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Azumi J, Takeda T, Shibata S, Shimada Y, Aso H, Nakamura T. The Organogermanium Compound 3-(trihydroxygermyl)propanoic Acid Exerts Anti-Inflammatory Effects via Adenosine-NR4A2 Signaling. Int J Mol Sci 2025; 26:2449. [PMID: 40141094 PMCID: PMC11941763 DOI: 10.3390/ijms26062449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 03/06/2025] [Accepted: 03/08/2025] [Indexed: 03/28/2025] Open
Abstract
We previously reported that 3-(trihydroxygermyl)propanoic acid (THGP) suppresses inflammasome activation in THP-1 cells following stimulation with lipopolysaccharide (LPS) and ATP (signals 1 and 2) by forming a complex with ATP, thereby inhibiting IL-1β secretion. Our findings also suggested that THGP inhibits inflammasome activation through mechanisms independent of ATP complex formation. This study investigated the anti-inflammatory effects of THGP on signal 1 (ATP-independent) of inflammasome activation. THGP suppressed NF-κB nuclear translocation in LPS-stimulated THP-1 cells, which reduced the mRNA expression of the proinflammatory cytokines TNF-α and IL-6, as well as IL-1β secretion. This mechanism was mediated by the formation of a THGP-adenosine complex, which inhibited adenosine degradation and subsequently activated adenosine-NR4A2 signaling. Thus, THGP exerts anti-inflammatory effects by forming a complex with adenosine, leading to adenosine-NR4A2 signaling pathway activation. This mechanism is distinct from the ATP-dependent pathway by which THGP was previously reported to function. By targeting both ATP-dependent and ATP-independent inflammasome activation pathways, THGP has potential as a broad-spectrum therapeutic agent for various inflammatory diseases.
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Affiliation(s)
- Junya Azumi
- Research Division, Asai Germanium Research Institute Co., Ltd., Suzuranoka 3-131, Hakodate 042-0958, Hokkaido, Japan; (T.T.); (S.S.); (Y.S.); (H.A.); (T.N.)
| | - Tomoya Takeda
- Research Division, Asai Germanium Research Institute Co., Ltd., Suzuranoka 3-131, Hakodate 042-0958, Hokkaido, Japan; (T.T.); (S.S.); (Y.S.); (H.A.); (T.N.)
| | - Shunya Shibata
- Research Division, Asai Germanium Research Institute Co., Ltd., Suzuranoka 3-131, Hakodate 042-0958, Hokkaido, Japan; (T.T.); (S.S.); (Y.S.); (H.A.); (T.N.)
| | - Yasuhiro Shimada
- Research Division, Asai Germanium Research Institute Co., Ltd., Suzuranoka 3-131, Hakodate 042-0958, Hokkaido, Japan; (T.T.); (S.S.); (Y.S.); (H.A.); (T.N.)
| | - Hisashi Aso
- Research Division, Asai Germanium Research Institute Co., Ltd., Suzuranoka 3-131, Hakodate 042-0958, Hokkaido, Japan; (T.T.); (S.S.); (Y.S.); (H.A.); (T.N.)
- Laboratory of Animal Health Science, Graduate School of Agricultural Science, Tohoku University, 468-1, Aramaki Aza, Aoba, Sendai 980-8578, Miyagi, Japan
| | - Takashi Nakamura
- Research Division, Asai Germanium Research Institute Co., Ltd., Suzuranoka 3-131, Hakodate 042-0958, Hokkaido, Japan; (T.T.); (S.S.); (Y.S.); (H.A.); (T.N.)
