The pharmacokinetics of dabigatran in a rat model of hyperlipidaemia induced by poloxamer 407.

Various pharmacokinetic changes have been reported in experimental hyperlipidemic (HL) animal models. To evaluate whether P-glycoprotein (P-gp) activity was affected in HL rats, we assessed the pharmacokinetics of dabigatran after oral administration of dabigatran etexilate (DABE); this is a dabigatran prodrug and a well-known P-gp substrate.HL and control rats exhibited similar area under the plasma concentration-time curve (AUC), total body clearance (CL), and steady state volume of distribution (V) values following intravenous administration of dabigatran (1 mg/kg).

Pharmacokinetics of the novel 5-HT receptor agonist, DA-6886, in dogs.

The pharmacokinetics of a new 5-hydroxytryptamine receptor 4 agonist, DA-6886, intended for the treatment of constipation-predominant irritable bowel syndrome, were evaluated in beagle dogs following both intravenous and oral administration of DA-6886 (1-10 mg/kg). The study also examined the effects of gender and food on the pharmacokinetics of DA-6886 in dogs.DA-6886 demonstrated dose-proportional area under the plasma concentration-time curve (AUC) values and dose-independent clearance (21.

Pharmacokinetic Comparison of Chitosan-Derived and Biofermentation-Derived Glucosamine in Nutritional Supplement for Bone Health.

Glucosamine and chondroitin sulfate have been used as nutritional supplementation for joint tissues and osteoarthritis (OA). Biofermented glucosamine is of great interest in the supplement industry as an alternative source of glucosamine. The purpose of this study is to compare the pharmacokinetics of chitosan-derived glucosamine and biofermentation-derived glucosamine as nutritional supplementation.

Pharmacokinetics of DA-6886, A New 5-HT Receptor Agonist, in Rats.

DA-6886 is a novel serotonin (5-hydroxytrypamine [5-HT]) receptor 4 agonist for the potential treatment of constipation-predominant irritable bowel syndrome. The purpose of this study was to validate the quantitative assay of DA-6886 in rat plasma and to evaluate the pharmacokinetics and tissue distribution of DA-6886 in rats. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the robust quantification of DA-6886 in rat plasma was successfully validated and applied to the pharmacokinetic studies in rats.

Metformin and Niclosamide Synergistically Suppress Wnt and YAP in APC-Mutated Colorectal Cancer.

The Wnt and Hippo pathways are tightly coordinated and understanding their reciprocal regulation may provide a novel therapeutic strategy for cancer. Anti-helminthic niclosamide is an effective inhibitor of Wnt and is now in a phase II trial for advanced colorectal cancer (CRC) patients. We found that Axin2, an authentic target gene of canonical Wnt, acts as aYAP phosphorylation activator in APC-mutated CRC.

Changes in digoxin pharmacokinetics associated with hepatic P-glycoprotein upregulation in rats with non-alcoholic fatty liver disease.

Background & Objectives: Upregulation of hepatic P-glycoprotein (P-gp) expression has been reported in patients with non-alcoholic fatty liver disease (NAFLD) and rodent models thereof. Here, we explored the changes hepatic P-gp expression and activity in a NAFLD rat model and the effects thereof on the pharmacokinetics of digoxin (a probe substrate of P-gp).

Methods: Rats were fed a 1% (w/w) orotic acid-containing diet for 20 days to induce NAFLD; control rats received a normal diet.

Development and Validation of an LC-MS/MS Method for Quantification of the Novel Antibacterial Candidate DA-7010 in Plasma and Application to a Preclinical Pharmacokinetic Study.

DA-7010 is a new candidate for an antibacterial agent that targets Gram-negative pathogens by acting as a leucyl-tRNA synthetase inhibitor. In this study, a simple and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed to determine DA-7010 levels in the plasma from mice, rats, and dogs. Plasma samples were mixed with methanol for protein precipitation.

Pharmacokinetic changes of clozapine and norclozapine in a rat model of non-alcoholic fatty liver disease induced by orotic acid.

Impaired oxidation of clozapine has been reported in steatotic rat liver due to downregulation of cytochrome P450 (CYP) 1A. Pharmacokinetic changes of clozapine and its major metabolite, norclozapine, were evaluated in a rat model of non-alcoholic fatty liver disease (NAFLD) induced by orotic acid. Significantly slower CL for formation of norclozapine from clozapine was observed in NAFLD rats than in control rats as a result of the reduced protein expression and metabolic activity of CYP1A1/2.

Transcriptional Expression in Human Periodontal Ligament Cells Subjected to Orthodontic Force: An RNA-Sequencing Study.

This study was performed to investigate the changes in gene expression in periodontal ligament (PDL) cells following mechanical stimulus through RNA sequencing. In this study, premolars extracted for orthodontic treatment were used. To stimulate the PDL cells, an orthodontic force of 100 was applied to the premolar (experimental group; = 11), whereas the tooth on the other side was left untreated (control group; = 11).

