Abstract. Autophagy is a cytoprotective process, which occurs following temozolomide (TMZ) treatment, and contributes to glioma chemoresistance and TMZ treatment failure. However, the molecular mechanisms by which TMZ induces autophagy are largely unknown. In the current study, the ataxia-telangiectasia mutated (ATM) inhibitor KU-55933, adenosine monophosphate-activated protein kinase (AMPK) inhibitor compound C, and U87MG and U251 cell lines were employed to investigate the molecular mechanisms of TMZ-induced autophagy in glioma, and to evaluate the effects of autophagy inhibition on TMZ cytotoxicity. KU-55933 and compound C were observed to inhibit the activation of autophagy-initiating kinase ULK1 and result in a significant decrease of autophagy as indicated by depressed LC3B cleavage and acidic vesicular organelle formation. The activation of AMPK-ULK1 was ATM dependent. Autophagy inhibition via the AMPK inhibitor compound C augmented TMZ cytotoxicity as observed by depressed cell viability, increased γH2AX-marked double-strand breaks (DSBs) and elevated numbers of apoptotic glioma cells. In conclusion, TMZ induced autophagy via ATM-AMPK-ULK1 pathways. TMZ chemoresistance may therefore be overwhelmed by targeting AMPK, particularly for the treatment of O 6 -methylguanine DNA methyltransferase-negative gliomas.
Alkannin is the major bioactive compound of Arnebia euchroma roots, which is used in many therapeutic remedies in Chinese traditional medicine. SYUNZ-16 is a new derivative of alkannin. In this study, anticancer effects of SYUNZ-16 on human lung adenocarcinoma cell line GLC-82 and human hepatocarcinoma cell line Hep3B were tested in vitro. The results showed SYUNZ-16 could obviously inhibit the proliferation of these cancer cell lines via induction of apoptosis, with the evidence of increasing AnnexinV-positive cells and cleaved caspase-3 and PARP fragments. More importantly, we found that SYUNZ-16 could inhibit AKT activity in cell-free system. Treatment of cancer cells with SYUNZ-16 decreased the phosphorylation of AKT. Additionally, SYUNZ-16 partially attenuated the phosphorylation levels of FKHR and FKHRL1 in a dose-dependent and timedependent fashion, and led to an increase in the nuclear accumulation of exogenous FKHR, and upregulated the mRNA expression of Bim and TRADD in cancer cells. Further study showed that constitutively activated AKT1 transfection could reduce apoptosis induction mediated by SYUNZ-16. The in vivo experiments showed that SYUNZ-16 had inhibitory effects on S-180 sarcoma implanted to mice. And in GLC-82 xenograft models, SYUNZ-16 at 20 mg/kg/qod remarkably inhibited the tumor growth with the T/C value of 45.3%. Taken together, SYUNZ-16 might be a potent inhibitor of AKT signaling pathway in tumor cells. These data provide evidence for the development of SYUNZ-16 as a potential antitumor drug candidate for further research and development.
BackgroundGlioma is a common primary brain tumor with extremely poor prognosis outcomes. Increasing evidences have proved the relation between lncRNAs and glioma onset and progression. LncRNA SNHG5 involves in the biological activities of tumor cells, such as proliferation, migration and metastasis. Nevertheless, it is still necessary to explain the molecular mechanism and biofunction of SNHG5 in glioma.Materials and methodsQuantitative real-time PCR (qRT-PCR) was performed to analyze expressions of SNHG5, miR-205-5p and ZEB2 in tumor tissues and cell lines. The cell counting kit-8 (CCK-8) assay, plate and soft agar colony formation assays were performed to evaluate cell proliferation ability. RNA immunoprecipitation assay and dual-luciferase reporter assay were used to confirm the interaction among SNHG5, miR-205-5p and ZEB2. The protein level of ZEB2 was measured by Western blot.ResultsBased on our findings, compared with normal tissues, the elevated expression of SNHG5 and decreased expression of miR-205-5p were observed in glioma tissues. The downregulation of SNHG5 exerted an obvious inhibitory effect on glioma cells in terms of their proliferation. With regard to the underlying mechanism, SNHG5 presented a direct inhibitory influence on miR-205-5p which targeted to the 3′-UTR region of zinc finger E-box binding homeobox 2 (ZEB2) mRNA. As a competing endogenous RNA (ceRNA), SNHG5 sponged miR-205-5p, regulating the expression of ZEB2 thereby.ConclusionThese discoveries indicate that SNHG5 promotes proliferation of glioma by regulating miR-205-5p/ZEB2 axis.
