ABSTRACT
The spread of multiresistant bacteria increases the need for new antibiotics. The observation that some nucleoside analogues have antibacterial activity led us to further investigate the antimicrobial activity and resistance of zidovudine (AZT). We determined the minimum inhibition concentration (MIC), studied time-kill curves, induced resistant bacteria and sequenced the gene for thymidine kinase. We demonstrate that AZT has a bactericidal effect on some enterobacteria. However, AZT could induce resistance in Escherichia coli. These resistances were associated with various modifications in the thymidine kinase gene. In particular, we observed the presence in this gene of an insertion sequence (IS) similar to IS911 of Shigella dysenteriae in two resistant clones. No cross-resistance with classical antibiotics in strains with modified thymidine kinase gene was observed. Finally, an additive or synergistic activity between AZT and the two aminoglycoside antibiotics amikacin and gentamicin was observed. We demonstrate the bactericidal activity of AZT and show synergy in association with gentamicin. Genetic modifications in resistant bacteria were identified. Our results indicate that AZT could potentially be added in the treatment of infections with enterobacteria or represent the basis for the development of derivatives with better activity and inducing less resistance.
Subject(s)
Anti-Bacterial Agents/pharmacology , Escherichia coli/drug effects , Mutagens/pharmacology , Zidovudine/pharmacology , Amikacin/pharmacology , Bacterial Proteins/genetics , DNA Mutational Analysis , Drug Resistance, Bacterial , Drug Synergism , Gentamicins/pharmacology , Humans , Microbial Sensitivity Tests , Microbial Viability/drug effects , Mutation , Sequence Analysis, DNA , Shigella dysenteriae , Staphylococcus aureus/drug effects , Thymidine Kinase/genetics , Time FactorsABSTRACT
The zinc-finger protein A20/TNFAIP3, an inhibitor of nuclear factor-kappaB (NF-kappaB) activation, has been shown to protect MCF-7 breast carcinoma cells from TNFalpha-induced apoptosis. As estrogen receptor (ER) status is an important parameter in the development and progression of breast cancer, we analysed the effect of 17beta-estradiol (E2) treatment on the expression of A20. We found that A20 is a new E2-regulated gene, whose expression correlates with ER expression in both cell lines and tumor samples. With the aim of investigating the impact of A20 expression on MCF-7 cells in response to ER ligands, we established stably transfected-MCF-7 cells overexpressing A20 (MCF-7-A20). These cells exhibited a phenotype of resistance to the 4-hydroxy-tamoxifen cytostatic and pro-apoptotic actions and of hyper-response to E2. Dysregulations in bax, bcl2, bak, phospho-bad, cyclin D1, cyclin E2, cyclin D2 and cyclin A2 proteins expression were shown to be related to the resistant phenotype developed by the MCF-7-A20 cells. Interestingly, we found that A20 was also overexpressed in MVLN and VP tamoxifen-resistant cell lines. Furthermore, high A20 expression levels were observed in more aggressive breast tumors (ER-negative, progesterone receptor-negative and high histological grade). These overall findings strongly suggest that A20 is a key protein involved in tamoxifen resistance, and thus represents both a new breast cancer marker and a promising target for developing new strategies to prevent the emergence of acquired mechanisms of drug resistance in breast cancer.
Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/drug therapy , Estradiol/pharmacology , Estrogen Antagonists/therapeutic use , Gene Expression Regulation, Neoplastic , Intracellular Signaling Peptides and Proteins/genetics , Nuclear Proteins/genetics , Tamoxifen/analogs & derivatives , Apoptosis , Apoptosis Regulatory Proteins/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Line, Tumor , Cyclins/metabolism , DNA-Binding Proteins , Drug Resistance, Neoplasm/genetics , Female , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Nuclear Proteins/metabolism , Tamoxifen/pharmacology , Tamoxifen/therapeutic use , Tumor Necrosis Factor alpha-Induced Protein 3ABSTRACT
Ligation of the posterior interventricular branch of the right coronary artery in rats induced bradyarrhythmia similar by its pathophysiological mechanisms to bradyarrhythmias developed in humans during acute ischemia of the posterior cardiac wall. The type and severity of arrhythmia and conduction disturbances, their latency and duration, and correlation with the volume of damaged myocardial tissue were determined. The efficacy and safety of the use of methylxanthines during acute myocardial ischemia was proved.
Subject(s)
Arteries/pathology , Bradycardia/etiology , Coronary Vessels/pathology , Animals , Bradycardia/physiopathology , Electrocardiography , Male , Myocardial Ischemia/physiopathology , Rats , Sinoatrial Block/physiopathologyABSTRACT
Leaves of the plant, Cassia podocarpa, were collected from Opah village near Accra, and dried. A suspension of the powdered leaf was given by gavage to groups of ten mice. A record was kept of the number of wet faeces passed in 24 hours. There was a linear relationship between the log dose of leaf and the number of wet faeces. The effect was maximal between 6 and 24 hours of administration and was larger than has been noted with senna.