Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0155339 (Brown)
 12,436 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transport of pro-cathepsin D from the trans-Golgi network (TGN) to the endosomal pathway is dependent on binding to the calcium-independent mannose 6-phosphate receptor (ci-M6PR), which is incorporated into TGN-derived clathrin-coated transport vesicles (CCVs). Inhibition of this transport step by wortmannin has led to the proposal that it is dependent upon a phosphoinositide 3-kinase activity necessary for ci-M6PR recruitment into TGN-derived CCVs or in the formation of those vesicles (Brown, W. J., DeWald, D. B., Emr, S. D., Plutner, H., and Balch, W. E. (1995) J. Cell Biol. 130, 781-796; Davidson, H. W. (1995) J. Cell Biol. 130, 797-806). In this study we have addressed the effect of wortmannin on the TGN step of the ci-M6PR cycle. CCVs from K562 cells, pretreated or not with 250 nM wortmannin, were purified on equilibrium density gradients. Quantification of TGN-derived CCVs, assessed by gamma-adaptin content in purified vesicle fractions, showed that the formation of the vesicles was only marginally decreased after 20 min of treatment with the drug, while for the same wortmannin treatment, the amount of ci-M6PR recruited into those vesicles was decreased by 70% compared with control. At a later time point (2 h), a reduction in the amount of gamma-adaptin in CCV fractions was also observed. These findings demonstrate that inhibition of ci-M6PR recruitment into CCVs but not of vesicle formation is the primary reason for the observed defect in cathepsin D transport following wortmannin treatment.
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PMID:Inhibition of calcium-independent mannose 6-phosphate receptor incorporation into trans-Golgi network-derived clathrin-coated vesicles by wortmannin. 930 67

Calorie restriction (CR), the purposeful reduction of energy intake with maintenance of adequate micronutrient intake, is well known to extend the lifespan of laboratory animals. Compounds like 2-deoxy-D-glucose (2DG) that can recapitulate the metabolic effects of CR are of great interest for their potential to extend lifespan. 2DG treatment has been shown to have potential therapeutic benefits for treating cancer and seizures. 2DG has also recapitulated some hallmarks of the CR phenotype including reduced body temperature and circulating insulin in short-term rodent trials, but one chronic feeding study in rats found toxic effects. The present studies were performed to further explore the long-term effects of 2DG in vivo. First we demonstrate that 2DG increases mortality of male Fischer-344 rats. Increased incidence of pheochromocytoma in the adrenal medulla was also noted in the 2DG treated rats. We reconfirm the cardiotoxicity of 2DG in a 6-week follow-up study evaluating male Brown Norway rats and a natural form of 2DG in addition to again examining effects in Fischer-344 rats and the original synthetic 2DG. High levels of both 2DG sources reduced weight gain secondary to reduced food intake in both strains. Histopathological analysis of the hearts revealed increasing vacuolization of cardiac myocytes with dose, and tissue staining revealed the vacuoles were free of both glycogen and lipid. We did, however, observe higher expression of both cathepsin D and LC3 in the hearts of 2DG-treated rats which indicates an increase in autophagic flux. Although a remarkable CR-like phenotype can be reproduced with 2DG treatment, the ultimate toxicity of 2DG seriously challenges 2DG as a potential CR mimetic in mammals and also raises concerns about other therapeutic applications of the compound.
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PMID:Chronic ingestion of 2-deoxy-D-glucose induces cardiac vacuolization and increases mortality in rats. 2002 95