目的探讨miR-204-5p对脂多糖(LPS)诱导的肺微血管内皮细胞损伤的影响及其可能作用机制。方法采用LPS诱导大鼠肺微血管内皮细胞(PMVEC)建立细胞损伤模型,实验分组:NC组、LPS组、LPS+miR-con组、LPS+miR-204-5p组、LPS+si-con组、LPS+si-T...目的探讨miR-204-5p对脂多糖(LPS)诱导的肺微血管内皮细胞损伤的影响及其可能作用机制。方法采用LPS诱导大鼠肺微血管内皮细胞(PMVEC)建立细胞损伤模型,实验分组:NC组、LPS组、LPS+miR-con组、LPS+miR-204-5p组、LPS+si-con组、LPS+si-TRIB3组、LPS+miR-204-5p+pcDNA组、LPS+miR-204-5p+pcDNA-TRIB3组;MTT法检测细胞活力;qRT-PCR、Western blot检测miR-204-5p、TRIB3表达;流式细胞术检测细胞凋亡;ELISA检测TNF-α、IL-6水平;双荧光素酶实验检测miR-204-5p与TRIB3的靶向关系。结果与NC组比较,LPS组细胞活力、miR-204-5p表达量降低(1.00±0.10比0.43±0.04),细胞凋亡率、TRIB3 mRNA(1.00±0.09 vs 2.13±0.18)和蛋白(0.40±0.04 vs 0.83±0.08)水平、TNF-α、IL-6水平升高(P<0.05);过表达miR-204-5p或敲低TRIB3可升高细胞活力,降低细胞凋亡率和TNF-α、IL-6水平(P<0.05);TRIB3是miR-204-5p的靶基因,上调TRIB3可减弱过表达miR-204-5p对细胞增殖、凋亡和炎症反应的影响。结论miR-204-5p过表达可靶向负调控TRIB3表达促进细胞增殖,抑制细胞凋亡和炎症反应,从而减轻LPS诱导的肺微血管内皮细胞损伤。展开更多
The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of ...The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of TRIB pseudokinases could provide new insights for disease development and help promote TRIB proteins as novel therapeutic targets for drug discovery. At the 2 nd International Symposium on Tribbles and Diseases held on May 7–9, 2018 in Beijing, China, a group of leading Tribbles scientists reported their findings and ongoing studies about the effects of the different TRIB proteins in the areas of immunity, metabolism, fundamental cell biology and cancer. Here, we summarize important and insightful overviews from 4 keynote lectures, 13 plenary lectures and 8 short talks that took place during this meeting. These findings may offer new insights for the understanding of the roles of TRIB pseudokinases in the development of various diseases.展开更多
The mammalian target of rapamycin(m TOR) pathway is abnormally activated in lung cancer.However, the anti-lung cancer effect of m TOR inhibitors as monotherapy is modest. Here, we identified that ginsenoside Rh2, an a...The mammalian target of rapamycin(m TOR) pathway is abnormally activated in lung cancer.However, the anti-lung cancer effect of m TOR inhibitors as monotherapy is modest. Here, we identified that ginsenoside Rh2, an active component of Panax ginseng C. A. Mey., enhanced the anti-cancer effect of the m TOR inhibitor everolimus both in vitro and in vivo. Moreover, ginsenoside Rh2 alleviated the hepatic fat accumulation caused by everolimus in xenograft nude mice models. The combination of everolimus and ginsenoside Rh2(labeled Eve-Rh2) induced caspase-independent cell death and cytoplasmic vacuolation in lung cancer cells, indicating that Eve-Rh2 prevented tumor progression by triggering paraptosis. EveRh2 up-regulated the expression of c-MYC in cancer cells as well as tumor tissues. The increased cMYC mediated the accumulation of tribbles homolog 3(TRIB3)/P62+ aggresomes and consequently triggered paraptosis, bypassing the classical c-MYC/MAX pathway. Our study offers a potential effective and safe strategy for the treatment of lung cancer. Moreover, we have identified a new mechanism of TRIB3/P62+ aggresomes-triggered paraptosis and revealed a unique function of c-MYC.展开更多
文摘目的探讨miR-204-5p对脂多糖(LPS)诱导的肺微血管内皮细胞损伤的影响及其可能作用机制。方法采用LPS诱导大鼠肺微血管内皮细胞(PMVEC)建立细胞损伤模型,实验分组:NC组、LPS组、LPS+miR-con组、LPS+miR-204-5p组、LPS+si-con组、LPS+si-TRIB3组、LPS+miR-204-5p+pcDNA组、LPS+miR-204-5p+pcDNA-TRIB3组;MTT法检测细胞活力;qRT-PCR、Western blot检测miR-204-5p、TRIB3表达;流式细胞术检测细胞凋亡;ELISA检测TNF-α、IL-6水平;双荧光素酶实验检测miR-204-5p与TRIB3的靶向关系。结果与NC组比较,LPS组细胞活力、miR-204-5p表达量降低(1.00±0.10比0.43±0.04),细胞凋亡率、TRIB3 mRNA(1.00±0.09 vs 2.13±0.18)和蛋白(0.40±0.04 vs 0.83±0.08)水平、TNF-α、IL-6水平升高(P<0.05);过表达miR-204-5p或敲低TRIB3可升高细胞活力,降低细胞凋亡率和TNF-α、IL-6水平(P<0.05);TRIB3是miR-204-5p的靶基因,上调TRIB3可减弱过表达miR-204-5p对细胞增殖、凋亡和炎症反应的影响。结论miR-204-5p过表达可靶向负调控TRIB3表达促进细胞增殖,抑制细胞凋亡和炎症反应,从而减轻LPS诱导的肺微血管内皮细胞损伤。
