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Mohammed HS, Ibrahim MH, Abdel-Aziz MM, Ghareeb MA. Anti- Helicobacter pylori, anti-biofilm activity, and molecular docking study of citropten, bergapten, and its positional isomer isolated from Citrus sinensis L. leaves. Heliyon 2024; 10:e25232. [PMID: 38352786 PMCID: PMC10861955 DOI: 10.1016/j.heliyon.2024.e25232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 01/22/2024] [Accepted: 01/23/2024] [Indexed: 02/16/2024] Open
Abstract
Introduction Citrus sinensis L. is a candidate plant with promising antimicrobial potential. In the current study, the phytochemical investigation of C. sinensis leaf extract led to the isolation of three coumarins, namely bergapten, xanthotoxin, and citropten. Methods The chemical structures of the isolated coumarins were elucidated using NMR and ESI-MS techniques. The total aqueous ethanol leaf extract and the isolated coumarins were evaluated for their antimicrobial effects against Helicobacter pylori using the MTT-micro-well dilution method and its anti-biofilm activity using MBEC assay, as compared to clarithromycin. Results The results showed that citropten scored the lowest MIC value at 3.9 μg/mL and completely inhibited the planktonic growth of H. pylori. In addition, it completely suppressed H. pylori biofilm at 31.25 μg/mL. These findings have been supported by molecular docking studies on the active sites of the H. pylori inosine 5'-monophosphate dehydrogenase (HpIMPDH) model and the urease enzyme, showing a strong binding affinity of citropten to HpIMPDH with seven hydrogen bonds and a binding energy of -6.9 kcal/mol. Xanthotoxin and bergapten showed good docking scores, both at -6.5 kcal/mol for HpIMPDH, with each having four hydrogen bondings. Furthermore, xanthotoxin showed many hydrophobic interactions, while bergapten formed one Pi-anion interaction. Concerning docking in the urease enzyme, the compounds showed mild to moderate binding affinities as compared to the ligand. Thus, based on docking results and good binding scores observed with the HpIMPDH active site, an in-vitro HpIMPDH inhibition assay was done for the compounds. Citropten showed the most promising inhibitory activity with an IC50 value of 2.4 μM. Conclusion: The present study demonstrates that C. sinensis L. leaves are a good source for supplying coumarins that can act as naturally effective anti-H. pylori agents.
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Affiliation(s)
- Hala Sh Mohammed
- Department of Pharmacognosy and Medicinal Plants, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, 11311, Egypt
| | - Mona H. Ibrahim
- Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, 11311, Egypt
| | - Marwa M. Abdel-Aziz
- The Regional Centre for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt
| | - Mosad A. Ghareeb
- Medicinal Chemistry Department, Theodor Bilharz Research Institute, Kornaish El-Nile, Warrak El-Hadar, Imbaba, P.O. Box 30, Giza, 12411, Egypt
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Sunagawa Y, Kawaguchi S, Miyazaki Y, Katanasaka Y, Funamoto M, Shimizu K, Shimizu S, Hamabe-Horiike T, Kawase Y, Komiyama M, Mori K, Murakami A, Hasegawa K, Morimoto T. Auraptene, a citrus peel-derived natural product, prevents myocardial infarction-induced heart failure by activating PPARα in rats. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 107:154457. [PMID: 36223697 DOI: 10.1016/j.phymed.2022.154457] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 09/05/2022] [Accepted: 09/13/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND Auraptene derived from the peel of Citrus hassaku possesses anti-tumor, anti-inflammatory, and neuroprotective activities. Thus, it could be a valuable pharmacological alternative to treat some diseases. However, the therapeutic value of auraptene for heart failure (HF) is unknown. STUDY DESIGN/METHODS In cultured cardiomyocytes from neonatal rats, the effect of auraptene on phenylephrine-induced hypertrophic responses and peroxisome proliferator-activated receptor-alpha (PPARα)-dependent gene transcriptions. To investigate whether auraptene prevents the development of heart failure after myocardial infarction (MI) in vivo, Sprague-Dawley rats with moderate MI (fractional shortening < 40%) were randomly assigned for treatment with low- or high-dose auraptene (5 or 50 mg/kg/day, respectively) or vehicle for 6 weeks. The effects of auraptene were evaluated by echocardiography, histological analysis, and the measurement of mRNA levels of hypertrophy, fibrosis, and PPARα-associated genes. RESULTS In cultured cardiomyocytes, auraptene repressed phenylephrine-induced hypertrophic responses, such as increases in cell size and activities of atrial natriuretic factor and endothelin-1 promoters. Auraptene induced PPARα-dependent gene activation by enhancing cardiomyocyte peroxisome proliferator-responsive element reporter activity. The inhibition of PPARα abrogated the protective effect of auraptene on phenylephrine-induced hypertrophic responses. In rats with MI, auraptene significantly improved MI-induced systolic dysfunction and increased posterior wall thickness compared to the vehicle. Auraptene treatment also suppressed MI-induced increases in myocardial cell diameter, perivascular fibrosis, and expression of hypertrophy and fibrosis response markers at the mRNA level compared with vehicle treatment. MI-induced decreases in the expression of PPARα-dependent genes were improved by auraptene treatment. CONCLUSIONS Auraptene has beneficial effects on MI-induced cardiac hypertrophy and left ventricular systolic dysfunction in rats, at least partly due to PPARα activation. Further clinical studies are required to evaluate the efficacy of auraptene in patients with HF.
