• 【蛋白激酶D2通过NF-κB介导未转化的人结肠上皮细胞中溶血磷脂酸诱导的白介素8的产生。】 复制标题 收藏 收藏
    DOI:10.1152/ajpcell.00308.2006 复制DOI
    作者列表:Chiu TT,Leung WY,Moyer MP,Strieter RM,Rozengurt E
    BACKGROUND & AIMS: :The signaling pathways mediating lysophosphatidic acid (LPA)-stimulated PKD(2) activation and the potential contribution of PKD(2) in regulating LPA-induced interleukin 8 (IL-8) secretion in nontransformed, human colonic epithelial NCM460 cells were examined. Treatment of serum-deprived NCM460 cells with LPA led to a rapid and striking activation of PKD(2), as measured by in vitro kinase assay and phosphorylation at the activation loop (Ser706/710) and autophosphorylation site (Ser876). PKD(2) activation induced by LPA was abrogated by preincubation with selective PKC inhibitors GF-I and Ro-31-8220 in a dose-dependent manner. These inhibitors did not have any direct inhibitory effect on PKD(2) activity. LPA induced a striking increase in IL-8 production and stimulated NF-kappaB activation, as measured by NF-kappaB-DNA binding, NF-kappaB-driven luciferase reporter activity, and IkappaBalpha phosphorylation. PKD(2) gene silencing utilizing small interfering RNAs targeting distinct PKD(2) sequences dramatically reduced LPA-stimulated NF-kappaB promoter activity and IL-8 production. PKD(2) activation is a novel early event in the biological action of LPA and mediates LPA-stimulated IL-8 secretion in NCM460 cells through a NF-kappaB-dependent pathway. Our results demonstrate, for the first time, the involvement of a member of the PKD family in the production of IL-8, a potent proinflammatory chemokine, by epithelial cells.
    背景与目标: :审查了介导溶血磷脂酸(LPA)刺激的PKD(2)活化和PKD(2)在调节LPA诱导的非转化型人结肠上皮NCM460细胞中LPA诱导的白介素8(IL-8)分泌中的潜在作用。用体外LPA处理血清缺乏的NCM460细胞会导致PKD(2)迅速而惊人的活化,这是通过体外激酶测定和活化环(Ser706 / 710)和自磷酸化位点(Ser876)的磷酸化来测量的。通过与选择性PKC抑制剂GF-1和Ro-31-8220呈剂量依赖性方式进行预孵育,可以消除LPA诱导的PKD(2)激活。这些抑制剂对PKD(2)活性没有任何直接的抑制作用。如通过NF-κB-DNA结合,NF-κB驱动的萤光素酶报道分子活性和IkappaBalpha磷酸化所测量,LPA诱导IL-8产量显着增加并刺激NF-κB活化。 PKD(2)基因沉默利用针对不同的PKD(2)序列的小干扰RNA,大大降低了LPA刺激的NF-κB启动子活性和IL-8的产生。 PKD(2)激活是LPA的生物学作用中的一个新的早期事件,并通过NF-kappaB依赖性途径介导LCM刺激NCM460细胞中IL-8的分泌。我们的结果首次证明,上皮细胞参与了PKD家族成员参与IL-8(一种有效的促炎趋化因子)的生产。
  • 【与DRA X2-box结合的NF-X2是激活蛋白1。c-Jun的表达克隆。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Andersson G,Peterlin BM
    BACKGROUND & AIMS: :Human class II MHC Ag are a family of cell surface glycoproteins. Their constitutive expression is limited to B lymphocytes and thymic epithelial cells. In many other cells their expression can be induced by IFN-gamma. Conserved upstream promoter sequences regulate this tissue-specific expression of class II genes. In the DRA promoter, one of these cis-acting regulatory motifs is the X2-box to which nuclear factor X2 (NF-X2) binds. Here, we present the isolation and characterization of the full-length cDNA clone encoding NF-X2. This cDNA clone was isolated by expression cDNA cloning, and encodes the human c-Jun protein, which together with c-Fos forms the heterodimeric activator protein-1 transcription complex. Whereas c-Fos/c-Jun heterodimers do not exist in B cells, they form and bind to the X2-box in class II nonexpressing cells. Thus, c-Fos/c-Jun heterodimers might contribute to the repression of DRA gene expression.
    背景与目标: :人类II类MHC Ag是细胞表面糖蛋白家族。它们的组成型表达仅限于B淋巴细胞和胸腺上皮细胞。在许多其他细胞中,它们的表达可以被IFN-γ诱导。保守的上游启动子序列调节II类基因的这种组织特异性表达。在DRA启动子中,这些顺式作用调控基元之一是X2-box,其与核因子X2(NF-X2)结合。在这里,我们介绍了编码NF-X2的全长cDNA克隆的分离和表征。该cDNA克隆通过表达cDNA克隆进行分离,并编码人c-Jun蛋白,该蛋白与c-Fos一起形成异二聚激活蛋白-1转录复合体。尽管B细胞中不存在c-Fos / c-Jun异二聚体,但它们在II类非表达细胞中形成并与X2-box结合。因此,c-Fos / c-Jun异二聚体可能有助于抑制DRA基因表达。
  • 【那瓦印度药用植物(墨西哥):作为一种消炎模型和抗菌作用,对NF-κB的抑制作用。】 复制标题 收藏 收藏
    DOI:10.1016/S0944-7113(96)80064-X 复制DOI
    作者列表:Bork PM,Schmitz ML,Weimann C,Kist M,Heinrich M
    BACKGROUND & AIMS: :Selected plants documented as medicinal in an ethnobotanical study with the Nahua of the Sierra de Zongolica (Veracruz, Mexico) were evaluated for anti-inflammatory and antibacterial activity. One of the potential sides of action of anti-inflammatory drugs is the transcription factor NF-κB. This factor is essential for the immune, inflammatory, and acute phase responses. We therefore tested extracts from a total of 28 plants used by the Nahua Indians for their potential effect on the activation of the transcription factor NF-κB. The leaves of Tithonia diversifolia (Hemsl.) A. Gray (Asteraceae) was the only extract which showed inhibitory activity. Nonspecific DNA binding activities were not noticably influenced. Phytochemical studies to isolate the active principle and further biochemical studies in order to better understand the mode of action of this NF-κB inhibitor have been initiated. Five plants showed noteworthy antibacterial activity against some pathogenic (Staphylococcus aureus ATCC 25933 and Yersinia enterocolitica 03) and nonpathogenic (E. coli DSM 1077, Micrococcus luteus DSM 348) microorganism: Acacia cornigera, Cuscuta tinctoria, Ludwigia octovalvis, Lysiloma divaricata, and Tithonia diversifolia.
