SMAD-4在肿瘤抑制方面有重要作用,但它在肿瘤发生中的作用及其与细胞周期进程中的一种关键调控因子——PTEN(phosphatase and tensin homolog deleted on chromosome 10)的关系仍存在争议.分别在人胚肾细胞(293T)及人胃癌细胞(MGC-803)...SMAD-4在肿瘤抑制方面有重要作用,但它在肿瘤发生中的作用及其与细胞周期进程中的一种关键调控因子——PTEN(phosphatase and tensin homolog deleted on chromosome 10)的关系仍存在争议.分别在人胚肾细胞(293T)及人胃癌细胞(MGC-803)中研究SMAD-4及TGF-β信号通路对PTEN基因表达的影响.结果发现,在293T细胞中,SMAD-4与TGF-β促进PTEN表达,而MGC-803细胞中,SMAD-4与TGF-β抑制PTEN转录.进一步研究发现,胃癌细胞中,SMAD-4与转化生长因子β(TGF-β)对PTEN的抑制可被PD98059(MEK抑制剂)解除.此外,SMAD-4的核转移也明显促进PTEN表达,并且PD98059存在下,SMAD-4与TGF-β协同刺激可促进胃癌细胞凋亡.综上,实验发现,SMAD-4作为一种co-Smad蛋白,通过TGF-β信号途径影响PTEN表达.展开更多
Yu Gan Long(YGL)is a Chinese traditional herbal formula which has been reported to attenuate liver fibrosis for many years and we have explored its anti-fibrotic mechanism through blocking transforming growth factor(T...Yu Gan Long(YGL)is a Chinese traditional herbal formula which has been reported to attenuate liver fibrosis for many years and we have explored its anti-fibrotic mechanism through blocking transforming growth factor(TGF-β)in the previous study.But the mechanisms associated with platelet-derived growth factor(PDGF)-BB remain obscure.In this study,we further investigated the mechanism of YGL reducing carbon tetrachloride(CCl4)-induced liver fibrosis in rats.Our results showed that YGL suppressed CCl4-induced upregulation of collagen IV(Col IV),type HI precollagen(PCHI),hyaluronuc acid(HA)and laminin(LN),which are implicated in liver fibrosis.Also,YGL reduced theα-smooth muscle actin(α-SMA)expression,which acts as the indicator of liver fibrosis.Furthermore,YGL decreased the serum levels of hepatic stellate cell(HSC)mitogen PDGF-BB and inflammation cytokines,including TNF-α,IL-1β,IL-6.Markers involved in liver fibrosis,such as Ras,p-Raf-1,p-ERK1/2,p-JNK,p-P38,p-PI3K,p-AKT,p-JAKl,p-STAT3 were downregulated significantly after treatment with YGL.Our results indicated that YGL ameliorated CCl4-induced liver fibrosis by reducing inflammation cytokines production,and suppressing Ras/ERK,PI3K/AKT,and JAK1/STAT3 signaling pathways,which provided further evidence towards elucidation of the anti-fibrotic mechanism of YGL.展开更多
Spaceflight-associated immune system weakening ultimately limits the ability of humans to expand their presence beyond the earth's orbit. A mechanistic study of microgravity-regulated immune cell function is neces...Spaceflight-associated immune system weakening ultimately limits the ability of humans to expand their presence beyond the earth's orbit. A mechanistic study of microgravity-regulated immune cell function is necessary to overcome this challenge. Here, we demonstrate that both spaceflight (real) and simulated microgravity significantly reduce macrophage differentiation, decrease macrophage quantity and functional polarization, and lead to metabolic reprogramming, as demonstrated by changes in gene expression profiles. Moreover, we identified RAS/ERK/NFκB as a major microgravity-regulated pathway. Exogenous ERK and NFκB activators significantly counteracted the effect of microgravity on macrophage differentiation. In addition, microgravity also affects the p53 pathway, which we verified by RT-qPCR and Western blot. Collectively, our data reveal a new mechanism for the effects of microgravity on macrophage development and provide potential molecular targets for the prevention or treatment of macrophage differentiation deficiency in spaceflight.展开更多
基金supported by grants from The National Natural Science Foundation of China(30971613,30671184)~~
文摘SMAD-4在肿瘤抑制方面有重要作用,但它在肿瘤发生中的作用及其与细胞周期进程中的一种关键调控因子——PTEN(phosphatase and tensin homolog deleted on chromosome 10)的关系仍存在争议.分别在人胚肾细胞(293T)及人胃癌细胞(MGC-803)中研究SMAD-4及TGF-β信号通路对PTEN基因表达的影响.结果发现,在293T细胞中,SMAD-4与TGF-β促进PTEN表达,而MGC-803细胞中,SMAD-4与TGF-β抑制PTEN转录.进一步研究发现,胃癌细胞中,SMAD-4与转化生长因子β(TGF-β)对PTEN的抑制可被PD98059(MEK抑制剂)解除.此外,SMAD-4的核转移也明显促进PTEN表达,并且PD98059存在下,SMAD-4与TGF-β协同刺激可促进胃癌细胞凋亡.综上,实验发现,SMAD-4作为一种co-Smad蛋白,通过TGF-β信号途径影响PTEN表达.
