Four new phenylpropanoid glucosides from L.

Four new phenylpropanoid glycosides (-) have been successfully isolated from L. The structures of these new compounds were characterised using a combination of spectroscopic techniques, including 1D and 2D NMR, HR-ESI-MS, and IR, along with chemical methods. Furthermore, the anti-inflammatory activity of these compounds was assessed by evaluating their effects on interleukin-6 (IL-6) production.

Evaluation of Encequidar as An Intestinal P-gp and BCRP Specific Inhibitor to Assess the Role of Intestinal P-gp and BCRP in Drug-Drug Interactions.

Purpose: The differences between intestinal and systemic (hepatic and renal) P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) roles in drug disposition are difficult to define. Accordingly, we characterized Encequidar (ECD) as an intestinal P-gp and BCRP specific inhibitor to evaluate their role in drug disposition.

Methods: We assessed the in vitro and in vivo inhibition potential of ECD towards human and animal P-gp and BCRP.

Metabolomic Profiling and Drug Interaction Characterization Reveal Riboflavin As a Breast Cancer Resistance Protein-Specific Endogenous Biomarker That Demonstrates Prediction of Transporter Activity In Vivo.

Advancement of endogenous biomarkers for drug transporters as a tool for assessing drug-drug interactions (DDIs) depends on initial identification of biomarker candidates and relies heavily on biomarker validation and its response to reference inhibitors in vivo. To identify endogenous biomarkers of breast cancer resistance protein (BCRP), we applied metabolomic approaches to profile plasma from Bcrp, multidrug resistance protein (Mdr)1a/1b, and Bcrp/Mdr1a/1b mice. Approximately 130 metabolites were significantly altered in Bcrp and P-glycoprotein (P-gp) knockout mice, indicating numerous metabolite-transporter interactions.

Repression of Organic Anion Transporting Polypeptide (OATP) 1B Expression and Increase of Plasma Coproporphyrin Level as Evidence for OATP1B Downregulation in Cynomolgus Monkeys Treated with Chenodeoxycholic Acid.

Farnesoid X receptor (FXR) is a nuclear receptor known to markedly alter expression of major transporters and enzymes in the liver. However, its effects toward organic anion transporting polypeptides (OATP) 1B1 and 1B3 remain poorly characterized. Therefore, the present study was aimed at determining the effects of chenodeoxycholic acid (CDCA), a naturally occurring FXR agonist, on OATP1B expression in cynomolgus monkeys.

Discovery of a Partial Glucokinase Activator Clinical Candidate: Diethyl ((3-(3-((5-(Azetidine-1-carbonyl)pyrazin-2-yl)oxy)-5-isopropoxybenzamido)-1-pyrazol-1-yl)methyl)phosphonate (BMS-820132).

Glucokinase (GK) is a key regulator of glucose homeostasis, and its small-molecule activators represent a promising opportunity for the treatment of type 2 diabetes. Several GK activators have been advanced into clinical trials and have demonstrated promising efficacy; however, hypoglycemia represents a key risk for this mechanism. In an effort to mitigate this hypoglycemia risk while maintaining the efficacy of the GK mechanism, we have investigated a series of amino heteroaryl phosphonate benzamides as ''partial" GK activators.

Discovery of a Hydroxypyridinone APJ Receptor Agonist as a Clinical Candidate.

Apelin-13 is an endogenous peptidic agonist of the apelin receptor (APJ) receptor with the potential for improving cardiac function in heart failure patients. However, the low plasma stability of apelin-13 necessitates continuous intravenous infusion for therapeutic use. There are several approaches to increase the stability of apelin-13 including attachment of pharmacokinetic enhancing groups, stabilized peptides, and Fc-fusion approaches.

In Vitro and In Vivo Evaluation of a Small-Molecule APJ (Apelin Receptor) Agonist, BMS-986224, as a Potential Treatment for Heart Failure.

Background: New heart failure therapies that safely augment cardiac contractility and output are needed. Previous apelin peptide studies have highlighted the potential for APJ (apelin receptor) agonism to enhance cardiac function in heart failure. However, apelin's short half-life limits its therapeutic utility.

Discovery of a phenylpyrazole amide ROCK inhibitor as a tool molecule for in vivo studies.

