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971.
Inhibition of yes‐associated protein suppresses brain metastasis of human lung adenocarcinoma in a murine model
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Ping‐Chih Hsu Jinbai Miao Zhen Huang Yi‐Lin Yang Zhidong Xu Joanna You Yuyuan Dai Che‐Chung Yeh Geraldine Chan Shu Liu Anatoly Urisman Cheng‐Ta Yang David M. Jablons Liang You 《Journal of cellular and molecular medicine》2018,22(6):3073-3085
Yes‐associated protein (YAP) is a main mediator of the Hippo pathway and promotes cancer development and progression in human lung cancer. We sought to determine whether inhibition of YAP suppresses metastasis of human lung adenocarcinoma in a murine model. We found that metastatic NSCLC cell lines H2030‐BrM3(K‐rasG12C mutation) and PC9‐BrM3 (EGFRΔexon19 mutation) had a significantly decreased p‐YAP(S127)/YAP ratio compared to parental H2030 (K‐rasG12C mutation) and PC9 (EGFRΔexon19 mutation) cells (P < .05). H2030‐BrM3 cells had significantly increased YAP mRNA and expression of Hippo downstream genes CTGF and CYR61 compared to parental H2030 cells (P < .05). Inhibition of YAP by short hairpin RNA (shRNA) and small interfering RNA (siRNA) significantly decreased mRNA expression in downstream genes CTGF and CYR61 in H2030‐BrM3 cells (P < .05). In addition, inhibiting YAP by YAP shRNA significantly decreased migration and invasion abilities of H2030‐BrM3 cells (P < .05). We are first to show that mice inoculated with YAP shRNA‐transfected H2030‐BrM3 cells had significantly decreased metastatic tumour burden and survived longer than control mice (P < .05). Collectively, our results suggest that YAP plays an important role in promoting lung adenocarcinoma brain metastasis and that direct inhibition of YAP by shRNA suppresses H2030‐BrM3 cell brain metastasis in a murine model. 相似文献
972.
IL‐35 recombinant protein reverses inflammatory bowel disease and psoriasis through regulation of inflammatory cytokines and immune cells
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Yuan Wang Ying Mao Junfeng Zhang Gang Shi Lin Cheng Yi Lin Yiming Li Xiaomei Zhang Yujing Zhang Xiaolei Chen Jie Deng Xiaolan Su Lei Dai Yang Yang Shuang Zhang Dechao Yu Yuquan Wei Hongxin Deng 《Journal of cellular and molecular medicine》2018,22(2):1014-1025
Interleukin‐35 (IL‐35), a member of the IL‐12 family, functions as a new anti‐inflammatory factor involved in arthritis, psoriasis, inflammatory bowel disease (IBD) and other immune diseases. Although IL‐35 can significantly prevent the development of inflammation in many diseases, there have been no early studies accounting for the role of IL‐35 recombinant protein in IBD and psoriasis. In this study, we assessed the therapeutic potential of IL‐35 recombinant protein in three well‐known mouse models: the dextransulfate sodium (DSS)‐induced colitis mouse model, the keratin14 (K14)‐vascular endothelial growth factor A (VEGF‐A)‐transgenic (Tg) psoriasis mouse model and the imiquimod (IMQ)‐induced psoriasis mouse model. Our results indicated that IL‐35 recombinant protein can slow down the pathologic process in DSS‐induced acute colitis mouse model by decreasing the infiltrations of macrophages, CD4+T and CD8+T cells and by promoting the infiltration of Treg cells. Further analysis demonstrated that IL‐35 recombinant protein may regulate inflammation through promoting the secretion of IL‐10 and inhibiting the expression of pro‐inflammatory cytokines such as IL‐6, TNF‐α and IL‐17 in acute colitis model. In addition, lower dose of IL‐35 recombinant protein could achieve long‐term treatment effects as TNF‐α monoclonal antibody did in the psoriasis mouse. In summary, the remarkable therapeutic effects of IL‐35 recombinant protein in acute colitis and psoriasis mouse models indicated that IL‐35 recombinant protein had a variety of anti‐inflammatory effects and was expected to become an effective candidate drug for the treatment of inflammatory diseases. 相似文献
973.