基金This study was supported by grants from China Postdoctoral Science Foundation(No.2016M592320,No.2016M600670)Hubei Provincial Natural Science Foundation of China(No.2018CFB657)the National Natural Science Foundation of China(No.81601605).
文摘Yu Gan Long(YGL)is a Chinese traditional herbal formula which has been reported to attenuate liver fibrosis for many years and we have explored its anti-fibrotic mechanism through blocking transforming growth factor(TGF-β)in the previous study.But the mechanisms associated with platelet-derived growth factor(PDGF)-BB remain obscure.In this study,we further investigated the mechanism of YGL reducing carbon tetrachloride(CCl4)-induced liver fibrosis in rats.Our results showed that YGL suppressed CCl4-induced upregulation of collagen IV(Col IV),type HI precollagen(PCHI),hyaluronuc acid(HA)and laminin(LN),which are implicated in liver fibrosis.Also,YGL reduced theα-smooth muscle actin(α-SMA)expression,which acts as the indicator of liver fibrosis.Furthermore,YGL decreased the serum levels of hepatic stellate cell(HSC)mitogen PDGF-BB and inflammation cytokines,including TNF-α,IL-1β,IL-6.Markers involved in liver fibrosis,such as Ras,p-Raf-1,p-ERK1/2,p-JNK,p-P38,p-PI3K,p-AKT,p-JAKl,p-STAT3 were downregulated significantly after treatment with YGL.Our results indicated that YGL ameliorated CCl4-induced liver fibrosis by reducing inflammation cytokines production,and suppressing Ras/ERK,PI3K/AKT,and JAK1/STAT3 signaling pathways,which provided further evidence towards elucidation of the anti-fibrotic mechanism of YGL.
基金supported by grants from the National Key Research and Development Program of China(2017YFA0105002,Y.Z.2017YFA0104402,L.L.)Joint Funds of the National Natural Science Foundation of China(U1738111,Y.Z.)+1 种基金the China Manned Space Flight Technology Project(TZ-1)the National Natural Science Foundation Youth Fund(31800741,L.S.).
文摘Spaceflight-associated immune system weakening ultimately limits the ability of humans to expand their presence beyond the earth's orbit. A mechanistic study of microgravity-regulated immune cell function is necessary to overcome this challenge. Here, we demonstrate that both spaceflight (real) and simulated microgravity significantly reduce macrophage differentiation, decrease macrophage quantity and functional polarization, and lead to metabolic reprogramming, as demonstrated by changes in gene expression profiles. Moreover, we identified RAS/ERK/NFκB as a major microgravity-regulated pathway. Exogenous ERK and NFκB activators significantly counteracted the effect of microgravity on macrophage differentiation. In addition, microgravity also affects the p53 pathway, which we verified by RT-qPCR and Western blot. Collectively, our data reveal a new mechanism for the effects of microgravity on macrophage development and provide potential molecular targets for the prevention or treatment of macrophage differentiation deficiency in spaceflight.
