nitrophenols and Diabetes-Mellitus

Glycogen synthase kinase-3 (GSK-3) is a regulator of signaling pathways. KRas is frequently mutated in pancreatic cancers. The growth of certain pancreatic cancers is KRas-dependent and can be suppressed by GSK-3 inhibitors, documenting a link between KRas and GSK-3. To further elucidate the roles of GSK-3β in drug-resistance, we transfected KRas-dependent MIA-PaCa-2 pancreatic cells with wild-type (WT) and kinase-dead (KD) forms of GSK-3β. Transfection of MIA-PaCa-2 cells with WT-GSK-3β increased their resistance to various chemotherapeutic drugs and certain small molecule inhibitors. Transfection of cells with KD-GSK-3β often increased therapeutic sensitivity. An exception was observed with cells transfected with WT-GSK-3β and sensitivity to the BCL2/BCLXL ABT737 inhibitor. WT-GSK-3β reduced glycolytic capacity of the cells but did not affect the basal glycolysis and mitochondrial respiration. KD-GSK-3β decreased both basal glycolysis and glycolytic capacity and reduced mitochondrial respiration in MIA-PaCa-2 cells. As a comparison, the effects of GSK-3 on MCF-7 breast cancer cells, which have mutant

Topics: Adenocarcinoma; Adenylate Kinase; Antineoplastic Agents; bcl-X Protein; Berberine; Biphenyl Compounds; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Diabetes Mellitus; Dietary Supplements; Disease Progression; Doxorubicin; Female; Fluorouracil; Gemcitabine; Glycogen Synthase Kinase 3 beta; Glycolysis; Humans; Inhibitory Concentration 50; Malaria; MCF-7 Cells; Metformin; Molecular Targeted Therapy; Neoplasm Metastasis; Nitrophenols; Pancreatic Neoplasms; Piperazines; Protein Kinase Inhibitors; Signal Transduction; Sulfonamides; Thiadiazoles; Tumor Stem Cell Assay

A new fluorescent biosensor has been designed to screen α-glucosidase inhibitors (AGIs) sensitively by utilizing signal amplification effect of conjugated polymers. The fluorescence of cationic poly(fluorenylene phenylene) (PFP) was quenched in the presence of para-nitrophenyl-α-d-glucopyranoside and α-glucosidase, and turned on upon addition of AGIs. Thus, a new method was developed for AGIs screening based on the fluorescence turn-off/turn-on. The IC(50) values obtained for inhibitors were compared with that reported using absorption spectroscopy. All results present the new method is more sensitive and promising in screening AGIs and inhibitors of other enzymes whose hydrolysis product is 4-nitrophenol.

Topics: alpha-Glucosidases; Biosensing Techniques; Cations; Diabetes Mellitus; Fluorenes; Fluorescent Dyes; Glucosides; Humans; Hydrolysis; Inhibitory Concentration 50; Kinetics; Nitrophenols; Nitrophenylgalactosides; Polymers; Quaternary Ammonium Compounds; Spectrophotometry

Single nucleotide polymorphisms that cause amino acid substitutions in enzymes involved in the metabolism of xenobiotics can potentially have a significant effect on the efficacy and safety of therapeutic drugs.. We have utilized a bioinformatic approach to identify new polymorphisms in the glutathione transferase super family.. In this report we describe a P110S polymorphism in GSTA2 that occurs at a low frequency in Africans, Chinese and Europeans. The serine containing isoform has significantly diminished activity with a range of substrates including, delta-Androsten-3,17-dione, 1-chloro-2,4-dinitrobenzene and cumene hydroperoxide. The activity with cumene hydroperoxide may reflect a diminished physiological function since the glutathione peroxidase activity of GSTA2-2 plays a role in prostaglandin synthesis. In contrast, activity with p-nitrophenol acetate was significantly elevated. The position of this polymorphism in the active site and its effects on model substrates suggest that further investigation of its capacity to conjugate alkylating drugs is warranted.

Topics: Africa; Androstenedione; Benzene Derivatives; Binding Sites; China; Computational Biology; Diabetes Mellitus; Dinitrochlorobenzene; DNA; Europe; Glutathione Transferase; Humans; Kinetics; Models, Molecular; Nitrophenols; Polymorphism, Genetic; Recombinant Proteins

Substituted aminomethylphenol dyes, low-molecular-mass isoelectric point (pI) markers and hemoglobin samples from normal individuals and diabetic patients were used to test a new set-up of capillary isoelectric focusing (cIEF) in uncoated capillaries. In previous cIEF methods, a mixture of sample components and carrier ampholytes was applied in the capillary and analyzed. In the new set-up a fractionated injection protocol is used to apply a 'sandwich' ampholyte-sample-ampholyte plug in the capillary for analysis. This new set-up allows the separation of amphoteric compounds having pI values outside the pH region of the ampholytes applied in the capillary with high precision. The high resolution power of this technique was proven with the analysis of hemoglobin variants.

Topics: Diabetes Mellitus; Hemoglobins; Humans; Hydrogen-Ion Concentration; Indicators and Reagents; Isoelectric Focusing; Nitrophenols

Topics: Adult; Child; Diabetes Mellitus; Enzymes; Female; Genetics, Medical; Glucuronidase; Humans; Hydrogen-Ion Concentration; Lactones; Liver Cirrhosis; Male; Neoplasms; Nitrophenols; Phenolphthaleins; Pregnancy; Quinolines

Topics: Diabetes Mellitus; Dinitrophenols; Humans; Nitrophenols

Topics: Aspirin; Diabetes Mellitus; Dinitrophenols; Humans; Nitrophenols; Salicylates

Topics: Animals; Diabetes Mellitus; Dinitrophenols; Dogs; Nitrophenols