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Role of neutrophil apoptosis in vanadium-induced pulmonary inflammation in mice. 中性粒细胞凋亡在钒诱导小鼠肺部炎症中的作用。
Liying Wang, D. Medan, R. Mercer, Xianglin Shi, Chuanshu Huang, V. Castranova, M. Ding, Y. Rojanasakul
Pulmonary exposure to airborne vanadium and vanadium-containing compounds is associated with acute pulmonary inflammation, characterized by a rapid influx of neutrophilic polymorphonuclear leukocytes with a peak response at 6 hours and resolution by 3 days. We hypothesized that neutrophil apoptosis is involved in the resolution of vanadium-induced lung inflammation. To test this hypothesis, mice were exposed to inspired vanadium or saline control and the bronchoalveolar lavage (BAL) cells were examined at various times for apoptosis using terminal deoxyribonucleotidyl transferase-mediated nick end labeling (TUNEL). Control mice showed only resident alveolar macrophages in the BAL with no evidence of apoptosis. In contrast, vanadium-treated mice showed clear apoptosis of BAL cells, which were predominantly neutrophils. The number of apoptotic cells gradually increased and reached a maximal level by 24 hours with subsequent decline. After 24 hours, when the vanadium-induced lung inflammation was in the resolution phase, we observed an increased number of alveolar macrophages in BAL and the engulfment of apoptotic bodies by these macrophages. At 72 hours, the total number of neutrophils in BAL fell to the baseline level, and the number of apoptotic cells was reduced. Clearance of the apoptotic product was demonstrated by the presence of apoptotic bodies in the cytoplasm of alveolar macrophages. We conclude that apoptosis of neutrophils and clearance by alveolar macrophages are important mechanisms in the resolution of vanadium-induced lung inflammation.
肺暴露于空气中的钒和含钒化合物与急性肺部炎症有关,其特征是中性粒细胞多形核白细胞快速涌入,6小时达到峰值,3天消退。我们假设中性粒细胞凋亡参与了钒诱导的肺部炎症的消退。为了验证这一假设,将小鼠暴露于激发钒或生理盐水对照中,并使用末端脱氧核糖核苷酸转移酶介导的缺口末端标记(TUNEL)在不同时间检测支气管肺泡灌洗(BAL)细胞的凋亡情况。对照组小鼠BAL中只有常驻肺泡巨噬细胞,无凋亡迹象。相反,钒处理小鼠BAL细胞明显凋亡,以中性粒细胞为主。凋亡细胞数量逐渐增加,在24小时达到最大,随后下降。24小时后,当钒诱导的肺部炎症处于消退期时,我们观察到BAL中肺泡巨噬细胞数量增加,这些巨噬细胞吞噬凋亡小体。72h时,BAL中中性粒细胞总数降至基线水平,凋亡细胞数量减少。肺泡巨噬细胞细胞质中凋亡小体的存在证明了凋亡产物的清除。我们认为中性粒细胞的凋亡和肺泡巨噬细胞的清除是解决钒诱导的肺部炎症的重要机制。
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引用次数: 9
Redox status-dependent regulation of cyclooxygenases mediates the capsaicin-induced apoptosis in human neuroblastoma cells. 环氧合酶的氧化还原状态依赖性调节介导辣椒素诱导的人神经母细胞瘤细胞凋亡。
Yong Soo Lee, E. Kwon, Da-qing Jin, S. Park, Y. Kang, K. Huh, Jung-Ae Kim
Cyclooxygenases (COX) appear to be involved in the mechanism of apoptosis in various cancer cells. In this study we investigated the role of COX in the capsaicin (Cap)-induced apoptosis in SK-N-SH human neuroblastoma cells. Cap induced decreased cell viability and apoptosis in a dose-dependent manner. Cap also significantly reduced the basal generation of reactive oxygen species (ROS) and lipid peroxidation in a time-dependent fashion. Cap markedly suppressed the expression of COX-1 and COX-2. Pretreatment with NS-398, a selective COX-2 inhibitor, or indomethacin, a nonselective COX inhibitor, significantly enhanced the Cap-induced decreased cell viability and apoptosis. Exogenous application of an oxidant, H2O2, significantly prevented the Cap-induced apoptosis and suppressed the expression of COX isoforms. These results suggest that redox status-dependent regulation of COX expression may mediate apoptosis induced by Cap in human neuroblastoma cells.
