Humic Acid-Induced Echinocyte Transformation in Human Erythrocytes: Characterization of Morphological Changes and Determination of the Mechanism Underlying Damage

Hseu, You‐Cheng; Lu, Fung‐Jou; Engelking, Larry R.; Chen, Chaoling; Chen, Ying-Hsiu; Yang, Hsin‐Ling

doi:10.1080/009841000156493

Cited by 16 publications

(2 citation statements)

References 35 publications

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“…Blackfoot disease (BFD) is an endemic chronic peripheral vascular disease that occurs along the southwest coast of Taiwan [1,2,3]. Patients with similar symptoms were also found in China, The Philippines, India, Romania, Mexico, Chile and Argentina [4,5,6].…”

Section: Introductionmentioning

confidence: 99%

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Chitosan, the Marine Functional Food, Is a Potent Adsorbent of Humic Acid

et al. 2011

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Chitosan is prepared by the deacetylation of chitin, the second-most abundant biopolymer in nature, and has applicability in the removal of dyes, heavy metals and radioactive waste for pollution control. In weight-reduction remedies, chitosan is used to form hydrogels with lipids and to depress the intestinal absorption of lipids. In this study, an experimental method was implemented to simulate the effect of chitosan on the adsorption of humic acid in the gastrointestinal tract. The adsorption capacity of chitosan was measured by its adsorption isotherm and analyzed using the Langmuir equation. The results showed that 3.3 grams of humic acid was absorbed by 1 gram of chitosan. The adsorption capacity of chitosan was much greater than that of chitin, diethylaminoethyl-cellulose or activated charcoal. Cellulose and carboxymethyl-cellulose, a cellulose derivative with a negative charge, could not adsorb humic acid in the gastrointestinal tract. This result suggests that chitosan entraps humic acid because of its positive charge.

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Section: Introductionmentioning

confidence: 99%

“…The disease results in black discoloration and ulceration of the extremities. After gangrene develops, entire limbs are eventually affected [1,2]. A causal association between BFD and drinking well water has been revealed by an epidemiological study [7].…”

Section: Introductionmentioning

confidence: 99%

Chitosan, the Marine Functional Food, Is a Potent Adsorbent of Humic Acid

et al. 2011

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Induction of macrophage cell‐cycle arrest and apoptosis by humic acid

Yang

Pei

Chen

et al. 2014

Environ and Mol Mutagen

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Humic acid (HA) in well water is associated with Blackfoot disease and various cancers. Previously, we reported that acute humic acid exposure (25–200 µg/mL for 24 hr) induces inflammation in RAW264.7 macrophages. In this study, we observed that prolonged (72 hr) HA exposure (25–200 µg/mL) induces cell‐cycle arrest and apoptosis in cultured RAW264.7 cells. We also observed that exposing macrophages to HA arrests cells in the G2/M phase of the cell cycle by reducing cyclin A/B1, Cdc2, and Cdc25C levels. Treating macrophages with HA triggers a sequence of events characteristic of apoptotic cell death including loss of cell viability, morphological changes, internucleosomal DNA fragmentation, sub‐G1 accumulation. Molecular markers of apoptosis associated with mitochondrial dysfunction were similarly observed, including cytochrome c release, caspase‐3 or caspase‐9 activation, and Bcl‐2/Bax dysregulation. In addition to the mitochondrial pathway, HA‐induced apoptosis may also be mediated through the death receptor and ER stress pathways, as evidence by induction of Fas, caspase‐8, caspase‐4, and caspase‐12 activity. HA also upregulates p53 expression and causes DNA damage as assessed by the comet assay. These findings yield new insight into the mechanisms by which HA exposure may trigger atherosclerosis through modulation of the macrophage‐mediated immune system. Environ. Mol. Mutagen. 55:741–750, 2014. © 2014 Wiley Periodicals, Inc.

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Humic acid induces G1 phase arrest and apoptosis in cultured vascular smooth muscle cells

Hseu

Lin

Chen

et al. 2008

Environmental Toxicology

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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.

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Humic Acid-Induced Echinocyte Transformation in Human Erythrocytes: Characterization of Morphological Changes and Determination of the Mechanism Underlying Damage

Cited by 16 publications

References 35 publications

Chitosan, the Marine Functional Food, Is a Potent Adsorbent of Humic Acid

Chitosan, the Marine Functional Food, Is a Potent Adsorbent of Humic Acid

Induction of macrophage cell‐cycle arrest and apoptosis by humic acid

Humic acid induces G1 phase arrest and apoptosis in cultured vascular smooth muscle cells

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