COX-derived prostanoid pathways in gastrointestinal cancer development and progression : novel targets for prevention and intervention

Arachidonic acid metabolism through cyclooxygenase (COX) pathways leads to the generation of biologically active eicosanoids. Eicosanoid expression levels vary during development and progression of gastrointestinal (GI) malignancies. COX-2 is the major COX-isoform responsible for G.I. cancer development/progression. COX-2 expression increases during progression from a normal to cancerous state. Evidence from observational studies has demonstrated that chronic NSAID use reduces the risk of cancer development, while both incidence and risk of death due to G.I. cancers were significantly reduced by daily aspirin intake. A number of randomized controlled trials (APC trial, Prevention of Sporadic Adenomatous Polyps trial, APPROVe trial) have also shown a significant protective effect in patients receiving selective COX-2 inhibitors. However, chronic use of selective COX-2 inhibitors at high doses was associated with increased cardiovascular risk, while NSAIDs have also been associated with increased risk. More recently, downstream effectors of COX-signaling have been investigated in cancer development/progression. PGE 2, which binds to both EP and PPAR receptors, is the major prostanoid implicated in the carcinogenesis of G.I. cancers. The role of TXA 2 in G.I. cancers has also been examined, although further studies are required to uncover its role in carcinogenesis. Other prostanoids investigated include PGD 2 and its metabolite 15d-PGJ2, PGF 1α and PGI 2. Targeting these prostanoids in G.I. cancers has the promise of avoiding cardiovascular toxicity associated with chronic selective COX-2 inhibition, while maintaining anti-tumor reactivity.A progressive sequence from normal to pre-malignant to a malignant state has been identified in G.I. cancers. In this review, we will discuss the role of the COX-derived prostanoids in G.I. cancer development and progression. Targeting these downstream prostanoids for chemoprevention and/or treatment of G.I. cancers will also be discussed. Finally, we will highlight the latest pre-clinical technologies as well as avenues for future investigation in this highly topical research field. © 2011 Elsevier B.V.

The role of the arachidonic acid pathway in NSCLC development and progression : novel approaches for therapeutic intervention

Arachidonic acid metabolism through cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P-450 epoxygenase (EPOX) pathways is responsible for the formation of biologically active eicosanoids, including prostanoids, leukotrienes, hydroxyeicosatetraenoic acid, epoxyeicosatrienoic acid and hydroperoxyeicosatetraenoic acids. Altered eicosanoid expression levels are commonly observed during tumour development and progression of a range of malignancies, including non-small cell lung cancer (NSCLC). Arachidonic acid-derived eicosanoids affect a range of biological phenomena to modulate tumour processes such as cell growth, survival, angiogenesis, cell adhesion, invasion and migration and metastatic potential. Numerous studies have demonstrated that eicosanoids modulate NSCLC development and progression, while targeting these pathways has generally been shown to inhibit tumour growth/progression. Modulation of these arachidonic acid-derived pathways for the prevention and/or treatment of NSCLC has been the subject of significant interest over the past number of years, with a number of clinical trials examining the potential of COX and LOX inhibitors in combination with traditional and novel molecular approaches. However, results from these trials have been largely disappointing. Furthermore, enthusiasm for the use of selective COX-2 inhibitors for cancer prevention/treatment waned, due to their association with adverse cardiovascular events in chemoprevention trials. While COX and LOX targeting may both retain promise for NSCLC prevention and/or treatment, there is an urgent need to understand the downstream signalling mechanisms through which these and other arachidonic acid-derived signalling pathways mediate their effects on tumourigenesis. This will allow for development of safer and potentially more effective strategies for NSCLC prevention and/or treatment. Chemoprevention studies with PGI2 analogues have demonstrated considerable promise, while binding to/signalling through PGE2 receptors have also been the subject of interest for NSCLC treatment. In this chapter, the role of the eicosanoid signalling pathways in non-small cell lung cancer will be discussed. In particular, the effect of the eicosanoids on tumour cell proliferation, their roles in induction of cell death, effects on angiogenesis, migration, invasion and their regulation of the immune response will be assessed, with signal transduction pathways involved in these processes also discussed. Finally, novel approaches targeting these arachidonic acid-derived eicosanoids (using pharmacological or natural agents) for chemoprevention and/or treatment of NSCLC will be outlined. Elucidating the molecular mechanisms underlying the effects of specific or general arachidonic acid pathway modulators may lead to the design of biologically and pharmacologically targeted therapeutic strategies for NSCLC prevention/treatment, which may be used alone or in combination with conventional therapies.

