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91.
Singh P Mittal A Bhardwaj A Kaur S Kumar S 《Bioorganic & medicinal chemistry letters》2008,18(1):85-89
Indoles carrying a cyclic ester (gamma-butyrolactone) at C-3 position have been synthesized by the allylation of 3-indoleglyoxylate followed by iodocyclisation and the nucleophilic replacement of the iodo-group. Screening of these molecules for COX-2 inhibition and anti-cancer activities has identified compounds 10 and 11 as highly potent and selective for COX-2 as well as showing remarkable anti-cancer activities (better than that of indomethacin). 相似文献
92.
Michael W.J. Cleeter Kai-Yin Chau Caroline Gluck Atul Mehta Derralynn A. Hughes Michael Duchen Nicholas William Wood John Hardy J. Mark Cooper Anthony Henry Schapira 《Neurochemistry international》2013
Mutations of the gene for glucocerebrosidase 1 (GBA) cause Gaucher disease (GD), an autosomal recessive lysosomal storage disorder. Individuals with homozygous or heterozygous (carrier) mutations of GBA have a significantly increased risk for the development of Parkinson’s disease (PD), with clinical and pathological features that mirror the sporadic disease. The mechanisms whereby GBA mutations induce dopaminergic cell death and Lewy body formation are unknown. There is evidence of mitochondrial dysfunction and oxidative stress in PD and so we have investigated the impact of glucocerebrosidase (GCase) inhibition on these parameters to determine if there may be a relationship of GBA loss-of-function mutations to the known pathogenetic pathways in PD. We have used exposure to a specific inhibitor (conduritol-β-epoxide, CβE) of GCase activity in a human dopaminergic cell line to identify the biochemical abnormalities that follow GCase inhibition. We show that GCase inhibition leads to decreased ADP phosphorylation, reduced mitochondrial membrane potential and increased free radical formation and damage, together with accumulation of alpha-synuclein. Taken together, inhibition of GCase by CβE induces abnormalities in mitochondrial function and oxidative stress in our cell culture model. We suggest that GBA mutations and reduced GCase activity may increase the risk for PD by inducing these same abnormalities in PD brain. 相似文献
93.
Atul Kumar Brian Donley 《Computer methods in biomechanics and biomedical engineering》2014,17(16):1777-1784
This study was designed to examine the three-dimensional geometry of the head of the first metatarsal bone of the foot. Ninety-seven adult first metatarsal head (MTH1) bones were scanned using a laser scanner at 400 dpi. A best-fit ellipsoid was obtained from the articular surfaces of MTH1 for each size group using nonlinear unconstrained optimisation. Average root mean square errors between the articulating surfaces and the optimal fit surfaces of the bone specimens were between 0.29 and 0.42 mm. After classification based on sex and size groups, the profile provided a good fit to individual bones. Consideration of the thickness of cartilage overlying the metatarsal head (MTH) may further improve the fit. The proposed approach provides the basis for a design of an MTH hemi-arthroplasty that has good anatomical congruence with the native joint. 相似文献
94.
The growth of mixed microbial cultures on mixtures of substrates is a problem of fundamental biological interest. In the last two decades, several unstructured models of mixed-substrate growth have been studied. It is well known, however, that the growth patterns in mixed-substrate environments are dictated by the enzymes that catalyse the transport of substrates into the cell. We have shown previously that a model taking due account of transport enzymes captures and explains all the observed patterns of growth of a single species on two substitutable substrates (J. Theor. Biol. 190 (1998) 241). Here, we extend the model to study the steady states of growth of two species on two substitutable substrates. The model is analysed to determine the conditions for existence and stability of the various steady states. Simulations are performed to determine the flow rates and feed concentrations at which both species coexist. We show that if the interaction between the two species is purely competitive, then at any given flow rate, coexistence is possible only if the ratio of the two feed concentrations lies within a certain interval; excessive supply of either one of the two substrates leads to annihilation of one of the species. This result simplifies the construction of the operating diagram for purely competing species. This is because the two-dimensional surface that bounds the flow rates and feed concentrations at which both species coexist has a particularly simple geometry: It is completely determined by only two coordinates, the flow rate and the ratio of the two feed concentrations. We also study commensalistic interactions between the two species by assuming that one of the species excretes a product that can support the growth of the other species. We show that such interactions enhance the coexistence region. 相似文献
95.
