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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.
Toxicol Appl Pharmacol. 2014 Jan 15; 274(2):249-62.TA

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 (25-200μg/mL) activated macrophages to produce pro-inflammatory molecules by activating their transcriptional factors. HA exposure induced NO and PGE2 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.

Authors+Show Affiliations

Department of Cosmeceutics, China Medical University, Taichung 40402, Taiwan; Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, TX 77030, USA.Department of Cosmeceutics, China Medical University, Taichung 40402, Taiwan.Institute of Nutrition, China Medical University, Taichung 40402, Taiwan.Institute of Nutrition, China Medical University, Taichung 40402, Taiwan.Institute of Nutrition, China Medical University, Taichung 40402, Taiwan.Institute of Nutrition, China Medical University, Taichung 40402, Taiwan.Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan.Institute of Medicine, Chun Shan Medical University, Taichung 40201, Taiwan.Institute of Nutrition, China Medical University, Taichung 40402, Taiwan; Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, TX 77030, USA. Electronic address: hlyang@mail.cmu.edu.tw.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24239652

Citation

Hseu, You-Cheng, et al. "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." Toxicology and Applied Pharmacology, vol. 274, no. 2, 2014, pp. 249-62.
Hseu YC, Senthil Kumar KJ, Chen CS, et al. 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. Toxicol Appl Pharmacol. 2014;274(2):249-62.
Hseu, Y. C., Senthil Kumar, K. J., Chen, C. S., Cho, H. J., Lin, S. W., Shen, P. C., Lin, C. W., Lu, F. J., & Yang, H. L. (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. Toxicology and Applied Pharmacology, 274(2), 249-62. https://doi.org/10.1016/j.taap.2013.11.002
Hseu YC, et al. 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. Toxicol Appl Pharmacol. 2014 Jan 15;274(2):249-62. PubMed PMID: 24239652.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Hseu,You-Cheng, AU - Senthil Kumar,K J, AU - Chen,Chih-Sheng, AU - Cho,Hsin-Ju, AU - Lin,Shu-Wei, AU - Shen,Pei-Chun, AU - Lin,Cheng-Wen, AU - Lu,Fung-Jou, AU - Yang,Hsin-Ling, Y1 - 2013/11/12/ PY - 2013/08/01/received PY - 2013/10/31/revised PY - 2013/11/02/accepted PY - 2013/11/19/entrez PY - 2013/11/19/pubmed PY - 2014/3/4/medline KW - AP-1 KW - Activating protein-1 KW - BFD KW - Blackfoot disease KW - COX-2 KW - ERK KW - HA KW - HO-1 KW - Heme oxygenase-1 KW - Humic acid KW - IL-1β KW - IκB KW - JNK KW - Keap-1 KW - Kelch-like ECH-associated protein 1 KW - MAPK KW - NF-E2-related factor-2 KW - NF-κB KW - NO KW - Nrf2 KW - PDTC KW - PGE(2) KW - ROS KW - TNF-α KW - c-JUN N-terminal kinase KW - cyclooxygenase-2 KW - extracellular signal-regulated kinase KW - humic acid KW - iNOS KW - inducible nitric oxide synthase KW - inhibitor kappa B KW - interleukin-1 beta KW - mitogen activated protein kinase KW - nitric oxide (NO) KW - nuclear factor-kappa B KW - prostaglandin E(2) KW - pyrrolidine dithiocarbamate KW - reactive oxygen species KW - tumor necrosis factor-alpha SP - 249 EP - 62 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 274 IS - 2 N2 - 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 (25-200μg/mL) activated macrophages to produce pro-inflammatory molecules by activating their transcriptional factors. HA exposure induced NO and PGE2 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. SN - 1096-0333 UR - https://www.unboundmedicine.com/medline/citation/24239652/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(13)00484-5 DB - PRIME DP - Unbound Medicine ER -