BACKGROUND & AIMS: :1α,25-Dihydroxyvitamin D3 (1α,25(OH)2D3) regulates osteoblasts through genomic and rapid membrane-mediated responses. Here we examined the interaction of protein disulfide isomerase family A, member 3 (Pdia3) and the traditional vitamin D receptor (VDR) in plasma membrane-associated responses to 1α,25(OH)2D3. We found that Pdia3 co-localized with VDR and the caveolae scaffolding protein, caveolin-1 on the surface of MC3T3-E1 osteoblasts. Immunoprecipitation showed that both Pdia3 and VDR interacted with caveolin-1. Pdia3 further interacted with phospholipase A2 activating protein (PLAA), whereas VDR interacted with c-Src. 1α,25(OH)2D3 changed the interactions and transport of the two receptors and rapidly activated phospholipase A2 (PLA2) and c-Src. Silencing either receptor or caveolin-1 inhibited both PLA2 and c-Src, indicating that the two receptors function interdependently. These two receptor dependent rapid responses to 1α,25(OH)2D3 regulated gene expression, proliferation and apoptosis of MC3T3-E1 cells. These data demonstrate the importance of both receptors and caveolin-1 in mediating membrane responses to 1α,25(OH)2D3 and subsequently regulating osteoblast biology.

背景与目标： ：1α，25-二羟基维生素D3（1α，25（OH）2D3）通过基因组和快速的膜介导反应调节成骨细胞。在这里，我们检查了蛋白质二硫键异构酶家族A，成员3（Pdia3）和传统维生素D受体（VDR）在质膜相关反应中对1α，25（OH）2D3的相互作用。我们发现Pdia3与VDR和MC3T3-E1成骨细胞表面的小窝支架蛋白caveolin-1共定位。免疫沉淀显示，Pdia3和VDR均与小窝蛋白1相互作用。 Pdia3进一步与磷脂酶A2激活蛋白（PLAA）相互作用，而VDR与c-Src相互作用。 1α，25（OH）2D3改变了两个受体的相互作用和转运，并迅速激活了磷脂酶A2（PLA2）和c-Src。使受体或caveolin-1沉默均可抑制PLA2和c-Src，这表明这两种受体相互依赖。这两个对1α，25（OH）2D3受体依赖性的快速反应调节了MC3T3-E1细胞的基因表达，增殖和凋亡。这些数据证明了受体和小窝蛋白1在介导对1α，25（OH）2D3的膜反应并随后调节成骨细胞生物学中的重要性。

BACKGROUND & AIMS: :Retinopathy of prematurity is a major cause of childhood blindness worldwide. Hence, exploring the proper treatment methods is a must in tacking this disease. qRT-PCR and western blot were used to detect the expression of genes and proteins, respectively. The proliferation of human retinal vascular endothelial cells (HRECs) was ensured by MTT assay. The luciferase activity was measured through luciferase assay. The inverted phase-contrast light microscope was used to observe the formation of a vascular tube. In the present study, our data demonstrated that circPDE4B was downregulated, while hypoxia-inducible factor-1α (HIF-1α) and VEGFA were upregulated in the retinopathy of prematurity model in vitro and in vivo. CircPDE4B increasing remarkably inhibited the expression of HIF-1α and VEGFA in hypoxia-induced HRECs and subsequent repressed cell proliferation and pathological angiogenesis. We further found that miR-181c suppressed the expression of von Hippel-Lindau (VHL), while circPDE4B could promote VHL expression via binding to miR-181c. Finally, our results revealed that circPDE4B inhibited the expression of VEGFA and pathological angiogenesis via facilitating VHL-mediated ubiquitin degradation of HIF-1α. In conclusion, circPDE4B suppressed the expression of VEGFA and pathological angiogenesis via promoting VHL-mediated ubiquitin degradation of HIF-1α through binding to miR-181c. Our study indicated that circPDE4B might be an effective therapeutic target of retinopathy of prematurity.

背景与目标： ：早产儿视网膜病变是全世界儿童失明的主要原因。因此，探索适当的治疗方法是应对这种疾病的必要条件。使用qRT-PCR和Western blot分别检测基因和蛋白质的表达。通过MTT测定确保人视网膜血管内皮细胞（HREC）的增殖。荧光素酶活性通过荧光素酶测定法测量。倒置相差光学显微镜用于观察血管的形成。在本研究中，我们的数据表明在早熟模型的视网膜病变中，体内和体外circPDE4B被下调，而缺氧诱导因子1α（HIF-1α）和VEGFA被上调。 CircPDE4B的增加显着抑制了缺氧诱导的HRECs中HIF-1α和VEGFA的表达，并随后抑制了细胞增殖和病理性血管生成。我们进一步发现miR-181c抑制了von Hippel-Lindau（VHL）的表达，而circPDE4B可以通过与miR-181c结合来促进VHL表达。最后，我们的结果表明，circPDE4B通过促进VHL介导的HIF-1α泛素降解来抑制VEGFA的表达和病理性血管生成。总之，circPDE4B通过与miR-181c结合促进VHL介导的HIF-1α泛素降解，从而抑制VEGFA的表达和病理性血管生成。我们的研究表明，circPDE4B可能是早产儿视网膜病变的有效治疗靶标。

