File Name: effect of aspirin on tumour cell colony formation and evolution .zip
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- Effect of aspirin on tumour cell colony formation and evolution
- NSAID use and somatic exomic mutations in Barrett’s esophagus
- Colorectal cancer
Metrics details. The esophagus is exposed to both intrinsic and extrinsic mutagens resulting from gastric reflux, chronic inflammation, and exposure to environmental carcinogens such as those found in cigarettes.
Aging Albany NY. Cisplatin is one of the most potent chemotherapeutic agents for the treatment of colon cancer. Nevertheless, the unavoidability of the notable toxicity and the development of the acquired resistance severely restricted its clinical application. Aspirin and some other non-steroidal anti-inflammatory drugs have been used to prevent colon tumorigenesis as chemopreventive agents. Here, we explored the possibility of aspirin as an adjuvant drug to boost the anti-cancer effect of cisplatin for colon cancer.
Effect of aspirin on tumour cell colony formation and evolution
Mechanisms in anti-inflammation and resolution: the role of lipoxins and aspirin-triggered lipoxins. Multicellular host responses to infection, injury or inflammatory stimuli lead to the formation of a broad range of chemical mediators by the host.
The integrated response of the host is essential to health and disease; thus it is important to achieve a more complete understanding of the molecular and cellular events governing the formation and actions of endogenous mediators of resolution that appear to control the duration of inflammation. Lipoxins are trihydroxytetraene-containing lipid mediators that can be formed during cell-cell interactions and are predominantly counterregulators of some well-known mediators of inflammation.
Since this circuit of lipoxin formation and action appears to be of physiological relevance for the resolution of inflammation, therapeutic modalities targeted at this system are likely to have fewer unwanted side effects than other candidates and current anti-inflammatory therapies. Here, we present an overview of the recent knowledge about the biosynthesis and bioactions of these anti-inflammatory lipid mediators. The vascular and cellular responses of both acute and chronic inflammation are mediated by endogenous chemical factors derived from plasma or cells and triggered by the inflammatory stimulus 1.
These different factors play key roles, not only initiating but also regulating the host responses, like the recently discovered inosine monophosphate-AMP deaminase system 2.
Such mediators, acting alone, in combination, or in tandem, then amplify the inflammatory response and influence its evolution and the outcome of the process Figure 1.
Biosynthesis of mediators by transcellular and cell-cell interactions is recognized as an important means of amplifying and generating lipid-derived mediators, particularly those produced by lipoxygenases LO. Arachidonic acid and its oxygenation products may transfer from one cell to another during cell-cell interaction undergoing further transformation to biologically active "pro-" and "anti-inflammatory" compounds.
Results from numerous studies have shown that lipoxins are formed in vitro from endogenous sources of arachidonate in isolated cells and also in vivo and across many species, from fish to humans. This review addresses the major routes and biological actions of lipoxins and whether their formation and actions can be of therapeutic value in regulating inflammation and other pathophysiologic events of interest in human disease. Multicellular host responses to infection, injury or inflammation stimuli lead to the formation of lipoxins "lipoxygenase interaction products" , trihydroxytetraene-containing bioactive lipid mediators that carry potent anti-inflammatory signals.
First reported in in mixed suspensions of human leukocytes incubated with exogenous substrates 3 , lipoxins are now known to be generated in humans during cell-cell interactions by one of at least three biosynthetic routes working independently or in concert, in particular biological settings or tissues.
During lipoxin formation, molecular oxygen is inserted at two sites in arachidonic acid C by distinct LO that are often segregated into different cell types. The first report on lipoxin biosynthesis rationalized lipoxin generation by routes involving insertion of molecular oxygen into carbon 15 of C, predominantly in the S configuration, which implied the involvement of a LO 3.