基金supported by National Key R&D Program of China(Grant No.2017YFA0205400,China)the National Natural Science Foundation of China(Grant Nos.81530093 and 81773781,China)+20 种基金Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(Grant No.2016-I2M-1-007,China)CAMS Central Public-interest Scientific Institution Basic Research Fund(Grant No.2017PT3104,China)supported by grants of the National Natural Science Foundation of China(Grant No.81874316,China)the CAMS Innovation Fund for Medical Sciences(Grant No.2016-I2M-3-008,China)supported by grants of from the BBSRC and NWCR(Grant Nos.1088 and 1097,UK)supported by grants of NSF(Grant No.IOS-1456023,USA)NIH(Grant No.NIH R21 CA197317,USA)supported by grants of Ministry of Education,Singapore(Grant Nos.MOE2014-T2-1-012 and 2012-T1-001-036,Singapore)supported by grants from the Health Research Council of New Zealandsupported by a Rutherford Discovery Fellowship from the New Zealand government administered by the Royal Society of New Zealandsupported by Funda??o para a Ciência e a Tecnologia(FCT)Research Center Grant UID/BIM/04773/2013 Centre for Biomedical Research 1334a research grant from Liga Portuguesa Contra o Cancro–Núcleo Regional do Sul(LPCC/NRS,Portugal)a FCT 2014 research grant SFRH/BPD/100434/2014a Pro Regem grant PD/BD/114258/2016(Portugal)supported by European Marie Sklodowska Curie ITN Project TRAIN-TRIBBLES Research and Innovation Network(Grant No.721532,EU)Innovation Network and the British Heart Foundation(PG/16/44/32146,UK)supported by grants from The Howat Foundation Ltd.(UK),Children with Cancer UK,Bloodwise and the Friends of Paul O'Gorman(UK)supported by grants of P-CREATE from Japan Agency for Medical Research and Developmentsupported by grants from the NIH(NIAID,USA),Alex's Lemonade Stand Foundation(USA)and the Samuel Waxman Cancer Research Foundation(USA)supported by European Marie Sklodowska Curie ITN Project TRAIN-TRIBBLES Research and Innovation Network(Grant No.721532,EU)the "Fondation Centaure"(RTRS),whic
文摘The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of TRIB pseudokinases could provide new insights for disease development and help promote TRIB proteins as novel therapeutic targets for drug discovery. At the 2 nd International Symposium on Tribbles and Diseases held on May 7–9, 2018 in Beijing, China, a group of leading Tribbles scientists reported their findings and ongoing studies about the effects of the different TRIB proteins in the areas of immunity, metabolism, fundamental cell biology and cancer. Here, we summarize important and insightful overviews from 4 keynote lectures, 13 plenary lectures and 8 short talks that took place during this meeting. These findings may offer new insights for the understanding of the roles of TRIB pseudokinases in the development of various diseases.
基金supported by the National Natural Science Foundation of China(No.81973516)partially supported by the Science and Technology Development Fund,Macao S.A.R,China(Nos.024/2016/A1 and 0129/2019/A3)University of Macao(No.CPG2021-00022-ICMS)。
文摘The mammalian target of rapamycin(m TOR) pathway is abnormally activated in lung cancer.However, the anti-lung cancer effect of m TOR inhibitors as monotherapy is modest. Here, we identified that ginsenoside Rh2, an active component of Panax ginseng C. A. Mey., enhanced the anti-cancer effect of the m TOR inhibitor everolimus both in vitro and in vivo. Moreover, ginsenoside Rh2 alleviated the hepatic fat accumulation caused by everolimus in xenograft nude mice models. The combination of everolimus and ginsenoside Rh2(labeled Eve-Rh2) induced caspase-independent cell death and cytoplasmic vacuolation in lung cancer cells, indicating that Eve-Rh2 prevented tumor progression by triggering paraptosis. EveRh2 up-regulated the expression of c-MYC in cancer cells as well as tumor tissues. The increased cMYC mediated the accumulation of tribbles homolog 3(TRIB3)/P62+ aggresomes and consequently triggered paraptosis, bypassing the classical c-MYC/MAX pathway. Our study offers a potential effective and safe strategy for the treatment of lung cancer. Moreover, we have identified a new mechanism of TRIB3/P62+ aggresomes-triggered paraptosis and revealed a unique function of c-MYC.