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Affiliation(s)
- Yoichi Sunagawa
- Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan; Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto 612-8555, Japan; Research Support Center, Shizuoka General Hospital, Shizuoka 420-8527, Japan
| | - Shogo Kawaguchi
- Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan
| | - Yusuke Miyazaki
- Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan; Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto 612-8555, Japan; Research Support Center, Shizuoka General Hospital, Shizuoka 420-8527, Japan
| | - Yasufumi Katanasaka
- Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan; Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto 612-8555, Japan; Research Support Center, Shizuoka General Hospital, Shizuoka 420-8527, Japan
| | - Masafumi Funamoto
- Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan; Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto 612-8555, Japan
| | - Kana Shimizu
- Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan; Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto 612-8555, Japan
| | - Satoshi Shimizu
- Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan; Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto 612-8555, Japan
| | - Toshihide Hamabe-Horiike
- Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan
| | - Yuto Kawase
- Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan
| | - Maki Komiyama
- Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto 612-8555, Japan
| | - Kiyoshi Mori
- Division of Molecular and Clinical Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan; Department of Nephrology, Shizuoka General Hospital, Shizuoka 420-8527, Japan; Shizuoka Graduate University of Public Health, Shizuoka 420-0881, Japan
| | - Akira Murakami
- School of Human Science and Environment, University of Hyogo, Hyogo 670-0092, Japan
| | - Koji Hasegawa
- Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan; Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto 612-8555, Japan
| | - Tatsuya Morimoto
- Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan; Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto 612-8555, Japan; Research Support Center, Shizuoka General Hospital, Shizuoka 420-8527, Japan.
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Bagheri R, Rassouli FB, Gholamhosseinian H, Ebrahimi K, Mahdavi S, Goudarzi S, Iranshahi M, Rafatpanah H, Keramati MR. Radiation Response of Human Leukemia/Lymphoma Cells was Improved by 7-Geranyloxycoumarin. Dose Response 2022; 20:15593258221124479. [PMID: 36158737 PMCID: PMC9500271 DOI: 10.1177/15593258221124479] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Objectives Adult T-cell leukemia/lymphoma (ATLL) is a blood neoplasm with specific geographic distribution. Although radiotherapy is a palliative treatment that provides long-term local control, single use of radiation leads to complications for patients. To introduce a novel multimodal approach against ATLL, we investigated combinatorial effects of 7-geranyloxycoumarin and radiation in vitro. Methods Viability of MT-2 cells was determined by resazurin assay upon administration of 7-geranyloxycoumarin alone and followed by radiation. Then, apoptosis was detected by annexin V and propidium iodide, and the expression of candidate genes was analyzed by qPCR. Results Findings revealed significant (P<.0001) improvement in radiation effects upon 7-geranyloxycoumarin pretreatment, most notably when cells were pretreated with 5 µg/ml 7-geranyloxycoumarin for 96 h, exposed to 6 Gy radiation and recovered for 48 h. These results were confirmed by flow cytometry, as the percentage of early and late apoptotic cells was increased after combinatorial treatment. In addition, significant (P< .0001) changes in CD44, c-MYC, cFLIPL, BMI-1, NF-κB (Rel A), and P53 expression was induced by 7-geranyloxycoumarin and radiation. Conclusions Current research indicated, for the first time, that combinatorial use of 7-geranyloxycoumarin and ionizing radiation could be considered as an effective therapeutic modality for ATLL.