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Rafieerad A, Saleth LR, Khanahmadi S, Amiri A, Alagarsamy KN, Dhingra S. Periodic Table of Immunomodulatory Elements and Derived Two-Dimensional Biomaterials. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2406324. [PMID: 39754328 PMCID: PMC11809427 DOI: 10.1002/advs.202406324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 10/09/2024] [Indexed: 01/06/2025]
Abstract
Periodic table of chemical elements serves as the foundation of material chemistry, impacting human health in many different ways. It contributes to the creation, growth, and manipulation of functional metallic, ceramic, metalloid, polymeric, and carbon-based materials on and near an atomic scale. Recent nanotechnology advancements have revolutionized the field of biomedical engineering to tackle longstanding clinical challenges. The use of nano-biomaterials has gained traction in medicine, specifically in the areas of nano-immunoengineering to treat inflammatory and infectious diseases. Two-dimensional (2D) nanomaterials have been found to possess high bioactive surface area and compatibility with human and mammalian cells at controlled doses. Furthermore, these biomaterials have intrinsic immunomodulatory properties, which is crucial for their application in immuno-nanomedicine. While significant progress has been made in understanding their bioactivity and biocompatibility, the exact immunomodulatory responses and mechanisms of these materials are still being explored. Current work outlines an innovative "immunomodulatory periodic table of elements" beyond the periodic table of life, medicine, and microbial genomics and comprehensively reviews the role of each element in designing immunoengineered 2D biomaterials in a group-wise manner. It recapitulates the most recent advances in immunomodulatory nanomaterials, paving the way for the development of new mono, hybrid, composite, and hetero-structured biomaterials.
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Affiliation(s)
- Alireza Rafieerad
- Institute of Cardiovascular SciencesSt. Boniface Hospital Albrechtsen Research CentreBiomedical Engineering ProgramDepartment of Physiology and PathophysiologyRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaR2H2A6Canada
| | - Leena Regi Saleth
- Institute of Cardiovascular SciencesSt. Boniface Hospital Albrechtsen Research CentreBiomedical Engineering ProgramDepartment of Physiology and PathophysiologyRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaR2H2A6Canada
| | - Soofia Khanahmadi
- Institute for Molecular BiosciencesJohann Wolfgang Goethe Universität60438Frankfurt am MainGermany
| | - Ahmad Amiri
- Russell School of Chemical EngineeringThe University of TulsaTulsaOK74104USA
| | - Keshav Narayan Alagarsamy
- Institute of Cardiovascular SciencesSt. Boniface Hospital Albrechtsen Research CentreBiomedical Engineering ProgramDepartment of Physiology and PathophysiologyRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaR2H2A6Canada
| | - Sanjiv Dhingra
- Institute of Cardiovascular SciencesSt. Boniface Hospital Albrechtsen Research CentreBiomedical Engineering ProgramDepartment of Physiology and PathophysiologyRady Faculty of Health SciencesUniversity of ManitobaWinnipegManitobaR2H2A6Canada
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Li Y, Liu L, Zhang J, Lan Y, Liang Y, Wang S, Chen M, He Y, Zhang M, Wang X, Wang Y. Trace elements exposure affects the outcomes of in vitro fertilization embryo transfer, a cohort study in Northern China. J Assist Reprod Genet 2024; 41:3405-3414. [PMID: 39477908 PMCID: PMC11706816 DOI: 10.1007/s10815-024-03300-9] [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: 06/24/2024] [Accepted: 10/17/2024] [Indexed: 01/11/2025] Open
Abstract
PURPOSE With urbanization and industrialization process accelerated, humans are exposed more and more trace elements. This study aimed to explore the potential associations of trace elements with the outcomes of in vitro fertilization embryo transfer (IVF-ET). METHODS Total 181 women who underwent IVF-ET were enrolled, among which 89 women underwent fresh ET after IVF. Trace elements were measured in the serum and follicular fluid (FF) samples by inductively coupled plasma-mass spectroscopy. The associations of the levels of different trace elements with IVF-ET outcomes, including normal fertilization, high-quality embryos, and clinical pregnancy (fresh ET) were analyzed. RESULTS Twenty-five out of twenty-eight trace elements showed higher concentrations in the serum than those in the FF. Normal fertilization was positively associated with Cu and Mn in the FF. High-quality embryos was positively associated with Cu in the serum and FF, and Zn in the serum. Clinical pregnancy was positively associated with Ge in the serum, and inversely associated with Al, Ba, and Pb in the serum. Additionally, poor outcomes of IVF-ET should be noticed in women with FF level of Cu < 955.38 ng/mL, FF level of Mn < 3.42 ng/mL, serum level of Ge < 6.11 ng/mL, serum level of Al > 28.44 ng/mL, and serum level of Pb > 0.90 ng/mL. CONCLUSIONS IVF-ET outcomes were positively associated with Cu, Mn, Zn, and Ge, and inversely associated with Al and Pb. Properly controlling the exposure of relevant trace elements is necessary for patients with the need of IVF-ET.
