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Artsen AM, Mayr CA, Weber K, Rytel K, Moalli PA. Polypropylene surgical mesh induces lipid oxidation in a nonhuman primate model. Acta Biomater 2025; 198:207-218. [PMID: 40187672 PMCID: PMC12065656 DOI: 10.1016/j.actbio.2025.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 03/10/2025] [Accepted: 04/02/2025] [Indexed: 04/07/2025]
Abstract
Polypropylene mesh is widely used in surgery to support weak connective tissue, but pain and exposure complications limit vaginal implantation for pelvic organ prolapse. The increased complication rate with vaginal implantation is incompletely understood. We sought to compare the host response to low vs high polypropylene mesh burden after vaginal or abdominal implantation in rhesus macaques. We hypothesized that in both sites an increased mesh burden would result in increased malondialdehyde (MDA; a marker of lipid oxidative damage), heightened macrophage response, and increased apoptosis. Gynemesh PS and Restorelle implanted on the anterior abdominal wall were compared to a nonhuman primate sacrocolpopexy vaginal implantation model with Restorelle, which was intentionally and successively deformed to produce low, high, and highest mesh burden groups. Abdominal Gynemesh showed more CD68+ macrophages than lower mesh burden vaginal groups but not the highest burden group. In abdominal mesh, apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling assay was limited to areas immediately surrounding mesh, while in deformed vaginal mesh, increased apoptosis was seen in the subepithelium. Macrophages and apoptotic cells were correlated at both sites and MDA was correlated with abdominal macrophages and vaginal apoptotic indices. Regardless of implantation site, macrophages, apoptotic indices, and MDA levels were strongly correlated with mesh burden. These data indicate that mesh burden is a main driver in the abdominal and vaginal mesh innate immune response and suggest a possible pathway through which prolonged inflammation contributes to tissue damage in mesh complications, namely through the immune cell production of reactive oxygen species or through stress-shielding. STATEMENT OF SIGNIFICANCE: When implanted on the vagina, polypropylene mesh is associated with a strong negative foreign body response that can result in mesh exposure into the vagina or other organs. The mechanistic pathway for mesh exposure is unknown. Here, we show that polypropylene mesh induced lipid oxidation, as measured by malondialdehyde, in both abdominal and vaginal mesh implants in a nonhuman primate model. Mesh burden was strongly correlated with macrophages, apoptotic indices, and MDA levels. Apoptosis in the subepithelium in deformed mesh samples may be a result of stress shielding or oxidative damage and may contribute to exposure complications. These data suggest a possible pathway through which prolonged inflammation surrounding a biomaterial implant results in tissue damage and implant exposure.
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Affiliation(s)
- Amanda M Artsen
- Division of Urogynecology and Reconstructive Pelvic Surgery, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA; Magee Women's Research Institute, 204 Craft Ave Pittsburgh, PA 15213, USA.
| | - Craig A Mayr
- Division of Urogynecology and Reconstructive Pelvic Surgery, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA; Magee Women's Research Institute, 204 Craft Ave Pittsburgh, PA 15213, USA
| | - Kristina Weber
- Division of Urogynecology and Reconstructive Pelvic Surgery, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA
| | - Krystyna Rytel
- Division of Urogynecology and Reconstructive Pelvic Surgery, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA
| | - Pamela A Moalli
- Division of Urogynecology and Reconstructive Pelvic Surgery, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA; Magee Women's Research Institute, 204 Craft Ave Pittsburgh, PA 15213, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA
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Sowton AP, Holzner LMW, Krause FN, Baxter R, Mocciaro G, Krzyzanska DK, Minnion M, O'Brien KA, Harrop MC, Darwin PM, Thackray BD, Vacca M, Feelisch M, Griffin JL, Murray AJ. Chronic inorganic nitrate supplementation does not improve metabolic health and worsens disease progression in mice with diet-induced obesity. Am J Physiol Endocrinol Metab 2025; 328:E69-E91. [PMID: 39653040 DOI: 10.1152/ajpendo.00256.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 10/16/2024] [Accepted: 11/07/2024] [Indexed: 01/11/2025]
Abstract
Inorganic nitrate (NO3-) has been proposed to be of therapeutic use as a dietary supplement in obesity and related conditions including the metabolic syndrome (MetS), type II diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). Administration of NO3- to endothelial nitric oxide synthase-deficient mice reversed aspects of MetS; however, the impact of NO3- supplementation in diet-induced obesity is not well understood. Here we investigated the whole body metabolic phenotype and cardiac and hepatic metabolism in mice fed a high-fat, high-sucrose (HFHS) diet for up to 12 mo of age, supplemented with 1 mM NaNO3 (or NaCl) in their drinking water. HFHS feeding was associated with a progressive obesogenic and diabetogenic phenotype, which was not ameliorated by NO3-. Furthermore, HFHS-fed mice supplemented with NO3- showed elevated levels of cardiac fibrosis and accelerated progression of MASLD including development of hepatocellular carcinoma in comparison with NaCl-supplemented mice. NO3- did not enhance mitochondrial β-oxidation capacity in any tissue assayed and did not suppress hepatic lipid accumulation, suggesting it does not prevent lipotoxicity. We conclude that NO3- is ineffective in preventing the metabolic consequences of an obesogenic diet and may instead be detrimental to metabolic health against the background of HFHS feeding. This is the first report of an unfavorable effect of long-term nitrate supplementation in the context of the metabolic challenges of overfeeding, warranting urgent further investigation into the mechanism of this interaction.NEW & NOTEWORTHY Inorganic nitrate has been suggested to be of therapeutic benefit in obesity-related conditions, as it increases nitric oxide bioavailability, enhances mitochondrial β-oxidation, and reverses metabolic syndrome in eNOS-/- mice. However, we here show that over 12 months nitrate was ineffective in preventing metabolic consequences in high fat, high sucrose-fed mice and worsened aspects of metabolic health, impairing cholesterol handling, increasing cardiac fibrosis, and exacerbating steatotic liver disease progression, with acceleration to hepatocellular carcinoma.
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Affiliation(s)
- Alice P Sowton
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Lorenz M W Holzner
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Fynn N Krause
- Department of Biochemistry and Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom
| | - Ruby Baxter
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Gabriele Mocciaro
- Department of Biochemistry and Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom
| | - Dominika K Krzyzanska
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Magdalena Minnion
- Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Katie A O'Brien
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Matthew C Harrop
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Paula M Darwin
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Benjamin D Thackray
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Michele Vacca
- Department of Biochemistry and Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom
- Wellcome Trust-MRC Institute of Metabolic Science Metabolic Research Laboratories, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Martin Feelisch
- Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Julian L Griffin
- Department of Biochemistry and Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom
- The Rowett Institute, University of Aberdeen, Aberdeen, United Kingdom
| | - Andrew J Murray
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
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Grobben Y. Targeting amino acid-metabolizing enzymes for cancer immunotherapy. Front Immunol 2024; 15:1440269. [PMID: 39211039 PMCID: PMC11359565 DOI: 10.3389/fimmu.2024.1440269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024] Open
Abstract
Despite the immune system's role in the detection and eradication of abnormal cells, cancer cells often evade elimination by exploitation of various immune escape mechanisms. Among these mechanisms is the ability of cancer cells to upregulate amino acid-metabolizing enzymes, or to induce these enzymes in tumor-infiltrating immunosuppressive cells. Amino acids are fundamental cellular nutrients required for a variety of physiological processes, and their inadequacy can severely impact immune cell function. Amino acid-derived metabolites can additionally dampen the anti-tumor immune response by means of their immunosuppressive activities, whilst some can also promote tumor growth directly. Based on their evident role in tumor immune escape, the amino acid-metabolizing enzymes glutaminase 1 (GLS1), arginase 1 (ARG1), inducible nitric oxide synthase (iNOS), indoleamine 2,3-dioxygenase 1 (IDO1), tryptophan 2,3-dioxygenase (TDO) and interleukin 4 induced 1 (IL4I1) each serve as a promising target for immunotherapeutic intervention. This review summarizes and discusses the involvement of these enzymes in cancer, their effect on the anti-tumor immune response and the recent progress made in the preclinical and clinical evaluation of inhibitors targeting these enzymes.
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Ghaderi A, Khoshakhlagh AH, Gruszecka-Kosowska A, Askari-Lemjiri F, Alemi F, Molavi N, Hazegh P, Farokhi B, Dehkohneh SG, Ghoreishi FS. Heavy metal concentrations and clinical symptoms in patients diagnosed with schizophrenia related to cigarette smoking. Sci Rep 2024; 14:15074. [PMID: 38956098 PMCID: PMC11219874 DOI: 10.1038/s41598-024-64333-9] [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: 12/27/2023] [Accepted: 06/07/2024] [Indexed: 07/04/2024] Open
Abstract
In our study, blood concentrations of lead (Pb), arsenic (As), and cadmium (Cd) and urine concentrations of thallium (Tl) were measured together with related symptoms of heavy metal poisoning in cigarette smoking volunteers diagnosed with schizophrenia, in cigarette smokers not diagnosed with schizophrenia, and in the control group of non-smokers and not diagnosed with schizophrenia volunteers. Our study was performed on 171 volunteers divided into the following subgroups: patients diagnosed with schizophrenia with at least 1 year of continuous cigarette smoking experience (56 participants), cigarette smokers not diagnosed with schizophrenia with at least one year of continuous smoking experience (58), and control group (not diagnosed with schizophrenia and non-smoking volunteers) (57). Smoking durations of cigarette smokers diagnosed with schizophrenia and cigarette smokers not diagnosed with schizophrenia are not similar (p = 0.431). Blood Pb, As, and Cd concentrations and urine Tl concentrations were the highest in the subgroup of cigarette smokers not diagnosed with schizophrenia, followed by the subgroup of cigarette smokers diagnosed with schizophrenia, and the control group. Only blood Pb concentrations were significantly higher (probability value p < 0.05) in the group of cigarette smokers not diagnosed with schizophrenia (5.16 μg/dL), comparing to the group of cigarette smokers diagnosed with schizophrenia (3.83 μg/dL) and to the control group (3.43 μg/dL). Blood Cd and As concentrations and urine Tl concentrations were significantly higher (p < 0.05) in cigarette smokers not diagnosed with schizophrenia than in the control group. The results revealed a statistically significant positive correlation (p < 0.001) in the cigarette smokers in the schizophrenia diagnosed group between blood Pb, blood As, and urine Tl concentrations and the duration of cigarette smoking.
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Affiliation(s)
- Amir Ghaderi
- Department of Addiction Studies, School of Medical and Clinical Research Development Unit-Matini/Kargarnejad Hospital, Kashan University of Medical Sciences, Kashan, Iran
| | - Amir Hossein Khoshakhlagh
- Department of Occupational Health Engineering, School of Health, Kashan University of Medical Sciences, Kashan, Iran.
| | - Agnieszka Gruszecka-Kosowska
- Faculty of Geology, Geophysics, and Environmental Protection, Department of Environmental Protection, AGH University of Krakow, Al. Mickiewicza 30, 30-059, Krakow, Poland
| | | | - Fatemeh Alemi
- Department of Toxicology and Pharmacology, School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Nader Molavi
- Department of Addiction Studies, School of Medical and Clinical Research Development Unit-Matini/Kargarnejad Hospital, Kashan University of Medical Sciences, Kashan, Iran
| | - Pooya Hazegh
- Department of Psychiatry, Kashan University of Medical Sciences, Kashan, Iran
| | - Bahareh Farokhi
- Department of Clinical Psychology, Allameh Tabataba'i University, Tehran, Iran
| | - Somayeh Ghadami Dehkohneh
- Department of Pharmacy, Acharya BM Ready College of Pharmacy, Rajive Gandhi University of Health Sciences, Banglore, Karnataka, India
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Yarangsee P, Khacha-ananda S, Pitchakarn P, Intayoung U, Sriuan S, Karinchai J, Wijaikhum A, Boonyawan D. A Nonclinical Safety Evaluation of Cold Atmospheric Plasma for Medical Applications: The Role of Genotoxicity and Mutagenicity Studies. Life (Basel) 2024; 14:759. [PMID: 38929742 PMCID: PMC11204557 DOI: 10.3390/life14060759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 05/21/2024] [Accepted: 06/12/2024] [Indexed: 06/28/2024] Open
Abstract
Atmospheric nonthermal plasma (ANTP) has rapidly evolved as an innovative tool in biomedicine with various applications, especially in treating skin diseases. In particular, the formation of reactive oxygen species (ROS) and nitrogen species (RNS), which are generated by ANTP, plays an important role in the biological signaling pathways of human cells. Unfortunately, excessive amounts of these reactive species significantly result in cellular damage and cell death induction. To ensure the safe application of ANTP, preclinical in vitro studies must be conducted before proceeding to in vivo or clinical trials involving humans. Our study aimed to investigate adverse effects on genetic substances in murine fibroblast cells exposed to ANTP. Cell viability and proliferation were markedly reduced after exposing the cells with plasma. Both extracellular and intracellular reactive species, especially RNS, were significantly increased upon plasma exposure in the culture medium and the cells. Notably, significant DNA damage in the cells was observed in the cells exposed to plasma. However, plasma was not classified as a mutagen in the Ames test. This suggested that plasma led to the generation of both extracellular and intracellular reactive species, particularly nitrogen species, which affect cell proliferation and are also known to induce genetic damage in fibroblast cells. These results highlight the genotoxic and mutagenic effects of ANTP, emphasizing the need for the cautious selection of plasma intensity in specific applications to avoid adverse side effects resulting from reactive species production.