BACKGROUND & AIMS: :Nickel (Ni), which is a carcinogenic workplace hazard, increases the risk of lung cancer. Angiopoietin-like protein 4 (ANGPTL4) is a multifunctional cytokine that is involved in both angiogenesis and metastasis, but its role in lung cancer is still not clear. In this study, we assessed the role of ANGPTL4 in lung carcinogenesis under nickel exposure and investigated the effects of the antidiabetic drug metformin on ANGPTL4 expression and lung cancer chemoprevention. Our results showed that ANGPTL4 is increased in NiCl2-treated lung cells in a dose- and time-course manner. The expression of ANGPTL4 and HIF-1α induced by NiCl2 were significantly repressed after metformin treatment. The downregulation of HIF-1α expression by ROS savenger and HIF-1α inhibitor or knockdown by lentiviral shRNA infection diminished NiCl2-activated ANGPTL4 expression. Chromatin immunoprecipitation and the luciferase assay revealed that NiCl2-induced HIF-1α hypoxia response element interactions activate ANGPTL4 expression, which is then inhibited by metformin. In conclusion, the increased presence of ANGPTL4 due to HIF-1α accumulation that is caused by nickel in lung cells may be one mechanism by which nickel exposure contributes to lung cancer progression. Additionally, metformin has the ability to prevent NiCl2-induced ANGPTL4 through inhibiting HIF-1α expression and its binding activity. These results provide evidence that metformin in oncology therapeutics could be a beneficial chemopreventive agent.

背景与目标： ：镍（Ni）是工作场所的致癌物质，会增加患肺癌的风险。血管生成素样蛋白4（ANGPTL4）是一种多功能细胞因子，参与血管生成和转移，但在肺癌中的作用仍不清楚。在这项研究中，我们评估了ANGPTL4在镍暴露下肺癌发生中的作用，并研究了抗糖尿病药物二甲双胍对ANGPTL4表达和肺癌化学预防的影响。我们的研究结果表明，ANGPTL4在经过NiCl2处理的肺细胞中呈剂量和时间过程增加。二甲双胍处理后，NiCl2诱导的ANGPTL4和HIF-1α的表达明显降低。 ROS savenger和HIF-1α抑制剂对HIF-1α表达的下调或慢病毒shRNA感染的抑制可降低NiCl2激活的ANGPTL4的表达。染色质的免疫沉淀和荧光素酶测定表明，NiCl2诱导的HIF-1α缺氧反应元件相互作用激活ANGPTL4表达，然后被二甲双胍抑制。总之，由镍在肺细胞中引起的HIF-1α积累导致ANGPTL4的存在增加，可能是镍暴露导致肺癌进展的一种机制。另外，二甲双胍具有通过抑制HIF-1α表达及其结合活性来预防NiCl2诱导的ANGPTL4的能力。这些结果提供证据表明二甲双胍在肿瘤治疗中可能是有益的化学预防剂。

BACKGROUND & AIMS: :Hypoxia is a major driving force of cancer invasion and metastasis. Here we show that death domain-associated protein (Daxx) acts to negatively regulate hypoxia-induced cell dissemination and invasion by inhibiting the HIF-1α/HDAC1/Slug pathway. Daxx directly binds to the DNA-binding domain of Slug, impeding histone deacetylase 1 (HDAC1) recruitment and antagonizing Slug E-box binding. This, in turn, stimulates E-cadherin and occludin expression and suppresses Slug-mediated epithelial-mesenchymal transition (EMT) and cell invasiveness. Under hypoxic conditions, stabilized hypoxia-inducible factor (HIF)-1α downregulates Daxx expression and promotes cancer invasion, whereas re-expression of Daxx represses hypoxia-induced cancer invasion. Daxx also suppresses Slug-mediated lung cancer metastasis in an orthotopic lung metastasis mouse model. Using clinical tumour samples, we confirmed that the HIF-1α/Daxx/Slug pathway is an outcome predictor. Our results support that Daxx can act as a repressor in controlling HIF-1α/HDAC1/Slug-mediated cancer cell invasion and is a potential therapeutic target for inhibition of cancer metastasis.

背景与目标： ：缺氧是癌症侵袭和转移的主要驱动力。在这里，我们显示死亡域相关蛋白（Daxx）通过抑制HIF-1α/ HDAC1 / Slug途径负调控缺氧诱导的细胞扩散和侵袭。 Daxx直接与Slug的DNA结合域结合，阻止组蛋白脱乙酰基酶1（HDAC1）募集并拮抗Slug E-box的结合。反过来，这会刺激E-cadherin和occludin的表达，并抑制Slug介导的上皮-间质转化（EMT）和细胞侵袭性。在缺氧条件下，稳定的缺氧诱导因子（HIF）-1α下调Daxx表达并促进癌症侵袭，而Daxx的重新表达则抑制缺氧诱导的癌症侵​​袭。 Daxx还可以在原位肺转移小鼠模型中抑制Slug介导的肺癌转移。使用临床肿瘤样本，我们证实了HIF-1α/ Daxx / Slug途径是结果的预测指标。我们的结果支持Daxx可以作为控制HIF-1α/ HDAC1 / Slug介导的癌细胞侵袭的阻遏物，并且是抑制癌症转移的潜在治疗靶标。

