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851.
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852.
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
853.
Norredam M 《Danish medical bulletin》2011,58(10):B4339
There are strong pragmatic and moral reasons for receiving societies to address access to healthcare for migrants. Receiving societies have a pragmatic interest in sustaining migrants' health to facilitate integration; they also have a moral obligation to ensure migrants' access to healthcare according to international human rights principles. The intention of this thesis is to increase the understanding of migrants' access to healthcare by exploring two study aims: 1) Are there differences in migrants' access to healthcare compared to that of non-migrants? (substudy I and II); and 2) Why are there possible differences in migrants' access to healthcare compared to that of non-migrants? (substudy III and IV). The thesis builds on different methodological approaches using both register-based retrospective cohort design, cross-sectional design and survey methods. Two different measures of access were used to explore differences: 1) cancer stage at diagnosis as a clinical outcome and 2) emergency room (ER) contacts as a utilisation measure. Both informal and formal barriers to access were studied to explore why possible differences existed including: 1) motivation for using ER; and 2) asylum seekers' healthcare entitlements. Different definitions of migration and ethnicity were investigated including: country of birth and residence status. Substudy I showed a tendency towards more advanced stage at diagnosis or unknown stage among most subgroups of migrant women with a history of cancer compared to non-migrant women. Sub-study II found that some migrants (those born in Somalia, Turkey and Ex-Yugoslavia) use ER services more frequently than do non-migrants whereas others have the same or lower utilisation levels. As a consequence, substudy III was undertaken, which documented that more migrant within all subgroups had considered contacting a primary caregiver before visiting the ER compared to non-migrants, but that migrants experienced communication problems herein. Additionally, more migrants had irrelevant ER visits as evaluated by caregivers. Substudy IV addressed formal and informal barriers to access and screening. According to the law asylum seekers are entitled to emergency care only in 10 out of 24 countries. Medical screening was carried out in all but one of the 24 EU countries; however, the content and extent of screening programmes vary. The thesis aimed to explore if there are differences in migrants' access to healthcare compared to that of non-migrants. Differences in utilisation and clinical outcome were identified between migrants and non-migrants. Reasons why disparities exist were also identified in relation to communication with primary care and on policy level. The thesis shows that various perspectives and scientific problems are important to get a full understanding of the process of access to healthcare for different migrant groups. Moreover, various complementary methodological approaches are needed when studying problems of migrants' access to healthcare. 相似文献
854.
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
855.
Ectrodactyly ectodermal dysplasia with clefting is a rare syndrome resulting from TP63 gene mutations. It is inherited in autosomal dominant manner or as a de novo transfiguration. It is characterized by a triad of ectodermal dysplasia, ectrodactyly, and facial clefts. This report represents a clinical case of 5 years and 6 months‐old male child with ectrodactyly ectodermal dysplasia cleft lip and palate syndrome requiring treatment of his carious teeth. After history taking and clinical examination, the necessary treatment was provided under general anesthesia due to the definitely negative behavior of the child. The treatment outcomes had a positive impact on the behavior and acceptance to dental treatment. This was evidenced by completion of the prosthetic and space management appliances on the dental chair. The child's quality of life was consequently improved. This was evidenced by the reduced response scores of the child perception questionnaire (CPQ11‐14) after treatment. This report highlighted the value of proper diagnosis and fulfillment of the unmet dental needs for patients with orofacial syndromes to improve their quality of life. 相似文献
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