Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1

Recognition of double-stranded RNA activates interferon-regulatory factor 3 (IRF3)-dependent expression of antiviral factors. Although the molecular mechanisms underlying the activation of IRF3 have been studied, the mechanisms by which IRF3 activity is reduced have not. Here we report that activation of IRF3 is negatively regulated by the peptidyl-prolyl isomerase Pin1. After stimulation by double-stranded RNA, induced phosphorylation of the Ser339-Pro340 motif of IRF3 led to its interaction with Pin1 and finally polyubiquitination and then proteasome-dependent degradation of IRF3. Suppression of Pin1 by RNA interference or genetic deletion resulted in enhanced IRF-3-dependent production of interferon-beta, with consequent reduction of virus replication. These results elucidate a previously unknown mechanism for controlling innate antiviral responses by negatively regulating IRF3 activity via Pin1.     

Therapeutic potential of histamine H3 receptor agonist for the treatment of obesity and diabetes mellitus

Histamine H3 receptors (H3Rs) are located on the presynaptic membranes and cell soma of histamine neurons, where they negatively regulate the synthesis and release of histamine. In addition, H3Rs are also located on nonhistaminergic neurons, acting as heteroreceptors to regulate the releases of other amines such as dopamine, serotonin, and norepinephrine. The present study investigated the effects of H3R ligands on appetite and body-weight regulation by using WT and H3R-deficient mice (H3RKO), because brain histamine plays a pivotal role in energy homeostasis. The results showed that thioperamide, an H3R inverse agonist, increases, whereas imetit, an H3R agonist, decreases appetite and body weight in diet-induced obese (DiO) WT mice. Moreover, in DiO WT mice, but not in DiO H3RKO mice, imetit reduced fat mass, plasma concentrations of leptin and insulin, and hepatic triglyceride content. The anorexigenic effects of imetit were associated with a reduction in histamine release, but a comparable reduction in histamine release with alpha-fluoromethylhistidine, an inhibitor of histamine synthesis, increased appetite. Moreover, the anorexigenic effects of imetit were independent of the melanocortin system, because imetit comparably reduced appetite in melanocortin 3 and 4 receptor-deficient mice. The results provide roles of H3Rs in energy homeostasis and suggest a therapeutic potential for H3R agonists in the treatment of obesity and diabetes mellitus.     

Enhancement of immediate allergic reactions by trichloroethylene ingestion via drinking water in mice

The prevalence of allergic disorders is increasing in industrial areas and countries. Recent reports suggest that some environmental pollutants are related to the increase in allergic diseases, and we reported that trichloroethylene (TCE) is a candidate chemical for causing the increase of allergic diseases, as TCE ingestion is associated with allergic reaction enhancement. TCE is widely used in many industries, and it is commonly detected as an environmental contaminant. This study aimed to clarify the immunotoxicity of TCE in detail. BALB/c mice were treated with TCE dissolved in drinking water for 2 and 4 weeks, and the mice were immunized with ovalbumin (OVA)/aluminum hydroxide (alum) twice. On the final day of the TCE exposure period, we measured the active cutaneous anaphylaxis (ACA) reaction and the antigen- specific IgE level in serum as well as the histamine level at the allergic reaction site and assayed the proliferation rates of splenocytes collected from the animals. The ACA reaction was enhanced by TCE ingestion. The OVA specific IgE level in mice was enhanced by TCE exposure for 4 weeks. The proliferation rate of the splenocytes was enhanced by TCE ingestion for 2 and 4 weeks. The enhancement of the ACA reaction by TCE ingestion via drinking water may be related to the increase in splenocyte proliferation. On the other hand, it may be weakly related to antigen-specific IgE production.     

Ablative margin states by magnetic resonance imaging with ferucarbotran in radiofrequency ablation for hepatocellular carcinoma can predict local tumor progression

Background

Our aim was to determine how well ablative margin (AM) grading assessed by magnetic resonance imaging (MRI) with ferucarbotran administered prior to radiofrequency ablation (RFA) predicts local tumor progression in comparison with enhanced computed tomography (CT).

Methods

101 hepatocellular carcinomas were treated by RFA after ferucarbotran administration. We performed T2*-weighted MRI after 1 week and enhanced CT after 1 month. The assessment was categorized in three grades: AM(+): high-intensity area with continuous low-intensity rim; AM zero: high-intensity area with discontinuous low-intensity rim; and AM(?): high-intensity area extending beyond the low-intensity rim.

Results

AM(+), AM zero, AM(?) and indeterminable were found in 47, 36, 8 and 10 nodules, respectively. The overall agreement rate between MRI and enhanced CT for the diagnosis of AM was 71.3 %. The κ coefficient was 0.523 (p < 0.001), indicating moderate agreement. Multivariate logistic regression showed that a significant factor for the achievement of AM(+) on MRI was only segment location (odds ratio 5.9, non-segment 4 + 8 vs. segment 4 + 8). The cumulative local tumor progression rates (4.4, 7.6, and 7.6 % in 1, 2, and 3 years) in 47 AM(+) nodules were significantly lower than those (13.9, 33.4, and 41.8 % in 1, 2, and 3 years) in 36 AM zero nodules. A multivariate Cox proportional hazards model identified contiguous vessels (odds ratio 12.0) and AM(+) on MRI (odds ratio 0.19) as independent factors for local tumor progression.

