5,284 research outputs found
A novel mode of action of YC-1 in HIF inhibition: stimulation of FIH-dependent p300 dissociation from HIF-1{alpha}
No full textHypoxia-inducible factor (HIF)-1 plays a key role in tumor promotion by inducing approximately 60 genes required for tumor adaptation to hypoxia; thus, it is viewed as a target for cancer therapy. For this reason, YC-1, which down-regulates HIF-1alpha and HIF-2alpha at the post-translational level, is being developed as a novel anticancer drug. We here found that YC-1 acts in a novel manner to inhibit HIF-1. In the Gal4 reporter system, which is not degraded by YC-1, YC-1 was found to significantly inactivate the COOH-terminal transactivation domain (CAD) of HIF-1alpha, whereas it failed to inactivate CAD(N803A) mutant. In coimmunoprecipitation assays, YC-1 stimulated factor inhibiting HIF (FIH) binding to CAD even in hypoxia, whereas it failed to increase the cellular levels of hydroxylated Asn803 of CAD. It was also found that YC-1 prevented p300 recruitment by CAD in mammalian two-hybrid and coimmunoprecipitation assays. The involvement of FIH in YC-1-induced CAD inactivation was confirmed in EPO-enhancer and Gal4 reporter systems using FIH small interfering RNA and dimethyloxalylglycine FIH inhibitor. Indeed, FIH inhibition rescued HIF target gene expressions repressed by YC-1. In cancer cell lines other than Hep3B, YC-1 inhibits HIF-1alpha via the FIH-dependent CAD inactivation as well as via the protein down-regulation. Given these results, we suggest that the functional inactivation of HIF-alpha contributes to the YC-1-induced deregulation of hypoxia-induced genes
YC-1 inhibits proliferation of breast cancer cells by down-regulating EZH2 expression via activation of c-Cbl and ERK
No full textBACKGROUND AND PURPOSE
YC-1 exhibits potent anticancer activity via numerous actions in many cancer cell lines. Hence, we investigated the in vivo antitumour efficacy of YC-1 in an MDA-MB-468 xenograft model and elucidated the mechanism of down-regulation of enhancer of zeste homology 2 (EZH2) by YC-1 in breast cancer cells.
EXPERIMENTAL APPROACH
In YC-1-treated breast cancer cells and tumour specimens from YC-1-treated MDA-MB-468 xenografts, EZH2 expression was analysed by Western blotting. Pharmacological inhibitors and short hairpin RNA-mediated knockdown were applied to identify possible signalling pathways involved in EZH2 down-regulation by YC-1.
KEY RESULTS
YC-1 reduced the viability of breast cancer cells and tumour growth in MDA-MB-468 xenografts. In breast cancer cells, YC-1 down-regulated EZH2 expression in a concentration-and time-dependent manner. Depletion of EZH2 reduced the proliferation and susceptibility of breast cancer cells to YC-1-induced apoptosis. EZH2 expression was suppressed in tumour specimens from YC-1-treated MDA-MB-468 xenograft mice. YC-1 enhanced both the degradation rate and ubiquitination of EZH2. The down-regulation of EZH2 by YC-1 was associated with activation of PKA and Src-Raf-ERK-mediated signalling pathways. Furthermore, depletion of Casitas B-lineage lymphoma (c-Cbl), an E3 ubiquitin ligase, abolished YC-1-induced apoptosis and suppression of EZH2. YC-1 rapidly activated c-Cbl to induce signalling associated with ERK and EZH2.
CONCLUSION AND IMPLICATIONS
We discovered that YC-1 induces apoptosis and inhibits tumour growth of breast cancer cells via down-regulation of EZH2 by activating c-Cbl and ERK. These data suggest that YC-1 is a potential anticancer drug candidate for triple-negative breast cancer
A study of Li Kaixian's sanqu
No full text
Li Kaixian (1502-1568), a scholar-official living in the mid-Ming dynasty, was renowned for his efforts in collecting books, both rare and common, and also for his talents in writing the literary genre called sanqu, a subcategory of the genre qu.
While qu consists of drama and sanqu, nonetheless the attention devoted to the latter has been much weaker than the former within the academic circle. In the case of Li Kaixian, his dramas such as The Tale of A Treasured Sword have been reviewed much more frequently than his sanqu compilations.