    背景与目标: :对与塞拉利昂德宗加利卡(Naerra of Zongolica)(墨西哥韦拉克鲁斯市)的纳瓦族人种植物学研究中证明为药用的植物进行了抗炎和抗菌活性评估。抗炎药的潜在作用之一是转录因子NF-κB。该因子对于免疫,炎症和急性期反应至关重要。因此,我们测试了纳瓦族印第安人使用的总共28种植物的提取物对转录因子NF-κB活化的潜在影响。 Tithonia diversifolia(Hemsl。)A. Gray(菊科)的叶子是唯一显示出抑制活性的提取物。非特异性DNA结合活性未受到明显影响。已经启动了植物化学研究以分离活性成分,并进行了进一步的生物化学研究以更好地了解这种NF-κB抑制剂的作用方式。五株植物对某些病原微生物(金黄色葡萄球菌ATCC 25933和小肠结肠炎耶尔森氏菌03)和非病原微生物(大肠杆菌DSM 1077,微球菌luteus DSM 348)表现出显着的抗菌活性:洋槐金合欢,弯角弯孢菌,路德维希氏八角形藻,香根草。
  • 【泛素:细胞内NF-κB抑制剂的工具和靶标。】 复制标题 收藏 收藏
    DOI:10.1016/j.it.2006.09.003 复制DOI
    作者列表:Wullaert A,Heyninck K,Janssens S,Beyaert R
    BACKGROUND & AIMS: :The transcription factor nuclear factor-kappaB (NF-kappaB) has a pivotal role in initiating inflammation and raising an effective immune response. Because NF-kappaB activation depends on ubiquitination, cells have developed ubiquitin (Ub)-mediated strategies for inhibiting NF-kappaB activation and preventing excessive inflammation. Recent findings concerning tumor necrosis factor (TNF) receptor and toll-like receptor (TLR)-interleukin-1 (IL-1) receptor signalling pathways show that Ub can be a tool as well as a target for NF-kappaB inhibitory proteins, either by labelling specific signalling proteins for proteasome-dependent degradation or by serving as a target for specific de-ubiquitinating enzymes that prevent the formation of pertinent signalling complexes. Interfering with ubiquitination therefore seems to be a versatile means for regulating NF-kappaB activity, indicating that studies of Ub-mediated signalling might hold the key for developing new therapeutic strategies for inflammatory disease.
    背景与目标: 转录因子核因子-κB(NF-kappaB)在引发炎症和提高有效免疫反应方面具有关键作用。由于NF-κB的活化依赖于泛素化,因此细胞已开发出由泛素(Ub)介导的抑制NF-κB活化和防止过度炎症的策略。有关肿瘤坏死因子(TNF)受体和toll样受体(TLR)-白介素1(IL-1)受体信号通路的最新发现表明,Ub既可以作为NF-κB抑制蛋白的工具,也可以作为靶标。通过为蛋白酶体依赖性降解标记特定的信号蛋白,或作为防止相关信号复合物形成的特定去泛素化酶的靶标。因此,干扰泛素化似乎是调节NF-κB活性的通用手段,这表明对Ub介导的信号传导的研究可能是开发炎症性疾病新治疗策略的关键。
  • 【SIRT3通过激活NF-κB保护心肌细胞免受氧化应激介导的细胞死亡。】 复制标题 收藏 收藏
    DOI:10.1016/j.bbrc.2012.11.066 复制DOI
    作者列表:Chen CJ,Fu YC,Yu W,Wang W
    BACKGROUND & AIMS: :Oxidative stress-mediated cell death in cardiomyocytes reportedly plays an important role in many cardiac pathologies. Our previous report demonstrated that mitochondrial SIRT3 plays an essential role in mediating cell survival in cardiac myocytes, and that resveratrol protects cardiomyocytes from oxidative stress-induced apoptosis by activating SIRT3. However, the exact mechanism by which SIRT3 prevents oxidative stress remains unknown. Here, we show that exposure of H9c2 cells to 50 μM H(2)O(2) for 6h caused a significant increase in cell death and the down-regulation of SIRT3. Reactive oxygen species (ROS)-mediated NF-κB activation was involved in this SIRT3 down-regulation. The SIRT3 activator, resveratrol, which is considered an important antioxidant, protected against H(2)O(2)-induced cell death, whereas the SIRT inhibitor, nicotinamide, enhanced cell death. Moreover, resveratrol negatively regulated H(2)O(2)-induced NF-κB activation, whereas nicotinamide enhanced H(2)O(2)-induced NF-κB activation. We also found that SOD2, Bcl-2 and Bax, the downstream genes of NF-κB, were involved in this pathological process. These results suggest that SIRT3 protects cardiomyocytes exposed to oxidative stress from apoptosis via a mechanism that may involve the NF-κB pathway.
