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Radziszewski M, Galus R, Łuszczyński K, Winiarski S, Wąsowski D, Malejczyk J, Włodarski P, Ścieżyńska A. The RAGE Pathway in Skin Pathology Development: A Comprehensive Review of Its Role and Therapeutic Potential. Int J Mol Sci 2024; 25:13570. [PMID: 39769332 PMCID: PMC11676465 DOI: 10.3390/ijms252413570] [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: 11/25/2024] [Revised: 12/15/2024] [Accepted: 12/17/2024] [Indexed: 01/11/2025] Open
Abstract
The receptor for advanced glycation end-products (RAGE), a member of the immunoglobulin superfamily, is expressed in various cell types and mediates cellular responses to a wide range of ligands. The activation of RAGE triggers complex signaling pathways that drive inflammatory, oxidative, and proliferative responses, which are increasingly implicated in the pathogenesis of skin diseases. Despite its well-established roles in conditions such as diabetes, cancer, and chronic inflammation, the contribution of RAGE to skin pathologies remains underexplored. This review synthesizes current findings on RAGE's involvement in the pathophysiology of skin diseases, including conditions such as psoriasis, atopic dermatitis, and lichen planus, focusing on its roles in inflammatory signaling, tissue remodeling, and skin cancer progression. Additionally, it examines RAGE-modulating treatments investigated in dermatological contexts, highlighting their potential as therapeutic options. Given RAGE's significance in a variety of skin conditions, further research into its mediated pathways may uncover new opportunities for targeted interventions in skin-specific RAGE signaling.
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Affiliation(s)
- Marcin Radziszewski
- Department of Histology and Embryology, Medical University of Warsaw, 02-004 Warsaw, Poland
- Department of Thoracic Surgery, National Medical Institute of the Ministry of the Interior and Administration, 02-507 Warsaw, Poland
| | - Ryszard Galus
- Department of Histology and Embryology, Medical University of Warsaw, 02-004 Warsaw, Poland
| | - Krzysztof Łuszczyński
- Department of Histology and Embryology, Medical University of Warsaw, 02-004 Warsaw, Poland
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine National Research Institute, 04-141 Warsaw, Poland
| | - Sebastian Winiarski
- Department of Thoracic Surgery, National Medical Institute of the Ministry of the Interior and Administration, 02-507 Warsaw, Poland
| | - Dariusz Wąsowski
- Department of Thoracic Surgery, National Medical Institute of the Ministry of the Interior and Administration, 02-507 Warsaw, Poland
| | - Jacek Malejczyk
- Department of Histology and Embryology, Medical University of Warsaw, 02-004 Warsaw, Poland
- Institute of Health Sciences, Faculty of Medical and Health Sciences, University of Siedlce, 08-110 Siedlce, Poland
| | - Paweł Włodarski
- Department of Histology and Embryology, Medical University of Warsaw, 02-004 Warsaw, Poland
| | - Aneta Ścieżyńska
- Department of Histology and Embryology, Medical University of Warsaw, 02-004 Warsaw, Poland
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine National Research Institute, 04-141 Warsaw, Poland
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A Review with Updated Perspectives on Nutritional and Therapeutic Benefits of Apricot and the Industrial Application of Its Underutilized Parts. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27155016. [PMID: 35956966 PMCID: PMC9370680 DOI: 10.3390/molecules27155016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 11/16/2022]
Abstract
Fruits maintain the image as the richest sources of vitamins. Focusing on apricots, utilization of apricot species for many applications is possible due to its various benefits. Many research studies demonstrated different perspectives of apricot, especially in medical used as it can act as antioxidant, anti-inflammatory, and antimicrobial agents. Moreover, in the industrial sectors, apricots can be used in the production of biofuels and batteries. All components of the apricot fruit, including seeds and kernels have been found to possess significant interest. This review is to breach the knowledge gap regarding the key nutrients and chemicals of apricot fruit, contributing to its health-promoting properties to emphasize the noble importance of this fruit in the diet and in the management of several diseases. We also cover the application of apricots in the industry that could be developed as a promising and sustainable source.
