Temocapril treatment ameliorates autoimmune myocarditis associated with enhanced cardiomyocyte thioredoxin expression

OBJECTIVE: Thioredoxin (TRX) is a redox regulatory protein that protects cells from various stresses. Angiotensin-converting enzyme (ACE) inhibitor was reported to enhance endogenous antioxidant enzyme activities. This study was carried out to investigate whether temocapril, a novel non-sulfhydryl-containing ACE inhibitor, reduces the severity of myocarditis via redox regulation mechanisms involving TRX. METHODS AND RESULTS: In normal rat myocytes in vitro and in vivo, Western blot showed that temocapril enhanced cytosolic redox regulatory protein TRX expression, but that neither mitochondrial TRX2 nor antioxidant enzymes, such as copper-zinc superoxide dismutase (Cu/Zn-SOD) or manganese superoxide dismutase (Mn-SOD) expression, was up-regulated by the preconditioning treatment. In rats with experimental autoimmune myocarditis (EAM), the severity of myocarditis and the protein carbonyl contents were less increased in temocapril treatment (10 mg/kg/day, orally) from day 1 to day 21, but not in temocapril treatment from day 15 to day 21. An immunohistochemical study showed that TRX stain was enhanced in infiltrating inflammatory cells and in damaged myocytes. Considering the characteristics of this model that myocardial inflammation begins around day 15 and increases until day 21, temocapril treatment for 3 weeks might be thought of as a preconditioning treatment. CONCLUSIONS: The results suggest that TRX and the redox state modified by TRX may play a crucial role in the pathophysiology of EAM. Temocapril ameliorates myocarditis associated with inducing TRX up-regulation in a preconditioning manner, although the mechanism of TRX up-regulation by temocapril remains to be elucidated.     

A Case of Interstitial Pneumonia Induced by Rituximab Therapy

International Journal of Hematology -     

Assessing the Evolution of Intracranial Hematomas by using Animal Models: A Review of the Progress and the Challenges

Metabolic Brain Disease - Stroke has become the second leading cause of death in people aged higher than 60 years, with cancer being the first. Intracerebral hemorrhage (ICH) is the most...     

Risk stratification and survival in post myocardial infarction patients: a large prospective and multicenter study in Japan

BACKGROUND: Recent clinical trials suggest that the mortality in high-risk patients with ischemic heart disease can be significantly reduced with the use of implantable cardioverter-defibrillator (ICD). Given the high cost and invasiveness of the procedure, it is important to apply it to the patients after myocardial infarction (MI) highly susceptible to sudden arrhythmic death. OBJECTIVE: The purpose of this study was to assess clinical predictors of mortality in post-MI patients in Japan. METHODS AND RESULTS: In 495 consecutive MI survivors, 350 (71%) received acute-reperfusion therapy, whereas 145 (29%) did not. Nonsustained ventricular tachycardia (NSVT) was present in 136 patients (28%) in 24-h ambulatory ECGs at 7+/-6 in-hospital days. Left ventricular dysfunction (LVEF< or =35%) was present in 20/347 patients (5.7%) at 13+/-8 days. Forty-eight patients (9.7%) died during the follow-up period (48+/-13 months); 23 from cardiac and 25 from noncardiac causes. Kaplan-Meier survival analyses showed that mortality rates were higher among patients who were > or =70 years old (log-rank test, P<0.0001); had heart failure at admission (Killip scale> or =2, P=0.001); did not receive acute-reperfusion (P=0.004); and had left ventricular dysfunction with LVEF< or =35% (P=0.02). The presence of NSVT was a significant predictor of death (P=0.036) only in the patients who did not receive acute-reperfusion. Multivariate Cox regression analysis revealed that an independent predictor of total mortality was an age> or =70 (odds ratio, 1.06; 95% confidence interval, 1.01-1.11; P<0.00001). CONCLUSIONS: High-risk patients after acute MI can be identified on the basis of age, ventricular dysfunction, heart failure and acute-reperfusion therapy. The presence of NSVT before discharge has a prognostic value only in the patients without acute-reperfusion.     

Effects of 17beta-estradiol, nonylphenol, and bisphenol-A on developing Xenopus laevis embryos

Many chemicals released into the environment have the capacity to disrupt the normal development of aquatic animals. We investigated the influence of nonylphenol (NP), bisphenol-A (BPA), and 17beta-estradiol (E2) on developing Xenopus laevis embryos, as a model animal in the aquatic environment. Embryos were exposed to eight different concentrations of NP, BPA or E2 between 3 and 96 h post-fertilization (p.f.). Short body length, microcephaly, flexure, edema, and abnormal gut coiling were induced by 20 microM NP, BPA or 10 microM E2 by 96 h p.f. To clarify sensitive stages to these compounds, embryos were exposed to chemicals for 45 or 48 h starting at different developmental stages and experiments were terminated 96 h p.f. BPA and NP induced abnormalities in developing X. laevis, though the sensitive stages of embryos to these chemicals are different, BPA affecting earlier stages and NP affecting at later stages. To analyze the functional mechanisms of BPA and NP in induction of morphological changes, we adapted a DNA array technology and identified 6 X. laevis genes, XIRG, alpha skeletal tropomyosin, cyclin G1, HGF, troponin C2, and ribosomal protein L9. These findings may provide important clues to elucidate common mechanisms underlying teratogenic effects of these chemicals.     

Adjuvant treatments for resectable hepatocellular carcinoma

Hepatocellular carcinoma often recurs even after curative resection. Although some encouraging data showing improvements in recurrence-free times have been reported with the use of intraarterial 131I-lipiodol infusion, retinoids, interferon, or immunotherapy after hepatectomy, there is no consensus regarding standard adjuvant therapy for resectable hepatocellular carcinoma. A novel target agent, sorafenib, which has recently become a standard of care for advanced disease, may also be promising in an adjuvant setting to prevent early recurrence after curative surgery. In future trials, it will be important to identify appropriate target populations for each type of adjuvant approach; that is, an agent with definitive antitumor activity for high-risk patients, and one that shows chemoprevention for low-risk patients.