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821.
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822.
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
823.
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
824.
Double-strand breaks may initiate the inversion mutation causing the Hunter syndrome 总被引:2,自引:2,他引:2
Lagerstedt K; Karsten SL; Carlberg BM; Kleijer WJ; Tonnesen T; Pettersson U; Bondeson ML 《Human molecular genetics》1997,6(4):627-633
We have previously shown that patients with the Hunter syndrome frequently
have suffered from a recombination event between the IDS gene and its
putative pseudogene, IDS-2, resulting in an inversion of the intervening
DNA. The inversion, which might be the consequence of an intrachromosomal
mispairing, is caused by homologous recombination between sequences located
in intron 7 of the IDS gene and sequences located distal of exon 3 in
IDS-2. In order to gain insight into the mechanisms causing the inversion,
we have isolated both inversion junctions in six unrelated patients. DNA
sequence analysis of the junctions showed that all recombinations have
taken place within a 1 kb region where the sequence identity is >98%. An
interesting finding was the identification of regions with alternating IDS
gene and IDS-2 sequences present at one inversion junction, suggesting that
the recombination event has been initiated by a double-strand break in
intron 7 of the IDS gene. The results from this study suggest that
homologous recombination in man could be explained by mechanisms similar to
those described for Saccharomyces cerevisiae. The results also have
practical implications for diagnosis of patients with the Hunter syndrome.
相似文献
825.
K Jarzabek S Wolczynski R Lesniewicz G Plessis ML Kottler 《Advances in medical sciences》2012,57(2):314-321
PurposeLoss-of-function mutations in FGFR1 have been identified in approximately 10% of the Kallmann syndrome (KS) patients. Previous reports have focused mainly on olfactory, reproductive, and some other features such as cleft lip/palate and dental agenesis. Given the ubiquitous expression of FGFR1 during development, other abnormal phenotypes might, however, have been overlooked in these patients. Here, we demonstrate skeletal phenotypic characterization of patients presented with KS and FGFR1 mutations.Material and MethodsUsing the Sanger DNA sequencing technique a cohort of 29 KS patients was screened.ResultsHere, we report on 5 KS patients who carry FGFR1 mutations (Gly270Asp, Gly97Ser, Met161Thr, Ser685Phe and Ala167Ser/Ala167Ser). Three patients presented with skeletal abnormalities, i.e. spine (hemivertebra and butterfly vertebra) and limb (oligodactyly of the feet, fusion of the 4th and 5th metacarpal bones) malformations in two patients and one patient, respectively. The hand phenotype found in the patient cannot be thought of as a counter-type of the hand phenotype resulting from FGFR1 gain-of-function mutations. The skeletal anomalies identified in the 3 KS patients are close to those observed in Fgfr1 conditional knockout mice.ConclusionsThis study demonstrates that FGFR1 loss-of-function mutations can be associated with skeletal abnormalities also in humans. Further investigations in KS patients who carry FGFR1 mutations are needed to evaluate the prevalence of skeletal defects in this genetic form of KS. Conversely, the presence of bone malformations in a KS patient should direct the geneticist towards a search for mutations in FGFR1. 相似文献
826.
Perepechaeva ML Seredina TA Sidorova YA Pivovarova EN Markel AL Lyakhovich VV Grishanova AY 《Biomedical and environmental sciences : BES》2017,30(4)
<正>We studied effects of nutrient quercetin on cytochromes’Р450 1А(CYP1A)activities(measured spectrofluorimetrically using 7-ethoxy-resorufin for CYP1A1 and 7-methoxy-resorufin for CYP1A2 as substrates),on mR NA levels(measured by RT-PCR),and on DNA-binding activities(evaluated by an electrophoretic mobility shift assay)of proteins regulating CYP1A expression in untreated and benzo(α)pyrene(Ba P)-treated rats.Wistar rats 相似文献
827.
1 临床资料 1996 - 0 8/ 1999- 0 8我科共收治重型颅脑损伤患者 82 (男 5 8,女 2 4)例 ,年龄 7~ 81(平均 32 .4)岁 .本组患者伤前均无糖尿病史 .GCS评分均 <8分 .其中 6~ 8分的 42例 ;3~ 5分的 2 8例 ;3分以下的 12例 .发病至入院时间均在2 4h以内 .应用美国产“One Touch”血糖仪每日在床旁测空腹血糖 1次[1 ] ,连续测 7d.对于空腹血糖 >10 mmol· L者 ,给予低糖饮食 ,不用激素 ,少量应用甘露醇 ,适当应用胰岛素及乳酸林格液等治疗 .在 82例中 ,首次测血糖值 >10 mmol· L[2 ] 的 49例 ,最高值为 19.4mmol· L ;经上述治疗 ,结果… 相似文献