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101.
Pangkhi Medhi Ololade Olatunji Atul Nayak Chandra Teja Uppuluri Richard T. Olsson Buchi N. Nalluri Diganta B. Das 《AAPS PharmSciTech》2017,18(5):1488-1494
Microneedle (MN) technology has emerged as an effective drug delivery system, and it has tremendous potential as a patient friendly substitute for conventional methods for transdermal drug delivery (TDD). In this paper, we report on the preparation of lidocaine-loaded biodegradable microneedles, which are manufactured from fish scale-derived collagen. Lidocaine, a common tissue numbing anaesthetic, is loaded in these microneedles with an aim of delivering the drug with controlled skin permeation. Evaluation of lidocaine permeation in porcine skin has been successfully performed using Franz diffusion cell (FDC) which has shown that the drug permeation rate increases from 2.5 to 7.5% w/w after 36 h and pseudo steady state profile is observed from 5.0 to 10.0% w/w lidocaine-loaded microneedle. Swelling experiments have suggested that the microneedles have negligible swellability which implies that the patch would stick to the tissue when inserted. The experiments on MN dissolution have depicted that the lidocaine loaded in the patch is lower than the theoretical loading, which is expected as there can be losses of the drug during initial process manufacture. 相似文献
102.
Identification of potential drug targets is the first step in the process of modern drug discovery, subjected to their validation
and drug development. Whole genome sequences of a number of organisms allow prediction of potential drug targets using sequence
comparison approaches. Here, we present a subtractive approach exploiting the knowledge of global gene expression along with
sequence comparisons to predict the potential drug targets more efficiently. Based on the knowledge of 155 known virulence
and their coexpressed genes mined from microarray database in the public domain, 357 coexpressed probable virulence genes
for Vibrio cholerae were predicted. Based on screening of Database of Essential Genes using blastn, a total of 102 genes out of these 357 were
enlisted as vitally essential genes, and hence good putative drug targets. As the effective drug target is a protein which
is only present in the pathogen, similarity search of these 102 essential genes against human genome sequence led to subtraction
of 66 genes, thus leaving behind a subset of 36 genes whose products have been called as potential drug targets. The gene
ontology analysis using Blast2GO of these 36 genes revealed their roles in important metabolic pathways of V. cholerae or on the surface of the pathogen. Thus, we propose that the products of these genes be evaluated as target sites of drugs
against V. cholerae in future investigations. 相似文献
103.
Wellman A Eckert DJ Jordan AS Edwards BA Passaglia CL Jackson AC Gautam S Owens RL Malhotra A White DP 《Journal of applied physiology (Bethesda, Md. : 1985)》2011,110(6):1627-1637
There is not a clinically available technique for measuring the physiological traits causing obstructive sleep apnea (OSA). Therefore, it is often difficult to determine why an individual has OSA or to what extent the various traits contribute to the development of OSA. In this study, we present a noninvasive method for measuring four important physiological traits causing OSA: 1) pharyngeal anatomy/collapsibility, 2) ventilatory control system gain (loop gain), 3) the ability of the upper airway to dilate/stiffen in response to an increase in ventilatory drive, and 4) arousal threshold. These variables are measured using a single maneuver in which continuous positive airway pressure (CPAP) is dropped from an optimum to various suboptimum pressures for 3- to 5-min intervals during sleep. Each individual's set of traits is entered into a physiological model of OSA that graphically illustrates the relative importance of each trait in that individual. Results from 14 subjects (10 with OSA) are described. Repeatability measurements from separate nights are also presented for four subjects. The measurements and model illustrate the multifactorial nature of OSA pathogenesis and how, in some individuals, small adjustments of one or another trait (which might be achievable with non-CPAP agents) could potentially treat OSA. This technique could conceivably be used clinically to define a patient's physiology and guide therapy based on the traits. 相似文献
104.
105.
Thakur AK Srivastava AK Srinivas V Chary KV Rao CM 《The Journal of biological chemistry》2011,286(44):38533-38545
Copper is reported to promote and prevent aggregation of prion protein. Conformational and functional consequences of Cu(2+)-binding to prion protein (PrP) are not well understood largely because most of the Cu(2+)-binding studies have been performed on fragments and truncated variants of the prion protein. In this context, we set out to investigate the conformational consequences of Cu(2+)-binding to full-length prion protein (PrP) by isothermal calorimetry, NMR, and small angle x-ray scattering. In this study, we report altered aggregation behavior of full-length PrP upon binding to Cu(2+). At physiological temperature, Cu(2+) did not promote aggregation suggesting that Cu(2+) may not play a role in the aggregation of PrP at physiological temperature (37 °C). However, Cu(2+)-bound PrP aggregated at lower temperatures. This temperature-dependent process is reversible. Our results show two novel intra-protein interactions upon Cu(2+)-binding. The N-terminal region (residues 90-120 that contain the site His-96/His-111) becomes proximal to helix-1 (residues 144-147) and its nearby loop region (residues 139-143), which may be important in preventing amyloid fibril formation in the presence of Cu(2+). In addition, we observed another novel interaction between the N-terminal region comprising the octapeptide repeats (residues 60-91) and helix-2 (residues 174-185) of PrP. Small angle x-ray scattering studies of full-length PrP show significant compactness upon Cu(2+)-binding. Our results demonstrate novel long range inter-domain interactions of the N- and C-terminal regions of PrP upon Cu(2+)-binding, which might have physiological significance. 相似文献
106.
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
107.
