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131.
132.
Renata Priscila Barros de Menezes Jssika de Oliveira Viana Eugene Muratov Luciana Scotti Marcus Tullius Scotti 《Current issues in molecular biology》2022,44(1):383
Schistosomiasis is a chronic parasitic disease caused by trematodes of the genus Schistosoma; it is commonly caused by Schistosoma mansoni, which is transmitted by Bioamphalaria snails. Studies show that more than 200 million people are infected and that more than 90% of them live in Africa. Treatment with praziquantel has the best cost–benefit result on the market. However, hypersensitivity, allergy, and drug resistance are frequently presented after administration. From this perspective, ligand-based and structure-based virtual screening (VS) techniques were combined to select potentially active alkaloids against S. mansoni from an internal dataset (SistematX). A set of molecules with known activity against S. mansoni was selected from the ChEMBL database to create two different models with accuracy greater than 84%, enabling ligand-based VS of the alkaloid bank. Subsequently, structure-based VS was performed through molecular docking using four targets of the parasite. Finally, five consensus hits (i.e., five alkaloids with schistosomicidal potential), were selected. In addition, in silico evaluations of the metabolism, toxicity, and drug-like profile of these five selected alkaloids were carried out. Two of them, namely, 11,12-methylethylenedioxypropoxy and methyl-3-oxo-12-methoxy-n(1)-decarbomethoxy-14,15-didehydrochanofruticosinate, had plausible toxicity, metabolomics, and toxicity profiles. These two alkaloids could serve as starting points for the development of new schistosomicidal compounds based on natural products. 相似文献
133.
Beta-carotene storage, conversion to retinoic acid, and induction of the lipocyte phenotype in hepatic stellate cells 总被引:1,自引:0,他引:1
Martucci RB Ziulkoski AL Fortuna VA Guaragna RM Guma FC Trugo LC Borojevic R 《Journal of cellular biochemistry》2004,92(2):414-423
Hepatic stellate cells (HSCs) are the major site of retinol (ROH) metabolism and storage. GRX is a permanent murine myofibroblastic cell line, derived from HSCs, which can be induced to display the fat-storing phenotype by treatment with retinoids. Little is known about hepatic or serum homeostasis of beta-carotene and retinoic acid (RA), although the direct biogenesis of RA from beta-carotene has been described in enterocytes. The aim of this study was to identify the uptake, metabolism, storage, and release of beta-carotene in HSCs. GRX cells were plated in 25 cm(2) tissue culture flasks, treated during 10 days with 3 micromol/L beta-carotene and subsequently transferred into the standard culture medium. beta-Carotene induced a full cell conversion into the fat-storing phenotype after 10 days. The total cell extracts, cell fractions, and culture medium were analyzed by reverse phase high-performance liquid chromatography for beta-carotene and retinoids. Cells accumulated 27.48 +/- 6.5 pmol/L beta-carotene/10(6) cells, but could not convert it to ROH nor produced retinyl esters (RE). beta-Carotene was directly converted to RA, which was found in total cell extracts and in the nuclear fraction (10.15 +/- 1.23 pmol/L/10(6) cells), promoting the phenotype conversion. After 24-h chase, cells contained 20.15 +/- 1.12 pmol/L beta-carotene/10(6) cells and steadily released beta-carotene into the medium (6.69 +/- 1.75 pmol/ml). We conclude that HSC are the site of the liver beta-carotene storage and release, which can be used for RA production as well as for maintenance of the homeostasis of circulating carotenoids in periods of low dietary uptake. 相似文献
134.
Pinto LM Pereira R de Paula E de Nucci G Santana MH Donato JL 《Journal of liposome research》2004,14(1-2):51-59
We assessed the effect of local anesthetics (LA) from different families such as esters (benzocaine), linear aminoamides (lidocaine) and cyclic aminoamides (bupivacaine) on the platelet aggregation induced by ADP. Liposomal formulations of the three LA, prepared with egg phosphatidylcholine:cholesterol alpha-tocopherol, were also tested. The three LA were able to inhibit platelet aggregation induced by ADP, in the following order: bupivacaine > lidocaine > benzocaine. After encapsulation into liposomes the inhibitory effect increased for all anesthetics studied, showing that aggregation tests could be used to assess the toxicity of new drug formulations. 相似文献
135.
The Eph family is the largest known group of structurally related receptor tyrosine kinases (RTKs). Each Eph receptor has a specific Ephrin ligand, and these function to define spatial boundaries during development. Analyses of EphA4 in mouse, chick, frog and zebrafish embryos have implicated this gene in a number of developmental processes, including maintenance of segmental boundaries, axon guidance, limb development, neural crest migration and patterning of the ear. In order to determine which components of EphA4 function may be primitive for gnathostomes, we cloned EphA4 from the lesser spotted catshark (Scyliorhinus canicula) and examined its expression pattern during shark embryonic development. Consistent with the patterns reported for bony fish and tetrapods, we observed segmental expression of EphA4 in the developing hindbrain and later in the pharyngeal arches of shark embryos. EphA4 was also detected during sensory organogenesis, in the developing ear, eye, nasal pits and lateral line. A dynamic pattern of EphA4 expression occurs during shark fin development, suggesting an early role in outgrowth and patterning of the fin buds and a later role in tissue differentiation. We also observed several novel domains of EphA4 expression that have not been reported in other vertebrates, including external gill buds, dermal denticles, median fins and claspers. While some of these domains may reflect co-option of EphA4 expression to novel sites for development of shark-specific characters, others are more likely to be ancestral patterns of expression that were lost in other vertebrate lineages.Edited by R. P. Elinson 相似文献
136.
