nitrophenols and Hyperglycemia

The clinical manifestations of acute poisoning by organophosphorus compounds in man are in accord with, initially, the stimulation and, later, the blocking of cholinergic transmission due to acetylcholinesterase inhibition. The manifestations involve mainly the para-sympathetic nerves, the neuromuscular junctions, and the central nerve synapses, and to a smaller degree the cholinergic sympathetic nerves. Miosis and muscle fasciculations are useful signs for diagnosis and for the control of therapy. Blood cholinesterase determination is the best diagnostic test. The cause of death is usually respiratory paralysis. Persistent manifestations have not been confirmed. Atropine and pralidoxime are effective for treatment and useful for diagnosis. Other oximes are promising but their clinical value has not been established. Poisoning by malathion is characterized by a prolonged course and by motor signs. Poisoning by organophosphorus compounds in man differs from animal experiments in several ways: in man, exposure may occur by several different routes, the manifestations are detected more easily, and therapy is given throughout the course of illness.

Topics: Acetylcholinesterase; Atropine; Chemical Phenomena; Chemistry; Child; Cholinesterase Inhibitors; Cholinesterases; Environmental Exposure; Glycosuria; Humans; Hyperglycemia; Neurologic Manifestations; Nitrophenols; Occupational Diseases; Organophosphate Poisoning; Organothiophosphorus Compounds; Oximes; Parasympatholytics; Parathion; Poisoning; Pralidoxime Compounds; Synapses

Type 1 diabetes (T1D) is an organ-specific autoimmune disease characterized by hyperglycemia due to progressive loss of pancreatic beta cells. Immune-mediated beta cell destruction drives the disease, but whether beta cells actively participate in the pathogenesis remains unclear. Here, we show that during the natural history of T1D in humans and the non-obese diabetic (NOD) mouse model, a subset of beta cells acquires a senescence-associated secretory phenotype (SASP). Senescent beta cells upregulated pro-survival mediator Bcl-2, and treatment of NOD mice with Bcl-2 inhibitors selectively eliminated these cells without altering the abundance of the immune cell types involved in the disease. Significantly, elimination of senescent beta cells halted immune-mediated beta cell destruction and was sufficient to prevent diabetes. Our findings demonstrate that beta cell senescence is a significant component of the pathogenesis of T1D and indicate that clearance of senescent beta cells could be a new therapeutic approach for T1D.

Topics: Adolescent; Adult; Aged; Animals; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cellular Senescence; Child; Child, Preschool; Cohort Studies; Diabetes Mellitus, Type 1; Female; Fibroblasts; Humans; Hyperglycemia; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; THP-1 Cells; Young Adult

Among substances which may prove useful in preventing or reducing the progression of glycooxidative modifications of proteins, heparin plays a unique role. To elucidate the mechanism whereby heparin may favourably influence the protein structure during glycation, human serum albumin (HSA) was glycated with both 25 and 50 mM glucose in the absence and presence of 12 microg.mL(-1) low-molecular-mass heparin. Glycation caused: (a) modifications of fluorescence emission and excitation spectra consistent with the covalent attachment of glucose to protein; (b) a significant increase in the esterase activity of HSA on p-nitrophenyl acetate; (c) a reduced susceptibility to tryptic digestion and (d) enhanced formation of high-molecular mass aggregates of HSA. These alterations were accompanied by oxidative reactions, as the EPR spectra showed a clear-cut radical signal, dependent on glucose concentration, further confirmed by measurement of the carbonyl content of HSA, as an indirect proof of oxidative damage. In the presence of heparin all the above alterations, especially at 25 mM glucose, turned out to be antagonized. The effects of heparin were dependent on its specific binding to HSA, which triggered an oxidative mechanism strikingly different from that caused by glucose. In the presence of heparin, only the radical species catalyzed by heparin was detected across all samples of glycated HSA, irrespective of glucose concentration. In addition, at 25 mM glucose, enhancement of the oxidative capacity of heparin was also observed. The results demonstrate that the oxidative mechanism sustained by heparin mediates biological effects that may be beneficial in reducing the extent of glycooxidative damage on HSA.

Topics: Dose-Response Relationship, Drug; Electron Spin Resonance Spectroscopy; Electrophoresis, Polyacrylamide Gel; Esterases; Free Radicals; Glucose; Heparin; Humans; Hyperglycemia; Nitrophenols; Oxygen; Serum Albumin; Spectrophotometry; Time Factors; Trypsin

Effect of hyperglycemia on the intestinal elimination of p-nitrophenol has been investigated in rats. Hyperglycemia was produced by a continuous i.v. infusion of glucose, p-nitrophenol was used as a model compound for the investigation of intestinal metabolism and excretion of drugs. Intestinal conjugation of p-nitrophenol with glucuronic acid did not change significantly in hyperglycemic rats, however, formation of sulfoconjugate of p-nitrophenol was enhanced by hyperglycemia. Sum of metabolites (p-nitrophenol glucuronide and sulfate) appeared in the intestinal lumen in hyperglycemic rats was similar to the total luminal appearance of these metabolites of control rats.

Topics: Animals; Glucuronates; Hyperglycemia; Intestinal Mucosa; Nitrobenzenes; Nitrophenols; Rats; Reference Values

Topics: Animals; Blood Glucose; Chlorpromazine; Drug Synergism; Epinephrine; Ethanolamines; Hyperglycemia; Nitrophenols; Propranolol; Rats; Sulfonamides