Enzalutamide is a second-generation androgen receptor (AR) antagonist for the treatment of metastatic castration-resistant prostate cancer (mCRPC).Unfortunately, AR dysfunction means that resistance to enzalutamide will eventually develop.Thus, novel agents are urgently needed to treat this devastating disease.Triptolide (TPL), a key active compound extracted from the Chinese herb Thunder God Vine (Tripterygium wilfordii Hook F.), possesses anti-cancer activity in human prostate cancer cells.However, the effects of TPL against CRPC cells and the underlying mechanism of any such effect are unknown.In this study, we found that TPL at low dose inhibits the transactivation activity of both full-length and truncated AR without changing their protein levels.Interestingly, TPL inhibits phosphorylation of AR and its CRPC-associated variant AR-V7 at Ser515 through XPB/CDK7.As a result, TPL suppresses the binding of AR to promoter regions in AR target genes along with reduced TFIIH and RNA Pol II recruitment.Moreover, TPL at low dose reduces the viability of prostate cancer cells expressing AR or AR-Vs.Low-dose TPL also shows a synergistic effect with enzalutamide to inhibit CRPC cell survival in vitro, and enhances the anti-cancer effect of enzalutamide on CRPC xenografts with minimal side effects.Taken together, our data demonstrate that TPL targets the transactivation activity of both full-length and truncated ARs.Our results also suggest that TPL is a potential drug for CRPC, and can be used in combination with enzalutamide to treat CRPC.
Histone demethylases are promising therapeutic targets as they play fundamental roles for survival of Mixed lineage leukemia rearranged acute leukemia ( MLL r AL). Here we focused on the catalytic Jumonji domain of histone H3 lysine 9 (H3K9) demethylase JMJD1C to screen for potential small molecular modulators from 149,519 natural products and 33,765 Chinese medicine components via virtual screening. JMJD1C Jumonji domain inhibitor 4 (JDI‐4) and JDI‐12 that share a common structural backbone were detected within the top 15 compounds. Surface plasmon resonance analysis showed that JDI‐4 and JDI‐12 bind to JMJD1C and its family homolog KDM3B with modest affinity. In vitro demethylation assays showed that JDI‐4 can reverse the H3K9 demethylation conferred by KDM3B. In vivo demethylation assays indicated that JDI‐4 and JDI‐12 could induce the global increase of H3K9 methylation. Cell proliferation and colony formation assays documented that JDI‐4 and JDI‐12 kill MLL r AL and other malignant hematopoietic cells, but not leukemia cells resistant to JMJD1C depletion or cord blood cells. Furthermore, JDI‐16, among multiple compounds structurally akin to JDI‐4/JDI‐12, exhibits superior killing activities against malignant hematopoietic cells compared to JDI‐4/JDI‐12. Mechanistically, JDI‐16 not only induces apoptosis but also differentiation of MLL r AL cells. RNA sequencing and quantitative PCR showed that JDI‐16 induced gene expression associated with cell metabolism; targeted metabolomics revealed that JDI‐16 downregulates lactic acids, NADP + and other metabolites. Moreover, JDI‐16 collaborates with all‐trans retinoic acid to repress MLL r AML cells. In summary, we identified bona fide JMJD1C inhibitors that induce preferential death of MLL r AL cells.
Objective
To evaluate the effect of sevoflurane preconditioning on autophagy in the operated lung tissues of the patients undergoing one-lung ventilation.
Methods
Forty patients of both sexes, with American Society of Anesthesiologists physical status Ⅰ-Ⅲ, aged 30-80 yr, weighing 45-84 kg, scheduled for elective radical operation for lung cancer performed via video-assisted thoracoscope under general anesthesia, were divided into control group(C group)and sevoflurane preconditioning group(SP group), with 20 patients in each group.In SP group, sevoflurane was inhaled for 30 min with the final concentration of 2.0%, followed by washout.The normal lung tissues(the distance from the edge of the lump>2 cm)around the lump were obtained for detection of the expression of microtubule-associated protein 1 light chain 3 Ⅱ by Western blot.
Results
Compared with C group, the expression of microtubule-associated protein 1 light chain 3 Ⅱ in lung tissues was significantly up-regulated in SP group(P<0.05).
Conclusion
Sevoflurane preconditioning can enhance autophagy in the operated lung tissues of the patients undergoing one-lung ventilation, which may be related to the lung protective effect.
Key words:
Anesthetics, inhalation; Ischemic preconditioning; Autophagy; Respiration, artificial; Respiratory distress syndrome, adult
As world resources and environmental constraints have increased, environmental cost has become a concern that affects the sustainable development of the logistics industry in various countries. Carbon emissions are an important part of any environmental cost assessment. How to scientifically and rationally evaluate the green GDP impact and regional efficiency in the logistics industry, especially when under carbon emission constraints, is of great significance to the realization of green and sustainable development. This study evaluated the logistics efficiency of 30 provinces in China from 2003 to 2016 by constructing a super SBM (Slack Based Model) model with undesirable output to explore provincial efficiency and its regional differences. The input–output ratio of the regional logistics industry was optimized through the calculation of the frontier slack variables. The research results showed that, first, it was more reasonable to adjust efficiency under carbon constraints, and it was consistent with the actual performance of the logistics industry. Second, technological progress and deeper capital investments promoted the development of the logistics industry, but technological barriers and low-scale efficiency between regions often limited technological efficiency. Therefore, decision-makers in the logistics industry should reconsider the challenges presented in each reason, encourage industrial technological innovation between regions, and especially promote energy-saving and emission-reduction technologies, so as to maintain the sustainable growth of the logistics industry.