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Hiraishi K, Jimma F, Soma H, Kagawa T, Yamaoka I. Investigating a novel hepatoprotective substance from ume extract (heated Japanese apricot juice concentrate). Part 1: Finding an active substance using a liver injury rat model. NFS JOURNAL 2022. [DOI: 10.1016/j.nfs.2021.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Investigating a novel hepatoprotective substance from ume extract (heated Japanese apricot juice concentrate). Part 2: Elucidation of chemical structure. NFS JOURNAL 2022. [DOI: 10.1016/j.nfs.2021.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Tian T, Cao H, Farag MA, Fan S, Liu L, Yang W, Wang Y, Zou L, Cheng KW, Wang M, Ze X, Simal-Gandara J, Yang C, Qin Z. Current and potential trends in the bioactive properties and health benefits of Prunus mume Sieb. Et Zucc: a comprehensive review for value maximization. Crit Rev Food Sci Nutr 2022; 63:7091-7107. [PMID: 35199615 DOI: 10.1080/10408398.2022.2042186] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Prunus mume Sieb. Et Zucc (P. mume) is an acidic fruit native to China (named Chinese Mei or greengage plum). It is currently cultivated in several Asian countries, including Japan ("Ume"), Korea (Maesil), and Vietnam (Mai or Mo). Due to its myriad nutritional and functional properties, it is accepted in different countries, and its characteristics account for its commercialization. In this review, we summarize the information on the bioactive compounds from the fruit of P. mume and their structure-activity relationships (SAR); the pulp has the highest enrichment of bioactive chemicals. The nutritional properties of P. mume and the numerous uses of its by-products make it a potential functional food. P. mume extracts exhibit antioxidant, anticancer, antimicrobial, and anti-hyperuricaemic properties, cardiovascular protective effects, and hormone regulatory properties in various in vitro and in vivo assays. SAR shows that the water solubility, molecular weight, and chemical conformation of P. mume extracts are closely related to their biological activity. However, further studies are needed to evaluate the fruit's potential nutritional and functional therapeutic mechanisms. The industrial process of large-scale production of P. mume and its extracts as functional foods or nutraceuticals needs to be further optimized.
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Affiliation(s)
- Tiantian Tian
- Center for Biological Science and Technology, Advanced Institute of Natural Sciences, Beijing Normal University at Zhuhai, Zhuhai, Guangdong, China
| | - Hui Cao
- College of Food Science and Technology, Guangdong Ocean University, Zhanjiang, Guangdong, China
| | - Mohamed A Farag
- Pharmacognosy Department, College of Pharmacy, Cairo University, Cairo, Egypt
- Department of Chemistry, School of Sciences & Engineering, The American University, Cairo, New Cairo, Egypt
| | - Siting Fan
- Center for Biological Science and Technology, Advanced Institute of Natural Sciences, Beijing Normal University at Zhuhai, Zhuhai, Guangdong, China
| | - Luxuan Liu
- Center for Biological Science and Technology, Advanced Institute of Natural Sciences, Beijing Normal University at Zhuhai, Zhuhai, Guangdong, China
| | - Wenjing Yang
- Center for Biological Science and Technology, Advanced Institute of Natural Sciences, Beijing Normal University at Zhuhai, Zhuhai, Guangdong, China
| | - Yuxuan Wang
- Center for Biological Science and Technology, Advanced Institute of Natural Sciences, Beijing Normal University at Zhuhai, Zhuhai, Guangdong, China
| | - Liang Zou
- Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural 18 Affairs, Chengdu University, Chengdu, China
| | - Ka-Wing Cheng
- Institute for Advanced Study, Shenzhen University, Shenzhen, China
| | - Mingfu Wang
- Institute for Advanced Study, Shenzhen University, Shenzhen, China
| | - Xiaolei Ze
