Oxidative stress-dependent cyclooxygenase-2-derived prostaglandin f(2α) impairs endothelial function in renovascular hypertensive rats

Abstract Aims: The role of endothelium-derived contracting factors (EDCFs) in regulating renovascular function is yet to be elucidated in renovascular hypertension (RH). The current study investigated whether oxidative stress-dependent cyclooxygenase (COX)-2-derived prostaglandin F(2α) (PGF(2α)) impairs endothelial function in renal arteries of renovascular hypertensive rats (RHR). Results: Renal hypertension was induced in rats by renal artery stenosis of both kidneys using the 2-kidney 2-clip model. Acute treatment with reactive oxygen species (ROS) scavengers, COX-2 inhibitors, and thromboxane-prostanoid receptor antagonists, but not COX-1 inhibitors, improved endothelium-dependent relaxations and eliminated endothelium-dependent contractions in RHR renal arteries. Five weeks of treatment with celecoxib or tempol reduced blood pressure, increased renal blood flow, and restored endothelial function in RHRs. Increased ROS production in RHR arteries was inhibited by ROS scavengers, but unaffected by COX-2 inhibitors; whereas increased PGF(2α) release was reduced by both ROS scavengers and COX-2 inhibitors. ROS also induced COX-2-dependent contraction in RHR renal arteries, which was accompanied by the release of COX-2-derived PGF(2α). Further, chronic tempol treatment reduced COX-2 and BMP4 upregulation, p38MAPK phosphorylation, and the nitrotyrosine level in RHR renal arteries. Conclusion: These findings demonstrate the functional importance of oxidative stress, which serves as an initiator of increased COX-2 activity, and that COX-2-derived PGF(2α) plays an important role in mediating endothelial dysfunction in RH. Innovation: The current study, thus, suggests that drugs targeting oxidative stress-dependent COX-2-derived PGF(2α) may be useful in the prevention and management of RH. Antioxid. Redox Signal. 16, 363-373.     

α_2巨球蛋白(α2M)是IL-6的载体蛋白

以往的实验表明,炎症部位产生的IL-6可以像多肽激素那样引起全身性的变化,如发热、合成急性期蛋白等;患Castleman氏疾病的患者血清中IL-6水平升高,已知此病患者血清中的IL-6主要是由受感染的淋巴结合成的;此外,IL-6血清清除动力学呈双相性,表明某种物质可阻止IL-6的代谢,     

α_2-巨球蛋白(α_2M)对白细胞促凝血活性的影响

<正> α_2M是血液中一种具有重要生物学活性的大分子糖蛋白,由四个结构与分子量均相同的亚单位组成,由淋巴细胞、单核细胞及成纤维母细胞合成和释放。在体外实验中α_2M能改变网状细胞对各种刺激的反应,并在白细胞与红细胞生成过程中起作用。近年来研究发现,α_2M是血浆中一种重要的蛋白酶抑制因子,可抑制四种内肽酶活性。α_2M     

15d-PGJ2: The anti-inflammatory prostaglandin?

15-Deoxy-Delta-12,14-prostaglandin J2 (15d-PGJ2) is the most recently discovered prostaglandin. This cyclopentanone, the dehydration end product of PGD2, differs from other prostaglandins in several respects. There is no specific prostaglandin synthase (PGS) leading to 15d-PGJ2 production and no specific 15d-PGJ2 receptor has been identified to date. Instead, 15d-PGJ2 has been shown to act via PGD2 receptors (DP1 and DP2) and through interaction with intracellular targets. In particular, 15d-PGJ2 is recognized as the endogenous ligand for the intranuclear receptor PPARgamma. This property is responsible for many of the 15d-PGJ2 anti-inflammatory functions. In this review, we summarize the current understanding of 15d-PGJ2 synthesis, biology and main effects both in molecular physiology and pathological states.     

