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71.
Nishiuma T Nishimura Y Okada T Kuramoto E Kotani Y Jahangeer S Nakamura S 《American journal of physiology. Lung cellular and molecular physiology》2008,294(6):L1085-L1093
Sphingosine 1-phosphate (S1P) produced by sphingosine kinase (SPHK) is implicated in acute immunoresponses, however, mechanisms of SPHK/S1P signaling in the pathogenesis of bronchial asthma are poorly understood. In this study, we hypothesized that SPHK inhibition could ameliorate lung inflammation in ovalbumin (OVA)-challenged mouse lungs. Six- to eight-week-old C57BL/6J mice were sensitized and exposed to OVA for 3 consecutive days. Twenty-four hours later, mice lungs and bronchoalveolar lavage (BAL) fluid were analyzed. For an inhibitory effect, either of the two different SPHK inhibitors, N,N-dimethylsphingosine (DMS) or SPHK inhibitor [SK-I; 2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole], was nebulized for 30 min before OVA inhalation. OVA inhalation caused S1P release into BAL fluid and high expression of SPHK1 around bronchial epithelial walls and inflammatory areas. DMS or SK-I inhalation resulted in a decrease in S1P amounts in BAL fluid to basal levels, accompanied by decreased eosinophil infiltration and peroxidase activity. The extent of inhibition caused by DMS inhalation was higher than that caused by SK-I. Like T helper 2 (Th2) cytokine release, OVA inhalation-induced increase in eotaxin expression was significantly suppressed by DMS pretreatment both at protein level in BAL fluid and at mRNA level in lung homogenates. Moreover, bronchial hyperresponsiveness to inhaled methacholine and goblet cell hyperplasia were improved by SPHK inhibitors. These data suggest that the inhibition of SPHK affected acute eosinophilic inflammation induced in antigen-challenged mouse model and that targeting SPHK may provide a novel therapeutic tool to treat bronchial asthma. 相似文献
72.
One of the main determinants of lung surfactant function is the complex interplay between its protein and lipid components. The lipid specificity of surfactant protein B (SP-B), however, and the protein's ability to selectively squeeze out lipids, has remained contradictory. In this work we present, for the first time to our knowledge, by means of time-of-flight secondary ion mass spectrometry chemical imaging, a direct evidence for colocalization of SP-B as well as its model peptide KL4 with negatively charged dipalmitoylphosphatidylglycerol under absolute calcium free conditions. Our results prove that protein/lipid localization depends on the miscibility of all surfactant components, which itself is influenced by subphase ionic conditions. In contrast to our earlier studies reporting SP-B/KL4 colocalization with zwitterionic dipalmitoylphosphatidylcholine, in the presence of even the smallest traces of calcium, we finally evidence an apparent reversal of protein/lipid mixing behavior upon calcium removal with ethylene diamine tetraacetic acid. In addition, scanning force microscopy measurements reveal that by depleting the subphase from calcium ions the protrusion formation ability of SP-B or KL4 is not hampered. However, in the case of KL4, distinct differences in protrusion morphology and height are visible. Our results support the idea that calcium ions act as a “miscibility switch” in surfactant model systems and probably are one of the major factors steering lipid/protein mixing behavior as well as influencing the protein's protrusion formation ability. 相似文献
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Muhammad Shakeel Farhat Jabeen Rehana Iqbal Abdul Shakoor Chaudhry Sadia Zafar Muhammad Ali Muhammad Saleem Khan Adeel Khalid Samina Shabbir Muhammad Saleem Asghar 《Biological trace element research》2018,182(1):57-69
This study assessed the protective effects of Cinnamomum cassia (cinnamon) bark extract in rats exposed to titanium dioxide nanoparticles or titanium dioxide bulk salt. For in vivo evaluation of the ameliorative role of the cinnamon extract, the experimental groups were orally administered with the cinnamon extract at different dose levels (50 or 100 or 150 mg/kg bodyweight) along with the subcutaneous injections of 150 mg/kg bodyweight titanium dioxide nanoparticles or titanium dioxide bulk salt. The extract showed significant ameliorative role on the antioxidant system in response to elevated levels of titanium dioxide nanoparticles or titanium dioxide bulk salt-induced oxidative stress. It aided in the recovery of the antioxidant system as well as protective role in histological damages and some haematological parameters in the rat liver treated with titanium dioxide nanoparticles or titanium dioxide bulk salt. 相似文献
76.
DNA topoisomerase I is a major cellular target for antitumor indolocarbazole derivatives (IND) such as the antibiotic rebeccamycin and the synthetic analogue NB-506 which is undergoing phase I clinical trials. We have investigated the mechanism of topoisomerase I inhibition by a rebeccamycin analogue, R-3, using the wild-type human topoisomerase I and a well-characterized recombinant enzyme, F361S. The catalytic activity of this mutant remains fully intact, but the enzyme is resistant to inhibition by camptothecin (CPT). Here we show that the mutated enzyme is cross-resistant to the rebeccamycin analogue. Despite their profound structural differences, CPT and R-3 interfere similarly with the activity of the wild-type and mutant topoisomerase I enzymes, and the drug-induced cleavable complexes are equally sensitive to the NaCl concentration. CPT and IND likely recognize identical structural elements of the topoisomerase I-DNA covalent complex; however, differences do exist in terms of sequence-specificity of topoisomerase I-mediated DNA cleavage. For the first time, a molecular model showing that CPT and IND share common steric and electronic features is proposed. The model helps to identify a specific pharmacophore for topoisomerase I inhibitors. 相似文献
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78.
