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Author (up) Barzilai, A.; Yamamoto, K.-I. file  url
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  Title DNA damage responses to oxidative stress Type Journal Article
  Year 2004 Publication DNA Repair Abbreviated Journal DNA Repair (Amst)  
  Volume 3 Issue 8-9 Pages 1109-1115  
  Keywords Animals; Apoptosis; Cell Cycle; Cell Lineage; *DNA Damage; *DNA Repair; Humans; Hypoxia; Mitochondria/pathology; Oxidation-Reduction; *Oxidative Stress; Reactive Oxygen Species  
  Abstract The DNA damage response is a hierarchical process. DNA damage is detected by sensor proteins such as the MRN complex that transmit the information to transducer proteins such as ATM and ATR, which control the damage response through the phosphorylation of effector proteins. The extent of the DNA damage determines cell fate: cell cycle arrest and DNA repair or the activation of apoptotic pathways. In aerobic cells, reactive oxygen species (ROS) are generated as a by-product of normal mitochondrial activity. If not properly controlled, ROS can cause severe damage to cellular macromolecules, especially the DNA. We describe here some of the cellular responses to alterations in the cellular redox state during hypoxia or oxidative stress. Oxidative damage in DNA is repaired primarily via the base excision repair (BER) pathway which appears to be the simplest of the three excision repair pathways. To allow time for DNA repair, the cells activate their cell cycle checkpoints, leading to cell cycle arrest and preventing the replication of damage and defective DNA.  
  Call Number Serial 1707  
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Author (up) Briggs, C.A.; Gronlien, J.H.; Curzon, P.; Timmermann, D.B.; Ween, H.; Thorin-Hagene, K.; Kerr, P.; Anderson, D.J.; Malysz, J.; Dyhring, T.; Olsen, G.M.; Peters, D.; Bunnelle, W.H.; Gopalakrishnan, M. file  url
openurl 
  Title Role of channel activation in cognitive enhancement mediated by alpha7 nicotinic acetylcholine receptors Type Journal Article
  Year 2009 Publication British Journal of Pharmacology Abbreviated Journal Br J Pharmacol  
  Volume 158 Issue 6 Pages 1486-1494  
  Keywords Allosteric Regulation; Animals; Avoidance Learning/drug effects; Azabicyclo Compounds/administration & dosage/*pharmacology; Behavior, Animal/drug effects; Cell Line; Cognition Disorders/drug therapy/physiopathology; Dose-Response Relationship, Drug; Furans/administration & dosage/*pharmacology; Humans; Male; Mice; Nicotinic Agonists/*pharmacology; Oocytes/drug effects/metabolism; Oxadiazoles/administration & dosage/*pharmacology; Pyridazines/pharmacology; Pyrroles/pharmacology; Rats; Receptors, Nicotinic/*drug effects/metabolism; Xenopus laevis; alpha7 Nicotinic Acetylcholine Receptor  
  Abstract BACKGROUND AND PURPOSE: Several agonists of the alpha7 nicotinic acetylcholine receptor (nAChR) have been developed for treatment of cognitive deficits. However, agonist efficacy in vivo is difficult to reconcile with rapid alpha7 nAChR desensitization in vitro; and furthermore, the correlation between in vitro receptor efficacy and in vivo behavioural efficacy is not well delineated. The possibility that agonists of this receptor actually function in vivo as inhibitors via desensitization has not been finally resolved. EXPERIMENTAL APPROACH: Two structurally related alpha7 nAChR agonists were characterized and used to assess the degree of efficacy required in a behavioural paradigm. KEY RESULTS: NS6784 activated human and rat alpha7 nAChR with EC(50)s of 0.72 and 0.88 microM, and apparent efficacies of 77 and 97% respectively. NS6740, in contrast, displayed little efficacy at alpha7 nAChR (<2% in oocytes, < or =8% in GH4C1 cells), although its agonist-like properties were revealed by adding a positive allosteric modulator of alpha7 nAChRs or using the slowly desensitizing alpha7V274T receptor. In mouse inhibitory avoidance (IA) memory retention, NS6784 enhanced performance as did the 60% partial agonist A-582941. In contrast, NS6740 did not enhance performance, but blocked effects of A-582941. CONCLUSIONS AND IMPLICATIONS: Collectively, these findings suggest that a degree of alpha7 nAChR agonist efficacy is required for behavioural effects in the IA paradigm, and that such behavioural efficacy is not due to alpha7 nAChR desensitization. Also, a partial agonist of very low efficacy for this receptor could be used as an inhibitor, in the absence of alpha7 nAChR antagonists with favourable CNS penetration.  
