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981.
982.
Neeraj Verma G Amresh PK Sahu Ch V Rao Anil Pratap Singh 《Asian Pacific Journal of Tropical Biomedicine》2012,2(9):696-701
Objective
To explore and identify the most potent antihyperglycemic fraction from the ethanol extract of Rhododendron arboreum (R. arboreum) flowers.Methods
Normal and streptozotocin induced diabetic rats were treated with all four fractions of R. arboreum flowers for short term and with fraction 3 for long term study. On completion of the treatment, a range of indicators were tested including fasting blood glucose, plasma protein, haemoglobin A1C, insulin secretion, body weight, blood lipid profile and carbohydrate metabolism regulating enzymes of liver.Results
In short term study, the fraction 3 (Active fraction) produced a significant (P<0.000 1) reduction (73.6%) in blood glucose level at a dose of 200 mg/kg after the treatment in the diabetic rats. Administration of active fraction (200 and 400 mg/kg) once daily for 30 d in streptozotocin diabetic rats resulted in a significant (P<0.001 to P<0.000 1) fall in blood glucose level, hemoglobin A1C, serum urea and creatinine with significant but a increase in insulin level similar to standard drug glybenclamide. Further, the active fraction showed antihyperlipidemic activity as evidenced by significant (P<0.001 to P<0.000 1) decreases in serum serum total cholesterol, triglycerides, low density lipoprotein cholesterol and very low density cholesterol levels coupled together with elevation of high density lipoprotein cholesterol in the diabetic rats.Conclusions
The active fraction of R. arboreum flowers decreases streptozotocin induced hyperglycemia by promoting insulin secretion and glycolysis and by decreasing gluconeogenesis. 相似文献983.
Reprofiling of existing drugs to treat conditions not originally targeted is an attractive means of addressing the problem of a decreasing stream of approved drugs. To determine if 3D shape similarity can be used to rationalize an otherwise serendipitous process, we employed 3D shape-based virtual screening to reprofile existing FDA-approved drugs. The study was conducted in two phases. First, multiple histamine H(1) receptor antagonists were identified to be used as query molecules, and these were compared to a database of approved drugs. Second, the hits were ranked according to 3D similarity and the top drugs evaluated in a cell-based assay. The virtual screening methodology proved highly successful, as 13 of 23 top drugs tested selectively inhibited histamine-induced calcium release with the best being chlorprothixene (IC(50) 1 nM). Finally, we confirmed that the drugs identified using the cell-based assay were all acting at the receptor level by conducting a radioligand-binding assay using rat membrane. 相似文献
984.
JM Axten JR Medina Y Feng A Shu SP Romeril SW Grant WH Li DA Heerding E Minthorn T Mencken C Atkins Q Liu S Rabindran R Kumar X Hong A Goetz T Stanley JD Taylor SD Sigethy GH Tomberlin AM Hassell KM Kahler LM Shewchuk RT Gampe 《Journal of medicinal chemistry》2012,55(16):7193-7207
Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is implicated in tumorigenesis and cancer cell survival stimulated our search for small molecule inhibitors. Through screening and lead optimization using the human PERK crystal structure, we discovered compound 38 (GSK2606414), an orally available, potent, and selective PERK inhibitor. Compound 38 inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice. 相似文献
985.
Rahul Vats Kanthikiran V.S. Varanasi Rambabu Arla Sridhar Veeraraghavan Shraddha Rajak Aditya Narasimha Murthy 《The Journal of pharmacy and pharmacology》2012,64(11):1638-1645
Objectives Atorvastatin (ATV) and cilostazol (CLZ) are often co‐prescribed to treat conditions such as peripheral arterial disease. In the present study, the drug–drug interaction potential of multi‐dose CLZ on both pharmacokinetics and the lipid‐lowering ability of single‐dose ATV is demonstrated. Method The pharmacokinetic parameters of ATV were determined in Wistar rats after per‐oral pre‐treatment with CLZ for 7 days in order to assess the interaction potential between ATV and CLZ. In‐vitro metabolic inhibition and everted gut sac studies were conducted to elucidate the mechanism of this interaction. Biochemistry analyser was used to estimate lipid profiles in Wistar rats. A validated LC‐MS/MS method was employed to simultaneously quantify both ATV and CLZ in rat plasma matrix. Key findings A statistically significant increase in systemic exposure to ATV after a single dose was observed in CLZ pre‐treated rats. In‐vitro metabolism studies using rat liver microsome (RLM) demonstrated statistically significant inhibition of ATV metabolism when co‐incubated with CLZ. No change in apparent permeability of ATV was observed in the presence of CLZ. The blood lipid profile study after ATV administration indicated a statistically significant decrease in total cholesterol, triglycerides and LDL‐cholesterol. Conclusions Multi‐dose administration of CLZ influences the pharmacokinetics and lipid‐lowering properties of ATV. Collectively, an apparent interaction between selected drugs was evident. 相似文献
986.