BACKGROUND & AIMS: :The pentose phosphate pathway (PPP) plays a critical role in maintaining cellular redox homeostasis in tumor cells and macromolecule biosynthesis. Upregulation of the PPP has been shown in several types of tumor. However, how the PPP is regulated to confer selective growth advantages on drug resistant tumor cells is not well understood. Here we show a metabolic shift from tricarboxylic acid cycle (TCA) to PPP after a long period induction of Imatinib (IM). One of the rate-limiting enzymes of the PPP-phosphogluconate dehydrogenase (PGD), is dramatically upregulated in gastrointestinal stromal tumors (GISTs) and GIST cell lines resistant to Imatinib (IM) compared with sensitive controls. Functional studies revealed that the overexpression of PGD in resistant GIST cell lines promoted cell proliferation and suppressed cell apoptosis. Mechanistic analyses suggested that the protein level of hypoxia inducible factor-1α (HIF-1α) increased during long time stimulation of reactive oxygen species (ROS) produced by IM. Importantly, we further demonstrated that HIF-1α also had positive correlation with PGD, resulting in the change of metabolic pathway, and ultimately causing drug resistance in GIST. Our findings show that long term use of IM alters the metabolic phenotype of GIST through ROS and HIF-1α, and this may contribute to IM resistance. Our work offers preclinical proof of metabolic target as an effective strategy for the treatment of drug resistance in GIST.

背景与目标： 磷酸戊糖途径（PPP）在维持肿瘤细胞中细胞氧化还原稳态和大分子生物合成中起关键作用。 PPP的上调已在几种类型的肿瘤中显示出来。然而，如何调节PPP以赋予抗药性肿瘤细胞选择性生长优势尚不清楚。在这里，我们显示了伊马替尼（IM）的长期诱导后从三羧酸循环（TCA）到PPP的代谢转变。与敏感对照相比，PPP-磷酸葡糖酸脱氢酶（PGD）的一种限速酶在胃肠道间质瘤（GIST）和对伊马替尼（IM）具有抗性的GIST细胞系中显着上调。功能研究表明，抗性GIST细胞系中PGD的过度表达促进细胞增殖并抑制细胞凋亡。机理分析表明，在长时间刺激IM产生的活性氧（ROS）后，缺氧诱导因子1α（HIF-1α）的蛋白水平升高。重要的是，我们进一步证明了HIF-1α也与PGD呈正相关，从而导致了代谢途径的改变，并最终导致了GIST的耐药性。我们的发现表明，长期使用IM会通过ROS和HIF-1α改变GIST的代谢表型，这可能会导致IM抵抗。我们的工作提供了代谢靶点的临床前证据，作为治疗GIST耐药性的有效策略。

BACKGROUND & AIMS: :Hypoxia inducible factor 1α (HIF-1α), a pivotal regulator of gene expression in response to hypoxia and ischemia, is now considered to regulate both pro-survival and pro-death responses depending on the duration and severity of the stress. We previously showed that chronic global cerebral hypoperfusion (CCH) triggered long-lasting accumulation of HIF-1α protein in the hippocampus of rats. However, the role of the stabilized HIF-1α in CCH is obscure. Here, we knock down endogenous HIF-1α to determine whether and how HIF-1α affects the disease processes and phenotypes of CCH. Lentivirus expressing HIF-1α small hairpin RNA was injected into the bilateral hippocampus and bilateral ventricles to knock down HIF-1α gene expression in the hippocampus and other brain areas. Permanent bilateral common carotid artery occlusions, known as 2-vessel occlusions (2VOs), were used to induce CCH in rats. Angiogenesis, oxidative stress, histopathological changes of the brain, and cognitive function were tested. Knockdown of HIF-1α prior to 2VO significantly exacerbates the impairment of learning and memory after four weeks of CCH. Mechanically, reduced cerebral angiogenesis, increased oxidative damage, and increased density of astrocytes and microglia in the cortex and some subregions of hippocampus are also shown after four weeks of CCH. Furthermore, HIF-1α knockdown also disrupts upregulation of regulated downstream genes. Our findings suggest that HIF-1α-protects the brain from oxidative stress and inflammation response in the disease process of CCH. Accumulated HIF-1α during CCH mediates endogenous adaptive processes to defend against more severe hypoperfusion injury of the brain, which may provide a therapeutic benefit.