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Affiliation(s)
- Piimwara Yarangsee
- Department of Forensic Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (P.Y.); (U.I.); (S.S.)
| | - Supakit Khacha-ananda
- Department of Forensic Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (P.Y.); (U.I.); (S.S.)
| | - Pornsiri Pitchakarn
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (P.P.); (J.K.)
| | - Unchisa Intayoung
- Department of Forensic Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (P.Y.); (U.I.); (S.S.)
| | - Sirikhwan Sriuan
- Department of Forensic Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (P.Y.); (U.I.); (S.S.)
| | - Jirarat Karinchai
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (P.P.); (J.K.)
| | - Apiwat Wijaikhum
- Research and Innovation Division, Electricity Generating Authority of Thailand, Nonthaburi 11130, Thailand;
| | - Dheerawan Boonyawan
- Plasma and Beam Physics Research Facility, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand;
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O Kadry M, Ali HM. Fischer's oligopeptide ratio in ischemic hypoxia: prophylactic amendment of sophoretin and melatonin supplementation. Future Sci OA 2024; 10:FSO911. [PMID: 38827802 PMCID: PMC11140683 DOI: 10.2144/fsoa-2023-0117] [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: 06/21/2023] [Accepted: 10/02/2023] [Indexed: 06/05/2024] Open
Abstract
Aim: The fundamental pathophysiology of ischemic-hypoxia is oxygen depletion. Fischer's ratio is essential for monitoring hypoxia intensity. Methods: the current study highlighted the prophylactic role of sophoretin (QRC) and/or melatonin (MLN) versus sodium nitrite (SN) brain hypoxia. Results: Prophylactic treatment with sophoretin and MLN, was preceded with hypoxia-induction via sodium nitrite (60 mg/kg, S.C.). SN decreased hemoglobin (Hb), elevated HIF-α, HSP-70, IL-6 and TNF-α. Sophoretin and/or MLN restored the ameliorated inflammatory biomarkers, modulated norepinephrine, dopamine, serotonin and gamma-aminobutyric acid (GABA). Similarly, single-cell gel electrophoresis (SCGE or COMET) DNA damage assay confirmed this finding. Conclusion: Treatment via sophoretin and MLN was the most effective therapy for improving sodium nitrite-induced brain injury.
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Affiliation(s)
- Mai O Kadry
- Therapeutic Chemistry Department, National Research Centre, El Buhouth St., Dokki, 12622, Egypt
| | - Hanaa Mahmoud Ali
- Department of Genetics & Cytology, National Research Centre, Dokki, 12622, Egypt
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Han X, Guo B, Wang L, Chen K, Zhou H, Huang S, Xu H, Pan X, Chen J, Gao X, Wang Z, Yang L, Laba C, Meng Q, Guo Y, Chen G, Hong F, Zhao X. The mediation role of blood lipids on the path from air pollution exposure to MAFLD: A longitudinal cohort study. THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 904:166347. [PMID: 37591384 DOI: 10.1016/j.scitotenv.2023.166347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 08/12/2023] [Accepted: 08/14/2023] [Indexed: 08/19/2023]
Abstract
BACKGROUND & AIMS Recent cross-sectional studies found that exposure to ambient air pollution (AP) was associated with an increased risk of metabolic dysfunction-associated fatty liver disease (MAFLD). The alternation of blood lipids may explain the association, but epidemiological evidence is lacking. We aimed to examine whether and to what extent the association between long-term exposure to AP and incident MAFLD is mediated by blood lipids and dyslipidemia in a prospective cohort. METHODS We included 6350 participants from the China Multi-Ethnic Cohort (CMEC, baseline 2018-2019, follow-up 2020-2021). Three-year average (2016-2018) of AP (PM1, PM2.5, PM10, NO2), blood lipids (TC, LDL-C, HDL-C, TG with their combinations) and incident MAFLD for each individual were assessed chronologically. Linear and logistic regression was used to assess the associations among AP, blood lipids, and MAFLD, and the potential mediation effects of blood lipids were evaluated using causal mediation analysis. RESULTS A total of 744 participants were newly diagnosed with MAFLD at follow-up. The odds ratios of MAFLD associated with a 10 μm increase in PM1, PM2.5, and NO2 were 1.35 (95 % CI: 1.14, 1.58), 1.34 (1.10, 1.65) and 1.28 (1.14, 1.44), respectively. Blood lipids are important mediators between AP and incident MAFLD. LDL-C (Proportion Mediated: 6.9 %), non-HDL (13.4 %), HDL-C (20.7 %), LDL/HDL (30.1 %), and dyslipidemia (6.5 %) significantly mediated the association between PM2.5 and MAFLD. For PM1, the indirect effects were similar to those for PM2.5, with a larger value for the direct effect, and the mediation proportion by blood lipids was less for NO2. CONCLUSION Blood lipids are important mediators between AP and MAFLD, and can explain 5 %-30 % of the association between AP and incident MAFLD, particularly cholesterol-related variables, indicating that AP could lead to MAFLD through the alternation of blood lipids. These findings provided mechanical evidence of AP leading to MAFLD in epidemiological studies.
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Affiliation(s)
- Xinyu Han
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Bing Guo
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lele Wang
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Kejun Chen
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hanwen Zhou
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Shourui Huang
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Huan Xu
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China; Institute for Disaster Management and Reconstruction, Sichuan University-The Hongkong Polytechnic University, Chengdu, Sichuan, China
| | - Xianmou Pan
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jinyao Chen
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xufang Gao
- Chengdu Center for Disease Control and Prevention, Chengdu, Sichuan, China
| | - Zhenghong Wang
- Chongqing Municipal Center for Disease Control and Prevention, Chongqing, China
| | - La Yang
- Tibet University, Lhasa, Tibet, China
| | - Ciren Laba
- Tibet Center for Disease Control and Prevention CN, Lhasa, Tibet, China
| | - Qiong Meng
- Department of Epidemiology and Health Statistics, School of public Health, Kunming Medical University, Kunming, Yunnan, China
| | - Yuming Guo
- Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC 3004, Australia
| | - Gongbo Chen
- Climate, Air Quality Research Unit, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
| | - Feng Hong
- School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, China.
| | - Xing Zhao
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China.
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Lee SM, Kim YH, Min J. Anti-inflammatory effects of yeast-derived vacuoles on LPS-induced murine macrophage activation. Microbiol Spectr 2023; 11:e0146623. [PMID: 37747185 PMCID: PMC10580869 DOI: 10.1128/spectrum.01466-23] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 08/01/2023] [Indexed: 09/26/2023] Open
Abstract
Saccharomyces cerevisiae is a single-celled fungal microorganism. S. cerevisiae-derived vacuoles are closely related to mammalian lysosomes, which play a role in the degradation of macromolecules by various hydrolytic enzymes. This study evaluated the anti-inflammatory efficacy of S. cerevisiae-vacuoles by inhibiting inflammatory mediators induced by lipopolysaccharide (LPS). The results showed that treatment with 5, 10, and 20 µg/mL of S. cerevisiae-derived vacuoles almost completely inhibited the LPS-induced expression of iNOS protein and mRNA. Moreover, vacuoles significantly reduced the mRNA expression of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6) in LPS-stimulated macrophages compared to the control cells. The immunofluorescence analysis confirmed that S. cerevisiae-derived vacuoles inhibited the translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in LPS-stimulated cells. Taken together, the treatment with S. cerevisiae-derived vacuoles alone activated macrophages, but LPS-activated macrophages modulated pro-inflammatory mediators by downregulating the NF-κB pathway. These results suggest that S. cerevisiae-derived vacuoles may have therapeutic potential in the treatment of inflammatory diseases. In conclusion, our study provides new insights into the immunomodulatory effects of S. cerevisiae-derived vacuoles and their potential as a novel anti-inflammatory agent. IMPORTANCE This study investigates the potential of using vacuoles derived from the yeast Saccharomyces cerevisiae as a new anti-inflammatory therapy. Inflammation is a natural response of the immune system to invading pathogens, but when it is dysregulated, it can lead to chronic diseases. The researchers found that treating macrophages with vacuoles significantly reduced the production of pro-inflammatory cytokines and iNOS, markers of inflammation when they were stimulated with lipopolysaccharide. The study also showed that vacuoles inhibited the NF-κB signaling pathway, which is involved in the induction of pro-inflammatory cytokines in macrophages. These findings suggest that S. cerevisiae-derived vacuoles may have potential as a new therapeutic agent for regulating the inflammatory response in various diseases. Further studies are needed to evaluate the efficacy and safety of vacuoles in vivo and to elucidate the underlying mechanisms of their anti-inflammatory effects.
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Affiliation(s)
- Su-Min Lee
- Graduate School of Semiconductor and Chemical Engineering, Jeonbuk National University, Jeonbuk, South Korea
| | - Yang-Hoon Kim
- School of Biological Sciences, Chungbuk National University, Cheongju, South Korea
| | - Jiho Min
- Graduate School of Semiconductor and Chemical Engineering, Jeonbuk National University, Jeonbuk, South Korea
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Carlson E, Savardekar H, Hu X, Lapurga G, Johnson C, Sun SH, Carson WE, Peterson BR. Fluorescent Detection of Peroxynitrite Produced by Myeloid-Derived Suppressor Cells in Cancer and Inhibition by Dasatinib. ACS Pharmacol Transl Sci 2023; 6:738-747. [PMID: 37200815 PMCID: PMC10186365 DOI: 10.1021/acsptsci.3c00014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Indexed: 05/20/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that expand dramatically in many cancer patients. This expansion contributes to immunosuppression in cancer and reduces the efficacy of immune-based cancer therapies. One mechanism of immunosuppression mediated by MDSCs involves production of the reactive nitrogen species peroxynitrite (PNT), where this strong oxidant inactivates immune effector cells through destructive nitration of tyrosine residues in immune signal transduction pathways. As an alternative to analysis of nitrotyrosines indirectly generated by PNT, we used an endoplasmic reticulum (ER)-targeted fluorescent sensor termed PS3 that allows direct detection of PNT produced by MDSCs. When the MDSC-like cell line MSC2 and primary MDSCs from mice and humans were treated with PS3 and antibody-opsonized TentaGel microspheres, phagocytosis of these beads led to production of PNT and generation of a highly fluorescent product. Using this method, we show that splenocytes from a EMT6 mouse model of cancer, but not normal control mice, produce high levels of PNT due to elevated numbers of granulocytic (PMN) MDSCs. Similarly, peripheral blood mononuclear cells (PBMCs) isolated from blood of human melanoma patients produced substantially higher levels of PNT than healthy human volunteers, coincident with higher peripheral MDSC levels. The kinase inhibitor dasatinib was found to potently block the production of PNT both by inhibiting phagocytosis in vitro and by reducing the number of granulocytic MDSCs in mice in vivo, providing a chemical tool to modulate the production of this reactive nitrogen species (RNS) in the tumor microenvironment.
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Affiliation(s)
- Erick
J. Carlson
- Division
of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio 43210, United States
| | - Himanshu Savardekar
- Division
of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, Ohio 43210, United States
| | - Xiaojun Hu
- Division
of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio 43210, United States
| | - Gabriella Lapurga
- Division
of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, Ohio 43210, United States
| | - Courtney Johnson
- Division
of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, Ohio 43210, United States
| | - Steven H. Sun
- Division
of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, Ohio 43210, United States
| | - William E. Carson
- Division
of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, Ohio 43210, United States
| | - Blake R. Peterson
- Division
of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio 43210, United States
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Cheng RYS, Burkett S, Ambs S, Moody T, Wink DA, Ridnour LA. Chronic Exposure to Nitric Oxide Induces P53 Mutations and Malignant-like Features in Human Breast Epithelial Cells. Biomolecules 2023; 13:311. [PMID: 36830680 PMCID: PMC9953427 DOI: 10.3390/biom13020311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 01/31/2023] [Accepted: 02/04/2023] [Indexed: 02/11/2023] Open
Abstract
The small endogenous signaling molecule nitric oxide (NO) has been linked with chronic inflammation and cancer. The effects of NO are both concentration and temporally dependent; under some conditions, NO protects against damage caused by reactive oxygen species and activates P53 signaling. During chronic inflammation, NO causes DNA damage and inhibits repair proteins. To extend our understanding of the roles of NO during carcinogenesis, we investigated the possible effects of chronic NO exposure on MCF10A breast epithelial cells, as defined by changes in cellular morphology, chromosome/genomic stability, RNA, and protein expression, and altered cell phenotypes. Human MCF10A cells were maintained in varying doses of the NO donor DETANO for three weeks. Distinct patterns of genomic modifications in TP53 and KRAS target genes were detected in NO-treated cells when compared to background mutations. In addition, quantitative real-time PCR demonstrated an increase in the expression of cancer stem cell (CSC) marker CD44 after prolonged exposure to 300 μM DETANO. While similar changes in cell morphology were found in cells exposed to 300-500 μM DETANO, cells cultured in 100 μM DETANO exhibited enhanced motility. In addition, 100 μM NO-treated cells proliferated in serum-free media and selected clonal populations and pooled cells formed colonies in soft agar that were clustered and disorganized. These findings show that chronic exposure to NO generates altered breast epithelial cell phenotypes with malignant characteristics.