环氧合酶(COX)似乎参与了多种癌细胞的凋亡机制。在这项研究中,我们研究了COX在辣椒素(Cap)诱导的SK-N-SH人神经母细胞瘤细胞凋亡中的作用。Cap诱导细胞活力降低和凋亡呈剂量依赖性。Cap还显着减少了活性氧(ROS)和脂质过氧化的基础生成,并具有时间依赖性。Cap显著抑制COX-1和COX-2的表达。用NS-398(一种选择性COX-2抑制剂)或吲哚美辛(一种非选择性COX抑制剂)预处理,可显著增强cap诱导的细胞活力下降和凋亡。外源应用氧化剂H2O2可显著阻止cap诱导的细胞凋亡并抑制COX亚型的表达。这些结果表明,氧化还原状态依赖性的COX表达调节可能介导Cap诱导的人神经母细胞瘤细胞凋亡。
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引用次数: 28
Epidemiological and clinical aspects of nonsteroidal anti-inflammatory drugs and cancer risks. 非甾体抗炎药与癌症风险的流行病学和临床研究。
E. Moran
It is well known that about 70% of cancer cases are due to environmental, dietary, or lifestyle factors. Accordingly, these cases maybe avoided by appropriate modifications. In addition, active chemoprevention has become a major interventional approach following the epidemiological observation of a beneficial effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in colon cancer prevention. This is chiefly due to the inhibition of the cyclooxygenase (COX) enzymes. The COX enzymatic system includes two isoenzymes, COX-1 and COX-2, that convert arachidonic acid to prostaglandins. COX-1 is constitutively expressed and synthesizes cytoprotective prostaglandins in the gastrointestinal tract. COX-2 is inducible by the oncogenes ras and scr and other cytokines; it is overexpressed in human cancer cells in which it stimulates cellular division and angiogenesis and inhibits apoptosis. NSAIDs restore apoptosis and decrease tumor mitogenesis and angiogenesis. Most cancer cells have been found to exhibit overexpression of COX-2. Epidemiological studies showed a lower risk of developing cancer of the colon, breast, esophagus, and stomach following the ingestion of NSAIDs. The use of NSAIDs in low dose was associated with a statistically significant decrease in the risk of adenomatous polyps and of overt colon cancer. The regressive effects of sulindac on foci of aberrant crypts in the colon (considered to be precursors of adenoma), and on adenocarcinoma of the colon, are of particular interest because this NSAID does not have an inhibitory effect on COX. This may support the view that the antineoplastic effect of NSAIDs may also be due to a mechanism other than COX-2 inhibition. In breast cancer, large cohort studies reported a 40 to 50% reduced risk of developing cancer, a smaller size of the primary tumor, and a reduction in the number of involved axillary lymph nodes. Similar findings have been reported in the esophagus and stomach, but not in gastric cardia adenocarcinoma. The recent development of selective COX-2 inhibitors resulted in better clinical tolerance than that associated with NSAIDs in general, with the absence of gastrointestinal side effects known to occur after the inhibition of COX-1. Encouraging results have been obtained with these new agents in familial adenomatous polyposis, colon, breast, and prostate cancer.