These lipoxins retain their precursors' alcohol configuration to carry their carbon 15 alcohol in the S configuration. The second pathway for lipoxin biosynthesis was determined for interactions that occur predominantly within the vasculature between 5-LO, present in myeloid cells, and LO, present in platelets 3. During neutrophil-platelet interaction and co-activation, LTA 4 has multiple potential enzymatic and non-enzymatic fates, including a conversion by LO to LXA 4 and B 4 , b non-enzymatic hydrolysis which occurs in seconds in aqueous environments , c conversion by LTA 4 hydrolase to LTB 4 a potent neutrophil and eosinophil chemoattractant or d converted by LTC 4 synthase to LTC 4 slow reacting substance of anaphylaxis.
Because LTB 4 and C 4 carry potent proinflammatory actions and lipoxins inhibit leukotriene-mediated responses in vivo , the balance of leukotriene to lipoxin formation is critical to cellular responses. Recently, a third major pathway for lipoxin generation was discovered that involves aspirin and the actions of cyclooxygenase COX 2 and 5-LO 4.
Endothelial and epithelial cells express COX-2 in response to diverse stimuli such as cytokines, hypoxia and bacterial infections. The route of lipoxin formation depends on the cells and enzymes present therein and can be subject to modulation by cytokines reviewed in 5. For example, interleukin 4 IL-4 and IL, which are thought to be negative regulators of the inflammatory response, both increase LO expression and activity, thereby enhancing lipoxin formation.
Proinflammatory cytokines up-regulate 5-LO e. Furthermore, addition of exogenous C to GM-CSF-primed neutrophils co-incubated with platelets enhances receptor-triggered formation of LXA 4 with either formyl-methionyl-leucyl-phenylalanine fMLP or platelet-derived growth factor 6 , establishing that lipoxins are indeed generated from endogenous sources of arachidonic acid following receptor-ligand interactions. Although first described in human leukocytes 3 , lipoxins are generated by bovine, porcine and rat cells, including basophils and macrophages reviewed in 7.
It appears that both the basic structure of lipoxins and the means of generating these compounds are conserved in the course of evolution. In this regard, it was shown that leukocytes or isolated phagocytic cells from several species of fish trout, salmon, catfish could generate substantial amounts of lipoxin from endogenous sources of substrate 8.
Lipoxins, as other autacoids, are rapidly biosynthesized in response to stimuli, act locally and then are rapidly enzymatically inactivated. The major route of lipoxin inactivation is through dehydrogenation by monocytes that convert LXA 4 to oxo-LXA 4 , followed by specific reduction of the double bond adjacent to the ketone 10 Figure 4.
Moreover, reduction of the oxo group by PGDH yields 13,dihydro-LXA 4 , revealing an additional catalytic activity for this enzyme It has recently been shown that oxo-LXA 4 is also produced from LXA 4 in mouse whole blood 13 , suggesting that the mouse shares with humans a common pathway for LXA 4 inactivation.
In view of the rapid transformation and inactivation of lipoxin by monocytes and, potentially, other cells in vivo , it was highly desirable to design lipoxin analogs that would resist this metabolism and maintain their structural integrity and potential beneficial biological actions.
Additional analogs of LXA 4 were synthesized with a phenoxy group attached to carbon 16 and replacing the w -end of the molecule. This design permits phenoxy-LXA 4 to resist potential w -oxidation and to be protected from dehydrogenation in vivo. Fluoride was added to the para-position of the phenoxy ring to yield para-fluoro -phenoxy-LXA 4 in order to hinder degradation of the phenoxy ring. The aspirin-triggered counterpart of para-fluoro -phenoxy-LXA 4 , epi para-fluoro -phenoxy-LXA 4 , was also synthesized.
These modifications not only prolong the half-life of the compounds in blood but also enhance their bioavailability and bioactivity This indicates that the dehydrogenation step is highly stereospecific and suggests that, when ATL are generated in vivo , their biological half-life is increased by about two-fold compared to that of native LXA 4 , thereby enhancing their ability to evoke bioactions.
