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101.
In our effort to identify the effective gastric sparing and protective anti-inflammatory agents, a series of cycloalkyl/aryl-3,4,5-trimethylgallates were synthesized and characterized. The physicochemical properties were studied to assess the lipophilicity and chemical stability. Subsequently, the compounds were evaluated for their anti-inflammatory activity and effect on gastric mucosa by most active compounds. All the compounds exhibited promising anti-inflammatory activity. In particular, 4a, 4b, 4g, and 4h emerged as the most active compounds in the series. The results of gastric mucosal studies and biochemical estimations suggested that these compounds are non-ulcerogenic and gastroprotective. The molecular docking analysis was performed to understand the binding interactions of these compounds to cyclooxygenase isoenzyme (COX-1 and COX-2). The results from this investigation suggests cycloalkyl/aryl-3,4,5-trimethylgallates as potent safer gastrosparing and protective anti-inflammatory agents.  相似文献   
102.
In absence of receptor cycling, human/rat neuropeptide Y was found to persistently occupy the guinea pig neuropeptide Y Y1 receptors expressed on the surface of Chinese hamster ovary (CHO) cells (IC50 approximately 8 nM); a lasting occupancy was also evident with active receptor cycling. A similar blockade was obtained with the human neuropeptide Y Y1 receptor (in CHO or SK-N-MC cells). Peptidic antagonists GR238118 (1229U91) and VD-11 blocked the Y1 receptor in the same molarity range. A neuropeptide Y-related Y1 agonist, (Leu31Pro34) human neuropeptide Y, also strongly adhered to the Y1 site. Similar blockade-like occupancy by neuropeptide Y was found with particulates from Y1-expressing CHO cells, and with native neuropeptide Y Y1 receptors of rat synaptosomes. Peptide YY and a related Y1-selective agonist, (Leu31Pro34) human peptide YY, showed a much less stable binding to the neuropeptide Y Y1 receptor with either the intact cells or particulates. The Y1 binding of neuropeptide Y was also less sensitive to chaotropic agents and guanine nucleotides than the binding of peptide YY, indicating a larger stability for association of neuropeptide Y with the receptor. Inhibition of forskolin-stimulated adenylyl cyclase showed a distinctly attenuating agonism for neuropeptide Y, with an activity similar to peptide YY below 1 nM, but considerably lower above 3 nM of the peptides. This activity was largely exerted via pertussis toxin-sensitive G-proteins of Y1-CHO cells. Our findings indicate that signaling by neuropeptide Y via its Y1 receptor could be self-restricting at higher levels of the peptide, in relation to a strong association of the agonist with the Y1 binding site.  相似文献   
103.
The article describes the development of a robust pharmacophore model and investigation of structure activity relationship analysis of 56 isothiazolidinedione derivatives reported as PTP1B inhibitors. A six-point pharmacophore model consisting of four aromatic rings (R), one hydrogen bond donor (D) and one hydrogen bond acceptor (A) with discrete geometries as pharmacophoric features was developed and the generated pharmacophore model was used to derive a predictive 3D QSAR model for the studied dataset. The obtained 3D QSAR model has an excellent correlation coefficient value (r 2 = 0.98) along with good statistical significance as shown by a high Fisher ratio (F = 428.60). The model also exhibits good predictive power confirmed by the high value of cross-validated correlation coefficient (q 2 = 0.62). The QSAR model suggests that hydrophobic aromatic character is crucial for the PTP1B inhibitory activity at the R-15 site.  相似文献   
104.
Treatment with pertussis toxin in addition to a stable inhibition of G(i)alpha subunits of G-proteins also strongly reduced human neuropeptide Y Y(1) receptors expressed in Chinese hamster ovary (CHO) cells. This was reflected in abolition of the inhibition by Y(1) agonists of forskolin-stimulated adenylyl cyclase in intact cells, and of Y(1) agonist stimulation of GTPgammaS binding to particulates from disrupted cells. The loss of both receptor and G(i)alpha subunit function was attenuated by ammonium chloride, an inhibitor of acid proteinases, pointing to a chaperoning co-protection of active pertussis toxin-sensitive Galpha subunits and Y(1) receptors. The surface complement of the Y(1) receptor was changed a little in conditions of approximately 85% decrease of the Y(1) population, but the rate of the Y(1) receptor-linked internalization of agonist peptides was reduced about 70%. The preserved receptor fraction consisted of monomers significantly coupled to G(q)alpha subunits. The persistent pertussis toxin-insensitive internalization of agonists with the Y(1) receptor may reflect a rescue or alternative switching that could be important for cell functioning in neuropeptide Y-rich environments. The results are compatible with a loss, due to G(i)alpha subunit inactivation by the toxin, of a large Y(1) receptor reserve constituted of oligomers associating with heterotrimeric G-proteins.  相似文献   
105.