Abstract Cadmium (Cd) extrusion is an important mechanism conferring Cd tolerance by decreasing its accumulation in plants. Previous studies have identified an Arabidopsis ABC transporter, PDR8, as a Cd extrusion pump conferring Cd tolerance. However, the regulation of PDR8 in response to Cd stress is still largely unknown. In this study, we identified an Arabidopsis cadmium‐tolerant dominant mutant, designated xcd3‐D , from the XVE‐tagging T‐DNA insertion lines by a gain‐of‐function genetic screen. The corresponding gene was cloned and shown to encode a nuclear WRKY transcription factor WRKY13. Expression of WRKY13 was induced by Cd stress. Overexpression of WRKY13 resulted in decreased Cd accumulation and enhanced Cd tolerance, whereas loss‐of‐function of WRKY13 led to increased Cd accumulation and sensitivity. Further analysis showed that WRKY13 activates the transcription of PDR8 by directly binding to its promoter. Genetic analysis indicated that WRKY13 acts upstream of PDR8 to positively regulate Cd tolerance. Our results provide evidence that WRKY13 directly targets PDR8 to positively regulate Cd tolerance in Arabidopsis .
To compare the image quality of low-dose CT urography (LD-CTU) using deep learning image reconstruction (DLIR) with conventional CTU (C-CTU) using adaptive statistical iterative reconstruction (ASIR-V).This was a prospective, single-institutional study using the excretory phase CTU images for analysis. Patients were assigned to the LD-DLIR group (100kV and automatic mA modulation for noise index (NI) of 23) and C-ASIR-V group (100kV and NI of 10) according to the scan protocols in the excretory phase. Two radiologists independently assessed the overall image quality, artifacts, noise and sharpness of urinary tracts. Additionally, the mean CT attenuation, signal-to-noise ratio (SNR) and contrast-to-noise (CNR) in the urinary tracts were evaluated.26 patients each were included in the LD-DLIR group (10 males and 16 females; mean age: 57.23 years, range: 33-76 years) and C-ASIR-V group (14 males and 12 females; mean age: 60 years, range: 33-77 years). LD-DLIR group used a significantly lower effective radiation dose compared with the C-ASIR-V group (2.01 ± 0.44 mSv vs 6.9 ± 1.46 mSv, p < 0.001). LD-DLIR group showed good overall image quality with average score >4 and was similar to that of the C-ASIR-V group. Both groups had adequate and similar attenuation value, SNR and CNR in most segments of urinary tracts.It is feasibility to provide comparable image quality while reducing 71% radiation dose in low-dose CTU with a deep learning image reconstruction algorithm compared to the conventional CTU with ASIR-V.(1) CT urography with deep learning reconstruction algorithm can reduce the radiation dose by 71% while still maintaining image quality.
// Fei Zhao 1, * , Weiwei Huang 1, * , Zhe Zhang 1 , Lin Mao 1, 3 , Yangyang Han 1, 3 , Jun Yan 3 , Ming Lei 1, 2 1 College of Life Sciences, Northwest A & F University, Yangling, Shaanxi Province, People's Republic of China 2 Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, People's Republic of China 3 State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, Jiangsu Province, People's Republic of China * These authors contributed equally to this work Correspondence to: Ming Lei, e-mail: leiming@ibp.ac.cn Keywords: triptolide, CaMKKβ, AMPK, autophagy, apoptosis Received: July 13, 2015 Accepted: December 05, 2015 Published: December 29, 2015 ABSTRACT Triptolide, an active compound extracted from the Chinese herb thunder god vine ( Tripterygium wilfordii Hook F.), has potent anti-tumor activity. Recently, triptolide was found to induce autophagy in cancer cells. However, the effects of triptolide on autophagy in human prostate cancer (PCa) cells have not yet been clearly elucidated. In this study, we demonstrated that triptolide induces autophagy in three PCa cell lines, PC-3, LNCaP and C4–2. Furthermore, we found that triptolide mediates intracellular accumulation of free calcium by stimulating the endoplasmic reticulum (ER) stress response. This activates the CaMKKβ-AMPK signaling pathway, which in turn inhibits mTOR and activates both ULK1 and Beclin 1, finally resulting in autophagy. Moreover, we found that treatment with autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) enhances triptolide-induced PCa cell death and growth inhibition. Using a PC-3-xenografted mouse model, we showed that blocking autophagy with CQ significantly promoted triptolide-induced tumor growth inhibition in vivo . Overall, our results show that triptolide induces protective autophagy through the CaMKKβ-AMPK pathway in PCa cells, implying that a combination of triptolide with autophagy inhibitors may potentially be an effective therapeutic strategy for PCa.
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