Hence, biologically stable analogs of lipoxin and ATL can be engineered to enhance their bioactions, a fact suggesting that they are useful tools for the development of novel therapeutic modalities. Lipoxins display vasodilatory and counterregulatory roles in in vivo and in vitro models 7, LXA 4 reverses the precontraction of the pulmonary artery induced by prostaglandin F 2 a and endothelin The mechanisms of LXA 4 - and LXB 4 -induced vasodilatation involve endothelium-dependent vasorelaxation and involve prostaglandin-dependent and -independent pathways reviewed in In certain tissues, lipoxin can stimulate the formation of, for example, prostacyclin by endothelial cells 29 , which can contribute to vasodilatation.
These prostanoid-dependent actions of lipoxin are inhibited by COX inhibitors 14 and indicate that lipoxins can stimulate the biosynthesis of a second set of mediators. These also include lipoxin-stimulated generation of nitric oxide 33 , which may mediate a component of lipoxin-regulated vascular tone.
The actions of lipoxins contrast with those of most other lipid mediators that are primarily proinflammatory, such as leukotrienes, platelet-activating factor PAF and prostanoids. It is now appreciated that lipoxins, LXA 4 in particular, are potent counterregulatory signals in vitro and in vivo for endogenous proinflammatory mediators, including lipids leukotrienes, PAF and cytokines TNF- a , IL-6 , resulting in inhibition of leukocyte-dependent inflammation reviewed in Lipoxins display selective actions on leukocytes Table 1 that include a inhibition of neutrophil chemotaxis 15 , b transmigration through epithelial cells 16 , and c adhesion and transmigration with endothelial cells LXB 4 has not been studied as extensively as LXA 4 ; it is chemically and biologically less stable because it isomerizes rapidly in vitro.
Therefore, it has been more difficult to handle previously, but now stable LXB 4 analogs have been prepared 12 that will help to expand the evaluation of their biological roles. There are specific and potent actions attributed to LXB 4 , including stimulating proliferation and differentiation of granulocyte-monocyte colonies from human mononuclear cells and sleep induction.
In addition to its specific actions, LXB 4 also shares actions with LXA 4 , selectively stimulating human peripheral blood monocytes and inhibiting human neutrophil transmigration and adherence as well as PMN-mediated increases in vascular permeability in mice 3, A considerable amount of data has well documented that lipoxin actions are closely linked with cytokine networks. It is thus likely that lipoxin bioactions in vivo are up-regulated by cytokines and that lipoxins directly modulate the cytokine composition in a local inflammatory milieu, a concept supported by recent findings showing that LXA 4 may be involved in a negative feedback loop opposing inflammatory cytokine-induced activation of human synovial fibroblasts Unlike PMN and eosinophils, lipoxins are potent stimuli for peripheral blood monocytes 3.
While LXA 4 and LXB 4 stimulate monocyte chemotaxis and adherence, these cells do not degranulate or release reactive oxygen species in response to lipoxins, suggesting that the actions of these lipoxins are specific for locomotion and may be related to the recruitment of monocytes to sites of injury. These monocyte activities may be host-protective in view of the important role of these cells in wound healing and resolution of inflammatory sites.
Along with these suggestions, LXA 4 and LXA 4 analogs were shown to accelerate the resolution of allergic pleural edema 37 and enhance phagocytosis of apoptotic PMN by monocyte-derived macrophages It is increasingly appreciated that the resolution of inflammation is a dynamically regulated process and these different observations raise the possibility that lipoxins play pivotal roles in the resolution phase of PMN-mediated inflammation.
Lipoxin formation is observed when cells are exposed to receptor-mediated soluble or phagocytic stimuli. Because cells routinely encounter these stimuli and lipoxins perform vasoactive and counterregulatory actions, LXA 4 and LXB 4 are likely to have physiologic roles during homeostatic responses even in the absence of illness. Lipoxins are generated in vivo in humans and in experimental animal models reviewed in 34 and are also associated with diseases Table 2.
