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Conceptual Density Functional Theory Study of the Chemical Reactivity Properties and Bioactivity Scores of the Leu-Enkephalin Opioid Peptide Neurotransmitter  [PDF]
Juan Frau, Norma Flores-Holguín, Daniel Glossman-Mitnik
Computational Molecular Bioscience (CMB) , 2019, DOI: 10.4236/cmb.2019.91002
Abstract: The SMD solvation model (Solvation Model based on the Density) and eight density functionals, CAM-B3LYP, LC-ωPBE, M11, MN12SX, N12SX, ωB97, ωB97X, and ωB97XD, were assessed in link with the Def2TZVP basis set for the calculation of the structure of the Leu-Enkephalin Opioid Peptide Neurotransmitter as well as their molecular properties. Through the Conceptual Density Functional Theory (CDFT), the entire chemical descriptors for the system were calculated. The active regions of the molecules necessary for electrophilic, nucleophilic and radical attacks were chosen through linking them with the corresponding Fukui functions. Furthermore, the prediction of the pKa value for the peptide is done with great accuracy as well as the ability of the studied molecule in acting as an efficient inhibitor of the formation of Advanced Glycation Endproducts (AGEs), which comprises of a useful knowledge for the development of drugs for preventing Alzheimer, Diabetes and Parkinson diseases. Lastly, the bioactivity scores for the studied peptides are predicted via various methodologies.
Cholecystokinin in the Pathogenesis of Bulimia Nervosa  [PDF]
Helena Trebbau López, Rosa María Molina-Ruiz, Laura Reyes Molón, Marina Díaz-Marsá
International Journal of Clinical Medicine (IJCM) , 2011, DOI: 10.4236/ijcm.2011.24085
Abstract: Objective: This review aims to describe the role of the hormone cholecystokinin (CCK) in the pathogenesis of bulimia nervosa (BN), the perpetuation of this illness and the possibility of its use as a target for future therapeutic advances. Methods: Search for cholecystokinin AND bulimia nervosa in Pubmed Central, with no limits, identified 38 articles published up to the present date. Results: It is well established that CCK is altered in the pathogenesis of BN, and that its main role is in the perpetuation of the disorder rather than the cause of it. Discussion: Additional studies will be needed to further understand the mechanisms by which CCK regulates orexigenic pathways. If an orally active, longer acting analogue of CCK could be developed, it would be of significant interest as an appetite suppressant and a key adjuvant in the treatment of patients suffering from BN, particularly in refractory cases.
Oxytocin and cholecystokinin secretion in women with colectomy
Bodil Ohlsson, Jens F Rehfeld, Mary L Forsling
BMC Gastroenterology , 2004, DOI: 10.1186/1471-230x-4-25
Abstract: Eleven women, mean age 34.4 ± 2.3 years, who had undergone colectomy because of ulcerative colitis or constipation were studied. Eleven age-matched healthy women served as controls. All subjects were fasted overnight and given 0.2 μg/kg body weight of CCK-8 i.v. in the morning. Samples were taken ten minutes and immediately before the injection, and 10, 20, 30, 45, 60, 90 and 120 min afterwards. Plasma was collected for measurement of CCK and oxytocin concentrations.The basal oxytocin and CCK concentrations in plasma were similar in the two groups. Intravenous injection of CCK increased the release of oxytocin from 1.31 ± 0.12 and 1.64 ± 0.19 pmol/l to 2.82 ± 0.35 and 3.26 ± 0.50 pmol/l in controls and colectomised women, respectively (p < 0.001). Given the short half-life of CCK-8 in plasma, the increased concentration following injection could not be demonstrated in the controls. On the other hand, in colectomised women, an increase of CCK in plasma was observed for up to 20 minutes after the injection, concentrations increasing from 1.00 ± 0.21 to a maximum of 1.81 ± 0.26 pmol/l (p < 0.002).CCK stimulates the release of oxytocin in women. There is no difference in plasma concentrations between colectomised and controls. However, colectomy seems to reduce the metabolic clearance of CCK. The hyperCCKemia in patients who had undergone colectomy is consequently not only dependent on CCK release, but may also depend on reduced clearance.The gut hormone cholecystokinin (CCK) is synthesised in endocrine I cells in the mucosa of the upper small intestine [1] and is released into the blood after ingestion of fatty and protein-rich meals [2]. CCK has various effects on the gastrointestinal (GI) tract and acts on afferent vagal nerves [3], neurons of the myenteric plexus [4], and directly on muscle cells [5]. It is also synthesised in central neurons including hypothalamic, oxytocinergic neurons [6]. Circulating CCK is degraded in several sites, namely the kidney, liver and
Cholecystokinin Elevates Mouse Plasma Lipids  [PDF]
Lichun Zhou, Hong Yang, Xinghua Lin, Emmanuel U. Okoro, Zhongmao Guo
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0051011