Regulation of Kinin receptor Expression in Heart Failure with a Focus on Vascular Endothelium

Accumulating evidence show that kinins, notably bradykinin (BK) and kallidin, have cardioprotective effects. To these include reduction of left ventricular hypertrophy (LVH) and progression of heart failure. The effects are mediated through two G protein-coupled receptors- bradykinin type-2 receptor (BK-2R) and bradykinin type -1 receptor (BK-1R). The widely accepted cardioprotective effects of BK-receptors relate to triggering the production and release of vasodilating nitric oxide (NO) by endothelial cells. They also exert anti-proliferative effects on fibroblasts and anti-hypertrophic effects on myocytes, and thus may play an essential role in the cardioprotective response to myocardial injury. The role for BK-1Rs in HF is based on experimental animal models, where the receptors have been linked to cardioprotective- but also to cardiotoxic -effects. The BK-1Rs are induced under inflammatory and ischemic conditions, shown in animal models; no previous reports, concerning BK-1Rs in human heart failure, have been presented. The expression of BK-2Rs is down-regulated in human end-stage heart failure. Present results showed that, in these patients, the BK-1Rs were up-regulated, suggesting that also BK-1Rs are involved in the pathogenesis of human heart failure. The receptors were localized mainly in the endothelium of intramyocardial coronary vessels, and correlated with the increased TNF-α expression in the myocardial coronary vessels. Moreover, in cultured endothelial cells, TNF-α was a potent trigger of BK-1Rs. These results suggest that cytokines may be responsible for the up-regulation of BK-1Rs in human heart failure. A linear relationship between BK-2R mRNA and protein expression in normal and failing human left ventricles implies that the BK-2Rs are regulated on the transcriptional level, at least in human myocardium. The expression of BK-2Rs correlated positively with age in normal and dilated hearts (IDC). The results suggest that human hearts adapts to age-related changes, by up-regulating the expression of cardioprotective BK-2Rs. Also, in the BK-2R promoter polymorphism -58 T/C, the C-allele was accumulated in cardiomyopathy patients which may partially explain the reduced number of BK-2Rs. Statins reduce the level of plasma cholesterol, but also exert several non-cholesterol-dependent effects. These effects were studied in human coronary arterial endothelial cells (hCAEC) and incubation with lovastatin induced both BK-1 and BK-2Rs in a time and concentration-dependent way. The induced BK-2Rs were functionally active, thus NO production and cGMP signaling was increased. Induction was abrogated by mevalonate, a direct HMG-CoA metabolite. Lovastatin is known to inhibit Rho activation, and by a selective RhoA kinase inhibitor (Y27632), a similar induction of BK-2R expression as with lovastatin. Interestingly a COX-2-inhibitor (NS398) inhibited this lovastatin-induction of BK-2Rs, suggesting that COX-2 inhibitors may affect the endothelial BK-2Rs, in a negative fashion. Hypoxia is a common denominator in HF but also in other cardiovascular diseases. An induction of BK-2Rs in mild hypoxic conditions was shown in cultured hCAECs, which was abolished by a specific BK-2R inhibitor Icatibant. These receptors were functionally active, thus BK increased and Icatibant inhibited the production of NO. In rat myocardium the expression of BK-2R was increased in the endothelium of vessels, forming at the border zone, between the scar tissue and the healthy myocardium. Moreover, in in vitro wound-healing assay, endothelial cells were cultured under hypoxic conditions and BK significantly increased the migration of these cells and as Icatibant inhibited it. These results show, that mild hypoxia triggers a temporal expression of functionally active BK-2Rs in human and rat endothelial cells, supporting a role for BK-2Rs, in hypoxia induced angiogenesis. Our and previous results show, that BK-Rs have an impact on the cardiovascular diseases. In humans, at the end stage of heart failure, the BK-2Rs are down-regulated and BK-1Rs induced. Whether the up-regulation of BK-1Rs, is a compensatory mechanism against the down-regulation of BK-2Rs, or merely reflects the end point of heart failure, remains to bee seen. In a clinical point of view, the up-regulation of BK-2Rs, under hypoxic conditions or statin treatment, suggests that, the induction of BK-2Rs is protective in cardiovascular pathologies and those treatments activating BK-2Rs, might give additional tools in treating heart failure.