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Affiliation(s)
- Ramin Bagheri
- Cancer Molecular Pathology Research Center, Department of Hematology and Blood Bank, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh B. Rassouli
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Hamid Gholamhosseinian
- Department of Medical Physics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Keyhan Ebrahimi
- Cancer Molecular Pathology Research Center, Department of Hematology and Blood Bank, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shakiba Mahdavi
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Sajad Goudarzi
- Cancer Molecular Pathology Research Center, Department of Hematology and Blood Bank, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehrdad Iranshahi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Houshang Rafatpanah
- Immunology Research Center, Inflammation and inflammatory Diseases Division, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Reza Keramati
- Cancer Molecular Pathology Research Center, Department of Hematology and Blood Bank, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Tayarani-Najaran Z, Tayarani-Najaran N, Eghbali S. A Review of Auraptene as an Anticancer Agent. Front Pharmacol 2021; 12:698352. [PMID: 34239445 PMCID: PMC8258114 DOI: 10.3389/fphar.2021.698352] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 06/09/2021] [Indexed: 11/13/2022] Open
Abstract
Auraptene is a bioactive monoterpene coumarin isolated from Citrus aurantium and Aegle marmelos that belong to the Rutaceae family. Auraptene can modulate intracellular signaling pathways that control cell growth, inflammation and apoptosis and can exert pharmacological properties such as anti-bacterial, anti-fungal, antileishmania and anti-oxidant activity. Auraptene had inhibitory and chemo-preventive effects on the proliferation, tumorigenesis and growth of several cancer cell lines through increase in the activity of glutathione S-transferase, formation of DNA adducts and reduction of the number of aberrant crypt foci. Auraptene exhibits anticancer effects via targeting different cell signaling pathways such as cytokines, genes modulating cellular proliferation, growth factors, transcription factors and apoptosis. The present review is a detailed survey of scientific researches on the cytotoxicity and anticancer activity of Auraptene on cancer cells and tumor bearing animals.
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Affiliation(s)
- Zahra Tayarani-Najaran
- Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nilufar Tayarani-Najaran
- Department of Prosthodontics, School of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Samira Eghbali
- Department of Pharmacognosy, School of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran.,Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
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Bibak B, Shakeri F, Barreto GE, Keshavarzi Z, Sathyapalan T, Sahebkar A. A review of the pharmacological and therapeutic effects of auraptene. Biofactors 2019; 45:867-879. [PMID: 31424600 DOI: 10.1002/biof.1550] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 07/26/2019] [Indexed: 12/25/2022]
Abstract
There is a growing awareness in herbal medications as they are usually safe and devoid of significant adverse effects. Auraptene is a natural bioactive monoterpene coumarin ether and is consumed all over the world. There is growing evidence of the therapeutic benefits of auraptene. Auraptene, also known as auraptene and 7-geranyloxycoumarin, is a bioactive monoterpene coumarin from Rutaceae family, which is isolated from Citrus aurantium (Seville orange) and Aegle marmelos (bael fruit). Auraptene is a highly pleiotropic molecule, which can modulate intracellular signaling pathways that control inflammation, cell growth, and apoptosis. It has a potential therapeutic role in the prevention and treatment of various diseases due to its anti-inflammatory and antioxidant activities as well as its excellent safety profile. In the present article, various pharmacological and therapeutic effects of auraptene were reviewed. Different online databases using keywords such as auraptene, therapeutic effects and pharmacological effects were searched until the end of September 2018, for this purpose. Auraptene has been suggested to be effective in the treatment of a broad range of disorders including inflammatory disorders, dysentery, wounds, scars, keloids, and pain. In addition, different studies have demonstrated that auraptene possesses numerous pharmacological properties including anti-inflammatory, anti-oxidative, anti-diabetic, anti-hypertensive and anti-cancer as well as neuroprotective effects. The present review provides a detailed survey of scientific researches regarding pharmacological properties and therapeutic effects of auraptene.