α_1(Ⅰ)、α_2和α_1(Ⅲ)三股胶原肽链顺序的比较分析

含有α_1(Ⅰ)和α_2链的Ⅰ型胶原以及由α_1(Ⅲ)链组成的Ⅲ型胶原,其氨基酸顺序已经明了,其中α_1(Ⅰ)与α_2链之比为2:1。作肽链内部分析,α链分为四个D单位,每个D单位具有234个氨基酸残基的长度。除D单位之外,还可观察到其它周期,有D/3(78个残基)、D/6(39个残基)、D/11(21个残基)和D/13(18个残基),这些周期在α_1(Ⅰ)和α_1(Ⅲ)中尤其突出。D单位为功能性重复单位,由能相互作用的极性残基与疏     

用抗α_2-M单克隆抗体ELISA技术测定尿液中α_2-M(摘要)

有关生理与病理情况下尿液中的α_2-M含量,至今未见正式报告。我们应用本科自制鼠抗人α_2-M单克隆抗体,建立ELISA技术,对尿液中α_2-M含量进行测定,发现此法敏感性高,可直接从尿液中测出低迷26ng/ml的α_2-M,批内误差(cv)为11％,现将结果报告如下: 料材和方法 1.鼠抗人α_2-M单克隆抗体、羊抗人α_2-M多克隆抗体、辣根过氧化物酶标记兔抗羊IgG均由本科自制。     

Tumour-derived prostaglandin E2 and transforming growth factor-β synergize to inhibit plasmacytoid dendritic cell-derived interferon-α

In previous studies we reported that plasmacytoid dendritic cells (PDC) infiltrating head and neck cancer tissue are functionally impaired, but the molecular basis for the functional deficiency remained unclear. Here we demonstrate that tumour-derived prostaglandin E2 (PGE₂) and transforming growth factor-β (TGF-β) increase interleukin-8 (IL-8) but synergistically inhibit interferon-α (IFN-α) and tumour necrosis factor (TNF) production of Toll-like receptor 7 (TLR7)- and Toll-like receptor 9 (TLR9)-stimulated PDC. The inhibitory effect of PGE₂ could be mimicked by the induction of cyclic AMP (cAMP) and by inhibitors of cyclooxygenase. The contribution of tumour-derived TGF-β was confirmed by the TGF-β antagonist SB-431542. Suppression of tumour-derived PGE₂ and TGF-β restored TLR-induced IFN-α production of PDC. Additionally, PGE₂- and TGF-β-treated PDC display a ‘tolerogenic’ phenotype because of a downregulation of CD40 accompanied by an upregulation of CD86. Finally, in TLR-stimulated PDC, PGE₂ and TGF-β reduce the CCR7 : CXCR4 ratio, suggesting that PDC are impaired in their ability to migrate to tumour-draining lymph nodes but are retained in stromal cell-derived factor 1 (SDF-1)-expressing tissues. Based on these data, cyclooxygenase inhibitors and TGF-β antagonists may improve TLR7- and TLR9-based tumour immunotherapy.     

α_2-血浆素抑制物缺乏(Miyasato病)

α_2—血浆素抑制物(简称α_2—P.I.)或称抗血浆素,是人血浆中最强和最快作用的血浆素抑制物,包括α_2巨球蛋白和α_1抗胰     

人α2(Ⅰ)型胶原基因启动子活性研究

目的探索器官纤维化形成中调控Ⅰ型胶原基因高水平转录的启动片段及TGF-β、PDGF-BB、IGF-1等细胞因子对其活性的影响. 方法从人α2(Ⅰ)胶原基因转录起始点上游-2.4kb至+58bp的片段中,取长度不等的片段作为启动子与含氯霉素乙酰基转移酶(CAT)报告基因的质粒组成5个重组体,转染上述重组体至正常人原代培养皮肤成纤维细胞,测定细胞CAT表达水平以比较各重组体的启动子活性,同时加入细胞因子,以测定其对Ⅰ型胶原启动序列的影响. 结果除 -129～+58bp序列外,其余4个重组体CAT表达水平均较高,其中-2292～+58bp、-1476～+58bp序列具较强启动CAT表达活性,-339～+58bp、-616～+58bp片段次之.TGF-β、IGF-1均能在一定程度上调人α2(Ⅰ)胶原基因启动活性. 结论人α2(Ⅰ)胶原基因片段-2292～+58bp、-1476～ +58bp、-339～+58bp有高启动活性,是进一步研究纤维化相关DNA结合蛋白的重要调控靶序列.TGF-β、IGF-1促进胶原表达,与其上调胶原基因启动活性有关.     

