Document Detail

Humic acid induces G1 phase arrest and apoptosis in cultured vascular smooth muscle cells.
MedLine Citation:
PMID:  18683188     Owner:  NLM     Status:  MEDLINE    
Humic acid (HA) in well water used by the inhabitants for drinking is one of the possible etiological factors for Blackfoot disease (BFD). In this study, the ability of HA to inhibit cell cycle progression and induce apoptosis in cultured smooth muscle cells (SMCs; A7r5) was investigated. Treatment of the SMCs at various HA concentrations (25-200 microg/mL) resulted in sequences of events marked by apoptosis, as shown by loss of cell viability, morphology change, and internucleosomal DNA fragmentation. HA-induced apoptotic cell death that is associated with loss of mitochondrial membrane potential (Delta Psi m), cytochrome c translocation, caspase-3, -8, and -9 activation, poly ADP-ribose polymerase (PARP) degradation, dysregulation of Bcl-2 and Bax, and upregulation of p53 and phospholyrated p53 (p-p53) in SMCs. Flow cytometry analysis demonstrated that HA blocked cell cycle progress in the G1 phase in SMCs. This blockade of cell cycle was associated with reduced amounts of cyclin D1, CDK4, cyclin E, CDK2, and hyperphosphorylated retinoblastoma protein (pRb) in a time-dependent manner. Apparent DNA strand breaks (DNA damage) were also detected in a dose-dependent manner using Single-cell gel electrophoresis assay (comet assay). Furthermore, HA induced dose-dependent elevation of reactive oxygen species (ROS) level in SMCs, and antioxidant vitamin C and Trolox effectively suppressed HA-induced DNA damage and dysregulation of Bcl-2/Bax. Our findings suggest that HA-induced DNA damage, cell cycle arrest, and apoptosis in SMCs may be an underlying mechanisms for the atherosclerosis and thrombosis observed in the BFD endemic region.
You-Cheng Hseu; Elong Lin; Jing-Yi Chen; Yi-Ru Liua; Chun-Yin Huang; Fung-Jou Lu; Jiunn-Wang Liao; Ssu-Ching Chen; Hsin-Ling Yang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Environmental toxicology     Volume:  24     ISSN:  1522-7278     ISO Abbreviation:  Environ. Toxicol.     Publication Date:  2009 Jun 
Date Detail:
Created Date:  2009-05-07     Completed Date:  2009-06-17     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  100885357     Medline TA:  Environ Toxicol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  243-58     Citation Subset:  IM    
Department of Cosmeceutics, China Medical University, Taichung, Taiwan.
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MeSH Terms
Caspases / metabolism
Cell Line
Cell Survival / drug effects
Collagen Type XI / metabolism
Cyclin D1 / drug effects,  genetics
Cyclin E / drug effects,  genetics
Cyclin-Dependent Kinase 2 / drug effects,  genetics
Cyclin-Dependent Kinase 4 / drug effects,  genetics
Cytochromes c / metabolism
DNA Fragmentation
G1 Phase / drug effects*
Humic Substances / toxicity*
Membrane Potential, Mitochondrial / drug effects
Muscle, Smooth, Vascular / cytology,  drug effects*,  metabolism
Proto-Oncogene Proteins c-bcl-2 / metabolism
Retinoblastoma Protein / metabolism
bcl-2-Associated X Protein / metabolism
Reg. No./Substance:
0/COL11A2 protein, human; 0/Collagen Type XI; 0/Cyclin E; 0/Humic Substances; 0/Proto-Oncogene Proteins c-bcl-2; 0/Retinoblastoma Protein; 0/bcl-2-Associated X Protein; 136601-57-5/Cyclin D1; 9007-43-6/Cytochromes c; EC Kinase 2; EC Kinase 4; EC 3.4.22.-/Caspases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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