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Affiliation(s)
- Bahram Bibak
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
- Department of Physiology, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Farzaneh Shakeri
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - George E Barreto
- Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile
| | - Zakieh Keshavarzi
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
- Department of Physiology, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Thozhukat Sathyapalan
- Department of Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, Hull, UK
| | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Lee JC, Shin EA, Kim B, Kim BI, Chitsazian-Yazdi M, Iranshahi M, Kim SH. Auraptene Induces Apoptosis via Myeloid Cell Leukemia 1-Mediated Activation of Caspases in PC3 and DU145 Prostate Cancer Cells. Phytother Res 2017; 31:891-898. [PMID: 28383142 DOI: 10.1002/ptr.5810] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Revised: 02/13/2017] [Accepted: 03/16/2017] [Indexed: 01/24/2023]
Abstract
Although auraptene, a prenyloxy coumarin from Citrus species, was known to have anti-oxidant, anti-bacterial, antiinflammatory, and anti-tumor activities, the underlying anti-tumor mechanism of auraptene in prostate cancers is not fully understood to date. Thus, in the present study, we have investigated the anti-tumor mechanism of auraptene mainly in PC3 and DU145 prostate cancer cells, because auraptene suppressed the viability of androgen-independent PC3 and DU145 prostate cancer cells better than androgen-sensitive LNCaP cells. Also, auraptene notably increased sub-G1 cell population and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells as features of apoptosis in two prostate cancer cells compared with untreated control. Consistently, auraptene cleaved poly(ADP-ribose) polymerase, activated caspase-9 and caspase-3, suppressed the expression of anti-apoptotic proteins, including Bcl-2 and myeloid cell leukemia 1 (Mcl-1), and also activated pro-apoptotic protein Bax in both prostate cancer cells. However, Mcl-1 overexpression reversed the apoptotic effect of auraptene to increase sub-G1 population and induce caspase-9/3 in both prostate cancer cells. Taken together, the results support scientific evidences that auraptene induces apoptosis in PC3 and DU145 prostate cancer cells via Mcl-1-mediated activation of caspases as a potent chemopreventive agent for prostate cancer prevention and treatment. Copyright © 2017 John Wiley & Sons, Ltd.
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Affiliation(s)
- Jae Chul Lee
- Department of East West Medical Science Graduate School of East West Medical Science, Kyung Hee University, Suwon, Korea
| | - Eun Ah Shin
- College of Korean Medicine, Kyung Hee University, Seoul, 130-701, Korea
| | - Bonglee Kim
- College of Korean Medicine, Kyung Hee University, Seoul, 130-701, Korea
| | - Bo-Im Kim
- College of Korean Medicine, Kyung Hee University, Seoul, 130-701, Korea
| | - Mahsa Chitsazian-Yazdi
- Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehrdad Iranshahi
- Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sung-Hoon Kim
- College of Korean Medicine, Kyung Hee University, Seoul, 130-701, Korea
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Effectiveness of Citrus Fruits on Helicobacter pylori. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 2017:8379262. [PMID: 28408943 PMCID: PMC5376954 DOI: 10.1155/2017/8379262] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 03/01/2017] [Indexed: 12/14/2022]
Abstract
It is known that Helicobacter pylori infection is associated with chronic gastritis, peptic ulcer, and gastric carcinoma. Due to the increased side effects of the treatment regimens and the development of antimicrobial resistance, a number of natural compounds have been tested as potential alternatives. In this review, we will examine the current knowledge on the effect of Citrus fruits and their derivatives against H. pylori, highlighting the remaining outstanding questions on the development of novel therapeutic strategies.
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Son DJ, Lee GR, Oh S, Lee SE, Choi WS. Gastroprotective efficacy and safety evaluation of scoparone derivatives on experimentally induced gastric lesions in rodents. Nutrients 2015; 7:1945-64. [PMID: 25781220 PMCID: PMC4377892 DOI: 10.3390/nu7031945] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 02/28/2015] [Accepted: 03/04/2015] [Indexed: 12/19/2022] Open
Abstract
This study investigated the gastroprotective efficacy of synthesized scoparone derivatives on experimentally induced gastritis and their toxicological safety. Six scoparone derivatives were synthesized and screened for gastroprotective activities against HCl/ethanol- and indomethacin-induced gastric ulcers in rats. Among these compounds, 5,6,7-trimethoxycoumarin and 6,7,8-trimethoxycoumarin were found to have gastroprotective activity greater than the standard drug rebamipide; 6-methoxy-7,8-methylenedioxycoumarin, 6-methoxy-7,8-(1-methoxy)-methylenedioxycoumarin, 6,7-methylenedioxycoumarin, and 6,7-(1-methoxy)-methylenedioxycoumarin were found to be equipotent or less potent that of rebamipide. Pharmacological studies suggest that the presence of a methoxy group at position C-5 or C-8 of the scoparone's phenyl ring significantly improves gastroprotective activity, whereas the presence of a dioxolane ring at C-6, C-7, or C-8 was found to have decreased activity. In order to assess toxicological safety, two of the potent gastroprotective scoparone derivatives-5,6,7-trimethoxycoumarin and 6,7,8-trimethoxycoumarin-were examined for their acute toxicity in mice as well as their effect on cytochrome P450 (CYP) enzyme activity. These two compounds showed low acute oral toxicity in adult male and female mice, and caused minimal changes to CYP3A4 and CYP2C9 enzyme activity. These results indicate that compared to other scoparone derivatives, 5,6,7-trimethoxycoumarin and 6,7,8-trimethoxycoumarin can improve gastroprotective effects, and they have low toxicity and minimal effects on drug-metabolizing enzymes.