Sahu D Saroha A Roy S Das S Srivastava PS Das HR 《International immunopharmacology》2012,12(1):288-293
Suramin, a polysulfonated polyaromatic symmetrical urea is known for multiple therapeutic effects including antineoplastic activity. It is known as an antagonist of ATP at P2X purinergic receptors. Suramin is also found to inhibit protein synthesis affecting both initiation and elongation of the polypeptide chain. As a growth factor blocker, it is reported to suppress experimental myocardial inflammation. Here, we describe the anti-arthritic property of suramin in the collagen induced arthritic (CIA) rat, a model of human rheumatoid arthritis (RA). Intraperitoneal (i.p) injection of suramin (10 mg/kg/day) for 3 weeks was found to reduce inflammation and repair joint destruction in CIA rats. Recovery of body weight (p<0.0001), reduction in splenic (p<0.05) and arthritic indices (p<0.0001) and reappearance of smooth synovial lining after suramin treatment to CIA rats were found to be significant. Levels of pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6 in plasma and joint extracts were reduced (p<0.0001) significantly in response to suramin treatment. Several acute phase proteins were normalized after suramin administration. 相似文献
987.
Sahu SC Amankwa-Sakyi M O'Donnell MW Sprando RL 《Journal of applied toxicology : JAT》2012,32(9):722-730
Usnic acid, a natural botanical product, is a constituent of some dietary supplements used for weight loss. It has been associated with clinical hepatotoxicity leading to liver failure in humans. The present study was undertaken for metabolism and toxicity evaluations of usnic acid in human hepatoblastoma HepG2 cells in culture. The cells were treated with the vehicle control and usnic acid at concentrations of 0–100 µm for 24 h at 37 °C in 5% CO2. Following the treatment period, the cells were evaluated by biochemical and toxicogenomic endpoints of toxicity that included cytochrome P450 activity, cytotoxicity, oxidative stress, mitochondrial dysfunction and changes in pathway focused gene expression profiles. Usnic acid exposure resulted in increased P450 activity, cytotoxicity, oxidative stress and mitochondrial dysfunction in HepG2 cells. The pathway‐focused gene expression analysis resulted in significantly altered expression of six genes out of a total of 84 genes examined. Of the six altered genes, three genes were up‐regulated and three genes down‐regulated. A marked up‐regulation of one gene CCL21 associated with inflammation, one gene CCNC associated with proliferation and carcinogenesis and one gene UGT1A4 associated with metabolism as well as DNA damage and repair were observed in the usnic acid‐treated cells compared with the vehicle control. Also a marked down‐regulation of one gene CSF2 associated with inflammation and two genes (CYP7A1 and CYP2E1) associated with oxidative metabolic stress were observed in the usnic acid‐treated cells compared with the control. The biomarkers used in this study demonstrate the toxicity of usnic acid in human hepatoblastoma HepG2 cells, suggesting an oxidative mechanism of action. Published 2011. This article is a US Government work and is in the public domain in the USA. 相似文献
988.
In silico docking studies and quantitative structure-activity relationship analysis of a number of in-house cytochrome P450 inhibitors have revealed important structural characteristics that are required for a molecule to function as a good inhibitor of P450 enzymes 1A1, 1A2, 2B1, and/or 2A6. These insights were incorporated into the design of pharmacophores used for a 2D search of the Chinese medicine database. Emodin, a natural anthraquinone isolated from Rheum emodi and known to be metabolized by cytochrome P450 enzymes, was one of the hits and was used as the lead compound. Emodin was found to inhibit P450s 1A1, 1A2, and 2B1 with IC(50) values of 12.25, 3.73, and 14.89 μM, respectively. On the basis of the emodin molecular structure, further similarity searches of the PubChem and ZINC chemical databases were conducted resulting in the identification of 12 emodin analogues for testing against P450s 1A1-, 1A2-, 2B1-, and 2A6-dependent activities. 1-Amino-4-chloro-2-methylanthracene-9,10-dione (compound 1) showed the best inhibition potency for P450 1A1 with an IC(50) value of 0.40 μM. 1-Amino-4-chloro-2-methylanthracene-9,10-dione (compound 1) and 1-amino-4-hydroxyanthracene-9,10-dione (compound 2) both inhibited P450 1A2 with the same IC(50) value of 0.53 μM. In addition, compound 1 acted as a mechanism-based inhibitor of cytochrome P450s 1A1 and 1A2 with K(I) and K(inactivation) values of 5.38 μM and 1.57 min(-1) for P450 1A1 and 0.50 μM and 0.08 min(-1) for P450 1A2. 2,6-Di-tert-butyl-5-hydroxynaphthalene-1,4-dione (compound 8) directly inhibited P450 2B1 with good selectivity and inhibition potency (IC(50) = 5.66 μM). Docking studies using the 3D structures of the enzymes were carried out on all of the compounds. The binding modes of these compounds revealed the structural characteristics responsible for their potency and selectivity. Compound 1, which is structurally similar to compound 2 with the presence of an amino group at position 1, showed a difference in the mechanism of inhibition toward P450s 1A1 and 1A2. The mechanism-based inhibition seen for compound 1 may be attributed to the presence of the methyl group at the 2-position, in close proximity to the amino group. Compound 2, which is otherwise similar, lacks that methyl moiety and did not show mechanism-based inhibition. 相似文献
989.
990.