- Science and Technology Center, BY-Health Co Ltd, Guangzhou, Guangdong, China
| | - Jesus Simal-Gandara
- Department of Analytical Chemistry and Food Science, Faculty of Food Science and Technology, University of Vigo, Vigo, Spain
| | - Chao Yang
- Center for Biological Science and Technology, Advanced Institute of Natural Sciences, Beijing Normal University at Zhuhai, Zhuhai, Guangdong, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macao University of Science and Technology, Macao, China
| | - Zhiwei Qin
- Center for Biological Science and Technology, Advanced Institute of Natural Sciences, Beijing Normal University at Zhuhai, Zhuhai, Guangdong, China
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Impact of Advanced Glycation End products (AGEs) and its receptor (RAGE) on cancer metabolic signaling pathways and its progression. Glycoconj J 2022; 38:717-734. [PMID: 35064413 DOI: 10.1007/s10719-021-10031-x] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/26/2021] [Accepted: 11/30/2021] [Indexed: 02/07/2023]
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Gong XP, Tang Y, Song YY, Du G, Li J. Comprehensive Review of Phytochemical Constituents, Pharmacological Properties, and Clinical Applications of Prunus mume. Front Pharmacol 2021; 12:679378. [PMID: 34122104 PMCID: PMC8195681 DOI: 10.3389/fphar.2021.679378] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 05/04/2021] [Indexed: 12/18/2022] Open
Abstract
Prunus mume is one of the most ancient medicinal herbs and health foods commonly used in Asian countries. It is widely used as a constituent of many medicinal preparations and as a food ingredient for its beneficial health effects. In this review, we retrieved reports from PubMed, embase, Scopus, and SciFinder databases, to collect extensive scientific evidence on the phytochemical constituents, pharmacological properties, and clinical applications of Prunus mume. The literature review revealed that approximately 192 compounds have been isolated from different parts of the plant, and their molecular structures have been identified. The pharmacological properties of the plant, including anti-diabetic, liver-protective, antitumor, antimicrobial, antioxidant, and anti-inflammatory activities, as well as their underlying mechanisms, have been clarified by in vitro and in vivo studies. Clinical studies, although very limited, have been highlighted in this review to provide a reference for further exploration on therapeutic applications of the plant.
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Affiliation(s)
- Xue-Peng Gong
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ying Tang
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan-Yuan Song
- Department of Pharmacy, General Hospital of Central Theater Command, Wuhan, China
| | - Guang Du
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Juan Li
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Bailly C. Anticancer properties of Prunus mume extracts (Chinese plum, Japanese apricot). JOURNAL OF ETHNOPHARMACOLOGY 2020; 246:112215. [PMID: 31491438 DOI: 10.1016/j.jep.2019.112215] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 08/30/2019] [Accepted: 09/02/2019] [Indexed: 05/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Extracts of the fruit of Prunus mume (Rosaceae) have been used for a long time in Eastern Asia, in many culinary and medicinal preparations. The plant originates from the south of mainland China (named méi) and was introduced later in Japan (ume), Korea (maesil) and Vietnam (mai or mo). Extracts of the fruits (Chinese plum or Japanese apricot, 'Nanko' mume cultivar of Prunus mume Sieb. et Zucc.) are used in traditional Chinese and Japanese medicine, and various Korean medical preparations, for more than 2000 years. The medicinal use of the flesh of the fruits is cited in ancient Japanese monographies (such as Shokokukodenhiho published in 1817). AIM OF THE STUDY To analyze