众所周知,大约70%的癌症病例是由环境、饮食或生活方式因素造成的。因此,这些情况可以通过适当的修改来避免。此外,在流行病学观察到非甾体抗炎药(NSAIDs)在预防结肠癌中的有益作用后,积极的化学预防已成为一种主要的干预方法。这主要是由于环加氧酶(COX)的抑制。COX酶系统包括两个同工酶,COX-1和COX-2,将花生四烯酸转化为前列腺素。COX-1在胃肠道中组成性表达和合成细胞保护性前列腺素。COX-2可被癌基因ras、scr等细胞因子诱导;它在人类癌细胞中过度表达,刺激细胞分裂和血管生成,抑制细胞凋亡。非甾体抗炎药恢复细胞凋亡,减少肿瘤有丝分裂和血管生成。大多数癌细胞被发现表现出COX-2的过度表达。流行病学研究表明,服用非甾体抗炎药后患结肠癌、乳腺癌、食道癌和胃癌的风险较低。低剂量使用非甾体抗炎药与腺瘤性息肉和显性结肠癌的风险显著降低相关。舒林酸对结肠异常隐窝灶(被认为是腺瘤的前体)和结肠腺癌的消退作用特别令人感兴趣,因为这种非甾体抗炎药对COX没有抑制作用。这可能支持非甾体抗炎药的抗肿瘤作用也可能是由于COX-2抑制以外的机制。在乳腺癌中,大型队列研究报告了40%到50%的患癌风险降低,原发肿瘤的大小减小,腋窝淋巴结的数量减少。在食道和胃中也有类似的发现,但在贲门腺癌中没有报道。选择性COX-2抑制剂的最新发展导致临床耐受性优于非甾体抗炎药,并且在抑制COX-1后没有已知的胃肠道副作用。这些新药在家族性腺瘤性息肉病、结肠癌、乳腺癌和前列腺癌的治疗中取得了令人鼓舞的结果。
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引用次数: 83
Escape mechanisms in tumor immunity: an update. 肿瘤免疫中的逃逸机制:最新进展。
Ludmila Müller, R. Kiessling, R. Rees, G. Pawelec
Evidence that tumors are immunogenic continues to accumulate. Although they frequently do express antigens in a form recognizable by the host immune system, tumors commonly "escape" the immune response. Tumors may therefore progress by evolving variants that can evade immune responses or by developing other strategies to avoid immune control. The purpose of this review is to consider the current status of knowledge concerning these different tumor-escape strategies, in the form of an update of previous publications in this journal.
肿瘤具有免疫原性的证据不断积累。尽管它们经常以宿主免疫系统可识别的形式表达抗原,但肿瘤通常会“逃避”免疫反应。因此,肿瘤可能通过进化能够逃避免疫反应的变异或通过发展其他策略来避免免疫控制而进展。这篇综述的目的是考虑关于这些不同的肿瘤逃逸策略的知识现状,以更新之前在该杂志上发表的文章的形式。
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引用次数: 16
Modulatory effect of phenolic fractions of Terminalia arjuna on the mutagenicity in Ames assay. 苦参酚类组分对Ames实验致突变性的调节作用。
K. Kaur, Saroj Arora, Subodh Kumar, A. Nagpal
We determined the antimutagenicity of phenolic fractions of Terminalia arjuna (soluble and insoluble in chloroform) against two direct-acting mutagens, 4-nitro-o-phenylenediamine (NPD) and sodium azide, and against the S9-dependent mutagen 2-aminofluorene (2AF), in TA98 and TA100 tester strains of Salmonella typhimurium. We found that the phenolic fractions of T. arjuna inhibited revertants induced by the S9-dependent mutagen more remarkably than the direct-acting mutagens. Furthermore, the phenolic fractions showed maximum inhibition of 98% and 101.55%, respectively, in the pre-incubation mode of treatment against the mutations induced by 2AF. Overall, the fractions inhibited the revertants induced by S9-dependent mutagens more effectively than those induced by direct-acting mutagens. The percentage of inhibition was higher in the pre-incubation than with direct acting mutagens. The fraction insoluble in chloroform showed more inhibition than the soluble one, which corresponds to a higher polyphenol content in the insoluble fraction than in the soluble extract.
