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Wang H.,U.S. National Institutes of Health | Park O.,U.S. National Institutes of Health | Lafdil F.,U.S. National Institutes of Health | Shen K.,U.S. National Institutes of Health | And 5 more authors.

Liver regeneration triggered by two-thirds partial hepatectomy is accompanied by elevated hepatic levels of endotoxin, which contributes to the regenerative process, but liver inflammation and apoptosis remain paradoxically limited. Here, we show that signal transducer and activator of transcription 3 (STAT3), an important anti-inflammatory signal, is activated in myeloid cells after partial hepatectomy and its conditional deletion results in an enhanced inflammatory response. Surprisingly, this is accompanied by an improved rather than impaired regenerative response with increased hepatic STAT3 activation, which may contribute to the enhanced liver regeneration. Indeed, conditional deletion of STAT3 in both hepatocytes and myeloid cells results in elevated activation of STAT1 and apoptosis of hepatocytes, and a dramatic reduction in survival after partial hepatectomy, whereas additional global deletion of STAT1 protects against these effects. Conclusion: An interplay of myeloid and hepatic STAT3 signaling is essential to prevent liver failure during liver regeneration through tempering a strong innate inflammatory response mediated by STAT1 signaling. Copyright © 2010 by the American Association for the Study of Liver Diseases. Source

Ishiwata T.,University of Utah | Ishiwata T.,National Defense Medical College | Orosz A.,University of Utah | Orosz A.,National Institute on Alcohol Abuse and Alcoholism NIAAA | And 7 more authors.

Background: CryAB (HspB5) and HspB2, two small heat shock genes located adjacently in the vertebrate genome, are hypothesized to play distinct roles. Mice lacking both cryab and hspb2 (DKO) are viable and exhibit adult-onset degeneration of skeletal muscle but confounding results from independent groups were reported for cardiac responses to different stressful conditions (i.e., ischemia/reperfusion or pressure overload). To determine the specific requirements of HSPB2 in heart, we generated cardiac-specific HSPB2 deficient (HSPB2cKO) mice and examined their cardiac function under basal conditions and following cardiac pressure overload. Methodology/Principal Findings: Transverse aortic constriction (TAC) or sham surgery was performed in HSPB2cKO mice and their littermates (HSPB2wt mice). Eight weeks after TAC, we found that expression of several small HSPs (HSPB2, 5, 6) was not markedly modified in HSPB2wt mice. Both cardiac function and the hypertrophic response remained similar in HSPB2cKO and HSPB2wt hearts. In addition, mitochondrial respiration and ATP production assays demonstrated that the absence of HSPB2 did not change mitochondrial metabolism in basal conditions. However, fatty acid supported state 3 respiration rate (ADP stimulated) in TAC operated HSPB2cKO hearts was significantly reduced in compared with TAC operated HSPB2wt mice (10.5±2.2 vs. 12.8±2.5 nmol O2/min/mg dry fiber weight, P<0.05), and ATP production in HSPB2cKO hearts was significantly reduced in TAC compared with sham operated mice (29.8±0.2 vs. 21.1±1.8 nmol ATP/min/mg dry fiber weight, P<0.05). Although HSPB2 was not associated with mitochondria under cardiac stress, absence of HSPB2 led to changes in transcript levels of several metabolic and mitochondrial regulator genes. Conclusions/Significance: The present study indicates that HSPB2 can be replaced by other members of the multigene small HSP family under basal conditions while HSPB2 is implicated in the regulation of metabolic/mitochondrial function under cardiac stress such pressure overload. © 2012 Ishiwata et al. Source

Spanagel R.,University of Heidelberg | Noori H.R.,University of Heidelberg | Heilig M.,National Institute on Alcohol Abuse and Alcoholism NIAAA
Trends in Neurosciences

Alcohol is frequently consumed for stress relief, but the individual determinants and the temporal course of stress-induced alcohol use are not well understood. Preclinical studies may help shed light on these factors. We synthesize here the findings from numerous rodent studies of stress and alcohol interactions. Stress-induced alcohol consumption is age-dependent, has a high genetic load, and results from an interaction of the stress and reward systems. Specifically, glucocorticoids, acting within the nucleus accumbens (NAc), are important mediators of this stress-induced alcohol intake. In addition, increased activation of the corticotropin-releasing hormone (CRH) system within the extended amygdala appears to mediate stress-induced relapse. Finally, these preclinical studies have helped to identify several attractive targets for novel treatments of alcohol abuse and addiction. © 2014 Elsevier Ltd. Source

Mueller S.C.,National Institute of Mental Health NIMH | Mueller S.C.,Ghent University | Aouidad A.,University Pierre and Marie Curie | Gorodetsky E.,Mood and Anxiety Disorders Program NIMH | And 3 more authors.
Journal of the American Academy of Child and Adolescent Psychiatry

Objective: Minimal research links anxiety disorders in adolescents to regional gray matter volume (GMV) abnormalities and their modulation by genetic factors. Prior research suggests that a brain-derived neurotrophic factor (BNDF) Val66Met polymorphism may modulate such brain morphometry profiles. Method: Using voxel-based morphometry and magnetic resonance imaging, associations of BDNF and clinical anxiety with regional GMVs of anterior cingulate cortex, insula, amygdala, and hippocampus were examined in 39 affected (17 Met allele carriers, 22 Val/Val homozygotes) and 63 nonaffected adolescents (33 Met allele carriers, 41 Val/Val homozygotes). Results: Amygdala and anterior hippocampal GMVs were significantly smaller in patients than in healthy comparison adolescents, with a reverse pattern for the insula. Post-hoc regression analyses indicated a specific contribution of social phobia to the GMV reductions in the amygdala and hippocampus. In addition, insula and dorsal-anterior cingulate cortex (ACC) GMVs were modulated by BDNF genotype. In both regions, and GMVs were larger in the Val/Val homozygote patients than in individuals carrying the Met allele. Conclusions: These results implicate reduced GMV in the amygdala and hippocampus in pediatric anxiety, particularly social phobia. In addition, the data suggest that genetic factors may modulate differences in the insula and dorsal ACC. Source

Polston J.E.,Pennsylvania State University | Pritchett C.E.,Pennsylvania State University | Tomasko J.M.,Pennsylvania State University | Rogers A.M.,Pennsylvania State University | And 6 more authors.

Roux-en-Y gastric bypass surgery (RYGB) is an effective treatment for severe obesity. Clinical studies however have reported susceptibility to increased alcohol use after RYGB, and preclinical studies have shown increased alcohol intake in obese rats after RYGB. This could reflect a direct enhancement of alcohol's rewarding effects in the brain or an indirect effect due to increased alcohol absorption after RGYB. To rule out the contribution that changes in alcohol absorption have on its rewarding effects, here we assessed the effects of RYGB on intravenously (IV) administered ethanol (1%). For this purpose, high fat (60% kcal from fat) diet-induced obese male Sprague Dawley rats were tested ∼2 months after RYGB or sham surgery (SHAM) using both fixed and progressive ratio schedules of reinforcement to evaluate if RGYB modified the reinforcing effects of IV ethanol. Compared to SHAM, RYGB rats made significantly more active spout responses to earn IV ethanol during the fixed ratio schedule, and achieved higher breakpoints during the progressive ratio schedule. Although additional studies are needed, our results provide preliminary evidence that RYGB increases the rewarding effects of alcohol independent of its effects on alcohol absorption. Source

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