the anticancer activities of P. mume extracts and their potential use to prevent or treat cancers. The use of P. mume extracts to alleviate the side effects of chemotherapy, notably drug-induced gastro-intestinal toxicities, is also reviewed. METHODS Extensive database retrieval, such as SciFinder and PubMed, was performed by using keywords such as "Prunus mume", "Chinese plum", "Japanese apricot", and "cancer". In addition, relevant textbooks, patents, reviews, and digital documents (in English) were consulted to collate all available scientific literature and to provide a complete science-based survey of the topic. RESULTS P. mume extracts display hepatoprotective, anti-inflammatory, antioxidative and antibacterial effects, as well as anticancer properties. A survey of the antitumor activities of MK615 and other P. mume extracts is provided here, with information about the natural products found in the extracts (such as ursolic acid and oleanic acid) and the mechanisms of action of these extracts. MK615 inhibits proliferation and induces apoptotic death of different types of cancer cells from both solid and hematological tumors. CONCLUSION The pool of in vitro data and signs of anticancer activities in mice models and in Human, although very limited, support the use of this extract to treat cancer, notably gastro-intestinal tumors. However, more robust evidence of anticancer activity in Human are awaited. Beyond cancer treatment, the use of P. mume extracts to prevent or to treat mucositis and other gastro-intestinal damages induced by anticancer drugs is underlined. The woody plant Prunus mume, a member of the Rosaceae family, has a long plantation history in China, and has widely been planted in Asia due to its high ornamental value (colorful corollas, pleasant fragrance, weeping trait) and the culinary, nutritional and medicinal potential of the fruits from the specie Prunus mume Sieb. et Zucc (Mei). Over the past 20 years the therapeutic potential of the extract of Japanese apricot "Ume" has been regularly reported. Anti-bacterial, anti-oxidative, anti-inflammatory and anti-cancer properties have been described. A complete analysis of the published scientific literature on Ume and cancer is presented here.
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Yanaki M, Kobayashi M, Aruga A, Nomura M, Ozaki M. In Vivo Antitumor Effects of MK615 Led by PD-L1 Downregulation. Integr Cancer Ther 2018; 17:646-653. [PMID: 29665734 PMCID: PMC6142083 DOI: 10.1177/1534735418766403] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background/Aim: MK615 extracted from Prunus mume
was reported to have anti-inflammatory effects. In this article, we examined the
in vivo antitumor effect of MK615 (an extract from Japanese apricot) using mouse
tumor xenografts and focusing on the downregulation of PD-L1 (programmed
death-ligand 1), a ligand of programmed cell death-1, a surface protein of
activated T cells. Materials and Methods: B16/BL6 melanoma cells
were injected into C57BL/6 or BALB/c-nu/nu mice to establish lung metastasis.
BALB/c-nu/nu mice (nude mice) were used as a T cell–deficient model. The mice
were given MK615 or saline orally every other day for approximately 8 weeks, and
their survival was observed. NF-κB (nuclear factor-κB) and PD-L1 expressions of
metastatic lung tissues were also examined. Results: The survival
rate was improved only in the MK615-treated C57BL/6 mice (P
< .05), not in the saline-given control mice or BALB/c-nu/nu mice. The
downregulations of NF-κB and PD-L1 were observed in both MK615-treated C57BL/6
and BALB/c-nu/nu mice. These results suggest that the antitumor effects of MK615
are associated with T cell–mediated immunity activated by MK-615-induced PD-L1
downregulation in tumor cells. Conclusion: MK615 is beneficial for
a prolonged host survival time in the B16/BL6 melanoma xenograft model
associated with T cell–mediated antitumor immunity.