    背景与目标: 氧化应激介导的心肌细胞死亡据报道在许多心脏疾病中起重要作用。我们以前的报告表明线粒体SIRT3在介导心肌细胞的存活中起着至关重要的作用,白藜芦醇通过激活SIRT3保护心肌细胞免受氧化应激诱导的细胞凋亡。但是,SIRT3防止氧化应激的确切机制仍然未知。在这里,我们显示H9c2细胞暴露于50μMH(2)O(2)6h导致细胞死亡和SIRT3下调的显着增加。活性氧(ROS)介导的NF-κB激活参与了SIRT3的下调。 SIRT3激活剂白藜芦醇,被认为是一种重要的抗氧化剂,可防止H(2)O(2)诱导的细胞死亡,而SIRT抑制剂烟酰胺可增强细胞死亡。此外,白藜芦醇负调节H(2)O(2)诱导NF-κB激活,而烟酰胺增强H(2)O(2)诱导NF-κB激活。我们还发现NF-κB的下游基因SOD2,Bcl-2和Bax参与了这一病理过程。这些结果表明SIRT3通过可能涉及NF-κB途径的机制保护了暴露于氧化应激的心肌细胞免于凋亡。
  • 【咖啡因通过抑制AKT / mTOR / S6K,NF-κB和MAPK途径诱导骨肉瘤细胞凋亡。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Miwa S,Sugimoto N,Yamamoto N,Shirai T,Nishida H,Hayashi K,Kimura H,Takeuchi A,Igarashi K,Yachie A,Tsuchiya H
    BACKGROUND & AIMS: :We previously reported that caffeine-assisted chemotherapy improved the treatment of malignant bone and soft tissue tumours such as osteosarcoma. Caffeine affects tumour cells through various pathways, including phosphatase and tensin homolog deleted on chromosome 10 (PTEN), AKT, Bcl-2-associated X protein (BAX), caspase-3 and p53, and has therefore been indicated as being useful for the treatment of malignant tumours. Here, the effects of caffeine on the proliferation of HOS osteosarcoma cells were assessed by WST-8 assay, and the effects on the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) pathways were assessed by western blot analyses. Caffeine inhibited proliferation of HOS cells and suppressed NF-κB, AKT, mTOR/S6K and ERK activities. Our results support those from previous studies relating to the use of caffeine in the treatment of osteosarcoma.
    背景与目标: :我们之前曾报道过咖啡因辅助的化疗改善了恶性骨和软组织肿瘤(如骨肉瘤)的治疗。咖啡因通过多种途径影响肿瘤细胞,包括在10号染色体(PTEN),AKT,Bcl-2相关X蛋白(BAX),caspase-3和p53缺失的磷酸酶和张力蛋白同源物,因此已被证明可用于恶性肿瘤的治疗。在这里,通过WST-8分析评估了咖啡因对HOS骨肉瘤细胞增殖的影响,以及对活化的B细胞(雷帕霉素的哺乳动物靶标)的核因子κ-轻链增强子(NF-κB)的影响(通过蛋白质印迹分析评估了mTOR)和有丝分裂原激活的蛋白激酶(MAPK)途径。咖啡因可抑制HOS细胞增殖,并抑制NF-κB,AKT,mTOR / S6K和ERK活性。我们的研究结果支持先前有关使用咖啡因治疗骨肉瘤的研究。
  • 【删除新描述的生存分子Pellino-1会增加氧化应激,下调cIAP2 /NF-κB细胞生存途径,降低血管生成反应,从而加重小鼠缺血模型的组织功能。】 复制标题 收藏 收藏
    DOI:10.1007/s00395-020-0804-4 复制DOI
    作者列表:Selvaraju V,Thirunavukkarasu M,Joshi M,Oriowo B,Shaikh IA,Rishi MT,Tapias L,Coca-Soliz V,Saad I,Campbell J,Pradeep SR,Swaminathan S,Yee SP,McFadden DW,Alexander Palesty J,Maulik N
    BACKGROUND & AIMS: INTRODUCTION:In the present study, we aimed to explore the functional role of Pellino-1 (Peli1) in inducing neovascularization after myocardial infarction (MI) and hindlimb ischemia (HLI) using Peli1 global knockout mice (Peli1-/-). Recently we have shown that Peli1, an E3 ubiquitin ligase, induce angiogenesis and improve survivability, with decreased necrosis of ischemic skin flaps. METHODS:Peli1fl/fl and Peli1-/- mice were subjected to either permanent ligation of the left anterior descending coronary artery (LAD) or sham surgery (S). Tissues from the left ventricular risk area were collected at different time points post-MI. In addition, Peli1fl/fl and Peli1-/- mice were also subjected to permanent ligation of the right femoral artery followed by motor function scores, Doppler analysis for blood perfusion and immunohistochemical analysis. RESULTS:Global Peli1 knockout exacerbated myocardial dysfunction, 30 and 60 days after MI compared to wild type (WT) mice as measured by echocardiogram. In addition, Peli1-/- mice also showed decreased motor function scores and perfusion ratios compared with Peli1fl/fl mice 28 days after the induction of HLI. The use of Peli1 in adenoviral gene therapy following HLI in CD1 mice improved the perfusion ratio at 28 days compared to Ad.LacZ-injected mice. CONCLUSION:These results suggest new insights into the protective role of Peli1 on ischemic tissues and its influence on survival signaling.
