ELF4)is the main upregulated transcription factor in ESCC.The results of the immunohistochemistry show that ELF4 is overexpressed in ESCC tissues and is significantly correlated with cancer staging and prognosis.Furthermore,we demonstrate that ELF4 could promote cancer cell proliferation,migration,invasion,and stemness by in vivo assays.Through RNA-seq and ChIP assays,we find that the stemness-related gene fucosyltransferase 9(FUT9)is transcriptionally activated by ELF4.Meanwhile,ELF4 is verified to affect ESCC cancer stemness by regulating FUT9 expression.Overall,we first discover that the transcription factor ELF4 is overexpressed in ESCC and can promote ESCC progression by transcriptionally upregulating the stemness-related gene FUT9.
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