Antioxidants ; metabolism ; pharmacology ; Down-Regulation ; Gene Expression Regulation ; Humans ; NF-E2-Related Factor 2 ; genetics ; metabolism ; physiology ; Neoplasms ; genetics ; metabolism ; Oxidative Stress ; genetics ; physiology ; Response Elements ; physiology ; Signal Transduction ; physiology

Gastrointestinal tract carcinoma is one of the leading causes of cancer-related death in China. Chemoprevention has been considered as a potential approach to control this type of disease. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that protects cells from oxidative/electrophilic stresses by activating the expression of a battery of cytoprotective genes through the antioxidant response element (ARE). Recently, Nrf2 has emerged as a novel target for chemoprevention. Several natural or synthetic chemicals, which activate Nrf2/ARE signaling pathway, have showed effect in animal models, and promises in many ongoing clinical trials. This review summarizes the recent findings on the regulation of Nrf2/ARE signaling pathway, and the developments in both preclinical and clinical studies.
Animals ; Anticarcinogenic Agents ; pharmacology ; Antioxidants ; metabolism ; Chemoprevention ; Digestive System Neoplasms ; genetics ; metabolism ; prevention & control ; Humans ; NF-E2-Related Factor 2 ; genetics ; metabolism ; Oxidative Stress ; drug effects ; Response Elements ; genetics ; Signal Transduction ; drug effects

Adolescent ; Child ; Child, Preschool ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Hepatolenticular Degeneration ; diagnosis ; drug therapy ; Humans ; Male ; Penicillamine ; administration & dosage ; adverse effects ; Zinc Sulfate ; administration & dosage ; adverse effects

The main obstacle for chemotherapy is tumor drug resistance. Studying the mechanisms of drug resistance and reversing drug resistance is the key to improve the effectiveness of chemotherapy. It has been reported that MKP-1 plays an important role in tumor drug resistance. MKP-1, as a negative regulator of MAPKs, is involved in the MAPKs mediated drug resistance and is regulated by ERK and p38 signaling pathways.However, the relationship between MKP-1 and other drug resistance-related signaling pathways is not clear and requires further investigation.
Drug Resistance, Neoplasm ; physiology ; Dual Specificity Phosphatase 1 ; metabolism ; physiology ; Humans ; Signal Transduction

OBJECTIVETo investigate the antitumor effect of apigenin on human lung cancer cells.

METHODSThe anti-proliferation and sensitization effects of apigenin on human lung cancer cells was accessed by counting cells after Trypan blue staining and MTS assay.

RESULTS(1) Apigenin significantly suppressed the proliferation of four types of human lung cancer cells (A549:P=0.041, H460:P=0.050, LTEP-a2:P=0.039, H292:P=0.016); (2) Apigenin significantly increased the susceptibility of human lung cancer cells to antitumor drugs (P<0.05 or P<0.01) in a synergistic way (almost all of the combination index values are less than 1).

CONCLUSIONApigenin widely inhibits cell proliferation of various lung cancer cell lines in a dose-dependent manner and the combination treatment of apigenin and antitumor drugs is very effective in human lung cancer cells, and Nrf2-ARE pathway may contribute to the mechanism.

Antineoplastic Agents ; pharmacology ; Apigenin ; pharmacology ; Cell Line, Tumor ; drug effects ; Cell Proliferation ; drug effects ; Drug Synergism ; Humans ; Lung Neoplasms ; pathology

Objective To study the relationship between coronary arteriographic and fluorescence fundus angiographic characteristics in type 2 diabetic patients with coronary heart disease.Methods The study was carried out by the analysis of the data from coronary arteriography and fluorescence fundus angiography in 203 type 2 diabetic patients with coronary heart disease in different groups divided according to age or total cholesterol level. Logisitic regression analysis was applied to explore various risk factors to angiographic characteristics.Results With advancing age,there were more involvement of 3 coronary vessels or the left main branch along with stageⅢretinopathy,but less single vessel diseases in the coronary arteries and less stageⅠretinopathy.The difference in coronary angiographic and fluorescence fundus angiographic characteristics between groups with different total cholesterol levels was not significant.Logistic regression analysis suggested that coronary artery diaease was related to age,sex and blood glucose and triglyceride levels while diabetic retinopathy was related to blood glucose level and age.Conclusion There is great difference in coronary arteriography and fluorescence fundus angiography among different age groups.Aging may aggravate the lesions both in the coronary arteries and fundal vessels in type 2 diabetic patients with coronary heart diseease.

OBJECTIVETo maked a Nrf2 down-regulated cell line by over-expressing Keap1 in H460 cells to study the role of Nrf2 in drug resistance.

METHODSTransfecting H460 cells with mKeap1-pEGFP and screenig for Keap1 expressing clones by Western blotting with antibodies against Nrf2, HO-1, NQO1 and AKR1C. The cell line with Keap1 over-expression was further confirmed by real-time PCR. The cytotoxicity of H460-N5 to anti-cancer drugs was evaluated by MTS assay.

RESULTMTS assay results showed the enhanced cytotoxicity of anticancer drugs (Oxaliplatin, Doxorubicin and Etopside) to the H460 cell line with keap1 overexpression compared to the control cell line. In H460-N0 cells, the IC(50) values of Oxaliplation and Etopside were 93 micromol/L and 100 micromol/L respectively whereas the IC(50) values of the two drugs were 42 micromol/L and 30 micromol/L correspondingly in H460-N5 cells. A Nrf2 down-regulated cell line H460-N5 and a control cell line with GFP over-expression have been identified.Down-regulation of Nrf2 enhanced the cytotoxicity of Oxaliplatin, Doxorubicin and Etopside. The IC(50) value of Doxorubicin to H460-N0 cell was above 3 mg/L, but that to H460-N5 cell was about 2 mg/L.