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Affiliation(s)
- Robert Y. S. Cheng
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
| | - Sandra Burkett
- Molecular Cytogenetics Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
| | - Stefan Ambs
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Terry Moody
- Center for Cancer Training Office of Training and Education, National Cancer Institute, Bethesda, MD 20892, USA
| | - David A. Wink
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
| | - Lisa A. Ridnour
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
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11
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Burke AJ, McAuliffe JD, Natoni A, Ridge S, Sullivan FJ, Glynn SA. Chronic nitric oxide exposure induces prostate cell carcinogenesis, involving genetic instability and a pro-tumorigenic secretory phenotype. Nitric Oxide 2022; 127:44-53. [PMID: 35872082 DOI: 10.1016/j.niox.2022.07.005] [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: 02/24/2022] [Revised: 07/12/2022] [Accepted: 07/15/2022] [Indexed: 11/26/2022]
Abstract
Prostate cancer is a leading cause of cancer death in men. Inflammation and overexpression of inducible nitric oxide synthase (NOS2) have been implicated in prostate carcinogenesis. We aimed to explore the hypothesis that nitric oxide NO exerts pro-tumorigenic effects on prostate cells at physiologically relevant levels contributing to carcinogenesis. We investigated the impact of acute exposure of normal immortalised prostate cells (RWPE-1) to NO on cell proliferation and activation of DNA damage repair pathways. Furthermore we investigated the long term effects of chronic NO exposure on RWPE-1 cell migration and invasion potential and hallmarks of transformation. Our results demonstrate that NO induces DNA damage as indicated by γH2AX foci and p53 activation resulting in a G1/S phase block and activation of 53BP1 DNA damage repair protein. Long term adaption to NO results in increased migration and invasion potential, acquisition of anchorage independent growth and increased resistance to chemotherapy. This was recapitulated in PC3 and DU145 prostate cancer cells which upon chronic exposure to NO displayed increased cell migration, colony formation and increased resistance to chemotherapeutics. These findings indicate that NO may play a key role in the development of prostate cancer and the acquisition of an aggressive metastatic phenotype.
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Affiliation(s)
- Amy J Burke
- Prostate Cancer Institute, School of Medicine, National University of Ireland Galway, Galway, H91 TK33, Ireland
| | - Jake D McAuliffe
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, Galway, H91 TK33, Ireland
| | - Alessandro Natoni
- Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
| | - Sarah Ridge
- Prostate Cancer Institute, School of Medicine, National University of Ireland Galway, Galway, H91 TK33, Ireland
| | - Francis J Sullivan
- Prostate Cancer Institute, School of Medicine, National University of Ireland Galway, Galway, H91 TK33, Ireland
| | - Sharon A Glynn
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, Galway, H91 TK33, Ireland.
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12
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Piacenza L, Zeida A, Trujillo M, Radi R. The superoxide radical switch in the biology of nitric oxide and peroxynitrite. Physiol Rev 2022; 102:1881-1906. [PMID: 35605280 DOI: 10.1152/physrev.00005.2022] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- Lucìa Piacenza
- Departamento de Bioquímica, Facultad de Medicina; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Uruguay
| | - Ari Zeida
- Departamento de Bioquímica, Facultad de Medicina; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay
| | - Madia Trujillo
- Departamento de Bioquímica, Facultad de Medicina; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay
| | - Rafael Radi
- Departamento de Bioquímica, Facultad de Medicina; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay
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13
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Brassea-Pérez E, Hernández-Camacho CJ, Labrada-Martagón V, Vázquez-Medina JP, Gaxiola-Robles R, Zenteno-Savín T. "Oxidative stress induced by phthalates in mammals: State of the art and potential biomarkers". ENVIRONMENTAL RESEARCH 2022; 206:112636. [PMID: 34973198 DOI: 10.1016/j.envres.2021.112636] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 11/20/2021] [Accepted: 12/25/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND Phthalates, plasticizers that are widely used in consumer products including toys, cosmetics, and food containers, have negative effects in liver, kidney, brain, lung and reproductive system of humans and other mammals. OBJECTIVES To summarize, describe and discuss the available information on the effects of phthalate exposure in mammals, with emphasis on oxidative stress, and to suggest potential biomarkers of the health risks associated with phthalate exposure. METHODS An assessment of scientific journals was performed using the PRISMA model for systematic reviews. Manuscripts reporting effects of phthalate exposure on mammalian health published in the last decade were selected according to originality, content, and association to health hazards. RESULTS AND DISCUSSION We identified 25 peer-reviewed articles published between January 1st, 2010 and June 1st, 2021 that fit the aims and selection criteria. Phthalates induce oxidative stress and cell degenerative processes by increasing intracellular reactive species. Antioxidant cytoprotective systems decrease with time of exposure; conversely, oxidative damage markers, including thiobarbituric acid-reactive substances (TBARS), 8-hydroxy-2'-desoxyguanosine (8-OHdG) and malondialdehyde (MDA), increase. Phthalates were associated with endocrine system disfunction, metabolic disorders, infertility, nonviable pregnancy, cell degeneration, growth impairment, tumor development, and cognitive disorders. Phthalates can also aggravate health conditions such as asthma, hepatitis, diabetes, allergies, chronic liver and kidney diseases. Among humans, the more vulnerable subjects to phthalate exposure effects were children and individuals with a prior health condition. CONCLUSION Chronic exposure to phthalates induces oxidative stress in mammals with concomitant adverse effects in reproductive, respiratory, endocrine, circulatory, and central nervous systems in both in vitro and in vivo trials. Oxidative damage markers and phthalate metabolites levels were the most common biomarkers of phthalate exposure effects. Studies in free-ranging and wild mammals are nil. Further studies on the pathways that lead to metabolic disruption are needed to identify potential treatments against phthalate-induced detrimental effects.
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Affiliation(s)
- Elizabeth Brassea-Pérez
- Centro de Investigaciones Biológicas Del Noroeste S.C, Planeación Ambiental y Conservación, Av. Instituto Politécnico Nacional #195, Col. Playa Palo Santa Rita Sur, CP 23096, La Paz, Baja California Sur, Mexico
| | - Claudia J Hernández-Camacho
- Centro Interdisciplinario de Ciencias Marinas. Instituto Politécnico Nacional, Av. Instituto Politécnico Nacional S/n, Col. Playa Palo de Santa Rita Sur, CP 23096, La Paz, Baja California Sur, Mexico
| | - Vanessa Labrada-Martagón
- Facultad de Ciencias, Universidad Autónoma de San Luis Potosí, Av. Chapultepec #1570, Col. Privadas Del Pedregal, CP 78295, San Luis Potosí, San Luis Potosí, Mexico
| | | | - Ramón Gaxiola-Robles
- Centro de Investigaciones Biológicas Del Noroeste S.C, Planeación Ambiental y Conservación, Av. Instituto Politécnico Nacional #195, Col. Playa Palo Santa Rita Sur, CP 23096, La Paz, Baja California Sur, Mexico; Hospital General de Zona No.1. Instituto Mexicano Del Seguro Social, 5 de Febrero y Héroes de La Independencia, Centro, La Paz, Baja California Sur, C.P. 23000, Mexico
| | - Tania Zenteno-Savín
- Centro de Investigaciones Biológicas Del Noroeste S.C, Planeación Ambiental y Conservación, Av. Instituto Politécnico Nacional #195, Col. Playa Palo Santa Rita Sur, CP 23096, La Paz, Baja California Sur, Mexico.
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14
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Camillo L, Grossini E, Farruggio S, Marotta P, Gironi LC, Zavattaro E, Savoia P. Alpha-Tocopherol Protects Human Dermal Fibroblasts by Modulating Nitric Oxide Release, Mitochondrial Function, Redox Status, and Inflammation. Skin Pharmacol Physiol 2021; 35:1-12. [PMID: 34237733 DOI: 10.1159/000517204] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 05/01/2021] [Indexed: 11/19/2022]
Abstract
BACKGROUND The altered balance between oxidants/antioxidants and inflammation, changes in nitric oxide (NO) release, and mitochondrial function have a role in skin aging through fibroblast modulation. Tocopherol is promising in counteracting the abovementioned events, but the effective mechanism of action needs to be clarified. OBJECTIVE The aim of this study was to examine the effects of α-tocopherol on cell viability/proliferation, NO release, mitochondrial function, oxidants/antioxidants, and inflammation in human dermal fibroblasts (HDF) subjected to oxidative stress. METHODS HDF were treated with H2O2 in the presence or absence of 1-10 μM α-tocopherol. Cell viability, reactive oxygen species (ROS), NO release, and mitochondrial membrane potential were measured; glutathione (GSH), superoxide dismutase (SOD)-1 and -2, glutathione peroxidase-1 (GPX-1), inducible NO synthase (iNOS), and Ki-67 were evaluated by RT-PCR and immunofluorescence; cell cycle was analyzed using FACS. Pro- and anti-inflammatory cytokine gene expression was analyzed through qRT-PCR. RESULTS α-Tocopherol counteracts H2O2, although it remains unclear whether this effect is dose dependent. Improvement of cell viability, mitochondrial membrane potential, Ki-67 expression, and G0/G1 and G2/M phases of the cell cycle was observed. These effects were accompanied by the increase of GSH content and the reduction of SOD-1 and -2, GPX-1, and ROS release. Also, iNOS expression and NO release were inhibited, and pro-inflammatory cytokine gene expression was decreased, confirming the putative role of α-tocopherol against inflammation. CONCLUSION α-Tocopherol exerts protective effects in HDF which underwent oxidative stress by modulating the redox status, inflammation, iNOS-dependent NO release, and mitochondrial function. These observations have a potential role in the prevention and treatment of photoaging-related skin cancers.
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Affiliation(s)
- Lara Camillo
- Department of Health Science, Dermatologic Unit, University of Eastern Piedmont, Novara, Italy
| | - Elena Grossini
- Laboratory of Physiology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | - Serena Farruggio
- Laboratory of Physiology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | - Patrizia Marotta
- Laboratory of Physiology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | | | - Elisa Zavattaro
- Azienda Ospedaliera Universitaria Maggiore della Carità, Novara, Italy
| | - Paola Savoia
- Department of Health Science, Dermatologic Unit, University of Eastern Piedmont, Novara, Italy
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15
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Nitric oxide-inducing Genistein elicits apoptosis-like death via an intense SOS response in Escherichia coli. Appl Microbiol Biotechnol 2020; 104:10711-10724. [PMID: 33170329 DOI: 10.1007/s00253-020-11003-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 10/26/2020] [Accepted: 11/03/2020] [Indexed: 01/06/2023]
Abstract
Increasing prevalence of multidrug-resistant untreatable infections has prompted researchers to trial alternative treatments such as a substitute for traditional antibiotics. This study endeavored to elucidate the antibacterial mechanism(s) of this isoflavone, via analysis of relationship between genistein and Escherichia coli. Furthermore, this investigation analyzed whether genistein generates nitric oxide (NO) in E. coli as NO contributes to cell death. RecA, an essential protein for the bacterial SOS response, was detected through western blot, and the activated caspases decreased without RecA. The results showed that the NO induced by genistein affected the bacterial DNA. Under conditions of acute DNA damage, an SOS response called apoptosis-like death occurred, affecting DNA repair. These results suggested that RecA was bacterial caspase-like protein. In addition, NO was toxic to the bacterial cells and induced dysfunction of the plasma membrane. Thus, membrane depolarization and phosphatidylserine exposure were observed similarly to eukaryotic apoptosis. In conclusion, the combined results demonstrated that the antibacterial mode of action(s) of genistein was a NO-induced apoptosis-like death, and the role of RecA suggested that it contributed to the SOS response of NO defense. KEY POINTS: • Genistein generates nitric oxide in E. coli. • Genistein exhibits intense SOS response in E. coli. • Genistein-induced NO causes apoptosis-like death in E. coli.
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16
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Gorska-Ponikowska M, Ploska A, Jacewicz D, Szkatula M, Barone G, Lo Bosco G, Lo Celso F, Dabrowska AM, Kuban-Jankowska A, Gorzynik-Debicka M, Knap N, Chmurzynski L, Dobrucki LW, Kalinowski L, Wozniak M. Modification of DNA structure by reactive nitrogen species as a result of 2-methoxyestradiol-induced neuronal nitric oxide synthase uncoupling in metastatic osteosarcoma cells. Redox Biol 2020; 32:101522. [PMID: 32305006 PMCID: PMC7162974 DOI: 10.1016/j.redox.2020.101522] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/23/2020] [Accepted: 03/24/2020] [Indexed: 12/16/2022] Open
Abstract
2-methoxyestradiol (2-ME) is a physiological anticancer compound, metabolite of 17β-estradiol. Previously, our group evidenced that from mechanistic point of view one of anticancer mechanisms of action of 2-ME is specific induction and nuclear hijacking of neuronal nitric oxide synthase (nNOS), resulting in local generation of nitro-oxidative stress and finally, cancer cell death. The current study aims to establish the substantial mechanism of generation of reactive nitrogen species by 2-ME. We further achieved to identify the specific reactive nitrogen species involved in DNA-damaging mechanism of 2-ME. The study was performed using metastatic osteosarcoma 143B cells. We detected the release of biologically active (free) nitric oxide (•NO) with concurrent measurements of peroxynitrite (ONOO−) in real time in a single cell of 143B cell line by using •NO/ONOO− sensitive microsensors after stimulation with calcium ionophore. Detection of nitrogen dioxide (•NO2) and determination of chemical rate constants were carried out by a stopped-flow technique. The affinity of reactive nitrogen species toward the guanine base of DNA was evaluated by density functional theory calculations. Expression and localization of nuclear factor NF-kB was determined using imaging cytometry, while cell viability assay was evaluated by MTT assay. Herein, we presented that 2-ME triggers pro-apoptotic signalling cascade by increasing cellular reactive nitrogen species overproduction – a result of enzymatic uncoupling of increased nNOS protein levels. In particular, we proved that ONOO− and •NO2 directly formed from peroxynitrous acid (ONOOH) and/or by auto-oxidation of •NO, are inducers of DNA damage in anticancer mechanism of 2-ME. Specifically, the affinity of reactive nitrogen species toward the guanine base of DNA, evaluated by density functional theory calculations, decreased in the order: ONOOH > ONOO− > •NO2 > •NO. Therefore, we propose to consider the specific inducers of nNOS as an effective tool in the field of chemotherapy.