聚乳酸与聚丙撑碳酸酯共混体系研究

近年来，由于“白色污染”日益严重，开发可降解塑料已成为世界范围的研究热点。聚乳酸（PLA）是人工合成的热塑性脂肪族聚酯。由于其具有良好的生物降解性能，优异的生物相容性和生物可吸收性，在医学领域已被认为是最具有前途的可降解生物高分子材料。PLA还具有较高的弹性模量和硬度，可以用于包装材料。在环保要求的推动下，人们对PLA产生了进一步的研究兴趣和重视，开始了将其作为通用塑料替代产品的探索和开发。但是PLA具有自身的不足之处：热稳定性较差，脆性严重。这些对产品的性能影响较大，严重阻碍了PLA市场的进一步扩大。本论文选用同样可生物降解的聚丙撑碳酸酯（PPC）与PLA进行共混，在确保共混物生物降解的前提下，改善PLA的加工性能和提高PLA的韧性，为PLA的应用奠定基础。 1．通过熔融共混的方法制备了一系列不同比例的PLA/PPC共混物。通过DSC和力学性能测试的方法对不同比例的共混物的相容性、力学性能、及其流变性能进行研究。研究结果表明PLA与PPC是不相容的。当PLA/PPC的共混比例为50/50时共混体系有较好的力学性能。但是PPC的加入不能有效的改善PLA的韧性。 2．PPC在室温为玻璃态，这可能是PPC不能直接增韧PLA的主要原因。采用增塑的方法降低PPC的玻璃化转变温度，磷酸三丁酯、邻苯二甲酸二丁酯、乙酰化柠檬酸三乙酯都可以作为PPC的增塑剂，其中乙酰化柠檬酸三乙酯的增塑效果最好。乙酰化柠檬酸三乙酯对PLA虽然也有一定的增塑作用，但是对PLA的增塑效果不如PPC的明显。 3．考虑到用增塑的PPC去增韧PLA会发生增塑剂在共混物中的重新分配， 本工作同时也对PLA/PPC/ATEC三元共混体系进行了研究。两种共混体系都是不相容体系。增塑的PPC（100PPC/5ATEC）在与PLA的共混过程中会发生增塑剂的重新分配。增塑剂的加入有效地改善了体系的力学性能，体系的断裂伸长率、冲击强度有明显的提高，但与增塑剂加入的先后顺序无关。