137.
Renata?A.?ZvyagilskayaEmail author Olga?A.?Parkhomenko Anna?V.?Gordeeva Yuliya?I.?Deryabina Bengt?L.?Persson 《Bioscience reports》2004,24(2):117-125
Energy status of the novel alkalitolerant Yarrowia lipolytica yeast strain grown at alkaline conditions (pH 9.7) was examined. Cells grown under such severe conditions were found to preserve high respiratory activity. The oxidative phosphorylation system dominated in the energy budget of the cell. A procedure was specially design to isolate tightly coupled mitochondria from yeast cells grown at alkaline conditions. The isolated mitochondrial preparations met known criteria of physiological intactness, as inferred from their ability to maintain distinctive state 4–3 respiration transition upon addition of ADP, high respiratory rates, good respiratory control values, and ADP/O ratios close to the theoretically expected maxima for the substrates used. 相似文献
138.
Kwiecień RA Rostkowski M Dybała-Defratyka A Paneth P 《Journal of inorganic biochemistry》2004,98(6):1078-1086
Several semiempirical methods (MNDO-d, PM3tm, PM3-d, PM5, PM6, and AM1-d) have been tested against experimental data and density functional theory (DFT) results in search for the best methods that can be used for quantum-mechanical-molecular mechanics (QM/MM) modeling of corrinoid systems of vitamin B(12) co-factor. It has been found that the PM6 parametrization in its present form gives results closest to hybrid DFT calculations that are most widely used thus far. In comparison with pure DFT and experimental data the best agreement is obtained for PM3tm parametrization, while PM6 yields slightly worse results. AM1-d yields bad geometry of the corrin moiety. The worst performance was observed for MNDO-d, which has severe problem with position and orientation of the alpha-ligands. 相似文献
139.
Kashyap SR Belfort R Berria R Suraamornkul S Pratipranawatr T Finlayson J Barrentine A Bajaj M Mandarino L DeFronzo R Cusi K 《American journal of physiology. Endocrinology and metabolism》2004,287(3):E537-E546
Muscle insulin resistance develops when plasma free fatty acids (FFAs) are acutely increased to supraphysiological levels (approximately 1,500-4,000 micromol/l). However, plasma FFA levels >1,000 micromol/l are rarely observed in humans under usual living conditions, and it is unknown whether insulin action may be impaired during a sustained but physiological FFA increase to levels seen in obesity and type 2 diabetes mellitus (T2DM) (approximately 600-800 micromol/l). It is also unclear whether normal glucose-tolerant subjects with a strong family history of T2DM (FH+) would respond to a low-dose lipid infusion as individuals without any family history of T2DM (CON). To examine these questions, we studied 7 FH+ and 10 CON subjects in whom we infused saline (SAL) or low-dose Liposyn (LIP) for 4 days. On day 4, a euglycemic insulin clamp with [3-3H]glucose and indirect calorimetry was performed to assess glucose turnover, combined with vastus lateralis muscle biopsies to examine insulin signaling. LIP increased plasma FFA approximately 1.5-fold, to levels seen in T2DM. Compared with CON, FH+ were markedly insulin resistant and had severely impaired insulin signaling in response to insulin stimulation. LIP in CON reduced insulin-stimulated glucose disposal (Rd) by 25%, insulin-stimulated insulin receptor tyrosine phosphorylation by 17%, phosphatidylinositol 3-kinase activity associated with insulin receptor substrate-1 by 20%, and insulin-stimulated glycogen synthase fractional velocity over baseline (44 vs. 15%; all P < 0.05). In contrast to CON, a physiological elevation in plasma FFA in FH+ led to no further deterioration in Rd or to any additional impairment of insulin signaling. In conclusion, a 4-day physiological increase in plasma FFA to levels seen in obesity and T2DM impairs insulin action/insulin signaling in CON but does not worsen insulin resistance in FH+. Whether this lack of additional deterioration in insulin signaling in FH+ is due to already well-established lipotoxicity, or to other molecular mechanisms related to insulin resistance that are nearly maximally expressed early in life, remains to be determined. 相似文献
140.
Watkins WJ Lemoine RC Chong L Cho A Renau TE Kuo B Wong V Ludwikow M Garizi N Iqbal N Barnard J Jankowska R Singh R Madsen D Lolans K Lomovskaya O Oza U Dudley MN 《Bioorganic & medicinal chemistry letters》2004,14(20):5133-5137
Structure-activity relationships of a novel series of fungal efflux pump inhibitors with respect to potentiation of the activity of fluconazole against strains of Candida albicans and Candida glabrata over-expressing ABC-type efflux pumps are systematically explored. 相似文献