Lipopolysaccharide-induced increases in porcine serum cortisol and progesterone concentrations are not mediated solely by prostaglandin F2α

The increase in steroid hormone blood levels in response to bacterial lipopolysaccharide (LPS) appears to be an important mechanism by which mammalian species regulate inflammation. This study examined changes in serum concentrations of cortisol, progesterone, and 13,14-dihydro-15-keto-prostaglandin F₂ (PGFM) in diestrous pigs following the intravenous injection of LPS and determined whether indomethacin would attenuate these changes. Serum cortisol and progesterone concentrations increased (P<0.05) within 30 min after the administration of LPS, and the increases in steroid hormones were accompanied by a sharp, transient increase (P<0.05) in PGFM levels. In the presence of indomethacin, serum PGFM levels did not change (P>0.05); however, LPS enhanced (P<0.05) cortisol and progesterone concentrations, although the increases were delayed. Serum concentrations of cortisol acutely increased (P<0.05) immediately following both infusions of indomethacin. In summary, cortisol and progesterone concentrations increased irrespective of serum PGFM concentrations, thereby indicating that prostaglandin F₂ was not the sole mediator of LPS-induced changes in cortisol and progesterone concentrations.     

The effect of hyaluronan on interleukin-1α-induced prostaglandin E2 production in human osteoarthritic synovial cells

Anin vitro study on the effects of hyaluronan (HA) on interleukin-1-induced prostaglandin E₂ (PGE₂) production in human osteoarthritic synovial cells indicated that PGE₂ induction was suppressed by HA in a dose-and molecular weight-dependent manner.     

前列腺素E_2及F_(2α)在流行性出血热发病机理中的作用

木文应用放射免疫法测定流行性出血热患者血浆中前列腺素E_2(PGE_2)和前列腺素F_2a(PGF_2a)的含量,应用竞争性蛋白结合法测定患者血浆中cAMP含量,应用反向间接血凝法测定患者血清中总IgE水平,并对各项指标间的相关性进行了研究。结果表明,各病期患者血浆中的PGE_2、PGF_2a和cAMP水平均显著低于正常人,P<0.01;血清中IgE水平显著高于正常人,P<0.01。PGE_2含量的动态变化与cAMP呈高度正相关(r=0.99),与IgE呈高度负相关(r=-0.985),与PGF_2a基本无相关(r=0.31)。     

Integrin alpha2beta1 (α2β1) promotes prostate cancer skeletal metastasis

Men who die of prostate cancer (PCa) do so because of systemic metastases, the most frequent of which are within the skeleton. Recent data suggest that the colonization of the skeleton is mediated in part by collagen type I, the most abundant protein within the bone. We have shown that enhanced collagen I binding through increased expression of integrin α₂β₁ stimulated in vitro invasion and promoted the growth of PCa cells within the bone. Accordingly, we sought to determine whether α₂β₁ integrin is a potential mediator of skeletal metastasis. To examine whether α₂β₁ integrin mediates PCa metastasis, α₂ integrin was over-expressed in low-tumorigenic LNCaP PCa cells or selectively knocked-down in highly metastatic LNCaP_col PCa cells. We document that the over-expression of α₂ cDNA stimulated whereas α₂ shRNA inhibited the ability of transduced cells to bind to or migrate towards collagen in vitro. Correspondingly, α₂ integrin knock-down reduced the tumor burden of intra-osseous tumors compared to control-transduced cells. To investigate the clinical significance of α₂β₁ expression in PCa, α₂β₁ protein was measured in prostatic tissues and in soft tissue and bone metastases. The data demonstrate that α₂β₁ protein was elevated in PCa skeletal metastases compared to either PCa primary lesions or soft tissue metastases suggesting that α₂β₁ contributes to the selective metastasis to the bone. Taken together, these data support that α₂β₁ integrin is needed for the efficient metastasis of PCa cells to the skeleton.     

