Anti-allergic effects of Teucrium japonicum on mast cell-mediated allergy model

The mast cell-mediated immediate-type allergic reaction is involved in many allergic diseases such as asthma, allergic rhinitis, and sinusitis. Stimulation of mast cells starts the process of degranulation resulting in release of mediators such as histamine and an array of inflammatory cytokines. In this report, we investigated the effect of aqueous extract of Teucrium japonicum Houttuyn (Labiatae) (AXTJ) on the mast cell-mediated allergy model and studied its possible mechanisms of action. AXTJ inhibited compound 48/80-induced systemic reactions and serum histamine release in mice. AXTJ decreased immunoglobulin E-mediated passive cutaneous anaphylaxis reaction. AXTJ reduced histamine release and intracellular calcium from rat peritoneal mast cells activated by compound 48/80. In addition, AXTJ attenuated activation of nuclear factor (NF)-κB, and downstream tumor necrosis factor (TNF)-α expression in phorbol 12-myristate 13-acetate and calcium ionophore A23187-stimulated human mast cells. Our findings provide evidence that AXTJ inhibits mast cell-derived allergic reactions and involvement of intracellular calcium, TNF-α, and NF-κB in these effects.     

Comparison of peroxyl radical scavenging capacity of commonly consumed beverages

The antioxidant potential of commercial beverages against peroxyl radical was determined using the Total Oxyradical Scavenging Capacity (TOSC) assay. Peroxyl radicals generated from thermal homolysis of 2,2′-azobis-amidinopropane oxidize α-keto-γ-methiolbutyric acid to ethylene, which is monitored by gas chromatography. The TOSC of each beverage is quantified from its ability to inhibit ethylene generation relative to a control reaction. Nine different beverages (green tea, jasmine tea, black tea, instant coffee, brewed coffee, cocoa mix, oolong tea, prune juice, and grape juice) were selected for this study. Their antioxidant capacities per a cup-serving (125 mL) were measured and compared to peroxyl radical scavenging capacity provided by a recommended daily dose of ascorbic acid (90 mg) dissolved in the same volume of water. The greatest antioxidant capacity was found in brewed coffee, which was followed, in decreasing order, by prune juice, instant coffee, green tea, cocoa mix, grape juice, jasmine tea, black tea, oolong tea, and ascorbic acid. There was an almost 7-fold difference in the TOSC between brewed coffee and ascorbic acid. The data suggest a potential role for commonly consumed beverages in lowering the risk of pathophysiologies associated with peroxyl radical-mediated events.     

Changes of Atrial Natriuretic Peptide System in Rats with Puromycin Aminonucleoside-Induced Nephrotic Syndrome

Sodium retention is a hallmark of nephrotic syndrome. We investigated whether sodium retention is associated with changes of natriuretic peptide system at different stages (i.e., a sodium retaining stage and a compensatory stage) of nephrotic syndrome. At day 7 after PAN (puromycin aminonucleoside) injection, the urinary excretion of sodium was decreased, along with the development of ascites and positive sodium balance. The plasma and urinary ANP (atrial natriuretic peptide) immunoreactivities were increased. ANP mRNA expression was increased in the heart and kidney, whereas that of NPR (natriuretic peptide receptor)-A and NPR-C mRNA was decreased in the kidney. The expression of NEP was decreased in the kidney. At day 14, urinary excretion of sodium did not differ from the control. The plasma ANP level and heart ANP mRNA expression returned to their control values. The expression of ANP mRNA in the kidney was increased in association with increased urinary ANP immunoreactivities. The expression of NPR-A in the kidney became normal, whereas that of NPR-C kept decreased. The expression of NEP (neutral endopeptidase) remained decreased. These findings suggest that the increased renal ANP synthesis in association with decreased metabolism via NEP and NPR-C may play a compensatory role against the development of sodium retention in nephrotic syndrome. The decreased of NPR-A expression in the kidney may contribute to the ANP resistance at day 7. The subsequent recovery of NPR-A expression may play a role in promoting sodium excretion in later stage (at day 14).     

