Tumor suppressive role of sestrin2 during colitis and colon carcinogenesis

The mTOR complex 1 (mTORC1) and endoplasmic reticulum (ER) stress pathways are critical regulators of intestinal inflammation and colon cancer growth. Sestrins are stress-inducible proteins, which suppress both mTORC1 and ER stress; however, the role of Sestrins in colon physiology and tumorigenesis has been elusive due to the lack of studies in human tissues or in appropriate animal models. In this study, we show that human SESN2 expression is elevated in the colon of ulcerative colitis patients but is lost upon p53 inactivation during colon carcinogenesis. In mouse colon, Sestrin2 was critical for limiting ER stress and promoting the recovery of epithelial cells after inflammatory injury. During colitis-promoted tumorigenesis, Sestrin2 was shown to be an important mediator of p53’s control over mTORC1 signaling and tumor cell growth. These results highlight Sestrin2 as a novel tumor suppressor, whose downregulation can accelerate both colitis and colon carcinogenesis

Clarithromycin expands CD11b+Gr-1+ MDSC-like cells

Macrolides are used to treat various inflammatory diseases owing to their immunomodulatory properties; however, little is known about their precise mechanism of action. In this study, we investigated the functional significance of the expansion of myeloid-derived suppressor cell (MDSC)-like CD11b+Gr-1+ cells in response to the macrolide antibiotic clarithromycin (CAM) in mouse models of shock and post-influenza pneumococcal pneumonia as well as in humans. Intraperitoneal administration of CAM markedly expanded splenic and lung CD11b+Gr-1+ cell populations in naïve mice. Notably, CAM pretreatment enhanced survival in a mouse model of lipopolysaccharide (LPS)-induced shock. In addition, adoptive transfer of CAM-treated CD11b+Gr-1+ cells protected mice against LPS-induced lethality via increased IL-10 expression. CAM also improved survival in post-influenza, CAM-resistant pneumococcal pneumonia, with improved lung pathology as well as decreased interferon (IFN)-γ and increased IL-10 levels. Adoptive transfer of CAM-treated CD11b+Gr-1+ cells protected mice from post-influenza pneumococcal pneumonia. Further analysis revealed that the CAM-induced CD11b+Gr-1+ cell expansion was dependent on STAT3-mediated Bv8 production and may be facilitated by the presence of gut commensal microbiota. Lastly, an analysis of peripheral blood obtained from healthy volunteers following oral CAM administration showed a trend toward the expansion of human MDSC-like cells (Lineage−HLA-DR−CD11b+CD33+) with increased arginase 1 mRNA expression. Thus, CAM promoted the expansion of a unique population of immunosuppressive CD11b+Gr-1+ cells essential for the immunomodulatory properties of macrolides

Association between Dopamine D4 Receptor Gene Polymorphism and Scores on a Continuous Performance Test in Korean Children with Attention Deficit Hyperactivity Disorder

OBJECTIVE: The aim of this study was to evaluate the association between a variable number of tandem repeats polymorphism at the dopamine D4 receptor gene (DRD4) and the performance of children with attention deficit hyperactivity disorder (ADHD) in a continuous performance test (CPT). METHODS: This study included 72 ADHD children (mean age=9.39+/-2.05 years) who were recruited from one child psychiatric clinic. The omission errors, commission errors, reaction time and reaction standardization in the CPT were computed. The number of 48-base pairs tandem repeats in the exon III of DRD4 was analyzed in a blind manner. RESULTS: The homozygosity of the 4-repeat allele at DRD4 was significantly associated with fewer commission errors (t=2.364, df=28.685, p=0.025) and standard deviation of reaction time (t=2.351, df=24.648, p=0.027) even after adjusting for age. The results of analyses of CPT measured values among three groups showed that the group with higher frequency of the 4-repeat allele showed a lower mean score of commission errors (F=4.268, df=2, p=0.018). CONCLUSION: These results suggest a protective role of 4-repeat allele of the DRD4 polymorphisms on commission errors in the CPT in children with ADHDope

Greater Impairment in Negative Emotion Evaluation Ability in Patients with Paranoid Schizophrenia

To explore whether or not patients with schizophrenia display a more profound impairment of negative emotion processing, we assessed the implicit evaluation of positive and negative emotional stimuli. Twenty patients with schizophrenia (9 paranoid, 11 non-paranoid) and 22 normal controls were instructed to classify emotional pictures according to the intrinsic valence if the pictures were black and white. If the stimuli were color-filtered, participants were instructed to press the positive/negative response key according to the extrinsic valence (assigned valence of color). The error rates of the color-filtered stimuli were used as dependent measures. Normal controls made more errors on trials of the positive pictures when the correct response was the negative response key than when the correct response was the positive response key. The reverse was true on trials of the negative pictures. Patients with schizophrenia, especially paranoid schizophrenia, committed more errors in trials of the positive pictures when the correct response key was the negative response key. However, the reverse was not true on trials of the negative pictures. These findings suggest that patients with paranoid schizophrenia might suffer from an impaired ability to evaluate negative emotions and have a loosening of association within their negative emotional networks

Effects of the common polymorphism in the human aldehyde dehydrogenase 2 (ALDH2) gene on the lung

BackgroundAldehyde dehydrogenases (ALDHs) play a major role in detoxification of aldehydes. High expression of ALDHs is a marker for stem cells of many organs including the lungs. A common polymorphism in ALDH2 gene (ALDH2*2) results in inactivation of the enzyme and is associated with alcohol flushing syndrome and increased risk for cardiovascular and Alzheimer’s diseases and some cancers. The effect of this ALDH2 polymorphism on the lung and its stem cells has not been thoroughly examined.MethodsWe examined the association between the ALDH2*2 allele and lung function parameters in a population of healthy individuals. We also examined its association with the incidence of asthma and COPD in patient cohorts. We used the in vitro colony forming assay to detect the effect of the polymorphism on lung epithelial stem cells from both primary human surgical samples and Aldh2*2 transgenic (Tg) and Aldh2 −/− mice. Response to acute and chronic lung injuries was compared between wild type (WT), Aldh2*2 Tg and Aldh2 −/− mice.ResultsIn humans, the ALDH2*2 allele was associated with lower FEV1/FVC in the general population, but not with the development of asthma or COPD. Both the bronchial and lung epithelium carrying the ALDH2*2 allele showed a tendency for lower colony forming efficiency (CFE) compared to ALDH2 allele. In mice, the tracheal epithelial thickness, nuclear density, and number of basal stem cells were significantly lower in Aldh2 −/− and Aldh2*2 Tg adult mice than in WT. Electron microscopy showed significantly increased number of morphologically abnormal mitochondria in the trachea of Aldh2 −/− mice. Aldh2 −/− tracheal and lung cells showed higher ROS levels and fewer functional mitochondria than those from WT mice. No significant differences were detected when tracheal and lung epithelial stem cells were examined for their in vitro CFE. When exposed to chronic cigarette smoke, Aldh2*2 Tg mice were resistant to emphysema development, whereas influenza infection caused more epithelial damage in Aldh2 −/− mice than in WT mice.ConclusionsALDH2 polymorphism has several subtle effects on the lungs, some of which are similar to changes observed during normal aging, suggesting a “premature lung aging” effect