The asymmetric Mannich reaction is one of the most useful carbon-carbon bond forming reactions for the synthesis of chiral molecules containing nitrogen. The resulting β-amino carbonyl compounds are valuable synthons in the preparation of many natural products with useful biological properties. This review provides an overview of asymmetric Mannich reactions in recent years under different organocatalytic systems, including: chiral amines, chiral bifunctional thiourea, chiral Brønsted acids and other chiral organocatalytic systems.
The Hippo pathway is an evolutionarily and functionally conserved signaling pathway that controls organ size by regulating cell proliferation, apoptosis, and differentiation. Emerging evidence has shown that the Hippo pathway plays critical roles in cardiac development, homeostasis, disease, and regeneration. Targeting the Hippo pathway has tremendous potential as a therapeutic strategy for treating intractable cardiovascular diseases such as heart failure. In this review, we summarize the function of the Hippo pathway in the heart. Particularly, we highlight the posttranslational modification of Hippo pathway components, including the core kinases LATS1/2 and their downstream effectors YAP/TAZ, in different contexts, which has provided new insights and avenues in cardiac research.
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by loss-of-function heterozygous mutations of methyl CpG-binding protein 2 ( MECP2 ) on the X chromosome in young females. Reactivation of the silent wild-type MECP2 allele from the inactive X chromosome (Xi) represents a promising therapeutic opportunity for female patients with RTT. Here, we applied a multiplex epigenome editing approach to reactivate MECP2 from Xi in RTT human embryonic stem cells (hESCs) and derived neurons. Demethylation of the MECP2 promoter by dCas9-Tet1 with target single-guide RNA reactivated MECP2 from Xi in RTT hESCs without detectable off-target effects at the transcriptional level. Neurons derived from methylation-edited RTT hESCs maintained MECP2 reactivation and reversed the smaller soma size and electrophysiological abnormalities, two hallmarks of RTT. In RTT neurons, insulation of the methylation-edited MECP2 locus by dCpf1-CTCF (a catalytically dead Cpf1 fused with CCCTC-binding factor) with target CRISPR RNA enhanced MECP2 reactivation and rescued RTT-related neuronal defects, providing a proof-of-concept study for epigenome editing to treat RTT and potentially other dominant X-linked diseases.
The present data suggest that DMTCCI has inhibitory effects on eukaryotic DNA primase and can induce apoptosis of BEL-7402 cells. The modulation of expression of p53 and Bcl-2 family proteins, and activation of Caspase-3 might be involved in the induction of apoptosis.
The first cyclopenta[b]benzofuran derivative, rocaglamide, from Aglaia elliptifolia, was found to exhibit considerable insecticidal activities and excellent potential as a therapeutic agent candidate in cancer chemotherapy; the genus Aglaia has been subjected to further investigation. Both the structural complexity of rocaglamide and its significant activity make it an attractive synthetic target. Stereoselective synthesis of the dense substitution pattern of these targets is a formidable synthetic challenge: the molecules bear five contiguous stereocenters and cis aryl groups on adjacent carbons. In past years of effort, only a handful of completed total syntheses have been reported, evidence of the difficulties associated with the synthesis of rocaglate natural products. The advance on total synthesis of rocaglamide was mainly reviewed from intramolecular cyclization and biomimetic cycloaddition approach.
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