To fill up this gap, this thesis attempts to study in depth Li Kaixian?s sanqu. It is organized into 6 major chapters.
The first chapter comes with an introduction reviewing the status of Ming sanqu as a whole and its social-ideological background, including a literature review on the subject. To facilitate a better understanding of Li?s rationales in writing sanqu, the second chapter deals with his life and the themes of his sanqu. The third chapter is an analysis of his thoughts towards the writing of sanqu,
The fourth and fifth chapters mainly provide a critical review on Li?s sanqu, both thematically and aesthetically. The sixth chapter, a tentative evaluation of the status of Li?s sanqu, serves as the conclusion.published_or_final_versionChineseMasterMaster of Philosoph
Differentially expressed miRNAs between Bama minipigs (YB) and Landrace (YC).
No full text<p>YB, YC represent Bama minipigs and Landrace pigs, respectively. miRNAs underlined represents this differential miRNAs is p ≤ 0.01 and the higher signal≥500.</p><p>Differentially expressed miRNAs between Bama minipigs (YB) and Landrace (YC).</p
LyraNET: A zero-copy TCP/IP protocol stack for embedded systems
No full text[[abstract]]Embedded systems are usually resource limited in terms of processing power, memory, and power consumption, thus embedded TCP/IP should be designed to make the best use of limited resources. Applying zero-copy mechanism can reduce memory usage and CPU processing time for data transmission. Power consumption can be reduced as well. In this paper, we present the design and implementation of zero-copy mechanism in the target embedded TCP/IP component, LyraNET, which is derived from Linux TCP/IP codes and remodeled as a reusable software component that is independent from operating systems and hardware. Performance evaluation shows that TCP/IP protocol processing overhead can be significantly decreased by 23-63%. Besides, object code size of this network component is only 77.64% of the size of the original Linux TCP/IP stack. The experience of this study can serve as the reference for embedding Linux TCP/IP stack into a target system that requires network connectivity and improving the transmission efficiency of Linux TCP/IP by zero-copy implementation.[[note]]SC
Safety and Feasibility of YC‐6 in Patients With Large Hemispheric Infarction: A Randomized Clinical Trial
No full textBackground Malignant cerebral edema is a critical cause of poor outcomes in large hemispheric infarction and novel neuroprotective agents are urgently needed. We aimed to assess the safety and preliminarily explored the feasibility of YC‐6 (5α‐androst‐3β,5,6β‐triol for injection) in large hemispheric infarction. Methods This study was a prospective, randomized, double‐blind, placebo‐controlled, proof‐of‐concept trial. Patients with large hemispheric infarction in middle cerebral artery within 12 hours of symptom onset were enrolled. Patients were assigned to receive either 300 mg YC‐6 or placebo twice a day for 10 days, randomly. The primary safety outcomes were serious adverse events and all‐cause death. The primary efficacy outcome was the distribution of the modified Rankin Scale score at 90 days. Results The incidence of serious adverse events (52.2% and 43.5%) and all‐cause death (39.1% and 40.0%) within 90 days were similar between YC‐6 and placebo group. There was no statistical difference between the groups in the distribution of modified Rankin Scale score (common odds ratio 0.73, 95% CI: 0.25 to 2.18). The proportion of a modified Rankin Scale score of 0 to 4 was 56.5% in YC‐6 group compared with 35.0% in placebo group (P=0.16). In addition, YC‐6 treatment numerically alleviated edema volume at 72 hours and 10 days (RD −15.02, 95% CI: −40.94 to 10.90; RD −10.35, 95% CI: −46.69 to 25.98) and decreased midline shift at 10 days (RD −0.6, 95% CI: −4.17 to 2.97). Conclusions This study preliminarily explored the safety and feasibility of YC‐6 in patients with large hemispheric infarction. Based on this trial, the phase 2 trial of YC‐6 was worthy of anticipation. Registration http://www.chinadrugtrials.org.cn; Unique identifier: CTR20192127; http://www.chictr.org.cn; Unique identifier: ChiCTR2400088887
Isolation and characterization of tetramicrosatellite DNA markers in the Eurasian otter (Lutra lutra).
No full textNational health insurance data in hospitalized patients with osteoporosis-related fractures
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