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Affiliation(s)
- Magdalena Gorska-Ponikowska
- Department of Medical Chemistry, Medical University of Gdansk, 1 Debinki St, 80-211, Gdansk, Poland; Euro-Mediterranean Institute of Science and Technology, Palermo, Italy; Department of Biophysics, Institute of Biomaterials and Biomolecular Systems, University of Stuttgart, Stuttgart, Germany.
| | - Agata Ploska
- Department of Medical Laboratory Diagnostics, Medical University of Gdansk, Gdansk, Poland; Biobanking and Biomolecular Resources Research Infrastructure Poland (BBMRI.PL), Gdansk, Poland
| | - Dagmara Jacewicz
- Department of General and Inorganic Chemistry, University of Gdansk, Gdansk, Poland
| | - Michal Szkatula
- Department of Medical Chemistry, Medical University of Gdansk, 1 Debinki St, 80-211, Gdansk, Poland
| | - Giampaolo Barone
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo,Palermo, Italy
| | - Giosuè Lo Bosco
- Euro-Mediterranean Institute of Science and Technology, Palermo, Italy; Department of Mathematics and Computer Science, University of Palermo, Palermo, Italy
| | - Fabrizio Lo Celso
- Department of Physics and Chemistry "Emilio Segrè", University of Palermo, Palermo, Italy
| | | | - Alicja Kuban-Jankowska
- Department of Medical Chemistry, Medical University of Gdansk, 1 Debinki St, 80-211, Gdansk, Poland
| | - Monika Gorzynik-Debicka
- Department of Medical Chemistry, Medical University of Gdansk, 1 Debinki St, 80-211, Gdansk, Poland
| | - Narcyz Knap
- Department of Medical Chemistry, Medical University of Gdansk, 1 Debinki St, 80-211, Gdansk, Poland
| | - Lech Chmurzynski
- Department of General and Inorganic Chemistry, University of Gdansk, Gdansk, Poland
| | - Lawrence Wawrzyniec Dobrucki
- Department of Medical Laboratory Diagnostics, Medical University of Gdansk, Gdansk, Poland; Biobanking and Biomolecular Resources Research Infrastructure Poland (BBMRI.PL), Gdansk, Poland; Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Beckman Institute for Advanced Science and Technology, Urbana, IL, USA
| | - Leszek Kalinowski
- Department of Medical Laboratory Diagnostics, Medical University of Gdansk, Gdansk, Poland; Biobanking and Biomolecular Resources Research Infrastructure Poland (BBMRI.PL), Gdansk, Poland
| | - Michal Wozniak
- Department of Medical Chemistry, Medical University of Gdansk, 1 Debinki St, 80-211, Gdansk, Poland
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17
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Saccol RDSP, da Silveira KL, Manzoni AG, Abdalla FH, de Oliveira JS, Dornelles GL, Barbisan F, Passos DF, Casali EA, de Andrade CM, da Cruz IBM, Leal DBR. Antioxidant, hepatoprotective, genoprotective, and cytoprotective effects of quercetin in a murine model of arthritis. J Cell Biochem 2019; 121:2792-2801. [PMID: 31691375 DOI: 10.1002/jcb.29502] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 10/08/2019] [Indexed: 12/11/2022]
Abstract
Rheumatoid arthritis is a highly debilitating inflammatory autoimmune disease which is characterized by joint destruction. The present study sought to investigate the effect of quercetin in rats with complete Freund's adjuvant-induced arthritis. Animals were divided into control/saline, control/quercetin (5 mg/kg, 25 mg/kg, and 50 mg/kg) arthritis/saline, and arthritis/quercetin (5 mg/kg, 25 mg/kg, and 50 mg/kg); the treatments were administered for 45 days. Biochemical, oxidative stress, genotoxicity, and cytotoxicity parameters were evaluated. All doses of quercetin reduced the levels of aspartate aminotransferase, thiobarbituric acid-reactive substances, and reactive oxygen species; however, only treatment with 25 or 50 mg/kg increased catalase activity. Total thiol and reduced glutathione levels were not significantly affected by the induction nor by the treatments. Genotoxicity assessed by DNA damage, and cytotoxicity through picogreen assay, decreased after treatments with quercetin. Our results present evidence of the antioxidant, cytoprotective, genoprotective and hepatoprotective, and effects of quercetin, demonstrating its potential as a candidate for coadjuvant therapy.
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Affiliation(s)
- Renata da Silva Pereira Saccol
- Programa de Pós-Graduação em Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil.,Laboratório de Imunobiologia Experimental e Aplicada, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil
| | - Karine Lanes da Silveira
- Programa de Pós-Graduação em Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil.,Laboratório de Imunobiologia Experimental e Aplicada, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil
| | - Alessandra Guedes Manzoni
- Laboratório de Imunobiologia Experimental e Aplicada, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil.,Programa de Pós-Graduação em Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil
| | - Fátima Husein Abdalla
- Laboratório de Imunobiologia Experimental e Aplicada, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil
| | - Juliana Sorraila de Oliveira
- Programa de Pós-Graduação em Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil
| | - Guilherme Lopes Dornelles
- Programa de Pós-Graduação em Medicina Veterinária, Centro de Ciências Rurais, Departamento de Pequenos Animais, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil
| | - Fernanda Barbisan
- Programa de Pós-Graduação em Gerontologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil.,Laboratório de Biogenômica, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil
| | - Daniela Ferreira Passos
- Laboratório de Imunobiologia Experimental e Aplicada, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil.,Programa de Pós-Graduação em Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil
| | - Emerson André Casali
- Departamento de Ciências Morfológicas, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, RS, Brasil
| | - Cinthia Melazzo de Andrade
- Programa de Pós-Graduação em Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil.,Programa de Pós-Graduação em Medicina Veterinária, Centro de Ciências Rurais, Departamento de Pequenos Animais, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil
| | - Ivana Beatrice Mânica da Cruz
- Programa de Pós-Graduação em Gerontologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil.,Laboratório de Biogenômica, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil
| | - Daniela Bitencourt Rosa Leal
- Programa de Pós-Graduação em Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil.,Laboratório de Imunobiologia Experimental e Aplicada, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil.,Programa de Pós-Graduação em Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil
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18
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Kamm A, Przychodzen P, Kuban-Jankowska A, Jacewicz D, Dabrowska AM, Nussberger S, Wozniak M, Gorska-Ponikowska M. Nitric oxide and its derivatives in the cancer battlefield. Nitric Oxide 2019; 93:102-114. [PMID: 31541733 DOI: 10.1016/j.niox.2019.09.005] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 08/06/2019] [Accepted: 09/16/2019] [Indexed: 12/14/2022]
Abstract
Elevated levels of reactive nitrogen species, alteration in redox balance and deregulated redox signaling are common hallmarks of cancer progression and chemoresistance. However, depending on the cellular context, distinct reactive nitrogen species are also hypothesized to mediate cytotoxic activity and are thus used in anticancer therapies. We present here the dual face of nitric oxide and its derivatives in cancer biology. Main derivatives of nitric oxide, such as nitrogen dioxide and peroxynitrite cause cell death by inducing protein and lipid peroxidation and/or DNA damage. Moreover, they control the activity of important protein players within the pro- and anti-apoptotic signaling pathways. Thus, the control of intracellular reactive nitrogen species may become a sophisticated tool in anticancer strategies.
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Affiliation(s)
- Anna Kamm
- Department of Medical Chemistry, Faculty of Medicine, Medical University of Gdansk, Gdansk, Poland
| | - Paulina Przychodzen
- Department of Medical Chemistry, Faculty of Medicine, Medical University of Gdansk, Gdansk, Poland
| | - Alicja Kuban-Jankowska
- Department of Medical Chemistry, Faculty of Medicine, Medical University of Gdansk, Gdansk, Poland
| | | | | | - Stephan Nussberger
- Department of Biophysics, Institute of Biomaterials and Biomolecular Systems, University of Stuttgart, Stuttgart, Germany
| | - Michal Wozniak
- Department of Medical Chemistry, Faculty of Medicine, Medical University of Gdansk, Gdansk, Poland
| | - Magdalena Gorska-Ponikowska
- Department of Medical Chemistry, Faculty of Medicine, Medical University of Gdansk, Gdansk, Poland; Department of Biophysics, Institute of Biomaterials and Biomolecular Systems, University of Stuttgart, Stuttgart, Germany; Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.
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19
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Phillips CM, Chen LW, Heude B, Bernard JY, Harvey NC, Duijts L, Mensink-Bout SM, Polanska K, Mancano G, Suderman M, Shivappa N, Hébert JR. Dietary Inflammatory Index and Non-Communicable Disease Risk: A Narrative Review. Nutrients 2019; 11:E1873. [PMID: 31408965 PMCID: PMC6722630 DOI: 10.3390/nu11081873] [Citation(s) in RCA: 220] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 07/30/2019] [Accepted: 08/05/2019] [Indexed: 12/13/2022] Open
Abstract
There are over 1,000,000 publications on diet and health and over 480,000 references on inflammation in the National Library of Medicine database. In addition, there have now been over 30,000 peer-reviewed articles published on the relationship between diet, inflammation, and health outcomes. Based on this voluminous literature, it is now recognized that low-grade, chronic systemic inflammation is associated with most non-communicable diseases (NCDs), including diabetes, obesity, cardiovascular disease, cancers, respiratory and musculoskeletal disorders, as well as impaired neurodevelopment and adverse mental health outcomes. Dietary components modulate inflammatory status. In recent years, the Dietary Inflammatory Index (DII®), a literature-derived dietary index, was developed to characterize the inflammatory potential of habitual diet. Subsequently, a large and rapidly growing body of research investigating associations between dietary inflammatory potential, determined by the DII, and risk of a wide range of NCDs has emerged. In this narrative review, we examine the current state of the science regarding relationships between the DII and cancer, cardiometabolic, respiratory and musculoskeletal diseases, neurodevelopment, and adverse mental health outcomes. We synthesize the findings from recent studies, discuss potential underlying mechanisms, and look to the future regarding novel applications of the adult and children's DII (C-DII) scores and new avenues of investigation in this field of nutritional research.
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Affiliation(s)
- Catherine M Phillips
- HRB Centre for Diet and Health Research, School of Public Health, Physiotherapy, and Sports Science, University College Dublin, Belfield, Dublin 4, Ireland.
- HRB Centre for Diet and Health Research, School of Public Health, University College Cork, Western Gateway Building, Western Rd, Cork, Co. Cork, Ireland.
| | - Ling-Wei Chen
- HRB Centre for Diet and Health Research, School of Public Health, Physiotherapy, and Sports Science, University College Dublin, Belfield, Dublin 4, Ireland
| | - Barbara Heude
- Research Team on the Early Life Origins of Health (EAROH), Centre for Research in Epidemiology and Statistics (CRESS), INSERM, Université de Paris, F-94807 Villejuif, France
| | - Jonathan Y Bernard
- Research Team on the Early Life Origins of Health (EAROH), Centre for Research in Epidemiology and Statistics (CRESS), INSERM, Université de Paris, F-94807 Villejuif, France
| | - Nicholas C Harvey
- MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK
| | - Liesbeth Duijts
- The Generation R Study Group, Erasmus MC, University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
- Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands
- Department of Pediatrics, Division of Neonatology, Erasmus MC, University Medical Center, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands
| | - Sara M Mensink-Bout
- The Generation R Study Group, Erasmus MC, University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
- Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands
| | - Kinga Polanska
- Department of Environmental Epidemiology, Nofer Institute of Occupational Medicine, 91-348 Lodz, Poland
| | - Giulia Mancano
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 2BN, UK
| | - Matthew Suderman
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 2BN, UK
| | - Nitin Shivappa
- Cancer Prevention and Control Program and Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA
| | - James R Hébert
- Cancer Prevention and Control Program and Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA
- Connecting Health Innovations LLC, Columbia, SC 29201, USA
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20
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Truong VL, Bak MJ, Jeong WS. Chemopreventive Activity of Red Ginseng Oil in a Mouse Model of Azoxymethane/Dextran Sulfate Sodium-Induced Inflammation-Associated Colon Carcinogenesis. J Med Food 2019; 22:578-586. [PMID: 30864851 DOI: 10.1089/jmf.2018.4328] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Our previous studies have demonstrated antioxidant and cytoprotective properties of red ginseng oil (RGO). However, the role of RGO in models of intestinal inflammation has not been elucidated. In this study, we evaluated the chemopreventive effect of RGO in a mouse model of azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis and explored its underlying mechanisms. Male C57BL/6 mice were intraperitoneally injected with a single dose of AOM (10 mg/kg), followed by 1.5% DSS in drinking water for 7 days to produce colon carcinogenesis. RGO at 10 or 100 mg/kg was orally given for 17 weeks. RGO supplementation reduced the plasma nitric oxide (NO) concentration as well as lipid peroxidation and inhibited the production of proinflammatory factors such as inducible NO synthase, cyclooxygenase-2, interleukin 1β, IL-6, and tumor necrosis factor-α in the mouse colitis tissue. Increased phosphorylation levels of p65 and IκB by AOM/DSS exposure were attenuated by the presence of RGO. In addition, RGO supplementation induced the activity of primary antioxidant enzymes such as superoxide dismutase and catalase as well as the expression of nuclear factor erythroid 2-related factor 2-mediated antioxidant enzyme hemeoxygenase-1 in the colons of AOM/DSS-treated mice. These findings indicate that RGO may be a potent natural chemopreventive agent for ameliorating inflammatory bowel diseases.
