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El-Mahrouk SR, El-Ghiaty MA, Alqahtani MA, El-Kadi AOS. Arsenic Trioxide (ATO III) Induces NAD(P)H Quinone Oxidoreductase 1 (NQO1) Expression in Hepatic and Extrahepatic Tissues of C57BL/6 Mice. Chem Res Toxicol 2024; 37:2040-2051. [PMID: 39630573 DOI: 10.1021/acs.chemrestox.4c00422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2024]
Abstract
Arsenic trioxide (ATOIII) has emerged as a potent therapeutic agent for acute promyelocytic leukemia (APL), yet its clinical application is often limited by significant adverse effects. This study investigates the molecular mechanisms underlying ATOIII's impact on cellular detoxification pathways, focusing on the regulation of NAD(P)H/quinone oxidoreductase (NQO1), a crucial enzyme in maintaining cellular homeostasis and cancer prevention. We explored ATOIII's effects on NQO1 expression in C57BL/6 mice and Hepa-1c1c7 cells, both independently and in combination with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a known NQO1 inducer. Our findings revealed that ATOIII significantly increased NQO1 expression in hepatic and extrahepatic tissues, as well as in Hepa-1c1c7 cells, at mRNA, protein, and activity levels. This upregulation occurred both in the presence and absence of TCDD. Mechanistically, we demonstrated that ATOIII promotes the nuclear translocation of both nuclear factor erythroid 2-related factor-2 (NRF2) and aryl hydrocarbon receptor (AHR) transcription factors. Furthermore, ATOIII exposure increased antioxidant response element (ARE)-driven reporter gene activity, indicating a transcriptional mechanism of NQO1 induction. Notably, gene silencing experiments confirmed the critical roles of both NRF2 and AHR in mediating ATOIII-induced NQO1 expression. In conclusion, ATOIII exposure is found to upregulate the NQO1 enzyme through a transcriptional mechanism via AHR- and NRF2- dependent mechanisms, offering valuable insights into its therapeutic mechanisms.
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Affiliation(s)
- Sara R El-Mahrouk
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2H1, Canada
- Faculty of Pharmacy, Tanta University, Gharbia, Tanta 31111, Egypt
| | - Mahmoud A El-Ghiaty
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2H1, Canada
| | - Mohammed A Alqahtani
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2H1, Canada
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia
| | - Ayman O S El-Kadi
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2H1, Canada
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Aztatzi-Mendoza MA, Porras-Núñez EL, Rivas-Galindo VM, Carranza-Rosales P, Carranza-Torres IE, García-Vielma C, Hernández Ahuactzi IF, López-Cortina S, López I, Hernández-Fernández E. Green synthesis of ethyl cinnamates under microwave irradiation: photophysical properties, cytotoxicity, and cell bioimaging. RSC Adv 2024; 14:2391-2401. [PMID: 38213976 PMCID: PMC10783162 DOI: 10.1039/d3ra06443c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 12/22/2023] [Indexed: 01/13/2024] Open
Abstract
A simple and green method for the synthesis of six ethyl cinnamates was performed via Horner-Wadsworth-Emmons reaction under microwave irradiation. The photoluminescent properties of all compounds in ethyl acetate solutions were evaluated demonstrating that all compounds exhibit fluorescence. Five compounds exhibited blue emissions in the 369-442 nm range, and another compound exhibited blue-green emission at 504 nm. This last compound showed the largest Stokes shift (134 nm), and the highest quantum yield (17.8%). Two compounds showed extinction coefficient values (ε) higher than 30 000 M-1 cm-1, which are appropriate for cell bioimaging applications. In this sense, cytotoxicity assays were performed using Vero cells at different concentrations; the results showed that these compounds were not cytotoxic at the highest concentration tested (20 μg mL-1). Finally, the analysis by fluorescence microscopy for localization and cellular staining using Vero cells demonstrated that the compounds stained the cytoplasm and the nuclei in a selective way.
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Affiliation(s)
- Miguel Angel Aztatzi-Mendoza
- Universidad Autónoma de Nuevo León, UANL, Facultad de Ciencias Químicas Pedro de Alba s/n, Ciudad Universitaria 66450 San Nicolás de los Garza Nuevo León Mexico +52-81-83294000 +52-81-83294000 ext. 6293
| | - Edgar Leonel Porras-Núñez
- Universidad Autónoma de Nuevo León, UANL, Facultad de Ciencias Químicas Pedro de Alba s/n, Ciudad Universitaria 66450 San Nicolás de los Garza Nuevo León Mexico +52-81-83294000 +52-81-83294000 ext. 6293
| | - Verónica M Rivas-Galindo
- Universidad Autónoma de Nuevo León, UANL, Facultad de Medicina Fco. I. Madero s/n, Mitras Centro 64460 Monterrey Nuevo León Mexico
| | - Pilar Carranza-Rosales
- Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social Monterrey 64720 Nuevo León Mexico
| | - Irma Edith Carranza-Torres
- Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social Monterrey 64720 Nuevo León Mexico
| | - Catalina García-Vielma
- Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social Monterrey 64720 Nuevo León Mexico
| | - Iran F Hernández Ahuactzi
- Centro Universitario de Tonalá, Universidad de Guadalajara Av. Nuevo Periférico 555, Ejido San José Tatepozco Tonalá 45425 Jalisco Mexico
| | - Susana López-Cortina
- Universidad Autónoma de Nuevo León, UANL, Facultad de Ciencias Químicas Pedro de Alba s/n, Ciudad Universitaria 66450 San Nicolás de los Garza Nuevo León Mexico +52-81-83294000 +52-81-83294000 ext. 6293
| | - Israel López
- Universidad Autónoma de Nuevo León (UANL), Facultad de Ciencias Químicas, Centro de Investigación en Biotecnología y Nanotecnología, Laboratorio de Nanociencias y Nanotecnología Autopista al Aeropuerto Internacional Mariano Escobedo Km. 10, Parque de Investigación e Innovación Tecnológica 66629 Apodaca Nuevo León Mexico +52-81-83294000 +52-81-83294000 ext. 4202
| | - Eugenio Hernández-Fernández
- Universidad Autónoma de Nuevo León, UANL, Facultad de Ciencias Químicas Pedro de Alba s/n, Ciudad Universitaria 66450 San Nicolás de los Garza Nuevo León Mexico +52-81-83294000 +52-81-83294000 ext. 6293
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Ariafar S, Makhdoomi S, Mohammadi M. Arsenic and Tau Phosphorylation: a Mechanistic Review. Biol Trace Elem Res 2023; 201:5708-5720. [PMID: 37211576 DOI: 10.1007/s12011-023-03634-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 03/14/2023] [Indexed: 05/23/2023]
Abstract
Arsenic poisoning can affect the peripheral nervous system and cause peripheral neuropathy. Despite different studies on the mechanism of intoxication, the complete process is not explained yet, which can prevent further intoxication and produce effective treatment. In the following paper, we would like to consider the idea that arsenic might cause some diseases via inflammation induction, and tauopathy in neurons. Tau protein, one of the microtubule-associated proteins expressed in neurons, contributes to neuronal microtubules structure. Arsenic may be involved in cellular cascades involved in modulating tau function or hyperphosphorylation of tau protein, which ultimately leads to nerve destruction. For proof of this assumption, some investigations have been planned to measure the association between arsenic and quantities of phosphorylation of tau protein. Additionally, some researchers have investigated the association between microtubule trafficking in neurons and the levels of tau protein phosphorylation. It should be noticed that changing tau phosphorylation in arsenic toxicity may add a new feature to understanding the mechanism of poisonousness and aid in discovering novel therapeutic candidates such as tau phosphorylation inhibitors for drug development.
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Affiliation(s)
- Saba Ariafar
- Department of Pharmacology & Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Sajjad Makhdoomi
- Department of Pharmacology & Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mojdeh Mohammadi
- Department of Pharmacology & Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran.
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García-Flores N, Jiménez-Suárez J, Garnés-García C, Fernández-Aroca DM, Sabater S, Andrés I, Fernández-Aramburo A, Ruiz-Hidalgo MJ, Belandia B, Sanchez-Prieto R, Cimas FJ. P38 MAPK and Radiotherapy: Foes or Friends? Cancers (Basel) 2023; 15:861. [PMID: 36765819 PMCID: PMC9913882 DOI: 10.3390/cancers15030861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 01/16/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023] Open
Abstract
Over the last 30 years, the study of the cellular response to ionizing radiation (IR) has increased exponentially. Among the various signaling pathways affected by IR, p38 MAPK has been shown to be activated both in vitro and in vivo, with involvement in key processes triggered by IR-mediated genotoxic insult, such as the cell cycle, apoptosis or senescence. However, we do not yet have a definitive clue about the role of p38 MAPK in terms of radioresistance/sensitivity and its potential use to improve current radiotherapy. In this review, we summarize the current knowledge on this family of MAPKs in response to IR as well as in different aspects related to radiotherapy, such as their role in the control of REDOX, fibrosis, and in the radiosensitizing effect of several compounds.
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Affiliation(s)
- Natalia García-Flores
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
| | - Jaime Jiménez-Suárez
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
| | - Cristina Garnés-García
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
| | - Diego M. Fernández-Aroca
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
| | - Sebastia Sabater
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
- Servicio de Oncología Radioterápica, Complejo Hospitalario Universitario de Albacete, 02006 Albacete, Spain
| | - Ignacio Andrés
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
- Servicio de Oncología Radioterápica, Complejo Hospitalario Universitario de Albacete, 02006 Albacete, Spain
| | - Antonio Fernández-Aramburo
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
- Servicio de Oncología Médica, Complejo Hospitalario Universitario de Albacete, 02006 Albacete, Spain
| | - María José Ruiz-Hidalgo
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
- Departamento de Química Inorgánica, Orgánica y Bioquímica, Área de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
| | - Borja Belandia
- Departamento de Biología del Cáncer, Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM), Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, 28029 Madrid, Spain
| | - Ricardo Sanchez-Prieto
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
- Departamento de Biología del Cáncer, Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM), Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, 28029 Madrid, Spain
- Departamento de Ciencias Médicas, Facultad de Medicina, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
| | - Francisco J. Cimas
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
- Departamento de Química Inorgánica, Orgánica y Bioquímica, Área de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
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Lee KT, Chen LY, Li WS, Lee HZ. Transcriptome analysis revealed the role of mTOR and MAPK signaling pathways in the white strain of Hypsizygus marmoreus extracts-induced cell death of human hepatoma Hep3B cells. Front Pharmacol 2022; 13:1039376. [PMID: 36506551 PMCID: PMC9732266 DOI: 10.3389/fphar.2022.1039376] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 11/17/2022] [Indexed: 11/27/2022] Open
Abstract
The aim of this study was to investigate the anticancer mechanisms of white genius mushroom (WGM). WGM is a popular edible mushroom in Taiwan and has been demonstrated to mediate potent antiproliferation effects against human Hep3B liver cancer cells in our previous study. According to next generation sequencing technology and KEGG pathway enrichment analysis, mTOR and MAPK signaling pathways were markedly changed during treatment with WGM extracts in Hep3B cells. Therefore, this study examined the effects of WGM extracts on the expression of mTOR and MAPK signaling pathway-related proteins, such as PI3K, Akt, mTOR, Ras, Raf, MEK, ERK, p38 and JNK in Hep3B cells. According to the results of immunoblotting, we demonstrated that the protein expression of the members of PI3K/Akt/mTOR and MAPK signaling pathways were involved in WGM extracts-induced cell death. Furthermore, the inhibitors of PI3K/Akt/mTOR and MAPK signaling pathways such as rapamycin, MK2206, LY3214996 and SB202190, blocked the induction of cell death and vacuoles formation induced by WGM extracts. This study also demonstrated that WGM extracts is able to inhibit Hep3B cell migration and colony formation in a dose-dependent manner. In addition to being a very popular food, WGM should be a pharmacologically safe natural agent for cancer treatment. Therefore, WGM might be designed to develop into a dietary chemopreventive agent for the cancer treatment.