在鼠伤寒沙门菌TA98和TA100试验菌株中,测定了沙麻酚类组分(可溶于氯仿和不溶于氯仿)对4-硝基-邻苯二胺(NPD)和叠氮化钠两种直接作用诱变剂以及对s9依赖性诱变剂2-氨基芴(2AF)的抗诱变作用。结果表明,与直接作用诱变剂相比,黄叶参酚类组分对s9依赖性诱变剂诱导的反复性抑制作用更显著。此外,在2AF诱导突变的预处理模式下,酚类组分分别表现出98%和101.55%的最大抑制作用。总的来说,这些组分比直接作用诱变剂更有效地抑制s9依赖性诱变剂诱导的逆转录。孵育前的抑制率高于直接作用诱变剂。不溶于氯仿的部位比溶于氯仿的部位具有更强的抑制作用,说明不溶于氯仿的部位比溶于氯仿的部位多酚含量高。
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引用次数: 14
Increased expression of COX-2 in the development of human lung cancers. COX-2在人肺癌发生过程中的表达增加。
Takashi Takahashi, K. Kozaki, Y. Yatabe, H. Achiwa, T. Hida
It is well accepted that an increase in the expression of cyclooxygenase-2 (COX-2), a key inducible enzyme involved in the production of prostaglandins and other eicosanoids, may play a significant role in carcinogenesis in addition to its well-known role in inflammatory reactions. Whereas previous studies were largely confined to colorectal tumorigenesis, we have shown that a significantly increased expression of COX-2 may also play a role in the development of lung cancer. COX-2 expression was found to be frequently elevated in lung cancer, especially in adenocarcinoma, and the proportion of lung cancer cells with marked COX-2 expression was much higher in lymph node metastases than in the corresponding primary tumors. It was also shown that early stage adenocarcinoma patients with increased COX-2 expression who were surgically treated had a shorter survival. Our studies, which used high- and low-metastatic human lung cancer cell sublines established in our laboratory, revealed an association between metastatic capabilities and COX-2 expression levels: COX-2-specific inhibitors could inhibit in vitro the invasion of the highly metastatic NCI-H460-LNM35 clone through Matrigel-containing basement membrane components as well as the spontaneous in vivo metastasis in SCID mice. Taken together, these findings suggest that an increase in COX-2 expression maybe associated with the development of lung cancer and possibly with the acquisition of an invasive and metastatic phenotype.
环氧化酶-2 (COX-2)是一种关键的诱导酶,参与前列腺素和其他类二十烷类物质的产生,其表达的增加除了在炎症反应中众所周知的作用外,还可能在癌变中发挥重要作用,这一点已被广泛接受。尽管之前的研究主要局限于结直肠肿瘤的发生,但我们已经表明,COX-2的显著表达增加也可能在肺癌的发展中发挥作用。COX-2在肺癌中表达频繁升高,尤其是在腺癌中,并且在淋巴结转移的肺癌细胞中COX-2表达显著的比例远高于相应的原发肿瘤。研究还表明,COX-2表达升高的早期腺癌患者接受手术治疗的生存期较短。我们的研究使用了我们实验室建立的高转移和低转移的人肺癌细胞亚群,揭示了转移能力与COX-2表达水平之间的关联:COX-2特异性抑制剂可以在体外抑制高转移的NCI-H460-LNM35克隆通过含有matrigel的基底膜组分侵袭SCID小鼠,以及体内自发转移。综上所述,这些发现表明COX-2表达的增加可能与肺癌的发展有关,并可能与浸润性和转移性表型的获得有关。
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引用次数: 39
DNA single strand breaks induced by low levels of occupational exposure to styrene: the gap between standards and reality. 低水平职业接触苯乙烯引起的DNA单链断裂:标准与现实之间的差距。
M. Shamy, Hazem H Osman, K. Kandeel, N. M. Abdel-Moneim, Said Khalid F El
Styrene is a known mutagen and suspected carcinogen, used in the reinforced plastic industry. This study aims to identify the occurrence of DNA single strand breaks (SSBs) in workers exposed to styrene levels far below the recommended standards. We compared 26 exposed workers with 26 control subjects and found a significant increase in the incidence of DNA-SSBs in the exposed individuals. The levels of the biological indices of exposure (urinary mandelic and phenyl glyoxylic acids) were less than 25% of the recommended limits. Reduction of the threshold limit values/time-weighted-average (TLV-TWA) applied is strongly recommended.