    背景与目标: 简介:在本研究中,我们旨在探讨Pellino-1(Peli1)在使用Peli1整体敲除小鼠(Peli1-/-)诱导心肌梗死(MI)和后肢缺血(HLI)后新生血管形成中的功能。最近,我们发现Peli1,一种E3泛素连接酶,可诱导血管生成并提高生存能力,并减少缺血性皮瓣的坏死。
    方法:对Peli1fl / fl和Peli1-/-小鼠进行永久性结扎左冠状动脉前降支(LAD)或假手术(S)。在MI后的不同时间点收集来自左心室风险区的组织。此外,还对Peli1fl / fl和Peli1-/-小鼠进行永久性右股动脉结扎,然后进行运动功能评分,多普勒血流灌注分析和免疫组化分析。
    结果:通过超声心动图测量,与野生型(WT)小鼠相比,MI后30天和60天,整体Peli1基因敲除加重了心肌功能障碍。此外,诱导HLI后28天,与Peli1fl / fl小鼠相比,Peli1-/-小鼠还显示出降低的运动功能评分和灌注比。与注射Ad.LacZ的小鼠相比,在CD1小鼠中进行HLI后在腺病毒基因治疗中使用Peli1可以改善28天的灌注率。
    结论:这些结果提示了Peli1对缺血组织的保护作用及其对生存信号的影响的新见解。
  • 【Vaccinium oldhamii的抗炎作用是通过抑制LPS刺激的RAW264.7细胞中的NF-κB和MAPK / ATF2信号激活来实现的。】 复制标题 收藏 收藏
    DOI:10.1186/s12906-019-2720-4 复制DOI
    作者列表:Kim HN,Baek JK,Park SB,Kim JD,Son HJ,Park GH,Eo HJ,Park JH,Jung HS,Jeong JB
    BACKGROUND & AIMS: BACKGROUND:Vaccinium oldhamii (V. oldhamii) has been reported to exert a variety of the pharmacological properties such as anti-oxidant activity, anti-cancer activity, and inhibitory activity of α-amylase and acetylcholinesterase. However, the anti-inflammatory activity of V. oldhamii has not been studied. In this study, we aimed to investigate anti-inflammatory activity of the stem extracts from V. oldhamii, and to elucidate the potential mechanisms in LPS-stimulated RAW264.7 cells. METHODS:Cell viability was evaluated by MTT assay. The determination of NO and PGE2 production was performed using Griess reagent and Prostaglandin E2 ELISA Kit, respectively. The change of mRNA or protein level was evaluated by RT-PCR and Western blot. RESULTS:Among VOS, VOL and VOF, the inhibitory effect of NO and PGE2 production induced by LPS was highest in VOS treatment. Thus, VOS was selected for the further study. VOS dose-dependently blocked LPS-induced NO and PGE2 production by inhibiting iNOS and COX-2 expression, respectively. VOS inhibited the expression of pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α. In addition, VOS suppressed TRAP activity and attenuated the expression of the osteoclast-specific genes such as NFATc1, c-FOS, TRAP, MMP-9, cathepsin K, CA2, OSCAR and ATPv06d2. VOS inhibited LPS-induced NF-κB signaling activation through blocking IκB-α degradation and p65 nuclear accumulation. VOS inhibited MAPK signaling activation by attenuating the phosphorylation of ERK1/2, p38 and JNK. Furthermore, VOS inhibited ATF2 phosphorylation and blocked ATF2 nuclear accumulation. CONCLUSIONS:These results indicate that VOS may exert anti-inflammatory activity by inhibiting NF-κB and MAPK/ATF2 signaling. From these findings, VOS has potential to be a candidate for the development of chemopreventive or therapeutic agents for the inflammatory diseases.
    背景与目标: 背景:越橘越桔(V. oldhamii)具有多种药理特性,例如抗氧化活性,抗癌活性以及α-淀粉酶和乙酰胆碱酯酶的抑制活性。然而,尚未研究oldhamii的抗炎活性。在这项研究中,我们旨在调查V. oldhamii茎提取物的抗炎活性,并阐明LPS刺激的RAW264.7细胞的潜在机制。
    方法:采用MTT法评价细胞活力。使用Griess试剂和前列腺素E2 ELISA试剂盒分别测定NO和PGE2的产生。通过RT-PCR和Western印迹评估mRNA或蛋白质水平的变化。
    结果:在VOS,VOL和VOF中,LPS诱导的NO和PGE2生成的抑制作用在VOS处理中最高。因此,选择了VOS进行进一步研究。 VOS分别通过抑制iNOS和COX-2表达来剂量依赖性地阻断LPS诱导的NO和PGE2的产生。 VOS抑制促炎细胞因子如IL-1β,IL-6和TNF-α的表达。此外,VOS抑制了TRAP活性并减弱了破骨细胞特异性基因(如NFATc1,c-FOS,TRAP,MMP-9,组织蛋白酶K,CA2,OSCAR和ATPv06d2)的表达。 VOS通过阻止IκB-α降解和p65核蓄积来抑制LPS诱导的NF-κB信号激活。 VOS通过减弱ERK1 / 2,p38和JNK的磷酸化来抑制MAPK信号激活。此外,VOS抑制了ATF2的磷酸化并阻止了ATF2的核积累。
    结论:这些结果表明VOS可能通过抑制NF-κB和MAPK / ATF2信号传导发挥抗炎活性。根据这些发现,VOS有潜力成为炎症性疾病的化学预防剂或治疗剂开发的候选者。
  • 【外泌体miR-1910-3p通过靶向MTMR3并激活NF-κB信号通路来促进乳腺癌细胞的增殖,转移和自噬。】 复制标题 收藏 收藏
    DOI:10.1016/j.canlet.2020.05.038 复制DOI
    作者列表:Wang B,Mao JH,Wang BY,Wang LX,Wen HY,Xu LJ,Fu JX,Yang H
    BACKGROUND & AIMS: :Exosomes are key mediators of intercellular communication and play a role in the pathogenesis and progression of cancer. Exosomes in circulating body fluids serve as molecular markers for cancer diagnosis. This study aimed to investigate the role of exosomal microRNA (miR)-1910-3p in breast cancer and determine its clinical diagnostic value. MiR-1910-3p promoted proliferation and migration of breast cancer cells in vitro and in vivo. In vitro, exosomes enriched in miR-1910-3p transferred miR-1910-3p to mammary epithelial cells and breast cancer cells, promoting proliferation and migration, inhibiting apoptosis, and inducing autophagy. In vivo, exosomes enriched in miR-1910-3p promoted the proliferation and migration of breast cancer cells. MiR-1910-3p downregulated myotubularin-related protein 3, activated the NF-κB and wnt/β-catenin signaling pathway, and promoted breast cancer progression. Serum miR-1910-3p in exosomes was an effective diagnostic marker that improved the sensitivity of breast cancer diagnosis when used in combination with the traditional tumor marker CA153. In conclusion, breast cancer cell-derived exosomes promoted the growth, metastasis, and autophagy of breast cancer cells by transferring miR-1910-3p. MiR-1910-3p in serum exosomes may serve as a novel molecular marker for breast cancer diagnosis.
