iridoids and verproside

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease which causes breathing problems. YPL-001, consisting of six iridoids, has potent inhibitory efficacy against COPD. Although YPL-001 has completed clinical trial phase 2a as a natural drug for COPD treatment, the most effective iridoid in YPL-001 and its mechanism for reducing airway inflammation remain unclear. To find an iridoid most effectively reducing airway inflammation, we examined the inhibitory effects of the six iridoids in YPL-001 on TNF or PMA-stimulated inflammation (IL-6, IL-8, or MUC5AC) in NCI-H292 cells. Here, we show that verproside among the six iridoids most strongly suppresses inflammation. Both TNF/NF-κB-induced MUC5AC expression and PMA/PKCδ/EGR-1-induced IL-6/-8 expression are successfully reduced by verproside. Verproside also shows anti-inflammatory effects on a broad range of airway stimulants in NCI-H292 cells. The inhibitory effect of verproside on the phosphorylation of PKC enzymes is specific to PKCδ. Finally, in vivo assay using the COPD-mouse model shows that verproside effectively reduces lung inflammation by suppressing PKCδ activation and mucus overproduction. Altogether, we propose YPL-001 and verproside as candidate drugs for treating inflammatory lung diseases that act by inhibiting PKCδ activation and its downstream pathways.

Topics: Animals; Epithelial Cells; Humans; Inflammation; Interleukin-6; Iridoids; Lung; Mice; NF-kappa B; Protein Kinase C-delta; Pulmonary Disease, Chronic Obstructive

Verproside, an active iridoid glycoside component of Veronica species, such as

Topics: Cells, Cultured; Cinnamates; Glucuronosyltransferase; Hepatocytes; Humans; Inactivation, Metabolic; Iridoid Glucosides; Iridoids; Kinetics; Microsomes, Liver; Sulfotransferases

Extracts from Veronica officinalis L. are traditionally used for the treatment of lung diseases; however, the effective compounds and the mode of action are still unknown.. Here we analyzed the effects of a standardized Veronica extract on genes expression and signalling protein production associated with the development of inflammatory lung diseases.. The degranulation capacity of primary mast cells, as well as gene expression and release of inflammatory mediators from human lung epithelial cells (A549 cells) were analyzed in relation to the synthetic drugs azelastine and dexamethasone. Gene and protein expression of cyclooxygenase-2 were investigated by semi-quantitative RT-PCR and western blotting, respectively. The involvement of phosphorylated mitogen-activated protein kinases and NF-κB signaling in regulation of these molecules were characterized by western blotting and electrophoretic mobility shift assays. Characteristic extract components were identified by LC-MS and verminoside was quantified by HPLC analysis.. We demonstrated that Veronica officinalis has a small influence on the degranulation capacity of mast cells but rather inhibits gene and protein expression of the chemokine eotaxin in A549 lung epithelial cells, which is essential for recruitment of inflammatory-associated cells in lung diseases. Furthermore, release of the inflammatory mediator PGE(2) was diminished through inhibition of COX-2 expression via the NF-κB signaling pathway in TNF-α-activated A549 cells. Phytochemical analysis identified verproside and verminoside as the most abundant iridoid glycosides.. Our results are a contribution to explaining the observed anti-inflammatory effects of Veronica offcinalis extract on a molecular level. However, its clinical potency has at first to be proven in animals and subsequently in clinical trials.

Topics: Animals; Bone Marrow Cells; Cell Line; Cell Survival; Cyclooxygenase 2; Dexamethasone; Epithelial Cells; Gene Expression; Humans; Inflammation Mediators; Iridoid Glucosides; Iridoids; Lung; Mast Cells; Medicine, Traditional; Mice; Mitogen-Activated Protein Kinases; NF-kappa B; Phosphorylation; Phthalazines; Plant Extracts; Signal Transduction; Veronica