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Affiliation(s)
- Dong Ju Son
- School of Applied Bioscience, Kyungpook National University, Daegu 702-701, Korea.
| | - Gyung Rak Lee
- Department of Biotechnology, College of Natural Sciences, Soonchunhyang University, Asan, Chungnam 336-745, Korea.
| | - Sungil Oh
- Department of Biotechnology, College of Natural Sciences, Soonchunhyang University, Asan, Chungnam 336-745, Korea.
| | - Sung Eun Lee
- School of Applied Bioscience, Kyungpook National University, Daegu 702-701, Korea.
| | - Won Sik Choi
- Department of Biotechnology, College of Natural Sciences, Soonchunhyang University, Asan, Chungnam 336-745, Korea.
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Liu YH, Lin JY. Recent advances of cluster of differentiation 74 in cancer. World J Immunol 2014; 4:174-184. [DOI: 10.5411/wji.v4.i3.174] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2014] [Revised: 06/03/2014] [Accepted: 07/29/2014] [Indexed: 02/05/2023] Open
Abstract
Cluster of differentiation 74 (CD74) performs multiple roles in B cells, T cells, and antigen-presenting cells within the immune system; it also participates in major histocompatibility complex class II-restricted antigen presentation and inflammation. Recently, a role for CD74 in carcinogenesis has been described. CD74 promotes cell proliferation and motility and prevents cell death in a macrophage migration inhibitory factor-dependent manner. Its roles as an accessory signal receptor on the cell surface and the ability to interact with other signaling molecules make CD74 an attractive therapeutic target for the treatment of cancer. This review focuses on the original role of CD74 in the immune system and its emerging tumor-related functions. First, the structure of CD74 will be summarized. Second, the current understandings about the expression, cellular localization, molecular mechanisms and signaling pathways of CD74 in immunity and cancer will be reviewed. Third, the examples that suggest CD74 is a promising molecular therapeutic target are reviewed and discussed. Although the safety and efficacy of CD74-targeted strategies are under development, deeply understanding of the regulation of CD74 will hold promise for the use of CD74 as a therapeutic target and may develop the CD74-targeted therapeutic agents such as neutralized antibody and compounds.
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Low expression of ERK signaling pathway affecting proliferation, cell cycle arrest and apoptosis of human gastric HGC-27 cells line. Mol Biol Rep 2014; 41:3659-69. [PMID: 24554029 DOI: 10.1007/s11033-014-3230-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2013] [Accepted: 02/04/2014] [Indexed: 10/25/2022]
Abstract
This study was carried out for the first time to examine the potential role and the underlying mechanisms of Lycopene in the gastric cancer HGC-27 cells. HGC-27 cells were seeded onto heat-sterilized coverslips in six-well plates and exposed to Lycopene (5, 10, 20, 30 and 40 μmol/L) for periods of 72 h at 37 °C. Results showed that Lycopene (5, 10, 20, 30 and 40 μmol/L) dose-dependently increased NBT positive rate and decreased lactate dehydrogenase activity in HGC-27 cells. In addition, Lycopene (5, 10, 20, 30 and 40 μmol/L) inhibited proliferation and induced G0-G1 phase cell cycle arrest in HGC-27 cells. Western blot and FQRT-PCR analysis showed that Lycopene decreased pERK and extracellular signal-regulated kinase (ERK) protein and mRNA expression in a dose-dependent manner. These findings demonstrate that Lycopene inhibited gastric cancer HGC-27 cells growth and stimulated its apoptosis via the suppressing ERK signaling pathway.