A novel one-pot synthesis of imidazo[1,2-c]pyrimido[5,4-e]pyrimidinones (2), tetraazaacenaphthene-3,6-diones (4), tetarazaphenalene-1,7-dione (4d) is delineated from the reaction of cyclic ketene aminal (1) and alkyl or aryl isothiocyanate through tandem addition-cyclization reactions. However, reaction of ketene aminal (1a) with alkyl isothiocyanate only yielded angularly cyclized product 5 which did not react further to yield 6. The structure of 2c and 4d was ascertained by single crystal X-ray diffraction analysis which demonstrated a network of various inter- and intramolecular interactions, responsible for the stability and packing of the molecules in the crystalline state. Some of the compounds (2a--h) were screened for hepatoprotective activity but only 2a was found most effective. 相似文献
108.
Atul Kakrana Reza Hammond Parth Patel Mayumi Nakano Blake C. Meyers 《Nucleic acids research》2014,42(18):e139
Parallel analysis of RNA ends (PARE) is a technique utilizing high-throughput sequencing to profile uncapped, mRNA cleavage or decay products on a genome-wide basis. Tools currently available to validate miRNA targets using PARE data employ only annotated genes, whereas important targets may be found in unannotated genomic regions. To handle such cases and to scale to the growing availability of PARE data and genomes, we developed a new tool, ‘sPARTA’ (small RNA-PARE target analyzer) that utilizes a built-in, plant-focused target prediction module (aka ‘miRferno’). sPARTA not only exhibits an unprecedented gain in speed but also it shows greater predictive power by validating more targets, compared to a popular alternative. In addition, the novel ‘seed-free’ mode, optimized to find targets irrespective of complementarity in the seed-region, identifies novel intergenic targets. To fully capitalize on the novelty and strengths of sPARTA, we developed a web resource, ‘comPARE’, for plant miRNA target analysis; this facilitates the systematic identification and analysis of miRNA-target interactions across multiple species, integrated with visualization tools. This collation of high-throughput small RNA and PARE datasets from different genomes further facilitates re-evaluation of existing miRNA annotations, resulting in a ‘cleaner’ set of microRNAs. 相似文献
109.
Atul Grover Maya Kumari Sadhana Singh Shivender Singh Rathode Sanjay Mohan Gupta Pankaj Pandey Sween Gilotra Devender Kumar Mohommad Arif Zakwan Ahmed 《Physiology and Molecular Biology of Plants》2014,20(1):139-142
Oil-rich seeds of Jatropha curcas are being focussed as a source of bio-diesel. However, prior to its industrial use, a lot of crop improvement efforts are required in Jatropha. Availability of a large number of EST sequences of Jatropha in public domain allow identification of candidate genes for several agronomic characters including oil content in seeds. Here, we have analysed 42,477 ESTs of Jatropha spanning 22.9 Mbp for microsatellites and fatty acid metabolism related sequences. Unigene sequences were built using CAP 3 programme resulted in 12,358 contigs and 5,730 singlets. Nearly, 8 % unigenes showed presence of microsatellites, slightly over-represented compared to their occurrence in ESTs. Most of the microsatellites were either di- or tri-nucleotide repeats, while other categories of tetra-, penta- and hexa-nucleotide repeats together constituted ~4 % of total microsatellites. Assessment of functional relevance of unigenes was carried out using Blast2GO using its default settings. The overall sequence similarity level against sequences in ‘nr’ database was >80 %. A total of 931 sequences that participated in any of the pathways related to fatty acid or lipid metabolism were found at GO level 6. Among these, GO terms “Fatty acid metabolic process” and “Fatty acid biosynthetic process” were most over-represented. Overall, our work has due relevance in identifying molecular markers for the candidate genes for oil content in Jatropha seeds, and will prove to be an important reference for further studies for identification of trait specific markers in Jatropha. 相似文献
110.
Adrian Egli Deanna M. Santer Daire O'Shea Khaled Barakat Mohammedyaseen Syedbasha Madeleine Vollmer Aliyah Baluch Rakesh Bhat Jody Groenendyk Michael A. Joyce Luiz F. Lisboa Brad S. Thomas Manuel Battegay Nina Khanna Thomas Mueller D. Lorne J. Tyrrell Michael Houghton Atul Humar Deepali Kumar 《PLoS pathogens》2014,10(12)
Influenza is a major cause of morbidity and mortality in immunosuppressed persons, and vaccination often confers insufficient protection. IL-28B, a member of the interferon (IFN)-λ family, has variable expression due to single nucleotide polymorphisms (SNPs). While type-I IFNs are well known to modulate adaptive immunity, the impact of IL-28B on B- and T-cell vaccine responses is unclear. Here we demonstrate that the presence of the IL-28B TG/GG genotype (rs8099917, minor-allele) was associated with increased seroconversion following influenza vaccination (OR 1.99 p = 0.038). Also, influenza A (H1N1)-stimulated T- and B-cells from minor-allele carriers showed increased IL-4 production (4-fold) and HLA-DR expression, respectively. In vitro, recombinant IL-28B increased Th1-cytokines (e.g. IFN-γ), and suppressed Th2-cytokines (e.g. IL-4, IL-5, and IL-13), H1N1-stimulated B-cell proliferation (reduced 70%), and IgG-production (reduced>70%). Since IL-28B inhibited B-cell responses, we designed antagonistic peptides to block the IL-28 receptor α-subunit (IL28RA). In vitro, these peptides significantly suppressed binding of IFN-λs to IL28RA, increased H1N1-stimulated B-cell activation and IgG-production in samples from healthy volunteers (2-fold) and from transplant patients previously unresponsive to vaccination (1.4-fold). Together, these findings identify IL-28B as a key regulator of the Th1/Th2 balance during influenza vaccination. Blockade of IL28RA offers a novel strategy to augment vaccine responses. 相似文献