CONCLUSIONA Nrf2 down-regulated cell line H460-N5 and a control cell line with GFP over-expression have been identified. Down-regulation of Nrf2 enhanced the cytotoxicity of Oxaliplatin, Doxorubicin and Etopside.

Antineoplastic Agents ; pharmacology ; Antioxidants ; metabolism ; pharmacology ; Carcinoma, Non-Small-Cell Lung ; metabolism ; pathology ; Cell Line, Tumor ; Down-Regulation ; Drug Resistance, Neoplasm ; genetics ; Gene Expression Regulation, Neoplastic ; drug effects ; Humans ; Intracellular Signaling Peptides and Proteins ; genetics ; metabolism ; Kelch-Like ECH-Associated Protein 1 ; Lung Neoplasms ; metabolism ; pathology ; NF-E2-Related Factor 2 ; genetics ; metabolism ; physiology ; Response Elements ; physiology ; Signal Transduction ; physiology ; Transfection

OBJECTIVETo investigate the effects of transcriptional inhibitors 5, 6-dichloro-1-b-D-ribofuranosylbenzimidazole (DRB) and alpha-Amanitin on the localization of Nrf2 in the nucleus.

METHODSA549 cells were treated with DRB (50 mg/L) or alpha-Amanitin (2.5 mg/L)for 1 h and 6 h in serum-free medium, respectively. The expressions of Nrf2, HO-1, NQO1 and AKR1C were detected by Western blotting analysis. The localization of Nrf2 was determined by laser scanning confocal microscopy after cells were treated with either DRB or agr:-Amanitin for 1 h.

RESULTSThe expressions of Nrf2 and Nrf2-ARE gene batteries HO-1, AKR1C and NQO1 were decreased after 6 h treated with either DRB or alpha-Amanitin. The expression of SC35 was up-regulated but RNA Pol II was down-regulated; Y12 and NPC did not significantly change. The localization of Nrf2 in the cell nucleus did not change significantly.

CONCLUSIONDRB and alpha-Amanitin can down-regulate the expression of Nrf2 and its targeting proteins HO-1, AKR1C and NQO1, but may have no effect on the localization of Nrf2.

20-Hydroxysteroid Dehydrogenases ; genetics ; metabolism ; Alpha-Amanitin ; pharmacology ; Carcinoma, Non-Small-Cell Lung ; genetics ; metabolism ; pathology ; Cell Line, Tumor ; Dichlororibofuranosylbenzimidazole ; pharmacology ; Heme Oxygenase-1 ; genetics ; metabolism ; Humans ; Lung Neoplasms ; metabolism ; pathology ; NF-E2-Related Factor 2 ; genetics ; metabolism ; Nucleic Acid Synthesis Inhibitors ; pharmacology

OBJECTIVETo establish a stable H460 cell line with Nrf2 down-regulation to study the role of Nrf2 in Oxaliplatin resistance.

METHODSNrf2 down-regulated H460 cell line was obtained by transfecting cells with pRS-hNrf2 and followed by screening for Nrf2 expression by Western blotting. The cell lines were further characterized by analysing cellular GSH levels and cytotoxicity to anti-cancer drugs with MTS.

RESULTNrf2 down-regulated H460 cell lines were established successfully. Cellular GSH level reduced significantly in the H460-C9 and H460-C13 compared to control cells (P(C9)= 0.00249, P(C13)= 0.03944). Down-regulation of Nrf2 in H460 sensitized the anti-cancer effect of Oxaliplatin and Doxorubicin.

CONCLUSIONNrf2 plays an important role in drug resistance. Down regulation of Nrf2 in H460 cell enhances cytotoxicity of Oxaliplatin.

Antineoplastic Agents ; pharmacology ; Carcinoma, Non-Small-Cell Lung ; genetics ; metabolism ; pathology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Down-Regulation ; Drug Resistance, Neoplasm ; genetics ; Humans ; Lung Neoplasms ; genetics ; metabolism ; pathology ; NF-E2-Related Factor 2 ; genetics ; metabolism ; Organoplatinum Compounds ; pharmacology ; Transfection

AIMTo investigate the coordinated role and its mechanism of the high protein and hypercholesterol intake on inducing rat myocardial fibrosis.

METHODSThe tissue level of the collagen in left ventricule, the concentrations of the plasma and the cardiac tissue angiotensin II (Ang II) and Aldosterone (Ald), the serum concentration of nitrite (NO2-), in the Wistar rats on diet which adding 20% protein or/and 100 mg/d cholesterin in the rat standard foods for 8 weeks, were measured by the colorimetric analysis of the hydroxyproline, by the radioimmunoassay, and by the assay of Griess, respectively.

RESULTS1.69 times left ventricular collagen contents, 0.7 times plasma concentrations of total cholesterin, 1.5 times levels of the plasma Ang II and 1 time myocardial ald contents were higher, and the serum NO2- concentration was significant lower, in the rats of the high protein and hypercholesterol intake than in the rats of the high protein intake. That 0.48 times left ventricular collagen contents, 0.23 times plasma Ang II in the high protein and hypercholesterol intake rats were higher than in the high cholesterin intake rats.

CONCLUSIONThe excessive protein and cholesterin intake can induce the coordinated effect on developing the myocardial fibrosis of rats. And the mechanism of the fibrosis in rat left ventricule maybe result with the activation of RAAS and the endothelial injury.

Animals ; Cardiomyopathies ; etiology ; pathology ; Cholesterol, Dietary ; adverse effects ; Dietary Proteins ; adverse effects ; Fibrosis ; Male ; Myocardium ; pathology ; Rats ; Rats, Wistar