Genetic Polymorphisms of IL-17F and TRAF3IP2 Could Be Predictive Factors of the Long-Term Effect of Infliximab against Crohn's Disease.

BACKGROUND: We aimed to identify certain genes related to response to infliximab (IFX) and biomarkers to predict the IFX effect for Japanese Crohn's disease (CD) patients by performing an association study of single nucleotide polymorphisms (SNPs) in candidate genes in the interleukin- (IL-) 17 signaling pathway with response to IFX after 1 year of treatment. METHODS: A total of 103 patients were divided into two groups, responders and nonresponders. Twenty-eight tag SNPs in 5 genes were genotyped. The frequencies of alleles and genotypes of each SNP were compared between responders and nonresponders in three different inheritance models. A genetic test was performed using a combination of the associated SNPs as biomarkers. RESULTS: Multivariate logistic regression analysis indicated that the four variable factors, concomitant use of immunomodulators, penetrating disease, a G/G genotype of rs766748 in IL-17F, and a C/C or C/A genotype of rs1883136 in TRAF3IP2, independently contributed to response to IFX after 1 year of treatment. Genetic test using the polymorphisms of these genes perfectly predicted the responder and nonresponder CD patients with both concomitant use of immunomodulators and penetrating disease. CONCLUSION: IL17F and TRAF3IP2 are one of IFX-related genes, useful as biomarkers of IFX response, and may be target molecules for new therapeutic drugs.

Daily inhalation of α-pinene in mice: effects on behavior and organ accumulation.

In phytotherapy, essential oils tend to be used daily for a period of days or weeks, rather than in a single application. However, the literature contains very little information on repeated use of essential oils. In this study, we investigated the effects on behavior and the accumulation in the brain and liver of α-pinene, an essential oil component, when inhaled by mice. Animals were individually housed in cages for 1 week. Mice inhaled α-pinene or water vapor (negative control) for 90 min/day for 1 day, 3 days, or 5 days, and they were then submitted to the elevated plus maze test for 10 min. We used gas chromatography with flame ionization detection to quantify concentrations of α-pinene in the brain and liver. There was significant anxiolytic-like activity, which remained constant for the 5 days' inhalation of α-pinene. On the other hand, the accumulation of α-pinene in the brain and liver peaked on the third day of inhalation. The existence of stress related to the new environment appears to have affected the change in the accumulation of α-pinene in the internal organs, keeping the anxiolytic-like action constant.

Impact of NAD(P)H oxidase-derived reactive oxygen species on coronary arterial remodeling: a comparative intravascular ultrasound and histochemical analysis of atherosclerotic lesions.

BACKGROUND: Coronary arterial remodeling, which is a response to the growth of atherosclerotic plaques, is associated with plaque vulnerability. Oxidative stress induced by reactive oxygen species (ROS) via NAD(P)H oxidase in the vasculature also plays a crucial role in the pathogenesis of atherosclerosis-based cardiovascular disease. In this study, the relationship between coronary arterial remodeling and ROS generation was examined by comparing preinterventional intravascular ultrasound findings of atherosclerotic lesions to the histochemical findings of corresponding specimens obtained by directional coronary atherectomy. METHODS AND RESULTS: Predirectional coronary atherectomy intravascular ultrasound images of 49 patients were analyzed. The remodeling index was calculated by dividing the target-lesion external elastic membrane cross-sectional area by the reference-segment external elastic membrane cross-sectional area. Expansive remodeling was defined as a remodeling index of >1.0. ROS generation and NAD(P)H oxidase p22(phox) expression in directional coronary atherectomy specimens were evaluated using the dihydroethidium staining method and immunohistochemistry as the ratio of the positive area to the total surface area in each specimen, respectively. ROS generation and p22(phox) expression were significantly greater in lesions with expansive remodeling than in lesions without remodeling (0.18+/-0.12 versus 0.03+/-0.02, P<0.0001, 0.10+/-0.08 versus 0.04+/-0.05, P=0.0039, respectively). Both ROS generation and p22(phox) expression significantly correlated with the intravascular ultrasound-derived remodeling index (r=0.77, P<0.0001, r=0.53, P<0.0001, respectively). CONCLUSIONS: Simultaneous examination with intravascular ultrasound and immunohistochemistry analyses suggests that NAD(P)H oxidase-derived ROS is related to the coronary arterial remodeling process associated with plaque vulnerability.

A novel neuroprotectant against retinal ganglion cell damage in a glaucoma model and an optic nerve crush model in the rat.

PURPOSE: To investigate the effects of repeated treatments with a neuroprotective compound, R(-)-1-(benzo [b] thiophen-5-yl)-2-[2-(N, N-diethylamino) ethoxy] ethanol hydrochloride (T-588), on retinal ganglion cell (RGC) survival in rat eyes with elevated intraocular pressure (IOP) or after optic nerve crush. METHODS: An increase in IOP was induced by a single laser treatment to the trabecular meshwork in one eye of adult Wistar rats. Crush injury was unilaterally produced by clipping the optic nerve 2 mm behind the globe. RGC density was estimated by counting fluorescent dye-labeled cells in the flatmount of the retina. The optic nerve damage in the crush model was also evaluated histologically. RESULTS: In the elevated IOP model, RGC survival decreased to 72.9% +/- 3.8% (mean +/- SEM) of that of the contralateral control eye on the eighth day after laser irradiation. Repeated treatments with T-588 at 30 mg/kg twice daily significantly enhanced RGC survival (86.0% +/- 2.2%, P = 0.0242) without the reduction of IOP. In the optic nerve crush model, RGC survival diminished to 37.2% +/- 8.4% of that of the contralateral control eye after 4 weeks. Repeated applications with T-588 at 10 mg/kg twice daily significantly enhanced RGC survival (77.8% +/- 2.1%, P = 0.0038). Histologically, the rat optic nerve in the group treated with T-588 at 10 mg/kg retained a near-normal morphology. CONCLUSIONS: T-588 has a neuroprotective effect against RGC death caused by elevated IOP and optic nerve crush in the rat.

Superoxide generation in directional coronary atherectomy specimens of patients with angina pectoris: important role of NAD(P)H oxidase.

OBJECTIVE: NADH/NADPH oxidase is an important source of reactive oxygen species (ROS) in the vasculature. Recently, we demonstrated that p22(phox), an essential component of this oxidase, was expressed in human coronary arteries and that its expression was enhanced with the progression of atherosclerosis. The present study was undertaken to investigate its functional importance in the pathogenesis of coronary artery disease. For this aim, the expression of p22(phox), the distribution of oxidized low density lipoprotein (LDL), and the generation of ROS in directional coronary atherectomy (DCA) specimens were examined. METHODS AND RESULTS: DCA specimens were obtained from patients with stable or unstable angina pectoris. The distribution of p22(phox) and of oxidized LDL was examined by immunohistochemistry. The generation of superoxide in DCA specimens was assessed by the dihydroethidium method and lucigenin-enhanced chemiluminescence. ROS were closely associated with the distribution of p22(phox) and oxidized LDL. Not only inflammatory cells but also smooth muscle cells and fibroblasts generated ROS. There was a correlation between ROS and the expression of p22(phox) or oxidized LDL. The generation of ROS was significantly higher in unstable angina pectoris compared with stable angina pectoris. CONCLUSIONS: ROS generated by p22(phox)-based NADH/NADPH oxidase likely mediate the oxidative modification of LDL and might play a major role in pathogenesis of atherosclerotic coronary artery disease.