Conclusion

AM assessment by MRI using ferucarbotran can predict local tumor progression after RFA and enable early and less invasive diagnosis.     

Complex Müllerian malformation without any present classification: Unilateral ovarian and tubal absence with an arcuate uterus

Müllerian duct anomalies are known to cause infertility and reproductive problems. The true incidence of such abnormalities is not well defined. The most widely accepted method of classification for a Müllerian duct anomaly is the American Society of Reproductive Medicine classification (1988). However, there are some rare anomalies inconsistent with the current classification. Herein, we report a rare case of Müllerian duct anomaly, unilateral ovarian and tubal absence with an arcuate uterus. The failure of the Müllerian ducts to canalize can also lead to the development of a unicornuate uterus and adnexal agenesis. An arcuate uterus indicates incomplete septal absorption after normal fusion of the Müllerian ducts. Therefore, its coexistence with adnexal absence and an arcuate uterus is considered to be extremely unlikely.     

Mitochondrial Delivery of Bongkrekic Acid Using a MITO-Porter Prevents the Induction of Apoptosis in Human HeLa Cells

The fact that mitochondrial dysfunction has been implicated in a variety of human diseases suggests that they would be expected as a target organelle for these diseases. Bongkrekic acid (BKA) is a chemical that functions as a ligand of the adenine nucleotide translocator and is known to potently inhibit the mitochondrial permeability transition that is associated with apoptosis. Thus, delivering it to mitochondria would be an innovative therapy for the treatment of mitochondrial diseases that are largely associated with apoptosis. Here, we report on the use of a MITO-Porter, an innovative nanocarrier for mitochondrial delivery via mitochondrial membrane fusion, for delivering BKA to mitochondria. We first constructed a BKA-MITO-Porter, in which BKA is contained in lipid envelopes of a MITO-Porter. We then confirmed that the BKA–MITO-Porter was efficiently internalized into cells and is delivered to mitochondria, similar to a conventional MITO-Porter. Moreover, we evaluated the antiapoptosis effect of the BKA–MITO-Porter in HeLa cells by measuring caspase 3/7 activity. The findings confirmed that the BKA–MITO-Porter showed a strong antiapoptosis effect compared with naked BKA. The results reported here demonstrate its potential for the use in therapies aimed at mitochondrial diseases, as a mitochondrial medicine candidate. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1008–1015, 2013     

Development of Meloxicam Salts with Improved Dissolution and Pharmacokinetic Behaviors in Rats with Impaired Gastric Motility

Purpose

Because of its poor solubility in acidic solution, oral absorption and efficacy of meloxicam (MEL) may be reduced in severe pain patients with impaired gastric motility. The present study aimed to develop salt forms to overcome these drawbacks.

Method

Upon MEL salt screening with eight counterions, five MEL salts were obtained. The physicochemical properties of these MEL salts were characterized with a focus on morphology, crystallinity, thermal behavior, dissolution, and chemical/photo-stability. Pharmacokinetic profiling of an orally administered MEL salt was also carried out in both normal rats and rats treated with propantheline for the suppression of gastric motility.

Results

Dissolution behaviors for all obtained MEL salts were markedly better than that of crystalline MEL; in particular, the initial dissolution rate of arginine MEL dihydrate (MEL/Arg) was ca. 14-fold higher than that of crystalline MEL. MEL/Arg was found to be chemically and physically stable. There was ca. 18-fold reduction of AUC_0–4 for orally dosed crystalline MEL (1.0 mg-MEL/kg) in propantheline-treated rats compared with that in normal rats. In contrast, there was only a ca. 3-fold difference in AUC_0–4 between normal and propantheline-treated rats after oral administration of MEL/Arg (1.0 mg-MEL/kg).

Conclusion

From these findings, MEL/Arg may provide improved oral absorption in severe pain patients.     

Neurodevelopmental aspects of spatial navigation: a virtual reality fMRI study.

Navigation in spatial contexts has been studied in diverse species, yielding insights into underlying neural mechanisms and their phylogenetic progression. Spatial navigation in humans is marked by age-related changes that may carry important implications for understanding cortical development. The emergence of "allocentric" processing, reflecting that ability to use viewer-independent spatial abstractions, represents an important developmental change. We used fMRI to map brain regions engaged during memory-guided navigation in a virtual reality environment in adolescents and adults. Blood oxygen level-dependent (BOLD) signal was monitored in eight adolescents and eight adults in a 1.5-T MRI scanner during three conditions: (1) memory-guided navigation (NAV); (2) arrow-guided navigation (ARROW); and (3) fixation (FIX). We quantified navigation ability during scanning and allocentric memory after scanning, based on subjects' ability to label a previously unseen, aerial view of the town. Adolescents and adults exhibited similar memory-guided navigation ability, but adults exhibited superior allocentric memory ability. Memory-guided navigation ability during scanning correlated with BOLD change between NAV/ARROWS in various regions, including a right frontal and right-anterior medial temporal lobe region. Age group and allocentric memory together explained significant variance in BOLD change in temporoparietal association cortex and the cerebellum, particularly in the left hemisphere. Consistent with developmental models, these findings relate maturation in the coding of spatial information to functional changes in a distributed, left-lateralized neural network.