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Bleomycins A(2) and B(2) are the two active components in the antineoplastic drug Blenoxane. DNA is targeted by this drug in cancer cells and the mode of action of this drug involves DNA binding. Ambiguity exists as to the way in which bleomycin binds to DNA. Raman spectroscopy was used to examine both calf thymus DNA and a bleomycin/DNA complex at two temperatures. A curvefitting technique was applied to these spectra for a spectral region obscured by many overlapping bands associated with the nucleotide bases in order to derive information about frequencies, bandwidths, and intensities of the vibrational modes in this region. This allowed identification and analysis of bands associated with specific assigned nucleotide base residues. Upon binding of bleomycin, several significant changes in bandwidth, intensities, and frequencies relative to uncomplexed DNA were observed consistently at both higher (30 degrees C) and lower (19 degrees C) temperature. The data presented here support at least a partial intercalation mode of binding for bleomycin that is temperature dependent and more pronounced at the more physiologically relevant temperature of 30 degrees C. 相似文献
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Previous studies have shown that ethanol enhanced [(3)H]dopamine uptake in Xenopus oocytes expressing the dopamine transporter (DAT). This increase in DAT activity was mirrored by an increase in the number of transporters expressed at the cell surface. In the present study, ethanol potentiated the function of DAT expressed in HeLa cells but inhibited the function of the related norepinephrine transporter (NET). Chimeras generated between DAT and NET were examined for ethanol sensitivity and demonstrated that a 76-amino acid region spanning transmembrane domains (TMD) 2 and 3 was essential for ethanol potentiation of DAT function. The second intracellular loop between TMD 2 and 3 of DAT, which differs from that of NET by four amino acids, was explored for possible sites of ethanol action. Site-directed mutagenesis was used to replace each of these residues in DAT with the corresponding residue in NET, and the resulting cRNA were expressed in Xenopus oocytes. We found that mutations G130T or I137F abolished ethanol potentiation of DAT function, whereas the mutations F123Y and L138F had no significant effect. These results identify novel sites in the second intracellular loop that are important for ethanol modulation of DAT activity. 相似文献
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Antioxidant defence is one of the important biological adaptations to thermal stress in animals. Micronutrients play crucial roles in the bioactivity of several antioxidant systems. Shelter management by providing a thermo-comfort micro-environment to animals may also combat the heat stress during summer. Hence, the aim of the present study was to assess the biological ability of Malpura lambs to counter thermal stress following supplementation of micronutrients and providing shelter in a temperature-controlled climatic chamber during the hot day-hours in summer. Twenty-one lambs of 3 - 5 months age were equally divided in to three group viz. Group1: control, Group2: micronutrient- supplemented and Group3: housing in thermo-neutral climatic chamber. Lambs in group1 and 2 were maintained in a shed having free access to hot wind while the lambs in group 3 were kept inside a climatic chamber (temperature and relative humidity about 30 °C and 40%, respectively) between 10 am to 4:30 pm. All the lambs were provided identical diet consisting of 2.5 kg concentrate and ad libitum quantities of Cenchrus ciliaris hay and clean water. Group3 lambs were additionally supplemented with 0.150 g micronutrient pellet per animal per day for a period of 30 days. Blood samples were collected at 0, 15, 30 days and plasma antioxidants activity were estimated. The catalase activity in the micronutrient-pellet supplemented group was significantly (p < 0.05) higher than the control both at day15 and day30. The superoxide dismutase activity was increased significantly (p < 0.05) at day30 than the day0 in both the micronutrient-supplemented and climatic chamber groups. In conclusion, both the micronutrient supplementation and housing in a thermo-comfort environment enhance the antioxidant defence and biological adaptation in lambs during thermal stress in summer. 相似文献
107.
Vijay Pawar Rushabh Thosani Ashish Kanhed Rajani Giridhar Mange Ram Yadav 《AAPS PharmSciTech》2015,16(3):518-527
Piperazinylalkyl ester prodrugs (4a–5d) of 6-methoxy-2-naphthylacetic acid (6-MNA) (1) were synthesized and evaluated in vitro for the purpose of percutaneous drug delivery. These ionizable prodrugs exhibited varying aqueous solubilities and lipophilicities depending on the pH of the medium. The prodrugs (4a–5c) showed higher aqueous solubility and similar lipophilicity at pH 5.0 and lower aqueous solubility and higher lipophilicity at pH 7.4 in comparison to 6-MNA. The chemical and enzymatic hydrolyses of the prodrugs was investigated in aqueous buffer solutions (pH 5.0 and 7.4) and in 80% human serum (pH 7.4) at 37°C. The prodrugs showed moderate chemical stability (t1/2 = 6–60 h) but got readily hydrolyzed enzymatically to 6-MNA with half-life ranging from 10–60 min. In the in vitro permeation study using rat skin, the flux of 6-MNA and the prodrugs was determined in aqueous buffers of pH 5.0 and 7.4. The prodrug (5b) showed 7.9- and 11.2-fold enhancement in skin permeation compared to 6-MNA (1) at pH 5.0 and 7.4, respectively. It was concluded that the parent NSAIDs having favorable pharmacokinetic and pharmacodynamic properties coupled with increased skin permeability of their prodrugs could give better options for the treatment of rheumatic diseases.