Forskolin Changes the Relationship between Cytosolic Ca2+ and Contraction in Guinea Pig Ileum

This study was designed to clarify the mechanism of the inhibitory effect of forskolin on contraction, cytosolic Ca²⁺ level ([Ca²⁺]_i), and Ca²⁺ sensitivity in guinea pig ileum. Forskolin (0.1 nM~10 µM) inhibited high K⁺ (25 mM and 40 mM)- or histamine (3 µM)-evoked contractions in a concentration-dependent manner. Histamine-evoked contractions were more sensitive to forskolin than high K⁺-evoked contractions. Spontaneous changes in [Ca²⁺]_i and contractions were inhibited by forskolin (1 µM) without changing the resting [Ca²⁺]_i. Forskoln (10 µM) inhibited muscle tension more strongly than [Ca²⁺]_i stimulated by high K⁺, and thus shifted the [Ca²⁺]_i-tension relationship to the lower-right. In histamine-stimulated contractions, forskolin (1 µM) inhibited both [Ca²⁺]_i and muscle tension without changing the [Ca²⁺]_i-tension relationship. In α-toxin-permeabilized tissues, forskolin (10 µM) inhibited the 0.3 µM Ca²⁺-evoked contractions in the presence of 0.1 mM GTP, but showed no effect on the Ca²⁺-tension relationship. We conclude that forskolin inhibits smooth muscle contractions by the following two mechanisms: a decrease in Ca²⁺ sensitivity of contractile elements in high K⁺-stimulated muscle and a decrease in [Ca²⁺]_i in histamine-stimulated muscle.     

Pharmacokinetic/pharmacodynamic modeling of the cardiovascular effects of beta blockers in humans

Pharmacokinetic-pharmacodynamic (PK/PD) analysis is useful study in clinical pharmacology, also PK/PD modeling is major tools for PK/PD analysis. In this study, we sought to characterize the relationship between the cardiovascular effects and plasma concentrations of the beta blocker drugs carvedilol and atenolol using PK/PD modeling in healthy humans. One group received oral doses of atenolol (50 mg) and the other group received oral doses of carvedilol (25 mg). Subsequently, blood samples were taken, and the effects of the drugs on blood pressure were determined. Plasma concentrations of drugs were measured by HPLC, and PK/PD modeling performed by applied biophase model, plasma drug concentrations were linked to the observed systolic blood pressure (SBP) and diastolic blood pressure (DBP) via an effect compartment. The model parameters were estimated using the ADAPT II program. In PK/PD analysis, it was observed the time delay between plasma concentration and effect and the time delay between SBP and DBP. The two time delays were properly explained by PD parameter "Keo" in applied biophase model. As conclusion, the biophase PK/PD model described the relationship between the plasma concentrations of the drugs and the cardiovascular effects, including the time delay between systolic blood pressure and diastolic blood pressure.     

(-)-Syringaresinol inhibits proliferation of human promyelocytic HL-60 leukemia cells via G1 arrest and apoptosis

We examined the effect of (-)-syringaresinol, a furofuran-type lignan isolated from Daphne genkwa, on cell cycle regulation in HL-60 human promyelocytic leukemia cells in vitro. (-)-Syringaresinol decreased the viability of HL-60 cells by inducing G(1) arrest followed by apoptosis in a dose- and time-dependent manner. The G(0)/G(1) phase of the cell cycle is regulated by cyclin-dependent kinases (Cdk), cyclins and cyclin-dependent kinase inhibitors (Cdki). We show by western blot analysis, that the (-)-syringaresinol-induced G(1) arrest was mediated through the increased expression of Cdki proteins (p21(cip1/waf1) and p27(kip1)) with a simultaneous decrease in cdk2, cdk4, cdk6, cyclin D(1), cyclin D(2), and cyclin E expression. The induction of apoptosis after treatment with (-)-syringaresinol for 24 h was demonstrated by morphological changes, DNA fragmentation, altered ratio of Bax/Bcl-2, cleavage of poly(ADP-ribose) polymerase and flow cytometry analysis. (-)-Syringaresinol also induced cytochrome c release and activation of caspase-3 and caspase-9. To our knowledge, this is the first time that (-)-syringaresinol has been reported to potently inhibit the proliferation of human promyelocytic HL-60 cells through G(1) arrest and induction of apoptosis. These findings suggest that (-)-syringaresinol may be a potential chemotherapeutic agent for the treatment of cancer.     