    背景与目标: :外来体是细胞间通讯的关键介质,在癌症的发病机理和进程中发挥作用。循环体液中的外来体可作为癌症诊断的分子标记。这项研究旨在调查外泌体微小RNA(miR)-1910-3p在乳腺癌中的作用,并确定其临床诊断价值。 MiR-1910-3p在体外和体内均可促进乳腺癌细胞的增殖和迁移。在体外,富含miR-1910-3p的外泌体将miR-1910-3p转移至乳腺上皮细胞和乳腺癌细胞,从而促进增殖和迁移,抑制细胞凋亡并诱导自噬。在体内,富含miR-1910-3p的外泌体促进了乳腺癌细胞的增殖和迁移。 MiR-1910-3p下调了肌微管蛋白相关蛋白3,激活了NF-κB和wnt /β-catenin信号通路,并促进了乳腺癌的进展。外泌体中的血清miR-1910-3p是有效的诊断标记物,当与传统的肿瘤标记物CA153结合使用时,可提高乳腺癌诊断的敏感性。总之,乳腺癌细胞衍生的外来体通过转移miR-1910-3p促进了乳腺癌细胞的生长,转移和自噬。血清外泌体中的MiR-1910-3p可以作为乳腺癌诊断的新型分子标记。
  • 【Piezo1激活由Ca2 /NF-κB途径介导的髓核细胞中的NLRP3炎性体。】 复制标题 收藏 收藏
    DOI:10.1016/j.intimp.2020.106681 复制DOI
    作者列表:Sun Y,Leng P,Song M,Li D,Guo P,Xu X,Gao H,Li Z,Li C,Zhang H
    BACKGROUND & AIMS: :Studying and understanding the mechanism of inflammation in nucleus pulposus is the key to understand and prevent intervertebral disc degeneration. We propose a model of mechanical sensitive ion channel Piezo1 mediated inflammation of nucleus pulposus cells. Piezo1 can up-regulate the level of interleukin-1β (IL-1β) in nucleus pulposus cells once it is activated. It is suggested that Piezo1 may mediate inflammation by activating Nod-like receptor protein 3 (NLRP3) inflammasome to accelerate the production and maturation of IL-1β. The primary objective of this study was to explore whether Piezo1 activates NLRP3 inflammasome in nucleus pulposus cells. Piezo1 sensitization was induced by mechanical stretch following which we analyzed the priming and assembly of NLRP3 inflammasome and also studied if the downstream Ca2+/NF-κB pathway mediated this activation in nucleus pulposus cells. The expression of Piezo1 and NLRP3 inflammasome increased in a time-dependent manner upon mechanical stretch. Piezo1 activation promoted NLRP3 inflammasome assembly, which was demonstrated by the upregulation of caspase-1 activation and IL-1β production. Transfection of Piezo1-siRNA reversed this process. The inhibition of Ca2+/NF-κB pathway reduced Piezo1-dependent activation of NLRP3 inflammasome. Thus, we propose that activation of NLRP3 inflammasome in nucleus pulposus cells mediated by Piezo1 through the Ca2+/NF-κB pathway is a novel pathogenesis for the progress of intervertebral disc degeneration. As per our knowledge this is the first study which has provided evidence linking Piezo1-mediated inflammation in nucleus pulposus cells with the production of NLRP3 inflammasome.