背景与目标： 低氧诱导因子1α（HIF-1α）是缺氧和局部缺血反应中基因表达的关键调节剂，现在被认为可根据应激的持续时间和严重程度来调节生存前反应和死亡前反应。我们先前显示慢性全脑灌注不足（CCH）触发了大鼠海马中HIF-1α蛋白的长期积累。但是，稳定的HIF-1α在CCH中的作用尚不清楚。在这里，我们敲除内源性HIF-1α，以确定HIF-1α是否以及如何影响CCH的疾病进程和表型。将表达HIF-1α小发夹RNA的慢病毒注射入双侧海马和双侧脑室，以敲低海马和其他脑区域中的HIF-1α基因表达。永久性双侧颈总动脉闭塞，称为2血管闭塞（2VOs），用于诱导大鼠CCH。测试了血管生成，氧化应激，大脑的组织病理学变化和认知功能。 2VO前敲低HIF-1α会严重加重CCH后四周的学习和记忆障碍。在机械上，经过四周的CCH后，还显示出大脑血管生成减少，氧化损伤增加以及皮质和海马体某些子区域中星形胶质细胞和小胶质细胞的密度增加。此外，HIF-1α敲低还破坏了调控下游基因的上调。我们的发现表明，在CCH的疾病过程中，HIF-1α保护大脑免受氧化应激和炎症反应的影响。 CCH期间积累的HIF-1α介导内源性适应性过程，以防御更严重的脑灌注不足损伤，这可能会提供治疗益处。

BACKGROUND & AIMS: :Ischemia/reperfusion (I/R) leads to Acute Kidney Injury. HIF-1α is a key factor during organ response to I/R. We previously demonstrated that HIF-1α is induced during renal reperfusion, after ischemia. Here we investigate the role of HIF-1α and the HIF-1α dependent mechanisms in renal repair after ischemia. By interference of HIF-1α in a rat model of renal I/R, we observed loss of expression and mis-localization of e-cadherin and induction of α-SMA, MMP-13, TGFβ, and collagen I. Moreover, we demonstrate that HIF-1α inhibition promotes renal cell infiltrates by inducing IL-1β, TNF-α, MCP-1 and VCAM-1, through NFkB activity. In addition, HIF-1α inhibition induced proximal tubule cells proliferation but it did not induce compensatory apoptosis, both in vivo. In vitro, HIF-1α knockdown in HK2 cells subjected to hypoxia/reoxygenation (H/R) promote cell entry into S phase, correlating with in vivo data. HIF-1α interference leads to downregulation of miR-127-3p and induction of its target gene Bcl6 in vivo. Moreover, modulation of miR-127-3p in HK2 cells subjected to H/R results in EMT regulation: miR127-3p inhibition promote loss of e-cadherin and induction of α-SMA and collagen I. In conclusion, HIF-1α induction during reperfusion is a protector mechanism implicated in a normal renal tissue repair after I/R.

背景与目标： ：缺血/再灌注（I / R）导致急性肾损伤。 HIF-1α是器官对I / R反应的关键因素。我们先前证明了缺血后肾脏再灌注过程中会诱导出HIF-1α。在这里，我们研究了HIF-1α和HIF-1α依赖性机制在缺血后肾脏修复中的作用。通过在大鼠肾脏I / R模型中干预HIF-1α，我们观察到了e-钙粘蛋白的表达和定位错误以及α-SMA，MMP-13，TGFβ和胶原蛋白I的诱导。 HIF-1α抑制作用通过NFkB活性诱导IL-1β，TNF-α，MCP-1和VCAM-1促进肾细胞浸润。此外，HIF-1α抑制可诱导近端小管细胞增殖，但在体内均不诱导代偿性细胞凋亡。在体外，经历缺氧/复氧（H / R）的HK2细胞中的HIF-1α敲低会促进细胞进入S期，这与体内数据相关。 HIF-1α干扰导致miR-127-3p的下调和体内靶基因Bcl6的诱导。此外，在受到H / R的HK2细胞中调节miR-127-3p会导致EMT调节：miR127-3p的抑制作用会促进e-钙黏着蛋白的损失以及α-SMA和胶原I的诱导。再灌注是I / R后正常肾脏组织修复的保护机制。

BACKGROUND & AIMS: :The integrin LFA-1 is essential for efficient activation and for cytotoxicity of NK cells because it initiates the assembly of the immunological synapse and mediates firm adhesion to the target. LFA-1 is also needed to polarize the cytotoxic machinery of the NK cell toward the target cell. The binding affinity and avidity of integrins can be regulated via inside-out signals from other receptors. In this article, we investigate the signals necessary to activate LFA-1 in human NK cells. Our data show that LFA-1 has a low ligand-binding activity in resting human NK cells, but it can be stimulated by triggering activating receptors, such as 2B4 or CD16, or by coactivation of different receptor combinations. Short-term stimulation of freshly isolated NK cells with cytokines, such as IL-15, IL-12, or IL-18, does not activate LFA-1 but increases the responsiveness of the cells to subsequent receptor stimulation. Different NK cell subsets vary in their ability to induce LFA-1 binding activity after activating receptor stimulation. Interestingly, the NK cell subsets that are more mature and possess higher cytotoxic potential also show the highest activation of LFA-1, which correlated with the expression of the small calcium-binding protein S100A4. Our data suggest that regulation of LFA-1 is one reason for the different activity of NK cells during differentiation.