可生物降解聚合物药物载体及其制备技术

药物释放体系因其具有提高药物的疗效，降低药物的毒副作用，减少药物的服用次数，拓宽给药途径等特点，而成为近几年来人们研究的热点。生物可降解高分子，由于它们在体内可以降解，降解产物可以被机体吸收或代谢，不存在积累在体内的危险，因此成为药物释放体系的载体的首选材料。特别是脂肪族聚酷类高分子，在与聚乙二醇形成嵌段共聚物后，不仅具有生物可降解性，而月＿大大地改善了材料与人体的生物相容性，作为药物载体材料时，延长了药物在体内的循环时间，降低了免疫响应性，引起了人们的极大兴趣。因此本论文主要是以MPEG-PLA两嵌段聚合物为药物的载体材料，详细研究了高分子量的MPEG-PLA两嵌段聚合物对紫杉醇的包裹，研究了MPEG-PLA和PLGA聚合物合金对胰岛素固体粉末的包裹，以及低分子量的MPEG-PLA的紫杉醇前药的合成、表征和由它制备而成的胶束的一些性质，取得了一些有意义的结果：1、采用改进的O／W乳液法，用高分子量的MPEG-PLA嵌段共聚物实现了对紫杉醇的纳米化包裹，并证实了聚合物的分子量对所制备的纳米微球的粒径的影响：分子量越大，粒径越大。同时发现了微球粒径越小，药物的包裹量越低。2、用扫描电镜（SEM）、光电子能谱（XPS）、差热分析（DSC）对纳米微球进行了分析和测定，结果表明，微球的尺寸在30Om-800nm范围，紫杉醇在纳米微球的表面几乎不存在，而是以无定形的状态分布在纳米微球中。3、对纳米微球中紫杉醇体外释放行为进行了侧定。它们显现出了明显的双相行为，即在初期释放速度很快，随后的释放速度变慢。同时，研究了MPEG-PLA的分子量对释放行为的影响：聚合物分子量越大，紫杉醇释放的速度就越慢。4、用固体粉末法和双乳液法对胰岛素进行了包裹，其中固体粉末法采用的是PLGA和MPEG-PLA两聚合物的混合溶液对纳米胰岛素颗粒进行了包裹，包裹率分析表明：固体粉末法对药物的包裹率高于双乳液法。所得的微球都是很好的球形，其尺寸在1-3um左右，它的剖面是核壳结构，胰岛素以晶粒的形式被包裹在微球中间。5、对固体粉末法和双乳液法制备的微球的体外释放行为进行了对比，发现由两种聚合物合金制备的微球的暴释现象得到了缓解，同时发现两种聚合物的配比不一样，其暴释缓解的程度不一样。6、以辛酸亚锡为催化剂成功地合成了低分子量的MPEG-PLA两嵌段聚合物。二经基乙酸配与过量的叔丁醇在DMAP存在下反应，成功制得了二轻基乙酸单叔丁酷。MPEG-PLA的端经基与二经基乙酸单叔丁酷在DCC参与下脱水酷化再将叔丁基去保护，便得到端梭基的MPEG-PLA。7、端基为梭基的MPEG-PLA与紫杉醇的2’-羟基或7-轻基进行了酷化反应，制备出MPEG-PLA-紫杉醇前药。8、制备了四种低分子量的MPEG-PLA-紫杉醇前药，用1H NMR和GPC进行了表征分析。紫杉醇前药中紫杉醇的含量最高可达到20％，依赖于MPEG-PLA中PLA段的长度。9、用荧光探针法考察了MPEG-PLA两嵌段聚合物和MPEG-PLA-紫杉醇前药的胶束化行为，发现前药总比相对应的两嵌段聚合物有更低的临界胶束浓度（CMC）。用透射电镜观察了胶束的形貌和尺寸大小，以及接药前后胶束尺寸的变化。发现都是很好的球状胶束，MPEG-PLA两嵌段聚合物和MPEG-PLA-紫杉醇前药胶束的平均粒径分别为25±3nm和33士Znm，说明聚合物在接药后，随着疏水部分分子量的增加，所形成的胶束粒径也增大。