Sequential decline in fruit resource allocation within inflorescences of Sagittaria trifolia: a test of non‐uniform pollination hypothesis
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Flowering plants often exhibit declining resource investment to floral organs, fruits and seeds temporally or spatially in an inflorescence. To account for such variances, non‐uniform pollination hypothesis, which highlights various mating environments each flower experiences, provides adaptive significance for allocation patterns but with controversial supports. Sagittaria trifolia (Alismataceae) was used to examine differences in seed number, seed weight and germination rate among sequential fruits within inflorescences. Ovule number was also investigated to evaluate allocation patterns in the floral stage. To test the non‐uniform pollination hypothesis, we used three polymorphic microsatellite loci of S. trifolia to estimate the seed outcrossing rate in proximal and distal fruits. The results showed that the seed number, average seed weight and seed germination rate of S. trifolia gradually decreased from proximal to distal fruits within inflorescences. The percent of decrease in seed number between two contiguous fruits was 14.68 ± 3.22%, which was much stronger than the percent of decrease in ovule number at 6.95 ± 1.60%. Both proximal and distal fruits within inflorescences had high outcrossing rates (81.5 ± 5.0%, proximal; 82.3 ± 6.9%, distal) and they did not differ significantly. Overall, there was an acropetal decline of resource allocation to fruits within inflorescences of S. trifolia. Allocation pattern to ovules was not a limiting factor for seed production. The lack of difference in outcrossing rate between proximal and distal fruits indicated that the allocation strategy was probably not caused by non‐uniform pollination, but more likely position effects. 相似文献
974.
Cerebrovascular smooth muscle cell proliferation and migration contribute to hyperplasia in case of cerebrovascular remodeling and stroke. In the present study, we investigated the effects of acetylshikonin, the main ingredient of a Chinese traditional medicine Zicao, on human brain vascular smooth muscle cell (HBVSMCs) proliferation and migration induced by angiotensin II (AngII), and the underlying mechanisms. We found that acetylshikonin treatment significantly inhibited AngII-induced HBVSMCs proliferation and cell cycle transition from G1 to S phase. Wound-healing assay and Transwell assay showed that AngII-induced cell migration and invasion were markedly attenuated by acetylshikonin. In addition, AngII challenge significantly induced Wnt/β-catenin signaling activation, as evidenced by increased β-catenin phosphorylation and nuclear translocation and GSK-3β phosphorylation. However, acetylshikonin treatment inhibited the activation of Wnt/β-catenin signaling. Consequently, western blotting analysis revealed that acetylshikonin effectively reduced the expression of downstream target genes in AngII-treated cells, including c-myc, survivin and cyclin D1, which contributed to the inhibitory effect of acetylshikonin on HBVSMCs proliferation. Further, stimulation with recombinant Wnt3a dramatically reversed acetylshikonin-mediated inhibition of proliferation and cell cycle transition in HBVSMCs. Our study demonstrates that acetylshikonin prevents AngII-induced cerebrovascular smooth muscle cells proliferation and migration through inhibition of Wnt/β-catenin pathway, indicating that acetylshikonin may present a potential option for the treatment of cerebrovascular remodeling. 相似文献
975.
Zhenzhen Sun Yujie Xie Yintong Chen Qinghu Yang Zhenzhen Quan Rongji Dai Hong Qing 《Molecular neurobiology》2018,55(5):3841-3855
γ-Secretase has been a therapeutical target for its key role in cleaving APP to generate β-amyloid (Aβ), the primary constituents of senile plaques and a hallmark of Alzheimer’s disease (AD) pathology. Recently, γ-secretase-associating proteins showed promising role in specifically modulating APP processing while sparing Notch signaling; however, the underlying mechanism is still unclear. A co-immunoprecipitation (Co-IP) coupled with mass spectrometry proteomic assay for Presenilin1 (PS1, the catalytic subunit of γ-secretase) was firstly conducted to find more γ-secretase-associating proteins. Gene ontology analysis of these results identified Rab21 as a potential PS1 interacting protein, and the interaction between them was validated by reciprocal Co-IP and immunofluorescence assay. Then, molecular and biochemical methods were used to investigate the effect of Rab21 on APP processing. Results showed that overexpression of Rab21 enhanced Aβ generation, while silencing of Rab21 reduced the accumulation of Aβ, which resulted due to change in γ-secretase activity rather than α- or β-secretase. Finally, we demonstrated that Rab21 had no effect on γ-secretase complex synthesis or metabolism but enhanced PS1 endocytosis and translocation to late endosome/lysosome. In conclusion, we identified a novel γ-secretase-associating protein Rab21 and illustrate that Rab21 promotes γ-secretase internalization and translocation to late endosome/lysosome. Moreover, silencing of Rab21 decreases the γ-secretase activity in APP processing thus production of Aβ. All these results open new gateways towards the understanding of γ-secretase-associating proteins in APP processing and make inhibition of Rab21 a promising strategy for AD therapy. 相似文献
976.