背景与目标： ：整联蛋白LFA-1对于NK细胞的有效激活和细胞毒性至关重要，因为它启动了免疫突触的组装并介导了对靶标的牢固粘附。还需要LFA-1才能使NK细胞的细胞毒性机制向靶细胞极化。整联蛋白的结合亲和力和亲合力可以通过来自其他受体的由内而外的信号来调节。在本文中，我们研究了激活人NK细胞中LFA-1所必需的信号。我们的数据表明，LFA-1在静止的人NK细胞中具有较低的配体结合活性，但可以通过触发活化受体（例如2B4或CD16）或通过共活化不同受体组合来刺激。用细胞因子（例如IL-15，IL-12或IL-18）短期刺激新鲜分离的NK细胞不会激活LFA-1，但会增加细胞对随后受体刺激的反应性。激活受体刺激后，不同的NK细胞亚群诱导LFA-1结合活性的能力各不相同。有趣的是，更成熟且具有较高细胞毒性潜能的NK细胞亚群也显示了LFA-1的最高活化，这与小钙结合蛋白S100A4的表达有关。我们的数据表明，LFA-1的调节是分化过程中NK细胞活性不同的原因之一。

BACKGROUND & AIMS: :Myocyte enhancer factor 2D (MEF2D) is involved in many aspects of cancer progression, including cell proliferation, invasion, and migration. However, little is known about the role of MEF2D in tumor angiogenesis. Using clinical specimens, colorectal cancer (CRC) cell lines and a mouse model in the present study, we found that MEF2D expression was positively correlated with CD31-positive microvascular density in CRC tissues. MEF2D promoted tumor angiogenesis in vitro and in vivo and induced the expression of proangiogenic cytokines in CRC cells. MEF2D was found to be a downstream effector of hypoxia-inducible factor (HIF)-1α in the induction of tumor angiogenesis. HIF-1α transactivates MEF2D expression by binding to the MEF2D gene promoter. These results demonstrate that the HIF-1α/MEF2D axis can serve as a therapeutic target for the treatment of CRC.

背景与目标： ：心肌细胞增强因子2D（MEF2D）参与了癌症进展的许多方面，包括细胞增殖，侵袭和迁移。然而，关于MEF2D在肿瘤血管生成中的作用知之甚少。在本研究中，使用临床标本，结直肠癌（CRC）细胞系和小鼠模型，我们发现MEF2D表达与CRC组织中CD31阳性微血管密度呈正相关。 MEF2D在体外和体内促进肿瘤血管生成，并诱导CRC细胞中促血管生成细胞因子的表达。发现MEF2D在诱导肿瘤血管生成中是缺氧诱导因子（HIF）-1α的下游效应子。 HIF-1α通过与MEF2D基因启动子结合来激活MEF2D表达。这些结果证明，HIF-1α/ MEF2D轴可以作为CRC治疗的治疗靶标。

BACKGROUND & AIMS: :The leukocyte function-associated molecule-1 (LFA-1) plays a key role in cell adhesion processes between cells of the immune system. We investigated the mechanism that may regulate LFA-1-ligand interactions, which result in cell-cell adhesion. To this end we employed an intriguing anti-LFA-1 alpha mAb (NKI-L16), capable of inducing rather than inhibiting cell adhesion. Aggregation induced by NKI-L16 or Fab fragments thereof is not the result of signals transmitted through LFA-1. The antibody was found to recognize a unique Ca2(+)-dependent activation epitope of LFA-1, which is essentially absent on resting lymphocytes, but becomes induced upon in vitro culture. Expression of this epitope correlates well with the capacity of cells to rapidly aggregate upon stimulation by PMA or through the TCR/CD3 complex, indicating that expression of the NKI-L16 epitope is essential for LFA-1 to mediate adhesion. However, expression of the NKI-L16 epitope in itself is not sufficient for cell binding since cloned T lymphocytes express the NKI-L16 epitope constitutively at high levels, but do not aggregate spontaneously. Based on these observations we propose the existence of three distinct forms of LFA-1: (a) an inactive form, which does not, or only partially exposes the NKI-L16 epitope, found on resting cells; (b) an intermediate, NKI-L16+ form, expressed by mature or previously activated cells; and (c) an active (NKI-L16+) form of LFA-1, capable of high affinity ligand binding, obtained after specific triggering of a lymphocyte through the TCR/CD3 complex, by PMA, or by binding of NKI-L16 antibodies.

背景与目标： ：白细胞功能相关分子1（LFA-1）在免疫系统细胞之间的细胞粘附过程中起关键作用。我们研究了可能调节LFA-1-配体相互作用的机制，该机制导致细胞间粘附。为此，我们使用了一种有趣的抗-LFA-1αmAb（NKI-L16），它能够诱导而不是抑制细胞粘附。 NKI-L16或其Fab片段诱导的聚集不是通过LFA-1传输的信号的结果。发现该抗体识别LFA-1的独特的Ca2（）依赖性活化表位，其在静止的淋巴细胞上基本不存在，但在体外培养时被诱导。该表位的表达与细胞在受到PMA刺激或通过TCR / CD3复合物刺激后迅速聚集的能力密切相关，这表明NKI-L16表位的表达对于LFA-1介导粘附至关重要。然而，NKI-L16表位本身的表达不足以与细胞结合，因为克隆的T淋巴细胞以高水平组成性表达NKI-L16表位，但不会自发聚集。基于这些观察，我们提出了LFA-1的三种不同形式的存在：（a）一种非活性形式，其不或仅部分暴露于静息细胞上的NKI-L16表位； （b）由成熟或先前活化的细胞表达的中间体NKI-L16形式； （c）LFA-1的活性（NKI-L16）形式，具有高亲和力配体结合，是通过TMA / CD3复合物，通过PMA或NKI-L16抗体特异性触发淋巴细胞后获得的。

