The mechanism of the protective effect of quercetin-3-O-β-D-glucuronopyranoside (QGC) from the leaves of Rumex aqauticus on indomethacin (IND, a representative NSAID)-induced gastric damage in rats was investigated. Pre-treatment with QGC significantly attenuated IND-induced gastric mucosal injury. An increase in myeloperoxidase (MPO) activity and expression of intercellular adhesion molecule (ICAM)-1 protein and mRNA expression of the pro-inflammatory cytokines tumor necrosis factor-α and interleukin-1β, as well as a decrease in gastric mucus secretion were detected in the gastric mucosa of IND-treated rats. QGC reversed the side effect of IND on MPO activity and mucus production. Furthermore, QGC pre-treatment notably decreased ICAM-1 protein and mRNA expression of the pro-inflammatory cytokines, suggesting that QGC protection from IND-induced damage is associated with increased gastric mucus secretion, inhibition of free radical production by activated neutrophils via ICAM-1, and pro-inflammatory cytokine downregulation.

W e have shown that myosin light chain kinase (MLCK) was required for the off-contraction in response to the electrical field stimulation (EFS) of feline esophageal smooth muscle. In this study, we investigated whether protein kinase C (PKC) may require the on-contraction in response to EFS using feline esophageal smooth muscle. The contractions were recorded using an isometric force transducer. On-contraction occurred in the presence of N G -nitro-L-arginine methyl ester (L-NAME), suggesting that nitric oxide acts as an inhibitory mediator in smooth muscle. The excitatory composition of both contractions was cholinergic dependent which was blocked by tetrodotoxin or atropine. The on-contraction was abolished in Ca 2＋ -free buffer but reappeared in normal Ca 2＋ -containing buffer indicating that the contraction was Ca 2＋ dependent. 4-aminopyridine (4-AP), voltage-dependent K＋ channel blocker, significantly enhanced on-contraction. Aluminum fluoride (a G-protein activator) increased on-contraction. Pertussis toxin (a Gi inactivator) and C3 exoenzyme (a rhoA inactivator) significantly decreased on-contraction suggesting that Gi or rhoA protein may be related with Ca 2＋ and K ＋ channel. ML-9, a MLCK inhibitor, significantly inhibited on-contraction, and chelerythrine (PKC inhibitor) affected on the contraction. These results suggest that endogenous cholinergic contractions activated directly by low-frequency EFS may be mediated by Ca 2＋ , and G proteins, such as Gi and rhoA, which resulted in the activation of MLCK, and PKC to produce the contraction in feline distal esophageal smooth muscle.

A series of new 3-alkyl-1-(1-methyl-2-phenylethyl)ureas related to ceramide was synthesized and evaluated for their in vitro cytotoxic activity against five human tumor cell lines. The urea analogue (2b) of B13 showed comparable or slightly more potent cytotoxic activity as compared to B13, indicating that urea does appear to serve as a bioisostere of amide.

Naphthyridine compounds are important, because they exhibit various biological activities including anticancer, antimicrobial, and anti-inflammatory activity. Some naphthyridines have antimitotic effects or demonstrate anticancer activity by inhibiting topoisomerase II. These compounds have been investigated as potential anticancer agents, and several compounds are now part of clinical trials. A series of naphthyridine derivatives were evaluated for their in vitro cytotoxic activities against human cervical cancer (HeLa), leukemia (HL-60), and prostate cancer (PC-3) cell lines using an MTT assay. Some compounds (14, 15, and 16) were more potent than colchicine against all three human cancer cell lines and compound (16) demonstrated potency with IC50 values of 0.7, 0.1, and 5.1 µM, respectively. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used for quantitative structure-activity relationship (QSAR) molecular modeling of these compounds. We obtained accurate and predictive three-dimensional QSAR (3D-QSAR) models as indicated by the high PLS parameters of the HeLa (q2, 0.857; r2, 0.984; r2pred, 0.966), HL-60 (q2, 0.777; r2, 0.937; r2pred, 0.913), and PC-3 (q2, 0.702; r2, 0.983; r2pred, 0.974) cell lines. The 3D-QSAR contour maps suggested that the C-1 NH and C-4 carbonyl group of the naphthyridine ring and the C-2 naphthyl ring were important for cytotoxicity in all three human cancer cell lines.

NO released by myenteric neurons controls the off contraction induced by electrical field stimulation (EFS) in distal esophageal smooth muscle, but in the presence of nitric oxide synthase (NOS) inhibitor, L-NAME, contraction by EFS occurs at the same time. The authors investigated the intracellular signaling pathways related with G protein and ionic channel EFS-induced contraction using cat esophageal muscles. EFS-induced contractions were significantly suppressed by tetrodotoxin (1 μM) and atropine (1 μM).