Resende R Moreira PI Proença T Deshpande A Busciglio J Pereira C Oliveira CR 《Free radical biology & medicine》2008,44(12):2051-2057
Alzheimer disease (AD) is a neurodegenerative disease which is characterized by the presence of extracellular senile plaques mainly composed of amyloid-beta peptide (Abeta), intracellular neurofibrillary tangles, and selective synaptic and neuronal loss. AD brains revealed elevated levels of oxidative stress markers which have been implicated in Abeta-induced toxicity. In the present work we addressed the hypothesis that oxidative stress occurs early in the development of AD and evaluated the extension of the oxidative stress and the levels of antioxidants in an in vivo model of AD, the triple-transgenic mouse, which develops plaques, tangles, and cognitive impairments and thus mimics AD progression in humans. We have shown that in this model, levels of antioxidants, namely, reduced glutathione and vitamin E, are decreased and the extent of lipid peroxidation is increased. We have also observed increased activity of the antioxidant enzymes glutathione peroxidase and superoxide dismutase. These alterations are evident during the Abeta oligomerization period, before the appearance of Abeta plaques and neurofibrillary tangles, supporting the view that oxidative stress occurs early in the development of the disease. 相似文献
96.
Atul C. Badhan Rajashree C. Mashru Punit P. Shah Arti R. Thakkar Nitin B. Dobaria 《AAPS PharmSciTech》2009,10(2):459-467
In the present work, sustained release gastroretentive minimatrices of amoxicillin have been designed and optimized using
central composite design. Effect of amount of xanthan gum, rate controlling polymers (HPMC K100M CR/PEO coagulant (1:1)),
carbopol 974P, and gas generating couple (sodium bicarbonate/citric acid (3:1)) was studied on dependent (response) variables,
i.e., buoyancy lag time, drug release at 1 h, time required for 95% drug release, swelling index, and bioadhesive strength.
Minimatrices were prepared by non aqueous granulation method using solution of PVP K30 in isopropyl alcohol. All the formulations
were found to contain 99.2% to 100.9% of amoxicillin per minimatrix. Optimum formulation (Formulation number AGT09) containing
high level of the independent variables was having buoyancy lag time of 7 min and drug release at 1 h was 32.5%. It required
9.39 h for 95% drug release while swelling index and bioadhesive strength were 341 and 17.9 dyn/cm2, respectively. This formulation was said to be optimum because it has minimum buoyancy lag time, requires maximum time for
95% drug release, and has higher bioadhesive capabilities. In vitro results of an optimized formulation indicate its sustained drug release and gastric retention capability, which may be very
useful for effective treatment of H. pylori infection. 相似文献
97.
Biosorption of dyes using dead macro fungi: effect of dye structure, ionic strength and pH 总被引:10,自引:0,他引:10
Biosorbents prepared from dead macro fungi, namely Fomes fomentarius and Phellinus igniarius, were applied for the uptake of Methylene Blue (MB) and Rhodamine B (RB). Equilibrium isotherm data could be well described by the Langmuir and Freundlich models. Methylene Blue was found to be more adsorbable than Rhodamine B. Langmuir monolayer coverage was determined as 204.38-232.73 mg/g and 25.12-36.82 mg/g for MB and RB, respectively. Molecular structure and ionic radius of dyes were found to be responsible for differences in their uptakes. Results showed that sorption of MB increased while that of RB decreased as pH of respective dye solutions changed from 3 to 11. An increase in ionic strength also exhibited an adverse effect on dye sorption capacity. Ionic strength and pH affected the sorption of MB more as compared to the sorption of RB. The presence of carboxylic (-ve) and amino (+ve) groups in RB could explain the lower sorption of RB compared to MB. 相似文献
98.
