Chronic allergen challenge induces bronchial mast cell accumulation in BALB/c but not C57BL/6 mice and is independent of IL-9

As genetically engineered mutant mice deficient in single genes are usually generated on a C57BL/6 background, to study mast cell trafficking in mutant mice, we initially investigated whether mast cells accumulated in bronchi in C57BL/6 mice challenged with OVA allergen acutely or chronically for 1 to 3 months. The total number of bronchial mast cells were quantitated using toluidine blue staining in airways of different sizes, i.e. , small (<90 µm), medium (90–155 µm), or large (>150 µm) airways. Non-OVA challenged and acute OVA challenged mice (C57BL/6 and BALB/c) had no detectable bronchial mast cells. Chronic OVA challenge in BALB/c mice for 1 or 3 months induced a significant increase in the number of bronchial mast cells in small-, medium-, and large-sized airways but minimal change in the number of bronchial mast cells in C57BL/6 mice. Both BALB/c and C57BL/6 mice developed significant lung eosinophilia following acute or chronic OVA challenge. Studies of IL-9-deficient mice on a BALB/c background demonstrated a significant increase in the number of bronchial mast cells in IL-9-deficient mice suggesting that IL-9 was not required for the bronchial accumulation of mast cells. Overall, these studies demonstrate that the chronic OVA challenge protocol we have utilized in BALB/c mice provides a model to study the mechanism of bronchial mast cell accumulation and that bronchial mast cell accumulation in chronic OVA challenged mice is independent of IL-9 in this model

Targeted Inactivation of p12Cdk2ap1, CDK2 Associating Protein 1, Leads to Early Embryonic Lethality

Targeted disruption of murine Cdk2ap1, an inhibitor of CDK2 function and hence G1/S transition, results in the embryonic lethality with a high penetration rate. Detailed timed pregnancy analysis of embryos showed that the lethality occurred between embryonic day 3.5 pc and 5.5 pc, a period of implantation and early development of implanted embryos. Two homozygous knockout mice that survived to term showed identical craniofacial defect, including a short snout and a round forehead. Examination of craniofacial morphology by measuring Snout Length (SL) vs. Face Width (FW) showed that the Cdk2ap1+/− mice were born with a reduced SL/FW ratio compared to the Cdk2ap1+/+ and the reduction was more pronounced in Cdk2ap1−/− mice. A transgenic rescue of the lethality was attempted by crossing Cdk2ap1+/− animals with K14-Cdk2ap1 transgenic mice. Resulting Cdk2ap1+/−:K14-Cdk2ap1 transgenic mice showed an improved incidence of full term animals (16.7% from 0.5%) on a Cdk2ap1−/− background. Transgenic expression of Cdk2ap1 in Cdk2ap1−/−:K14-Cdk2ap1 animals restored SL/FW ratio to the level of Cdk2ap1+/−:K14-Cdk2ap1 mice, but not to that of the Cdk2ap1+/+:K14-Cdk2ap1 mice. Teratoma formation analysis using mESCs showed an abrogated in vivo pluripotency of Cdk2ap1−/− mESCs towards a restricted mesoderm lineage specification. This study demonstrates that Cdk2ap1 plays an essential role in the early stage of embryogenesis and has a potential role during craniofacial morphogenesis

Two Naturally Occurring Terpenes, Dehydrocostuslactone and Costunolide, Decrease Intracellular GSH Content and Inhibit STAT3 Activation

The main purpose of the present study is to envisage the molecular mechanism of inhibitory action ofdehydrocostuslactone (DCE) andcostunolide (CS), two naturally occurring sesquiterpene lactones, towards the activation of signal transducer and activator of transcription 3 (STAT3). We report that, in human THP-1 cell line, they inhibit IL-6-elicited tyrosine phosphorylation of STAT3 and its DNA binding activity with EC50 of 10 µM with concomitantdown-regulation ofthe phosphorylation of the tyrosine Janus kinases JAK1, JAK2 and Tyk2. Furthermore, these compounds that contain an α-β-unsatured carbonyl moiety and function as potent Michael reaction acceptor, induce a rapid drop in intracellular glutathione (GSH) concentration by direct interaction with it, thereby triggering S-glutathionylation of STAT3. Dehydrocostunolide (HCS), the reduced form of CS lacking only the α-β-unsaturated carbonyl group, fails to exert any inhibitory action. Finally, the glutathione ethylene ester (GEE), the cell permeable GSH form, reverts the inhibitory action of DCE and CS on STAT3 tyrosine phosphorylation. We conclude that these two sesquiterpene lactones are able to induce redox-dependent post-translational modification of cysteine residues of STAT3 protein in order to regulate its function

Investigation of Epistasis Between DAOA and 5HTR1A Variants on Clinical Outcomes in Patients with Schizophrenia.

