Cyclosporine A (CyA), an immunosuppressant administered to transplant patients, causes adverse effects such as nephrotoxicity and hepatotoxicity. In kidney slices of rats treated with 25 mg/kg/day of CyA we observed interstitial fibrosis. Ultrastructure revealed edematized mitochondria with loss of internal structure. In previous work with Trimetazidina (TMZ), cytoprotective drug used in cardiac patients, we found that TMZ prevents CyA toxicity. The pretreatment in wister rats with 20 mg/kg/day of TMZ during 20 days and them simultaneously TMZ with cyclosporine A for 120 days, counteracts the interstitial fibrosis. The aim of this work is to elucidate the effect of TMZ on interstitial fibrosis and interpret its mechanism. Four groups of eight male Wister rats were prepared. A, control; B, 25 mg/Kg/day CyA; C, 20 mg/Kg/day TMZ +25 mg/Kg/day CyA and D, 20 mg/Kg/day TMZ for 20 days and then TMZ 20 mg/Kg/day + CyA 25 mg/Kg/day. The experiment lasted 140 days. Slices of rats treated with CyA revealed fibrosis, which was quantified using Image Pro-Plus software (NIH). Immunohistochemical techniques evidenced Collagen type I, Transforming Growth Factor β1 (TGF-β1) and Monocyte Chemoattractant Protein-1 (MCP-1). However, pretreatment with TMZ for 20 days and then with CyA + TMZ prevented fibrosis and immunohistochemistry was negative for the markers studied. We concluded that TMZ protects the cells against the changes produced by the CyA-induced oxygen deficit. TMZ could offset ATP synthesis caused by the chronic administration of CyA. TMZ optimizes the energetic metabolism of the ischemic cell through a metabolic exchange (“switch”) between the fatty acid and glucose oxidation. In theory TMZ would reduce strongly the fatty acid oxidation towards glucose, without affecting the mitochondrial respiratory chain efficiency. Furthermore, TMZ increases the production of phospholipids in the mitochondrial membranes, which confers stability to these structures. In previous work check the effect of CyA on the complex I and II of the mitochondrial respiratory chain located in mitochondrial membranes which are the target of the toxic action of CyA.
Aims: To investigate the putative usefulness of the in silico determination of transmural dispersion of repolarization (TDR) for early cardiac safety pharmacology. Study Design: Computational simulations. Place and Duration of Study: SCAP Test, Belgium, between September 2014 and March 2015. Methodology: TDR was calculated as the difference between epicardial-midmyocardial action potential duration (APD95) determined in non-failing human ventricular myocytes using the O’Hara-Rudy dynamic algorithm. The role of each ionic current in TDR was investigated by modifying its conductance in the algorithm. The effects of each tested drug on TDR were studied by reducing the IKr, INa and ICaL conductances in the algorithm by a scaling factor which is a function of the IC50 of the drug for IKr, INa and ICaL ionic currents and the maximal effective free therapeutic plasma concentration (EFTPCmax) of the drug. Results: Our simulations showed that TDR was increased by a preferential midmyocardial APD95 prolongation which was induced by net repolarising current reduction via IKr or IKs inhibition and/or ICaL or INaL activation. Drugs’ effects on TDR were in good agreement with their torsade de pointes (TdP) risk according to the CredibleMeds or the Redfern classifications: most torsadogenic tested drugs induced a TDR increase via IKr vs. ICaL and/or INa selective inhibition; while most non-torsadogenic tested drugs induced a TDR decrease via ICaLvs. IKr and/or INa selective inhibition. Conclusion: Based on computer simulations within the human situation, the present study identified the effects of various cardiac ionic currents on TDR amplitude and suggested that in silico study of drugs’ effects on TDR could be informative for early cardiac safety pharmacology.
Aims:Rhizophora apiculata is a traditional medicine used to treat pain, ulcer, and inflammation in southeast coast of India without scientific evidence. Therefore, we aimed to evaluate antinociceptive effect of R. apiculata to chemical and thermal induced nociceptive models. Place and Duration of Study: Centre of Advanced Study in Marine Biology, Faculty of Marine Sciences, Annamalai University, Parangipettai, Tamil Nadu, India, between June 2012 and September 2012. Methodology: Albino mice received 10, 15, 20, or 25 mg/kg of alkaline chloroform fraction (Alk-CF) by orally and dose-dependently decreased the writhing numbers (P<0.01) compared to control, also potent antinociceptive agent with the involvement of opioid receptors. Results: Myricetin was identified as a potent major component of Alk-CF using HPLC and docked with protein cyclooxygenase. Myricetin articulated more interaction and produce number of hydrogen bonds with cyclooxygenase. Conclusion: These results suggested Alk-CF posses both peripheral and central analgesic activities with the involvement of opioid receptors might be the action of Myricetin.
