Humic acid in drinking well water induces inflammation through reactive oxygen species generation and activation of nuclear factor-κB/activator protein-1 signaling pathways: A possible role in atherosclerosis

Hseu, You-Cheng; Senthil Kumar, K. J.; Chen, Chih-Sheng; Cho, Hsin-Ju; Lin, Shu-Wei; Shen, Pei-Chun; Lin, Cheng-Wen; Lu, Fung-Jou; Yang, Hsin-Ling

doi:10.1016/J.TAAP.2013.11.002

Title: Humic acid in drinking well water induces inflammation through reactive oxygen species generation and activation of nuclear factor-κB/activator protein-1 signaling pathways: A possible role in atherosclerosis

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Abstract

Humic acid (HA) has been implicated as one of the etiological factors in the peripheral vasculopathy of blackfoot disease (BFD) in Taiwan. However, the underlying pathophysiological mechanisms of BFD are not well defined. In this study, we used an in vitro and in vivo model, in which HA (25–200 μg/mL) activated macrophages to produce pro-inflammatory molecules by activating their transcriptional factors. HA exposure induced NO and PGE{sub 2} production followed by induction of iNOS and COX-2 through NF-κB/AP-1 transactivation in macrophages. In addition, the production of TNF-α and IL-1β was significantly increased by HA. Moreover, HA-induced iNOS and COX-2 expression were down-regulated by the NF-κB and AP-1 inhibitors pyrrolidine dithiocarbamate (PDTC) and Tanshinone, respectively. Furthermore, generations of ROS and nitrotyrosine, as well as activation of the AKT and MAPKs signaling cascades were observed after HA exposure. Specifically, HA-induced NF-κB activation was mediated by ROS and AKT, and that HA-induced AP-1 activation was mediated by JNK and ERK. Notably, HA-mediated AKT, JNK, and ERK activation was ROS-independent. The inflammatory potential of HA was correlated with increased expression of HO-1 and Nrf2. Furthermore, an in vivo study confirms that mice exposed to HA, the serum levels of TNF-α and IL-1β was significantlymore »« less

Authors:

Hseu, You-Cheng ^[1]; Senthil Kumar, K. J. ^[1]; Chen, Chih-Sheng; Cho, Hsin-Ju; Lin, Shu-Wei; Shen, Pei-Chun ^[2]; Lin, Cheng-Wen ^[3]; Lu, Fung-Jou ^[4]; Yang, Hsin-Ling ^[2]

Department of Cosmeceutics, China Medical University, Taichung 40402, Taiwan (China)
Institute of Nutrition, China Medical University, Taichung 40402, Taiwan (China)
Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan (China)
Institute of Medicine, Chun Shan Medical University, Taichung 40201, Taiwan (China)

Publication Date:: Wed Jan 15 00:00:00 EST 2014

OSTI Identifier:: 22285577

Resource Type:: Journal Article

Journal Name:: Toxicology and Applied Pharmacology

Additional Journal Information:: Journal Volume: 274; Journal Issue: 2; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES; ARTERIOSCLEROSIS; HUMIC ACIDS; INFLAMMATION; LYMPHOKINES; MACROPHAGES; MICE; NITRIC OXIDE; WATER

Citation Formats


                    Hseu, You-Cheng, Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, TX 77030, Senthil Kumar, K. J., Chen, Chih-Sheng, Cho, Hsin-Ju, Lin, Shu-Wei, Shen, Pei-Chun, Lin, Cheng-Wen, Lu, Fung-Jou, Yang, Hsin-Ling, and Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, TX 77030. Humic acid in drinking well water induces inflammation through reactive oxygen species generation and activation of nuclear factor-κB/activator protein-1 signaling pathways: A possible role in atherosclerosis.  United States: N. p., 2014. 
        Web.  doi:10.1016/J.TAAP.2013.11.002.