Abstract: Cholecystokinin (CCK) is a peptide hormone that induces bile release into the intestinal lumen which in turn aids in fat digestion and absorption in the intestine. While excretion of bile acids and cholesterol into the feces eliminates cholesterol from the body, this report examined the effect of CCK on increasing plasma cholesterol and triglycerides in mice. Our data demonstrated that intravenous injection of [Thr28, Nle31]-CCK at a dose of 50 ng/kg significantly increased plasma triglyceride and cholesterol levels by 22 and 31%, respectively, in fasting low-density lipoprotein receptor knockout (LDLR?/?) mice. The same dose of [Thr28, Nle31]-CCK induced 6 and 13% increases in plasma triglyceride and cholesterol, respectively, in wild-type mice. However, these particular before and after CCK treatment values did not achieve statistical significance. Oral feeding of olive oil further elevated plasma triglycerides, but did not alter plasma cholesterol levels in CCK-treated mice. The increased plasma cholesterol in CCK-treated mice was distributed in very-low, low and high density lipoproteins (VLDL, LDL and HDL) with less of an increase in HDL. Correspondingly, the plasma apolipoprotein (apo) B48, B100, apoE and apoAI levels were significantly higher in the CCK-treated mice than in untreated control mice. Ligation of the bile duct, blocking CCK receptors with proglumide or inhibition of Niemann-Pick C1 Like 1 transporter with ezetimibe reduced the hypercholesterolemic effect of [Thr28, Nle31]-CCK in LDLR?/? mice. These findings suggest that CCK-increased plasma cholesterol and triglycerides as a result of the reabsorption of biliary lipids from the intestine.
Computational Study of the Chemical Reactivity and Bioactivity Rates of Marine Peptides Hemiasterlin and Its A and B Derivatives Used in the Cancer Treatment through Conceptual Density Functional Theory  [PDF]
Norma Flores-Holguín, Juan Frau, Daniel Glossman-Mitnik
Computational Molecular Bioscience (CMB) , 2019, DOI: 10.4236/cmb.2019.94008
Abstract: This study involved the assessment of the MNI2SX/Def2TZVP/H2O model chemistry to enhance the understanding of the structural composition of the marine peptide Hemiasterlin and its derivatives A and B used in cancer treatment. The Conceptual Density Functional theory was used in the calculation of molecular properties of the system chemical descriptors during the study. Integration of the active molecular regions into their respective Fukui functions was used in the selection of electrophilic and nucleophilic attacks. Additionally, the proposed correlation between global hardness and the pKa was used as the basis of deriving accurate predictions for the pKa values while a homology technique was used in the prediction of bioactivity and bioavailability scores of the peptides under investigation.
International Research Journal of Pharmacy , 2012,
Abstract: Phytochemicals in medicinal plants can deliver potential therapeutic drugs such as anticancer, antiviral, antioxidant etc. The plant kingdom is a treasure house of potential drugs and each phytochemical cannot be tested in the wetlab preparations. Hence the main aim of the study is the drug likeness activity of phytochemicals in medicinal plants such as Anethum graveolens, Apium graveolens against hepatocellular carcinoma. These plants have anticancer, antilivercancer, hepatoprotective, antiviral activities. Focusing on these activities, the phytochemicals from these plants were collected from Dr.Duke Phytochemical and ethnobotanical database. The drug likeness is evaluated by satisfying Lipinski’s rule of five, ADMET properties, Partition coefficient analyzed through Accelerys Discovery studio. The results screen the phytochemicals and these interpretations can be further preceded for the drug designing.
Understanding and Classifying Metabolite Space and Metabolite-Likeness  [PDF]
Julio E. Peironcely, Theo Reijmers, Leon Coulier, Andreas Bender, Thomas Hankemeier
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028966
Abstract: While the entirety of ‘Chemical Space’ is huge (and assumed to contain between 1063 and 10200 ‘small molecules’), distinct subsets of this space can nonetheless be defined according to certain structural parameters. An example of such a subspace is the chemical space spanned by endogenous metabolites, defined as ‘naturally occurring’ products of an organisms' metabolism. In order to understand this part of chemical space in more detail, we analyzed the chemical space populated by human metabolites in two ways. Firstly, in order to understand metabolite space better, we performed Principal Component Analysis (PCA), hierarchical clustering and scaffold analysis of metabolites and non-metabolites in order to analyze which chemical features are characteristic for both classes of compounds. Here we found that heteroatom (both oxygen and nitrogen) content, as well as the presence of particular ring systems was able to distinguish both groups of compounds. Secondly, we established which molecular descriptors and classifiers are capable of distinguishing metabolites from non-metabolites, by assigning a ‘metabolite-likeness’ score. It was found that the combination of MDL Public Keys and Random Forest exhibited best overall classification performance with an AUC value of 99.13%, a specificity of 99.84% and a selectivity of 88.79%. This performance is slightly better than previous classifiers; and interestingly we found that drugs occupy two distinct areas of metabolite-likeness, the one being more ‘synthetic’ and the other being more ‘metabolite-like’. Also, on a truly prospective dataset of 457 compounds, 95.84% correct classification was achieved. Overall, we are confident that we contributed to the tasks of classifying metabolites, as well as to understanding metabolite chemical space better. This knowledge can now be used in the development of new drugs that need to resemble metabolites, and in our work particularly for assessing the metabolite-likeness of candidate molecules during metabolite identification in the metabolomics field.
