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991.
Synthesis of a new series of 3,4-diarylpyrazole-1-carboxamide derivatives is described. Their antiproliferative activity against A375P human melanoma cell line was tested and the effect of substituents on the diarylpyrazole scaffold was investigated. The biological results indicated that five synthesized compounds (Ig, Ii, IIc, IIg, and IIh) exhibited similar activity to Sorafenib. In addition, three compounds (IIa, IIb, and IIi) were more potent than Sorafenib. Among all of these derivatives, compound IIa which has dimethylamino and phenolic moieties showed the most potent antiproliferative activity against A375P human melanoma cell line. Virtual screening was carried out through docking of the most potent compound IIa into the domain of V600E-b-Raf and the binding mode was studied. 相似文献
992.
Khan S Elshaer A Rahman AS Hanson P Perrie Y Mohammed AR 《International journal of pharmaceutics》2011,417(1-2):272-279
Physiological changes that take place at cellular level are usually reflective of their level of gene expression. Different formulation excipients have an impact on physiological behavior of the exposed cells and in turn affect transporter genes, enterocyte-mediated metabolism and toxicity biomarkers. The aim of this study was to prepare solid dispersion of paracetamol and evaluate genetic changes that occur in Caco-2 cell lines during the permeability of paracetamol alone and paracetamol solid dispersion formulations. Paracetamol-PEG 8000 solid dispersion was prepared by melt fusion method and the formulation was characterised using differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). Formulation of solid dispersion resulted in the conversion of crystalline drug into an amorphous form. Permeability studies showed that paracetamol absorption was higher from the solid dispersion formulation. DNA microarrays analysis was carried out in order to investigate the involvement of any efflux/uptake transporters in paracetamol or its solid dispersion permeability. Neither transporter carriers nor efflux proteins were found to be involved in the absorption of paracetamol or its PEG solid dispersion. Gene expression analysis established that paracetamol toxicity was potentially reduced upon formulation into solid dispersion when ATP binding cassette (ABC) and solute carrier transporter (SLC) genes were analyzed. 相似文献
993.
Islam MA 《Recent patents on cardiovascular drug discovery》2012,7(2):88-99
Recently, there is a growing interest in the cardiovascular beneficial effects of green tea. Epidemiological and clinical studies have suggested that consumption of green tea is inversely associated with the risk of developing cardiovascular diseases. Catechins, the major flavonoid constituents of green tea, exert cardioprotective effects through diverse mechanisms that include reversal of endothelial dysfunctions, decreasing inflammatory biomarkers, and providing antioxidant, antiplatelet and antiproliferative effects. Moreover, dietary consumption of green tea catechins has beneficial effects on blood pressure and lipid parameters. This review will focus on discussing the latest research on the cardioprotective effects of green tea catechins and their underlying molecular mechanisms. Several recent patents pertinent to green tea and cardiovascular health will also be discussed. It is noteworthy that clinical studies involving green tea are fraught with multiple complexity and confounding factors. Therefore, a rigorous assessment of the effects of green tea catechins in well-controlled human trials will be required for better understanding of the effects of green tea in cardiovascular health. 相似文献
994.
Oo ZY Deng R Hu M Ni M Kandasamy K bin Ibrahim MS Ying JY Zink D 《Biomaterials》2011,32(34):8806-8815
Bioartificial kidneys (BAKs) containing human primary renal proximal tubule cells (HPTCs) have been applied in clinical trials. The results were encouraging, but also showed that more research is required. Animal cells or cell lines are not suitable for clinical applications, but have been mainly used in studies on BAK development as large numbers of such cells could be easily obtained. It is difficult to predict HPTC performance based on data obtained with other cell types. To enable more extensive studies on HPTCs, we have developed a bioreactor containing single hollow fiber membranes that requires relatively small amounts of cells. Special hollow fiber membranes with the skin layer on the outer surface and consisting of polyethersulfone/polyvinylpyrrolidone were developed. The results suggested that such hollow fiber membranes were more suitable for the bioreactor unit of BAKs than membranes with an inner skin layer. An HPTC-compatible double coating was applied to the insides of the hollow fiber membranes, which sustained the formation of functional epithelia under bioreactor conditions. Nevertheless, the state of differentiation of the primary human cells remained a critical issue and should be further addressed. The bioreactor system described here will facilitate further studies on the relevant human cell type. 相似文献
995.
