Hereditary Angioedema with Recurrent Abdominal Pain in a Patient with a Novel Mutation.

We describe a patient with hereditary angioedema type I. The patient had experienced recurrent abdominal pain around the time of her menstrual period for 13 years. A laboratory examination showed reduced functional and antigenic levels of C4 and C1 inhibitor (C1-INH).

Antiviral activities against herpes simplex virus type 1 by HPH derivatives and their structure-activity relationships.

The compound named Histidine-pyridine-histidine (HPH) is an oxygen-activating ligand derived from the structure of bleomycin. We synthesized HPH derivatives, namely HPH-1 to -8, and investigated their antiviral activities against herpes simplex virus type 1. HPH-8 showed potent antiviral activity with an EC50 of 15 microM, and relatively high cytotoxicity with a CC50 of 37 microM.

Fusaristatins A and B, two new cyclic lipopeptides from an endophytic Fusarium sp.

Two new cyclic lipopeptides, fusaristatins A (1) and B (2) were isolated from rice cultures of a Fusarium sp. YG-45 in the course of a screening of endophytic fungi. Their structures of 1 and 2 were determined by spectroscopic methods.

Genetic evidence for a protective role of heat shock factor 1 against irritant-induced gastric lesions.

Gastric lesions result from an imbalance between aggressive and defensive factors. Indirect lines of evidence suggest that heat shock proteins (HSPs) induced by various aggressive factors provide a major protective mechanism. In this study, we compared gastric ulcerogenic response in wild-type mice and in those lacking heat shock factor 1 (HSF1), a transcription factor for hsp genes.

Up-regulation of 150-kDa oxygen-regulated protein by celecoxib in human gastric carcinoma cells.

Induction of apoptosis by nonsteroidal anti-inflammatory drugs, such as celecoxib, is involved in their antitumor activity. An endoplasmic reticulum chaperone, 150-kDa oxygen-regulated protein (ORP150) is essential for the maintenance of cellular viability under hypoxia and is reported to be overexpressed in clinically isolated tumors. We here found that ORP150 was up-regulated by celecoxib in human gastric carcinoma cells.

Endoplasmic reticulum chaperones inhibit the production of amyloid-beta peptides.

Abeta (amyloid-beta peptides) generated by proteolysis of APP (beta-amyloid precursor protein), play an important role in the pathogenesis of AD (Alzheimer's disease). ER (endoplasmic reticulum) chaperones, such as GRP78 (glucose-regulated protein 78), make a major contribution to protein quality control in the ER. In the present study, we examined the effect of overexpression of various ER chaperones on the production of Abeta in cultured cells, which produce a mutant type of APP (APPsw).

Mechanism for the degradation of origin recognition complex containing Orc5p with a defective Walker A motif and its suppression by over-production of Orc4p in yeast cells.

Orc5p is one of six subunits constituting the ORC (origin recognition complex), a possible initiator of chromosomal DNA replication in eukaryotes. Orc5p contains a Walker A motif. We recently reported that a strain of Saccharomyces cerevisiae having a mutation in Orc5p's Walker A motif (orc5-A), showed cell-cycle arrest at G2/M and degradation of ORC at high temperatures (37 degrees C).

Heme oxygenase-1 protects gastric mucosal cells against non-steroidal anti-inflammatory drugs.

Gastric mucosal cell death by non-steroidal anti-inflammatory drugs (NSAIDs) is suggested to be involved in NSAID-induced gastric lesions. Therefore, cellular factors that suppress this cell death are important for protection of the gastric mucosa from NSAIDs. Heme oxygenase-1 (HO-1) is up-regulated by various stressors and protects cells against stressors.

Low direct cytotoxicity and cytoprotective effects of nitric oxide releasing indomethacin.

Nitric oxide (NO) releasing non-steroidal anti-inflammatory drugs (NSAIDs) have shown a marked reduction of gastrointestinal side effects and we here examined the cytotoxicity of NCX 530 (NO-indomethacin). Under conditions where indomethacin clearly induced both necrosis and apoptosis, NCX 530 induced neither. NCX 530 protected cells from celecoxib-induced necrosis and apoptosis.

Low direct cytotoxicity of nabumetone on gastric mucosal cells.