苯乙烯是一种已知的诱变剂和疑似致癌物,用于增强塑料工业。这项研究的目的是确定DNA单链断裂(SSBs)的工人暴露于苯乙烯水平远低于推荐标准。我们将26名暴露工人与26名对照进行了比较,发现暴露个体中DNA-SSBs的发生率显著增加。暴露的生物学指标(尿扁桃酸和苯乙醛酸)水平低于建议限值的25%。强烈建议减少阈值限值/时间加权平均值(TLV-TWA)的应用。
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引用次数: 10
Organ selectivity of chemical carcinogens. 化学致癌物的器官选择性。
Jasbir Singh, Kovleen, H. M. Dani, Rajeshwar Sharmar
Chemical carcinogens are organ selective and not organ specific. Microsomal degranulation elution profiles employing sepharose CL-2B gel filtration for the separation of microsomes from different organs of rats before and after treatment with some known chemical carcinogens have shown for the first time that carcinogens selectively detach maximum ribosomes from rough reticular membranes of their target organs. The detachment of ribosomes from other organs varies, but is comparatively lesser than that in the target organs. A chemical carcinogen might, therefore, be tumorigenic for several organs, possibly depending on the dose reaching a particular organ and its activation to the ultimate form of the carcinogen.
化学致癌物是器官选择性的,而不是器官特异性的。用蔗糖CL-2B凝胶过滤分离大鼠不同器官微粒体的微粒体脱颗粒洗脱谱首次表明,致癌物可选择性地从靶器官的粗网状膜上最大限度地分离核糖体。核糖体从其他器官分离的情况各不相同,但相对较少。因此,化学致癌物可能对几个器官具有致瘤性,这可能取决于到达特定器官的剂量及其对致癌物最终形式的激活。
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引用次数: 0
Suppressive effect of natural sesquiterpenoids on inducible cyclooxygenase (COX-2) and nitric oxide synthase (iNOS) activity in mouse macrophage cells. 天然倍半萜对小鼠巨噬细胞诱导型环氧合酶(COX-2)和一氧化氮合酶(iNOS)活性的抑制作用。
S. Lee, C. Hong, S. Huh, Sun-Sook Kim, Omer Oh, H. Min, Kwang-Kyun Park, W. Chung, J. Hwang
Prostaglandins and nitric oxide produced by inducible cyclooygenase (COX-2) and nitric oxide synthase (iNOS), respectively, have been implicated as important mediators in the processes of inflammation and carcinogenesis. These potential COX-2 and iNOS inhibitors have been considered as antiinflammatory and cancer chemopreventive agents. In this study, we investigated the effect of natural sesquiterpenoids isolated from plants of the Zingiberaceae family on the activities of COX-2 and iNOS in cultured lipopolysaccharide (LPS)-activated mouse macrophage cell RAW 264.7 to discover new lead compounds as COX-2 or iNOS inhibitors. Xanthorrhizol, a sesquiterpenoid, isolated from the rhizome of Curcuma xanthorrhiza Roxb. (Zingiberaceae), exhibited a potent inhibition of COX-2 (IC50 = 0.2 microg/mL) and iNOS activity (IC50 = 1.0 microg/mL) in the assay system of prostaglandin E2 (PGE2) accumulation and nitric oxide production, respectively. Western blot analyses revealed that the inhibitory potential of xanthorrhizol on the COX-2 activity coincided well with the suppression of COX-2 protein expression in LPS-induced macrophages. In addition, sesquiterpenoids beta-turmerone and ar-turmerone isolated from the rhizome of Curcuma zedoaria Roscoe (Zingiberaceae) also showed a potent inhibitory activity of COX-2 (beta-turmerone, IC50 = 1.6 microg/mL; ar-turmerone, IC50 = 5.2 microg/mL) and iNOS (beta-turmerone, IC50 = 4.6 microg/mL; ar-turmerone, IC50 = 3.2 microg/mL). These results suggest that natural sesquiterpenoids from C. xanthorrhiza and C. zedoaria might be lead candidates for further developing COX-2 or iNOS inhibitors possessing cancer chemopreventive or anti-inflammatory properties.
