dihydrotachysterol and Necrosis

Topics: Chlorides; Desoxycorticosterone; Dihydrotachysterol; Heart; Humans; Hypokalemia; Isoproterenol; Magnesium; Metabolism; Myocardial Infarction; Necrosis; Pathology; Potassium; Potassium Deficiency; Research; Sodium

The mechanisms by which polyglutamine expansion causes common features of neuronal death remain unclear. Here we describe an approach for delivering polyglutamine expansions directly into cultured sympathetic neurons. Glutamine (Q) residues (n = 10, 22, 30) were conjugated with a peptide possessing translocation properties across plasma membranes (PDP) and a nuclear localization signal (NLS). These peptides were rapidly incorporated into sympathetic neurons and showed neurotoxicity in a length- and dose-dependent manner. A robust induction of c-jun and cyclin D1 occurred following treatment with PDP-Q22-NLS. Enhanced c-Jun phosphorylation showed c-Jun N-terminal kinase (JNK) activation. Coincidentally, TrkA tyrosine phosphorylation was decreased in association with loss of phospho-Akt, the downstream target of PI-3 kinase. Despite such proapoptotic signals, neither release of cytochrome c from mitochondria nor caspase-3/7 activation was detected. TdT-mediated dUTP nick-end labeling-positive nuclear condensation, but no fragmentation, occurred. At 24 hr of treatment, cytoplasmic Ca2+ levels began to become elevated, and the cellular level of ATP was decreased. Cytoplasmic Ca2+ responses to KCl depolarization displayed a delayed recovery, providing evidence for lack of Ca2+ homeostasis. The neurons became committed to death at about 36 hr when mitochondrial Ca2+ uptake declined concurrently with loss of mitochondrial membrane potential. Collectively, these results show that, despite induction of early apoptotic signals, nonapoptotic neuronal cell death occurred via perturbed Ca2+ homeostasis and suggest that mitochondrial permeability transition may play important roles in this model of neuronal death.

Topics: Amino Acid Chloromethyl Ketones; Animals; Animals, Newborn; Apoptosis; Blotting, Western; Calcium; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Caspase 3; Caspase 7; Caspases; Cell Count; Cells, Cultured; Colforsin; Cyclin D1; Cycloheximide; Dihydrotachysterol; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Homeostasis; Immunohistochemistry; In Situ Nick-End Labeling; Ionophores; Lactic Acid; Mitochondria; Models, Biological; Necrosis; Nerve Growth Factor; Neurons; Neuroprotective Agents; Peptides; Permeability; Protein Synthesis Inhibitors; Proto-Oncogene Proteins c-jun; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Staurosporine; Superior Cervical Ganglion; Time Factors

A patient with longstanding pseudohypoparathyroidism undergoing substitution with dihydrotachysterin, with normal to low serum calcium and phosphorus levels, developed extensive calcification of the subcutaneous tissue and an obliterative and calcified arteriopathy of the small subcutaneous arteries with ischemic skin signs (livedo reticularis, skin infarction and ulcerative necrosis). After stimulation with exogenous parathyroid hormone there was no increase in urinary cyclic AMP and the G-unit was significantly decreased. It was concluded that the patient is suffering from pseudohypoparathyroidism type 1a. The likely pathophysiological mechanisms and the therapeutic implications are discussed.

Topics: Arteries; Calcinosis; Calcium; Cyclic AMP; Dihydrotachysterol; Female; Humans; Middle Aged; Necrosis; Pseudohypoparathyroidism; Skin; Vascular Diseases

Topics: Animals; Calcium; Cardiomyopathies; Dihydrotachysterol; Heart Rate; Hydralazine; Male; Necrosis; Propranolol; Rats

Topics: Angiotensin II; Animals; Calcium; Dihydrotachysterol; Magnesium; Male; Microscopy, Electron; Mitochondria, Heart; Myocardium; Myofibrils; Necrosis; Norepinephrine; Ouabain; Rats; Water-Electrolyte Imbalance

Ca ions are highly cardiotoxic if their influx into the myocardial fibres becomes abundant. The intracellular Ca overload initiates a deleterious high-energy phosphate deficiency by excessive activation of Ca-dependent intracellular ATPases and by impairing the phosphorylating capacity of mitochondria. This Ca-induced high-energy phosphate exhaustion is a crucial point in the etiology of the myocardial fibre necroses produced in rats by large doses of beta-adrenergic catecholamines, particularly isoproterenol, or by a number of other cardiotoxic agents. Accordinly, the myocardium is sensitized to necrotization by factors which favour Ca overload (dihydrotachysterol, 9alpha-flourocortisol acetate, NaH2PO4). Conversely, the structural integrity of the hearts can be protected by any substance or procedure which prevents an excessive intracellular Ca accumulation, particularly by inhibitors of the transmembrane Ca influx, such as verapamil, D 600 or prenylamine.

Topics: Adenosine Triphosphate; Animals; Calcium; Catecholamines; Dihydrotachysterol; Fludrocortisone; Heart; Isoproterenol; Mitochondria; Myocardial Infarction; Myocardium; Necrosis; Phosphates; Prenylamine; Rats; Verapamil

Topics: Adrenal Cortex Hormones; Animals; Autoradiography; Calcium; Calcium Radioisotopes; Dihydrotachysterol; Heart Diseases; Isoproterenol; Microscopy, Electron; Myocardium; Necrosis; Phosphates; Prenylamine; Verapamil

Topics: Ammonium Chloride; Animals; Biological Transport; Calcitonin; Calcium; Cardiomyopathies; Dihydrotachysterol; Dose-Response Relationship, Drug; Drug Synergism; Guinea Pigs; Heart; Hydrogen-Ion Concentration; Isoproterenol; Magnesium; Myocardium; Necrosis; Phosphates; Potassium; Prenylamine; Rats; Verapamil

Topics: Animals; Bile Acids and Salts; Cholesterol; Diet, Atherogenic; Dietary Fats; Dihydrotachysterol; Fludrocortisone; Heart Diseases; Myocardial Infarction; Necrosis; Nephrocalcinosis; Phosphates; Propylthiouracil; Rats; Stress, Physiological; Thrombosis

Topics: Adaptation, Physiological; Aging; Anabolic Agents; Animals; Calcium Metabolism Disorders; Chlorides; Dihydrotachysterol; Disease Models, Animal; Female; Humans; Magnesium; Myocardial Infarction; Necrosis; Potassium Chloride; Progeria; Rats; Sodium; Steroids; Stress, Physiological

Topics: Animals; Arsenicals; Calcinosis; Dermatitis, Contact; Dihydrotachysterol; Dimethyl Sulfoxide; Dinitrophenols; Eczema; Female; Guinea Pigs; Hemorrhage; Hypersensitivity; Necrosis; Rats; Skin Diseases

Topics: Anaphylaxis; Animals; Calcinosis; Calciphylaxis; Connective Tissue; Dihydrotachysterol; Edema; Female; Foot Diseases; Formaldehyde; Hemorrhage; Inflammation; Ischemia; Lead; Necrosis; Pharmacology; Potassium Permanganate; Rats; Serotonin; Stress, Physiological; Thrombosis

Topics: Animals; Calcinosis; Calciphylaxis; Dihydrotachysterol; Necrosis; Phosphates; Rats; Skin Diseases; X-Ray Diffraction

Topics: Calcification, Physiologic; Calcinosis; Dihydrotachysterol; Hypophysectomy; Myocardium; Necrosis; Parathyroid Glands; Pathology; Rats; Research; Serotonin; Triamcinolone

Topics: Animals; Dihydrotachysterol; Myocardial Infarction; Necrosis; Rats