湖南尖吻蝮(D. acutus)蛇毒出血毒素的纯化、性质和溶液构象研究

通过Sephadex G-75凝胶过滤，QAE-Sephadex A-50和CM_Sephadex C-25离子交换的步骤，我们从湖南产尖吻蝮(Dienagkistrodon acutus)蛇毒中纯化出两个出血毒素，分别称之为DaHT-1和DaHT-2。在聚丙烯酰胺凝胶电泳(PAGE)和SDS-聚丙烯酰胺凝胶电泳中均呈单一蛋白带，显示两个出血毒素皆为电泳纯。DaHT-1和DaHT-2的分子量相同，都为23,500道尔顿，具有相似的氨基酸组成，其中酸性氨基酸(Asx和GLx)分别占23%和24%。经等电聚焦(IEF)测得它们的等电点分别为5.6和5.2。两个出血毒素具有较强的出血活性(MHD分别为0.5和0.8μg)，都具蛋白水解酶活力，无精氨酸水解酶和PLA~2活性，但蛋白水解酶活性与出血活性并非正相关。DaHT-1，DaHT-2的最适温度分别为35 ℃，40 ℃；最适pH为6-9。对热不稳定，温度变高于60 ℃，活性完全丧失。在中性和碱性条件下稳定，在酸性条件下不稳定，pH<3，出血活性丧失。EDTA完全抑制，半胱氨酸部分抑制它们的出血活性，表明两个出血毒素都是依赖金属离子的蛋白酶，且二硫键对其活性是必需的。金属离子的分析表明每摩尔毒蛋白大约含0.5摩尔的Zn，1摩尔的Ca，较多的Na，K。Mg，不含Co。两者是糖蛋白，含糖总量分别为11%和7%。用远紫外CD谱探讨DaHT-1和DaHT-2的溶液构象所得DaHT-1的α-螺旋，β-折叠和无规卷曲分别为36.9%，27.6%和31.4%；DaHT-2的α-螺旋，β-折迭和无规卷曲分别为23.4%，37.3%和45.3%。随着pH的增大或减少，DaHT-1和DaHT-2的峰位蓝移，在酸性条件下的变化比在碱性条件下大，计算表明：α-螺旋减少，无规卷曲增多，β-折迭基本未变。温度的影响和pH相似，50 ℃时峰位蓝移，α-螺旋减少，无规卷曲增多。EDTA对其影响很大，0.02M EDTA便导致两个出血毒素呈极度的无序状态。

Partial characterization of the hemolytic activity of the nematocyst venom from the jellyfish Cyanea nozakii Kishinouye

Using a recently developed technique to extract jellyfish venom from nematocysts, the present study investigated the hemolytic activity of Cyanea nozakii Kishinouye nematocyst venom on chicken erythrocytes. Venom extract caused a significant concentration-dependent hemolytic effect. The extract could retain its activity at -80 degrees C but was unstable when kept at 4 degrees C and -20 degrees C for 2 days. The hemolytic activity was inhibited by heating within the range of 37-100 degrees C. The extract was active over a pH range of 5.0-8.63 and the pH optima for the extract was 7.8. Incubation of the venom with sphingomyelin specially inhibited hemolytic activity by up to 70%. Cu2+ and Mn2+ greatly reduced the hemolytic activity while Mg2+, Sr2+ and Ba2+ produced a relatively low inhibiting effect on the hemolytic activity. Treatment with Ca2+ induced a concentration-dependent increase in the hemolytic activity. In the presence of 5 mM EDTA, all the hemolytic activity was lost, however, the venom containing 1.5 mM EDTA was stable in the long-term storage. PLA(2) activity was also found in the nematocyst venom of C. nozakii. These characteristics provide us a fundamental knowledge in the C. nozakii nematocyst venom which would benefit future research. (C) 2010 Published by Elsevier Ltd.

Oncogenic Kras Promotes Chemotherapy-Induced Growth Factor Shedding via ADAM17.