Mushtaq A. Saleem Abdul Rauf Shakoori David Mantle 《Archives of insect biochemistry and physiology》1998,39(4):144-154
The effects of a synthetic pyrethroid insecticide, cypermethrin, administered as a formulation Ripcord 25EC (emulsified concentrate), to adult beetles of a stored grain pest, Tribolium castaneum, have been studied, with an objective to ascertain its toxicity on enzymes such as carbohydrases, phosphatases, dehydrogenases, aminotransferases, and concentration of various biochemical components such as monosaccharides, glycogen, cholesterol, nucleic acids, urea, total lipids, and total proteins. Almost all the enzymes and biochemical components were sensitive to sublethal doses of Ripcord 25 EC and these effects were found to be dependent on the duration of treatment. All carbohydrate metabolizing enzymes (amylase, invertase, lactase, maltase, lactate dehydrogenase) were elevated, except for trehalase, which was also elevated up to day 3 but returned to normal levels subsequently. Phosphatases (alkaline as well as acidic) were increased first and decreased thereafter, while isocitrate dehydrogenase decreased throughout the experimental period. Transaminases (aspartate aminotransferase and alanine aminotransferase) showed a decreasing trend. Of the other biochemical components tested, glucose content decreased during the first 3 days but increased subsequently. Fructose content showed an increase, while the glycogen content decreased throughout the study. Total lipid content was not disturbed up to day 3 but increased thereafter. Cholesterol content was depleted by day 7. Total proteins started decreasing from day 3 onwards, while soluble proteins were not affected. DNA, RNA, and urea contents exhibited elevated levels, while uric acid showed a decreasing trend. Sublethal doses of Ripcord, therefore, resulted in extensive enzyme induction, and utilization of carbohydrates, proteins, and lipids, in the given order, perhaps to produce extra energy to combat insecticidal stress. Arch. Insect Biochem. Physiol. 39:144–154, 1998. © 1998 Wiley-Liss, Inc. 相似文献
79.
Sunniya Iftikhar Sardraz Khan Aishah Bilal Safia Manzoor Muhammad Abdullah Abdel-Hamid Emwas Salim Sioud Xin Gao Ghayoor Abbas Chotana Amir Faisal Rahman Shah Zaib Saleem 《Bioorganic & medicinal chemistry letters》2017,27(17):4101-4106
Tumor suppressor protein p53 induces cell cycle arrest and apoptotic cell death in response to various cellular stresses thereby preventing cancer development. Activation and stabilization of p53 through small organic molecules is, therefore, an attractive approach for the treatment of cancers retaining wild-type p53. In this context, a series of nineteen chalcones with various substitution patterns of functional groups including chloro, fluoro, methoxy, nitro, benzyloxy, 4-methyl benzyloxy was prepared using Claisen-Schmidt condensation. The compounds were characterized using NMR, HRMS, IR and melting points. Evaluation of synthesized compounds against human colorectal (HCT116) and breast (CAL-51) cancer cell lines revealed potent antiproliferative activities. Nine compounds displayed GI50 values in the low micromolar to submicromolar range; for example (E)-1-phenyl-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (SSE14108) showed GI50 of 0.473 ± 0.043 µM against HCT116 cells. Further analysis of these compounds revealed that (E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one (SSE14105) and (E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (SSE14106) caused rapid (4 and 8-h post-treatment) accumulation of p53 in HCT116 cells similar to its induction by positive control, Nutlin-3. Such activities were absent in 3-(4-methoxyphenyl)propiophenone (SSE14106H2) demonstrating the importance of conjugated ketone for antiproliferative and p53 stabilizing activity of the chalcones. We further evaluated p53 levels in the presence of cycloheximide (CHX) and the results showed that the p53 stabilization was regulated at post-translational level through blockage of its degradation. These chalcones can, therefore, act as fragment leads for further structure optimization to obtain more potent p53 stabilizing agents with enhanced anti-proliferative activities. 相似文献
80.
Isorhamnetin, a flavonoid compound extracted from the Chinese herb Hippophae rhamnoides L., is well known for its anti-inflammatory, anti-oxidative, anti-adipogenic, anti-proliferative, and anti-tumor activities. However, the role of isorhamnetin in cardiac hypertrophy has not been reported. The aims of the present study were to find whether isorhamnetin could alleviate cardiac hypertrophy and to define the underlying molecular mechanisms. Here, we investigated the effects of isorhamnetin (100 mg/kg/day) on cardiac hypertrophy induced by aortic banding in mice. Cardiac hypertrophy was evaluated by echocardiographic, hemodynamic, pathological, and molecular analyses. Our data demonstrated that isorhamnetin could inhibit cardiac hypertrophy and fibrosis 8 weeks after aortic banding. The results further revealed that the effect of isorhamnetin on cardiac hypertrophy was mediated by blocking the activation of phosphatidylinositol 3-kinase–AKT signaling pathway. In vitro studies performed in neonatal rat cardiomyocytes confirmed that isorhamnetin could attenuate cardiomyocyte hypertrophy induced by angiotensin II, which was associated with phosphatidylinositol 3-kinase–AKT signaling pathway. In conclusion, these data indicate for the first time that isorhamnetin has protective potential for targeting cardiac hypertrophy by blocking the phosphatidylinositol 3-kinase–AKT signaling pathway. Thus, our study suggests that isorhamnetin may represent a potential therapeutic strategy for the treatment of cardiac hypertrophy and heart failure. 相似文献