Prodrugs of non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for clinical purposes because they are not harmful to the gastrointestinal mucosa. We recently showed that NSAIDs have direct cytotoxicity in NSAID-induced gastric lesions. We show here that under conditions where the NSAIDs indomethacin and celecoxib clearly induce cell death, an NSAID prodrug, nabumetone, and its active metabolite 6-methoxy-2-naphthylacetic acid (6MNA), did not have such effects.

Involvement of intracellular Ca2+ levels in nonsteroidal anti-inflammatory drug-induced apoptosis.

We recently reported that nonsteroidal anti-inflammatory drug (NSAID)-induced gastric lesions involve NSAID-induced apoptosis of gastric mucosal cells, which in turn involves the endoplasmic reticulum stress response, in particular the up-regulation of CCAAT/enhancer-binding protein homologous transcription factor (CHOP). In this study, we have examined the molecular mechanism governing this NSAID-induced apoptosis in primary cultures of gastric mucosal cells. Various NSAIDs showed membrane permeabilization activity that correlated with their apoptosis-inducing activity.

Inhibitory activities against topoisomerase I and II by isoaurostatin derivatives and their structure-activity relationships.

Isoaurostatin A (IAS-A) isolated from Thermomonospora alba showed weak inhibition against topoisomerase (topo) I (IC(50)=307microM). To get more strong inhibition, derivatives of IAS-A were prepared and their structure-activity relationships against topo I and II were investigated. The addition of hydroxyl group on aromatic rings increased the activities, 3-(3,4,5-trihydroxybenzylidene)-5-hydroxy-3H-benzofuran-2-one (IAS-9) showed strong inhibition (IC(50)=3microM) against topo I.

Induction of claudin-4 by nonsteroidal anti-inflammatory drugs and its contribution to their chemopreventive effect.

Nonsteroidal anti-inflammatory drugs (NSAID) have shown chemopreventive effects in both preclinical and clinical studies; however, the precise molecular mechanism governing this response remains unclear. We used DNA microarray techniques to search for genes whose expression is induced by the NSAID indomethacin in human gastric carcinoma (AGS) cells. Among identified genes, we focused on those related to tight junction function (claudin-4, claudin-1, and occludin), particularly claudin-4.

Membrane permeabilization by non-steroidal anti-inflammatory drugs.

The cytotoxicity of non-steroidal anti-inflammatory drugs (NSAIDs) is involved in the formation of NSAID-induced gastric lesions. The mechanism(s) behind these cytotoxic effects, however, is not well understood. We found here that several NSAIDs tested caused hemolysis when employed at concentrations similar to those that result in cytotoxicity.

Inhibitory activities against topoisomerase I and II by polyhydroxybenzoyl amide derivatives and their structure-activity relationship.

o-, m-, p-Phenylenediamines having 2,3,4-trihydroxy, 3,4 dihydroxy, and 4-hydroxybenzoyl moieties were prepared and their inhibitory activities were measured against topoisomerase I and II. More hydroxy groups on two aromatic rings increased the activities. Bis(trihydroxybenzoyl)-o-phenylenediamide showed IC(50)=0.

2070-DTI, a topoisomerase inhibitor produced by Streptomyces sp. strain No. 2070.

A novel inhibitor of topoisomerase II designated as 2070-DTI was isolated from the culture filtrate of Streptomyces sp. strain No. 2070.

Inhibition of hyaluronidases and chondroitinases by fatty acids.

The inhibitory effects of various fatty acids on three hyaluronidases (h-ST, h-SH and h-SD) and four chondroitinases (c-ABC, c-B, c-ACI and c-ACII) were examined, and their structure-activity relationships and mechanism of action were studied. The fatty acids used in this experiment showed various inhibitory activities against the enzymes. None of the fatty acids did not inhibit h-ST and h-SH.

Inhibitory properties of antitumor prostaglandins against topoisomerases.

Prostaglandins (PGs) having antitumor activity such as delta12,14-PGJ2, delta12-PGJ2, PGA2 and PGA1 strongly inhibited topoisomerase II (topo II) from human placenta, the potential order of inhibitory activity of the PGs resembling that of the antitumor activity. PGs having no antitumor activity did not inhibit topo II. Delta12,14-PGJ2 to be a potent inhibitor showed inhibitions to some extent against topo I from wheat germ, NIH3T3 and calf thymus gland, and showed no inhibition against the enzymes from Vero, A549, HeLa and COLO 201 cells.