Oncogenic mutations in Kras occur in 40% to 45% of patients with advanced colorectal cancer (CRC). We have previously shown that chemotherapy acutely activates ADAM17, resulting in growth factor shedding, growth factor receptor activation, and drug resistance in CRC tumors. In this study, we examined the role of mutant Kras in regulating growth factor shedding and ADAM17 activity, using isogenic Kras mutant (MT) and wild-type (WT) HCT116 CRC cells. Significantly higher levels of TGF-a and VEGF were shed from KrasMT HCT116 cells, both basally and following chemotherapy treatment, and this correlated with increased pErk (phosphorylated extracellular signal regulated kinase)1/2 levels and ADAM17 activity. Inhibition of Kras, MEK (MAP/ERK kinase)1/2, or Erk1/2 inhibition abrogated chemotherapy-induced ADAM17 activity and TGF-a shedding. Moreover, we found that these effects were not drug or cell line specific. In addition, MEK1/2 inhibition in KrasMT xenografts resulted in significant decreases in ADAM17 activity and growth factor shedding in vivo, which correlated with dramatically attenuated tumor growth. Furthermore, we found that MEK1/2 inhibition significantly induced apoptosis both alone and when combined with chemotherapy in KrasMT cells. Importantly, we found that sensitivity to MEK1/2 inhibition was ADAM17 dependent in vitro and in vivo. Collectively, our findings indicate that oncogenic Kras regulates ADAM17 activity and thereby growth factor ligand shedding in a MEK1/2/Erk1/2-dependent manner and that KrasMT CRC tumors are vulnerable to MEK1/2 inhibitors, at least in part, due to their dependency on ADAM17 activity.

Predictive markers for colorectal cancer:current status and future prospects

Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. Although there is clear evidence of the benefit of chemotherapy in adjuvant and metastatic settings, its use continues to be suboptimal because of intrinsic or acquired drug resistance. 5-Fluorouracil continues to be the mainstay of CRC therapy, and combinations with newer chemotherapeutic agents such as irinotecan and oxaliplatin have resulted in improved response rates and survival. The role of other agents including cyclooxygenase-2 inhibitors, epidermal growth factor receptor, and farnsyl transferase inhibitors remains to be elucidated. Despite these improvements, many patients undergo chemotherapy without benefit. Increased understanding of the biology of CRC has led to the identification of prognostic markers that may help identify patients who will benefit from chemotherapy. Furthermore, studies have also begun to identify markers that predict whether a tumor will respond to a particular chemotherapy. The ultimate goal of this research is to prospectively identify patients who should receive chemotherapy and, thus, to tailor treatment to the molecular profile of the tumor and patient. Such an approach has the potential to dramatically improve response rates. This review highlights potentially important prognostic and predictive factors in CRC and discusses the potential for their use in the treatment of this disease.

Apparent tolerance of turkey vultures (Cathartes aura) to the non-steroidal anti-inflammatory drug diclofenac

The nonsteroidal anti-inflammatory drug diclofenac is extremely toxic to Old World Gyps vultures (median lethal dose -0.1-0.2 mg/kg), evoking visceral gout, renal necrosis, and mortality within a few days of exposure. Unintentional secondary poisoning of vultures that fed upon carcasses of diclofenac-treated livestock decimated populations in the Indian subcontinent. Because of the widespread use of diclofenac and other cyclooxygenase-2 inhibiting drugs, a toxicological study was undertaken in turkey vultures (Cathartes aura) as an initial step in examining sensitivity of New World scavenging birds. Two trials were conducted entailing oral gavage of diclofenac at doses ranging from 0.08 to 25 mg/kg body weight. Birds were observed for 7 d, blood samples were collected for plasma chemistry (predose and 12, 24, and 48 h and 7 d postdose), and select individuals were necropsied. Diclofenac failed to evoke overt signs of toxicity, visceral gout, renal necrosis, or elevate plasma uric acid at concentrations greater than 100 times the estimated median lethal dose reported for Gyps vultures. For turkey vultures receiving 8 or 25 mg/kg, the plasma half-life of diclofenac was estimated to be 6 h, and it was apparently cleared after several days as no residues were detectable in liver or kidney at necropsy. Differential sensitivity among avian species is a hallmark of cyclooxygenase-2 inhibitors, and despite the tolerance of turkey vultures to diclofenac, additional studies in related scavenging species seem warranted.

