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Shuling Wang Xiaoyu Jiang Xiaoli Xie Jie Yin Jiuna Zhang Ting Liu Shujia Chen Yijun Wang Xue Zhou Yongjuan Wang Ruolin Cui Huiqing Jiang 《Cell death & disease》2022,13(5)
Mitophagy plays a vital role in the maintenance of mitochondrial homeostasis and tumorigenesis. Noncoding RNA piR-823 contributes to colorectal tumorigenesis. In this study, we aim to evaluate piR-823-mediated mitophagy and its mechanistic association with colorectal cancer (CRC). Digital gene expression analysis was performed to explore the potential functions of piR-823. A piR-823 antagomir (Ant-823) was used to inhibit piR-823 expression, and piR-823 mimics (mimics-823) were used to increase piR-823 expression. Mitophagy was measured in vivo and in vitro by immunofluorescence and western blot analysis. JC-1 staining, ATP production, real-time PCR, and western blot analysis were used to measure changes in mitochondrial quality and number. siRNA transfection was used to inhibit mitophagy, and CCCP was used to induce mitophagy. RNA pull-down assays and RNA-binding protein immunoprecipitation assays were conducted to investigate the molecular mechanisms. Here, we found that CRC cells transfected with Ant-823 presented an altered expression of autophagic and mitophagy genes by Digital gene expression analysis. Ant-823 could promote Parkin activation and mitophagy in vitro and in vivo, followed by mitochondrial loss and dysfunction of some mitochondria, whereas mimics-823 exerted the opposite effects in CRC cells. The inhibition of mitophagy by siParkin alleviated Ant-823-induced mitochondrial loss and dysfunction, as well as apoptosis to a certain extent. Furthermore, piR-823 was found to interact with PINK1 and promote its ubiquitination and proteasome-dependent degradation, thus alleviating mitophagy. Finally, these findings were verifed in samples obtained by patients affected by colorectal cancer. In conclusion, we identify a novel mechanism by which piR-823 regulates mitophagy during CRC tumorigenesis by increasing PINK1 degradation. Subject terms: Colorectal cancer, Gastrointestinal cancer 相似文献
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Yuxiang Liu Tao V. Wang Yunfeng Cui Chaoyi Li Lifen Jiang Yi Rao 《The Journal of biological chemistry》2022,298(5)
We have recently purified mammalian sterile 20 (STE20)–like kinase 3 (MST3) as a kinase for the multifunctional kinases, AMP-activated protein kinase–related kinases (ARKs). However, unresolved questions from this study, such as remaining phosphorylation activities following deletion of the Mst3 gene from human embryonic kidney cells and mice, led us to conclude that there were additional kinases for ARKs. Further purification recovered Ca2+/calmodulin-dependent protein kinase kinases 1 and 2 (CaMKK1 and 2), and a third round of purification revealed mitogen-activated protein kinase kinase kinase kinase 5 (MAP4K5) as potential kinases of ARKs. We then demonstrated that MST3 and MAP4K5, both belonging to the STE20-like kinase family, could phosphorylate all 14 ARKs both in vivo and in vitro. Further examination of all 28 STE20 kinases detected variable phosphorylation activity on AMP-activated protein kinase (AMPK) and the salt-inducible kinase 3 (SIK3). Taken together, our results have revealed novel relationships between STE20 kinases and ARKs, with potential physiological and pathological implications. 相似文献
