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。

BACKGROUND & AIMS: :Convergent syntheses of three new analogues of 1α,25-dihydroxyvitamin D3 with α-hydroxyalkyl substituents at C12 (4a-c) are described. The A-ring and triene system of each analogue were assembled by a tandem Pd-catalysed intramolecular cyclization and Suzuki-Miyaura coupling process. The stereoselective introduction of substituents at C12 was achieved by Johnson-Claisen rearrangement on allylic alcohol 15 as the key step. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

背景与目标： ：描述了在C12（4a-c）具有α-羟烷基取代基的1α，25-二羟基维生素D3的三个新类似物的会聚合成。通过串联的钯催化的分子内环化和Suzuki-Miyaura偶联过程组装每个类似物的A环和三烯系统。通过在烯丙基醇15上进行Johnson-Claisen重排作为关键步骤，实现了在C12处的取代基的立体选择性引入。本文是名为“维生素D车间”的特刊的一部分。

BACKGROUND & AIMS: :The aim of the study was to investigate whether serum hypoxia-inducible factor-1alpha (HIF-1α), hepcidin and interleukin-6 (IL-6) concentrations differed between threatened preterm labour (TPL) and uncomplicated pregnancies. This study was conducted on 54 women with TDL pregnancies and 26 healthy pregnant women. The TPL group was further divided into two subgroups according to the gestational age at delivery. Patients who gave birth within 48-72 h after the hospitalisation were referred to as preterm delivery (PD) and who gave birth at ≥37 weeks were referred to as term delivery (TD). Maternal levels of serum HIF-1α, hepcidin and IL-6 were measured with the use of enzyme-linked immunosorbent assay kits. The mean maternal serum HIF-1α, hepcidin and IL-6 levels of PD were significantly higher than TD (p < .001*) and control group (p < .001*). The mean maternal serum HIF-1α and hepcidin levels of TD were no significantly higher than the control group (p=.058, p = .064). The mean maternal serum IL-6 level of TD was significantly higher than the control group (p < .001*). A negative correlation was found between serum concentration of HIF1α, hepcidin, IL-6 with the gestational week of delivery (r = -0.421, p < .01* for HIF-1α; r = -0.578, p < .01* for hepcidin and r = -0.435, p < .01* for IL-6). High levels of HIF-1α, hepcidin and IL-6 may have potential to be used as biomarkers for the differentiation of PD and TD.Impact statementWhat is already knownon this subject? It is known that hypoxia-inducible factor-1alpha (HIF-1α) is a hypoxia marker and hepcidin and interleukin-6 (IL-6) increase in inflammation. Our study is the comparison of maternal serum HIF-1α, hepcidin and IL-6 levels between the TPL group (TD and PD) and healthy control group.Whatthe resultsof this study add? The present study demonstrates that serum HIF-1α, hepcidin and IL-6 levels were significantly higher in TPD group than uncomplicated group. The mean maternal serum HIF-1α and hepcidin levels of TD were no significantly higher than the control group.Whatthe implicationsareof these findings for clinical practice and/or further research? High levels of HIF-1α, hepcidin and IL-6 may be biomarkers in the determination of true preterm labour within the TPL group.

背景与目标： ：这项研究的目的是调查先兆早产（TPL）和单纯妊娠之间的血清低氧诱导因子1α（HIF-1α），铁调素和白介素6（IL-6）浓度是否存在差异。这项研究是针对54例TDL妊娠妇女和26例健康孕妇进行的。根据分娩时的胎龄，TPL组又分为两个亚组。在住院后48-72 h内分娩的患者被称为早产（PD），而在≥37周内分娩的患者被称为足月分娩（TD）。使用酶联免疫吸附测定试剂盒测量孕妇的血清HIF-1α，铁调素和IL-6水平。孕妇的平均血清HIF-1α，铁调素和IL-6的PD水平显着高于TD（p <0.001）*和对照组（p <0.001。*）。孕妇的平均血清HIF-1α和铁调素的TD水平没有显着高于对照组（p = .058，p = .064）。孕妇的平均TD血清IL-6水平显着高于对照组（p <0.001。*）。发现HIF1α，hepcidin，IL-6的血清浓度与分娩的孕周之间呈负相关（HIF-1α的r = -0.421，p <.01 *; hepcidin的r = -0.578，p <.01 *和r = -0.435，对于IL-6，p <.01 *）。高水平的HIF-1α，铁调素和IL-6可能有潜力用作PD和TD分化的生物标志物。已知缺氧诱导因子-1α（HIF-1α）是缺氧标志物，铁调素和白介素6（IL-6）会增加炎症。我们的研究是比较TPL组（TD和PD）与健康对照组的孕妇血清HIF-1α，铁调素和IL-6水平的比较。本研究表明，TPD组的血清HIF-1α，铁调素和IL-6水平显着高于单纯并发症组。孕妇平均血清TD的HIF-1α和hepcidin水平没有明显高于对照组。这些发现对临床实践和/或进一步研究有何意义？高水平的HIF-1α，铁调素和IL-6可能是确定TPL组内真正早产的生物标志物。