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Marcus EA, Vagin O, Tokhtaeva E, Sachs G, Scott DR. Helicobacter pylori impedes acid-induced tightening of gastric epithelial junctions. Am J Physiol Gastrointest Liver Physiol 2013; 305:G731-9. [PMID: 23989011 PMCID: PMC3840231 DOI: 10.1152/ajpgi.00209.2013] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Gastric infection by Helicobacter pylori is the most common cause of ulcer disease and gastric cancer. The mechanism of progression from gastritis and inflammation to ulcers and cancer in a fraction of those infected is not definitively known. Significant acidity is unique to the gastric environment and is required for ulcer development. The interplay between gastric acidity and H. pylori pathogenesis is important in progression to advanced disease. The aim of this study was to characterize the impact of acid on gastric epithelial integrity and cytokine release and how H. pylori infection alters these responses. Human gastric epithelial (HGE-20) cells were grown on porous inserts, and survival, barrier function, and cytokine release were studied at various apical pH levels in the presence and absence of H. pylori. With apical acidity, gastric epithelial cells demonstrate increased barrier function, as evidenced by increased transepithelial electrical resistance (TEER) and decreased paracellular permeability. This effect is reduced in the presence of wild-type, but not urease knockout, H. pylori. The epithelial inflammatory response is also modulated by acidity and H. pylori infection. Without H. pylori, epithelial IL-8 release decreases in acid, while IL-6 release increases. In the presence of H. pylori, acidic pH diminishes the magnitude of the previously reported increase in IL-8 and IL-6 release. H. pylori interferes with the gastric epithelial response to acid, contributing to altered barrier function and inflammatory response. H. pylori diminishes acid-induced tightening of cell junctions in a urease-dependent manner, suggesting that local pH elevation promotes barrier compromise and progression to mucosal damage.
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Affiliation(s)
- Elizabeth A. Marcus
- 1Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; ,4Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, California
| | - Olga Vagin
- 2Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; ,4Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, California
| | - Elmira Tokhtaeva
- 2Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; ,4Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, California
| | - George Sachs
- 2Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; ,3Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; and ,4Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, California
| | - David R. Scott
- 2Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; ,4Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, California
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Giordano A, Cito L. Advances in gastric cancer prevention. World J Clin Oncol 2012; 3:128-36. [PMID: 23061031 PMCID: PMC3468701 DOI: 10.5306/wjco.v3.i9.128] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2012] [Revised: 08/19/2012] [Accepted: 09/06/2012] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is a multifactorial neoplastic pathology numbering among its causes both environmental and genetic predisposing factors. It is mainly diffused in South America and South-East Asia, where it shows the highest morbility percentages and it is relatively scarcely diffused in Western countries and North America. Although molecular mechanisms leading to gastric cancer development are only partially known, three main causes are well characterized: Helicobacter pylori (H. pylori) infection, diet rich in salted and/or smoked food and red meat, and epithelial cadherin (E-cadherin) mutations. Unhealthy diet and H. pylori infection are able to induce in stomach cancer cells genotypic and phenotypic transformation, but their effects may be crossed by a diet rich in vegetables and fresh fruits. Various authors have recently focused their attention on the importance of a well balanced diet, suggesting a necessary dietary education starting from childhood. A constant surveillance will be necessary in people carrying E-cadherin mutations, since they are highly prone in developing gastric cancer, also within the inner stomach layers. Above all in the United States, several carriers decided to undergo a gastrectomy, preferring changing their lifestyle than living with the awareness of the development of a possible gastric cancer. This kind of choice is strictly personal, hence a decision cannot be suggested within the clinical management. Here we summarize the key points of gastric cancer prevention analyzing possible strategies referred to the different predisposing factors. We will discuss about the effects of diet, H. pylori infection and E-cadherin mutations and how each of them can be handled.
