Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidized low-density lipoprotein- (Ox-LDL-) induced autophagy dysfunction in human vascular endothelial cells contributes to the development of atherosclerosis (AS). Resveratrol (RSV) protects against Ox-LDL-induced endothelium injury. The objective of this study was to determine the mechanisms underlying Ox-LDL-induced autophagy dysfunction and RSV-mediated protection in human umbilical vein endothelial cells (HUVECs). The results showed that Ox-LDL suppressed the expression of sirtuin 1 (SIRT1) and increased LC3-II and sequestosome 1 (p62) protein levels without altering p62 mRNA levels in HUVECs. Pretreatment with bafilomycin A1 (BafA1) to inhibit lysosomal degradation abrogated the Ox-LDL-induced increase in LC3-II protein level. Ox-LDL increased colocalization of GFP and RFP puncta in mRFP-GFP-tandem fluorescent LC3- (tf-LC3-) transfected cells. Moreover, Ox-LDL decreased the expression of mature cathepsin D and attenuated cathepsin D activity. Pretreatment with RSV increased the expression of SIRT1 and LC3-II and increased p62 protein degradation. RSV induced RFP-LC3 aggregation more than GFP-LC3 aggregation. RSV restored lysosomal function and promoted Ox-LDL degradation in HUVECs. All the protective effects of RSV were blocked after SIRT1 was knocked down. These findings demonstrated that RSV upregulated the expression of SIRT1, restored lysosomal function, enhanced Ox-LDL-induced impaired autophagic flux, and promoted Ox-LDL degradation through the autophagy-lysosome degradation pathway in HUVECs.
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PMID:Resveratrol Enhances Autophagic Flux and Promotes Ox-LDL Degradation in HUVECs via Upregulation of SIRT1. 2706 32

Macroautophagy impairment plays a key role in sporadic Alzheimer's disease (sAD) neurodegenerative process. Nevertheless, the mechanism(s) that lead to a deficiency in macroautophagy in AD remains elusive. In this work, we identify, for the first time that Beclin-1 acetylation status is implicated in the alterations in autophagy observed in AD neurodegeneration. We observed that Beclin-1 is deacetylated by sirtuin 1 (SIRT1) and acetylated by p300. In addition, Beclin-1 acetylation inhibits autophagosome maturation, leading to impairment in autophagic flux. We also analyzed some proteins known to be involved in the maturation of autophagosomes such as Rab7, which participates in the fusion step with lysosomes. We observed that increased expression of Rab7 might represent a response to boost the formation of large perinuclear lysosome clusters in accordance with an increase in lysosomal biogenesis determined by increase in LAMP-2A, LAMP-1, and cathepsin D expression in AD cells. Thus, our data provides strong evidences that Beclin-1 acetylation impairs the autophagic flux, and despite lysosomal biogenesis seems to be triggered as a compensatory response, autophagosome fusion with lysosomes is compromised contributing to AD neurodegeneration.
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PMID:The Role of Beclin-1 Acetylation on Autophagic Flux in Alzheimer's Disease. 3066 Dec 6