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Affiliation(s)
- Ying Li
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, No. 251 Yaojiayuan Road, Chaoyang District, Beijing, 100026, China
| | - Lin Liu
- Key Laboratory of Digital Technology in Medical Diagnostics of Zhejiang Province, Dian Diagnostics Group Co., Ltd., Hangzhou, 310030, China
| | - Jun Zhang
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, No. 251 Yaojiayuan Road, Chaoyang District, Beijing, 100026, China
| | - Yonglian Lan
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, No. 251 Yaojiayuan Road, Chaoyang District, Beijing, 100026, China
| | - Yu Liang
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, No. 251 Yaojiayuan Road, Chaoyang District, Beijing, 100026, China
| | - Shuyu Wang
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, No. 251 Yaojiayuan Road, Chaoyang District, Beijing, 100026, China
| | - Miaomiao Chen
- Key Laboratory of Digital Technology in Medical Diagnostics of Zhejiang Province, Dian Diagnostics Group Co., Ltd., Hangzhou, 310030, China
| | - Yanbin He
- Key Laboratory of Digital Technology in Medical Diagnostics of Zhejiang Province, Dian Diagnostics Group Co., Ltd., Hangzhou, 310030, China
| | - Meng Zhang
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, No. 251 Yaojiayuan Road, Chaoyang District, Beijing, 100026, China
| | - Xin Wang
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, No. 251 Yaojiayuan Road, Chaoyang District, Beijing, 100026, China
| | - Yipeng Wang
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, No. 251 Yaojiayuan Road, Chaoyang District, Beijing, 100026, China.
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Li J, Yin W, Liang Y, Yang Z, Li L, Mai Z, Yu X, Lu Y, Zhang Z, Abula S, Wu Y, Wusiman A, Guo Q. Pomegranate flower polysaccharide improves mastitis in mice by regulating intestinal flora and restoring the blood-milk barrier. Front Pharmacol 2024; 15:1427355. [PMID: 39211783 PMCID: PMC11357933 DOI: 10.3389/fphar.2024.1427355] [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: 05/03/2024] [Accepted: 07/22/2024] [Indexed: 09/04/2024] Open
Abstract
This study explored the inhibitory effect of pomegranate flower polysaccharide (PFPS) on mastitis through in vitro and in vivo models. PFPS is a new type of polysaccharide isolated and extracted from pomegranate flowers. The result revealed that PFPS consists of GalA, Ara, and Gal, and the residues consist of 1,4-GalpA, 1,4-Galp, and 1,3,6-Galp, which contain HG-type and RG-I-type pectin structural domains. In vitro studies showed that PFPS could inhibit LPS-enhanced phagocytosis of RAW 264.7 cells and the release of IL-1β, IL-10, and TNF-α. In vivo, studies showed that PFPS improved xylene-induced mouse ear swelling and carrageenan-induced mouse paw edema by inhibiting inflammatory factors. In the mouse mastitis model, PFPS significantly improved LPS-induced inflammation and oxidative stress in mammary tissue. Intestinal flora sequencing results showed that PFPS could effectively regulate the intestinal flora of mice, reduce the relative abundance of pathogenic bacteria Oscillospira and AF12, and increase the probiotics Blautia, Parabacteroides, Allobaculum, and Clostridiaceae_Clostridium. Therefore, PFPS ultimately played a role in preventing mastitis by regulating the intestinal flora and further improving the blood-milk barrier. This study provides a scientific basis for PFPS as a potential candidate drug for the treatment of mastitis.