Aim: Various drugs used for pain relief show the diversity of pharmacological properties besides their intrinsic analgesic activity. In order to verify a common mechanism, we studied the effects of selected analgesic agents on lipid bilayer membranes by paying attention to their induced physicochemical membrane modification and stereostructure specificity. Methodology: Biomimetic membranes were prepared with different phospholipids and cholesterol to be unilamellar vesicle suspensions. The membrane preparations were treated with local anesthetics (lidocaine, bupivacaine and ropivacaine), phenolic sedatives/anesthetics (thymol, eugenol, guaiacol and propofol), non-steroidal anti-inflammatory drugs (ibuprofen and indomethacin), N-methyl-D-aspartate receptor antagonist (ketamine), and their stereoisomers at clinically-relevant concentrations, followed by measuring fluorescence polarization to determine the changes in membrane fluidity. Results: All the tested drugs interacted with lipid bilayer membranes to modify their fluidity. Lidocaine, bupivacaine, ropivacaine, thymol, eugenol, guaiacol, propofol and ketamine increased the fluidity of neuronal mimetic membranes at 0.1-200 μM, whereas ibuprofen and indomethacin decreased the membrane fluidity at 100-200 μM. In neuronal and myocardial mimetic membranes consisting of 35-40 mol% chiral cholesterol, stereoisomers (25-200 μM) showed the enantiomer-specific membrane effects with the relative potencies being R(+)-bupivacaine > racemic bupivacaine > S(–)-bupivacaine, S(+)-ketamine > racemic ketamine, and S(+)-ibuprofen > racemic ibuprofen > R(–)-ibuprofen, which were correlated with those of their analgesic, anesthetic or cardiotoxic effects. Conclusion: Analgesic agents share the ability to interact with lipid bilayers, directly influencing the properties and functions of biomembranes at a lipid level and indirectly modulating the activities of membrane-associated ion channels, receptors and enzymes through the conformational changes of proteins. The membrane interactivity possibly accounts for their pharmacological diversity.
Luana K. S. Gonçalves, Josinete B. Viera, Nayara S. R. Silva, César F. Santos, Francinaldo S. Braga, Josivan S. Costa, Williams J. C. Macêdo, Carlos H. T. P. Silva, Lorane I. S. Hage-Melim, Cleydson Breno R. Santos
Aims: To study and propose new caffeine derivatives with epithelial anticancer activity using quantum chemistry methods and multivariate analysis (PCA, HCA, PLS and PCR). Place and Duration of Study: Laboratory of Modeling and Computational Chemistry at Federal University of Amapá (UNIFAP), Macapá, Brazil, between March 2014 and February 2015. Methodology: Caffeine and 31 derivatives with epithelial anticancer activity were selected from the literature, and modeled with the GaussView 3.0 program. The optimization was performed using the DFT method and B3LYP/6-31G** base set implemented in the Gaussian 03 program. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were employed to select the molecular descriptors related to epithelial anticancer activity. The Pearson correlation between activity and important descriptors were used for the regression partial least squares (PLS) and principal component regression (PCR) models built, and these models were used to predict the anticancer activity of fourteen new caffeine derivatives (test set) with unknown activity. Results: The PCA results showed that the descriptors related to the compounds with anticancer activity were: area (A2), distance radical 1 (dR1), distance radical 3 (dR3), radical partition coefficient 1 (logPR1) and radical partition coefficient 3 (logPR3). HCA showed similar results obtained with PCA, and the compounds were grouped in accordance with their biological activities. The results obtained with the PLS and PCR models were close, with variation between the models of R2=±0.005, R2ajust=±0.1998, s=±0.0053, F(5,27)=±49.2261, Q2=±0.012, SEV=±0.0117, PRESS=±0.0473 and SPRESS=±0.0087. The PLS model showed that eight compounds of the test set (37 and 40-46) are predicted to be more active, and they had values of ICT50<0.48mM. However, the PCR model only seven compounds of all test sets (33-36, 38, 39 and 42) were predicted as most active, which showed values of ICT50≥0.48mM, a total of 7 compounds proposed as less active of fourteen suggested compounds. However, compounds 37, 40, 41, 43, 44, 45 and 46 were the ones that had values of ICT50<0.48mM in both PLS and PCR models, suggesting that these new compounds in the two models are more potent than caffeine may be tested for epithelial anticancer activity. Conclusion: The PLS and PCR models showed good predictive ability. The test set showed for seven new caffeine compounds satisfactory results for epithelial anticancer activity. This strategy is fundamental for use in experimental syntheses and biological evaluation, and to understand the structural requirements for designing new ligands as anticancer agents.
Ulcerative colitis is a chronic, relapsing and progressive inflammatory bowel disease (IBD) characterized by diffused mucosal inflammation of the colon. DPP-IV inhibitors may provide a new treatment strategy for IBD. Thus, the aim of this study is to evaluate effect of different doses of sitagliptin as an early treatment of experimentally induced ulcerative colitis in mice. Sitagliptin was administered after the appearance of signs and symptoms of the disease as an early treatment. Twenty four mice were divided into four groups; control group, non treated DSS-induced colitis group, sitagliptin (20 mg/kg/d)-treated DSS-induced colitis group and sitagliptin (100 mg/kg/d)-treated DSS-induced colitis group. The disease activity index (DAI) was calculated by summarizing the scores for weight loss, stool consistency, hemoccult positivity. The length of colon was measured as an indirect marker of inflammation (rate of colon shortening) for each mouse. Serum tumour necrosis factor- α (TNF-α) was measured. Reduced glutathione, Nitrite, Malondialdehyde were measured in Colonic homogenates. Histopathological examination was done and the lesion was scored. Reduced glutathione in colonic homogenates was increased. Histopathological score was improved. It can be concluded that sitagliptin is partially effective for treatment of mice with experimentally induced ulcerative colitis.
Present review article reveals the importance of species Withania somnifera (L.) Dunal, distributed in India and other parts of the world, this extensive research information on this species is highly significant for future researchers worldwide. In this article cytomorphological, phytochemical and biological activities inputs have been extensively recorded and discussed. As a part of our investigation on cytomorphological and phytochemical aspects for important medicinal plants from India, the aim of this pioneer attempt is to provide precise, truthful and detailed information of W. somnifera (L.). As per our knowledge, there is not even a single, combined, constructive review report available about this species, evaluated by using cytomorphological, phytochemical and biological activities based aspects.