The pharmacokinetics of mycophenolic acid in rats with orotic acid induced nonalcoholic fatty liver disease.

Post-transplantation nonalcoholic fatty liver disease (NAFLD) is common in liver transplant recipients. Changes in the expression levels and activities of drug-metabolizing enzymes and drug transporters have been reported in patients with NAFLD and relevant rodent models. Here, we evaluated whether the pharmacokinetics of mycophenolic acid (MPA), an immunosuppressant, would be altered in rats with NAFLD.

Optimization of Canalicular ABC Transporter Function in HuH-7 Cells by Modification of Culture Conditions.

Human hepatoma cell lines are useful for evaluation of drug-induced hepatotoxicity, hepatic drug disposition, and drug-drug interactions. However, their applicability is compromised by aberrant expression of hepatobiliary transporters. This study was designed to evaluate whether extracellular matrix (Matrigel) overlay and dexamethasone (DEX) treatment would support cellular maturation of long-term HuH-7 hepatoma cell cultures and improve the expression, localization, and activity of canalicular ATP-binding cassette (ABC) transporters, multidrug resistance protein 1 (MDR1/P-glycoprotein/ABCB1), multidrug resistance-associated protein 2 (MRP2/ABCC2), and bile salt export pump (BSEP/ABCB11).

Effects of Orotic Acid-Induced Non-Alcoholic Fatty Liver on the Pharmacokinetics of Metoprolol and its Metabolites in Rats.

Purpose: Preliminary study results have shown that rats with non-alcoholic fatty liver disease (NAFLD) induced by 1% orotic acid-containing diet have decreased hepatic CYP2D activity. This study aims to evaluate the possible pharmacokinetic changes in NAFLD as a result of reduced metabolic activity of CYP2D.

Methods: The pharmacokinetics of metoprolol and its metabolites, O-desmethyl metoprolol (DMM) and α-hydroxy metoprolol (HM), was investigated in NAFLD and control rats following intravenous (1 mg/kg) and oral (2 mg/kg) administration of metoprolol.

Protein expression and function of organic anion transporters in short-term and long-term cultures of Huh7 human hepatoma cells.

Human-derived hepatic cell lines are a valuable alternative to primary hepatocytes for drug metabolism, transport and toxicity studies. However, their relevance for investigations of drug-drug and drug-organic anion (e.g.

Therapeutic implications of cancer epithelial-mesenchymal transition (EMT).

The epithelial-mesenchymal transition (EMT) comprises an essential biological process involving cancer progression as well as initiation. While the EMT has been regarded as a phenotypic conversion from epithelial to mesenchymal cells, recent evidence indicates that it plays a critical role in stemness, metabolic reprogramming, immune evasion and therapeutic resistance of cancer cells. Interestingly, several transcriptional repressors including Snail (SNAI1), Slug (SNAI2) and the ZEB family constitute key players for EMT in cancer as well as in the developmental process.

Pharmacokinetics and Brain Distribution of the Active Components of DA-9805, Saikosaponin A, Paeonol, and Imperatorin in Rats.

DA-9805 is a botanical anti-Parkinson's drug candidate formulated from ethanol extracts of the root of , the root cortex of , and the root of . The pharmacokinetics (PKs) and brain distribution of active/representative ingredients of DA-9805, Saikosaponin a (SSa; 1.1⁻4.

Dishevelled has a YAP nuclear export function in a tumor suppressor context-dependent manner.

Phosphorylation-dependent YAP translocation is a well-known intracellular mechanism of the Hippo pathway; however, the molecular effectors governing YAP cytoplasmic translocation remains undefined. Recent findings indicate that oncogenic YAP paradoxically suppresses Wnt activity. Here, we show that Wnt scaffolding protein Dishevelled (DVL) is responsible for cytosolic translocation of phosphorylated YAP.

Pharmacokinetic alterations in poloxamer 407-induced hyperlipidemic rats.

1. Plasma lipid profile abnormalities in hyperlipidemia can potentially alter the pharmacokinetics of a drug in a complex manner. To evaluate these pharmacokinetic alterations in hyperlipidemia and to determine the underlying mechanism(s), poloxamer 407-induced hyperlipidemic rats (HL rats), a well-established animal model of hyperlipidemia have been used.

Simultaneous determination of saikosaponin a, paeonol, and imperatorin, components of DA-9805, in rat plasma by LC-MS/MS and application to a pharmacokinetic study.