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Affiliation(s)
- Kun-Tsung Lee
- Department of Oral Hygiene, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan,Department of Dentistry, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Li-Yun Chen
- School of Pharmacy, China Medical University, Taichung, Taiwan
| | - Wei-Sung Li
- Plant Pathology Division, Taiwan Agricultural Research Institute, Council of Agriculture, Executive Yuan, Taichung, Taiwan
| | - Hong-Zin Lee
- School of Pharmacy, China Medical University, Taichung, Taiwan,*Correspondence: Hong-Zin Lee,
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Heavy Metal Contamination of Natural Foods Is a Serious Health Issue: A Review. SUSTAINABILITY 2021. [DOI: 10.3390/su14010161] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Heavy metals play an important role in the homeostasis of living cells. However, these elements induce several adverse environmental effects and toxicities, and therefore seriously affect living cells and organisms. In recent years, some heavy metal pollutants have been reported to cause harmful effects on crop quality, and thus affect both food security and human health. For example, chromium, cadmium, copper, lead, and mercury were detected in natural foods. Evidence suggests that these elements are environmental contaminants in natural foods. Consequently, this review highlights the risks of heavy metal contamination of the soil and food crops, and their impact on human health. The data were retrieved from different databases such as Science Direct, PubMed, Google scholar, and the Directory of Open Access Journals. Results show that vegetable and fruit crops grown in polluted soil accumulate higher levels of heavy metals than crops grown in unpolluted soil. Moreover, heavy metals in water, air, and soil can reduce the benefits of eating fruits and vegetables. A healthy diet requires a rational consumption of foods. Physical, chemical, and biological processes have been developed to reduce heavy metal concentration and bioavailability to reduce heavy metal aggregation in the ecosystem. However, mechanisms by which these heavy metals exhibit their action on human health are not well elucidated. In addition, the positive and negative effects of heavy metals are not very well established, suggesting the need for further investigation.
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Medda N, De SK, Maiti S. Different mechanisms of arsenic related signaling in cellular proliferation, apoptosis and neo-plastic transformation. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 208:111752. [PMID: 33396077 DOI: 10.1016/j.ecoenv.2020.111752] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 11/12/2020] [Accepted: 11/29/2020] [Indexed: 06/12/2023]
Abstract
Arsenic is a toxic heavy metal vastly dispersed all over the earth crust. It manifests several major adverse health issues to millions of arsenic exposed populations. Arsenic is associated with different types of cancer, cardiovascular disorders, diabetes, hypertension and many other diseases. On the contrary, arsenic (arsenic trioxide, As2O3) is used as a chemotherapeutic agent in the treatment of acute promyelocytic leukemia. Balance between arsenic induced cellular proliferations and apoptosis finally decide the outcome of its transformation rate. Arsenic propagates signals via cellular and nuclear pathways depending upon the chemical nature, and metabolic-fates of the arsenical compounds. Arsenic toxicity is propagated via ROS induced stress to DNA-repair mechanism and mitochondrial stability in the cell. ROS induced alteration in p53 regulation and some mitogen/ oncogenic functions determine the transformation outcome influencing cyclin-cdk complexes. Growth factor regulator proteins such as c-Jun, c-fos and c-myc are influenced by chronic arsenic exposure. In this review we have delineated arsenic induced ROS regulations of epidermal growth factor receptor (EGFR), NF-ĸβ, MAP kinase, matrix-metalloproteinases (MMPs). The role of these signaling molecules has been discussed in relation to cellular apoptosis, cellular proliferation and neoplastic transformation. The arsenic stimulated pathways which help in proliferation and neoplastic transformation ultimately resulted in cancer manifestation whereas apoptotic pathways inhibited carcinogenesis. Therapeutic strategies against arsenic should be designed taking into account all these factors.
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Affiliation(s)
- Nandita Medda
- Center for Life Sciences, Vidyasagar University, Midnapore-721102, West Bengal, India; Post Graduate Department of Biochemistry and Biotechnology Cell and Molecular Therapeutics Laboratory, Oriental Institute of Science and Technology, Midnapore-721102, West Bengal, India
| | - Subrata Kumar De
- Professor, Dept. of Zoology, Vidyasagar University, Midnapore, 721102, West Bengal, India; (on lien) Vice Chancellor, Mahatma Gandhi University, Purba Medinipur, 721628, West Bengal, India.
| | - Smarajit Maiti
- Post Graduate Department of Biochemistry and Biotechnology Cell and Molecular Therapeutics Laboratory, Oriental Institute of Science and Technology, Midnapore-721102, West Bengal, India.
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Rehman AU, Nazir S, Irshad R, Tahir K, ur Rehman K, Islam RU, Wahab Z. Toxicity of heavy metals in plants and animals and their uptake by magnetic iron oxide nanoparticles. J Mol Liq 2021. [DOI: 10.1016/j.molliq.2020.114455] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Abstract
Exposure to arsenic in contaminated drinking water is an emerging public health problem that impacts more than 200 million people worldwide. Accumulating lines of evidence from epidemiological studies revealed that chronic exposure to arsenic can result in various human diseases including cancer, type 2 diabetes, and neurodegenerative disorders. Arsenic is also classified as a Group I human carcinogen. In this review, we survey extensively different modes of action for arsenic-induced carcinogenesis, with focus being placed on arsenic-mediated impairment of DNA repair pathways. Inorganic arsenic can be bioactivated by methylation, and the ensuing products are highly genotoxic. Bioactivation of arsenicals also elicits the production of reactive oxygen and nitrogen species (ROS and RNS), which can directly damage DNA and modify cysteine residues in proteins. Results from recent studies suggest zinc finger proteins as crucial molecular targets for direct binding to As3+ or for modifications by arsenic-induced ROS/RNS, which may constitute a common mechanism underlying arsenic-induced perturbations of DNA repair.
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Suthprasertporn N, Suwanna N, Thangnipon W. Protective effects of diarylpropionitrile against hydrogen peroxide-induced damage in human neuroblastoma SH-SY5Y cells. Drug Chem Toxicol 2019; 45:44-51. [PMID: 31495239 DOI: 10.1080/01480545.2019.1658768] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Oxidative stress is implicated in pathogenesis of neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. The study demonstrates diarylpropionitrile (DPN), an antioxidant selective agonist of estrogen receptor β, protected human neuroblastoma SH-SY5Y cells against H2O2-induced toxicity by attenuating production of reactive oxygen species, apoptosis, autophagy, NF-κB activation, MAPK p38, JNK and ERK 1/2 signaling pathways, and β-site amyloid precursor protein cleaving enzyme level, but, interestingly, stimulating Akt pathway. These findings indicate the important potential of DPN to ameliorate oxidative stress-associated damage in neurodegenerative disorders.
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Affiliation(s)
- Nopparat Suthprasertporn
- Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University , Salaya , Nakhonpathom , 73170 , Thailand
| | - Nirut Suwanna
- Department of Companion Animal Clinical Sciences, Faculty of Veterinary Medicine, Kasetsart University , Kamphaeng Saen , Nakhonpathom , 73140 , Thailand
| | - Wipawan Thangnipon
- Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University , Salaya , Nakhonpathom , 73170 , Thailand
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Glorieux C, Huang P. Regulation of CD137 expression through K-Ras signaling in pancreatic cancer cells. Cancer Commun (Lond) 2019; 39:41. [PMID: 31288851 PMCID: PMC6615207 DOI: 10.1186/s40880-019-0386-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2019] [Accepted: 06/28/2019] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND The interaction between CD137 and its ligand (CD137L) plays a major role in the regulation of immune functions and affects cancer immunotherapy. CD137 is a cell surface protein mainly located on activated T cells, and its regulation and functions in immune cells are well established. However, the expression of CD137 and its regulation in cancer cells remain poorly understood. The main purposes of this study were to examine the expression of CD137 in pancreatic cancer cells and to investigate its underlying mechanisms. METHODS Cells containing inducible K-RasG12V expression vector or with different K-Ras mutational statuses were used as in vitro models to examine the regulation of CD137 expression by K-Ras. Various molecular assays were employed to explore the regulatory mechanisms. Tumor specimens from 15 pancreatic cancer patients and serum samples from 10 patients and 10 healthy donors were used to test if the expression of CD137 could be validated in clinical samples. RESULTS We found that the CD137 protein was expressed on the cell surface in pancreatic cancer tissues and cancer cell lines. Enzyme-linked immunosorbent assay revealed no difference in the levels of secreted CD137 in the sera of patients and healthy donors. By using the K-Ras inducible cell system, we further showed that oncogenic K-Ras up-regulated CD137 through the activation of MAPK (mitogen-activated protein kinases) and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathways, as evidenced by significantly reduced CD137 mRNA expression led by genetic silencing of MAPK1 and p65, the key proteins involved in the respective pathways. Furthermore, we also found that the NF-κB pathway was mainly stimulated by the K-Ras-induced secretion of interleukin-1α (IL-1α) which promoted the transcription of the CD137 gene in pancreatic cancer cell lines. Analysis of the TCGA (the cancer genome atlas) database also revealed a significant correlation between IL-1α and CD137 expression (r = 0.274) in tumor samples from pancreatic cancer patients (P < 0.001). CONCLUSIONS The present study has demonstrated that the CD137 protein was expressed on pancreatic cancer cell surface, and has identified a novel mechanism by which K-Ras regulates CD137 in pancreatic cancer cells through MAPK and NF-κB pathways stimulated by IL-1α.
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Affiliation(s)
- Christophe Glorieux
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China.
| | - Peng Huang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China.