Inhibition of tumor angiogenesis by non-steroidal anti-inflammatory drugs: emerging mechanisms and therapeutic perspectives.

Chronic intake of non steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced risk of developing gastrointestinal tumors, in particular colon cancer. Increasing evidence indicates that NSAID exert tumor-suppressive activity on pre-malignant lesions (polyps) in humans and on established experimental tumors in mice. Some of the tumor-suppressive effects of NSAIDs depend on the inhibition of cyclooxygenase-2 (COX-2), a key enzyme in the synthesis of prostaglandins and thromboxane, which is highly expressed in inflammation and cancer. Recent findings indicate that NSAIDs exert their anti-tumor effects by suppressing tumor angiogenesis. The availability of COX-2-specific NSAIDs opens the possibility of using this drug class as anti-angiogenic agents in combination with chemotheapy or radiotherapy for the treatment of human cancer. Here we will briefly review recent advances in the understanding of the mechanism by which NSAIDs suppress tumor angiogenesis and discuss their potential clinical application as anti-cancer agents.

Rôle des acides gras polyinsaturés essentiels dans l'infarctus du myocarde

Les maladies cardiovasculaires représentent la deuxième cause de mortalité en Amérique du Nord. Ceci peut s'expliquer par la consommation riche en gras des Nord-Américains et par un apport élevé en oméga-6. Inversement, des populations qui ont un apport moindre en oméga-6 et plus riche en oméga-3, telles que les Japonais et les Inuits, ont une incidence peu élevée de maladies cardiovasculaires. Les oméga-3 s'avèrent effectivement bénéfiques pour prévenir l'apparition de maladies cardiovasculaires. Dans le cadre d'un infarctus du myocarde, les oméga-3 sont bénéfiques en prévention secondaire et s'avèrent cardioprotecteurs lorsque consommés avant l'épisode d'infarctus. De manière à utiliser les oméga-3 de façon plus clinique, le but de la première étude était de vérifier si un métabolite des oméga-3 impliqué dans la résolution de l'inflammation, la résolvine D1, pouvait s'avérer cardioprotecteur lorsque donné au moment de l'infarctus. Effectivement, la résolvine D1, donnée juste avant l'ischémie, s'avère cardioprotectrice en entraînant une diminution de l'inflammation, soit en favorisant la résolution de l'inflammation, et en activant une voie de cardioprotection qui entraîne la survie cellulaire. Par ailleurs, étant donné que la diète de la population canadienne est riche en oméga-6, l’objectif de la deuxième étude était de vérifier si l'effet de la résolvine D1 est conservé en présence d'un oméga-6, l'acide linoléique. Nos résultats nous indiquent que la résolvine D1 perd son effet cardioprotecteur en présence de l'acide linoléique. Celle-ci semble aggraver les lésions ischémiques, possiblement, par, la génération de métabolites pro-inflammatoires et vasoconstricteurs qui accroît les effets de l'ischémie. Ainsi, il est essentiel de tenir compte de l'apport en oméga-6 pour envisager un traitement à la résolvine D1 et d'encourager une diminution des oméga-6 dans l'alimentation au profit des oméga-3. Enfin, la troisième étude de cette thèse visait à vérifier le mécanisme de cardioprotection des oméga-3 afin de savoir si ce sont les métabolites issus des oméga-3 qui génèrent la cardioprotection. L'utilisation des inhibiteurs du métabolisme des oméga-3, soit la 15-lipoxygénase et la cyclo-oxygénase 2, inhibe la cardioprotection conférée par une diète riche en oméga-3. De plus, les inhibiteurs diminuent les concentrations de résolvine D1 plasmatique. Puis, la résolvine D1, donnée en présence des inhibiteurs, restaure la cardioprotection. De ce fait, les métabolites générés par les oméga-3, dont la résolvine D1, sont importants dans l’effet cardioprotecteur des acides gras oméga-3. En conclusion, la résolvine D1 peut s'avérer une option intéressante pour bénéficier des effets des oméga-3 lorsque celle-ci est donnée au moment de l'infarctus. D'ailleurs, les métabolites, tels que la résolvine D1, sont essentiels pour obtenir la cardioprotection avec les oméga-3. Toutefois, l'alimentation des patients doit contenir moins d’oméga-6 afin de bénéficier des aspects cardioprotecteurs des oméga-3. Les oméga-6 sont trop proéminents dans l'alimentation nord-américaine, ce qui est néfaste pour le système cardiovasculaire.