Narang A 《Journal of theoretical biology》2006,242(2):489-501
Mixed-substrate microbial growth is of fundamental interest in microbiology and bioengineering. Several mathematical models have been developed to account for the genetic regulation of such systems, especially those resulting in diauxic growth. In this work, we compare the dynamics of three such models (Narang, 1998a. The dynamical analogy between microbial growth on mixtures of substrates and population growth of competing species. Biotechnol. Bioeng. 59, 116-121; Thattai and Shraiman, 2003. Metabolic switching in the sugar phosphotransferase system of Escherichia coli. Biophys. J. 85(2), 744-754; Brandt et al., 2004. Modelling microbial adaptation to changing availability of substrates. Water Res. 38, 1004-1013). We show that these models are dynamically similar--the initial motion of the inducible enzymes in all the models is described by the Lotka-Volterra equations for competing species. In particular, the prediction of diauxic growth corresponds to "extinction" of one of the enzymes during the first few hours of growth. The dynamic similarity occurs because in all the models, the inducible enzymes possess properties characteristic of competing species: they are required for their own synthesis, and they inhibit each other. Despite this dynamic similarity, the models vary with respect to the range of dynamics captured. The Brandt et al. model always predicts the diauxic growth pattern, whereas the remaining two models exhibit both diauxic and non-diauxic growth patterns. The models also differ with respect to the mechanisms that generate the mutual inhibition between the enzymes. In the Narang model, mutual inhibition occurs because the enzymes for each substrate enhance the dilution of the enzymes for the other substrate. The Brandt et al. model superimposes upon this dilution effect an additional mechanism of mutual inhibition. In the Thattai and Shraiman model, the mutual inhibition is entirely due to competition for the phosphoryl groups. For quantitative agreement with the data, all models must be modified to account for specific mechanisms of mutual inhibition, such as inducer exclusion. 相似文献
99.
100.
The effects of 2-substituted oestrogen sulphamates on the growth of prostate and ovarian cancer cells 总被引:2,自引:0,他引:2
Day JM Newman SP Comninos A Solomon C Purohit A Leese MP Potter BV Reed MJ 《The Journal of steroid biochemistry and molecular biology》2003,84(2-3):317-325
The human endogenous metabolite 2-methoxyoestradiol (2-MeOE2) has been shown to inhibit the proliferation of breast cancer cells. We have previously shown that sulphamoylation of a series of 2-substituted oestrogens greatly enhances their ability to inhibit breast cancer cell proliferation and induce apoptosis. In this study, we have investigated the ability of a number of 2-substituted oestrogens and their sulphamoylated derivatives to inhibit the proliferation of two prostate cancer cell lines, an ovarian cancer cell line and its drug-resistant derivatives. 2-Methoxyoestrone, 2-ethyloestrone and 2-ethyloestradiol had little effect on the growth of the cell lines tested (IC(50)>10 microM). 2-MeOE2 did inhibit the growth of the cells (IC(50)<10 microM), but to a lesser extent than any of the sulphamoylated derivatives tested (IC(50)<1.0 microM). Cells treated with the sulphamoylated derivatives became detached and rounded, displaying a characteristic apoptotic appearance. FACS analysis revealed induced G(2)/M cell cycle arrest. Treatment of cells and subsequent drug removal indicated that the effects of the drugs on the cells were irreversible. Immunoblot analysis indicated that apoptosis may be induced by phosphorylation of BCL-2. From these studies, 2-substituted oestrogen sulphamates are emerging as a potent new class of drug that may be effective against AR+/AR- prostate and ovarian tumours, and against tumours that are resistant to conventional chemotherapeutic regimens. 相似文献