Angiotensin II produces nociceptive behavior through spinal AT1 receptor-mediated p38 mitogen-activated protein kinase activation in mice

Background: It has been demonstrated that angiotensin II (Ang II) participates in either the inhibition or the facilitation of nociceptive transmission depending on the brain area. Neuronal Ang II is locally synthesized not only in the brain, but also in the spinal cord. Though the spinal cord is an important area for the modulation of nociception, the role of spinal Ang II in nociceptive transmission remains unclear. Therefore, in order to elucidate the role of Ang II in nociceptive transmission in the spinal cord, we examined the effect of intrathecal (i.t.) administration of Ang II into mice.Results: I.t. administration of Ang II produced a behavioral response in mice mainly consisting of biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank. The behavior induced by Ang II (3 pmol) was dose-dependently inhibited by intraperitoneal injection of morphine (0.1-0.3 mg/kg), suggesting that the behavioral response is related to nociception. The nociceptive behavior was also inhibited dose-dependently by i.t. co-administration of losartan (0.3-3 nmol), an Ang II type 1 (AT1) receptor antagonist, and SB203580 (0.1-1 nmol), a p38 MAPK inhibitor. However, the Ang II type 2 (AT2) receptor antagonist PD123319, the upstream inhibitor of ERK1/2 phosphorylation U0126, and the JNK inhibitor SP600125 had no effect on Ang II-induced nociceptive behavior. Western blot analysis showed that the i.t. injection of Ang II induced phosphorylation of p38 MAPK in the lumbar dorsal spinal cord, which was inhibited by losartan, without affecting ERK1/2 and JNK. Furthermore, we found that AT1 receptor expression was relatively high in the lumbar superficial dorsal horn.Conclusions: Our data show that i.t. administration of Ang II induces nociceptive behavior accompanied by the activation of p38 MAPK signaling mediated through AT1 receptors. This observation indicates that Ang II may act as a neurotransmitter and/or neuromodulator in the spinal transmission of nociceptive information. © 2013 Nemoto et al.; licensee BioMed Central Ltd

RAW 264.7細胞におけるLPSで誘導される誘導型NO合成酵素の発現に対するCaffeic Acid Undecyl Esterの阻害について

We synthesized caffeic acid undecyl ester (CAUE),and found that it exhibited strong inhibitory effect of lipopolysaccharide (LPS) -induced nitric oxide (NO) production in murine macrophage-like RAW 264.7 cells.We examined the effect of CAUE on the expression inducible nitric oxide synthase (iNOS) in LPS-stimulated RAW 264.7 cells.Western blot analysis performed with specific anti-iNOS antibody showed that a decrease in NO was accompanied by a decrease in the level of iNOS protein with dose-dependent manner (CAUE:0.1～1.0μM).To clarify the mechanistic basis for CAUE\u27s ability to inhibit the induction of iNOS,we examined the effect of CAUE on nuclear factor (NF)-κB,Inhibitor-κB (IκB) degradation and phosphorylation of extracellular-signaling regulated Kinases,ERK 1/2.CAUE potently suppressed the transcriptional activity of NF-κB,IκB degradation and activation of ERK.Since NF-κB was activated by following IκBα degradation,the recovery of IκBα protein indicating that CAUE inhibited the activation of degradation following NF-κB.These finding suggest that CAUE has the inhibitory effect on LPS-induced NO production and expression of iNOS in macrophage by the inhibition of IκB degradation and NF-κB activation,which may be mediated through blockage in the phospholylation ERK

Structures and Biological Evaluations of Agelasines Isolated from the Okinawan Marine Sponge Agelas nakamurai

Three new <i>N</i>-methyladenine-containing diterpenes, 2-oxoagelasines A (<b>1</b>) and F (<b>2</b>) and 10-hydro-9-hydroxyagelasine F (<b>3</b>), were isolated from the Okinawan marine sponge Agelas nakamurai Hoshino together with eight known agelasine derivatives, 2-oxoagelasine B (<b>4</b>), agelasines A (<b>5</b>), B (<b>6</b>), D (<b>7</b>), E (<b>8</b>), F (<b>9</b>), and G (<b>10</b>), and ageline B (<b>11</b>). The structures of <b>1</b>–<b>3</b> were assigned on the basis of their spectroscopic data and their comparison with those of the literature. Compounds <b>3</b> and <b>5</b>–<b>11</b> inhibited the growth of Mycobacterium smegmatis with inhibition zones of 10, 14, 15, 18, 14, 20, 12, and 12 mm at 20 μg/disc, respectively. All compounds were inactive (IC₅₀ > 10 μM) against Huh-7 (hepatoma) and EJ-1 (bladder carcinoma) human cancer cell lines. Three 2-oxo derivatives (<b>1</b>, <b>2</b>, and <b>4</b>) exhibited markedly reduced biological activity against M. smegmatis. Moreover, compound <b>10</b> inhibited protein tyrosine phosphatase 1B (PTP1B) activity with an IC₅₀ value of 15 μM

Haliclonadiamine Derivatives and 6-<i>epi</i>-Monanchorin from the Marine Sponge <i>Halichondria panicea</i> Collected at Iriomote Island

Four new haliclonadiamine analogues, (10<i>Z</i>,12<i>E</i>)-haliclonadiamine (<b>1</b>), (10<i>E</i>,12<i>Z</i>)-haliclonadiamine (<b>2</b>), and halichondriamines A (<b>3</b>) and B (<b>4</b>), were isolated from the Okinawan marine sponge <i>Halichondria panicea</i> together with haliclonadiamine (<b>5</b>) and papuamine (<b>6</b>). The structures of <b>1</b>–<b>4</b> were elucidated on the basis of their spectroscopic data by comparisons with those for <b>5</b> and <b>6</b>. Further separation of the remaining fraction led to the isolation of a new bicyclic guanidine alkaloid, 6-<i>epi</i>-monanchorin (<b>7</b>), along with monanchorin (<b>8</b>). Compound <b>7</b> is the epimer of <b>8</b> at the 6 position. Compounds <b>1</b>–<b>6</b> inhibited the growth of <i>Mycobacterium smegmatis</i> with inhibition zones of 12, 7, 8, 7, 16, and 12 mm at 10 μg/disc, respectively. Compounds <b>2</b>–<b>4</b> exhibited weak cytotoxicities against the Huh-7 (hepatoma) human cancer cell line and were 2-fold less active than <b>5</b> and <b>6</b>. Compounds <b>7</b> and <b>8</b> were not active against <i>M. smegmatis</i> at 20 μg/disc or the cancer cell line at 10 μM