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Singh P, Tiwari D, Mishra M, Kumar D. Molecular Mechanisms of Heavy Metal Toxicity in Cancer Progression. NETWORKING OF MUTAGENS IN ENVIRONMENTAL TOXICOLOGY 2019. [DOI: 10.1007/978-3-319-96511-6_3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Elbirt KK, Bonkovsky HL. Heme Oxygenase: Recent Advances in Understanding Its Regulation and Role. ACTA ACUST UNITED AC 2018. [DOI: 10.1111/paa.1999.111.5.438] [Citation(s) in RCA: 228] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Mir SA, Renuse S, Sathe G, Khan AA, Patil AH, Nanjappa V, Bhat FA, Prasad TSK, Giri AK, Chatterjee A, Gowda H. Altered signaling associated with chronic arsenic exposure in human skin keratinocytes. Proteomics Clin Appl 2017; 11. [PMID: 28731282 DOI: 10.1002/prca.201700004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 06/22/2017] [Accepted: 07/18/2017] [Indexed: 11/07/2022]
Abstract
Modulation of signaling pathways upon chronic arsenic exposure remains poorly studied. Here, we carried out SILAC-based quantitative phosphoproteomics analysis to dissect the signaling induced upon chronic arsenic exposure in human skin keratinocyte cell line, HaCaT. We identified 4171 unique phosphosites derived from 2000 proteins. We observed differential phosphorylation of 406 phosphosites (twofold) corresponding to 305 proteins. Several pathways involved in cytoskeleton maintenance and organization were found to be significantly enriched (p<0.05). Our data revealed altered phosphorylation of proteins associated with adherens junction remodeling and actin polymerization. Kinases such as protein kinase C iota type (PRKCI), mitogen-activated protein kinase kinase kinase 1 (MAP3K1), tyrosine-protein kinase BAZ1B (BAZ1B) and STE20 like kinase (SLK) were found to be hyperphosphorylated. Our study provides novel insights into signaling perturbations associated with chronic arsenic exposure in human skin keratinocytes. All MS/MS data have been deposited to the ProteomeXchange with identifier PXD004868.
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Affiliation(s)
- Sartaj Ahmad Mir
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal University, Manipal, India
| | - Santosh Renuse
- Center for Proteomics Discovery, Johns Hopkins University School of Medicine, Baltimore, MA, USA
| | - Gajanan Sathe
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal University, Manipal, India
| | - Aafaque Ahmad Khan
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- School of Biotechnology, KIIT University, Bhubaneswar, India
| | - Arun H Patil
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- School of Biotechnology, KIIT University, Bhubaneswar, India
| | | | - Firdous Ahmad Bhat
- Institute of Bioinformatics, International Technology Park, Bangalore, India
| | - T S Keshava Prasad
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- NIMHANS-IOB Proteomics and Bioinformatics Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences, Bangalore, India
- YU-IOB Center for Systems Biology and Molecular Medicine, Yenepoya University, Mangalore, India
| | - Ashok K Giri
- Molecular Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Aditi Chatterjee
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- YU-IOB Center for Systems Biology and Molecular Medicine, Yenepoya University, Mangalore, India
| | - Harsha Gowda
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- YU-IOB Center for Systems Biology and Molecular Medicine, Yenepoya University, Mangalore, India
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15
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Akanda MR, Kim IS, Ahn D, Tae HJ, Tian W, Nam HH, Choo BK, Park BY. In Vivo and In Vitro Hepatoprotective Effects of Geranium koreanum Methanolic Extract via Downregulation of MAPK/Caspase-3 Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2017; 2017:8137627. [PMID: 28757890 PMCID: PMC5516716 DOI: 10.1155/2017/8137627] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 06/05/2017] [Indexed: 12/13/2022]
Abstract
Geranium koreanum (GK) is an indigenous Chinese herbal medicine widely used for the treatment of various inflammation and liver disorders. However, the exact mechanism of action of GK remains unknown. This study aimed to investigate the protective effect and related molecular mechanism of GK on NaAsO2-induced cytotoxicity in HepG2 cells and liver damage in mice. The cytoprotective role of GK was assessed on HepG2 cells using MTT assay. Oxidative stress and lactate dehydrogenase levels were measured with ROS and LDH assay. Histopathology and serum enzymes levels were estimated. The molecular mechanism was evaluated by qPCR and immunoblotting to ensure the hepatoprotective role of GK against NaAsO2 intoxication in mice. We found cotreatment with GK significantly attenuated NaAsO2-induced cell viability loss, intracellular ROS, and LDH release. Hepatic histopathology and serum biochemical parameters, ALT, and AST were notably improved by cotreatment with GK. Beside, GK markedly altered both mRNA and protein expression level of MAPK. The proapoptotic and antiapoptotic protein Bax/Bcl-2 ratio was significantly regulated by GK. Moreover, GK remarkably suppressed the postapoptotic transcription protein cleaved caspase-3 expression. The present study reveals that GK possesses hepatoprotective activity which is probably involved in the modulation of the MAPK/caspase-3 pathway.
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Affiliation(s)
- Md Rashedunnabi Akanda
- College of Veterinary Medicine and Biosafety Research Institute, Chonbuk National University, Iksan 54596, Republic of Korea
- Department of Pharmacology and Toxicology, Sylhet Agricultural University, Sylhet 3100, Bangladesh
| | - In-Shik Kim
- College of Veterinary Medicine and Biosafety Research Institute, Chonbuk National University, Iksan 54596, Republic of Korea
| | - Dongchoon Ahn
- College of Veterinary Medicine and Biosafety Research Institute, Chonbuk National University, Iksan 54596, Republic of Korea
| | - Hyun-Jin Tae
- College of Veterinary Medicine and Biosafety Research Institute, Chonbuk National University, Iksan 54596, Republic of Korea
| | - Weishun Tian
- College of Veterinary Medicine and Biosafety Research Institute, Chonbuk National University, Iksan 54596, Republic of Korea
| | - Hyeon-Hwa Nam
- Department of Crop Science & Biotechnology, Chonbuk National University, Jeonju 54896, Republic of Korea
| | - Byung-Kil Choo
- Department of Crop Science & Biotechnology, Chonbuk National University, Jeonju 54896, Republic of Korea
| | - Byung-Yong Park
- College of Veterinary Medicine and Biosafety Research Institute, Chonbuk National University, Iksan 54596, Republic of Korea
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16
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Mardirosian MN, Ceschin DG, Lascano CI, Venturino A. Molecular effectors in the chronic exposure to arsenic as early and sensitive biomarkers in developing Rhinella arenarum toads. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2017; 186:19-27. [PMID: 28249226 DOI: 10.1016/j.aquatox.2017.02.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Revised: 02/15/2017] [Accepted: 02/16/2017] [Indexed: 06/06/2023]
Abstract
Arsenic, a natural element of ecological relevance, is one of the most toxic elements present in various regions of the world. It can be found in natural water sources throughout Argentina in concentrations between 0.01 and 15mgL-1. The Argentinean autochthonous toad Rhinella arenarum was selected to study the molecular mechanisms involved in the effects and response to the chronic As exposure along its embryonic and larval development. We evaluated the effects on MAPK signal transduction pathway and transcription factors c-FOS and c-JUN, and the regulation of the expression at protein levels of different antioxidant enzymes. Our results indicated that As is modulating the MAPK pathway, increasing MEK and ERK levels both in the nuclear and post-nuclear fraction along the embryonic development and mainly at the beginning of the larval stage. Through this pathway, As can upregulate transcription factors like c-FOS and c-JUN, impacting the antioxidant response of the exposed embryos and larvae through antioxidant enzymes and recycling of GSH. Arsenic triggered specifically the synthesis of antioxidant enzymes in exposed R. arenarum embryo and larvae. In particular, the expression levels of SOD, CAT and GST enzymes analyzed by Western blot showed a similar behavior to their enzymatic activities in our previous work. This fact suggests that not only the synthesis of these antioxidant enzymes but also their rapid degradation after inactivation would be regulated in response to ROS levels. Antioxidant enzymes may show dual responses of induction and inactivation followed by degradation depending on the levels of oxidative stress and impact on ROS targets when the exposure is sustained in time and intensity. We also performed a probability of exceedence analysis including our previous results to visualize a progression of the response in time and also established the best early-responding biomarkers at the lowest As concentrations. As a conclusion, the molecular biomarkers such as the MAPKs MEK and ERK and transcription factors c-FOS and c-JUN are early induced in the response of developing toad embryos exposed to very low As concentrations in water. The advantage of counting with molecular biomarkers early responding to low concentrations of As in a chronic exposure is that they may anticipate the irreversible damage at later developmental stages due to the constant oxidative challenge.
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Affiliation(s)
- Mariana Noelia Mardirosian
- Center for Research in Environmental Toxicology and Agrobiotechnology of Comahue, National Council of Scientific and Technical Research-National University of Comahue, Buenos Aires 1400, Neuquén, CP 8300 Neuquén, Argentina
| | - Danilo Guillermo Ceschin
- Center for Research in Environmental Toxicology and Agrobiotechnology of Comahue, National Council of Scientific and Technical Research-National University of Comahue, Buenos Aires 1400, Neuquén, CP 8300 Neuquén, Argentina
| | - Cecilia Inés Lascano
- Center for Research in Environmental Toxicology and Agrobiotechnology of Comahue, National Council of Scientific and Technical Research-National University of Comahue, Buenos Aires 1400, Neuquén, CP 8300 Neuquén, Argentina
| | - Andrés Venturino
- Center for Research in Environmental Toxicology and Agrobiotechnology of Comahue, National Council of Scientific and Technical Research-National University of Comahue, Buenos Aires 1400, Neuquén, CP 8300 Neuquén, Argentina.
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17
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Beeravolu N, McKee C, Chaudhry GR. Mechanism of arsenite toxicity in embryonic stem cells. J Appl Toxicol 2017; 37:1151-1161. [PMID: 28370166 DOI: 10.1002/jat.3469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2016] [Revised: 01/31/2017] [Accepted: 02/21/2017] [Indexed: 11/11/2022]
Abstract
Environmental arsenite exposure has been linked to cancer as well as other diseases, presenting an important and serious public health problem. Toxicity of inorganic arsenite (iAs) has been investigated using animal models and cell culture, yet its developmental effects are poorly understood. This study investigated the molecular mechanism of iAs toxicity to ascertain insight into development and differentiation processes using mouse embryonic stem cells (ESCs). The results showed that iAs exposure affected morphology and integrity of ESC colonies as well as inhibited cell growth in a concentration-dependent manner, excluding concentrations <1 μM iAs which stimulated ESC growth. ESCs self-renewal and pluripotency was also affected as evident from the downregulation of transcription circuitry, Oct4, Nanog, Sox2 and Klf4 resulting in non-specific differentiation. ESCs exposed to iAs randomly differentiated into three germ layers, mesoderm, endoderm and ectoderm, as judged by transcriptional expression of Brachyury, Gata4 and FGF2, as well as translational expression of BRACHYURY, GATA4 and TUJ1 respectively. The differentiated cells represented osteogenic, chondrogenic, myogenic and neurogenic lineages as evident from upregulation of Col1, Sox9, Col2, Myog, Notch, Nes and Nef. Although iAs caused slight apoptosis with a concomitant increase in ROS levels, the exposed ESCs had significant Bcl2 expression, which could be involved in the protection against apoptosis. Further analysis revealed upregulation of Jun and P38 in ESCs with an increase in iAs concentration. These observations indicated that iAs stress caused random differentiation of ESCs via JNK/P38 pathways. These findings suggest that iAs exposure may cause teratogenicity during early fetal development. Copyright © 2017 John Wiley & Sons, Ltd.