三 干扰素-α(interferon alpha,IFN-α)

干扰素-α历史上曾用名为：B-细胞干扰素（B—cell interferon）；血浆沉淀淡黄色表层干扰素（Buffy coat interferon）；外源性细胞干扰素（Foreign cellinduced interferon）；白细胞干扰素（Leukocyte interferon，LeIFN）；淋巴母细胞干扰素（Lymphoblast interferon，LyIFN—alpha）；类淋巴母细胞干扰素（Lymphoblastoid interferon，LyIFN—alpha）；Namalwa细胞干扰素（Namalwa interferon）；pH2-稳定干扰素（pH2-stable interferon）；I型干扰素（Type—1 interferon）；RSV-诱导因子（RSV—induced factor）。     

血浆蛋白酶抑制剂α_2-巨球蛋白(α2M)和α2M蛋白酶复合物对自然杀伤和抗体依赖性细胞介导细胞毒的抑制作用

近来的一些报导已经指出细胞免疫机制能被自然发生的蛋白酶抑制剂所抑制,而且蛋白酶和蛋白酶抑制剂之间的平衡在免疫调节上起一定作用.两种主要的血清蛋白酶抑制剂是α_1-蛋白酶抑制剂(α_1-抗胰蛋白酶)和α2M.已知α2M存在于淋巴细胞和单核细胞表面而且由单核细胞和B细胞亚群产生.α2M在体外可抑制包括混合淋巴细胞反应(MLR)、有丝分裂原刺激和母细胞化的免疫反应.α2M可分成快的α2M和慢     

Selektive Hemmung der Vermehrung von Enteroviren durch 2-(α-Oxy-benzyl)-benzimidazol

Ohne ZusammenfassungDie Arbeit wurde durch Mittel der National Foundation, USA, unterstützt. Vorgetragen auf der 28. Wissenschaftlichen Tagung der Deutschen Gesellschaft für Hygiene und Mikrobiologie in Düsseldorf, Mai 1961.     

α干扰素(IFNα)药动学研究的进展

自从干扰素的发现35年来,对多种肿瘤,尤其血液学的恶性肿瘤,如毛细胞白血病,慢性髓性白血病具有明显的生物活性。近年来研究证明基因重组和天然来源的两类干扰素具有广谱的抗病毒活性,IFNα对40％的丙肝病人有效,经IFNα治疗后的乙肝通常可长期缓解,故其临床应用日益广泛。但有关IFNα的药动学研究相对比较少,现将近年来国内外有关药动学的研究作一综述,以便为临床应用提供药动学的理论基础。     

α(1)-antitrypsin deficiency and inflammation

α(1)-antitrypsin deficiency is an autosomal recessive disorder that results from point mutations in the SERPINA1 gene. The Z mutation (Glu342Lys) accounts for the majority of cases of severe α(1)-antitrypsin deficiency. It causes the protein to misfold into ordered polymers that accumulate within the endoplasmic reticulum of hepatocytes. It is these polymers that form the periodic acid Schiff positive inclusions that are characteristic of this condition. These inclusions are associated with neonatal hepatitis, cirrhosis and hepatocellular carcinoma. The lack of circulating α(1)-antitrypsin exposes the lungs to uncontrolled proteolytic attack and so can predispose the Z α(1)-antitrypsin homozygote to early-onset emphysema. α(1)-antitrypsin polymers can also form in extracellular tissues where they activate and sustain inflammatory cascades. This may provide an explanation for both progressive emphysema in individuals who receive adequate replacement therapy and the selective advantage associated with α(1)-antitrypsin deficiency. Therapeutic strategies are now being developed to block the aberrant conformational transitions of mutant α(1)-antitrypsin and so treat the associated disease.     

遗传性Lp(α)变异的临床意义

由遗传决定的Lp(α)表现型是自婴儿起就存在于个体血清中的稳定特征。由于Lp(α)脂蛋白相似于低密度脂蛋白(LDL),认为其功能可与LDL相比拟。冠心病病人Lp(α+)的出现频率高于健康人。Lp(α)型对血清胆固醇和三酸甘油脂水平有轻度影响。此外,Lp(α+)和 Lp(α-)也有个体间的生化差异(如空腹胰岛素水平、胰岛素反应、游离甲状腺素因子)。LP型对脂类水平的影响似乎太小,不足以充