Verproside, isovanilloylcatalpol, catalposide and 6-O-veratroyl catalpol are bioactive iridoid glucosides isolated from in a number of folk medicinal plants. A rapid, sensitive and selective liquid chromatography/mass spectrometric (LC/MS) method for the simultaneous determination of verproside, isovanilloylcatalpol, catalposide and 6-O-veratroyl catalpol in rat plasma was developed. The analytes were extracted from 50 microL of rat plasma with ethyl acetate using 7-carboxymethyloxy-3',4',5-trimethoxyflavone as internal standard and analyzed on an X-Bridge C(18) column within 6.5 min with 40% methanol in 10 mm ammonium formate (pH 3.0). The analytes were quantified using an electrospray ionization mass spectrometry in the selected ion monitoring mode. The standard curves were linear over the concentration ranges of 10-2000 ng/mL for verproside, isovanilloylcatalpol and catalposide and 20-2000 ng/mL for 6-O-veratroyl catalpol. The coefficients of variation and relative errors of verproside, isovanilloylcatalpol, catalposide and 6-O-veratroyl catalpol for intra- and inter-assay at four quality control levels were 2.5-8.0 and-4.0-6.6%, respectively. This method was successfully applied to the pharmacokinetic study of verproside and its possible metabolite isovanilloylcatalpol after intravenous administration of verproside, a candidate anti-asthma drug, in male Sprague-Dawley rats.

Topics: Animals; Area Under Curve; Calibration; Chromatography, Liquid; Glucosides; Iridoid Glucosides; Iridoids; Least-Squares Analysis; Male; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization

Verproside, a catalpol derivative iridoid glucoside isolated from Pseudolysimachion longifolium, is a candidate for anti-asthmatic drug. The dose-dependency of the pharmacokinetics of verproside was evaluated in rats after intravenous and oral administration. After intravenous administration of verproside (2, 5 and 10 mg/kg doses), the systemic clearance (Cl) was significantly reduced and AUC was significantly increased at 10 mg/kg dose compared to 2 and 5 mg/kg doses. The volume of distribution at steady state (V (ss)) remained unchanged as the dose was increased. The extent of urinary excretion was low for both intravenous (3.3-6.2%) and oral (0.01-0.04%) doses. Isovanilloylcatalpol was identified as a metabolite after intravenous administration of verproside and showed the significant decreases in AUC and C (max) at 10 mg/kg verproside dose. The reduced systemic clearance of verproside at high doses appears to be due to the saturable metabolism. Upon oral administration of verproside (20, 50 and 100 mg/kg doses), C (max) was nonlinearly increased. The extent of verproside recovered from the gastrointestinal tract at 24 h after oral administration was 0.01-0.72% for all three doses studied. The absolute oral bioavailability (F) was 0.3 and 0.5% for 50 and 100 mg/kg doses, respectively. Low F appears to be due to first-pass metabolism.

Topics: Administration, Oral; Animals; Anti-Asthmatic Agents; Biological Availability; Biotransformation; Dose-Response Relationship, Drug; Drug Stability; Glucosides; Hydrogen-Ion Concentration; Injections, Intravenous; Iridoid Glucosides; Iridoids; Male; Microsomes, Liver; Rats; Rats, Sprague-Dawley

Allergic inflammation of the airways has a critical role in asthma development. We investigated a suppressive effect of verproside (3,4-dihydroxy catalpol) isolated from the extract of Pseudolysimachion longifolium on asthmatic parameters--such as immunoglobulin E (IgE) level, cytokine release, eosinophilia, airway hyperresponsiveness and mucus hypersecretion--in an OVA-sensitized/challenged mouse model. Verproside significantly inhibited the increase of total IgE and the cytokines IL-4 and IL-13 in plasma and bronchoalveolar lavage fluid, and also effectively suppressed airway hyperresponsiveness, eosinophilia and mucus hypersecretion in OVA-induced asthmatic mice. The efficacy of verproside was comparable to montelukast, an anti-asthmatic drug that is currently available. These results suggest that verproside could be a major marker in herbal medicines that are used for asthma treatment, and could also act as a lead for anti-asthmatic drugs.

Topics: Acetates; Animals; Anti-Asthmatic Agents; Asthma; Bronchoalveolar Lavage Fluid; Cyclopropanes; Disease Models, Animal; Female; Glucosides; Immunoglobulin E; Interleukin-13; Interleukin-4; Iridoid Glucosides; Iridoids; Lung; Methacholine Chloride; Mice; Mice, Inbred BALB C; Molecular Structure; Mucus; Ovalbumin; Plant Extracts; Pneumonia; Pulmonary Eosinophilia; Quinolines; Sulfides; Veronica