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Affiliation(s)
- Jianlong Li
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, China
| | - Wen Yin
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Yuan Liang
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, China
| | - Zhaoran Yang
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, China
| | - Liangliang Li
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, China
| | - Zhanhai Mai
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, China
| | - Xingjian Yu
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, United States
| | - Yabin Lu
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, China
| | - Zhenping Zhang
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, China
| | - Saifuding Abula
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, China
| | - Yi Wu
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
- College of Veterinary Medicine, Yunnan Agricultural University, Kunming, China
| | - Adelijiang Wusiman
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, China
| | - Qingyong Guo
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, China
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Takeda T, Azumi J, Masaki M, Nagasawa T, Shimada Y, Aso H, Nakamura T. Organogermanium, Ge-132, promotes the clearance of senescent red blood cells via macrophage-mediated phagocyte activation. Heliyon 2024; 10:e23296. [PMID: 38163191 PMCID: PMC10754881 DOI: 10.1016/j.heliyon.2023.e23296] [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: 04/30/2023] [Revised: 11/22/2023] [Accepted: 11/30/2023] [Indexed: 01/03/2024] Open
Abstract
Red blood cells (RBCs) are renewed in a cyclic manner. Aging RBCs are captured and degraded by phagocytic cells, and heme metabolic pigments are subsequently excreted in feces. We evaluated the effect of an organogermanium compound on RBC metabolism and found that the phagocytosis of RAW264.7 macrophage-like cells was increased by treatment with 3-(trihydroxygermyl)propanoic acid (THGP). Additionally, consumption of Ge-132 (a dehydrate polymer of THGP) changed the fecal color to bright yellow and increased the erythrocyte metabolic pigment levels and antioxidant activity in feces. These data suggest that Ge-132 may activate macrophages in the body and promote the degradation of aged RBCs. Furthermore, Ge-132 intake promoted not only increases in RBC degradation but also the induction of erythroblast differentiation in bone marrow cells. The normal hematocrit levels were maintained due to the maintenance of homeostasis, even though Ge-132 ingestion increased erythrocyte degradation. Therefore, Ge-132 enhances the degradation of senescent RBCs by macrophages. In turn, RBC production is increased to compensate for the amount of degradation, and RBC metabolism is increased.
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Affiliation(s)
- Tomoya Takeda
- Asai Germanium Research Institute Co., Ltd., 3-131, Suzuranoka, Hakodate, Hokkaido, 042-0958, Japan
| | - Junya Azumi
- Asai Germanium Research Institute Co., Ltd., 3-131, Suzuranoka, Hakodate, Hokkaido, 042-0958, Japan
| | - Mika Masaki
- Asai Germanium Research Institute Co., Ltd., 3-131, Suzuranoka, Hakodate, Hokkaido, 042-0958, Japan
| | - Takae Nagasawa
- Asai Germanium Research Institute Co., Ltd., 3-131, Suzuranoka, Hakodate, Hokkaido, 042-0958, Japan
| | - Yasuhiro Shimada
- Asai Germanium Research Institute Co., Ltd., 3-131, Suzuranoka, Hakodate, Hokkaido, 042-0958, Japan
| | - Hisashi Aso
- Laboratory of Animal Health Science, Graduate School of Agricultural Science, Tohoku University, 468-1, Aramaki aza, Aoba, Sendai, Miyagi, 980-8578, Japan
| | - Takashi Nakamura
- Asai Germanium Research Institute Co., Ltd., 3-131, Suzuranoka, Hakodate, Hokkaido, 042-0958, Japan
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Luo X, Sun J, Kong D, Lei Y, Gong F, Zhang T, Shen Z, Wang K, Luo H, Xu Y. The role of germanium in diseases: exploring its important biological effects. J Transl Med 2023; 21:795. [PMID: 37940963 PMCID: PMC10634018 DOI: 10.1186/s12967-023-04643-0] [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: 09/26/2023] [Accepted: 10/20/2023] [Indexed: 11/10/2023] Open
Abstract
With the development of organic germanium and nanotechnology, germanium serves multiple biological functions, and its potential value in biochemistry and medicine has increasingly captured the attention of researchers. In recent years, germanium has gradually gained significance as a material in the field of biomedicine and shows promising application prospects. However, there has been a limited amount of research conducted on the biological effects and mechanisms of germanium, and a systematic evaluation is still lacking. Therefore, the aim of this review is to systematically examine the application of germanium in the field of biomedicine and contribute new insights for future research on the functions and mechanisms of germanium in disease treatment. By conducting a comprehensive search on MEDLINE, EMBASE, and Web of Science databases, we systematically reviewed the relevant literature on the relationship between germanium and biomedicine. In this review, we will describe the biological activities of germanium in inflammation, immunity, and antioxidation. Furthermore, we will discuss its role in the treatment of neuroscience and oncology-related conditions. This comprehensive exploration of germanium provides a valuable foundation for the future application of this element in disease intervention, diagnosis, and prevention.