The effect of cholecystokinin octapeptide upon the migrating myoelectric complex in the ovine small bowel
Romanski Krzysztof W.
Acta Veterinaria , 2007, DOI: 10.2298/avb0703113r
Abstract: There is no evident and precise data regarding the effect of cholecystokinin octapeptide (CCK-OP) on the migrating myoelectric complex (MMC) in sheep. Thus, in five rams seven bipolar platinum electrodes were implanted in the abomasal antrum and entire small intestine. The strain gauge force transducer was also attached near the duodenal electrode in three of these animals. During the experiments the myoelectric and motor activity was continuously recorded in fasted and non-fasted sheep. During the recordings two normal consecutive phases 3 of the MMC were recorded. Then, slow injections of CCK-OP of 0.02; 0.2 and 2.0 _g/kg of body weight were given intravenously during phase 1, 2a or 2b of the MMC, identified in the duodenum, until next two consecutive phases 3 MMC were recorded. The moderate dose of CCK-OP administered during phase 2a in non-fasted animals shortened the MMC cycles significantly while the highest dose of the hormone increased the cycle duration and inhibited phase 3 MMC in the duodenum. No such effect was observed in the jejunum. However, duration of phase 3 in this region was decreased mostly by the highest dose of CCK-OP. It can be concluded that CCK inhibits the MMC in ovine small bowel and its effect in the duodenum is most pronounced.
Evaluation of the In Vitro Bioactivity of Bioceramics
Chengtie Wu and Yin Xiao
Bone and Tissue Regeneration Insights , 2012,
Abstract: Two common methods have been used to evaluate the in vitro bioactivity of bioceramics for the application of bone repair. One is to evaluate the ability of apatite formation by soaking ceramics in simulated body fluids (SBF); the other method is to evaluate the effect of ceramics on osteogenic differentiation using cell experiments. Both methods have their own drawbacks in evaluating the in vitro bioactivity of bioceramics. In this commentary paper we review the application of both methods in bioactivity of bioceramics and conclude that (i) SBF method is an efficient method to investigate the in vitro bioactivity of silicate-based bioceramics, (ii) cellular bioactivity of bioceramics should be investigated by evaluating their stimulatory ability using standard bioceramics as controls; and (iii) the combination of these two methods to evaluate the in vitro bioactivity of bioceramics can improve the screening efficiency for the selection of bioactive ceramics for bone regeneration.
Transcriptional Activation of the Cholecystokinin Gene by DJ-1 through Interaction of DJ-1 with RREB1 and the Effect of DJ-1 on the Cholecystokinin Level in Mice  [PDF]
Takuya Yamane, Sayaka Suzui, Hirotake Kitaura, Kazuko Takahashi-Niki, Sanae M. M. Iguchi-Ariga, Hiroyoshi Ariga
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0078374
Abstract: DJ-1 is an oncogene and also causative gene for familial Parkinson’s disease. DJ-1 has multiple functions, including transcriptional regulation. DJ-1 acts as a coactivator that binds to various transcription factors, resulting in stimulation or repression of the expression of their target genes. In this study, we found that the cholecystokinin (CCK) gene is a transcriptional target gene for DJ-1. CCK is a peptide hormone and plays roles in contraction of the gallbladder and in promotion of secretion of pancreatic fluid. CCK is co-localized with dopamine in the substantia nigra to regulate release of dopamine. Reduced expression of CCK mRNA was observed in DJ-1-knockdown cells. The Ras-responsive element (RRE) and Sp1 site were essential for promoter activity, and DJ-1 stimulated promoter activity by binding to RRE-binding protein 1 (RREBP1). The complex of DJ-1 with RREB1 but not with Sp1 bound to the RRE. Furthermore, the reduced CCK level in the serum from DJ-1-knockout mice compared to that from wild-type mice was observed. This is the first report showing that DJ-1 participates in peptide hormone synthesis.
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