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Affiliation(s)
- Naimisha Beeravolu
- Department of Biological Sciences, Oakland University, Rochester, Michigan, USA.,OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, Michigan, USA
| | - Christina McKee
- Department of Biological Sciences, Oakland University, Rochester, Michigan, USA.,OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, Michigan, USA
| | - G Rasul Chaudhry
- Department of Biological Sciences, Oakland University, Rochester, Michigan, USA.,OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, Michigan, USA
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18
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Mir SA, Pinto SM, Paul S, Raja R, Nanjappa V, Syed N, Advani J, Renuse S, Sahasrabuddhe NA, Prasad TSK, Giri AK, Gowda H, Chatterjee A. SILAC-based quantitative proteomic analysis reveals widespread molecular alterations in human skin keratinocytes upon chronic arsenic exposure. Proteomics 2016; 17. [DOI: 10.1002/pmic.201600257] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 09/10/2016] [Accepted: 10/17/2016] [Indexed: 12/21/2022]
Affiliation(s)
- Sartaj Ahmad Mir
- Institute of Bioinformatics; International Technology Park; Bangalore India
- Manipal University; Manipal Karnataka India
| | - Sneha M. Pinto
- Institute of Bioinformatics; International Technology Park; Bangalore India
- YU-IOB Center for Systems Biology and Molecular Medicine; Yenepoya University; Mangalore India
| | - Somnath Paul
- Molecular Genetics Division; CSIR-Indian Institute of Chemical Biology; Kolkata India
| | - Remya Raja
- Institute of Bioinformatics; International Technology Park; Bangalore India
| | - Vishalakshi Nanjappa
- Institute of Bioinformatics; International Technology Park; Bangalore India
- Amrita School of Biotechnology; Amrita University; Kollam India
| | - Nazia Syed
- Institute of Bioinformatics; International Technology Park; Bangalore India
- Department of Biochemistry and Molecular Biology; Pondicherry University; Puducherry India
| | - Jayshree Advani
- Institute of Bioinformatics; International Technology Park; Bangalore India
- Manipal University; Manipal Karnataka India
| | - Santosh Renuse
- Institute of Bioinformatics; International Technology Park; Bangalore India
| | | | - T. S. Keshava Prasad
- Institute of Bioinformatics; International Technology Park; Bangalore India
- YU-IOB Center for Systems Biology and Molecular Medicine; Yenepoya University; Mangalore India
- NIMHANS-IOB Proteomics and Bioinformatics Laboratory; Neurobiology Research Centre; National Institute of Mental Health and Neurosciences; Bangalore India
| | - Ashok K. Giri
- Molecular Genetics Division; CSIR-Indian Institute of Chemical Biology; Kolkata India
| | - Harsha Gowda
- Institute of Bioinformatics; International Technology Park; Bangalore India
- YU-IOB Center for Systems Biology and Molecular Medicine; Yenepoya University; Mangalore India
| | - Aditi Chatterjee
- Institute of Bioinformatics; International Technology Park; Bangalore India
- YU-IOB Center for Systems Biology and Molecular Medicine; Yenepoya University; Mangalore India
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19
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He Y, Sun B, Li S, Sun X, Guo Y, Zhao H, Wang Y, Jiang G, Xing M. Simultaneous analysis 26 mineral element contents from highly consumed cultured chicken overexposed to arsenic trioxide by inductively coupled plasma mass spectrometry. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2016; 23:21741-21750. [PMID: 27522209 DOI: 10.1007/s11356-016-7318-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 07/22/2016] [Indexed: 06/06/2023]
Abstract
This study assessed the impacts of dietary arsenic trioxide (As2O3) on 26 mineral element contents in the liver and kidney of chicken. A total of 100 male Hy-line cocks were randomly divided into 2 groups (50 chickens in each group), including an arsenic-treated group (basic diet supplemented with As2O3 at 30 mg/kg) and a control group (basal diet). The feeding experiment lasted for 90 days and the experimental animals were given free access to feed and water. We determined 26 mineral elements in the liver and kidney by inductively coupled plasma mass spectrometry (ICP-MS). The results showed that nine element levels (Al, Mn, Co, Cu, Zn, Se, Cd, Ba, and Pb) were significantly decreased (P < 0.05) in the liver of chickens exposed to As2O3 compared to the control chickens where three element levels (Ni, As, and Hg) increased significantly (P < 0.05). The results in the kidney showed that nine element levels (Al, K, Ca, Cr, Mn, Ni, Sb, Ba, and Pb) were significantly decreased (P < 0.05) in the chickens exposed to As2O3 compared to the control chickens where four element levels (Mo, As, Cd, and Hg) increased significantly (P < 0.05). These results suggest that supplementation of high levels of arsenic affected trace mineral levels in the liver and kidney of chicken, and the effects vary from organ to organ. The aim of this study is to provide references for further study of heavy metal poisoning by detecting the contents of minerals induced by arsenic in chicken.
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Affiliation(s)
- Ying He
- College of Wildlife Resource, Northeast Forestry University, PRC, 26 Hexing Rd, Xiangfang District, Harbin, 150040, People's Republic of China
| | - Bonan Sun
- Department of Chemical Engineering and Bioengineering, McMaster University, 1280 Main Street West, Hamilton, ON, L8S4L8, Canada
| | - Siwen Li
- College of Wildlife Resource, Northeast Forestry University, PRC, 26 Hexing Rd, Xiangfang District, Harbin, 150040, People's Republic of China
| | - Xiao Sun
- College of Wildlife Resource, Northeast Forestry University, PRC, 26 Hexing Rd, Xiangfang District, Harbin, 150040, People's Republic of China
| | - Ying Guo
- College of Wildlife Resource, Northeast Forestry University, PRC, 26 Hexing Rd, Xiangfang District, Harbin, 150040, People's Republic of China
| | - Hongjing Zhao
- College of Wildlife Resource, Northeast Forestry University, PRC, 26 Hexing Rd, Xiangfang District, Harbin, 150040, People's Republic of China
| | - Yu Wang
- College of Wildlife Resource, Northeast Forestry University, PRC, 26 Hexing Rd, Xiangfang District, Harbin, 150040, People's Republic of China
| | - Guangshun Jiang
- College of Wildlife Resource, Northeast Forestry University, PRC, 26 Hexing Rd, Xiangfang District, Harbin, 150040, People's Republic of China.
| | - Mingwei Xing
- College of Wildlife Resource, Northeast Forestry University, PRC, 26 Hexing Rd, Xiangfang District, Harbin, 150040, People's Republic of China.
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20
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Peng CY, You BJ, Lee CL, Wu YC, Lin WH, Lu TL, Chang FC, Lee HZ. The Roles of 4β-Hydroxywithanolide E from Physalis peruviana on the Nrf2-Anti-Oxidant System and the Cell Cycle in Breast Cancer Cells. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2016; 44:617-36. [PMID: 27109152 DOI: 10.1142/s0192415x16500348] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
4[Formula: see text]-Hydroxywithanolide E is an active component of the extract of Physalis peruviana that has been reported to exhibit antitumor effects. Although the involvement of reactive oxygen species (ROS) production and the ataxia-telangiectasia mutated protein (ATM)-dependent DNA damage signaling pathway in 4[Formula: see text]-hydroxywithanolide E-induced apoptosis of breast cancer MCF-7 cells was demonstrated in our previous study, the relationship between ROS production and the cellular defense system response in 4[Formula: see text]-hydroxywithanolide E-induced cell death requires further verification. The present study suggests that ROS play an important role in 4[Formula: see text]-hydroxywithanolide E-induced MCF-7 cell death in which anti-oxidants, such as glutathione or N-acetylcysteine, can resist the 4[Formula: see text]-hydroxywithanolide E-induced accumulation of ROS and cell death. Furthermore, N-acetylcysteine or glutathione can reverse the 4[Formula: see text]-hydroxywithanolide E-induced changes in the cell cycle distribution and the expression of cell cycle regulators. We found that the 4[Formula: see text]-hydroxywithanolide E-induced ROS accumulation was correlated with the upregulation of Nrf2 and Nrf2-downstream genes, such as antioxidative defense enzymes. In general, the activity of Nrf2 is regulated by the Ras signalling pathway. However, we demonstrated that Nrf2 was activated during 4[Formula: see text]-hydroxywithanolide E-induced MCF-7 cell death in spite of the 4[Formula: see text]-hydroxywithanolide E-induced inhibition of the Ras/Raf/ERK pathway. The activity and protein expression of superoxide dismutase and catalase were involved in the 4[Formula: see text]-hydroxywithanolide E-induced ROS production in MCF-7 cells. Furthermore, 4[Formula: see text]-hydroxywithanolide E was demonstrated to significantly reduce the sizes of the tumor nodules in the human breast cancer MDA-MB231 xenograft tumor model.