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Affiliation(s)
- Xiao Luo
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, 650032, China
- Department of Gastrointestinal and Hernia Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Jiaxue Sun
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, 650032, China
- Department of Gastrointestinal and Hernia Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Deshenyue Kong
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, 650032, China
- Department of Gastrointestinal and Hernia Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Yi Lei
- Department of Gastrointestinal and Hernia Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Fangyou Gong
- Department of Gastrointestinal and Hernia Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Tong Zhang
- Department of Gastrointestinal and Hernia Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Zongwen Shen
- Department of Gastrointestinal and Hernia Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Kunhua Wang
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, 650032, China.
- Yunnan University, Kunming, 650032, China.
| | - Huayou Luo
- Department of Gastrointestinal and Hernia Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China.
| | - Yu Xu
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, 650032, China.
- Department of Gastrointestinal and Hernia Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China.
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Menchikov LG, Popov AV. Physiological Activity of Trace Element Germanium including Anticancer Properties. Biomedicines 2023; 11:1535. [PMID: 37371629 PMCID: PMC10295216 DOI: 10.3390/biomedicines11061535] [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: 04/27/2023] [Revised: 05/20/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023] Open
Abstract
Germanium is an essential microelement, and its deficiency can result in numerous diseases, particularly oncogenic conditions. Consequently, water-soluble germanium compounds, including inorganic and coordination compounds, have attracted significant attention due to their biological activity. The review analyzes the primary research from the last decade related to the anticancer activity of germanium compounds. Furthermore, the review clarifies their actual toxicity, identifies errors and misconceptions that have contributed to the discrediting of their biological activity, and briefly suggests a putative mechanism of germanium-mediated protection from oxidative stress. Finally, the review provides clarifications on the discovery history of water-soluble organic germanium compounds, which was distorted and suppressed for a long time.
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Affiliation(s)
- Leonid G. Menchikov
- N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prosp. 47, 119991 Moscow, Russia;
| | - Anatoliy V. Popov
- Department of Radiology, University of Pennsylvania, 3620 Hamilton Walk, Anatomy Chemistry Building, Rm 317, Philadelphia, PA 19104, USA
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Azumi J, Takeda T, Shimada Y, Zhuang T, Tokuji Y, Sakamoto N, Aso H, Nakamura T. Organogermanium THGP Induces Differentiation into M1 Macrophages and Suppresses the Proliferation of Melanoma Cells via Phagocytosis. Int J Mol Sci 2023; 24:ijms24031885. [PMID: 36768216 PMCID: PMC9915250 DOI: 10.3390/ijms24031885] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 01/12/2023] [Accepted: 01/15/2023] [Indexed: 01/21/2023] Open
Abstract
M1 macrophages are an important cell type related to tumor immunology and are known to phagocytose cancer cells. In previous studies, the organogermanium compound poly-trans-[(2-carboxyethyl)germasesquioxane] (Ge-132) and its hydrolysate, 3-(trihydroxygermyl) propanoic acid (THGP), have been reported to exert antitumor effects by activating NK cells and macrophages through the induction of IFN-γ activity in vivo. However, the detailed molecular mechanism has not been clarified. In this study, we found that macrophages differentiate into the M1 phenotype via NF-κB activation under long-term culture in the presence of THGP in vitro and in vivo. Furthermore, long-term culture with THGP increases the ability of RAW 264.7 cells to suppress B16 4A5 melanoma cell proliferation. These mechanisms indicate that THGP promotes the M1 polarization of macrophages and suppresses the expression of signal-regulatory protein alpha (SIRP-α) in macrophages and CD47 in cancers. Based on these results, THGP may be considered a new regulatory reagent that suppresses tumor immunity.