Dey D Inayathullah M Lee AS LeMieux MC Zhang X Wu Y Nag D De Almeida PE Han L Rajadas J Wu JC 《Biomaterials》2011,32(20):4647-4658
Polyethylenimine (PEI) based polymers are efficient agents for cell transfection. However, their use has been hampered due to high cell death associated with transfection thereby resulting in low efficiency of gene delivery within the cells. To circumvent the problem of cellular toxicity, metal binding peptides were linked to PEI. Eight peptide-PEI derivatives were synthesized to improve cell survival and transfection efficiency. TAT linked PEI was used as a control polymer. Peptides linked with PEI amines formed nanogels as shown by electron microscopy and atomic force microscopic measurements. Polymers were characterized by spectroscopic methods and their ability to form complexes with plasmids was tested using electrophoretic studies. These modifications improved polymer biocompatibility as well as cell survival markedly, when compared to PEI alone. A subset of the modified peptide-polymers also showed significantly higher transfection efficiency in primary human cells with respect to the widely used transfection agent, lipofectamine. Study of the underlying mechanism of the observed phenomena revealed lower levels of 'reactive oxygen species' (ROS) in the presence of the peptide-polymers when compared to PEI alone. This was further corroborated with global gene expression analysis which showed upregulation of multiple genes and pathways involved in regulating intracellular oxidative stress. 相似文献
996.
Prabhakar PV Reddy UA Singh SP Balasubramanyam A Rahman MF Indu Kumari S Agawane SB Murty US Grover P Mahboob M 《Journal of applied toxicology : JAT》2012,32(6):436-445
This study investigated the oxidative stress induced after acute oral treatment with 500, 1000 and 2000 mg kg?1 doses of Al2O3‐30 and ?40 nm and bulk Al2O3 in Wistar rats. Both the nanomaterials induced significant oxidative stress in a dose‐dependent manner in comparison to the bulk. There was no significant difference between the two nanomaterials. However, the effect decreased with increase with time after treatment. The histopathological examination showed lesions only in liver with Al2O3 nanomaterials at 2000 mg kg?1. Copyright © 2011 John Wiley & Sons, Ltd. 相似文献
997.
Hossain MI Kamaruddin MA Cheng HC 《Clinical and experimental pharmacology & physiology》2012,39(8):684-691
Excitotoxicity, a major cause of neuronal death in acute and chronic neurodegenerative diseases and conditions such as stroke and Parkinson's disease, is initiated by overstimulation of glutamate receptors, leading to calcium overload in affected neurons. The sustained high concentration of intracellular calcium constitutively activates a host of enzymes, notably the calcium-activated proteases calpains, neuronal nitric oxide synthase (nNOS) and NADPH oxidase (NOX), to antagonise the cell survival signalling pathways and induce cell death. Upon overactivation by calcium, calpains catalyse limited proteolysis of specific cellular proteins to modulate their functions; nNOS produces excessive amounts of nitric oxide (NO), which, in turn, covalently modifies specific enzymes by S-nitrosylation; and NOX produces excessive amounts of reactive oxygen species (ROS) to inflict damage to key metabolic enzymes. Presumably, key regulatory enzymes governing cell survival and cell death are aberrantly modified and regulated by calpains, NO and ROS in affected neurons; these aberrantly modified enzymes then cooperate to induce the death of affected neurons. c-Src, an Src family kinase (SFK) member, is one of the aberrantly regulated enzymes involved in excitotoxic neuronal death. Herein we review how SFKs are functionally linked to the glutamate receptors and the biochemical and structural basis of the aberrant regulation of SFKs. Results in the literature suggest that SFKs are aberrantly activated by calpain-mediated truncation and S-nitrosylation. Thus, the aberrantly activated SFKs are targets for therapeutic intervention to reduce the extent of brain damage caused by stroke. 相似文献
998.
