Simvastatin induces heme oxygenase-1 via NF-E2-related factor 2 (Nrf2) activation through ERK and PI3K/Akt pathway in colon cancer.

Statin has been known not only as their cholesterol-lowering action but also on their pleiotropic effects including anti-inflammatory and anti-oxidant as well as anti-cancer effect. Nrf2 (NF-E2-related factor 2) is a transcription factor to activate cellular antioxidant response to oxidative stress. There are little known whether statins affect activation of Nrf2 and Nrf2 signaling pathway in colon cancer cells. We investigated whether simvastatin stimulates the expression of Nrf2 and nuclear translocation of Nrf2 and which signal pathway is involved in the expression of Nrf2 and antioxidant enzymes. We investigated the effect of simvastatin on the expression of Nrf2 and nuclear translocation of Nrf2 in two human colon cancer cell lines, HT-29 and HCT 116 through cell proliferation assay, Western blotting and immunocytochemical analysis. We evaluated which signal pathway such as ERK or PI3K pathway affect Nrf2 activation and whether simvastatin induces antioxidant enzymes (heme oxygenase-1 (HO-1), NAD(P)H: quinine oxidoreductase 1 (NQO1), γ-glutamate-cysteine ligase catalytic subunit (GCLC)). We demonstrated simvastatin-induced dose-dependent up-regulation of Nrf2 expression and stimulated Nrf2 nuclear translocation in colon cancer cells. We also demonstrated that simvastatin-induced anti-oxidant enzymes (HO-1, NQO1, and GCLC) in HT-29 and HCT 116 cells. PI3K/Akt inhibitor (LY294002) and ERK inhibitor (PD98059) suppressed simvastatin-induced Nrf2 and HO-1 expression in both HT-29 and HCT 116 cells. This study shows that simvastatin induces the activation and nuclear translocation of Nrf2 and the expression of various anti-oxidant enzymes via ERK and PI3K/Akt pathway in colon cancer cells.

Synergistic Effects of Simvastatin and Irinotecan against Colon Cancer Cells with or without Irinotecan Resistance.

Aims. We here investigated whether the combination of simvastatin and irinotecan could induce the synergistic effect on colon cancer cells with or without resistance to irinotecan. Methods. We investigated cell proliferation assay and assessed cell death detection ELISA and caspase-3 activity assay of various concentrations of simvastatin and irinotecan to evaluate the efficacy of drug combination on colon cancer cells with or without irinotecan resistance. Results. The IC50 values of simvastatin alone and irinotecan alone were 115.4 ± 0.14 µM (r = 0.98) and 62.5 ± 0.18 µM (r = 0.98) in HT-29 cells without resistance to irinotecan. The IC50 values of these two drugs were 221.9 ± 0.22 µM (r = 0.98) and 195.9 ± 0.16 µM (r = 0.99), respectively, in HT-29 cell with resistance to irinotecan. The results of combinations of the various concentrations of two drugs showed that combined treatment with irinotecan and simvastatin more efficiently suppressed cell proliferation of HT-29 cells even with resistance to irinotecan as well as without resistance. Furthermore, the combination of simvastatin and irinotecan at 2 : 1 molar ratio showed the best synergistic interaction. Conclusion. Simvastatin could act synergistically with irinotecan to overcome irinotecan resistance of colon cancer.

Blood stream infections in patients in the burn intensive care unit.

BACKGROUND: The study on bacteremia helps empirically select the proper antibiotics before the results of culture test about causative pathogen. The purpose of this study is to investigate causative pathogen in bloodstream infection, changing aspects based on elapsed time after burn, relationship with other sites and resistance of important causative pathogen against antibiotics through analysis on bacteria isolated from blood culture of patients hospitalized in burn intensive care unit (BICU). MATERIALS AND METHODS: A retrospective study was conducted targeting patients hospitalized in BICU from January 2007 to June 2011. Changes of causative pathogen in bloodstream infection based on elapsed time after injury were analyzed. We would like to examine the relationship between bloodstream infection and infection on other body parts by comparing results of cultures in burn wound site, sputum, urine and catheter tip. Antibiotics resistance patterns of Pseudomonas aeruginosa, Acinetobacter baumannii, Staphylococcus aureus, Enterococcus species, and Klebsiella pneumoniae were studied. RESULTS: A total of 2,337 burn patients were hospitalized in BICU for 54 months. Causative pathogen was cultured in blood cultures from 397 patients (17.0%). P. aeruginosa (169, 30.1%) was the most cultured and A. baumannii (107, 19.0%) and S. aureus (81, 14.4%) were followed. It was confirmed that the relative frequency of A. baumannii tended to get lower as the period got longer after injury, but the relative frequency of K. pneumoniae got higher as the period got longer after injury. With comparison without bacteremia, P. aeruginosa bacteremia showed high probability in which the same bacteria were cultured in wound site, sputum and cathether tip, and A. baumannii bacteremia and candida bacteremia had high probability in sputum, and urine and catheter tip, respectively. 95.9% of P. aeruginosa and 95.3% of A. baumannii showed the resistance against carbapenem. 96.3% of S. aureus was methicillin resistant and 36.2% of Enterococcus species were vancomycin resistant. 75.0% of K. pneumonia were extended-spectrum beta-lactamase (ESBL)-producing bacteria. CONCLUSIONS: Since the highly antibiotic resistant microorganisms were isolated from the patients hospitalized in BICU during early phase, the empirical selection of antibiotics targeting these pathogens should be considered before the results of microbiologic culture test. In addition, use of empirical antifungal agent after 1 week of injury can be considered for patients who have risk factor of fungal infection.

A case of synchronous presentation of primary non-small cell lung carcinoma and pheochromocytoma.

We report a rare synchronous presentation of primary lung cancer and adrenal pheochromocytoma. A 59-year-old woman was diagnosed with right upper lobe non-small cell lung carcinoma measuring 2.8 cm and a right adrenal gland mass measuring 3.5 cm, which displayed increased metabolic activity on (18)F-fluorodeoxyglucose positron emission tomography-computed tomography. The adrenal lesion was revealed to be asymptomatic. The patient underwent right adrenalectomy and histological examination revealed a pheochromocytoma. Ten days later, right upper lobectomy was performed for lung cancer. This case indicates that incidental adrenal lesions found in cases of resectable primary lung cancer should be investigated.

An Elderly Man with Fatal Respiratory Failure after Eating a Poisonous Mushroom Podostroma cornu-damae.

A 73-year-old, previously healthy man presented with nausea, vomiting, diarrhea, dry mouth and febrile sensation 3 hours after eating boiled wild mushrooms. After admission, he showed progressive severe respiratory distress, pancytopenia, azotemia, hypotension, hypoxemia and consolidation of the entire left lung on chest radiography. With a preliminary diagnosis of necrotizing pneumonia, he underwent left pneumonectomy in order to remove all necrotic lung tissue. Lung histology showed extensive hemorrhagic necrosis, massive inflammatory cell infiltration, prominent proliferation of young fibroblasts and the formation of an early-stage hyaline membrane along the alveolar wall. Despite aggressive treatment, including mechanical ventilation, continuous renal replacement therapy and administration of granulocyte colony stimulating factor and broad spectrum antibiotics, he died on hospitalization day 13. Subsequently, the mushroom was identified as Podostroma cornu-damae. This is the first case of a histological evidence of lung involvement by Podostroma cornu-damae poisoning in Korea.