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Affiliation(s)
- Chieh Yu Peng
- School of Pharmacy, China Medical University Hospital, Taichung, Taiwan
| | - Bang Jau You
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, Taiwan
| | - Chia Lin Lee
- Department of Cosmeceutics and Graduate Institute of Cosmeceutics, China Medical University, Taichung, Taiwan
- Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
| | - Yang Chang Wu
- School of Pharmacy, China Medical University Hospital, Taichung, Taiwan
- Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
| | - Wen Hsin Lin
- School of Pharmacy, China Medical University Hospital, Taichung, Taiwan
| | - Te Ling Lu
- School of Pharmacy, China Medical University Hospital, Taichung, Taiwan
| | - Fei-Ching Chang
- Pharmacy Department, Tainan Municipal An-Nan Hospital-China Medical University, Tainan, Taiwan
| | - Hong Zin Lee
- School of Pharmacy, China Medical University Hospital, Taichung, Taiwan
- Pharmacy Department, Tainan Municipal An-Nan Hospital-China Medical University, Tainan, Taiwan
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21
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Swallowing a bitter pill–oral arsenic trioxide for acute promyelocytic leukemia. Blood Rev 2016; 30:201-11. [DOI: 10.1016/j.blre.2015.11.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Revised: 11/18/2015] [Accepted: 11/24/2015] [Indexed: 11/23/2022]
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22
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Hashmi MZ, Khan KY, Hu J, Su X, Abbas G, Yu C, Shen C. Hormetic effects of noncoplanar PCB exposed to human lung fibroblast cells (HELF) and possible role of oxidative stress. ENVIRONMENTAL TOXICOLOGY 2015; 30:1385-1392. [PMID: 24942145 DOI: 10.1002/tox.22008] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Revised: 05/18/2014] [Accepted: 05/27/2014] [Indexed: 06/03/2023]
Abstract
Hormesis, a biphasic dose-response phenomenon, which is characterized by stimulation of an end point at a low-dose and inhibition at a high-dose. In the present study we used human lungs fibroblast (HELF) cells as a test model to evaluate the role of oxidative stress (OS) in hormetic effects of non coplanar PCB 101. Results from 3-(4,5-dime-thylthiazol-2-yl)-2,5-diphenyltetrazo-lium bromide (MTT) assay indicated that PCB101 at lower concentrations (10(-5) to 10(-1) μg mL(-1) ) stimulated HELF cell proliferation and inhibited at high concentrations (1, 5, 10, and 20 μg mL(-1) ) in a dose- and time-dependent manner. Reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) (except 48 h) showed a significant increase at higher concentrations of PCB 101 than those at the lower concentrations with the passage of time. Antioxidant enzymes such as glutathione peroxidase (GSH-Px) exhibited decreasing trends in dose and time dependent manner. Lipid peroxidation assay resulted in a significant increase (P < 0.05) of MDA level in PCB 101-treated HELF cells compared with controls, suggesting that OS plays a key role in PCB 101-induced toxicity. Comet assay indicated a significant increase in genotoxicity at higher concentrations of PCB 101 exposure compared to lower concentrations. Overall, we found that HELF cell proliferation was higher at low ROS level and vice versa, which revealed activation of cell signaling-mediated hormetic mechanisms. The results suggested that PCB 101 has hormetic effects to HELF cells and these were associated with oxidative stress.
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Affiliation(s)
- Muhammad Zaffar Hashmi
- Department of Environmental Engineering, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Kiran Yasmin Khan
- Ministry of Education Key Laboratory of Environmental Remediation and Ecological Health, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Jinxing Hu
- Department of Environmental Engineering, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Xiaomei Su
- Department of Environmental Engineering, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Ghulam Abbas
- Department of Environmental Engineering, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Chunna Yu
- Center for Biomedicine and Health, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China
| | - Chaofeng Shen
- Department of Environmental Engineering, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China
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23
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Abstract
The transcription factor Miz1 negatively regulates TNF-induced JNK activation and cell death by suppressing TRAF2 K63-polyubiquitination; upon TNF stimulation, the suppression is relieved by Mule/ARF-BP1-mediated Miz1 ubiquitination and subsequent degradation. It is not known how Mule is activated by TNF. Here we report that TNF activates Mule by inducing the dissociation of Mule from its inhibitor ARF. ARF binds to and thereby inhibits the E3 ligase activity of Mule in the steady state. TNF induces tyrosine phosphorylation of Mule, which subsequently dissociates from ARF and becomes activated. Inhibition of Mule phosphorylation by silencing of the Spleen Tyrosine Kinase (Syk) prevents its dissociation from ARF, thereby inhibiting Mule E3 ligase activity and TNF-induced JNK activation and cell death. Our data provides a missing link in TNF signaling pathway that leads to JNK activation and cell death.
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24
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Arsenic causes aortic dysfunction and systemic hypertension in rats: Augmentation of angiotensin II signaling. Chem Biol Interact 2015; 237:104-14. [PMID: 26079204 DOI: 10.1016/j.cbi.2015.06.014] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Revised: 04/28/2015] [Accepted: 06/08/2015] [Indexed: 02/07/2023]
Abstract
The groundwater pollutant arsenic can cause various cardiovascular disorders. Angiotensin II, a potent vasoconstrictor, plays an important role in vascular dysfunction by promoting changes in endothelial function, vascular reactivity, tissue remodeling and oxidative stress. We investigated whether modulation of angiotensin II signaling and redox homeostasis could be a mechanism contributing to arsenic-induced vascular disorder. Rats were exposed to arsenic at 25, 50 and 100ppm of sodium arsenite through drinking water consecutively for 90 days. Blood pressure was recorded weekly. On the 91st day, the rats were sacrificed for blood collection and isolation of thoracic aorta. Angiotensin converting enzyme and angiotensin II levels were assessed in plasma. Aortic reactivity to angiotensin II was assessed in organ-bath system. Western blot of AT1 receptors and G protein (Gαq/11), ELISA of signal transducers of MAP kinase pathway and reactive oxygen species (ROS) generation were assessed in aorta. Arsenic caused concentration-dependent increase in systolic, diastolic and mean arterial blood pressure from the 10th, 8th and 7th week onwards, respectively. Arsenic caused concentration-dependent enhancement of the angiotensin II-induced aortic contractile response. Arsenic also caused concentration-dependent increase in the plasma levels of angiotensin II and angiotensin converting enzyme and the expression of aortic AT1 receptor and Gαq/11 proteins. Arsenic increased aortic protein kinase C activity and the concentrations of protein tyrosine kinase, extracellular signal-regulated kinase-1/2 and vascular endothelial growth factor. Further, arsenic increased aortic mRNA expression of Nox2, Nox4 and p22phox, NADPH oxidase activity and ROS generation. The results suggest that arsenic-mediated enhancement of angiotensin II signaling could be an important mechanism in the arsenic-induced vascular disorder, where ROS could augment the angiotensin II signaling through activation of MAP kinase pathway.
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25
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Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ. Heavy metal toxicity and the environment. EXPERIENTIA SUPPLEMENTUM (2012) 2015; 101:133-64. [PMID: 22945569 PMCID: PMC4144270 DOI: 10.1007/978-3-7643-8340-4_6] [Citation(s) in RCA: 2172] [Impact Index Per Article: 217.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Heavy metals are naturally occurring elements that have a high atomic weight and a density at least five times greater than that of water. Their multiple industrial, domestic, agricultural, medical, and technological applications have led to their wide distribution in the environment, raising concerns over their potential effects on human health and the environment. Their toxicity depends on several factors including the dose, route of exposure, and chemical species, as well as the age, gender, genetics, and nutritional status of exposed individuals. Because of their high degree of toxicity, arsenic, cadmium, chromium, lead, and mercury rank among the priority metals that are of public health significance. These metallic elements are considered systemic toxicants that are known to induce multiple organ damage, even at lower levels of exposure. They are also classified as human carcinogens (known or probable) according to the US Environmental Protection Agency and the International Agency for Research on Cancer. This review provides an analysis of their environmental occurrence, production and use, potential for human exposure, and molecular mechanisms of toxicity, genotoxicity, and carcinogenicity.
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Affiliation(s)
- Paul B Tchounwou
- NIH-RCMI Center for Environmental Health, College of Science, Engineering and Technology, Jackson State University, 1400 Lynch Street, 18750, Jackson, MS, 39217, USA,
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Chang YW, Huang YS. Arsenite-activated JNK signaling enhances CPEB4-Vinexin interaction to facilitate stress granule assembly and cell survival. PLoS One 2014; 9:e107961. [PMID: 25237887 PMCID: PMC4169592 DOI: 10.1371/journal.pone.0107961] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Accepted: 08/18/2014] [Indexed: 01/15/2023] Open
Abstract
Stress granules (SGs) are compartmentalized messenger ribonucleoprotein particles (mRNPs) where translationally repressed mRNAs are stored when cells encounter environmental stress. Cytoplasmic polyadenylation element-binding protein (CPEB)4 is a sequence-specific RNA-binding protein and translational regulator. In keeping with the results obtained from the study of other RNA-binding proteins, we found CPEB4 localized in SGs in various arsenite-treated cells. In this study, we identified that Vinexin, a CPEB4-interacting protein, is a novel component of SGs. Vinexin is a SH3-domain-containing adaptor protein and affects cell migration through its association with Vinculin to localize at focal adhesions (FAs). Unexpectedly, Vinexin is translocated from FAs to SGs under arsenite-induced stress. The recruitment of Vinexin to SGs depends on its interaction with CPEB4 and influences SG formation and cell survival. Arsenite-activated c-Jun N-terminal kinase (JNK) signaling enhances the association between CPEB4 and Vinexin, which consequently facilitates SG localization of Vinexin. Taken together, this study uncovers a novel interaction between a translational regulator and an adaptor protein to influence SG assembly and cell survival.
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Affiliation(s)
- Yu-Wei Chang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Yi-Shuian Huang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
- * E-mail:
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Suwanna N, Thangnipon W, Soi-Ampornkul R. Neuroprotective effects of diarylpropionitrile against β-amyloid peptide-induced neurotoxicity in rat cultured cortical neurons. Neurosci Lett 2014; 578:44-9. [PMID: 24960633 DOI: 10.1016/j.neulet.2014.06.029] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Revised: 06/02/2014] [Accepted: 06/12/2014] [Indexed: 01/12/2023]
Abstract
Alzheimer's disease is a major cause of dementia in the elderly that involves a β-amyloid peptide (Aβ)-induced cascade of an increase in oxidative damage and inflammation. The present study demonstrated the neuroprotective effects of diarylpropionitrile (DPN), a non-steroidal estrogen receptor β selective ligand, against 10 μM Aβ1-42-induced oxidative stress and inflammation in primary rat cortical cell culture. Pre-treatment with 1-100 nM DPN significantly decreased neuronal cell death by increasing cell viability through a significant attenuation in the reactive oxygen species level, downregulation of pro-apoptotic activated caspase-3 and Bax, and upregulation of anti-apoptotic Bcl-2, thereby mitigating apoptotic morphological alterations. DPN pre-treatment decreased the expression levels of pro-inflammatory cytokines IL-1β and IL-6 through attenuation of Aβ1-42-induced phosphorylation of mitogen-activated protein kinases JNK and p38. In addition, DPN enhanced ERK1/2 and Akt phosphorylation depressed by Aβ1-42. These findings suggest that DPN protects neurons from Aβ1-42-induced neurotoxicity through a variety of mechanisms, ranging from anti-oxidation, anti-apoptosis, through to anti-inflammation.