Lowes S Jersey J Shoup R Garofolo F Needham S Couerbe P Lansing T Bhatti M Sheldon C Hayes R Islam R Lin Z Garofolo W Moussallie M Teixeira Lde S Rocha T Jardieu P Truog J Lin J Lundberg R Breau A Dilger C Bouhajib M Levesque A Gagnon-Carignan S Jenkins R Nicholson R Lin MH Karnik S DeMaio W Smith K Cojocaru L Allen M Fatmi S Sayyarpour F Malone M Fang X 《Bioanalysis》2012,4(7):763-768
The Global CRO Council for Bioanalysis (GCC) was formed in September 2010. Since then, the representatives of the member companies come together periodically to openly discuss bioanalysis and the regulatory challenges unique to the outsourcing industry. The 4th GCC Closed Forum brought together experts from bioanalytical CROs to share and discuss recent issues in regulated bioanalysis, such as the impact of coadministered drugs on stability, some differences between European Medicines Agency and US FDA bioanalytical guidance documents and lessons learned following recent Untitled Letters. Recent 483s and agency findings, as well as issues on method carryover, were also part of the topics discussed. 相似文献
999.
Helegbe GK Yanagi T Senba M Huy NT Shuaibu MN Yamazaki A Kikuchi M Yasunami M Hirayama K 《Parasitology research》2011,108(4):807-814
To mimic a human malaria infection in the endemic condition, two strains of mice (Balb/c and CBA) were infected and treated
several times to generate so-called semi-immune status. As previously reported, neither mice (Balb/c and CBA) strain showed
cerebral malaria, even in the susceptible C57BL/6 (B6). The significant difference between the mice strains in our previous
study was the rate of destruction of uninfected red blood cells (uRBCs) at infection. After the established repeated cycles
of infection and treatment and the final challenge with 104
Plasmodium berghei ANKA until minimum Hb, Balb/c and CBA mice were sacrificed. The spleen, liver, brain, kidney, lung, heart, and muscle were
removed, stained with hematoxylin–eosin and analyzed with light microscopy. Previous observation suggested that Balb/c destroyed
uRBC at much higher rate than the other strains although the parasitemia was very low. Pathological investigation carried
out in this study revealed that this destruction was mainly contributed by the uRBCs as no parasite sequestration was observed
in any of the organs. However, malaria pigment deposition was observed in spleen and liver of all the semi-immune mice strains.
This histopathological study in the severe malaria anemia model, which is difficult to conduct in humans, will be helpful
in taking into account different responses to malaria infection when designing therapeutic interventions and vaccine studies. 相似文献
1000.
Taguchi T Nazneen A Al-Shihri AA Turkistani KA Razzaque MS 《ACTA HISTOCHEMICA ET CYTOCHEMICA》2011,44(2):35-41
Heat shock protein 47 (HSP47) is a collagen-specific molecular chaperone that helps the molecular maturation of various types of collagens. A close association between increased expression of HSP47 and the excessive accumulation of collagens is found in various human and experimental fibrotic diseases. Increased levels of HSP47 in fibrotic diseases are thought to assist in the increased assembly of procollagen, and thereby contribute to the excessive deposition of collagens in fibrotic areas. Currently, there is not a good universal histological marker to identify collagen-producing cells. Identifying phenotypically altered collagen-producing cells is essential for the development of cell-based therapies to reduce the progression of fibrotic diseases. Since HSP47 has a single substrate, which is collagen, the HSP47 cellular expression provides a novel universal biomarker to identify phenotypically altered collagen-producing cells during wound healing and fibrosis. In this brief article, we explained why HSP47 could be used as a universal marker for identifying phenotypically altered collagen-producing cells. 相似文献