BACKGROUND & AIMS: :An imbalance in mitochondrial dynamics induced by oxidative stress may lead to hepatocyte epithelial mesenchymal transition (EMT) and liver fibrosis. However, the underlying molecular mechanisms have not been fully elucidated. This study investigated the role of mitochondrial dynamics in hepatocyte EMT and liver fibrosis using an in vitro human (L-02 cells, hepatic cell line) and an in vivo mouse model of liver fibrosis. Findings showed that oxidative stress-induced mitochondrial DNA damage was associated with abnormal mitochondrial fission and hepatocyte EMT. The reactive oxygen species (ROS) scavengers apocynin and mito-tempo effectively attenuated carbon tetrachloride (CCl4)-induced abnormal mitochondrial fission and liver fibrosis. Restoring mitochondrial biogenesis attenuated hepatocyte EMT. Oxidative stress-induced abnormal hepatocyte mitochondrial fission events by a mechanism that involved the down regulation of PGC-1α. PGC-1α knockout mice challenged with CCl4 had increased abnormal mitochondrial fission and more severe liver fibrosis than wild type mice. These results indicate that PGC-1α has a protective role in oxidative stress-induced-hepatocyte EMT and liver fibrosis.

背景与目标： 氧化应激引起的线粒体动力学失衡可能导致肝细胞上皮间质转化（EMT）和肝纤维化。但是，尚未完全阐明潜在的分子机制。这项研究使用体外人类（L-02细胞，肝细胞系）和体内小鼠肝纤维化模型研究了线粒体动力学在肝细胞EMT和肝纤维化中的作用。研究结果表明，氧化应激诱导的线粒体DNA损伤与线粒体异常分裂和肝细胞EMT有关。活性氧（ROS）清除了Apocynin和Mito-tempo可以有效减弱四氯化碳（CCl4）诱导的异常线粒体裂变和肝纤维化。恢复线粒体生物发生减弱了肝细胞EMT。氧化应激诱导的异常肝细胞线粒体裂变事件的发生机制涉及下调PGC-1α。与野生型小鼠相比，用CCl4攻击的PGC-1α基因敲除小鼠的线粒体异常分裂增加，肝脏纤维化更为严重。这些结果表明PGC-1α在氧化应激诱导的肝细胞EMT和肝纤维化中具有保护作用。

BACKGROUND & AIMS: :This study aimed to investigate the long-term effects of training intervention and resting on protein expression and stability of peroxisome proliferator-activated receptor β/δ (PPARβ), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α), glucose transporter type 4 (GLUT4), and mitochondrial proteins, and determine whether glucose homeostasis can be regulated through stable expression of these proteins after training. Rats swam daily for 3, 6, 9, 14, or 28 days, and then allowed to rest for 5 days post-training. Protein and mRNA levels were measured in the skeletal muscles of these rats. PPARβ was overexpressed and knocked down in myotubes in the skeletal muscle to investigate the effects of swimming training on various signaling cascades of PGC-1α transcription, insulin signaling, and glucose uptake. Exercise training (Ext) upregulated PPARβ, PGC-1α, GLUT4, and mitochondrial enzymes, including NADH-ubiquinone oxidoreductase (NUO), cytochrome c oxidase subunit I (COX1), citrate synthase (CS), and cytochrome c (Cyto C) in a time-dependent manner and promoted the protein stability of PPARβ, PGC-1α, GLUT4, NUO, CS, and Cyto C, such that they were significantly upregulated 5 days after training cessation. PPARβ overexpression increased the PGC-1α protein levels post-translation and improved insulin-induced signaling responsiveness and glucose uptake. The present results indicate that Ext promotes the protein stability of key mitochondria enzymes GLUT4, PGC-1α, and PPARβ even after Ext cessation.