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Affiliation(s)
- Van-Long Truong
- 1 Department of Food and Life Sciences, College of BNIT, Inje University, Gimhae, Korea
| | - Min Ji Bak
- 1 Department of Food and Life Sciences, College of BNIT, Inje University, Gimhae, Korea.,2 Department of Chemical Biology, Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA
| | - Woo-Sik Jeong
- 1 Department of Food and Life Sciences, College of BNIT, Inje University, Gimhae, Korea
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21
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Yagüe-Capilla M, García-Caballero D, Aguilar-Pereyra F, Castillo-Acosta VM, Ruiz-Pérez LM, Vidal AE, González-Pacanowska D. Base excision repair plays an important role in the protection against nitric oxide- and in vivo-induced DNA damage in Trypanosoma brucei. Free Radic Biol Med 2019; 131:59-71. [PMID: 30472364 DOI: 10.1016/j.freeradbiomed.2018.11.025] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 10/22/2018] [Accepted: 11/21/2018] [Indexed: 11/17/2022]
Abstract
Uracil-DNA glycosylase (UNG) initiates the base excision repair pathway by excising uracil from DNA. We have previously shown that Trypanosoma brucei cells defective in UNG exhibit reduced infectivity thus demonstrating the relevance of this glycosylase for survival within the mammalian host. In the early steps of the immune response, nitric oxide (NO) is released by phagocytes, which in combination with oxygen radicals produce reactive nitrogen species (RNS). These species can react with DNA generating strand breaks and base modifications including deaminations. Since deaminated cytosines are the main substrate for UNG, we hypothesized that the glycosylase might confer protection towards nitrosative stress. Our work establishes the occurrence of genotoxic damage in Trypanosoma brucei upon exposure to NO in vitro and shows that deficient base excision repair results in increased levels of damage in DNA and a hypermutator phenotype. We also evaluate the incidence of DNA damage during infection in vivo and show that parasites recovered from mice exhibit higher levels of DNA strand breaks, base deamination and repair foci compared to cells cultured in vitro. Notably, the absence of UNG leads to reduced infectivity and enhanced DNA damage also in animal infections. By analysing mRNA and protein levels, we found that surviving UNG-KO trypanosomes highly express tryparedoxin peroxidase involved in trypanothione/tryparedoxin metabolism. These observations suggest that the immune response developed by the host enhances the activation of genes required to counteract oxidative stress and emphasize the importance of DNA repair pathways in the protection to genotoxic and oxidative stress in trypanosomes.
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Affiliation(s)
- Miriam Yagüe-Capilla
- Instituto de Parasitología y Biomedicina "López-Neyra". Consejo Superior de Investigaciones Científicas. Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento, 17, 18016 Armilla, Granada, Spain
| | - Daniel García-Caballero
- Instituto de Parasitología y Biomedicina "López-Neyra". Consejo Superior de Investigaciones Científicas. Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento, 17, 18016 Armilla, Granada, Spain
| | - Fernando Aguilar-Pereyra
- Instituto de Parasitología y Biomedicina "López-Neyra". Consejo Superior de Investigaciones Científicas. Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento, 17, 18016 Armilla, Granada, Spain
| | - Víctor M Castillo-Acosta
- Instituto de Parasitología y Biomedicina "López-Neyra". Consejo Superior de Investigaciones Científicas. Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento, 17, 18016 Armilla, Granada, Spain
| | - Luis M Ruiz-Pérez
- Instituto de Parasitología y Biomedicina "López-Neyra". Consejo Superior de Investigaciones Científicas. Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento, 17, 18016 Armilla, Granada, Spain
| | - Antonio E Vidal
- Instituto de Parasitología y Biomedicina "López-Neyra". Consejo Superior de Investigaciones Científicas. Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento, 17, 18016 Armilla, Granada, Spain
| | - Dolores González-Pacanowska
- Instituto de Parasitología y Biomedicina "López-Neyra". Consejo Superior de Investigaciones Científicas. Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento, 17, 18016 Armilla, Granada, Spain.
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22
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Oxidative Stress in Poultry: Lessons from the Viral Infections. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:5123147. [PMID: 30647810 PMCID: PMC6311761 DOI: 10.1155/2018/5123147] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 10/25/2018] [Indexed: 12/13/2022]
Abstract
Reactive species (RS), generally known as reactive oxygen species (ROS) and reactive nitrogen species (RNS), are produced during regular metabolism in the host and are required for many cellular processes such as cytokine transcription, immunomodulation, ion transport, and apoptosis. Intriguingly, both RNS and ROS are commonly triggered by the pathogenic viruses and are famous for their dual roles in the clearance of viruses and pathological implications. Uncontrolled production of reactive species results in oxidative stress and causes damage in proteins, lipids, DNA, and cellular structures. In this review, we describe the production of RS, their detoxification by a cellular antioxidant system, and how these RS damage the proteins, lipids, and DNA. Given the widespread importance of RS in avian viral diseases, oxidative stress pathways are of utmost importance for targeted therapeutics. Therefore, a special focus is provided on avian virus-mediated oxidative stresses. Finally, future research perspectives are discussed on the exploitation of these pathways to treat viral diseases of poultry.
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23
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Uchida D, Takaki A, Adachi T, Okada H. Beneficial and Paradoxical Roles of Anti-Oxidative Nutritional Support for Non-Alcoholic Fatty Liver Disease. Nutrients 2018; 10:E977. [PMID: 30060482 PMCID: PMC6116036 DOI: 10.3390/nu10080977] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Revised: 07/17/2018] [Accepted: 07/24/2018] [Indexed: 02/06/2023] Open
Abstract
Oxidative stress is being recognized as a key factor in the progression of chronic liver disease (CLD), especially non-alcoholic fatty liver disease (NAFLD). Many NAFLD treatment guidelines recommend the use of antioxidants, especially vitamin E. Many prospective studies have described the beneficial effects of such agents for the clinical course of NAFLD. However, as these studies are usually short-term evaluations, lasting only a few years, whether or not antioxidants continue to exert favorable long-term effects, including in cases of concomitant hepatocellular carcinoma, remains unclear. Antioxidants are generally believed to be beneficial for human health and are often commercially available as health-food products. Patients with lifestyle-related diseases often use such products to try to be healthier without practicing lifestyle intervention. However, under some experimental NAFLD conditions, antioxidants have been shown to encourage the progression of hepatocellular carcinoma, as oxidative stress is toxic for cancer cells, just as for normal cells. In this review, we will highlight the paradoxical effects of antioxidants against NAFLD and related hepatocellular carcinoma.
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Affiliation(s)
- Daisuke Uchida
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
| | - Akinobu Takaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
| | - Takuya Adachi
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
| | - Hiroyuki Okada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
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24
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Swanson A, Wolf T, Sitzmann A, Willette AA. Neuroinflammation in Alzheimer's disease: Pleiotropic roles for cytokines and neuronal pentraxins. Behav Brain Res 2018; 347:49-56. [PMID: 29462653 PMCID: PMC5988985 DOI: 10.1016/j.bbr.2018.02.015] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 01/30/2018] [Accepted: 02/13/2018] [Indexed: 12/14/2022]
Abstract
Neuroinflammation is a potential factor speculated to underlie Alzheimer's disease (AD) etiopathogenesis and progression. The overwhelming focus in this area of research to date has been on the chronic upregulation of pro-inflammatory cytokines to understand how neuroinflammatory mechanisms contribute to neurodegeneration. Yet, it is important to understand the pleiotropic roles of these cytokines in modulating neuroinflammation in which they cannot be labeled as a strictly "good" or "bad" biomarker phenotype. As such, biomarkers with more precise functions are needed to better understand how neuroinflammation impacts the brain in AD. Neuronal pentraxins are a concentration- dependent group of pro- or anti- inflammatory cytokines. There is contradictory evidence of these pentraxins as being both neuroprotective and potentially detrimental in AD. Potential neuroprotective examples include their ability to predict AD-related outcomes such as cognition, memory function and synaptic refinement. This review will briefly outline the basis of AD and subsequently summarize findings for neuropathological mechanisms of neuroinflammation, roles for traditional pro-and anti-inflammatory cytokines, and data found thus far on the neuronal pentraxins.
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Affiliation(s)
- Ashley Swanson
- Department of Food Science and Human Nutrition, Iowa State University, 2312 Food Sciences Building, 536 Farm House Lane, Ames, IA 50011, United States.
| | - Tovah Wolf
- Department of Food Science and Human Nutrition, Iowa State University, 2312 Food Sciences Building, 536 Farm House Lane, Ames, IA 50011, United States.
| | - Alli Sitzmann
- Department of Psychology, Iowa State University, W112 Lagomarcino Hall, 901 Stange Road, Ames, IA 50011, United States.
| | - Auriel A Willette
- Department of Food Science and Human Nutrition, Iowa State University, 2312 Food Sciences Building, 536 Farm House Lane, Ames, IA 50011, United States; Department of Psychology, Iowa State University, W112 Lagomarcino Hall, 901 Stange Road, Ames, IA 50011, United States; Department of Biomedical Sciences, Iowa State University, 2008 Veterinary Medicine, Ames, IA 50011, United States; Department of Neurology, University of Iowa, 2007 Roy Carver Pavilion, 200 Hawkins Drive, Iowa City, IA 52242, United States.
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25
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Ghaderi A, NasehGhafoori P, Rasouli-Azad M, Sehat M, Mehrzad F, Nekuei M, Aaseth J, Banafshe HR, Mehrpour O. Examining of Thallium in Cigarette Smokers. Biol Trace Elem Res 2018; 182:224-230. [PMID: 28766107 DOI: 10.1007/s12011-017-1107-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Accepted: 07/25/2017] [Indexed: 12/29/2022]
Abstract
Smoking is one of the sources of thallium which is considered as a toxic heavy metal. The aim of this study was to determine urinary thallium levels and related variables in smokers, compared to a control group. The study was conducted on 56 participants who had smoked continuously during the year before they were referred to Kashan Smoking Cessation Clinic. Fifty-three nonsmokers who were family members or friends of the smokers were selected as the control group. Urinary thallium was measured in both groups (n = 109) using atomic absorption spectrophotometry. The mean value (with SD) for urinary thallium in the smokers (10.16 ± 1.82 μg/L) was significantly higher than in the control group (2.39 ± 0.63 μg/L). There was a significant relationship between smoking duration and urinary thallium levels (P = 0.003). In a subgroup of smokers who was addicted to opium and opium residues (n = 9), the mean level of thallium (37.5 ± 13.09 μg/L) was significantly higher than in the other smokers (4.93 ± 4.45; P = 0.001). Multiple regression analysis showed opioid abuse, insomnia, and chronic obstructive pulmonary disease (COPD), together were strong predictors of urinary thallium levels in smokers. There was no significant difference in thallium level in hookah smokers (P = 0.299) or in those with COPD compared to other smokers (P = 0.375). Urinary thallium levels of smokers with clinical signs of depression, sleep disorders, memory loss, and sweating were higher than those of smokers without these signs. Since thallium, as other toxic metals is accumulated in the body, and cigarette smoking also involves carcinogenic exposures and health hazards for passively exposed people, the need for cigarette control policies is emphasized.
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Affiliation(s)
- Amir Ghaderi
- Department of Addiction Studies, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Physiology Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Payam NasehGhafoori
- Physiology Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Morad Rasouli-Azad
- Department of Clinical Psychology, School of Medicine, Kashan University of Medical Science, Kashan, Iran
- Substance Abuse and Dependence Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Mojtaba Sehat
- Department of Community Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Fateme Mehrzad
- Department of Psychiatry, School of Medicine, Kashan University of Medical Science, Kashan, Iran
| | - Mina Nekuei
- Department of Medicine, Najafabad Branch, Islamic Azad University, Najafabad, Iran
| | - Jan Aaseth
- Elverum, and Research Department, Innlandet Hospital, Norway University of Applied Sciences, Brumunddal, Norway
| | - Hamid Reza Banafshe
- Department of Addiction Studies, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran.
- Physiology Research Center, Kashan University of Medical Sciences, Kashan, Iran.