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The blood-brain barrier (BBB) is an interface between cerebral blood and the brain parenchyma. As a gate keeper, BBB regulates passage of nutrients and exogeneous compounds. Owing to this highly selective barrier, many drugs targeting brain diseases are not likely to pass through the BBB. Thus, a large amount of time and cost have been paid for the development of BBB targeted therapeutics. However, many drugs validated in in vitro models and animal models have failed in clinical trials primarily due to the lack of an appropriate BBB model. Human BBB has a unique cellular architecture. Different physiologies between human and animal BBB hinder the prediction of drug responses. Therefore, a more physiologically relevant alternative BBB model needs to be developed. In this review, we summarize major features of human BBB and current BBB models and describe organ-on-chip models for BBB modeling and their applications in neurological complications. 相似文献
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植被恢复过程中芒萁覆盖对侵蚀红壤氮组分的影响 总被引:1,自引:0,他引:1
氮素是限制陆地生态系统生产力的重要因子。采用时空代换法,以红壤侵蚀区未治理、恢复12年和30年的马尾松林为研究对象,对比分析了林下芒萁覆盖地与裸地表层土壤之间氮同位素、不同形态氮组分含量以及不同组分氮含量所占比例之间的差异。结果表明:在所有马尾松林中,芒萁覆盖增加了表层土壤的全氮含量,δ~(15)N值则比林下裸地显著降低了33. 8%—83.1%(P0.05)。随着恢复年限增加,林下芒萁覆盖地表层土壤δ~(15)N值显著下降,而林下裸露地δ~(15)N值没有显著变化(P0.05)。不同恢复年限马尾松林的芒萁覆盖地表层土壤微生物生物量氮、可溶性有机氮和铵态氮含量显著高于林下裸地(P 0.05),而硝态氮含量则显著低于林下裸地(P0.05)。随恢复年限增加,表层土壤微生物生物量氮、可溶性有机氮、铵态氮含量均呈增加趋势,而硝态氮含量则呈下降趋势,不同形态氮占全氮比例表现为:微生物生物量氮铵态氮可溶性有机氮硝态氮。相关分析表明土壤δ~(15)N值与硝态氮极显著正相关,与其他氮组分极显著负相关(P0.01)。由此可见,与林下裸地相比,芒萁覆盖在植被恢复过程中有助于提高表层土壤中全氮、微生物生物量氮、可溶性有机氮和铵态氮含量,降低硝态氮的淋溶损失风险,促进土壤氮保持和积累,从而有利于退化红壤生态系统的恢复。 相似文献
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为探究三峡库区消落带水位变化下落羽杉根系有机酸和非结构性碳水化合物(NSC)的响应特征,以适生木本植物落羽杉为对象,在消落带原位环境中设置对照-SS(海拔175 m,试验期间无水淹)、MS(海拔170 m,中度水淹胁迫)和DS(海拔165 m,深度水淹胁迫)3个处理,分别于海拔170 m和165 m退水时采集样品,测定并分析根系有机酸和NSC的变化。结果表明:(1)库区水淹对落羽杉基径无显著影响,仅有DS组明显抑制了高生长,落羽杉生长能较积极地响应库区水淹。(2)库区水淹对落羽杉侧根和总根有机酸的影响一致,侧根有机酸代谢作用优于主根。与SS组相比,MS组根系有机酸含量增高,DS组根系有机酸含量降低,除部分根系酒石酸、苹果酸、柠檬酸变化达到显著水平外,其余有机酸均无显著变化。(3)库区不同强度水淹对落羽杉根系NSC有不同程度的影响。与SS组相比,MS组可溶性糖无显著变化,淀粉、NSC含量显著增加,但总根NSC在水淹前与水淹后无明显差异;形成鲜明对比的是,DS组显著降低了可溶性糖、NSC含量,对淀粉无显著影响,且水淹后总根NSC显著低于水淹前。(4)相关分析表明,主根、总根草酸、苹果酸、柠檬酸及侧根、总根莽草酸分别与淀粉、NSC间表现出显著相关性(P0.05)。研究结果表明,在三峡库区消落带水淹胁迫下,落羽杉根系有机酸与NSC代谢联系紧密。通过维持一定的根系淀粉含量,保持植株正常的有机酸代谢水平,较好地适应三峡库区消落带生境。 相似文献
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ObjectivesThere are presently a few viable ways to reduce cardiotoxicity of doxorubicin (Dox). The combination of chemotherapy agents with natural compounds delivers greater efficacy and reduces adverse effects in recent researches for cancer treatment. Here, we examined the potential effect of ginsenoside Rh2 on a Dox‐based regimen in chemotherapy treatment.Materials and MethodsHuman breast tumour (MDA‐MB‐231) xenograft nude mice, human cardiac ventricle fibroblasts, and human umbilical vein endothelial cells (HUVEC) were employed in the present study. Histology, immunohistochemistry, immunofluorescence, western blot, antibody array, and RNA‐sequencing analyses were utilized to assess the protective effect of Rh2 on cardiotoxicity induced by Dox and the underlying mechanisms.ResultsRh2‐reduced cardiotoxicity by inhibiting the cardiac histopathological changes, apoptosis and necrosis, and consequent inflammation. Pathological remodelling was attenuated by reducing fibroblast to myofibroblast transition (FMT) and endothelial–mesenchymal transition (EndMT) in hearts. RNA‐sequencing analysis showed that Dox treatment predominantly targets cell cycle and attachment of microtubules and boosted tumour necrosis, chemokine and interferon‐gamma production, response to cytokine and chemokine, and T cell activation, whereas Rh2 regulated these effects. Intriguingly, Rh2 also attenuated fibrosis via promoting senescence in myofibroblasts and reversing established myofibroblast differentiation in EndMT.ConclusionsRh2 regulates multiple pathways in the Dox‐provoked heart, proposing a potential candidate for cancer supplement and therapy‐associated cardiotoxicity.Doxorubicin is extensively reported to induce severe cardiotoxicity in clinical applications. Our work proposed a natural herbal compound, ginsenoside Rh2, as a potential candidate for attenuating this side effect. Rh2 significantly inhibited cardiac apoptosis and necrosis, inflammation, and pathological remodelling in Dox‐challenged hearts. 相似文献