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                    Hseu, You-Cheng, Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, TX 77030, Senthil Kumar, K. J., Chen, Chih-Sheng, Cho, Hsin-Ju, Lin, Shu-Wei, Shen, Pei-Chun, Lin, Cheng-Wen, Lu, Fung-Jou, Yang, Hsin-Ling, & Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, TX 77030. Humic acid in drinking well water induces inflammation through reactive oxygen species generation and activation of nuclear factor-κB/activator protein-1 signaling pathways: A possible role in atherosclerosis.  United States.  https://doi.org/10.1016/J.TAAP.2013.11.002

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                    Hseu, You-Cheng, Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, TX 77030, Senthil Kumar, K. J., Chen, Chih-Sheng, Cho, Hsin-Ju, Lin, Shu-Wei, Shen, Pei-Chun, Lin, Cheng-Wen, Lu, Fung-Jou, Yang, Hsin-Ling, and Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, TX 77030. 2014.  
        "Humic acid in drinking well water induces inflammation through reactive oxygen species generation and activation of nuclear factor-κB/activator protein-1 signaling pathways: A possible role in atherosclerosis".  United States.  https://doi.org/10.1016/J.TAAP.2013.11.002.

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@article{osti_22285577,

  title        = {Humic acid in drinking well water induces inflammation through reactive oxygen species generation and activation of nuclear factor-κB/activator protein-1 signaling pathways: A possible role in atherosclerosis},

  author       = {Hseu, You-Cheng and Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, TX 77030 and Senthil Kumar, K. J. and Chen, Chih-Sheng and Cho, Hsin-Ju and Lin, Shu-Wei and Shen, Pei-Chun and Lin, Cheng-Wen and Lu, Fung-Jou and Yang, Hsin-Ling and Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, TX 77030},

  abstractNote = {Humic acid (HA) has been implicated as one of the etiological factors in the peripheral vasculopathy of blackfoot disease (BFD) in Taiwan. However, the underlying pathophysiological mechanisms of BFD are not well defined. In this study, we used an in vitro and in vivo model, in which HA (25–200 μg/mL) activated macrophages to produce pro-inflammatory molecules by activating their transcriptional factors. HA exposure induced NO and PGE{sub 2} production followed by induction of iNOS and COX-2 through NF-κB/AP-1 transactivation in macrophages. In addition, the production of TNF-α and IL-1β was significantly increased by HA. Moreover, HA-induced iNOS and COX-2 expression were down-regulated by the NF-κB and AP-1 inhibitors pyrrolidine dithiocarbamate (PDTC) and Tanshinone, respectively. Furthermore, generations of ROS and nitrotyrosine, as well as activation of the AKT and MAPKs signaling cascades were observed after HA exposure. Specifically, HA-induced NF-κB activation was mediated by ROS and AKT, and that HA-induced AP-1 activation was mediated by JNK and ERK. Notably, HA-mediated AKT, JNK, and ERK activation was ROS-independent. The inflammatory potential of HA was correlated with increased expression of HO-1 and Nrf2. Furthermore, an in vivo study confirms that mice exposed to HA, the serum levels of TNF-α and IL-1β was significantly increased in a dose-dependent manner. This report marks the first confirmation that environmental exposure of HA induces inflammation in macrophages, which may be one of the main causes of early atherogenesis in blackfoot disease. - Highlights: • Humic acid (HA) induce pro-inflammatory cytokines and mediators in macrophages. • HA-induced inflammation is mediated by ROS and NF-κB/AP-1 signaling pathways. • The inflammatory potential of HA correlated with activation of Nrf2/HO-1 genes. • HA exposure to mice increased pro-inflammatory cytokines production in vivo. • HA may be one of the main causes of early atherogenesis in blackfoot disease.},

  doi          = {10.1016/J.TAAP.2013.11.002},

  url          = {https://www.osti.gov/biblio/22285577},
  journal      = {Toxicology and Applied Pharmacology},

  issn         = {0041-008X},

  number       = 2,

  volume       = 274,

  place        = {United States},

  year         = {Wed Jan 15 00:00:00 EST 2014},

  month        = {Wed Jan 15 00:00:00 EST 2014}

}

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