- Department of Pharmacology, School of Medicine, Kashan University of Medical Sciences, Ravand Street, Kashan, 87159-88141, Iran.
| | - Omid Mehrpour
- Medical Toxicology and Drug Abuse Research Center (MTDRC), Birjand University of Medical Sciences, Birjand, Iran
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26
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Hu CW, Chang YJ, Chen JL, Hsu YW, Chao MR. Sensitive Detection of 8-Nitroguanine in DNA by Chemical Derivatization Coupled with Online Solid-Phase Extraction LC-MS/MS. Molecules 2018. [PMID: 29517997 PMCID: PMC6017919 DOI: 10.3390/molecules23030605] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
8-Nitroguanine (8-nitroG) is a major mutagenic nucleobase lesion generated by peroxynitrite during inflammation and has been used as a potential biomarker to evaluate inflammation-related carcinogenesis. Here, we present an online solid-phase extraction (SPE) LC-MS/MS method with 6-methoxy-2-naphthyl glyoxal hydrate (MTNG) derivatization for a sensitive and precise measurement of 8-nitroG in DNA. Derivatization optimization revealed that an excess of MTNG is required to achieve complete derivatization in DNA hydrolysates (MTNG: 8-nitroG molar ratio of 3740:1). The use of online SPE effectively avoided ion-source contamination from derivatization reagent by washing away all unreacted MTNG before column chromatography and the ionization process in mass spectrometry. With the use of isotope-labeled internal standard, the detection limit was as low as 0.015 nM. Inter- and intraday imprecision was <5.0%. This method was compared to a previous direct LC-MS/MS method without derivatization. The comparison showed an excellent fit and consistency, suggesting that the present method has satisfactory effectiveness and reliability for 8-nitroG analysis. This method was further applied to determine the 8-nitroG in human urine. 8-NitroG was not detectable using LC-MS/MS with derivatization, whereas a significant false-positive signal was detected without derivatization. It highlights the use of MTNG derivatization in 8-nitroG analysis for increasing the method specificity.
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Affiliation(s)
- Chiung-Wen Hu
- Department of Public Health, Chung Shan Medical University, Taichung 402, Taiwan.
| | - Yuan-Jhe Chang
- Department of Occupational Safety and Health, Chung Shan Medical University, Taichung 402, Taiwan.
| | - Jian-Lian Chen
- School of Pharmacy, China Medical University, Taichung 404, Taiwan.
| | - Yu-Wen Hsu
- Department of Occupational Safety and Health, Chung Shan Medical University, Taichung 402, Taiwan.
- Department of Optometry, Da-Yeh University, Changhua 515, Taiwan.
| | - Mu-Rong Chao
- Department of Occupational Safety and Health, Chung Shan Medical University, Taichung 402, Taiwan.
- Department of Occupational Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan.
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27
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De Angelis PM, Schjølberg AR, Hughes JB, Huitfeldt HS, Norheim Andersen S, Østvold AC. Nondysplastic Ulcerative Colitis Has High Levels of the Homologous Recombination Repair Protein NUCKS1 and Low Levels of the DNA Damage Marker Gamma-H2AX. Inflamm Bowel Dis 2018; 24:593-600. [PMID: 29462394 DOI: 10.1093/ibd/izx071] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND The colon and rectum are continuously exposed to oxidative stress that generates reactive oxygen species, which are a major cause of DNA double-strand breaks (DSB). Furthermore, chronic inflammatory diseases such as ulcerative colitis (UC) are characterized by an excess of reactive nitrogen species that can also lead to DNA double-strand breakage and genomic instability. We investigated the expression of the nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) protein in UC and sporadic colorectal cancer (CRC) due to its involvement in both DNA double-strand break repair and inflammatory signaling. METHODS NUCKS1 expression and expression of the DNA double-strand break marker gamma-H2AX (γH2AX) were assessed in formalin-fixed, paraffin-embedded UC and CRC patient biopsies using peroxidase immunohistochemistry. Expression levels for both proteins were evaluated together with previously published expression-level data for hTERT and TP53 proteins in the same material. RESULTS Nondysplastic UC lesions had 10-fold lower γH2AX expression and approximately 4-fold higher NUCKS1 expression compared with sporadic CRC, indicating minimal DNA DSB damage and heightened DNA DSB repair in these lesions, respectively. NUCKS1 expression in UC tended to decrease with increasing grades of dysplasia, whereas γH2AX, hTERT, and TP53 expression tended to increase with increasing grades of dysplasia. The highest γH2AX expression was seen in sporadic CRC, indicating considerable DNA DSB damage, whereas the highest NUCKS1 expression and hTERT expression were seen in nondysplastic UC. CONCLUSIONS Overall, our data suggest that NUCKS1 may be involved in DNA DSB repair and/or inflammatory signaling in UC, but a more thorough investigation of both pathways in UC is warranted.
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Affiliation(s)
- Paula M De Angelis
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Aasa R Schjølberg
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Juliana B Hughes
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Henrik S Huitfeldt
- Department of Pathology, Faculty of Medicine, University of Oslo, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | | | - Anne Carine Østvold
- Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
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28
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Fadda LM, Attia HA, Al-Rasheed NM, Ali HM, Al-Rasheed NM. Roles of some antioxidants in modulation of cardiac myopathy induced by sodium nitrite via down-regulation of mRNA expression of NF-κB, Bax, and flt-1 and suppressing DNA damage. Saudi Pharm J 2017; 26:217-223. [PMID: 30166919 PMCID: PMC6111199 DOI: 10.1016/j.jsps.2017.12.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2017] [Accepted: 12/10/2017] [Indexed: 12/30/2022] Open
Abstract
The underlying pathology of cardiac damage involves various molecular and signaling pathways. Therefore, this study aimed to explore the role of Quercetin (Querc), alone or in combination with Melatonin (Melat) against cardiac damage induced by sodium nitrite (Sod nit), as well as to elucidate different signaling pathways. Querc and Melat were injected intraperitoneally (i.p.), followed by induction of hypoxia in rats by using a single dose of Sod nit (60 mg/kg, s.c.). Treatment with Sod nit significantly decreased hemoglobin (Hb) levels in blood. Pretreatment of hypoxic rats with Querc and/or Melat elevated the declined Hb concentration. The forementioned antioxidants also successfully ameliorated the alteration of heat shock protein 70 (HSP-70) and markers of cardiac injury, including troponin T (Trop. T), creatine kinase-MB (CK-MB), tumor necrosis factor-α (TNF α), and C-reactive protein (CRP) in the rats serum. Furthermore, RT-PCR revealed that these antioxidants successfully modulated mRNA expression of NF-κB, Bax, Bcl-2, and flt-1. They also regulated vascular endothelial growth factor (VEGF), the apoptosis marker caspase 3, and oxidative DNA damage in cardiac tissue, compared to Sod nit-intoxicated rats. The present biochemical results are reinforced by histopathological examination. IN CONCLUSION The results reflected that treatment with Querc in combination with Melat was most effective in improving Sod nit-toxicity induced cardiac damage, thus confirming the promising role of this combination as an effective treatment for cardiac damage induced by other cardio-toxic agents.
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Affiliation(s)
- Laila Mohamed Fadda
- Pharmacology Department, Faculty of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Hala A Attia
- Pharmacology Department, Faculty of Pharmacy, King Saud University, Riyadh, Saudi Arabia.,Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | | | - Hanaa Mahmoud Ali
- Department of Genetics and Cytology, National Research Center, Dokki, Egypt.,Common First Year Deanship, King Saud University, Riyadh, Saudi Arabia
| | - Nawal Mohamed Al-Rasheed
- Pharmacology Department, Faculty of Pharmacy, King Saud University, Riyadh, Saudi Arabia.,Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
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30
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Gharun K, Senges J, Seidl M, Lösslein A, Kolter J, Lohrmann F, Fliegauf M, Elgizouli M, Alber M, Vavra M, Schachtrup K, Illert AL, Gilleron M, Kirschning CJ, Triantafyllopoulou A, Henneke P. Mycobacteria exploit nitric oxide-induced transformation of macrophages into permissive giant cells. EMBO Rep 2017; 18:2144-2159. [PMID: 29097394 DOI: 10.15252/embr.201744121] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 09/23/2017] [Accepted: 10/02/2017] [Indexed: 12/11/2022] Open
Abstract
Immunity to mycobacteria involves the formation of granulomas, characterized by a unique macrophage (MΦ) species, so-called multinucleated giant cells (MGC). It remains unresolved whether MGC are beneficial to the host, that is, by prevention of bacterial spread, or whether they promote mycobacterial persistence. Here, we show that the prototypical antimycobacterial molecule nitric oxide (NO), which is produced by MGC in excessive amounts, is a double-edged sword. Next to its antibacterial capacity, NO propagates the transformation of MΦ into MGC, which are relatively permissive for mycobacterial persistence. The mechanism underlying MGC formation involves NO-induced DNA damage and impairment of p53 function. Moreover, MGC have an unsurpassed potential to engulf mycobacteria-infected apoptotic cells, which adds a further burden to their antimycobacterial capacity. Accordingly, mycobacteria take paradoxical advantage of antimicrobial cellular efforts by driving effector MΦ into a permissive MGC state.
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Affiliation(s)
- Kourosh Gharun
- Center for Chronic Immunodeficiency (CCI), Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Julia Senges
- Center for Chronic Immunodeficiency (CCI), Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Maximilian Seidl
- Center for Chronic Immunodeficiency (CCI), Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Department of Pathology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Anne Lösslein
- Center for Chronic Immunodeficiency (CCI), Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Julia Kolter
- Center for Chronic Immunodeficiency (CCI), Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Florens Lohrmann
- Center for Chronic Immunodeficiency (CCI), Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Spemann Graduate School for Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany.,Department of Rheumatology and Clinical Immunology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Manfred Fliegauf
- Center for Chronic Immunodeficiency (CCI), Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Magdeldin Elgizouli
- Center for Chronic Immunodeficiency (CCI), Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | | | - Martina Vavra
- Division of Infectious Diseases, Department of Internal Medicine 2, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Kristina Schachtrup
- Center for Chronic Immunodeficiency (CCI), Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Anna L Illert
- Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine University of Freiburg, Freiburg, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Martine Gilleron
- Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Carsten J Kirschning
- Institute of Medical Microbiology, Medical Center, University Duisburg-Essen, Essen, Germany
| | - Antigoni Triantafyllopoulou
- Center for Chronic Immunodeficiency (CCI), Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Department of Rheumatology and Clinical Immunology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Philipp Henneke
- Center for Chronic Immunodeficiency (CCI), Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany .,Center for Pediatrics and Adolescent Medicine, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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31
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Jiménez-Garza O, Guo L, Byun HM, Carrieri M, Bartolucci GB, Zhong J, Baccarelli AA. Promoter methylation status in genes related with inflammation, nitrosative stress and xenobiotic metabolism in low-level benzene exposure: Searching for biomarkers of oncogenesis. Food Chem Toxicol 2017; 109:669-676. [DOI: 10.1016/j.fct.2017.08.019] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Accepted: 08/15/2017] [Indexed: 12/13/2022]
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32
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Thwe PM, Amiel E. The role of nitric oxide in metabolic regulation of Dendritic cell immune function. Cancer Lett 2017; 412:236-242. [PMID: 29107106 DOI: 10.1016/j.canlet.2017.10.032] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 09/30/2017] [Accepted: 10/22/2017] [Indexed: 01/10/2023]
Abstract
Dendritic cells (DCs) are canonical antigen presenting cells of the immune system and serve as a bridge between innate and adaptive immune responses. When DCs are activated by a stimulus through toll-like receptors (TLRs), DCs undergo a process of maturation defined by cytokine & chemokine secretion, co-stimulatory molecule expression, antigen processing and presentation, and the ability to activate T cells. DC maturation is coupled with an increase in biosynthetic demand, which is fulfilled by a TLR-driven upregulation in glycolytic metabolism. Up-regulation of glycolysis in activated DCs provides these cells with molecular building blocks and cellular energy required for DC activation, and inhibition of glycolysis during initial activation impairs both the survival and effector function of activated DCs. Evidence shows that DC glycolytic upregulation is controlled by two distinct pathways, an early burst of glycolysis that is nitric oxide (NO) -independent, and a sustained commitment to glycolysis in NO-producing DC subsets. This review will address the complex role of NO in regulating DC metabolism and effector function.
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Affiliation(s)
- Phyu M Thwe
- Cell, Molecular, and Biomedical Sciences Program, University of Vermont, Burlington, VT 05405, USA; Department of Medical Laboratory and Radiation Sciences, College of Nursing and Health Sciences, University of Vermont, Burlington, VT 05405, USA
| | - Eyal Amiel
- Cell, Molecular, and Biomedical Sciences Program, University of Vermont, Burlington, VT 05405, USA; Department of Medical Laboratory and Radiation Sciences, College of Nursing and Health Sciences, University of Vermont, Burlington, VT 05405, USA.
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33
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Insights into the role of endonuclease V in RNA metabolism in Trypanosoma brucei. Sci Rep 2017; 7:8505. [PMID: 28819113 PMCID: PMC5561087 DOI: 10.1038/s41598-017-08910-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 07/14/2017] [Indexed: 01/05/2023] Open
Abstract
Inosine may arise in DNA as a result of oxidative deamination of adenine or misincorporation of deoxyinosine triphosphate during replication. On the other hand, the occurrence of inosine in RNA is considered a normal and essential modification induced by specific adenosine deaminases acting on mRNA and tRNA. In prokaryotes, endonuclease V (EndoV) can recognize and cleave inosine-containing DNA. In contrast, mammalian EndoVs preferentially cleave inosine-containing RNA, suggesting a role in RNA metabolism for the eukaryotic members of this protein family. We have performed a biochemical characterization of EndoV from the protozoan parasite Trypanosoma brucei. In vitro, TbEndoV efficiently processes single-stranded RNA oligonucleotides with inosine, including A to I-edited tRNA-like substrates but exhibits weak activity over DNA, except when a ribonucleotide is placed 3' to the inosine. Immunolocalization studies performed in procyclic forms indicate that TbEndoV is mainly cytosolic yet upon nutritional stress it redistributes and accumulates in stress granules colocalizing with the DEAD-box helicase TbDhh1. RNAi-mediated depletion of TbEndoV results in moderate growth defects in procyclic cells while the two EndoV alleles could be readily knocked out in bloodstream forms. Taken together, these observations suggest an important role of TbEndoV in RNA metabolism in procyclic forms of the parasite.