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Affiliation(s)
| | | | | | | | - Makoto Ozaki
- 1 Tokyo Women's Medical University, Tokyo, Japan
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Hattori M, Kawakami K, Akimoto M, Takenaga K, Suzumiya J, Honma Y. Antitumor Effect of Japanese Apricot Extract (MK615) on Human Cancer Cells in Vitro and in Vivo through a Reactive Oxygen Species-Dependent Mechanism. TUMORI JOURNAL 2018; 99:239-48. [DOI: 10.1177/030089161309900220] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Aims and background MK615 is produced from Japanese apricot and contains several cyclic triterpenes, such as oleanolic and ursolic acids. MK615 was shown to strongly suppress cutaneous in-transit metastasis in a patient with malignant melanoma. The present investigation was undertaken to clarify the antitumor effects of MK615 in vitro and in vivo. Methods Several human cancer cell lines were exposed to MK615 for 7 days to examine its antiproliferative effects. The effect of MK615 on in vivo growth of human pancreatic cancer MIAPaCa-2 cells was also examined. Results MK615 inhibited the growth of several human cancer cell lines in a concentration-dependent way. Pancreatic cancer MIAPaCa-2 cells were highly sensitive to the growth-inhibiting effects of MK615. Treatment with MK615 preferentially induced cell death in human cancer cells while sparing normal cells such as human umbilical vein endothelial cells (HUVEC) and mouse bone marrow cells. When MIAPaCa-2 cells were incubated with MK615 in the presence of antioxidant, growth-inhibition was significantly reduced, and MK615 induced the accumulation of reactive oxygen species in cancer cells but not in HUVEC. MK615, in both the presence and absence of gemcitabine, significantly inhibited the growth of human pancreatic cancer cells as xenografts without apparent adverse effects. Conclusions MK615, a supplement produced from Japanese apricot, may have therapeutic value in treating human cancers through a reactive oxygen species-dependent mechanism.
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Affiliation(s)
- Miho Hattori
- Department of Life Science, Shimane University, Izumo, Shimane, Japan
| | - Koshi Kawakami
- Department of Life Science, Shimane University, Izumo, Shimane, Japan
- Cancer Center, Faculty of Medicine, Shimane University, Izumo, Shimane, Japan
| | - Miho Akimoto
- Department of Life Science, Shimane University, Izumo, Shimane, Japan
| | - Keizo Takenaga
- Department of Life Science, Shimane University, Izumo, Shimane, Japan
| | - Junji Suzumiya
- Cancer Center, Faculty of Medicine, Shimane University, Izumo, Shimane, Japan
| | - Yoshio Honma
- Department of Life Science, Shimane University, Izumo, Shimane, Japan
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Syed DN, Aljohani A, Waseem D, Mukhtar H. Ousting RAGE in melanoma: A viable therapeutic target? Semin Cancer Biol 2017; 49:20-28. [PMID: 29079306 DOI: 10.1016/j.semcancer.2017.10.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 09/28/2017] [Accepted: 10/23/2017] [Indexed: 01/11/2023]
Abstract
Melanoma remains an important health concern, given the steady increase in incidence and acquisition of resistance to systemic therapies. The receptor for advanced glycation end products (RAGE) initially identified for its binding to advanced glycation end products was subsequently acknowledged as a pattern recognition receptor given its ability to recognize similar structural elements within numerous ligands. Recent studies have elucidated a plausible role of RAGE in melanoma progression through modulation of inflammatory, proliferative and invasive cellular responses. Several of its ligands including the S100 proteins and HMGB1 are being investigated for their involvement in melanoma metastasis and as potential biomarkers of the disease. Targeting RAGE signaling represents a viable therapeutic strategy which remains underexplored in cutaneous malignancies. Here we have summarized current knowledge on the functionality of RAGE with special focus on specific ligands enumerated in various in vitro and in vivo melanoma models.
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Affiliation(s)
- Deeba N Syed
- Department of Dermatology, University of Wisconsin-Madison, United States.