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Affiliation(s)
- Antonio Giordano
- Antonio Giordano, Letizia Cito, INT-CROM, "Pascale Foundation" National Cancer Institute-Cancer Research Center, 83013 Mercogliano, Italy
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Da Li Q, Li H, Li FJ, Wang MS, Li ZJ, Han J, Li QH, Ma XJ, Wang DN. Nutrition deficiency increases the risk of stomach cancer mortality. BMC Cancer 2012; 12:315. [PMID: 22838407 PMCID: PMC3443031 DOI: 10.1186/1471-2407-12-315] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Accepted: 07/17/2012] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The purpose of the study is to determine whether exposure to malnutrition during early life is associated with increased risk of stomach cancer in later life. METHODS The design protocol included analyzing the trend of gastric cancer mortality and nutrition and evaluating the association between nutrient deficiency in early life and the risk of gastric cancer by hierarchical age-period-birth cohort (APC) analysis using general log-linear Poisson models and to compare the difference between birth cohorts who were exposed to the 1959-1961 Chinese famine and those who were not exposed to the famine. Data on stomach cancer mortality from 1970 to 2009 and the dietary patterns from 1955 to 1985 which included the 1959-1961 Chinese famine period in the Zhaoyuan County population were obtained. The nutrition information was collected 15 years prior to the mortality data as based on the latest reference of disease incubation. RESULTS APC analysis revealed that severe nutrition deficiency during early life may increase the risk of stomach cancer. Compared with the 1960-1964 birth cohort, the risk for stomach cancer in all birth cohorts from 1900 to 1959 significantly increased; compared with the 1970-1974 cohort, the risk for stomach cancer in the 1975-1979 cohort significantly increased, whereas the others had a steadily decreased risk; compared with 85-89 age group in the 2005-2009 death survey, the ORs decreased with younger age and reached significant levels for the 50-54 age group after adjusting the confounding factors. The 1930 to 1964 group (exposed to famine) had a higher mortality rate than the 1965 to 1999 group (not exposed to famine). For males, the relative risk (RR) was 2.39 and the 95% confidence interval (CI) was 1.51 to 3.77. For females, RR was 1.64 and 95% CI was 1.02 to 2.62. CONCLUSION The results of the present study suggested that prolonged malnutrition during early life may increase the risk of stomach cancer mortality in later life.
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Affiliation(s)
- Qing Da Li
- Department of Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Hao Li
- Tumor Center, Qilu Hospital of Shandong University, Jinan, China
| | - Fu Ji Li
- Department of Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Mei Shu Wang
- Department of Epidemiology, College of Public Health of Shandong University, Jinan, China
| | - Zhuo Jian Li
- Center of Disease Control and Prevention of Jinan, Jinan, China
| | - Jing Han
- Department of Environmental Medicine, School of Medicine New York University, New York, USA
| | - Qing Hui Li
- Department of Epidemiology, Institute of Basic Medicine of Shandong Academy of Medical Sciences, Jinan, China
| | - Xiang Ji Ma
- Center of Disease Control and Prevention of Shandong Province, Jinan, China
| | - Da Nan Wang
- Center of Disease Control and Prevention of Zhaoyuan, Zhaoyuan, China
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14
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Zheng YX, Yang M, Rong TT, Yuan XL, Ma YH, Wang ZH, Shen LS, Cui L. CD74 and macrophage migration inhibitory factor as therapeutic targets in gastric cancer. World J Gastroenterol 2012; 18:2253-61. [PMID: 22611320 PMCID: PMC3351777 DOI: 10.3748/wjg.v18.i18.2253] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2011] [Revised: 02/06/2012] [Accepted: 02/16/2012] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the relationship and molecular features of CD74/macrophage migration inhibitory factor (MIF)/Toll-like receptor 4 (TLR4) in gastric cancer. METHODS CD74, MIF and TLR4 expression in the paraffin-embedded sections of gastric cancer from 120 patients were detected by immunohistochemical staining. Knock down of CD74 expression in gastric cancer cell line MKN-45 was performed by lentivirus transduction and detected by Western blotting. MKN-45 cell proliferation assay under the stimulants was measured by the cell counting kit 8 (CCK8) assay and MIF concentration in the culture medium was detected by enzyme-linked immunosorbent assay. Surface staining of CD74 in the MKN-45 cell line under the stimulation of lipopolysaccharide (LPS) was measured by flow cytometry. MIF, CD74 and TLR4 co-localization in the MKN-45 cell line was performed by the immunoprecipitation. RESULTS CD74, MIF and TLR4 were found to be expressed in gastric cancer and increased significantly in the advanced stage, and were also associated with lymph node metastasis. Correlation analysis revealed that CD74 was positively correlated with MIF (r = 0.2367, P < 0.01) and both proteins were also associated with TLR4 (r = 0.4414, r = 0.5001, respectively, P < 0.01). LPS can significantly promote MKN-45 cell proliferation (3.027 ± 0.388 vs 4.201 ± 0.092, P < 0.05), induce MIF production (54.333 ± 2.906 pg/mL vs 29.667 ± 3.180 pg/mL, P < 0.01) and cell surface expression of CD74 (75.6% ± 4.046% vs 9.4% ± 0.964%, P < 0.01) at LPS concentration of 1 μg/mL compared to medium control. Knockdown of CD74 or using anti-CD74 and MIF antagonist ISO-1 significantly reduced LPS-induced MKN-45 cell proliferation (4.201 ± 0.092 vs 3.337 ± 0.087, 4.534 ± 0.222 vs 3.368 ± 0.290, 4.058 ± 0.292 vs 2.934 ± 0.197, respectively, P < 0.01). MIF, CD74 and TLR4 could co-localize in the MKN-45 cell line. CONCLUSION Upregulation of MIF, CD74 and TLR4 are associated with increasing clinical stage and provide an opportunity as novel gastric cancer chemoprevention and/or treatment strategy.