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Affiliation(s)
- Nirut Suwanna
- Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhonpathom, Thailand
| | - Wipawan Thangnipon
- Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhonpathom, Thailand.
| | - Rungtip Soi-Ampornkul
- Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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Hashmi MZ, Shen H, Zhu S, Yu C, Shen C. Growth, bioluminescence and shoal behavior hormetic responses to inorganic and/or organic chemicals: a review. ENVIRONMENT INTERNATIONAL 2014; 64:28-39. [PMID: 24361513 DOI: 10.1016/j.envint.2013.11.018] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Revised: 11/25/2013] [Accepted: 11/26/2013] [Indexed: 06/03/2023]
Abstract
A biphasic dose response, termed hormesis, is characterized by beneficial effects of a chemical at a low dose and harmful effects at a high dose. This biphasic dose response phenomenon has the potential to strongly alter toxicology in a broad range. The present review focuses on the progress of research into hormetic responses in terms of growth (in plants, birds, algae and humans), bioluminescence, and shoal behavior as end points. The paper describes how both inorganic and organic chemicals at a low dose show stimulatory responses while at higher doses are inhibitory. The article highlights how factors such as symbiosis, density-dependent factors, time, and contrasting environmental factors (availability of nutrients, temperature, light, etc.) affect both the range and amplitude of hormetic responses. Furthermore, the possible underlying mechanisms are also discussed and we suggest that, for every end point, different hormetic mechanisms may exist. The occurrences of varying interacting receptor systems or receptor systems affecting the assessment of hormesis for each endpoint are discussed. The present review suggests that a hormetic model should be adopted for toxicological evaluations instead of the older threshold and linear non-threshold models.
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Affiliation(s)
- Muhammad Zaffar Hashmi
- Department of Environmental Engineering, College of Environmental & Resource Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China
| | - Hui Shen
- Department of Environmental Engineering, College of Environmental & Resource Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China
| | - Shenhai Zhu
- Department of Environmental Engineering, College of Environmental & Resource Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China
| | - Chunna Yu
- Center for Biomedicine and Health, Hangzhou Normal University, Hangzhou 311121, People's Republic of China
| | - Chaofeng Shen
- Department of Environmental Engineering, College of Environmental & Resource Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China.
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Yang CR, Liao WS, Wu YH, Murugan K, Chen C, Chao JI. CR108, a novel vitamin K3 derivative induces apoptosis and breast tumor inhibition by reactive oxygen species and mitochondrial dysfunction. Toxicol Appl Pharmacol 2013; 273:611-22. [PMID: 24128853 DOI: 10.1016/j.taap.2013.10.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Revised: 09/27/2013] [Accepted: 10/05/2013] [Indexed: 11/26/2022]
Abstract
Vitamin K3 derivatives have been shown to exert anticancer activities. Here we show a novel vitamin K3 derivative (S)-2-(2-hydroxy-3-methylbutylthio)naphthalene-1,4-dione, which is named as CR108 that induces apoptosis and tumor inhibition through reactive oxygen species (ROS) and mitochondrial dysfunction in human breast cancer. CR108 is more effective on the breast cancer cell death than other vitamin K3 derivatives. Moreover, CR108 induced apoptosis in both the non-HER-2-overexpressed MCF-7 and HER-2-overexpressed BT-474 breast cancer cells. CR108 caused the loss of mitochondrial membrane potential, cytochrome c released from mitochondria to cytosol, and cleaved PARP proteins for apoptosis induction. CR108 markedly increased ROS levels in breast cancer cells. N-acetylcysteine (NAC), a general ROS scavenger, completely blocked the CR108-induced ROS levels, mitochondrial dysfunction and apoptosis. Interestingly, CR108 increased the phosphorylation of p38 MAP kinase but conversely inhibited the survivin protein expression. NAC treatment prevented the activation of p38 MAP kinase and rescued the survivin protein levels. SB202190, a specific p38 MAP kinase inhibitor, recovered the survivin protein levels and attenuated the cytotoxicity of CR108-treated cells. Furthermore, CR108 inhibited the xenografted human breast tumor growth in nude mice. Together, we demonstrate that CR108 is a novel vitamin K3 derivative that induces apoptosis and tumor inhibition by ROS production and mitochondrial dysfunction and associates with the phosphorylation of p38 MAP kinase and the inhibition of survivin in the human breast cancer.
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Affiliation(s)
- Chun-Ru Yang
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu 30068, Taiwan
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Thangnipon W, Puangmalai N, Chinchalongporn V, Jantrachotechatchawan C, Kitiyanant N, Soi-Ampornkul R, Tuchinda P, Nobsathian S. N-benzylcinnamide protects rat cultured cortical neurons from β-amyloid peptide-induced neurotoxicity. Neurosci Lett 2013; 556:20-5. [PMID: 24120429 DOI: 10.1016/j.neulet.2013.09.071] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Revised: 09/04/2013] [Accepted: 09/29/2013] [Indexed: 01/22/2023]
Abstract
The pathogenesis of Alzheimer's disease involves an amyloid β-peptide (Aβ)-induced cascade of elevated oxidative damage and inflammation. The present study investigates the protective effects and the underlying mechanisms of N-benzylcinnamide (PT-3), purified from Piper submultinerve. Against Aβ-induced oxidative stress and inflammation in rat primary cortical cell cultures. Pre-treatment with 10-00nM PT-3 significantly attenuated neuronal cell death induced by 10μM Aβ1-42. PT-3 was found to enhance cell viability through a significant reduction in the level of reactive oxygen species, down-regulated expression of pro-apoptotic activated caspase-3 and Bax, increased expression of anti-apoptotic Bcl-2, and mitigation of Aβ-induced morphological alterations. Regarding its effects on inflammatory responses, PT-3 pre-treatment decreased the expression of pro-inflammatory cytokines IL-1β and IL-6. The mechanisms of PT-3 neuronal protection against inflammation may be associated with the mitogen-activated protein kinases (MAPK) pathway. Aβ1-42-induced phosphorylation of JNK and p38 MAPK was inhibited by pretreatment with PT-3 in a dose-dependent manner. However, phosphorylation of ERK1/2 was not affected by either PT-3 or Aβ1-42. PT-3 did not stimulate Akt phosphorylation, which was inhibited by Aβ1-42. These findings suggest that PT-3 protects neurons from Aβ1-42-induced neurotoxicity through its anti-apoptotic, anti-oxidative, and anti-inflammatory properties with inhibition of JNK and p38 MAPK phosphorylation as the potential underlying mechanism.
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Affiliation(s)
- Wipawan Thangnipon
- Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhonpathom, Thailand.
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Pišlar AH, Kos J. C-terminal peptide of γ-enolase impairs amyloid-β-induced apoptosis through p75(NTR) signaling. Neuromolecular Med 2013; 15:623-35. [PMID: 23842744 DOI: 10.1007/s12017-013-8247-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Accepted: 06/28/2013] [Indexed: 01/03/2023]
Abstract
γ-Enolase acts as a neurotrophic-like factor promoting growth, differentiation, survival and regeneration of neurons. It is shown in this study to exert a protective effect against amyloid-β-peptide (Aβ)-induced neurotoxicity in rat pheochromocytoma PC12 cells. Aβ-induced toxicity was abolished in the presence of the active C-terminal peptide of γ-enolase (γ-Eno) as measured by cell viability, lactate dehydrogenase release, sub-G1 cell population, intracellular reactive oxygen species, mitochondrial functions and apoptotic morphology. γ-Eno caused downregulation of the pro-apoptotic protein Bax and upregulation of the anti-apoptotic protein Bcl-2, as well as reduced caspase-3 activation. Exposure to Aβ increased surface expression of p75 neurotrophin receptor (p75(NTR)), and the increase was abolished in the presence of γ-Eno peptide. Further, pretreatment with γ-Eno suppressed the activation of mitogen-activated protein kinases p38 and Jun-N-terminal kinase, which are p75(NTR) downstream effectors in apoptotic signaling. Moreover, Aβ triggered γ-enolase co-immunoprecipitation with p75(NTR) as well as their strong association in the perimembrane region as shown by confocal microscopy, which further supports the interaction between these two proteins in cells insulted by Aβ peptide. Our results indicate the possible use of γ-enolase C-terminal peptide for treating or preventing Alzheimer's disease.
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Affiliation(s)
- Anja Hafner Pišlar
- Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000, Ljubljana, Slovenia.
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Hour MJ, Lee KT, Wu YC, Wu CY, You BJ, Chen TL, Lee HZ. A novel antitubulin agent, DPQZ, induces cell apoptosis in human oral cancer cells through Ras/Raf inhibition and MAP kinases activation. Arch Toxicol 2012; 87:835-46. [DOI: 10.1007/s00204-012-0991-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2012] [Accepted: 11/21/2012] [Indexed: 11/25/2022]
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Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ. Heavy metal toxicity and the environment. EXPERIENTIA SUPPLEMENTUM (2012) 2012. [PMID: 22945569 DOI: 10.1007/978‐3‐7643‐8340‐4_6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 09/29/2022]
Abstract
Heavy metals are naturally occurring elements that have a high atomic weight and a density at least five times greater than that of water. Their multiple industrial, domestic, agricultural, medical, and technological applications have led to their wide distribution in the environment, raising concerns over their potential effects on human health and the environment. Their toxicity depends on several factors including the dose, route of exposure, and chemical species, as well as the age, gender, genetics, and nutritional status of exposed individuals. Because of their high degree of toxicity, arsenic, cadmium, chromium, lead, and mercury rank among the priority metals that are of public health significance. These metallic elements are considered systemic toxicants that are known to induce multiple organ damage, even at lower levels of exposure. They are also classified as human carcinogens (known or probable) according to the US Environmental Protection Agency and the International Agency for Research on Cancer. This review provides an analysis of their environmental occurrence, production and use, potential for human exposure, and molecular mechanisms of toxicity, genotoxicity, and carcinogenicity.
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Affiliation(s)
- Paul B Tchounwou
- NIH-RCMI Center for Environmental Health, College of Science, Engineering and Technology, Jackson State University, 1400 Lynch Street, 18750, Jackson, MS, 39217, USA,
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Hughes MF, Beck BD, Chen Y, Lewis AS, Thomas DJ. Arsenic exposure and toxicology: a historical perspective. Toxicol Sci 2011; 123:305-32. [PMID: 21750349 PMCID: PMC3179678 DOI: 10.1093/toxsci/kfr184] [Citation(s) in RCA: 758] [Impact Index Per Article: 54.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2011] [Accepted: 06/30/2011] [Indexed: 12/23/2022] Open
Abstract
The metalloid arsenic is a natural environmental contaminant to which humans are routinely exposed in food, water, air, and soil. Arsenic has a long history of use as a homicidal agent, but in the past 100 years arsenic, has been used as a pesticide, a chemotherapeutic agent and a constituent of consumer products. In some areas of the world, high levels of arsenic are naturally present in drinking water and are a toxicological concern. There are several structural forms and oxidation states of arsenic because it forms alloys with metals and covalent bonds with hydrogen, oxygen, carbon, and other elements. Environmentally relevant forms of arsenic are inorganic and organic existing in the trivalent or pentavalent state. Metabolism of arsenic, catalyzed by arsenic (+3 oxidation state) methyltransferase, is a sequential process of reduction from pentavalency to trivalency followed by oxidative methylation back to pentavalency. Trivalent arsenic is generally more toxicologically potent than pentavalent arsenic. Acute effects of arsenic range from gastrointestinal distress to death. Depending on the dose, chronic arsenic exposure may affect several major organ systems. A major concern of ingested arsenic is cancer, primarily of skin, bladder, and lung. The mode of action of arsenic for its disease endpoints is currently under study. Two key areas are the interaction of trivalent arsenicals with sulfur in proteins and the ability of arsenic to generate oxidative stress. With advances in technology and the recent development of animal models for arsenic carcinogenicity, understanding of the toxicology of arsenic will continue to improve.