  Call Number Serial 1881  
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Author (up) Buttke, T.M.; McCubrey, J.A.; Owen, T.C. file  url
openurl 
  Title Use of an aqueous soluble tetrazolium/formazan assay to measure viability and proliferation of lymphokine-dependent cell lines Type Journal Article
  Year 1993 Publication Journal of Immunological Methods Abbreviated Journal J Immunol Methods  
  Volume 157 Issue 1-2 Pages 233-240  
  Keywords Animals; *Cell Division; Cell Line; *Cell Survival; Colorimetry; Formazans/*analysis; Interleukin-2/analysis/*physiology; Interleukin-3/analysis/*physiology; Mice; Tetrazolium Salts/*pharmacology; Thiazoles/pharmacology  
  Abstract A new tetrazolium compound, MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt), has recently been described which in the presence of phenazine methosulfate (PMS) is reduced by living cells to yield a formazan product that can be assayed colorimetrically. An important advantage of MTS/PMS over other tetrazolium dyes (e.g., MTT) is the aqueous solubility of the reduced formazan product which eliminates the need for detergent solubilization or organic solvent extraction steps. Its advantages over XTT/PMS, another tetrazolium which yields a water-soluble formazan product, include the absorbance range of color produced (515-580 nm as opposed to 450 nm), the rapidity of color development, and the storage stability of the MTS/PMS reagent solution. In the present study, MTS/PMS was used to assay viability and proliferation of the IL-2-dependent HT-2 and CTLL-2 cell lines and the IL-3-dependent FDC-P1 and FL5.12 cell lines. With each cell line, the amount of formazan product was time-dependent and proportional to the number of viable cells. Furthermore, with both HT-2 and CTLL-2 cells it was found that cultures could be simultaneously labeled with MTS/PMS and [3H]thymidine, with relatively little effect of the dye on uptake of the latter. This feature was further capitalized upon in studies with FDC-P1 cells, in which the co-addition of MTS/PMS and [3H]thymidine was used to distinguish between cell viability and proliferation.  
  Call Number Serial 1376  
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Author (up) Chen, C.; Chan, H.M.; Kubow, S. file  url
openurl 
  Title Kefir extracts suppress in vitro proliferation of estrogen-dependent human breast cancer cells but not normal mammary epithelial cells Type Journal Article
  Year 2007 Publication Journal of Medicinal Food Abbreviated Journal J Med Food  
  Volume 10 Issue 3 Pages 416-422  
  Keywords Animals; Breast/cytology; Breast Neoplasms/*pathology; Cell Division/*drug effects; Cell Line, Tumor; Cultured Milk Products/*chemistry; Epithelial Cells/drug effects; Fermentation; Humans; Milk/chemistry; Milk Proteins/analysis; Peptides/analysis; Yogurt/analysis  
  Abstract Anti-tumorigenic effects have been demonstrated in animal studies from the intake of kefir, a traditional fermented milk product believed to originate from the Caucasian mountains of Russia. In the present study, the antiproliferative effects of extracts of kefir, yogurt, and pasteurized cow's milk on human mammary cancer cells (MCF-7) and normal human mammary epithelial cells (HMECs) was investigated at doses of 0.31%, 0.63%, 1.25%, 2.5%, 5%, and 10% (vol/vol). After 6 days of culture, extracts of kefir-fermented milk depressed MCF-7 cell growth in a dose-dependent manner, showing 29% inhibition of proliferation at a concentration as low as 0.63%, whereas yogurt extracts began to show dose-dependent antiproliferative effects only at the 2.5% dose. Moreover, at the 2.5% dose, kefir extracts decreased the MCF-7 cell numbers by 56%, while yogurt extracts decreased MCF-7 cell proliferation by only 14%. No antiproliferative effects of kefir extracts were observed in the HMECs, while the yogurt extracts exerted antiproliferative effects on HMECs at the 5% and 10% doses. Unfermented milk extracts stimulated proliferation of MCF-7 cells and HMECs at concentrations above 0.31%. Peptide content and capillary electrophoresis analyses showed that kefir-mediated milk fermentation led to an increase in peptide concentrations and a change in peptide profiles relative to milk or yogurt. The present findings suggest that kefir extracts contain constituents that specifically inhibit the growth of human breast cancer cells, which might eventually be useful in the prevention or treatment of breast cancer.  
  Call Number Serial 1055  
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Author (up) Henkenius, K.; Greene, B.H.; Barckhausen, C.; Hartmann, R.; Marken, M.; Kaiser, T.; Rehberger, M.; Metzelder, S.K.; Parak, W.J.; Neubauer, A.; Brendel, C.; Mack, E. file  url
openurl 
  Title Maintenance of cellular respiration indicates drug resistance in acute myeloid leukemia Type Journal Article
  Year 2017 Publication Leukemia Research Abbreviated Journal Leuk Res  
  Volume 62 Issue Pages 56-63  
  Keywords Cell Line, Tumor; Cell Respiration/*physiology; Drug Resistance, Neoplasm/*physiology; Glycolysis/drug effects/physiology; Humans; Leukemia, Myeloid, Acute/*metabolism; Oxidative Phosphorylation/drug effects; Aml; Drug resistance; Mitochondrial membrane potential; Respiration  
  Abstract Primary resistance to induction therapy is an unsolved clinical problem in acute myeloid leukemia (AML). Here we investigated drug resistance in AML at the level of cellular metabolism in order to identify early predictors of therapeutic response. Using extracellular flux analysis, we compared metabolic drug responses in AML cell lines sensitive or resistant to cytarabine or sorafenib after 24h of drug treatment to a small cell lung cancer (SCLC) cell line exposed to etoposide. Only drug-resistant AML cells maintained oxidative metabolism upon drug exposure while SCLC cells displayed an overall metabolic shift towards glycolysis, i.e. a Warburg effect to escape drug toxicity. Moreover, primary AML blasts displayed very low glycolytic activity, while oxygen consumption was readily detectable, indicating an essential role of oxidative pathways in the bioenergetics of AML blasts. In line with these observations, analysis of the mitochondrial membrane potential using tetramethylrhodamine ethyl ester staining and flow cytometry allowed for clear discrimination between drug sensitive and resistant AML cell line clones and primary blasts after 24h of treatment with cytarabine or sorafenib. Our data reveal a distinct metabolic phenotype of resistant AML cells and suggest that disrupting oxidative metabolism rather than glycolysis may enhance the cytotoxic effects of chemotherapy in AML.  
  Call Number Serial 2125  
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