查看更多>>摘要：Programmed cell death 2(PDCD2)is related to cancer progression and chemo-therapy sensitivity.The role of PDCD2 in solid cancers(excluding hematopoietic malignancies)and their diagnosis and prognosis remains unclear.The TCGA,CGGA,GEPIA,cBioPortal,and GTEx databases were analyzed for expression,prognostic value,and genetic modifications of PDCD2 in cancer patients.Functional enrichment analysis,CCK8,colony formation assay,transwell assay,and xenograft tumor model were undertaken to study the PDCD2's biological function in glioma(GBMLGG).The PDCD2 gene was associated with solid cancer progression.In the functional enrichment analysis results,PDCD2 was shown to participate in several impor-tant GBMLGG biological processes.GBMLGG cells may be inhibited in their proliferation,migra-tion,invasion,and xenograft tumor growth by knocking down PDCD2.Our research can provide new insights into solid cancer prognostic biomarkers of PDCD2.
查看更多>>摘要：Aging is a contributor to liver disease.Hence,the concept of liver aging has become prominent and has attracted considerable interest,but its underlying mechanism remains poorly understood.In our study,the internal mechanism of liver aging was explored via mul-ti-omics analysis and molecular experiments to support future targeted therapy.An aged rat liver model was established with D-galactose,and two other senescent hepatocyte models were established by treating HepG2 cells with D-galactose and H2O2.We then performed tran-scriptomic and metabolomic assays of the aged liver model and transcriptome analyses of the senescent hepatocyte models.In livers,genes related to peroxisomes,fatty acid elongation,and fatty acid degradation exhibited down-regulated expression with aging,and the hepato-kine Fgf21 expression was positively correlated with the down-regulation of these genes.In se-nescent hepatocytes,similar to the results found in aged livers,FGF21 expression was also decreased.Moreover,the expressions of cell cycle-related genes were significantly down-regu-lated,and the down-regulated gene E2F8 was the key cell cycle-regulating transcription fac-tor.We then validated that FGF21 overexpression can protect against liver aging and that FGF21 can attenuate the declines in the antioxidant and regenerative capacities in the aging liver.We successfully validated the results from cellular and animal experiments using human liver and blood samples.Our study indicated that FGF21 is an important target for inhibiting liver aging and suggested that pharmacological prevention of the reduction in FGF21 expres-sion due to aging may be used to treat liver aging-related diseases.
查看更多>>摘要：IL-17 A is a promoter of colorectal cancer initiation and progression.Narciclasine is a polyhydroxy alkaloid compound isolated from Narcissus plants,which has potent anti-inflam-matory and antitumor actions.The effects of narciclasine on colorectal tumors were evalu-ated,with a focus on IL-17 A.Narciclasine reduced the growth of HCT-116 and SW-480 colon cancer cells in vitro and in vivo in munne xenografts.The results of flow cytometry on JC-1 and Annexin V/PI revealed that narciclasine significantly reduced the mitochondnal membrane potential and induced apoptosis,findings confirmed by western blotting results of reduced Bcl-2 and enhanced Bax expression,as well as accumulation of cleaved Caspase-3,Caspase-8,Cas-pase-9,and cytoplasmic Cytochrome-c.After narciclasine incubation,IL-17 A,Act1,and TRAF6 were down-regulated,while p-P65(Ser536)accumulated in the cytoplasm,a finding confirmed by laser scanning confocal microscopy.IL17A substitution could partly reverse these narcicla-sine effects while they were elevated by IL17A silencing.Moreover,IL-17 A,Act1,and TRAF6 were significantly expressed to greater extents in human colorectal cancer compared to normal adjacent tissue specimens and were closely linked with a poor prognosis.This study provided evidence that narciclasine may be a useful therapeutic drug for colorectal cancer treatment through its actions in down-regulating the L-17A/Act1/TRAF6/NF-KB anti-apoptotic signaling pathway.