    背景与目标: 研究和了解髓核炎症的机制是了解和预防椎间盘退变的关键。我们提出了机械敏感离子通道Piezo1介导的髓核细胞炎症模型。一旦激活,Piezo1可以上调髓核细胞中白介素-1β(IL-1β)的水平。推测Piezo1可能通过激活Nod样受体蛋白3(NLRP3)炎症小体来促进IL-1β的产生和成熟,从而介导炎症。这项研究的主要目的是探讨Piezo1是否激活髓核细胞中的NLRP3炎性小体。机械拉伸诱导Piezo1致敏,随后我们分析了NLRP3炎性小体的引发和组装,还研究了下游Ca2 /NF-κB通路是否在髓核细胞中介导了这种活化。机械拉伸后,Piezo1和NLRP3炎性小体的表达以时间依赖性方式增加。 Piezo1激活促进了NLRP3炎性小体组装,这通过caspase-1激活和IL-1β产生的上调来证明。 Piezo1-siRNA的转染逆转了这一过程。 Ca2 /NF-κB途径的抑制减少了NLRP3炎性小体的Piezo1依赖性激活。因此,我们认为,Piezo1通过Ca2 /NF-κB途径介导的髓核细胞中NLRP3炎性小体的激活是椎间盘退变进展的新发病机制。据我们所知,这是第一项研究,提供了将髓核细胞中Piezo1介导的炎症与NLRP3炎性体产生联系起来的证据。
  • 【果蝇中微生物群的饮食适应需要翻译调节因子4E-BP依赖NF-κB的控制。】 复制标题 收藏 收藏
    DOI:10.1016/j.celrep.2020.107736 复制DOI
    作者列表:Vandehoef C,Molaei M,Karpac J
    BACKGROUND & AIMS: :Dietary nutrients shape complex interactions between hosts and their commensal gut bacteria, further promoting flexibility in host-microbiota associations that can drive nutritional symbiosis. However, it remains less clear if diet-dependent host signaling mechanisms also influence these associations. Using Drosophila, we show here that nuclear factor κB (NF-κB)/Relish, an innate immune transcription factor emerging as a signaling node linking nutrient-immune-metabolic interactions, is vital to adapt gut microbiota species composition to host diet macronutrient composition. We find that Relish is required within midgut enterocytes to amplify host-Lactobacillus associations, an important bacterial mediator of nutritional symbiosis, and thus modulate microbiota composition in response to dietary adaptation. Relish limits diet-dependent transcriptional inducibility of the cap-dependent translation inhibitor 4E-BP/Thor to control microbiota composition. Furthermore, maintaining cap-dependent translation in response to dietary adaptation is critical to amplify host-Lactobacillus associations. These results highlight that NF-κB-dependent host signaling mechanisms, in coordination with host translation control, shape diet-microbiota interactions.
    背景与目标: 饮食营养素塑造宿主与其肠道菌之间复杂的相互作用,从而进一步促进宿主微生物群关联的灵活性,从而推动营养共生。然而,尚不清楚饮食依赖性宿主信号传导机制是否也影响这些关联。使用果蝇,我们在这里显示核因子κB(NF-κB)/ Relish,一种先天免疫转录因子,作为连接营养物-免疫-代谢相互作用的信号节点而出现,对于适应肠道微生物群组成来容纳饮食中的大量营养素组成至关重要。我们发现,中肠肠上皮细胞内需要Relish来放大宿主-乳酸杆菌,营养共生的重要细菌介体,从而调节微生物群组成以适应饮食适应。津津有味地限制了帽依赖性翻译抑制剂4E-BP / Thor的饮食依赖性转录诱导性,以控制微生物群的组成。此外,响应于饮食适应性而维持帽依赖性翻译对于扩增宿主-乳酸杆菌协会是至关重要的。这些结果表明,与宿主翻译控制协同作用,依赖于NF-κB的宿主信号传导机制影响了饮食-微生物群落的相互作用。
  • 【大头翁通过调节NF-κB/IκB-α,Akt和STAT信号通路来减轻巨噬细胞中脂多糖诱导的炎症。】 复制标题 收藏 收藏
    DOI:10.1142/S0192415X13500626 复制DOI
    作者列表:Koppula S,Kim WJ,Jiang J,Shim DW,Oh NH,Kim TJ,Kang TB,Lee KH
    BACKGROUND & AIMS: :Carpesium macrocephalum (CM) Fr. et Sav. (Compositae) has been used in Chinese folk medicine as an analgesic, hemostatic, antipyretic, and to suppress inflammatory conditions. In the present study we aimed to provide scientific evidence for the anti-inflammatory properties of CM extract and evaluate the intrinsic mechanisms involved in both in vitro and in vivo experimental models. In in vitro findings, CM significantly inhibited the LPS-stimulated release of proinflammatory mediators such as nitric oxide, tumor necrosis factor-alpha, prostaglandin E2, and interleukin-6 in RAW264.7 macrophages in a concentration-dependent fashion. The attenuation of inflammatory responses in LPS-activated RAW264.7 cells by CM was closely associated with the suppression of nuclear factor-kappa B (NF-κB) phosphorylation, IκB-α degradation, and phosphorylation of Akt. CM treatment also attenuated the phosphorylation of STAT through TRIF dependent pathways in LPS-activated RAW264.7 cells. In vivo studies revealed that CM extract concentration dependently suppressed the acetic acid-induced vascular permeability in mice. Considering the data obtained regulation of multiple signaling mechanisms involving TRIF and Akt/NF-κB pathways might be responsible for the potent anti-inflammatory action of CM, substantiating its traditional use in inflammatory diseases.