Primary Prevention and Screening Strategies for Colorectal Cancer: Which Strategy Should Take?

Objective: To explore and define the utility of different strategies for primary prevention (ASA, diet, physical activity) and strategies of screening test (FOBT, sigmoidoscopy, colonoscopy, etc.) for colorectal cancer. Data source: Databases consulted were MEDLINE (1966 to 2006), DARE (1980 to 2006), Cochrane Central Register of Controlled Trials, Cochrane Collaboration’s Registry of Clinical Trials, Cochrane Database of Systematic Reviews and LILACS. Study selection: Studies such clinical trial, cohort and case-control studies of the effectiveness of tests for screening and primary prevention adenoma and colorectal cancer were identified by two reviewers. Data Extraction: The extraction of data and its evaluation is done in most of the process so paired. Limitations: Not strictly complies with the methodology of a systematic review and therefore reproducibility is questionable, the conclusions of this study should be extrapolated with caution. Conclusions: The major strategy of screening on the effectiveness of early detection of premalignant lesions or cancer is colonoscopy every 5 years, however it is necessary to evaluate this measure cost-effectiveness studies. For primary prevention, aspirin and cyclooxygenase-2 inhibitors reduce the incidence of colorectal adenomas. Aspirin can reduce colorectal cancer incidence. However, these medications may be associated with a significant risk of cardiovascular events and gastrointestinal bleeding. The balance between risks and benefits must be evaluated in future studies.

Evaluación de intervención de alertas para riesgo cardiovascular por diclofenaco en afiliados al régimen contributivo 2014 -2015

El objetivo fue evaluar la intervención de las alertas en la prescripción de diclofenaco. Estudio observacional, comparativo, post intervención, de un antes después, en pacientes con prescripción de diclofenaco. Se evaluó la intervención de las alertas restrictivas antes y después de su implementación en los pacientes prescritos con diclofenaco y que tenían asociado un diagnóstico de riesgo cardiovascular según CIE 10 o eran mayores de 65 años. Un total de 315.135 transacciones con prescripción de diclofenaco, en 49.355 pacientes promedio mes. El 94,8% (298.674) de las transacciones fueron prescritas por médicos generales.

Avaliação de diterpenos isolados de P. ornatus como potenciais inibidores da COX-1

Os produtos naturais são uma importante fonte de possíveis novos fármacos para uso clínico. O Plectranthus ornatus Codd. pertence a um género associado ao isolamento de diterpenos que são compostos responsáveis ??por diversas actividades biológicas. Os três diterpenos em estudo foram isolados no passado de P. ornatus e são agora avaliados como potenciais inibidores da COX-1. Os resultados obtidos sugerem que o ácido rinocerotinoico (2), mas não a plectrornatina C (1) e o halimano (3), apresenta uma ligeira actividade inibidora da COX-1. Estudos em desenvolvimento visam entender se estes compostos têm efeito como inibidores da COX-2. Deste modo, pretendese verificar o seu possível interesse como agentes anti-inflamatórios.