R, Rabkin R. Leucine-stimulated mTOR signaling is partly attenuated in skeletal muscle of chronically uremic rats.

Muscle wasting in chronic renal failure is associated with increased morbidity and mortality; however, resistance exercise is effective at increasing muscle mass while improving muscle strength and function. To study the mechanism by which this occurs, we compared uremic and control rats where work overload was surgically induced unilaterally in the plantaris muscle. We found that work overload increases muscle insulin-like growth factor-1 and mechano-growth factor expression. This in addition to direct mechanical activation of signaling was likely the cause of the observed increased in the protein levels and phosphorylation of the mediators of these growth factors, the insulin receptor substrate-1/phosphoinositide 3-kinase/Akt pathway. The mechanical enhancement of signal transduction appeared to be mediated in part by increased signal protein levels and decreased SOCS2 mRNA expression (suppressor of cytokine signaling-2). Despite impaired basal signaling, the work-induced signaling response was similar to that observed in nonuremic rats and produced changes consistent with decreased muscle protein degradation, increased protein synthetic capacity, and an increased number of multinucleated muscle cells. Our studies suggest that these work-induced changes account for the improved uremic muscle mass reaching levels comparable to those seen in normal rats.

Background: Esophageal reflux and Barrett's esophagus represent two major risk factors for the development of esophageal adenocarcinoma. Previous studies have shown that brief exposure of the Barrett's-associated adenocarcinoma cell line, SEG-1, or primary cultures of Barrett's esophageal tissues to acid or bile results in changes consistent with cell proliferation. In this study, we determined whether similar exposure to acid or bile salts results in gene expression changes that provide insights into malignant transformation.

Summary Background  Reducing mucosal cyclo‐oxygenase‐2 and prostaglandin E2 production and suppressing intraoesophageal acid may be effective chemopreventive strategies in patients with Barrett's oesophagus. Aim  To compare the effects of aspirin and rofecoxib when administered with esomeprazole on prostaglandin E2 production, cyclo‐oxygenase‐2 expression and proliferating cell nuclear antigen expression in patients with Barrett's oesophagus. Methods  This exploratory, multicentre, randomized, open‐label, four‐way crossover study in 45 patients with Barrett's oesophagus evaluated prostaglandin E2 content, proliferating cell nuclear antigen expression, and cyclo‐oxygenase‐2 expression after 10 days of sequential treatments with: esomeprazole 40 mg twice daily plus aspirin 325 mg once daily (E40 b.d. + A325); E40 b.d. plus rofecoxib 25 mg once daily (E40 b.d. + R25); E40 b.d.; and rofecoxib 25 mg once daily (R25). Results  Prostaglandin E2 content reduction in Barrett's oesophagus tissue was significantly greater with E40 b.d. + A325 compared with E40 b.d. + R25, E40 b.d. or R25 (P < 0.05). All treatments containing E40 b.d. significantly decreased proliferating cell nuclear antigen expression from baseline (P < 0.05). None of the treatments significantly reduced cyclo‐oxygenase‐2 expression. Conclusions  The combined treatment of esomeprazole 40 mg b.d. and aspirin 325 mg significantly decreased mucosal prostaglandin E2 content and all treatments containing esomeprazole significantly reduced proliferating cell nuclear antigen expression in patients with Barrett's oesophagus.