查看更多>>摘要：The clearance of apoptotic cell debris,containing professional phagocytosis and non-professional phagocytosis,is essential for maintaining the homeostasis of healthy tissues.Here,we discovered that endothelial cells could engulf apoptotic cell debris in atherosclerotic plaque.Single-cell RNA sequencing(RNA-seq)has revealed a unique endothelial cell subpopu-lation in atherosclerosis,which was strongly associated with vascular injury-related pathways.Moreover,integrated analysis of three vascular injury-related RNA-seq datasets showed that the expression of scavenger receptor class B type 1(SR-B1)was up-regulated and specifically enriched in the phagocytosis pathway under vascular injury circumstances.Single-cell RNA-seq and bulk RNA-seq indicate that SR-B1 was highly expressed in a unique endothelial cell subpop-ulation of mouse aorta and strongly associated with the reorganization of cellular adherent junctions and cytoskeleton which were necessary for phagocytosis.Furthermore,SR-B1 was strongly required for endothelial cells to engulf apoptotic cell debhs in atherosclerotic plaque of both mouse and human aorta.Overall,this study demonstrated that apoptotic cell debris could be engulfed by endothelial cells through SR-B1 and associated with the reorganization of cellular adherent junctions and cytoskeleton.
查看更多>>摘要：Transcriptional factor Forkhead box M1(FOXM1)plays an important role in pancre-atic ductal adenocarcinoma(PDAC)development and progression.The molecular mechanisms underlying its dysregulation remain unclear.We identified and functionally validated the mi-croRNAs(miRNAs)that critically regulate FOXM1 expression in PDAC.The expression levels of miRNA-23a(miR-23a-3p and-5p)were altered in PDAC cell lines and their effects on FOXM1 signaling and cell proliferation and migration and tumorigenesis were examined in vitro and in vivo using mouse PDAC models.Compared with non-tumor pancreatic tissues,PDAC tissues and cell lines exhibited significantly reduced levels of miR-23a expression.Reduced miR-23a expression and concomitant increase in FOXM1 expression were also observed in acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia,the major premalignant lesions of PDAC.Transgenic expression of miR-23a reduced the expression of FOXM1 and suppressed cell proliferation and migration in PDAC cells,whereas the inhibitors of miR-23a did the oppo-site.Loss or reduced levels of miR-23a increased the levels of FOXM1 expression,while increased expression of FOXM1 down-regulated miR-23a expression,suggesting that miR-23a and FOXM1 were mutual negative regulators of their expression in PDAC cells.Therefore,the miR-23a/FOXM1 signaling axis is important in PDAC initiation and progression and could serve as an interventional or therapeutic target for patients with early or late stages of PDAC.
查看更多>>摘要：Cancer stem cells(CSCs)play a crucial role in tumor initiation,recurrence,metas-tasis,and drug resistance.However,the current understanding of CSCs in hepatocellular car-cinoma(HCC)remains incomplete.Through a comprehensive analysis of the database,it has been observed that 3-hydroxy-3-methylglutaryl-coenzyme A reductase(HMGCR),a critical enzyme involved in cholesterol synthesis,is up-regulated in HCC tissues and liver CSCs.More-over,high expression of HMGCR is associated with a poor prognosis in patients with HCC.Func-tionally,HMGCR promotes the stemness and metastasis of HCC both in vitro and in vivo.By screening various signaling pathway inhibitors,we have determined that HMGCR regulates stemness and metastasis by activating the Hedgehog signaling in HCC.Mechanistically,HMGCR positively correlates with the expression of the Smoothened receptor and facilitates the nu-clear translocation of the transcriptional activator GLI family zinc finger 1.Inhibition of the Hedgehog pathway can reverse the stimulatory effects of HMGCR on stemness and metastasis in HCC.Notably,simvastatin,an FDA-approved cholesterol-lowering drug,has been shown to inhibit stemness and metastasis of HCC by targeting HMGCR.Taken together,our findings sug-gest that HMGCR promotes the regeneration and metastasis of HCC through the activation of Hedgehog signaling,and simvastatin holds the potential for clinical suppression of HCC metas-tasis.
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