Structure-activity relationship optimization on a series of phenylpyrazole amides led to the identification of a dual ROCK1 and ROCK2 inhibitor (25) which demonstrated good potency, kinome selectivity and favorable pharmacokinetic profiles. Compound 25 was selected as a tool molecule for in vivo studies including evaluating hemodynamic effects in telemeterized mice, from which moderate decreases in blood pressure were observed.

Absence of OATP1B (Organic Anion-Transporting Polypeptide) Induction by Rifampin in Cynomolgus Monkeys: Determination Using the Endogenous OATP1B Marker Coproporphyrin and Tissue Gene Expression.

Organic anion-transporting polypeptide (OATP) 1B induction is an evolving mechanism of drug disposition and interaction. However, there are contradictory reports describing OATP1B expression in hepatocytes and liver biopsies after administration of an inducer. This study investigated the in vivo effects of the common inducer rifampin (RIF) on the activity and expression of cynomolgus monkey OATP1B1 and OATP1B3 transporters, which are structurally and functionally similar their human OATP1B counterparts.

[The characteristics of decomposition and nutrient release of Vicia villosa under different fertilization treatments.].

The effects of three fertilization treatments (no fertilizer, nitrogen fertilizer, and lime) on the characteristics of Vicia villosa decomposition and nutrient release were studied using the nylon bag method in the fields. The results showed that the cumulative decomposition rate of V. villosa was 65.

Long-term follow-up of auditory performance and speech perception and effects of age on cochlear implantation in children with pre-lingual deafness.

Background: The development of auditory and speech perception ability of children with hearing loss is affected by many factors after they undergo cochlear implantation (CI). Age at CI (CI age) appears to play an important role among these factors. This study aimed to evaluate the development of auditory and speech perception ability and explore the impact of CI age on children with pre-lingual deafness present before 3 years of age.

Discovery of a Lead Triphenylethanamine Cholesterol Ester Transfer Protein (CETP) Inhibitor.

Lead optimization of the diphenylpyridylethanamine (DPPE) and triphenylethanamine (TPE) series of CETP inhibitors to improve their pharmaceutical profile is described. Polar groups at the -terminus position in the DPPE series resulted in further improvement in potency and pharmaceutical properties concomitant with retaining the safety, efficacy, and pharmacokinetic (PK) profile. A structure-activity relationship observed in the DPPE series was extended to the corresponding analogs in the more potent TPE series, and further optimization resulted in the identification of 2-amino--(()-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanamide ().

Identification of substituted benzothiazole sulfones as potent and selective inhibitors of endothelial lipase.

A low level of high density lipoprotein (HDL) is an independent risk factor for cardiovascular disease. HDL reduces inflammation and plays a central role in reverse cholesterol transport, where cholesterol is removed from peripheral tissues and atherosclerotic plaque. One approach to increase plasma HDL is through inhibition of endothelial lipase (EL).

Anti-inflammation action of xanthones from Swertia chirayita by regulating COX-2/NF-κB/MAPKs/Akt signaling pathways in RAW 264.7 macrophage cells.

Background: Swertia chirayita, has been commonly used under the name "Zang-yin-chen" for the treatment of liver infections, inflammation, abdominal pain, and bacterial infection in traditional Tibetan medicine. However, the bioactive components with anti-inflammatory activities and underlying mechanisms remain poorly evaluated.

Study Design/methods: Repeated column chromatography yielded two main xanthones from petroleum ether (PE) and ethyl acetate fractions of whole plants of S.

Sulfonylated Benzothiazoles as Inhibitors of Endothelial Lipase.

Endothelial lipase (EL) selectively metabolizes high density lipoprotein (HDL) particles. Inhibition of EL has been shown to increase HDL concentration in preclinical animal models and was targeted as a potential treatment of atherosclerosis. We describe the introduction of an α-sulfone moiety to a benzothiazole series of EL inhibitors resulting in increased potency versus EL.

Linking (Pyr)apelin-13 pharmacokinetics to efficacy: Stabilization and measurement of a high clearance peptide in rodents.