    背景与目标: :大头翁(CM)Fr.等(菊科)在中国民间医学中已用作止痛,止血,解热和抑制炎性疾病的药物。在本研究中,我们旨在为CM提取物的抗炎特性提供科学依据,并评估涉及体内和体外实验模型的内在机制。在体外研究中,CM以浓度依赖性方式显着抑制RAW264.7巨噬细胞中LPS刺激的促炎性介质如一氧化氮,肿瘤坏死因子-α,前列腺素E2和白介素6的释放。 CM在LPS激活的RAW264.7细胞中减轻炎症反应与抑制核因子-κB(NF-κB)磷酸化,IκB-α降解和Akt磷酸化密切相关。 CM处理还通过LPS激活的RAW264.7细胞中的TRIF依赖性途径减弱了STAT的磷酸化。体内研究表明,CM提取物的浓度可依赖性地抑制乙酸诱导的小鼠血管通透性。考虑到所获得的数据,涉及TRIF和Akt /NF-κB途径的多种信号传导机制的调控可能是CM强大的抗炎作用,从而证实了其在炎性疾病中的传统用途。
  • 【Polyphyllin II通过下调cofilin活性和AKT /NF-κB途径抑制肝癌细胞的增殖,迁移和侵袭。】 复制标题 收藏 收藏
    DOI:10.1242/bio.046854 复制DOI
    作者列表:Pang D,Yang C,Li C,Zou Y,Feng B,Li L,Liu W,Luo Q,Chen Z,Huang C
    BACKGROUND & AIMS: :The morbidity and mortality of primary liver cancer is one of the highest amongst all cancers. Deficiency of effective treatment and characteristics of cancer metastasis are believed to be responsible for this situation, thus a great demand is required for new agent development. Polyphyllin II (PP2), an important steroidal saponin extracted from Rhizoma Paris, has emerged as a potential anti-cancer agent, but the effects of PP2 in liver cancers and its underlying mechanisms remain unexplored. In our study, we found that PP2 could remarkably suppress the proliferation of two liver cancer cell lines, HepG2 and BEL7402, resulting in significant cell death. Besides, low doses of PP2 have displayed properties that inhibit cellular motility and invasion of liver cancer cells. In addition, we have found that PP2-mediated cofilin activity suppression was implicated in the inhibition of liver cancer cell motility. Decreased expression of two major hydrolytic enzymes (MMP2/MMP9), through the AKT/NF-κB signaling pathway may also be also responsible for this process. Rescue experiments done with either non-phosphorylatable mutant cofilin-1 (S3A) transfection or an activator of the AKT pathway significantly reversed the inhibition effects of PP2 on liver cancer cells. Taken together, we report a potential agent for liver cancer treatment and reveal its underlying mechanisms.
    背景与目标: :原发性肝癌的发病率和死亡率是所有癌症中最高的之一。人们认为有效治疗的缺乏和癌症转移的特征是造成这种情况的原因,因此对新药的开发有很大的需求。 Polyphyllin II(PP2)是从巴黎大根茎中提取的一种重要的甾体皂苷,已成为一种潜在的抗癌剂,但PP2在肝癌中的作用及其潜在机制尚待探索。在我们的研究中,我们发现PP2可以显着抑制两种肝癌细胞系HepG2和BEL7402的增殖,从而导致大量细胞死亡。此外,低剂量的PP2具有抑制细胞运动和侵袭肝癌细胞的特性。另外,我们发现PP2介导的cofilin活性抑制与肝癌细胞运动的抑制有关。通过AKT /NF-κB信号通路减少的两种主要水解酶(MMP2 / MMP9)的表达也可能是这一过程的原因。用不可磷酸化突变体cofilin-1(S3A)转染或AKT途径激活剂进行的抢救实验显着逆转了PP2对肝癌细胞的抑制作用。综上所述,我们报告了一种潜在的肝癌治疗药物,并揭示了其潜在机制。
  • 【吡格列酮减弱小鼠脂多糖诱导的抑郁样行为,调节小鼠的NF-κB/ IL-6 / STAT3,CREB ​​/ BDNF途径和中枢5-羟色胺能神经传递。】 复制标题 收藏 收藏
    DOI:10.1016/j.intimp.2017.05.036 复制DOI
    作者列表:Liao L,Zhang XD,Li J,Zhang ZW,Yang CC,Rao CL,Zhou CJ,Zeng L,Zhao LB,Fang L,Yang DY,Xie P
    BACKGROUND & AIMS: :Immune activation and inflammation are closely associated with the development of depression. Pioglitazone (PIO), a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, has exhibited antidepressant-like effects in a couple of studies. However, the underlying mechanisms are far from being fully elucidated. The study aimed to investigate the effects of PIO on depression-like behaviors induced by lipopolysaccharide (LPS) and to explore the possible underlying mechanisms. The results showed that PIO pretreatment attenuated the depression-like behaviors in mice challenged with intracerebroventricular (i.c.v.) LPS administration. Moreover, Western blot analysis revealed the effects of PIO on inhibiting activation of the nuclear factor kappa B/interleukin 6/signal transducer and activator of transcription 3 (NF-κB/IL-6/STAT3) pathway, improving down-regulation of the cAMP response-element-binding protein/brain derived neurotrophic factor (CREB/BDNF) pathway, as well as regulating disturbed expression of proteins involved in central serotonergic neurotransmission following LPS administration. The beneficial effects of PIO, at both the behavioral and molecular level, were significantly inhibited by the PPAR-γ specific antagonist GW9662. In summary, our data reveals for the first time that the modulation of the NF-κB/IL-6/STAT3 and CREB/BDNF pathways, as well as the potential impact on central serotonergic neurotransmission, may be involved in the PPAR-γ-dependent effects of PIO on depression-like behaviors induced by LPS. Additionally, our findings may provide a novel therapeutic target for the treatment of depression-like behaviors in patients with inflammatory status.