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Affiliation(s)
- Michael F Hughes
- Office of Research and Development, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
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Carpenter RL, Jiang Y, Jing Y, He J, Rojanasakul Y, Liu LZ, Jiang BH. Arsenite induces cell transformation by reactive oxygen species, AKT, ERK1/2, and p70S6K1. Biochem Biophys Res Commun 2011; 414:533-8. [PMID: 21971544 DOI: 10.1016/j.bbrc.2011.09.102] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2011] [Accepted: 09/20/2011] [Indexed: 11/18/2022]
Abstract
Arsenic is naturally occurring element that exists in both organic and inorganic formulations. The inorganic form arsenite has a positive association with development of multiple cancer types. There are significant populations throughout the world with high exposure to arsenite via drinking water. Thus, human exposure to arsenic has become a significant public health problem. Recent evidence suggests that reactive oxygen species (ROS) mediate multiple changes to cell behavior after acute arsenic exposure, including activation of proliferative signaling and angiogenesis. However, the role of ROS in mediating cell transformation by chronic arsenic exposure is unknown. We found that cells chronically exposed to sodium arsenite increased proliferation and gained anchorage-independent growth. This cell transformation phenotype required constitutive activation of AKT, ERK1/2, mTOR, and p70S6K1. We also observed these cells constitutively produce ROS, which was required for the constitutive activation of AKT, ERK1/2, mTOR, and p70S6K1. Suppression of ROS levels by forced expression of catalase also reduced cell proliferation and anchorage-independent growth. These results indicate cell transformation induced by chronic arsenic exposure is mediated by increased cellular levels of ROS, which mediates activation of AKT, ERK1/2, and p70S6K1.
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Affiliation(s)
- Richard L Carpenter
- Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, United States
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Ventura-Lima J, Bogo MR, Monserrat JM. Arsenic toxicity in mammals and aquatic animals: a comparative biochemical approach. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2011; 74:211-218. [PMID: 21112631 DOI: 10.1016/j.ecoenv.2010.11.002] [Citation(s) in RCA: 121] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2010] [Revised: 09/16/2010] [Accepted: 11/08/2010] [Indexed: 05/30/2023]
Abstract
Arsenic (As) is a widespread pollutant in the world and its toxicity is related to its chemical form, with inorganic forms being considered more toxic than the organic form, and huge differences in effects and processes of metabolism. This paper reviews the potential biochemical mechanisms of uptake of arsenic by aquaporins, capacity for metabolism and cellular efflux of As. It is known that As can affect signaling pathways since it can activate proteins such as ERK2, p38 and JNK, as shown in mammals. A comparison between phosphorylation sites of these proteins is presented in order to determine whether the same effect triggered by As in mammals might be observed in aquatic animals. The toxicity resulting from As exposure is considered to be linked to an imbalance between pro-oxidant and antioxidant homeostasis that results in oxidative stress. So, present review analyzes examples of oxidative stress generation by arsenic. Biotransformation of As is a process where firstly the arsenate is converted into arsenite and then transformed into mono-, di-, and trimethylated products. In the methylation process, the role of the omega isoform of glutathione-S-transferase (GST) is discussed. In addition, a phylogenetic tree was constructed for aquaporin proteins of different species, including aquatic animals, taking into account their importance in trivalent arsenic uptake.
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Affiliation(s)
- Juliane Ventura-Lima
- Instituto de Ciências Biológicas, Universidade Federal do Rio Grande-FURG, Cx. P. 474, CEP 96.201-900, Rio Grande, RS, Brazil
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Rottlerin Inhibits Lonicera japonica-Induced Photokilling in Human Lung Cancer Cells through Cytoskeleton-Related Signaling Cascade. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2011; 2011:193842. [PMID: 21331326 PMCID: PMC3038619 DOI: 10.1155/2011/193842] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/23/2010] [Revised: 12/11/2010] [Accepted: 01/05/2011] [Indexed: 11/21/2022]
Abstract
This study demonstrated that many apoptotic signaling pathways, such as Rho family, PKC family, MAP kinase family, and mitochondria-mediated apoptotic pathway, were triggered by Lonicera japonica extracts and irradiation in CH27 cells. Rottlerin, a PKCδ
-selective inhibitor, reversed the photoactivated Lonicera japonica extract-induced decrease in PKCδ protein expression and change in cell morphology in this study. In addition, rottlerin inhibited the photoactivated Lonicera japonica-induced decrease in protein expression of Ras, ERK, p38, PKCα, and PKCε, which are the kinases of prosurvival signaling pathway. We also demonstrated that pretreatment with rottlerin prevented actin microfilaments and microtubules from damage during the photoactivated Lonicera japonica-induced CH27 cell death. Furthermore, the promotion of the cytoskeleton-related signaling cascade following rottlerin by upregulation of cytoskeleton-related mediators (p38, HSP27, FAK, paxillin, and tubulin) and molecules of downstream of F-actin (mitochondria-mediated apoptosis pathway) reduces CH27 cell death, indicating that cytoskeleton is the potential target in the photoactivated Lonicera japonicaextract-induced photokilling of CH27 cells.
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Eguchi R, Fujimori Y, Takeda H, Tabata C, Ohta T, Kuribayashi K, Fukuoka K, Nakano T. Arsenic trioxide induces apoptosis through JNK and ERK in human mesothelioma cells. J Cell Physiol 2010; 226:762-8. [DOI: 10.1002/jcp.22397] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Druwe IL, Vaillancourt RR. Influence of arsenate and arsenite on signal transduction pathways: an update. Arch Toxicol 2010; 84:585-96. [PMID: 20502880 PMCID: PMC2911141 DOI: 10.1007/s00204-010-0554-4] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2010] [Accepted: 04/29/2010] [Indexed: 11/29/2022]
Abstract
Arsenic has been a recognized contaminant and toxicant, as well as a medicinal compound throughout human history. Populations throughout the world are exposed to arsenic and these exposures have been associated with a number of human cancers. Not much is known about the role of arsenic as a human carcinogen and more recently its role in non-cancerous diseases, such as cardiovascular disease, hypertension and diabetes mellitus have been uncovered. The health effects associated with arsenic are numerous and the association between arsenic exposure and human disease has intensified the search for molecular mechanisms that describe the biological activity of arsenic in humans and leads to the aforementioned disease states. Arsenic poses a human health risk due in part to the regulation of cellular signal transduction pathways and over the last few decades, some cellular mechanisms that account for arsenic toxicity, as well as, signal transduction pathways have been discovered. However, given the ubiquitous nature of arsenic in the environment, making sense of all the data remains a challenge. This review will focus on our knowledge of signal transduction pathways that are regulated by arsenic.
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Affiliation(s)
- Ingrid L. Druwe
- Department of Pharmacology and Toxicology, The University of Arizona College of Pharmacy, 1703 E. Mabel Street, Tucson, AZ 85721, USA
| | - Richard R. Vaillancourt
- Department of Pharmacology and Toxicology, The University of Arizona College of Pharmacy, 1703 E. Mabel Street, Tucson, AZ 85721, USA
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MacKinnon Y, Kapron CM. Reduction in cadmium-induced toxicity and c-Jun N-terminal kinase activation by glutathione in cultured mouse embryonic cells. ACTA ACUST UNITED AC 2010; 88:707-14. [DOI: 10.1002/bdra.20703] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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E3 ubiquitin ligase Mule ubiquitinates Miz1 and is required for TNFalpha-induced JNK activation. Proc Natl Acad Sci U S A 2010; 107:13444-9. [PMID: 20624960 DOI: 10.1073/pnas.0913690107] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The zinc finger transcription factor Miz1 is a negative regulator of TNFalpha-induced JNK activation and cell death through inhibition of TRAF2 K63-polyubiquitination in a transcription-independent manner. Upon TNFalpha stimulation, Miz1 undergoes K48-linked polyubiquitination and proteasomal degradation, thereby relieving its inhibition. However, the underling regulatory mechanism is not known. Here, we report that HECT-domain-containing Mule is the E3 ligase that catalyzes TNFalpha-induced Miz1 polyubiquitination. Mule is a Miz1-associated protein and catalyzes its K48-linked polyubiquitination. TNFalpha-induced polyubiquitination and degradation of Miz1 were inhibited by silencing of Mule and were promoted by ectopic expression of Mule. The interaction between Mule and Miz1 was promoted by TNFalpha independently of the pox virus and zinc finger domain of Miz1. Silencing of Mule stabilized Miz1, thereby suppressing TNFalpha-induced JNK activation and cell death. Thus, our study reveals a molecular mechanism by which Mule regulates TNFalpha-induced JNK activation and apoptosis by catalyzing the polyubiquitination of Miz1.
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Sumi D, Shinkai Y, Kumagai Y. Signal transduction pathways and transcription factors triggered by arsenic trioxide in leukemia cells. Toxicol Appl Pharmacol 2010; 244:385-92. [PMID: 20193703 DOI: 10.1016/j.taap.2010.02.012] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2009] [Revised: 02/09/2010] [Accepted: 02/21/2010] [Indexed: 12/23/2022]
Abstract
Arsenic trioxide (As(2)O(3)) is widely used to treat acute promyelocytic leukemia (APL). Several lines of evidence have indicated that As(2)O(3) affects signal transduction and transactivation of transcription factors, resulting in the stimulation of apoptosis in leukemia cells, because some transcription factors are reported to associate with the redox condition of the cells, and arsenicals cause oxidative stress. Thus, the disturbance and activation of the cellular signaling pathway and transcription factors due to reactive oxygen species (ROS) generation during arsenic exposure may explain the ability of As(2)O(3) to induce a complete remission in relapsed APL patients. In this report, we review recent findings on ROS generation and alterations in signal transduction and in transactivation of transcription factors during As(2)O(3) exposure in leukemia cells.
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Affiliation(s)
- Daigo Sumi
- Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180, Yamashiro-cho, Tokushima-city, Tokushima 770-8514, Japan.