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34
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Dick S, Bell SEJ, Alexander KJ, O'Neil IA, Cosstick R. SERS and SERRS Detection of the DNA Lesion 8-Nitroguanine: A Self-Labeling Modification. Chemistry 2017; 23:10663-10669. [PMID: 28558174 DOI: 10.1002/chem.201701791] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Indexed: 01/06/2023]
Abstract
Rapid and sensitive methods to detect DNA lesions are essential in order to understand their role in carcinogenesis and for potential diagnosis of cancers. The 8-nitroguanine DNA lesion, which is closely associated with inflammation-induced cancers, has been characterized for the first time by surface-enhanced Raman spectroscopy (SERS). This lesion has been studied as the free base, as well as part of a dinucleotide and oligodeoxynucleotides (ODNs) at 5 different excitation wavelengths in the range 785-488 nm. All nitrated samples produced distinctly different spectra from their control guanine counterparts, with nitro bands being assigned by DFT calculations. Additional resonance enhancement was observed at the shorter excitation wavelengths, these SERRS measurements allowed the detection of one nitrated guanine in over 1,300 bases. In addition, SER(R)S can be used to detect whether the unstable lesion is covalently attached to the ODN or has been released by hydrolytic depurination.
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Affiliation(s)
- Susan Dick
- Innovative Molecular Materials Group, School of Chemistry and Chemical Engineering, Queen's University, Belfast, BT9 5AG, UK
| | - Steven E J Bell
- Innovative Molecular Materials Group, School of Chemistry and Chemical Engineering, Queen's University, Belfast, BT9 5AG, UK
| | - Katie J Alexander
- Department of Chemistry, University of Liverpool, Crown Street, Liverpool, L69 7ZD, UK
| | - Ian A O'Neil
- Department of Chemistry, University of Liverpool, Crown Street, Liverpool, L69 7ZD, UK
| | - Richard Cosstick
- Department of Chemistry, University of Liverpool, Crown Street, Liverpool, L69 7ZD, UK
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Burke AJ, Garrido P, Johnson C, Sullivan FJ, Glynn SA. Inflammation and Nitrosative Stress Effects in Ovarian and Prostate Pathology and Carcinogenesis. Antioxid Redox Signal 2017; 26:1078-1090. [PMID: 28326819 DOI: 10.1089/ars.2017.7004] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
SIGNIFICANCE Prostate and ovarian cancers are major contributors to cancer-related deaths worldwide. Recently, inflammation and nitrosative stress have been implicated in carcinogenesis, with the overexpression of NOS2 and concomitant release of nitric oxide (NO) associated with cancer initiation and progression. Recent Advances: An increasing body of evidence indicates an association between NOS2 expression and aggressive ovarian cancer. Research also indicates a role for NO in prostate disease pathology and prostate cancer. A therapeutic role for NOS2 inhibition and/or NO drugs exists for the treatment of both ovarian and prostate tumors. CRITICAL ISSUES Herein, we review the key molecular effects associated with NOS2 in ovarian and prostate cancer. NOS2 increases angiogenesis and tumor proliferation and correlates with aggressive type II ovarian tumors. NOS2 expressing tumors are sensitive to cisplatin chemotherapy, and NO may be used to sensitize cisplatin-resistant tumors to chemotherapy. NOS2 is highly expressed in prostate tumors compared to non-neoplastic prostate pathologies. NO may play a role in the development of androgen-independent prostate cancer via s-nitrosylation of the androgen receptor. Moreover, NOS2 inhibitors and NO donor drugs show therapeutic potential in ovarian and prostate cancer as single agents or dual drugs, by either inhibiting the effects of NOS2 or increasing NO levels to induce cytotoxic effects. FUTURE DIRECTIONS NOS2 and NO present new targets for the treatment of ovarian and prostate tumors. Furthermore, understanding NO-related tumor biology in these cancers presents a new means for improved patient stratification to the appropriate treatment regimen. Antioxid. Redox Signal. 26, 1078-1090.
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Affiliation(s)
- Amy J Burke
- 1 Prostate Cancer Institute, School of Medicine, National University of Ireland Galway , Galway, Ireland
| | - Pablo Garrido
- 1 Prostate Cancer Institute, School of Medicine, National University of Ireland Galway , Galway, Ireland .,2 Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway , Galway, Ireland
| | - Carol Johnson
- 1 Prostate Cancer Institute, School of Medicine, National University of Ireland Galway , Galway, Ireland .,2 Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway , Galway, Ireland
| | - Francis J Sullivan
- 1 Prostate Cancer Institute, School of Medicine, National University of Ireland Galway , Galway, Ireland
| | - Sharon A Glynn
- 1 Prostate Cancer Institute, School of Medicine, National University of Ireland Galway , Galway, Ireland .,2 Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway , Galway, Ireland .,3 Apoptosis Research Centre, Biomedical Sciences, National University of Ireland Galway , Galway, Ireland
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Abstract
Germline mutation of BRCA2 induces hereditary pancreatic cancer. However, how BRCA2 mutation specifically induces pancreatic tumorigenesis remains elusive. Here, we have examined a mouse model of Brca2-deficiency-induced pancreatic tumors and found that excessive reactive nitrogen species (RNS), such as nitrite, are generated in precancerous pancreases, which induce massive DNA damage, including DNA double-strand breaks. RNS-induced DNA lesions cause genomic instability in the absence of Brca2. Moreover, with the treatment of antioxidant tempol to suppress RNS, not only are DNA lesions significantly reduced, but also the onset of pancreatic cancer is delayed. Thus, this study demonstrates that excess RNS are a nongenetic driving force for Brca2-deficiency-induced pancreatic tumors. Suppression of RNS could be an important strategy for pancreatic cancer prevention.
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Kanda Y, Osaki M, Okada F. Chemopreventive Strategies for Inflammation-Related Carcinogenesis: Current Status and Future Direction. Int J Mol Sci 2017; 18:E867. [PMID: 28422073 PMCID: PMC5412448 DOI: 10.3390/ijms18040867] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 04/14/2017] [Accepted: 04/17/2017] [Indexed: 02/07/2023] Open
Abstract
A sustained and chronically-inflamed environment is characterized by the presence of heterogeneous inflammatory cellular components, including neutrophils, macrophages, lymphocytes and fibroblasts. These infiltrated cells produce growth stimulating mediators (inflammatory cytokines and growth factors), chemotactic factors (chemokines) and genotoxic substances (reactive oxygen species and nitrogen oxide) and induce DNA damage and methylation. Therefore, chronic inflammation serves as an intrinsic niche for carcinogenesis and tumor progression. In this article, we summarize the up-to-date findings regarding definitive/possible causes and mechanisms of inflammation-related carcinogenesis derived from experimental and clinical studies. We also propose 10 strategies, as well as candidate agents for the prevention of inflammation-related carcinogenesis.
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Affiliation(s)
- Yusuke Kanda
- Division of Pathological Biochemistry, Tottori University Faculty of Medicine, Yonago, Tottori 683-8503, Japan.
| | - Mitsuhiko Osaki
- Division of Pathological Biochemistry, Tottori University Faculty of Medicine, Yonago, Tottori 683-8503, Japan.
- Chromosome Engineering Research Center, Tottori University, Yonago, Tottori 683-8503, Japan.
| | - Futoshi Okada
- Division of Pathological Biochemistry, Tottori University Faculty of Medicine, Yonago, Tottori 683-8503, Japan.
- Chromosome Engineering Research Center, Tottori University, Yonago, Tottori 683-8503, Japan.
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Acute oral dose of sodium nitrite induces redox imbalance, DNA damage, metabolic and histological changes in rat intestine. PLoS One 2017; 12:e0175196. [PMID: 28384248 PMCID: PMC5383256 DOI: 10.1371/journal.pone.0175196] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 03/22/2017] [Indexed: 12/16/2022] Open
Abstract
Industrialization and unchecked use of nitrate/nitrite salts for various purposes has increased human exposure to high levels of sodium nitrite (NaNO2) which can act as a pro-oxidant and pro-carcinogen. Oral exposure makes the gastrointestinal tract particularly susceptible to nitrite toxicity. In this work, the effect of administration of a single acute oral dose of NaNO2 on rat intestine was studied. Animals were randomly divided into four groups and given single doses of 20, 40, 60 and 75 mg NaNO2/kg body weight. Untreated animals served as the control group. An NaNO2 dose-dependent decline in the activities of brush border membrane enzymes, increase in lipid peroxidation, protein oxidation, hydrogen peroxide levels and decreased thiol content was observed in all treated groups. The activities of various metabolic and antioxidant defense enzymes were also altered. NaNO2 induced a dose-dependent increase in DNA damage and DNA-protein crosslinking. Histopathological studies showed marked morphological damage in intestinal cells. The intestinal damage might be due to nitrite-induced oxidative stress, direct action of nitrite anion or chemical modification by reaction intermediates.
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Singh AK, Pandey P, Tewari M, Pandey HP, Gambhir IS, Shukla HS. Free radicals hasten head and neck cancer risk: A study of total oxidant, total antioxidant, DNA damage, and histological grade. J Postgrad Med 2017; 62:96-101. [PMID: 27089108 PMCID: PMC4944358 DOI: 10.4103/0022-3859.180555] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Background: Free radicals such as reactive oxygen species (ROS), which induce oxidative stress, are the main contributors to head and neck carcinogenesis (HNC). The present study was conducted with the aim to assess the oxidant/antioxidant status and DNA damage analysis in head and neck cancer/control patients. Materials and Methods: This prospective study was conducted on 60 patients with biopsy-proven HNC and 17 patients of head and neck disease (HND). The total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) were determined by novel automatic colorimetric methods from tissue homogenate. DNA damage analysis was determined by single cell gel electrophoresis (SCGE). Results: The mean age of the study cohort was 46.65 ± 14.84 years for HNC patients, while it was 49.41 ± 13.00 years for HND patients. There were no significant differences found between the two groups with respect to demographic presentation except tobacco addiction. The association between oxidative stress parameters and DNA damage analysis with study group revealed the following. (A) DNA damage - tissue homogenate TOS and OSI were significantly higher in HNC subjects than in HND (16.06 ± 1.78 AU vs 7.86 ± 5.97 AU, P < 0.001; 53.00 ± 40.61 vs 19.67 ± 21.90, P < 0.01; 7.221 ± 5.80 vs 2.40 ± 2.54, P < 0.01, respectively), while TAS was significantly decreased. (B) Aggressive histological features were identified, more commonly with higher TOS and lower TAS [probability (P) = 0.002, relative risk (RR) = 11.838, 95% confidence interval CI = 2.514-55.730 and P = 0.043, RR = 0.271, 95% CI = 0.077-0.960, respectively]. Conclusion: The increase in free radicals may be the event that led to the reduction of antioxidant status in HNC, thus explaining the oxidative damage of DNA and the severity of disease. Increased OSI represents a general mechanism in its pathogenesis.
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Affiliation(s)
| | | | | | | | | | - H S Shukla
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
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Yoon CS, Kim DC, Quang TH, Seo J, Kang DG, Lee HS, Oh H, Kim YC. A Prenylated Xanthone, Cudratricusxanthone A, Isolated from Cudrania tricuspidata Inhibits Lipopolysaccharide-Induced Neuroinflammation through Inhibition of NF-κB and p38 MAPK Pathways in BV2 Microglia. Molecules 2016; 21:E1240. [PMID: 27649130 PMCID: PMC6272989 DOI: 10.3390/molecules21091240] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 08/30/2016] [Accepted: 09/11/2016] [Indexed: 12/22/2022] Open
Abstract
Cudrania tricuspidata Bureau (Moraceae) is an important source of traditional Korean and Chinese medicines used to treat neuritis and inflammation. Cudratricusxanthone A (1), a prenylated xanthone, isolated from C. tricuspidata, has a variety of biological and therapeutic activities. The goal of this study was to examine the effects of compound 1 on neuroinflammation and characterize its mechanism of action in lipopolysaccharide (LPS)-stimulated BV2 microglia. Cudratricusxanthone A (1) suppressed the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 enzymes and decreased the production of iNOS-derived nitric oxide and COX-2-derived prostaglandin E2 in LPS-stimulated mouse BV2 microglia. The compound also decreased tumor necrosis factor-α, interleukin (IL)-1β, and IL-12 production; inhibited the phosphorylation and degradation of IκB-α; and blocked the nuclear translocation of p50 and p65 in mouse BV2 microglia induced by LPS. Cudratricusxanthone A (1) had inhibitory effects on nuclear factor kappa B DNA-binding activity. Additionally, it inhibited the p38 mitogen-activated protein kinase signaling pathway. Our data suggests that cudratricusxanthone A (1) may be a useful therapeutic agent in the treatment of neurodegenerative diseases caused by neuroinflammation.