Clinicopathological features of female gastric carcinoma patients with curative resection: comparison with male patients

Little is known about the clinicopathological features of female gastric carcinoma (FGC) patients. We compared the clinicopathologic features and outcomes of FGC patients with curative resection with those of male gastric carcinoma (MGC) patients. We reviewed the hospital records of 940 FGC patients between 1986 and 2005 at Chonnam National University Hospital. Multivariate analysis showed that presence of serosal invasion, lymph node metastasis, and operative type were significant prognostic factors for survival of FGC patients with curative resection. Furthermore, the overall 5-year survival rate of FGC patients with curative resection (53.4%) was higher than that of MGC patients (47.6%, p<0.05). In advanced cases, no significant difference was observed in the overall 5-year survival rate between the FGC and MGC patients (41.6% vs 37.4%, p>0.05). Therefore, serosal invasion, lymph node metastasis, and type of operation were statistically significant parameters associated with survival. Early detection is more important for improving the prognosis of female patients with gastric cancer than for male patients.     

Synthesis and analgesic and anti-inflammatory activities of 1,2-benzothiazine derivatives

Three 1,2-benzothiazine derivatives were synthesized, and their analgesic/anti-inflammatory efficacy and their effects on gastric irritation were evaluated. Among the three compounds, 39 exhibited the most potent analgesic action, but the effect was weaker than that of piroxicam. Nonetheless, the compound showed 4 times more potent analgesic action with less gastric damage than did ibuprofen. These compounds did not show anti-inflammatory effect at an oral dose of 5 mg/kg.     

Inducible nitric oxide synthase inhibitors fromMelia azedarach var.Japonica

In bioassay-guided search for inducible nitric oxide synthase (iNOS) inhibitory compounds from higher plants of South Korea, two beta-carboline alkaloids, 4-methoxy-1-vinyl-beta-carboline (1) and 4,8-dimethoxy-l-vinyl-beta-carboline (2) have been isolated from the cortex of Melia azedarach var. japonica. The structures of these compounds were elucidated on the basis of spectroscopic data. Compounds 1 and 2 showed marked inhibitory activity of iNOS on LPS- and interferon-gamma-stimulated RAW 264.7 cells.     

Metabolism-based anticancer drug design

Many conventional anticancer drugs display relatively poor selectivity for neoplastic cells, in particular for solid tumors. Furthermore, expression or development of drug resistance, increased glutathione transferases as well as enhanced DNA repair decrease the efficacy of these drugs. Research efforts continue to overcome these problems by understanding these mechanisms and by developing more effective anticancer drugs. Cyclophosphamide is one of the most widely used alkylating anticancer agents. Because of its unique activation mechanism, numerous bioreversible prodrugs of phosphoramide mustard, the active species of cyclophosphamide, have been investigated in an attempt to improve the therapeutic index. Solid tumors are particularly resistant to radiation and chemotherapy. There has been considerable interest in designing drugs selective for hypoxic environments prevalent in solid tumors. Much of the work had been centered on nitroheterocyclics that utilize nitroreductase enzyme systems for their activation. In this article, recent developments of anticancer prodrug design are described with a particular emphasis on exploitation of selective metabolic processes for their activation.