Currently, only limited data on the effects of lipoxins in clinical investigation are available. Lipoxins are generated from endogenous sources during provocative challenge in asthma 6 , suggesting that they may play roles in modulating airway hyperresponsiveness. Asthmatic patients possess the capacity to generate both lipoxins and epi-lipoxins, but aspirin-intolerant asthmatics display a lower biosynthetic capacity than aspirin-tolerant asthmatics for these potentially protective lipid mediators In addition, lipoxins are formed in human airways in vivo during certain inflammatory lung diseases e.
Together, these data support a physiological role for lipoxins in vivo. Lipoxin actions are cell type, species and organ specific. These actions can be assigned to one or a combination of three mechanisms: a lipoxins act at their own specific cell surface receptors i.
LXA 4 and LXB 4 act at two distinct sites, and in some cell types, they evoke similar actions, but their actions are distinct in others. The bioactions of LXA 4 , epi-LXA 4 and stable analogs are transduced by this high affinity receptor lipoxin A 4 receptor, ALXR that has been sequenced and cloned for both mouse 46 and human leukocytes 19,22 , as well as human enterocytes 26 and, more recently, for mesangial cells In addition, LXA 4 actions on vascular endothelial cells are mediated via a distinct non-myeloid receptor that remains to be cloned.
In several tissues and cell types other than leukocytes, results of pharmacological experiments have indicated that LXA 4 can also interact with a subclass of peptido-leukotriene receptors cysLT 1 as a partial agonist mediating their actions In addition to specific binding to membrane surface receptors, specific binding of labeled LXA 4 is associated with subcellular fractions including granules and nucleus In this regard, it was recently reported that LXA 4 binds to and activates the aryl hydrocarbon receptor, a ligand-activated transcription factor, in a murine hepatoma cell line Our current understanding of the LXA 4 receptor's intracellular down-regulatory signals remains incomplete.
But, LXA 4 binding to its receptor triggers the activation of GTPase, phospholipase A 2 and phospholipase D reviewed in 7 , responses that are inhibited by pretreatment of the cells with pertussis toxin. Recently, a novel polyisoprenyl phosphate signaling pathway was identified 59 with one of its components, presqualene diphosphate PSDP , being a potent negative intracellular signal in PMN.
The receptor coupling in monocytes and PMN is similar to G-protein activation, being critical in both cell types. However, there could be different G-protein subtypes that diverge downstream in the signal transduction pathway to stimulate monocytes and inhibit PMN Figure 5.
It was recently shown 54 that small peptides selectively compete for specific 3 H-LXA 4 binding with PMN and recombinant human ALXR, increasing extracellular acidification rates and inducing cell chemotaxis and migration in vivo.
Chimeric receptors constructed from receptors with opposing functions, namely ALXR and LTB 4 54 , revealed that the seventh transmembrane segment and adjacent regions of ALXR are essential for LXA 4 recognition, and additional regions of this receptor are required for high affinity binding of the peptide ligands.
It appears, however, that the G-protein interactions evoked by ligand-receptor binding and their intracellular amplification mechanisms are different for peptide versus lipid ligands of ALXR, and hence they can dictate different functional responses. Lipoxins are the trihydroxytetraene-containing class of eicosanoids primarily generated by cell-cell interactions via transcellular biosynthesis, serving as local endogenous anti-inflammatory mediators.
These stop signals in inflammation and other related processes may be involved in switching the cellular response from additional PMN recruitment to monocytes that could lead to resolution of the inflammatory response or promotion of repair and wound healing. Aspirin impinges on this system and evokes the endogenous biosynthesis of the 15 epimers of lipoxins, namely ATL, that can modulate in part the beneficial actions of aspirin.