Jun-Jun Huang Zhi-Han Zhang Fei He Xia-Wen Liu Xing-Jie Xu Li-Jun Dai Qi-Meng Liu Mu Yuan 《Bioorganic & medicinal chemistry letters》2018,28(4):547-551
α1-Adrenoceptor (α1-AR) antagonists are considered to be the most effective monotherapy agents for lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). In this study, we synthesized compounds 2–17, which are novel piperazine derivatives that contain methyl phenylacetate. We then evaluated the vasodilatory activities of these compounds. Among them, we found that compounds 2, 7, 12, which contain 2-OCH3, 2-CH3 or 2, 5-CH3, respectively, exhibited potent α1-blocking activity similar to protype drug naftopidil (1). The antagonistic effects of 2, 7, and 12 on the (?)-noradrenaline-induced contractile response of isolated rat prostatic vas deferens (α1A), spleen (α1B) and thoracic aorta (α1D) were further characterized to assess the sub receptor selectivity. Compared with naftopidil (1) and terazosin, compound 12 showed the most desirable α1D/1A subtype selectivity, especially improved α1A subtype selectivity, and the ratios pA2 (α1D)/pA2 (α1B) and pA2 (α1A)/pA2 (α1B) were 17.0- and 19.5-fold, respectively, indicating less cardiovascular side effects when used to treat LUTS/BPH. Finally, we investigated the chiral pharmacology of 12. We found, however, that the activity of enantiomers (R)-12 and (S)-12 are not significantly different from that of rac-12. 相似文献
977.
The Auxin-Regulated CrRLK1L Kinase ERULUS Controls Cell Wall Composition during Root Hair Tip Growth 总被引:1,自引:0,他引:1
Sébastjen Schoenaers Daria Balcerowicz Gordon Breen Kristine Hill Malgorzata Zdanio Grégory Mouille Tara J. Holman Jaesung Oh Michael H. Wilson Natalia Nikonorova Lam Dai Vu Ive De Smet Ranjan Swarup Winnok H. De Vos Isabel Pintelon Dirk Adriaensen Claire Grierson Malcolm J. Bennett Kris Vissenberg 《Current biology : CB》2018,28(5):722-732.e6
978.
Steven D. Fidanze Dachun Liu Robert A. Mantei Lisa A. Hasvold John K. Pratt George S. Sheppard Le Wang James H. Holms Yujia Dai Ana Aguirre Andrew Bogdan Justin D. Dietrich Jasmina Marjanovic Chang H. Park Charles W. Hutchins Xiaoyu Lin Mai H. Bui Xiaoli Huang Keith F. McDaniel 《Bioorganic & medicinal chemistry letters》2018,28(10):1804-1810
Novel conformationally constrained BET bromodomain inhibitors have been developed. These inhibitors were optimized in two similar, yet distinct chemical series, the 6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (A) and the 1-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (B). Each series demonstrated excellent activity in binding and cellular assays, and lead compounds from each series demonstrated significant efficacy in in vivo tumor xenograft models. 相似文献
979.
Chalada Suebsuwong Daniel M. Pinkas Soumya S. Ray Joshua C. Bufton Bing Dai Alex N. Bullock Alexei Degterev Gregory D. Cuny 《Bioorganic & medicinal chemistry letters》2018,28(4):577-583
Development of selective kinase inhibitors remains a challenge due to considerable amino acid sequence similarity among family members particularly in the ATP binding site. Targeting the activation loop might offer improved inhibitor selectivity since this region of kinases is less conserved. However, the strategy presents difficulties due to activation loop flexibility. Herein, we report the design of receptor-interacting protein kinase 2 (RIPK2) inhibitors based on pan-kinase inhibitor regorafenib that aim to engage basic activation loop residues Lys169 or Arg171. We report development of CSR35 that displayed >10-fold selective inhibition of RIPK2 versus VEGFR2, the target of regorafenib. A co-crystal structure of CSR35 with RIPK2 revealed a resolved activation loop with an ionic interaction between the carboxylic acid installed in the inhibitor and the side-chain of Lys169. Our data provides principle feasibility of developing activation loop targeting type II inhibitors as a complementary strategy for achieving improved selectivity. 相似文献
980.
Ji Cheng Jianping Guo Zhiwei Wang Brian J. North Kaixiong Tao Xiangpeng Dai Wenyi Wei 《生物化学与生物物理学报:癌评论》2018,1869(1):11-28
Cullin 3-RING ligases (CRL3) play pivotal roles in the regulation of various physiological and pathological processes, including neoplastic events. The substrate adaptors of CRL3 typically contain a BTB domain that mediates the interaction between Cullin 3 and target substrates to promote their ubiquitination and subsequent degradation. The biological implications of CRL3 adaptor proteins have been well described where they have been found to play a role as either an oncogene, tumor suppressor, or can mediate either of these effects in a context-dependent manner. Among the extensively studied CRL3-based E3 ligases, the role of the adaptor protein SPOP (speckle type BTB/POZ protein) in tumorigenesis appears to be tissue or cellular context dependent. Specifically, SPOP acts as a tumor suppressor via destabilizing downstream oncoproteins in many malignancies, especially in prostate cancer. However, SPOP has largely an oncogenic role in kidney cancer. Keap1, another well-characterized CRL3 adaptor protein, likely serves as a tumor suppressor within diverse malignancies, mainly due to its specific turnover of its downstream oncogenic substrate, NRF2 (nuclear factor erythroid 2-related factor 2). In accordance with the physiological role the various CRL3 adaptors exhibit, several pharmacological agents have been developed to disrupt its E3 ligase activity, therefore blocking its potential oncogenic activity to mitigate tumorigenesis. 相似文献