Purpose: In two recent studies of our group, rs10042486, a single-nucleotide polymorphism (SNP) within 5HTR1A, and rs7139958, a SNP within the d-amino acid oxidase activator (DAOA) were found to be associated with clinical improvement, as detected by the positive symptom subscale of the Positive and Negative Symptoms Scale (PANSS) in a sample 221 Korean schizophrenia patients treated with various antipsychotics. Methods: The existence of possible epistatic interactions between rs10042486 and rs7139958 influencing PANSS-positive subscale improvement scores in the same sample was investigated. Results: No significant epistatic interaction was observed. Furthermore, the independent associations observed between rs10042486, rs7139958, and PANSS-positive subscale improvement scores in earlier studies were no longer significant when they were included in our model. Conclusion: Although limited by some methodological shortcomings, our results preliminarily point to the possibility that positive genetic associations observed in some samples could not be replicated in different samples because of the existence of consistent differences in the genotype frequencies of other genetic polymorphisms that epistatically interact with the specific variants under investigation in a given study

The association of personality trait on treatment outcomes in patients with chronic prostatitis/chronic pelvic pain syndrome: an exploratory study.

OBJECTIVE: This study investigated the association of personality traits with the baseline clinical characteristics and treatment outcomes of patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: Subjects were evaluated at baseline and at week 12 following routine treatment for CP/CPPS using the Korean version of the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) to measure the severity of CP/CPPS; the Korean version of the Patient Health Questionnaire-9 (PHQ-9) to assess depression; the Korean version of the Patient Health Questionnaire-15 (PHQ-15) to evaluate somatization; and the Korean version of the EuroQol Questionnaire-5 Dimensions (EQ-5D), specifically the EQ-5D utility index and the EQ-5D visual analog scale (EQ-5D VAS), to assess quality of life (QoL). Personality traits including extraversion, agreeableness, conscientiousness, neuroticism, and openness were determined at baseline using the 44-item Big Five Inventory (BFI). The influence of personality traits on the clinical characteristics and treatment outcomes of patients with CP/CPPS was assessed using relevant statistical analyses. RESULTS: Neuroticism was associated with a significantly poorer treatment response and higher levels of depression and somatization. Extraversion, agreeableness, and conscientiousness had some influence on clinical characteristics but openness did not affect overall symptoms or the treatment response in patients with CP/CPPS. CONCLUSIONS: We found that neuroticism may be the most important personality trait associated with treatment response and the severity of depression and somatization in patients with CP/CPPS. However, our exploratory findings should be confirmed by additional studies with adequate power and improved designs

Investigation of possible epistatic interactions between GRIA2 and GRIA4 variants on clinical outcomes in patients with major depressive disorder.

Abstract OBJECTIVES: To investigate the effects of glutamate receptor, ionotropic, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) 2 (GRIA2) rs4260586 and glutamate receptor, ionotropic, AMPA 4 (GRIA4) rs10736648 single nucleotide polymorphisms (SNPs) on response to antidepressants in Korean patients with major depressive disorder (MDD), and to ascertain whether epistatic interactions might exist between these SNPs. METHODS: In this retrospective analysis, patients were assessed at hospital admission and discharge using the Montgomery-\uc5sberg depression rating scale (MADRS). A multiple regression model was employed to investigate the effects of the two SNP variants on clinical/sociodemographic outcomes relating to MDD. RESULTS: Out of 145 Korean patients, the presence of both GRIA2 rs4260586 and GRIA4 rs10736648 polymorphisms had no significant association with MADRS improvement scores or other clinical/sociodemographic variables. CONCLUSIONS: These data potentially suggest a lack of epistatic interaction between GRIA2 and GRIA4 variants, regarding clinical outcomes in patients with MDD. The study was limited by small sample size, use of different antidepressants and incomplete coverage of genes under investigation. Future research should include larger patient samples treated with different antidepressants, analysis of different SNPs and/or investigation of different gene-gene interactions within the glutamatergic system. KEYWORDS: AMPA 2 (GRIA2), AMPA 4 (GRIA4), Glutamate receptor, epistasis, glutamate receptor, glutamatergic, ionotropic, major depression, single nucleotide polymorphis

Case-control association study of 36 single-nucleotide polymorphisms within 10 candidate genes for major depression and bipolar disorder

In this study we investigated 36 single nucleotide polymorphisms within 10 genes previously associated with major depression and bipolar disorder, as well as with the response to their treatment (ABCB1, ABCB4, TAP2, CLOCK, CPLX1, CPLX2, SYN2, NRG1, 5HTR1A and GPRIN2). No association with mood disorders and clinical outcomes was observed