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Sekiguchi H, Takabayashi F, Irie K, Murakami A. Auraptene attenuates gastritis via reduction of Helicobacter pylori colonization and pro-inflammatory mediator production in C57BL/6 mice. J Med Food 2012; 15:658-63. [PMID: 22471969 DOI: 10.1089/jmf.2011.1844] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori is a major human pathogen that plays central roles in chronic gastritis and gastric cancer. Recently, we reported that auraptene suppressed H. pylori adhesion via expression of CD74, which has been identified as a new receptor for H. pylori urease. In this study, we attempted to clarify the effects of oral feeding of auraptene on H. pylori infection and resultant inflammatory responses in C57BL/6 mice and found that it remarkably attenuated H. pylori colonization and gastritis. Biochemical analyses revealed that auraptene inhibited H. pylori-induced expression and/or production of CD74, macrophage migration inhibitory factor, interleukin-1β, and tumor necrosis factor-α in gastric mucosa, together with serum macrophage inhibitory protein-2. It is notable that treatment with this coumarin during the pretreatment period was more effective than that during posttreatment. Our results suggest that auraptene is a promising phytochemical for reducing the risk of H. pylori-induced gastritis and carcinogenesis.
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Affiliation(s)
- Hirotaka Sekiguchi
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
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Verbeke H, Geboes K, Van Damme J, Struyf S. The role of CXC chemokines in the transition of chronic inflammation to esophageal and gastric cancer. Biochim Biophys Acta Rev Cancer 2011; 1825:117-29. [PMID: 22079531 DOI: 10.1016/j.bbcan.2011.10.008] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2011] [Revised: 10/28/2011] [Accepted: 10/29/2011] [Indexed: 12/12/2022]
Abstract
Chronic inflammation may increase the risk to develop cancer, for instance esophagitis or gastritis may lead to development of esophageal or gastric cancer, respectively. The key molecules attracting leukocytes to local inflammatory sites are chemokines. We here provide a systematic review on the impact of CXC chemokines (binding the receptors CXCR1, CXCR2, CXCR3 and CXCR4) on the transition of chronic inflammation in the upper gastrointestinal tract to neoplasia. CXCR2 ligands, including GRO-α,β,γ/CXCL1,2,3, ENA-78/CXCL5 and IL-8/CXCL8 chemoattract pro-tumoral neutrophils. In addition, angiogenic CXCR2 ligands stimulate the formation of new blood vessels, facilitating tumor progression. The CXCR4 ligand SDF-1/CXCL12 also promotes tumor development by stimulating angiogenesis and by favoring metastasis of CXCR4-positive tumor cells to distant organs producing SDF-1/CXCL12. Furthermore, these angiogenic chemokines also directly enhance tumor cell survival and proliferation. In contrast, the CXCR3 ligands Mig/CXCL9, IP-10/CXCL10 and I-TAC/CXCL11 are angiostatic and attract anti-tumoral T lymphocytes and may therefore mediate tumor growth retardation and regression. Thus, chemokines exert diverging, sometimes dual roles in tumor biology as described for esophageal and gastric cancer. Therefore extensive research is needed to completely unravel the complex chemokine code in specific cancers. Possibly, chemokine-targeted cancer therapy will have to be adapted to the individual's chemokine profile.
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Affiliation(s)
- Hannelien Verbeke
- Laboratory of Molecular Immunology, Rega Institute for Medical Research, University of Leuven (K.U.Leuven), Belgium
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