Lipoxins and ATL analogs represent useful tools to evaluate the potential of pharmacological manipulation of the inflammatory process as a means to develop new and selective anti-inflammatory therapies with reduced unwanted toxic side effects. In this context, it was recently described 60 that aspirin and other nonsteroidal anti-inflammatory drugs together with dietary omega-3 polyunsaturated fatty acid supplementation induce the generation of a novel array of bioactive compounds such as 5,12,18 R -tri HEPE.
Together with lipoxins and epi-lipoxins, the identification of these novel endogenous anti-inflammatory lipid mediators opens new avenues in the therapeutics of inflammation, cardiovascular diseases and cancer. Robbins Pathologic Basis of Disease. Saunders Co. Serhan CN Lipoxins and aspirin-triggered epi-lipoxins. Basic Principles and Clinical Correlates. Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions.
Lipid mediator networks in cell signaling: update and impact of cytokines.
NSAID use and somatic exomic mutations in Barrett’s esophagus
Colorectal cancer CRC , also known as bowel cancer , colon cancer , or rectal cancer , is the development of cancer from the colon or rectum parts of the large intestine. Most colorectal cancers are due to old age and lifestyle factors, with only a small number of cases due to underlying genetic disorders. Bowel cancer may be diagnosed by obtaining a sample of the colon during a sigmoidoscopy or colonoscopy. Aspirin and other non-steroidal anti-inflammatory drugs decrease the risk. Treatments used for colorectal cancer may include some combination of surgery, radiation therapy , chemotherapy and targeted therapy.
Mechanisms in anti-inflammation and resolution: the role of lipoxins and aspirin-triggered lipoxins. Multicellular host responses to infection, injury or inflammatory stimuli lead to the formation of a broad range of chemical mediators by the host. The integrated response of the host is essential to health and disease; thus it is important to achieve a more complete understanding of the molecular and cellular events governing the formation and actions of endogenous mediators of resolution that appear to control the duration of inflammation. Lipoxins are trihydroxytetraene-containing lipid mediators that can be formed during cell-cell interactions and are predominantly counterregulators of some well-known mediators of inflammation. Since this circuit of lipoxin formation and action appears to be of physiological relevance for the resolution of inflammation, therapeutic modalities targeted at this system are likely to have fewer unwanted side effects than other candidates and current anti-inflammatory therapies.
Inflammation and cancer · Coussens L · Werb Z. Nature. Citations. Readers. Add to library. View PDF. This artice is free to access.
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Было подсчитано, что для успешной атаки на стандартный ключ самому быстрому компьютеру АНБ - секретнейшему Крей-Джозефсону II - потребуется более девятнадцати лет. К тому времени когда компьютер разгадает пароль и взломает шифр, информация, содержащаяся в послании, утратит всякую ценность. Оказавшись в условиях подлинного разведывательного затемнения, АНБ выпустило секретную директиву, одобренную президентом Соединенных Штатов. Заручившись поддержкой федеральных фондов и получив карт-бланш на все необходимые меры для решения проблемы, АНБ приступило к созданию невозможного - первой универсальной машины для вскрытия шифров. Вопреки широко распространенному мнению о том, что такой компьютер создать невозможно, АНБ осталось верным своему девизу: возможно все; на невозможное просто требуется больше времени. Через пять лет, истратив полмиллиона рабочих часов и почти два миллиарда долларов, АН Б вновь доказало жизненность своего девиза.
Все вокруг светилось ярко-красными огнями. Шифровалка умирала. То же самое будет и со мной, - подумала. Сьюзан вспомнила о единственном остающемся выходе - личном лифте Стратмора.
Ну давай. Окажись дома. Через пять гудков он услышал ее голос. - Здравствуйте, Это Сьюзан Флетчер.
Если информация верна, выходит, Танкадо и его партнер - это одно и то же лицо. Мысли ее смешались. Хоть бы замолчала эта омерзительная сирена.
Беккер остановился, недоумевая, откуда им известно его имя. - Кто… кто вы. - Пройдемте с нами, пожалуйста.