DA-9805 is a new botanical antiparkinson drug candidate formulated using an ethanolic extract of the root of Bupleurum falcatum, the root cortex of Paeonia suffruticosa, and the root of Angelica dahurica. In this study, a sensitive and rapid LC-MS/MS method was developed to simultaneously determine, saikosaponin a, paeonol, and imperatorin, three active/representative ingredients of DA-9805, in rat plasma. Plasma was extracted by mixture of ethyl acetate and methyl tertiary butyl ether.

Frequent oncogenic BRAF V600E mutation in odontogenic keratocyst.

Objectives: Odontogenic keratocyst (OKC), also known as keratocystic odontogenic tumor (KCOT), has clinical significance due to its high incidence as well as high recurrence rate after surgical enucleation. Current clinical management for OCK is entirely dependent on surgical approach. While various genetic alterations, such as PTCH1 mutation and loss of heterozygosity in tumor suppressor genes, have been reported, the molecular background of OKC is not well-understood.

Anti-helminthic niclosamide inhibits Ras-driven oncogenic transformation via activation of GSK-3.

Despite the importance of Ras oncogenes as a therapeutic target in human cancer, their 'undruggable' tertiary structures limit the effectiveness of anti-Ras drugs. Canonical Wnt signaling contributes to Ras activity by glycogen synthase kinase 3 (GSK-3)-dependent phosphorylation at the C-terminus and subsequent degradation. In the accompanying report, we show that the anti-helminthic niclosamide directly binds to GSK-3 and inhibits Axin functions in colon cancer cells, with reversion of Snail-mediated epithelial-mesenchymal transition.

Effects of poloxamer 407-induced hyperlipidemia on hepatic multidrug resistance protein 2 (Mrp2/Abcc2) and the pharmacokinetics of mycophenolic acid in rats.

Hepatic multidrug resistance-associated protein 2 (Mrp2) is responsible for the majority of the biliary elimination of endogenous and exogenous substances, therefore it is important to evaluate possible functional changes in Mrp2 activity under conditions of hyperlipidemia (HL). Thus, the present study assessed the protein expression and transporting activity of hepatic Mrp2 based on the in vivo biliary excretion of phenolsulfonphthalein (PSP) as a model anionic substrate for Mrp2 in poloxamer 407-induced hyperlipidemic rats (HL rats) and compared these values with those for control rats. The pharmacokinetics of mycophenolic acid (MPA) and mycophenolic acid-7-O-glucuronide (MPAG) were evaluated after the intravenous (5 mg/kg) and oral (10 mg/kg) administration of MPA to control and HL rats.

Herbacetin Is a Novel Allosteric Inhibitor of Ornithine Decarboxylase with Antitumor Activity.

Ornithine decarboxylase (ODC) is a rate-limiting enzyme in the first step of polyamine biosynthesis that is associated with cell growth and tumor formation. Existing catalytic inhibitors of ODC have lacked efficacy in clinical testing or displayed unacceptable toxicity. In this study, we report the identification of an effective and nontoxic allosteric inhibitor of ODC.

Metabolic interactions of magnolol with cytochrome P450 enzymes: uncompetitive inhibition of CYP1A and competitive inhibition of CYP2C.

Magnolol (MAG; 5,5'-diallyl-2,2'-biphenyldiol) is a major bioactive component of Magnolia officinalis. We investigated the metabolic interactions of MAG with hepatic cytochrome P450 monooxygenase (CYP) through in vitro microsomal metabolism study using human (HLM) and rat liver microsomes (RLM). CYP2C and 3A subfamilies were significantly involved in the metabolism of MAG, while CYP1A subfamily was not in HLM and RLM.

Biphasic Effects of Ingenol 3,20-Dibenzoate on the Erythropoietin Receptor: Synergism at Low Doses and Antagonism at High Doses.

Although ingenol 3,20-dibenzoate (IDB) is known as a selective novel protein kinase C (PKC) agonist, its biologic actions and underlying mechanisms remain incompletely understood. In this study, we identified IDB as a proliferative agent for an erythropoietin (EPO)-dependent cell line, UT-7/EPO, through the screening of a natural compound library. To clarify the underlying mechanism of IDB's EPO-like activities, we thoroughly analyzed the mutual relation between EPO and IDB in terms of in vitro and in vivo activities, signaling molecules, and a cellular receptor.

Pharmacokinetics and brain distribution of tetrahydropalmatine and tetrahydroberberine after oral administration of DA-9701, a new botanical gastroprokinetic agent, in rats.

DA-9701, a new botanical gastroprokinetic agent, has potential for the management of delayed gastric emptying in Parkinson's disease if it has no central anti-dopaminergic activity. Therefore, we examined the pharmacokinetics of DA-9701 components having dopamine D2 receptor antagonizing activity, tetrahydropalmatine (THP) and tetrahydroberberine (THB), following various oral doses (80-328 mg/kg) of DA-9701. The distribution of THP and THB to the brain and/or other tissues was also evaluated after single or multiple oral administrations of DA-9701.