Apelin, the endogenous ligand for the APJ receptor, has generated interest due to its beneficial effects on the cardiovascular system. Synthesized as a 77 amino acid preproprotein, apelin is post-translationally cleaved to a series of shorter peptides. Though (Pyr)apelin-13 represents the major circulating form in plasma, it is highly susceptible to proteolytic degradation and has an extremely short half-life, making it challenging to quantify.

Peptic Ulcer Is the Most Common Cause of Non-Variceal Upper-Gastrointestinal Bleeding (NVUGIB) in China.

BACKGROUND This study aimed to discover the common cause of non-variceal upper-gastrointestinal bleeding (NVUGIB) by conducting a multi-center retrospective study from 2008 to 2012. MATERIAL AND METHODS Hospitalized patients ages ≥18 years old, from 8 hospitals in China, diagnosed with NVUGIB by endoscopy from 1 January 2008 to 31 December 2012 were enrolled. Questionnaires were developed and a data-entry graphical user interface was designed by using EpiData software.

Oral Delivery of Highly Lipophilic, Poorly Water-Soluble Drugs: Self-Emulsifying Drug Delivery Systems to Improve Oral Absorption and Enable High-Dose Toxicology Studies of a Cholesteryl Ester Transfer Protein Inhibitor in Preclinical Species.

BMS-A is an inhibitor of cholesteryl ester transfer protein and is a highly lipophilic compound (clogP 10.5) with poor aqueous solubility (<0.0001 mg/mL at pH 6.

[Chemical constituents from petroleum ether fraction of Swertia chirayita and their activities in vitro].

The present work is to study the chemical constituents from petroleum ether fraction of Tibetan medicine Swertia chirayita by column chromatography and recrystallization. The structures were identified by physical and chemical properties and spectral data as swerchirin (1), decussatin (2), 1,8-dihydroxy-3,5,7-trimethoxyxanthone (3), 1-hydroxy-3,5,7,8-tetramethoxyxanthone (4), bellidifolin (5), 1-hydroxy-3, 7-dimethoxyxanthone (6), methylswertianin (7), 1-hydroxy-3,5-dimethoxyxanthone (8), erythrodiol (9), oleanolic acid (10), gnetiolactone (11), scopoletin (12), sinapaldehyde (13), syringaldehyde (14), and β-sitosterol (15). Compounds 3, 4, 9, 11-14 were isolated from S.

Lipophilic salts of poorly soluble compounds to enable high-dose lipidic SEDDS formulations in drug discovery.

Self-emulsifying drug delivery systems (SEDDS) have been used to solubilize poorly water-soluble drugs to improve exposure in high-dose pharmacokinetic (PK) and toxicokinetic (TK) studies. However, the absorbable dose is often limited by drug solubility in the lipidic SEDDS vehicle. This study focuses on increasing solubility and drug loading of ionizable drugs in SEDDS vehicles using lipophilic counterions to prepare lipophilic salts of drugs.

Correlation study of biological characteristics of non-small cell lung cancer A549 cells after transfecting plasmid by microbubble ultrasound contrast agent.

Objective: To explore the role of the abnormal expression of miRNAs in the development process of non-small cell lung cancer and the feasibility of ultrasound microbubble-mediated gene therapy after transfecting antisense miRNA-224 and miRNA-122a plasmids into non-small cell lung cancer A549 cells.

Methods: Antisense miRNA-224 and miRNA-122a plasmids were transfected into non-small cell lung cancer A549 cells on the optimal ultrasound microbubble-mediated condition. We set up a control group.

Electrochemical fabrication and interfacial charge-transfer process of Ni/GaN(0001) electrodes.

The electrodeposition of Ni on single-crystal n-GaN(0001) film from acetate solution was investigated using scanning electron microscopy, X-ray diffraction, energy dispersive X-ray analysis, atomic force microscopy, and electrochemical techniques. The as-deposited Ni/n-GaN(0001) had a flat band potential of Ufb = -1.0 V vs.

Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of N-[(1R)-1-(3-Cyclopropoxy-4-fluorophenyl)-1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)benzamide (BMS-795311).

Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters.

Oral delivery of highly lipophilic poorly water-soluble drugs: spray-dried dispersions to improve oral absorption and enable high-dose toxicology studies of a P2Y1 antagonist.

BMS-B is a highly lipophilic compound (clog P 7.72) with poor aqueous solubility (<10 ng/mL at pH 1 and 6.5).