Glabridin, a flavonoid present in licorice root, is known to have antiinflammatory and cardiovascular protective activities. The present study reports an inhibitory effect of glabridin on microglial activation. Glabridin dose-dependently attenuated lipopolysaccharide (LPS)-induced production of inflammatory mediators, including nitric oxide, tumor necrosis factor-alpha and interleukin-1beta, in BV-2 cells, a murine microglia cell line. Moreover, mRNA expression of these inflammatory mediators was also suppressed by glabridin in LPS-stimulated BV-2 cells. Further study demonstrated that glabridin inhibited LPS-induced DNA binding activity of NF-kappaB and AP-1 in BV-2 cells. Collectively, the results presented in this report demonstrate that glabridin inhibits the production of inflammatory mediators in BV-2 cells and this is mediated, at least in part, by blocking NF-kappaB and AP-1 activation. The results suggest that glabridin might be a potential therapeutic agent for the treatment of neuroinflammatory and neurodegenerative diseases.

The pharmacokinetics and metabolism of 2'-benzoyloxycinnamaldehyde (BCA) was characterized in male Sprague-Dawley rats as part of the preclinical evaluations for developing this compound as an antitumour agent. BCA was not detected in the plasma following either intravenous or oral dose, whereas its putative metabolites 2'-hydroxycinnamaldehyde (HCA) and o-coumaric acid were present at considerable levels. In separate pharmacokinetics studies, HCA exhibited a high systemic clearance and a large volume of distribution, whereas both pharmacokinetic parameters were much lower for o-coumaric acid. The terminal half-life of both metabolites was approximately 2 h. BCA was converted rapidly to HCA in rat serum, liver microsomes and cytosol in vitro; HCA was subsequently converted to o-coumaric acid in a quantitative manner only in the liver cytosol. In addition, the formation of o-coumaric acid was inhibited significantly by menadione, a specific inhibitor for aldehyde oxidase. Taken collectively, the results suggest that the rapid systemic clearance of HCA is likely due mainly to hepatic clearance occurring from aldehyde oxidase-catalysed biotransformation to o- coumaric acid. In conclusion, the present work demonstrates that the anticancer drug candidate BCA is highly likely to work as its active metabolite HCA in the body.

The Janus kinase (JAK) family comprises four members (JAK1, JAK2, JAK3, and Tyk2) that play a key role in mediating cytokine receptor signaling. JAK inhibition thus modulates cytokine-mediated effects. In particular, selective inhibition of JAK1 or JAK3 may provide an efficient therapeutic agent for the treatment of inflammatory diseases, with minimized side effects. In this study, as part of our continued efforts to develop a selective JAK1 inhibitor, a series of 1,2-disubstituted benzimidazole-5-carboxamide derivatives was prepared and their inhibitory activities against all four JAK isozymes were evaluated. A clear structure-activity relationship was observed with respect to JAK1 selectivity; this highlighted the importance of hydrogen bond donors at both N(1) and R2 positions located within a specific distance from the benzimidazole core. One of the synthesized compounds, 1-(2-aminoethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole-5-carboxamide (5c), showed remarkable JAK1 selectivity (63-fold vs JAK2, 25-fold vs JAK3, and 74-fold vs Tyk2). Molecular docking revealed that the 2-aminoethyl and piperidin-4-yl substituents of 5c function as probes to differentiate the ATP-binding site of JAK1 from that of JAK2, resulting in preferential JAK1 binding. A kinase panel assay confirmed the JAK1 selectivity of 5c, which showed no appreciable inhibitory activity against 26 other protein kinases at 10 μM.

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The antiallergic activity of the natural disaccharide, 5-O-alpha-D-(3-C-hydroxymethyl)lyxofuranosyl-beta-D-(2-C-hydroxymethyl)arabinofuranose was evaluated using both in vivo and in vitro experimental models. Intravenously administered compound inhibited the passive cutaneous anaphylaxis response in rats in a dose-dependent manner (ED(50) = 9.6 mg/kg). The compound inhibited histamine release evoked by both compound 48/80 and calcium ionophore A23187 in rat peritoneal mast cells indicating that mast cell stabilization is the major mechanism of action for its antiallergic activity. In passively sensitized isolated guinea-pig hearts, an in vitro anaphylaxis model in which histamine release plays a key role for functional deterioration, the compound markedly diminished both coronary flow reduction and histamine release on challenge to the antigen. These data demonstrate that this antiallergic natural disaccharide exerts its effect via inhibition of mast cell mediator release.

The water extract of Sophorae radix was tested for its preventive effects against cardiovascular anaphylaxis elicited in experimental animals. In actively sensitized pithed rats, the extract partially protected the animals from death resulting from antigen challenge. Of the cardiovascular changes observed during the anaphylaxis in the pithed animals, the initial pressor response was significantly attenuated by the extract. The extract also improved anaphylactic cardiac dysfunction in passively sensitized isolated guinea hearts: improvement was noted in the contractility, arrhythmic duration and lactate dehydrogenase elevation. The perfusion pressure change to antigen challenge was not altered by the extract in passively sensitized isolated mesenteric artery preparations. The extract however significantly inhibited homologous passive cutaneous anaphylaxis responses in rats. When examined in isolated guinea pig tracheal muscle, the extract did not influence at reasonable concentrations on the contraction elicited by three major anaphylactic mediators, histamine, leukotriene D4 and serotonin. These results suggest that the water extract of Sophorae radix possesses anti-anaphylactic effect in cardiovascular system, primarily acting on the heart not the peripheral resistance vessels.

No abstract

The global prevalence of GERD is substantially increasing each year, and GERD is a chronic disease that reduces the quality of life of patients. The efficacy of conventional drugs is diverse, and most require long‐term or lifetime administration; thus, the development of more effective therapeutic agents is needed. Herein, a more effective treatment for GERD was tested. We investigated whether JP‐1366 affected gastric H+/K+‐ATPase activity and used the Na+/K+‐ATPase assay to confirm the selectivity of H+/K+‐ATPase inhibition. To clarify the mechanism of enzyme inhibition, JP‐1366 and TAK‐438 were analyzed by Lineweaver–Burk. Also, we investigated the effects of JP‐1366 in various models involving reflux esophagitis. We found that JP‐1366 mediates strong, selective, and dose‐dependent inhibition of H+/K+‐ATPase. We found that JP‐1366 significantly suppressed gastric acid secretion in histamine‐treated pylorus‐ligated rats in a dose‐dependent manner. Additionally, we confirmed that JP‐1366 inhibited histamine‐stimulated gastric acid secretion in the HPD model. JP‐1366 exhibited a more than 2‐fold higher inhibitory effect on esophageal injury than TAK‐438 in GERD lesions and had a more potent inhibitory effect in indomethacin‐ or aspirin‐induced gastric ulcer rat models than TAK‐438. Additionally, JP‐1366 inhibited gastric ulcers. These results support the possibility that JP‐1366 is a good candidate drug for treating acid‐related diseases.