前列腺素和一氧化氮分别由诱导环合酶(COX-2)和一氧化氮合酶(iNOS)产生,在炎症和癌变过程中被认为是重要的介质。这些潜在的COX-2和iNOS抑制剂被认为是抗炎和癌症化学预防剂。本研究通过研究姜科植物天然倍半萜类化合物对脂多糖(LPS)激活小鼠巨噬细胞RAW 264.7中COX-2和iNOS活性的影响,以发现新的COX-2或iNOS抑制剂先导化合物。黄嘌呤是一种从姜黄根茎中分离得到的倍半萜。在前列腺素E2 (PGE2)积累和一氧化氮生成的检测系统中,姜黄对COX-2 (IC50 = 0.2 μ g/mL)和iNOS活性(IC50 = 1.0 μ g/mL)均有明显的抑制作用。Western blot分析显示,黄菌根醇对lps诱导的巨噬细胞中COX-2蛋白表达的抑制作用与对COX-2蛋白表达的抑制作用相吻合。此外,莪术根中提取的倍半萜类β -姜黄酮和ar-姜黄酮也对COX-2 (β -姜黄酮)具有较强的抑制活性,IC50 = 1.6微克/mL;ar-姜黄酮,IC50 = 5.2微克/毫升)和iNOS (β -姜黄酮,IC50 = 4.6微克/毫升;ar-turmerone, IC50 = 3.2 μ g/mL)。这些结果表明,黄芍和莪麻中的天然倍半萜可能是进一步开发具有癌症化学预防或抗炎特性的COX-2或iNOS抑制剂的主要候选者。
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引用次数: 87
Studies on sister chromatid exchanges in peripheral lymphocytes of spray painters. 喷绘者外周血淋巴细胞姊妹染色单体交换的研究。
P. Gajalakshmi, P. Mallick, P. Venkatesan, S. T. Santhiya, A. Ramesh
In a comparative study of sister chromatid exchanges (SCEs) in cultured lymphocytes, we evaluated the genotoxic risk in 104 male spray painters employed in repair workshops in Chennai City, India, and 50 matched healthy, unexposed controls. We found a higher frequency of SCEs among painters (3.74 +/- 0.11, mean +/- SE) than among controls (2.15 +/- 0.08), and among smoking painters (4.03 +/- 0.21) than among nonsmoking painters (3.55 +/- 0.13), with no significant difference in controls (smokers: 2.1 +/- 0.2; nonsmokers: 2.2 +/- 0.1). Alcoholism did not contribute to an increased SCE frequency. Stepwise multiple linear regression analysis on painters showed that duration of service, smoking, and alcoholism significantly affected SCE scores and explained the 14% variation observed.
在一项培养淋巴细胞姐妹染色单体交换(ses)的比较研究中,我们评估了印度钦奈市维修车间雇用的104名男性喷漆工和50名匹配的健康未暴露对照者的遗传毒性风险。我们发现,画家的sce发生率(3.74 +/- 0.11,平均+/- SE)高于对照组(2.15 +/- 0.08),吸烟画家的sce发生率(4.03 +/- 0.21)高于不吸烟画家的sce发生率(3.55 +/- 0.13),对照组无显著差异(吸烟者:2.1 +/- 0.2;不吸烟者:2.2±0.1)。酒精中毒并不会增加SCE的发生频率。对画家的逐步多元线性回归分析显示,工作时间、吸烟和酗酒显著影响SCE得分,并解释了观察到的14%的变异。
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引用次数: 0
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Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer
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