Electronic supplementary material
The online version of this article (doi:10.1208/s12249-014-0240-6) contains supplementary material, which is available to authorized users.KEY WORDS: 6-MNA, NSAID, piperazinylalkylester, prodrug, skin permeation 相似文献108.
Gary W. Wood Elda Hausmann Rajani Choudhuri 《Molecular reproduction and development》1997,46(1):62-70
It has been previously demonstrated that macrophage colony stimulating factor (CSF-1) is produced by uterine epithelial cells in response to estrogen and progesterone. Studies in normal and op/op mice demonstrated that accumulation of a portion of the uterine macrophage population could be attributed to the chemotactic properties of CSF-1. Op/op mice exhibit greatly reduced rates of fertility, but successful pregnancy is not completely blocked. Also, uteri from op/op mice are not completely macrophage deficient. There are two possible explanations for this. One is that not all tissue macrophages are recruited from the bone marrow pool; some may be derived from primitive mesenchyme. Alternatively, tissue macrophages may be recruited from the bone marrow pool through expression of other type I chemokines such as JE, RANTES, MIP-1α, MIP-1β, IP-10, and KC. Both RANTES and JE are expressed at higher levels than CSF-1 during early pregnancy. The variable expression and relative role of these various chemokines in pregnancy was addressed by measuring mRNA expression during the first 8 days of pregnancy and in a pseudopregnant model. The expression of these various genes relative to macrophage numbers and macrophage distribution will be discussed. The relative role of these various factors in preparing the uterus for blastocyst implantation will be discussed. Mol Reprod Dev 46:62–70, 1997. © 1997 Wiley-Liss, Inc. 相似文献
109.
Xiaojiao Zheng Fengjie Huang Aihua Zhao Sha Lei Yunjing Zhang Guoxiang Xie Tianlu Chen Chun Qu Cynthia Rajani Bing Dong Defa Li Wei Jia 《BMC biology》2017,15(1):120
Background
Intestinal bacteria are known to regulate bile acid (BA) homeostasis via intestinal biotransformation of BAs and stimulation of the expression of fibroblast growth factor 19 through intestinal nuclear farnesoid X receptor (FXR). On the other hand, BAs directly regulate the gut microbiota with their strong antimicrobial activities. It remains unclear, however, how mammalian BAs cross-talk with gut microbiome and shape microbial composition in a dynamic and interactive way.Results
We quantitatively profiled small molecule metabolites derived from host-microbial co-metabolism in mice, demonstrating that BAs were the most significant factor correlated with microbial alterations among all types of endogenous metabolites. A high-fat diet (HFD) intervention resulted in a rapid and significant increase in the intestinal BA pool within 12 h, followed by an alteration in microbial composition at 24 h, providing supporting evidence that BAs are major dietary factors regulating gut microbiota. Feeding mice with BAs along with a normal diet induced an obese phenotype and obesity-associated gut microbial composition, similar to HFD-fed mice. Inhibition of hepatic BA biosynthesis under HFD conditions attenuated the HFD-induced gut microbiome alterations. Both inhibition of BAs and direct suppression of microbiota improved obese phenotypes.Conclusions
Our study highlights a liver–BA–gut microbiome metabolic axis that drives significant modifications of BA and microbiota compositions capable of triggering metabolic disorders, suggesting new therapeutic strategies targeting BA metabolism for metabolic diseases.110.
Adam J. Fournier James D. Hogan Labchan Rajbhandari Shiva Shrestha Arun Venkatesan K. T. Ramesh 《PloS one》2015,10(6)
Although a number of cytoskeletal derangements have been described in the setting of traumatic axonal injury (TAI), little is known of early structural changes that may serve to initiate a cascade of further axonal degeneration. Recent work by the authors has examined conformational changes in cytoskeletal constituents of neuronal axons undergoing traumatic axonal injury (TAI) following focal compression through confocal imaging data taken in vitro and in situ. The present study uses electron microscopy to understand and quantify in vitro alterations in the ultrastructural composition of microtubules and neurofilaments within neuronal axons of rats following focal compression. Standard transmission electron microscopy processing methods are used to identify microtubules, while neurofilament identification is performed using antibody labeling through gold nanoparticles. The number, density, and spacing of microtubules and neurofilaments are quantified for specimens in sham Control and Crushed groups with fixation at <1min following load. Our results indicate that the axon caliber dependency known to exist for microtubule and neurofilament metrics extends to axons undergoing TAI, with the exception of neurofilament spacing, which appears to remain constant across all Crushed axon diameters. Confidence interval comparisons between Control and Crushed cytoskeletal measures suggests early changes in the neurofilament spatial distributions within axons undergoing TAI may precede microtubule changes in response to applied loads. This may serve as a trigger for further secondary damage to the axon, representing a key insight into the temporal aspects of cytoskeletal degeneration at the component level, and suggests the rapid removal of neurofilament sidearms as one possible mechanism. 相似文献