    背景与目标: 免疫激活和炎症与抑郁症的发展密切相关。吡格列酮(PIO)是一种过氧化物酶体增殖物激活的受体γ(PPAR-γ)激动剂,在两项研究中显示出抗抑郁样作用。但是,根本的机制远未得到充分阐明。这项研究旨在调查PIO对脂多糖(LPS)诱导的抑郁样行为的影响,并探讨可能的潜在机制。结果表明,PIO预处理可减轻经脑室内(i.c.v.)LPS给药攻击的小鼠的抑郁样行为。此外,蛋白质印迹分析揭示了PIO对抑制核因子κB/白介素6 /信号转导子和转录激活子3(NF-κB/ IL-6 / STAT3)通路的激活,改善了cAMP的下调响应元素结合蛋白/脑源性神经营养因子(CREB ​​/ BDNF)途径,以及在LPS给药后调节参与中枢5-羟色胺能神经传递的蛋白的表达紊乱。 PIO在行为和分子水平上的有益作用均被PPAR-γ特异性拮抗剂GW9662显着抑制。总而言之,我们的数据首次揭示了NF-κB/ IL-6 / STAT3和CREB ​​/ BDNF信号通路的调节,以及对中枢5-羟色胺能神经传递的潜在影响,可能与PPAR-γ-有关。 PIO对LPS诱导的抑郁样行为的依赖效应。此外,我们的发现可能为炎症状态患者的抑郁症样行为的治疗提供新的治疗目标。
  • 【BAFF通过激活肾小球系膜细胞中的TRAF6 /NF-κB信号通路参与IgA肾病的发病机制。】 复制标题 收藏 收藏
    DOI:10.3892/mmr.2019.10870 复制DOI
    作者列表:Cao Y,Lu G,Chen X,Chen X,Guo N,Li W
    BACKGROUND & AIMS: :The aim of the present study was to investigate the involvement of B cell‑activating factor (BAFF) in the pathogenesis of IgA nephropathy by activating the tumor necrosis factor receptor‑associated factor 6 (TRAF6)/NF‑κB signaling pathway in glomerular mesangial cells. For the clinical analysis, blood, urine and kidney tissue samples were collected from 58 patients diagnosed with primary IgA nephropathy by renal biopsy. For the in vitro study, glomerular mesangial cells were divided into five groups: Control (con)‑short hairpin RNA (shRNA) (control group); con‑shRNA + BAFF (20 ng/ml); con‑shRNA + BAFF + BAFF‑RFc chimera protein (500 µg/ml); TRAF6‑shRNA; and TRAF6‑shRNA + BAFF (20 ng/ml). For the in vivo experiments, 60 Sprague‑Dawley rats were randomly divided into four groups: Con‑small interfering RNA (siRNA) (control group); con‑siRNA + IgA (IgA nephropathy group), BAFF‑RFc chimera protein (2 µg/ml) + IgA, and TRAF6‑siRNA (0.2 µM) + IgA. Reverse transcription‑quantitative PCR was performed to evaluate the mRNA expression levels of TRAF6, connective tissue growth factor (CTGF), fibronectin (FN) and NF‑κBP65. Western blot analysis was used to detect the protein expression levels of TRAF6, FN, CTGF and phosphorylated‑NF‑κBP65 in glomerular mesangial cells and kidney tissues. The results revealed that plasma BAFF levels were positively correlated with the severity of pathological damage in patients with IgA nephropathy. In vitro, BAFF induced the mRNA and protein expression of TRAF6, CTGF, FN and NF‑κBP65 in glomerular mesangial cells. After the BAFF‑RFc chimera protein was added to inhibit the binding of BAFF and BAFF‑receptor (‑R), this effect was reduced. In vivo, inhibition of the effects of BAFF via injection with the BAFF‑R Fc chimera protein reduced kidney damage in rats suffering from IgA nephropathy. The effect on the expression of signaling pathway‑associated proteins was also alleviated. In conclusion, BAFF enhanced the expression of fibroblast factors in the kidneys by activating the TRAF6/NF‑κB signaling pathway.
    背景与目标: :本研究的目的是通过激活肾小球系膜中的肿瘤坏死因子受体相关因子6(TRAF6)/NF-κB信号通路,研究B细胞激活因子(BAFF)在IgA肾病发病机制中的参与细胞。为了进行临床分析,收集了58例经肾活检诊断为原发性IgA肾病的患者的血液,尿液和肾脏组织样本。对于体外研究,将肾小球系膜细胞分为五组:对照组(con)-短发夹RNA(shRNA)(对照组);肾小球系膜细胞(shRNA)。 con‑shRNA BAFF(20 ng / ml); con‑shRNA BAFF BAFF‑RFc嵌合蛋白(500 µg / ml); TRAF6-shRNA;和TRAF6‑shRNA BAFF(20 ng / ml)。对于体内实验,将60只Sprague-Dawley大鼠随机分为四组:超小型干扰RNA(siRNA)(对照组); con‑siRNA IgA(IgA肾病组),BAFF‑RFc嵌合蛋白(2 µg / ml)IgA和TRAF6‑siRNA(0.2 µM)IgA。进行逆转录定量PCR评估TRAF6,结缔组织生长因子(CTGF),纤连蛋白(FN)和NF-κBP65的mRNA表达水平。 Western blot分析用于检测肾小球系膜细胞和肾组织中TRAF6,FN,CTGF和磷酸化的NF-κBP65的蛋白表达水平。结果显示,血浆BAFF水平与IgA肾病患者的病理损害严重程度呈正相关。在体外,BAFF诱导肾小球系膜细胞中TRAF6,CTGF,FN和NF-κBP65的mRNA和蛋白表达。加入BAFF‑RFc嵌合蛋白以抑制BAFF和BAFF受体(‑R)结合后,这种作用减弱了。在体内,通过注射BAFF‑R Fc嵌合蛋白抑制BAFF的作用可减少IgA肾病大鼠的肾脏损害。也减轻了对信号通路相关蛋白表达的影响。总之,BAFF通过激活TRAF6 / NF‑κB信号通路增强了肾脏中成纤维细胞因子的表达。

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