BackgroundWide variability exists in the frequency of pharmacogenetic markers for anticoagulant response in different populations. There is insufficient data on the prevalence of these variant genotypes in the Indian population. This study aims to determine the frequency of various genotype combinations of CYP2C9*2, *3 and VKORC1-1639G>A polymorphisms in the South and North Indians.MethodsGenotyping was carried out by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) technique in 209 North Indians (NI) and 82 South Indians (SI). Warfarin maintenance dose was predicted for all subjects based on FDA approved genotype-based dose estimates from revised COUMADIN medication guide. Fisher exact test and χ2 test were applied to compare categorical data among the SI and NI groups.ResultsIn SI and NI, the allele frequency of CYP2C9*2 was 0.006 and 0.05 (significant variation; p < 0.001); of CYP2C9*3 was 0.09 and 0.11; and of VKORC1-1639A was 0.14 and 0.19 (not significant), respectively. The variation in the frequency of combined CYP2C9/ VKORC1 genotypes revealed plausible difference in warfarin response among SI and NI. Based on the FDA approved revised dosing guidelines, significantly higher percentage of NI were likely to require intermediate dose (3–4 mg/day; p = 0.015, RR = 2.16) and were also predicted to have an increased risk of bleeding episodes and over anticoagulation (p = 0.012, RR = 1.93).ConclusionsGenotype frequency of CYP2C9 and VKORC1 SNPs is variable among the two ethno-geographically distinct Indian populations. This could translate into diverse warfarin response among the Indian population.  相似文献   
106.
107.
Summary The acute effect of alloxan on the incorporation of14C-leucine into isolated rat islets of Langerhans was studied. I.v. administration of alloxan (40 mg/kg body weight) in rats inhibited the subsequentin vitro incorporation of14C-leucine into (pro-)insulin in the isolated islets. Glucose (750 mg/kg body weight), when administered 5 min prior to alloxan, completely protected the islets against alloxan toxicity. The protective effect of glucose was partly reversed when the concentration of alloxan was raised to 80 mg/kg body weight. Similar results of inhibition of (pro-)insulin biosynthesis by alloxan and its protection by glucose were obtained when isolated rat islets were exposed to alloxan and/or glucosein vitro. Islets exposed to glucosein vitro immediately after alloxan exposure showed a slower rate of inhibition of (pro-)insulin biosynthesis, as compared to islets washed before exposure to D-glucose. In view of these findings, it is suggested that there is a common recognition site on B-cell for alloxan and glucose. CDRI Communication No. 2617.  相似文献   
108.
Summary Purified bovine cathepsin B, when incubated with isolated rat islets of Langerhans, completely converts proinsulin to insulin as demonstrated by the incorporation of14C-leucine into islet proteins, releasing lysine as the only basic amino acid. Cathepsin B antibodies raised in rabbit inhibited the above conversion. CDRI Communication No. 2703  相似文献   
109.
The cytologic features of a case of mixed hepatoblastoma diagnosed by fine-needle aspiration biopsy (FNAB) in a 2½-yr-old child are described. FNAB was carried out on a large, firm mass in the upper abdomen, without any complications. The characteristic cytologic features were clusters of polyhedral cells with mild anisonucleosis, and intracytoplasmic bile pigment. Focal areas of mesenchymal elements were seen. Immature hematopoietic cells were present. FNAB offers a safe and accurate method of diagnosis. Diagn. Cytopathol. 1998;19:306–308. © 1998 Wiley-Liss, Inc.  相似文献   
110.
Tetracyclines were implicated in the 1950s in induction of protracted diarrhea and pseudomembranous colitis. Because the pathogenetic mechanism of these illnesses has been questioned recently, we studied tetracycline in hamster models of antibiotic-associated colitis. Orogastric administration of tetracycline caused diarrhea and death, with evidence of hemorrhagic typhlitis. Filtrates of cecal contents were toxic when inoculated into normal hamsters and cell culture monolayers, and toxicity was neutralized with Clostridium sordellii antitoxin. Tetracycline-resistant C. difficile was cultured from stools of these hamsters, but Staphylococcus aureus was not isolated. The value of tetracycline for treatment or prevention of clindamycin-induced colitis in hamsters was also studied, and it was found that daily orogastric administration of tetracycline was poorly protective against clindamycin-induced colitis.  相似文献   
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