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Affiliation(s)
- Chi-Su Yoon
- Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan 54538, Korea.
| | - Dong-Cheol Kim
- Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan 54538, Korea.
| | - Tran Hong Quang
- Institute of Marine Biochemistry, Vietnam Academy of Science and Technology (VAST), 18 Hoang Quoc Viet, Caugiay, Hanoi 100000, Vietnam.
| | - Jungwon Seo
- Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan 54538, Korea.
| | - Dae Gill Kang
- Hanbang Body-Fluid Research Center, Wonkwang University, Iksan 54538, Korea.
| | - Ho Sub Lee
- Hanbang Body-Fluid Research Center, Wonkwang University, Iksan 54538, Korea.
| | - Hyuncheol Oh
- Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan 54538, Korea.
| | - Youn-Chul Kim
- Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan 54538, Korea.
- Hanbang Body-Fluid Research Center, Wonkwang University, Iksan 54538, Korea.
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Prenylated Flavonoids from Cudrania tricuspidata Suppress Lipopolysaccharide-Induced Neuroinflammatory Activities in BV2 Microglial Cells. Int J Mol Sci 2016; 17:255. [PMID: 26907256 PMCID: PMC4783984 DOI: 10.3390/ijms17020255] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Revised: 01/12/2016] [Accepted: 02/05/2016] [Indexed: 11/16/2022] Open
Abstract
In Korea and China, Cudrania tricuspidata Bureau (Moraceae) is an important traditional medicinal plant used to treat lumbago, hemoptysis, and contusions. The C. tricuspidata methanol extract suppressed both production of NO and PGE2 in BV2 microglial cells. Cudraflavanone D (1), isolated from this extract, remarkably suppressed the protein expression of inducible NO synthase and cyclooxygenase-2, and decreased the levels of NO and PGE2 in BV2 microglial cells exposed to lipopolysaccharide. Cudraflavanone D (1) also decreased IL-6, TNF-α, IL-12, and IL-1β production, blocked nuclear translocation of NF-κB heterodimers (p50 and p65) by interrupting the degradation and phosphorylation of inhibitor of IκB-α, and inhibited NF-κB binding. In addition, cudraflavanone D (1) suppressed the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAPK pathways. This study indicated that cudraflavanone D (1) can be a potential drug candidate for the cure of neuroinflammation.
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Bagheri N, Azadegan-Dehkordi F, Rahimian G, Hashemzadeh-Chaleshtori M, Rafieian-Kopaei M, Kheiri S, Gholipour A, Shirzad H. Altered Th17 Cytokine Expression inHelicobacter pyloriPatients with TLR4 (D299G) Polymorphism. Immunol Invest 2016; 45:161-71. [DOI: 10.3109/08820139.2015.1122615] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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43
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Fang J, Yin H, Liao L, Qin H, Ueda F, Uemura K, Eguchi K, Bharate GY, Maeda H. Water soluble PEG-conjugate of xanthine oxidase inhibitor, PEG–AHPP micelles, as a novel therapeutic for ROS related inflammatory bowel diseases. J Control Release 2016; 223:188-196. [DOI: 10.1016/j.jconrel.2015.12.049] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Revised: 12/21/2015] [Accepted: 12/24/2015] [Indexed: 01/08/2023]
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44
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Barral M, Dohan A, Allez M, Boudiaf M, Camus M, Laurent V, Hoeffel C, Soyer P. Gastrointestinal cancers in inflammatory bowel disease: An update with emphasis on imaging findings. Crit Rev Oncol Hematol 2016; 97:30-46. [DOI: 10.1016/j.critrevonc.2015.08.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Revised: 06/15/2015] [Accepted: 08/04/2015] [Indexed: 12/20/2022] Open
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45
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The carvacrol ameliorates acute pancreatitis-induced liver injury via antioxidant response. Cytotechnology 2015; 68:1131-46. [PMID: 26350272 DOI: 10.1007/s10616-015-9871-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 03/26/2015] [Indexed: 12/21/2022] Open
Abstract
Acute pancreatitis (AP) may cause significant persistent multi-organ dysfunction. Carvacrol (CAR) possesses a variety of biological and pharmacological properties. The aim of the present study was to analyze the hepatic protection of CAR on AP induced by cerulein and to explore the underlying mechanism using in vivo studies. The rats were randomized into groups to receive (1) no therapy; (2) 50 µg/kg cerulein at 1-h intervals by four intraperitoneal injection (i.p.); (3) 50, 100 and 200 mg/kg CAR by one i.p.; and (4) cerulein + CAR after 2 h of cerulein injection. 12 h later, serum was provided to assess the blood AST, ALT and LDH values. Also, liver tissues were obtained for histological and biochemical measurements. Liver oxidative stress markers were evaluated by changes in the amount of lipid peroxides measured as MDA and changes in tissue antioxidant enzyme levels, SOD, CAT and GSH-Px. Histopathological examination was performed using scoring systems. Oxidative damage to DNA was quantitated in studied tissues of experimental animals by measuring the increase in 8-hydroxydeoxyguanosine (8-OHdG) formations. We found that the increasing doses of CAR decreased pancreatitis-induced MDA and 8-OH-dG levels. Moreover, the liver SOD, CAT and GSH-Px activities in the AP + CAR group were higher than that of the rats in the AP group. In the treatment groups, AST, ALT and LDH were reduced. Besides, necrosis, coagulation and inflammation in the liver were alleviated (p < 0.05). We suggest that CAR could be a safe and potent new drug candidate for treating AP through its antioxidative mechanism of action for the treatment of a wide range of disorders related to hepatic dysfunction.
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Dilek F, Ozkaya E, Kocyigit A, Yazici M, Kesgin S, Gedik AH, Cakir E. Effect of montelukast monotherapy on oxidative stress parameters and DNA damage in children with asthma. Int Arch Allergy Immunol 2015; 167:119-26. [PMID: 26303984 DOI: 10.1159/000436967] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 06/11/2015] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND There is ample knowledge reported in the literature about the role of oxidative stress in asthma pathogenesis. It is also known that the interaction of reactive oxygen species with DNA may result in DNA strand breaks. The aim of this study was to investigate if montelukast monotherapy affects oxidative stress and DNA damage parameters in a population of pediatric asthma patients. METHODS Group I consisted of 31 newly diagnosed asthmatic patients not taking any medication, and group II consisted of 32 patients who had been treated with montelukast for at least 6 months. Forty healthy control subjects were also enrolled in the study. Plasma total oxidant status (TOS) and total antioxidant status (TAS) were measured to assess oxidative stress. DNA damage was assessed by means of alkaline comet assay. RESULTS The patients in both group I and group II had statistically significant higher plasma TOS (13.1 ± 4 and 11.1 ± 4.1 μmol H2O2 equivalent/liter, respectively) and low TAS levels (1.4 ± 0.5 and 1.5 ± 0.5 mmol Trolox equivalent/liter, respectively) compared with the control group (TOS: 6.3 ± 3.5 μmol H2O2 equivalent/liter and TAS: 2.7 ± 0.6 mmol Trolox equivalent/liter; p < 0.05). DNA damage was 18.2 ± 1.0 arbitrary units (a.u.) in group I, 16.7 ± 8.2 a.u. in group II and 13.7 ± 3.4 a.u. in the control group. There were statistically significant differences only between group I and the control group (p < 0.05). CONCLUSIONS According to the findings, montelukast therapy makes only minimal but not statistically significant improvement in all TOS, TAS and DNA damage parameters.
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Affiliation(s)
- Fatih Dilek
- Divisions of Pediatric Allergy and Immunology, Department of Pediatrics, Bezmialem Vakif University Medical Faculty, Istanbul, Turkey
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Li W, Han W, Ma Y, Cui L, Tian Y, Zhou Z, Wang H. P53-dependent miRNAs mediate nitric oxide-induced apoptosis in colonic carcinogenesis. Free Radic Biol Med 2015; 85:105-113. [PMID: 25912478 DOI: 10.1016/j.freeradbiomed.2015.04.016] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Revised: 03/18/2015] [Accepted: 04/13/2015] [Indexed: 01/30/2023]
Abstract
Both miRNAs and nitric oxide (NO) play important roles in colonic inflammation and tumorigenesis. Resistance of colonic epithelial cells to apoptosis may contribute to tumor development. We hypothesized that some miRNAs could increase the resistance of colonic cancer cells to nitric oxide-induced apoptotic cell death. Here we show that NO induced apoptosis and stimulated expression of some miRNAs. Loss of p53 not only blocked NO-induced apoptosis but also dramatically inhibited the expression of NO-related miRNAs, such as miR-34, miR-203, and miR-1301. In addition, blockage of p53-dependent miRNAs significantly reduced NO-induced apoptosis. Furthermore, forced expression of these miRNAs rendered HT-29 cells, which are resistant to apoptosis with mutant p53, more sensitive to NO-induced apoptotic cell death. Most interestingly, in a colitis-associated colon cancer mouse model, the level of miRNAs dropped significantly, accompanied by downregulation of p21, which is a key target gene of p53. In human colorectal cancer samples, the expression of miR-34 significantly correlated with the level of inducible nitric oxide synthase (iNOS). We contend that increased NO production may select cells with low levels of p53-dependent miRNAs which contributes to human colonic carcinogenesis and tumor progression.
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Affiliation(s)
- Weiwei Li
- State Key Laboratory of Molecular Oncology, Peking Union Medical College, Beijing, China
| | - Wenxiao Han
- State Key Laboratory of Molecular Oncology, Peking Union Medical College, Beijing, China
| | - Yiming Ma
- State Key Laboratory of Molecular Oncology, Peking Union Medical College, Beijing, China
| | - Liang Cui
- Department of Gastrointestinal Cancer Surgery, Cancer Institute/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Yantao Tian
- Department of Gastrointestinal Cancer Surgery, Cancer Institute/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Zhixiang Zhou
- Department of Gastrointestinal Cancer Surgery, Cancer Institute/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Hongying Wang
- State Key Laboratory of Molecular Oncology, Peking Union Medical College, Beijing, China.
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Villaño D, Vilaplana C, Medina S, Cejuela-Anta R, Martínez-Sanz JM, Gil P, Genieser HG, Ferreres F, Gil-Izquierdo A. Effect of elite physical exercise by triathletes on seven catabolites of DNA oxidation. Free Radic Res 2015; 49:973-83. [PMID: 25786325 DOI: 10.3109/10715762.2015.1025388] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The oxidized nucleoside 8-hydroxy-2'-deoxyguanosine has been widely studied as a marker of DNA oxidation; however, data on the occurrence of other metabolites in plasma that are related to DNA damage are scarce. We have applied an improved, sensitive, robust, and reliable method, involving solid phase extraction and ultrahigh-performance liquid chromatography (UHPLC)-tandem mass spectrometry (MS/MS), to the precise quantitation of seven metabolites in the plasma of 15 elite triathletes after a 2-week training program. All compounds were eluted in the first 1.6 min, with limits of detection and quantification ranging between 0.001 and 0.3 ng.mL(-1) and 0.009 and 0.6 ng.mL(-1), respectively. Four compounds were detected in plasma: guanosine-3'-5'-cyclic monophosphate, 8-hydroxyguanine, 8-hydroxy-2'-deoxyguanosine, and 8-nitroguanosine. After two weeks of training, 8-hydroxyguanine exhibited the highest increase (from 0.031 ± 0.008 nM to 0.036 ± 0.012 nM) (p < 0.05), which could be related to the enhanced activity of DNA-repairing enzymes that excise this oxidized base. Increased levels of guanosine-3'-5'-cyclic monophosphate and 8-hydroxy-2'-deoxyguanosine were also observed. In contrast, levels of 8-nitroguanosine (p < 0.05) were significantly reduced, which might be a protective measure as this compound strongly stimulates the generation of superoxide radicals, and its excess is related to pathologies such as microbial (viral) infections and other inflammatory and degenerative disorders. The results obtained indicate an induced adaptive response to the increased oxidative stress related to elite training, and point to the benefits associated with regular exercise.
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Affiliation(s)
- D Villaño
- Department of Food Science and Technology, CEBAS-CSIC , Murcia , Spain
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The biological functions of IL-17 in different clinical expressions of Helicobacter pylori-infection. Microb Pathog 2015; 81:33-8. [DOI: 10.1016/j.micpath.2015.03.010] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Revised: 03/04/2015] [Accepted: 03/11/2015] [Indexed: 02/06/2023]
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Bogdan C. Nitric oxide synthase in innate and adaptive immunity: an update. Trends Immunol 2015; 36:161-78. [PMID: 25687683 DOI: 10.1016/j.it.2015.01.003] [Citation(s) in RCA: 589] [Impact Index Per Article: 58.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Revised: 01/14/2015] [Accepted: 01/14/2015] [Indexed: 12/22/2022]
Abstract
Thirty years after the discovery of its production by activated macrophages, our appreciation of the diverse roles of nitric oxide (NO) continues to grow. Recent findings have not only expanded our understanding of the mechanisms controlling the expression of NO synthases (NOS) in innate and adaptive immune cells, but have also revealed new functions and modes of action of NO in the control and escape of infectious pathogens, in T and B cell differentiation, and in tumor defense. I discuss these findings, in the context of a comprehensive overview of the various sources and multiple reaction partners of NO, and of the regulation of NOS2 by micromilieu factors, antisense RNAs, and 'unexpected' cytokines.
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Affiliation(s)
- Christian Bogdan
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie, und Hygiene, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Wasserturmstraße 3/5, 91054 Erlangen, Germany.
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