背景与目标： ：这项研究旨在探讨长期训练干预和静息对过氧化物酶体增殖物激活受体β/δ（PPARβ），过氧化物酶体增殖物激活受体γ辅激活物1-α（PGC1α），葡萄糖转运蛋白的蛋白表达和稳定性的影响。 4型（GLUT4）和线粒体蛋白，并确定是否可以通过训练后这些蛋白的稳定表达来调节葡萄糖稳态。大鼠每天游泳3、6、9、14或28天，然后在训练后休息5天。在这些大鼠的骨骼肌中测量蛋白质和mRNA水平。 PPARβ在骨骼肌肌管中过度表达并被敲低，以研究游泳训练对PGC-1α转录，胰岛素信号传导和葡萄糖摄取的各种信号传导级联的影响。运动训练（Ext）上调了PPARβ，PGC-1α，GLUT4和线粒体酶，包括NADH，泛醌氧化还原酶（NUO），细胞色素c氧化酶亚基I（COX1），柠檬酸合酶（CS）和细胞色素c（Cyto C）。 PPARβ，PGC-1α，GLUT4，NUO，CS和Cyto C具有时间依赖性，并促进了蛋白质的稳定性，因此在停止训练后的5天它们显着上调。 PPARβ的过表达增加了翻译后PGC-1α的蛋白水平，并改善了胰岛素诱导的信号响应和葡萄糖摄取。目前的结果表明，即使在Ext停止后，Ext仍可促进关键线粒体酶GLUT4，PGC-1α和PPARβ的蛋白质稳定性。

BACKGROUND & AIMS: :The leukocyte integrin LFA-1 plays a critical role in T cell trafficking and T cell adhesion to APCs. It is known that integrin-mediated adhesion is regulated by changes in integrin ligand-binding affinity and valency through inside-out signaling. However, the molecular mechanisms involved in TCR-mediated LFA-1 regulation are not well understood. In this study, we show that the cytoskeletal protein talin1 is required for TCR-mediated activation of LFA-1 through regulation of LFA-1 affinity and clustering. Depletion of talin1 from human T cells by small interfering RNAs impairs TCR-induced adhesion to ICAM-1 and T cell-APC conjugation. TCR-induced LFA-1 polarization, but not actin polarization, is defective in talin1-deficient T cells. Although LFA-1 affinity is also reduced in talin1-deficient T cells, rescue of LFA-1 affinity alone is not sufficient to restore LFA-1 adhesive function. Together, our findings indicate that TCR-induced up-regulation of LFA-1-dependent adhesiveness and resulting T cell-APC conjugation require talin1.

背景与目标： ：白细胞整合素LFA-1在T细胞运输和T细胞对APC的粘附中起关键作用。已知整联蛋白介导的粘附受整联蛋白配体结合亲和力和通过内外信号传导的价数变化的调节。但是，TCR介导的LFA-1调节所涉及的分子机制还不是很清楚。在这项研究中，我们表明，通过调节LFA-1亲和力和聚类，TCR介导的LFA-1活化需要细胞骨架蛋白talin1。小干扰RNA从人T细胞中去除talin1会损害TCR诱导的对ICAM-1的粘附以及T细胞与APC的结合。 TCR诱导的LFA-1极化而不是肌动蛋白极化在talin1缺陷型T细胞中存在缺陷。尽管在缺乏talin1的T细胞中LFA-1亲和力也降低了，但仅靠挽救LFA-1亲和力仍不足以恢复LFA-1粘附功能。在一起，我们的发现表明，TCR诱导的LFA-1依赖性粘附性上调和由此产生的T细胞-APC结合需要talin1。

BACKGROUND & AIMS: BACKGROUND:Interleukin 1 (IL-1) is involved in bone resorption. However, the role of IL-1 in periapical lesions characterized by periapical bone destruction in primary teeth has not yet been fully elucidated. This study aimed to detect the distribution and expression of IL-1 in periapical lesions in primary teeth and assess the relationship between the cytokines and the degree of inflammatory cell infiltration. METHODS:A total of 106 chronic periapical lesions in primary teeth were harvested. Haematoxylin and eosin (H&E) staining was used to determine the histological type and the inflammatory cell infiltration grade (mild, moderate, and severe), and immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) were used to detect the distribution and expression of IL-1α and IL-1β. RESULTS:Of the 106 chronic periapical lesion samples, there were 85 cases of periapical granuloma, accounting for 80.19% of the total samples, and 21 cases of radicular cysts, accounting for 19.81%; no cases of abscess were detected. Immunohistochemistry results showed that both IL-1α and IL-1β were expressed in periapical granulomas and cysts. ELISA results showed that IL-1α and IL-1β levels were higher in the periapical granuloma group than in the radicular cyst and normal control groups (P < 0.05). In the periapical granuloma group, IL-1α and IL-1β were detected at higher levels in the severe inflammatory cell infiltration subgroup than in the mild-inflammatory cell infiltration subgroup (P < 0.05), and IL-1β expression was also higher in the moderate inflammatory cell infiltration subgroup than in the mild inflammatory cell infiltration subgroup (P < 0.01). A significant positive correlation was observed between the protein expression levels of IL-1α and IL-1β and the inflammation grade in periapical granulomas from primary teeth (P < 0.05). CONCLUSION:Expression levels of the cytokines IL-1α and IL-1β in periapical granulomas from primary teeth increased with increasing inflammatory severity and appeared to be a contributing factor to the progression of periapical lesions.