| | - Ahmed Aljohani
- School of Medicine and Public Health, Endocrinology and Reproductive Physiology Graduate Training Program, University of Wisconsin-Madison, Madison WI 53706, United States; King Saud bin Abdulaziz University for Health Sciences, Riyadh 11481, Saudi Arabia
| | - Durdana Waseem
- Department of Dermatology, University of Wisconsin-Madison, United States
| | - Hasan Mukhtar
- Department of Dermatology, University of Wisconsin-Madison, United States
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Inoue M, Honma Y, Urano T, Suzumiya J. Japanese apricot extract (MK615) potentiates bendamustine-induced apoptosis via impairment of the DNA damage response in lymphoma cells. Oncol Lett 2017; 14:792-800. [PMID: 28693235 PMCID: PMC5494765 DOI: 10.3892/ol.2017.6219] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 02/27/2017] [Indexed: 11/06/2022] Open
Abstract
Bendamustine, a hybrid molecule of a purine analog and alkylator, induces cell death by the activation of apoptosis and the DNA damage response. The agent MK615 is produced from Japanese apricot and contains a number of cyclic triterpenes that exhibit antitumor activities. In the present study, the combined effects of bendamustine and MK615 on lymphoma cells were investigated. The combined compounds synergistically induced apoptosis in all lymphoid cell lines examined. MK615 inhibited the bendamustine-induced phosphorylation of checkpoint kinase 1 and 2. As ataxia telangiectasia mutated (ATM) and ataxia telangiectasia- and Rad3-related (ATR) kinases are key mediators of the DNA damage response, the effects of the combination of bendamustine and ATM/ATR inhibitors (KU-60019 and VE-821) on lymphoma cells were investigated. KU-60019 and/or VE-821 potentiated bendamustine activity in all cell lines tested, but did not affect MK615 activity, suggesting that these inhibitors have the same underlying mechanism of action as that of MK615. The results of the present study suggest that it may be feasible to use ATM/ATR inhibitors in combination with bendamustine for treating malignant lymphoma.
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Affiliation(s)
- Masaya Inoue
- Department of Oncology/Hematology, Faculty of Medicine, Shimane University, Izumo, Shimane 693-8501, Japan
| | - Yoshio Honma
- Department of Oncology/Hematology, Faculty of Medicine, Shimane University, Izumo, Shimane 693-8501, Japan
| | - Takeshi Urano
- Department of Biochemistry, Faculty of Medicine, Shimane University, Izumo, Shimane 693-8501, Japan
| | - Junji Suzumiya
- Department of Oncology/Hematology, Faculty of Medicine, Shimane University, Izumo, Shimane 693-8501, Japan
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Pan JH, Lee KY, Kim JH, Shin H, Lee JH, Kim YJ. Prunus mume Sieb. et Zucc. fruit ameliorates alcoholic liver injury in mice by inhibiting apoptosis and inflammation through oxidative stress. J Funct Foods 2016. [DOI: 10.1016/j.jff.2016.04.024] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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Hokari A, Ishikawa T, Tajiri H, Matsuda T, Ishii O, Matsumoto N, Okuse C, Takahashi H, Kurihara T, Kawahara KI, Maruyama I, Zeniya M. Efficacy of MK615 for the treatment of patients with liver disorders. World J Gastroenterol 2012; 18:4118-26. [PMID: 22919243 PMCID: PMC3422791 DOI: 10.3748/wjg.v18.i31.4118] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2011] [Revised: 05/10/2012] [Accepted: 05/26/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the hepatoprotective effect of MK615, a Japanese apricot extract, in an animal model, and its clinical therapeutic effect.
METHODS: Wistar rats were administered physiological saline (4 mL/kg) or MK615 solution (4 mL/kg) for 7 d. On the sixth d, acute hepatic injury was induced by administering a single intraperitoneal injection (ip) of D-galactosamine hydrochloride (D-GalN) (600 mg/kg). Plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined, and liver tissues were used for histopathological analysis. Fifty-eight patients with liver disorders [hepatitis C (n = 40), non-alcoholic fatty liver disease (n = 15), and autoimmune liver disease (n = 3)] were orally administered commercially available Misatol ME-containing MK615 (13 g/d) daily for 12 wk. Blood and urine were sampled immediately before and 6 wk, 12 wk, and 16 wk after the start of intake to measure various biochemical parameters. The percentage change in ALT and AST levels after 12 wk from the pre-intake baseline served as a primary endpoint.