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Kawata K, Shimazaki R, Okabe S. Comparison of gene expression profiles in HepG2 cells exposed to arsenic, cadmium, nickel, and three model carcinogens for investigating the mechanisms of metal carcinogenesis. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2009; 50:46-59. [PMID: 19031421 DOI: 10.1002/em.20438] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
Carcinogenesis is an important chronic toxicity of metals and metalloids, although their mechanisms of action are still unclear. Comparison of gene expression patterns induced by carcinogenic metals, metalloids, and model carcinogens would give an insight into understanding of their carcinogenic mechanisms. In this study, we examined the gene expression alteration in human hepatoma cell line, HepG2, after exposing to two metals (cadmium and nickel), a metalloid (arsenic), and three model carcinogenic chemicals N-dimethylnitrosoamine (DMN), 12-O-tetradecanoylphorbol-13-acetate (TPA), and tetrachloroethylene (TCE) using DNA microarrays with 8,795 human genes. Of the genes altered by As, Cd, and Ni exposures, 31-55% were overlapped with those altered by three model carcinogenic chemical exposures in our experiments. In particular, the metals and metalloid shared certain characteristics with TPA and TCE in remarkable upregulations of the genes associated with progression of cell cycle, which might play a central role in As, Cd, and Ni carcinogenesis. This characteristic of gene expression alteration was partially counteracted by intracellular accumulation of vitamin C in As-exposed cells, whereas the number of cell-cycle associated genes was increased in Cd- and Ni-exposed cells. In our experimental conditions, ROS might have an accelerative effect on the cell proliferation mechanisms of As, but have an inhibitory effect on those of other two heavy metals. Furthermore, based on the results of Q-PCR, the oncogene PTTG1, which was upregulated by all carcinogenic chemical exposures in the array experiments, might be a useful biomarker for evaluation of the carcinogenesis of inorganic carcinogens.
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Affiliation(s)
- Koji Kawata
- Department of Urban and Environmental Engineering, Graduate School of Engineering, Hokkaido University, Kita-ku, Sapporo 060-8628, Japan
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Hansen TE, Puntervoll P, Seternes OM, Jørgensen JB. Atlantic salmon possess three mitogen activated protein kinase kinase 6 paralogs responding differently to stress. FEBS J 2008; 275:4887-902. [DOI: 10.1111/j.1742-4658.2008.06628.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Korashy HM, El-Kadi AOS. NF-κB and AP-1 are key signaling pathways in the modulation of NAD(P)H:Quinone oxidoreductase 1 gene by mercury, lead, and copper. J Biochem Mol Toxicol 2008; 22:274-83. [DOI: 10.1002/jbt.20238] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Monteiro HP, Arai RJ, Travassos LR. Protein tyrosine phosphorylation and protein tyrosine nitration in redox signaling. Antioxid Redox Signal 2008; 10:843-89. [PMID: 18220476 DOI: 10.1089/ars.2007.1853] [Citation(s) in RCA: 114] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Reversible phosphorylation of protein tyrosine residues by polypeptide growth factor-receptor protein tyrosine kinases is implicated in the control of fundamental cellular processes including the cell cycle, cell adhesion, and cell survival, as well as cell proliferation and differentiation. During the last decade, it has become apparent that receptor protein tyrosine kinases and the signaling pathways they activate belong to a large signaling network. Such a network can be regulated by various extracellular cues, which include cell adhesion, agonists of G protein-coupled receptors, and oxidants. It is well documented that signaling initiated by receptor protein tyrosine kinases is directly dependent on the intracellular production of oxidants, including reactive oxygen and nitrogen species. Accumulated evidence indicates that the intracellular redox environment plays a major role in the mechanisms underlying the actions of growth factors. Oxidation of cysteine thiols and nitration of tyrosine residues on signaling proteins are described as posttranslational modifications that regulate, positively or negatively, protein tyrosine phosphorylation (PTP). Early observations described the inhibition of PTP activities by oxidants, resulting in increased levels of proteins phosphorylated on tyrosine. Therefore, a redox circuitry involving the increasing production of intracellular oxidants associated with growth-factor stimulation/cell adhesion, oxidative reversible inhibition of protein tyrosine phosphatases, and the activation of protein tyrosine kinases can be delineated.
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Affiliation(s)
- Hugo P Monteiro
- Department of Biochemistry/Molecular Biology and CINTERGEN, Universidade Federal de São Paulo, São Paulo, Brazil.
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Posey T, Weng T, Chen Z, Chintagari NR, Wang P, Jin N, Stricker H, Liu L. Arsenic-induced changes in the gene expression of lung epithelial L2 cells: implications in carcinogenesis. BMC Genomics 2008; 9:115. [PMID: 18315880 PMCID: PMC2292705 DOI: 10.1186/1471-2164-9-115] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2007] [Accepted: 03/03/2008] [Indexed: 11/21/2022] Open
Abstract
Background Arsenic is a carcinogen that is known to induce cell transformation and tumor formation. Although studies have been performed to examine the modulation of signaling molecules caused by arsenic exposure, the molecular mechanisms by which arsenic causes cancer are still unclear. We hypothesized that arsenic alters gene expression leading to carcinogenesis in the lung. Results In this study, we examined global gene expression in response to 0.75 μM arsenic treatment for 1–7 days in a rat lung epithelial cell line (L2) using an in-house 10 k rat DNA microarray. One hundred thirty one genes were identified using the one-class statistical analysis of microarray (SAM) test. Of them, 33 genes had a fold change of ≥ 2 between at least two time points. These genes were then clustered into 5 groups using K-means cluster analysis based on their expression patterns. Seven selected genes, all associated with cancer, were confirmed by real-time PCR. These genes have functions directly or indirectly related to metabolism, glycolysis, cell proliferation and differentiation, and regulation of transcription. Conclusion Our findings provide important insight for the future studies of arsenic-mediated lung cancer.
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Affiliation(s)
- Tisha Posey
- Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
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Role of extracellular signal-regulated kinase (ERK) signaling in nucleotide excision repair and genotoxicity in response to As(III) and Pb(II). PURE APPL CHEM 2008. [DOI: 10.1351/pac200880122735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Abstract
Arsenic and lead can induce genetic injuries and epigenetic signaling pathways in cultured mammalian cells. To test whether signaling pathways affect the extent of genetic injuries, we explored the impacts of extracellular signal-regulated kinase 1 and 2 (ERK) on nucleotide excision repair (NER), cytotoxicity, and genotoxicity following sodium arsenite [As(III)] and lead acetate [Pb(II)]. Sustained ERK activation was observed in human cells exposed to As(III) and Pb(II). As(III) inhibited the cellular NER synthesis capability; conversely, Pb(II) stimulated it. ERK activation contributed to the As(III)-induced NER inhibition and micronucleus formation. In contrast, this signal was required for inducing cellular NER activity and preventing mutagenesis following Pb(II). ERK activation by Pb(II) was dependent on protein kinase C (PKCα) that also exhibited anti-mutagenicity. Enforced expression of ERK signaling markedly elevated the cellular NER activity, which was suppressed by As(III). Nonetheless, ERK activation could counteract the cytotoxicity caused by these two metals. Together, the results indicate that pro-survival ERK signaling exhibits dual and opposing impacts on NER process following As(III) and Pb(II) exposures. The findings also suggest that ERK is an important epigenetic signaling in the determination of metal genotoxicity.
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DeFuria J, Shea TB. Arsenic inhibits neurofilament transport and induces perikaryal accumulation of phosphorylated neurofilaments: Roles of JNK and GSK-3β. Brain Res 2007; 1181:74-82. [DOI: 10.1016/j.brainres.2007.04.019] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2007] [Revised: 04/04/2007] [Accepted: 04/07/2007] [Indexed: 11/15/2022]
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Anozie O, Ross R, Oyekan AO, Yakubu MA. Differential modulation of bradykinin-induced relaxation of endothelin-1 and phenylephrine contractions of rat aorta by antioxidants. Acta Pharmacol Sin 2007; 28:1566-72. [PMID: 17883941 PMCID: PMC4503219 DOI: 10.1111/j.1745-7254.2007.00631.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
AIM We tested the hypothesis that bradykinin (BK)-induced relaxation of phenylephrine (PE) and endothelin-1 (ET-1) contractions can be differentially modulated by reactive oxygen species (ROS). METHODS Aortic rings isolated from Sprague-Dawley rats were used for the study. The contribution of ROS to PE (1 x 10(-9)-1 x 10(-5) mol/L)- and ET-1 (1 x 10(-10)-1 x 10(-8) mol/L)-induced contractions and the influence of ROS in BK (1 x 10(-9)-1 x 10(-5) mol/L) relaxation of PE (1 x 10(-7) mol/L) or ET-1 (1 x 10(-9) mol/L)-induced tension was evaluated in the aorta in the presence or absence of the following antioxidants: catalase (CAT, 300 U/mL), superoxide dismutase (SOD, 300 U/mL), and vitamin C (1 x 10(-4) mol/L). RESULTS Tension generated by ET-1 (1 x 10(-9) mol/L) or PE (1 x 10(-7) mol/L) was differentially relaxed by BK (1 x 10(-5) mol/L), producing a maximal relaxation of 75%+/-5% and 35+/-4%, respectively. The BK (1 x 10(-5) mol/L)-induced relaxation of PE (1 x 10(-7) mol/L) tension was significantly enhanced from 35%+/-4% (control) to 56%+/-9%, 60%+/-5%, and 49%+/-6% by SOD, CAT, and vitamin C, respectively (P<0.05, n=8). However, the relaxation of ET-1 (1 x 10(-9) mol/L) tension was significantly attenuated from 75%+/-5% (control) to 37%+/-9%, 63%+/-4%, and 39%+/-7% by SOD, CAT, and vitamin C, respectively (P<0.05, n=8). On the other hand, CAT had no effect on PE-induced tension, while SOD enhanced PE-induced tension (36%, P<0.05, n=10) and vitamin C attenuated (66%, P<0.05, n=8) the tension induced by PE. By contrast, SOD or vitamin C had no effect, but CAT attenuated (44%, P<0.05, n=9) the tension induced by ET-1. CONCLUSION We have demonstrated that O2(-) and H2O2 differentially modulate BK relaxation in an agonist-specific manner. O2(-) attenuates BK-induced relaxation of PE contraction, but contributes to the relaxation of ET-1 contraction. O2(-) seems to inhibit PE contraction, while H2O2 contributes to ET-1-induced contraction. Thus, ROS differentially modulate vascular tone depending on the vasoactive agent that is used to generate the tone.
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Affiliation(s)
- Ogechukwu Anozie
- Vascular Biology Unit, Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas 77004, USA
| | - Richonda Ross
- Vascular Biology Unit, Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas 77004, USA
| | - Adebayo O Oyekan
- Vascular Biology Unit, Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas 77004, USA
| | - Momoh A Yakubu
- Vascular Biology Unit, Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas 77004, USA
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