背景与目标： 背景：白介素1（IL-1）参与骨吸收。然而，IL-1在以乳牙根尖周围骨破坏为特征的根尖周围病变中的作用尚未完全阐明。这项研究旨在检测乳牙根尖周病变中IL-1的分布和表达，并评估细胞因子与炎性细胞浸润程度之间的关系。
方法：总共收集了106例乳牙的慢性根尖周病变。使用苏木精和曙红（H＆E）染色确定组织学类型和炎性细胞浸润等级（轻度，中度和重度），并使用免疫组化和酶联免疫吸附法（ELISA）检测IL的分布和表达-1α和IL-1β。
结果：106例慢性根尖周病变标本中，根尖肉芽肿85例，占总标本的80.19％；根尖囊肿21例，占19.81％。没有发现脓肿病例。免疫组织化学结果显示，IL-1α和IL-1β均在根尖肉芽肿和囊肿中表达。 ELISA结果显示，根尖肉芽肿组的IL-1α和IL-1β水平高于根尖囊肿和正常对照组（P <0.05）。在根尖肉芽肿组中，重度炎性细胞浸润亚组中IL-1α和IL-1β的水平高于轻度炎性细胞浸润亚组（P <0.05），IL-1β的表达也高于轻度炎性细胞浸润组。中度炎症细胞浸润亚组比轻度炎症细胞浸润亚组（P <0.01）。乳齿根尖肉芽肿中IL-1α和IL-1β的蛋白表达水平与炎症程度呈显着正相关（P <0.05）。
结论：乳牙根尖肉芽肿中细胞因子IL-1α和IL-1β的表达水平随着炎症程度的增加而增加，并可能是导致根尖周病变发展的因素。

BACKGROUND & AIMS: BACKGROUND:Oral squamous cell carcinoma (OSCC) is a life-threatening disease. It could be preceded by oral potentially malignant disorders (OPMDs). It was confirmed that chronic inflammation can promote carcinogenesis. Cytokines play a crucial role in this process. The aim of the study was to evaluate interleukin-1alpha (IL-1α), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-α) in tissue specimens and saliva of patients with OSCC and OPMDs. METHODS:Cytokines were evaluated in 60 tissue specimens of pathological lesions (OSCCs or OPMDs) and in 7 controls (normal oral mucosa, NOM) by immunohistochemistry and in saliva of 45 patients with OSCC or OPMDs and 9 controls (healthy volunteers) by enzyme-linked immunosorbent assays. RESULTS:Immunohistochemical analysis revealed significantly higher expression of IL-8 in OSCC specimens and TNF-α in OSCCs and OPMDs with dysplasia as compared to NOM. Moreover, expression of TNF-α was significantly higher in oral leukoplakia and oral lichen planus without dysplasia, whereas expression of IL-8 only in oral leukoplakia without dysplasia in comparison with NOM. Salivary concentrations of all evaluated cytokines were significantly higher in patients with OSCC than in controls. Moreover, levels of IL-8 were significantly higher in saliva of patients with OPMDs with dysplasia as compared to controls and in OSCC patients as compared to patients with dysplastic lesions. There was also significant increase in salivary concentrations of IL-6, IL-8 and TNF-α in patients with OSCC as compared to patients with OPMDs without dysplasia. CONCLUSION:The study confirmed that proinflammatory, NF-kappaB dependent cytokines are involved in pathogenesis of OPMDs and OSCC. The most important biomarker of malignant transformation process within oral mucosa among all assessed cytokines seems to be IL-8. Further studies on a larger sample size are needed to corroborate these results.

背景与目标： 背景：口腔鳞状细胞癌（OSCC）是一种威胁生命的疾病。在此之前可能会出现口腔潜在的恶性疾病（OPMD）。证实了慢性炎症可以促进癌变。细胞因子在这一过程中起着至关重要的作用。该研究的目的是评估组织标本和唾液中的白细胞介素-1α（IL-1α），白细胞介素6（IL-6），白细胞介素8（IL-8）和肿瘤坏死因子α（TNF-α）。 OSCC和OPMDs患者的比例。
方法：采用免疫组织化学方法对60例病理性病变（OSCCs或OPMDs）组织标本和7例对照（正常口腔粘膜，NOM）的细胞因子进行了评估，对45例OSCC或OPMDs患者的唾液中的细胞因子进行了评估，对9例对照（健康志愿者）进行了酶促评估链接的免疫吸附测定。
结果：免疫组织化学分析显示，不典型增生的OSCC和OPMD中IL-8在OSCC标本中的表达显着升高，TNF-α的表达明显高于NOM。此外，与NOM相比，在没有发育异常的口腔白斑和口腔扁平苔藓中，TNF-α的表达显着较高，而在没有发育异常的口腔白斑中IL-8的表达只有NOM。 OSCC患者的所有评估细胞因子的唾液浓度均显着高于对照组。此外，与对照组相比，发育异常的OPMD患者唾液中的IL-8水平显着高于对照组，而在OSCC患者中与发育异常病变的患者相比，IL-8水平更高。与没有发育异常的OPMD患者相比，OSCC患者唾液中IL-6，IL-8和TNF-α的浓度也显着增加。
结论：该研究证实促炎性，NF-κB依赖性细胞因子与OPMDs和OSCC的发病有关。在所有评估的细胞因子中，口腔黏膜内恶性转化过程最重要的生物标志物似乎是IL-8。为了证实这些结果，需要对更大的样本量进行进一步的研究。