RESULTS: D-GalN effectively induced acute hepatic injury in the rats. At 48 h after the ip injection of D-GalN, the plasma levels of ALT (475.6 ± 191.5 IU/L vs 225.3 ± 194.2 IU/L, P < 0.05) and AST (1253.9 ± 223.4 IU/L vs 621.9 ± 478.2 IU/L, P < 0.05) in the MK615 group were significantly lower than the control group. Scattered single cell necrosis, loss of hepatocytes, and extensive inflammatory cell infiltration were observed in hepatic tissue samples collected from the control group. However, these findings were less pronounced in the group receiving MK615. At the end of the clinical study, serum ALT and AST levels were significantly decreased compared with pre-intake baseline levels from 103.5 ± 58.8 IU/L to 71.8 ± 39.3 IU/L (P < 0.05) and from 93.5 ± 55.6 IU/L to 65.5 ± 34.8 IU/L (P < 0.05), respectively. A reduction of ≥ 30% from the pre-study baseline ALT level was observed in 26 (45%) of the 58 patients, while 25 (43%) patients exhibited similar AST level reductions. The chronic hepatitis C group exhibited significant ALT and AST level reductions from 93.4 ± 51.1 IU/L to 64.6 ± 35.1 IU/L (P < 0.05) and from 94.2 ± 55.5 IU/L to 67.2 ± 35.6 IU/L (P < 0.05), respectively. A reduction of ≥ 30% from the pre-study baseline ALT level was observed in 20 (50%) of the 40 patients. ALT levels in both the combined ursodeoxycholic acid (UDCA) treatment and the UDCA uncombined groups were significantly lower after Misatol ME administration. MK615 protected hepatocytes from D-GalN-induced cytotoxicity in rats. Misatol ME decreased elevated ALT and AST levels in patients with liver disorders.
CONCLUSION: These results suggest that MK615 and Misatol ME are promising hepatoprotective agents for patients with liver disorders.
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Tada KI, Kawahara KI, Matsushita S, Hashiguchi T, Maruyama I, Kanekura T. MK615, a Prunus mume Steb. Et Zucc ('Ume') extract, attenuates the growth of A375 melanoma cells by inhibiting the ERK1/2-Id-1 pathway. Phytother Res 2011; 26:833-8. [PMID: 22076920 DOI: 10.1002/ptr.3645] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2010] [Revised: 07/14/2011] [Accepted: 07/14/2011] [Indexed: 01/13/2023]
Abstract
The Japanese apricot, a commonly consumed food called 'Ume' in Japan, has been used for a traditional Japanese medicine for centuries. MK615, an extract of compounds from 'Ume', has strong antitumorigenic and antiinflammatory effects including the induction of apoptosis and autophagy, and inhibition of cytokine production mediated via the inhibition of MAPKs signaling including ERK-1/2, JNK and p38MAPK. The inhibitor of DNA binding 1 (Id-1), a basic helix-loop-helix (bHLH) transcription factor family, is essential for DNA binding and the transcriptional regulation of various proteins that play important roles in the development, progression and invasion of tumors. In melanoma, Id-1 is constitutively expressed in the late and early stages, suggesting it as a therapeutic target in patients with melanoma. This study reports that MK615 profoundly reduced both the mRNA- and protein expression levels of Id-1 and inhibited cell growth in A375 melanoma cells. MK615 markedly inhibited the phosphorylation of ERK1/2, which is associated with Id-1 protein expression in A375 cells. Id-1-specific RNAi induced the death of A375 cells. Moreover, the expression of Bcl-2 was decreased by both MK615 and Id-1-specific RNAi in A375 cells. The results suggest that MK615 is a potential therapeutic agent for treating malignant melanoma.
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Affiliation(s)
- Ko-ichi Tada
- Department of Dermatology, Cardiovascular and Respiratory Disorders Advanced Therapeutics, Kagoshima University, Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan
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