BACKGROUND & AIMS: :Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss among the elderly population. Vascular endothelial growth factor (VEGF) is essential for choroidal neovascularization (CNV) development in advanced, wet AMD. Chrysin (5,7-dihydroxyflavone) is a natural flavonoid with anti-inflammatory, anti-oxidative, and anti-angiogenic effects. We hypothesized that intravitreally injected chrysin may inhibit CNV due to its inhibitory effect on angiogenesis. To determine the effects of chrysin on an experimental CNV model, we induced CNV in Brown Norway rats with a diode laser. One week later, rats were injected intravitreally with chrysin in the right eye and vehicle in the left eye. The following week, we evaluated chrysin's effects via the CNV grade assessed with fluorescein angiography and histologic analyses. Hypoxia-inducible factor-1 alpha (HIF-1α) and VEGF expression in the retina/choroid complex were also measured in both eyes. The mean CNV grade was significantly lower in chrysin-treated vs. control eyes (2.34 ± 1.14 vs. 2.97 ± 1.05, p < 0.001), as was the mean CNV thickness (33.90 ± 4.89 vs. 38.50 ± 5.43 μm, p < 0.001) and mean HIF-1α and VEGF levels (both p < 0.001). Compared to chrysin-treated eyes, the relative risk of control eyes developing high-leakage lesions was 2.03 (95% confidence interval: 1.46-2.83). Since chrysin inhibited laser-induced CNV and downregulated HIF-1α and VEGF expression, it is a candidate for treating wet AMD and other CNV-associated conditions.

背景与目标： ：与年龄有关的黄斑变性（AMD）是老年人口不可逆视力丧失的主要原因。血管内皮生长因子（VEGF）对于晚期湿性AMD的脉络膜新血管形成（CNV）发育至关重要。菊花（5,7-二羟基黄酮）是一种天然的类黄酮，具有抗炎，抗氧化和抗血管生成的作用。我们假设玻璃体内注射的chrysin可能由于其对血管生成的抑制作用而抑制CNV。为了确定chrysin对实验性CNV模型的影响，我们用二极管激光器在Brown Norway大鼠中诱导了CNV。一周后，向大鼠右眼玻璃体注射白素，向左眼注射媒介物。在接下来的一周，我们通过荧光素血管造影和组织学分析评估的CNV等级评估了Chrysin的作用。还在两只眼睛中测量了缺氧诱导因子-1α（HIF-1α）和视网膜/脉络膜复合物中的VEGF表达。相对于对照，用新霉素处理的眼睛，平均CNV等级显着降低（2.34±1.14 vs. 2.97±1.05，p <0.001），平均CNV厚度（33.90±4.89 vs. 38.50±5.43μm，p <0.001） ）和平均HIF-1α和VEGF水平（均p <0.001）。相较于用菊酯治疗的眼睛，对照组眼睛发生高渗漏性病变的相对风险为2.03（95％置信区间：1.46-2.83）。由于chrysin抑制了激光诱导的CNV并下调了HIF-1α和VEGF的表达，因此它是治疗湿性AMD和其他CNV相关疾病的候选药物。

BACKGROUND & AIMS: AIMS:Following acute myocardial infarction (AMI), pro-angiogenic progenitor cells (PCs) are released from the bone marrow into the circulation and home to the ischaemic site attracted by a chemokine gradient. It is unknown if components of this early homeostatic response might help forecast the long-term clinical outcome. This study investigates if the number and migratory activity of circulating PCs predict adverse events in patients with AMI (clinical trial: NCT01271309). METHODS AND RESULTS:Basal counts and in vitro migratory activity of CD34/CD45/CD133/CXCR4 PCs and serum cytokine levels were assessed during the first 5 days after AMI in a consecutive series of 172 patients. Clinical outcomes of the study were death, repeat AMI, and new-onset heart failure at a 1-year follow-up. The association between PC counts and cytokine levels with the incidence of clinical outcomes was assessed by multivariable regression models. AMI patients who underwent an event showed higher serum stromal cell-derived factor 1α (SDF-1α) levels and reduced spontaneous motility of PCs in an in vitro migration assay when compared with event-free subjects. After adjustment for age, gender, the presence or absence of ST elevation, or diabetes, the percentage of PCs non-migrated towards vehicle or SDF-1α were both independent predictors of death or repeat AMI and new-onset heart failure (odds ratio [OR] = 2, P = 0.015 and OR = 1.90, P = 0.018, respectively). Moreover, serum SDF-1α levels predict adverse events (OR = 3.8, P = 0.007). CONCLUSION:Biomarkers reflecting the migratory activity of circulating PCs may aid the assessment of secondary risk in AMI patients.

背景与目标： 目的：继急性心肌梗塞（AMI）之后，促血管生成祖细胞（PCs）从骨髓释放到循环系统中，并返回到趋化因子梯度吸引的缺血部位。目前尚不清楚这种早期体内稳态反应的成分是否有助于预测长期临床结果。本研究调查循环PC的数量和迁移活动是否可预测AMI患者的不良事件（临床试验：NCT01271309）。
方法和结果：连续172例患者在AMI后的前5天评估了CD34 / CD45 / CD133 / CXCR4 PC的基础计数和体外迁移活性以及血清细胞因子水平。该研究的临床结果是死亡，重复AMI和1年随访中的新发性心力衰竭。 PC计数和细胞因子水平与临床结果发生率之间的关联通过多变量回归模型进行评估。与无事件受试者相比，经历事件的AMI患者在体外迁移试验中显示出较高的血清基质细胞衍生因子1α（SDF-1α）水平和PC的自发运动能力降低。在调整了年龄，性别，ST升高的存在与否或糖尿病后，未向媒介物或SDF-1α迁移的PC的百分比都是死亡或重复AMI和新发性心力衰竭的独立预测因子（几率[ OR] = 2，P = 0.015，OR = 1.90，P = 0.018）。此外，血清SDF-1α水平可预测不良事件（OR = 3.8，P = 0.007）。
结论：反映循环PCs迁移活动的生物标志物可能有助于评估AMI患者的继发风险。