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871.
Malcolm R Alison Naomi J Guppy Susan ML Lim Linda J Nicholson 《The Journal of pathology》2010,222(4):335-344
Despite many years of intensive effort, there is surprisingly little consensus on the most suitable markers with which to locate and isolate stem cells from adult tissues. By comparison, the study of cancer stem cells is still in its infancy; so, unsurprisingly, there is great uncertainty as to the identity of these cells. Stem cell markers can be broadly categorized into molecular determinants of self‐renewal, clonogenicity, multipotentiality, adherence to the niche, and longevity. This review assesses the utility of recognizing cancer stem cells by virtue of high expression of aldehyde dehydrogenases (ALDHs), probably significant determinants of cell survival through their ability to detoxify many potentially cytotoxic molecules, and contributing to drug resistance. Antibodies are available against the ALDH enzyme family, but the vast majority of studies have used cell sorting techniques to enrich for cells expressing these enzymes. Live cells expressing high ALDH activity are usually identified by the ALDEFLUOR kit and sorted by fluorescence activated cell sorting (FACS). For many human tumours, but notably breast cancer, cell selection based upon ALDH activity appears to be a useful marker for enriching for cells with tumour‐initiating activity (presumed cancer stem cells) in immunodeficient mice, and indeed the frequency of so‐called ALDHbri cells in many tumours can be an independent prognostic indicator. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 相似文献
872.
L Navarro-Nú?ez J Rivera JA Guerrero C Martínez V Vicente ML Lozano 《British journal of pharmacology》2009,158(6):1548-1556
Background and purpose:
The modulation by flavonoids of platelet responses induced by thrombin has been little investigated, and the antiplatelet activity, as well as possible inhibitory mechanisms of these compounds on thrombin signalling, has not yet been elucidated. We explored whether flavonoids affect platelet signalling pathways triggered by thrombin and by the selective activation of its protease-activated receptors (PARs) 1 and 4, and analysed the antagonism of these polyphenols at thrombin receptors.Experimental approach:
We investigated the effect of a range of polyphenolic compounds on platelet aggregation, 5-HT secretion, intracellular calcium mobilization, protein kinase activity and tyrosine phosphorylation, triggered by thrombin and PAR agonist peptides (PAR-APs). The ability of these flavonoids to bind to thrombin receptors was investigated by competitive radioligand binding assays using 125I-thrombin.Key results:
Quercetin, apigenin and genistein impaired platelet aggregation, as well as 5-HT release and calcium mobilization, induced by thrombin and PAR-APs. Quercetin and apigenin were inhibitors of protein kinases, but genistein exhibited a minimal ability to suppress platelet phosphorylation. Binding assays did not establish any kind of interaction between thrombin receptors and any of the flavonoids tested.Conclusions and implications:
Quercetin, apigenin and genistein did not inhibit thrombin responses by interacting with thrombin receptors, but by interfering with intracellular signalling. While inhibition by genistein may be a consequence of affecting calcium mobilization, subsequent platelet secretion and aggregation, for quercetin and apigenin, inhibition of kinase activation may also be involved in the impairment of platelet responses. 相似文献873.
Antinarelli LM Carmo AM Pavan FR Leite CQ Da Silva AD Coimbra ES Salunke DB 《Organic and medicinal chemistry letters》2012,2(1):16
ABSTRACT: BACKGROUND: Aminoquinoline/steroid conjugates were synthesized based on the fact that steroid transporters have been shown to accept and carry a variety of drugs. So, in continuing our research of antileishmanial and antitubercular drugs, aminoquinoline/steroid conjugates (12, 13, and 14) were regioselectively synthesized via 1,3-dipolar cycloaddition of alkynes 3, 5, and 7 with azide 12. The aminoquinoline/steroids conjugates were evaluated in vitro against Leishmania major and Mycobacterium tuberculosis. RESULTS: The regioselective synthesis of the novel aminoquinoline/steroid conjugates was achieved in very high yield. All aminoquinoline/steroid conjugates (12, 13, and 14) exhibited best results against Leishmania and M. tuberculosis than the respective alkyne intermediate structures (3, 5, and 7, respectively). Among them, the compound 12 exhibited the best activity for M. tuberculosis (MIC = 8.8 uM). This result is comparable to drugs commonly used in tuberculosis treatment. Also, for antileishmanial assay, the aminoquinoline/steroid conjugates demonstrated a significant activity against promastigote and amastigote forms of L. major. These results highlight the importance of steroids as carrier. KEYWORDS: antileishmanial drugs; antituberculosis drugs; click chemistry; quinoline; steroid. 相似文献
874.
Gorlov IP, Gorlova OY, Frazier ML, Spitz MR, Amos CI. Evolutionary evidence of the effect of rare variants on disease etiology. The common disease/common variant hypothesis has been popular for describing the genetic architecture of common human diseases for several years. According to the originally stated hypothesis, one or a few common genetic variants with a large effect size control the risk of common diseases. A growing body of evidence, however, suggests that rare single‐nucleotide polymorphisms (SNPs), i.e. those with a minor allele frequency of less than 5%, are also an important component of the genetic architecture of common human diseases. In this study, we analyzed the relevance of rare SNPs to the risk of common diseases from an evolutionary perspective and found that rare SNPs are more likely than common SNPs to be functional and tend to have a stronger effect size than do common SNPs. This observation, and the fact that most of the SNPs in the human genome are rare, suggests that rare SNPs are a crucial element of the genetic architecture of common human diseases. We propose that the next generation of genomic studies should focus on analyzing rare SNPs. Further, targeting patients with a family history of the disease, an extreme phenotype, or early disease onset may facilitate the detection of risk‐associated rare SNPs. 相似文献
875.