Involvement of K(+) channels in the augmented nasal venous responsiveness to nitric oxide in rat model of allergic rhinitis

Objective

One of the factors of nasal obstruction observed in allergic rhinitis is thought to be a dilatation of microveins in nasal mucosa, although the exact mechanism(s) is not fully understood. In nasal mucosae of repeatedly antigen challenged rats, NO-induced venodilatation itself is augmented. In the present study, the roles of K⁺ channels in sodium nitroprusside (NO donor; SNP)-induced venodilatation of nasal mucosae in antigen-challenged rats were investigated.

Methods

Actively sensitized rats were repeatedly challenged with aerosolized antigen. Twenty-four hours after the final antigen challenge, nasal septum mucosa was exposed surgically and observed directly in vivo under a stereoscopic microscope. The 20 μl reagents were administered onto the exposed septal mucosal surface, and the venous diameters of nasal mucosa were observed.

Results

The SNP-induced venodilatation of septal mucosa was markedly and significantly increased in the antigen-challenged rats. The SNP-induced venodilatation was significantly inhibited by pretreatment with either tetraethylammonium [TEA; a large-conductance Ca²⁺ activated-K⁺ (K_Ca) and voltage dependent K⁺ (Kv) channel inhibitor] or glibenclamide [an ATP sensitive K⁺ (K_ATP) channel inhibitor].

Conclusions

These findings suggest that NO-induced venodilatation is augmented in nasal mucosae of challenged rats, and K⁺ channels play an important role in the augmented venous responsiveness to NO in nasal mucosae of repeatedly antigen challenged rats.     

Post-liberation cleavage of signal peptides is catalyzed by the site-2 protease (S2P) in bacteria

A signal peptide (SP) is cleaved off from presecretory proteins by signal peptidase during or immediately after insertion into the membrane. In metazoan cells, the cleaved SP then receives proteolysis by signal peptide peptidase, an intramembrane-cleaving protease (I-CLiP). However, bacteria lack any signal peptide peptidase member I-CLiP, and little is known about the metabolic fate of bacterial SPs. Here we show that Escherichia coli RseP, an site-2 protease (S2P) family I-CLiP, introduces a cleavage into SPs after their signal peptidase-mediated liberation from preproteins. A Bacillus subtilis S2P protease, RasP, is also shown to be involved in SP cleavage. These results uncover a physiological role of bacterial S2P proteases and update the basic knowledge about the fate of signal peptides in bacterial cells.     

Lansoprazole for secondary prevention of gastric or duodenal ulcers associated with long-term low-dose aspirin therapy: results of a prospective, multicenter, double-blind, randomized, double-dummy, active-controlled trial

Background

The efficacy of low-dose lansoprazole has not been established for the prevention of recurrent gastric or duodenal ulcers in those receiving long-term low-dose aspirin (LDA) for cardiovascular and cerebrovascular protection. This study sought to examine the efficacy of low-dose lansoprazole (15?mg once daily) for the secondary prevention of LDA-associated gastric or duodenal ulcers.

Methods

Patients were randomized to receive lansoprazole 15?mg daily (n?=?226) or gefarnate 50?mg twice daily (n?=?235) for 12?months or longer in a prospective, multicenter, double-blind, randomized active-controlled trial, followed by a 6-month follow-up study with open-label lansoprazole treatment. The study utilized 94 sites in Japan and 461 Japanese patients with a history of gastric or duodenal ulcers who required long-term LDA therapy for cardiovascular and cerebrovascular disease.

Results

The primary endpoint was the development of gastric or duodenal ulcers. The cumulative incidence of gastric or duodenal ulcers on days 91, 181, and 361 from the start of the study was calculated by the Kaplan?CMeier method as 1.5, 2.1, and 3.7%, respectively, in the lansoprazole group versus 15.2, 24.0, and 31.7%, respectively, in the gefarnate group. The risk of ulcer development was significantly (log-rank test, P?Conclusion Lansoprazole was superior to gefarnate in reducing the risk of gastric or duodenal ulcer recurrence in patients with a definite history of gastric or duodenal ulcers who required long-term LDA therapy.     

Clinical importance of serum hepatitis B surface antigen levels in chronic hepatitis B

Quantitative serology for hepatitis B surface antigen (HBsAg) is a new candidate marker for prediction of clinical outcome. The aim of this study was to investigate the clinical significance of quantifying HBsAg in patients with hepatitis B virus (HBV) infection. A total of 424 patients who tested positive for HBsAg and were referred to Chiba University Hospital between January 1985 and April 2008 were included in the study, and the following characteristics were analyzed: age, gender, status of hepatitis B e antigen (HBeAg), alanine aminotransferase level (ALT), HBV DNA level, number of platelets and development of hepatocellular carcinoma. Measurement of HBsAg was performed using the chemiluminescent enzyme immunoassay method. The study group consisted of 239 men and 185 women, and their average age was 40.6 ± 14.0 years. HBsAg showed a positive correlation with HBV DNA level (Pearson's product moment correlation, r = 0.586, P < 0.001) and a weak inverse correlation with age (r = 0.3325, P < 0.001). A control study, matched with age and sex, was performed between two groups with and without HBeAg seroconversion during follow-up period. Compared with the age and sex-matched controls, the change in HBsAg levels per year showed a significant decrease 2 years before seroconversion (paired t-test, P < 0.05). The serial measurement of quantitative HBsAg level has the possibility of predicting the occurrence of HBeAg seroconversion.     

Proteomic identification of hippocampal proteins vulnerable to oxidative stress in excitotoxin-induced acute neuronal injury

Excitotoxicity is involved in seizure-induced acute neuronal death, hypoxic-ischemic encephalopathy, and chronic neurodegenerative conditions such as Alzheimer's disease. Although oxidative stress has been implicated in excitotoxicity, the target proteins of oxidative damage during the course of excitotoxic cell death are still unclear. In the present study, we performed 2D-oxyblot analysis and mass spectrometric amino acid sequencing to identify proteins that were vulnerable to oxidative damage in the rat hippocampus during kainic acid (KA)-induced status epilepticus. We first investigated the time course in which oxidative protein damage occurred using immunohistochemistry. Carbonylated proteins, a manifestation of protein oxidation, were detected in hippocampal neurons as early as 3h after KA administration. Immunoreactivity for 8-hydroxy-2'-deoxyguanosine (8-OHdG) was also elevated at the same time point. The increase in oxidative damage to proteins and DNA occurred concomitantly with the early morphological changes in KA-treated rat hippocampus, i.e., changes in chromatin distribution and swelling of rough endoplasmic reticulum and mitochondria, which preceded the appearance of morphological features of neuronal death such as pyknotic nuclei and hypereosinophilic cytoplasm. Proteomic analysis revealed that several hippocampal proteins were consistently carbonylated at this time point, including heat shock 70kDa protein 4, valosin-containing protein, mitochondrial inner membrane protein (mitofilin), α-internexin, and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein (14-3-3 protein). We propose that oxidative damage to these proteins may be one of the upstream events in the molecular pathway leading to excitotoxic cell death in KA-treated rat hippocampus, and these proteins may be targets of therapeutic intervention for seizure-induced neuronal death.