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Affiliation(s)
- Junya Azumi
- Research Division, Asai Germanium Research Institute Co., Ltd., Suzuranoka 3-131, Hakodate 042-0958, Japan
| | - Tomoya Takeda
- Research Division, Asai Germanium Research Institute Co., Ltd., Suzuranoka 3-131, Hakodate 042-0958, Japan
| | - Yasuhiro Shimada
- Research Division, Asai Germanium Research Institute Co., Ltd., Suzuranoka 3-131, Hakodate 042-0958, Japan
| | - Tao Zhuang
- Laboratory of Animal Health Science, Graduate School of Agricultural Science, Tohoku University, 468-1 Aoba, Aramaki, Aoba-ku, Sendai 980-8572, Japan
| | - Yoshihiko Tokuji
- Department of Human Sciences, Obihiro University of Agriculture and Veterinary Medicine, Nishi 2 Sen, Inada, Obihiro 080-8555, Japan
| | - Naoya Sakamoto
- Isotope Imaging Laboratory, Creative Research Institution, Hokkaido University, Kita 10 Jo-Nishi 5, Kita, Sapporo 060-0810, Japan
| | - Hisashi Aso
- Laboratory of Animal Health Science, Graduate School of Agricultural Science, Tohoku University, 468-1 Aoba, Aramaki, Aoba-ku, Sendai 980-8572, Japan
| | - Takashi Nakamura
- Research Division, Asai Germanium Research Institute Co., Ltd., Suzuranoka 3-131, Hakodate 042-0958, Japan
- Correspondence: ; Tel.: +81-138-32-0032; Fax: +81-138-31-0132
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Azumi J, Shimada Y, Takeda T, Aso H, Nakamura T. The Organogermanium Compound 3-(Trihydroxygermyl) Propanoic Acid (THGP) Suppresses Inflammasome Activation Via Complexation with ATP. Int J Mol Sci 2022; 23:13364. [PMID: 36362152 PMCID: PMC9654755 DOI: 10.3390/ijms232113364] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 10/29/2022] [Accepted: 10/29/2022] [Indexed: 11/10/2023] Open
Abstract
Inflammasome activity is a key indicator of inflammation. The inflammasome is activated by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), which activate the p38-NF-κB pathway and promote IL-1β transcription (signaling step 1). Next, extracellular adenosine triphosphate (ATP) activates the inflammasome (a protein complex consisting of a signal recognition protein, an adapter protein, and Caspase-1) and secretion of inflammatory cytokines such as IL-1β (signaling step 2). Inflammasome activation causes excessive inflammation, leading to inflammasome-active diseases such as atherosclerosis and type 2 diabetes. A hydrolysate of the organogermanium compound Ge-132, 3-(Trihydroxygermyl) propanoic acid (THGP) can form a complex with a cis-diol structure. We investigated the inhibitory effect of THGP on inflammasome activity in human THP-1 monocytes. THGP inhibited IL-1β secretion and caspase-1 activation (signaling step 2) in an ATP-dependent manner. On the other hand, THGP did not suppress IL-1β secretion induced by only lipopolysaccharide (LPS) stimulation. In addition, as IL-6 is an ATP-independent inflammatory cytokine, THGP did not decrease its secretion. THGP also suppressed pyroptosis, which is a caspase-1 activity-dependent form of cell death. Therefore, THGP is expected to become a new therapeutic or prophylactic agent for inflammasome-associated diseases.
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Affiliation(s)
- Junya Azumi
- Asai Germanium Research Institute Co., Ltd. Suzuranoka 3-131, Hakodate 042-0958, Hokkaido, Japan
| | - Yasuhiro Shimada
- Asai Germanium Research Institute Co., Ltd. Suzuranoka 3-131, Hakodate 042-0958, Hokkaido, Japan
| | - Tomoya Takeda
- Asai Germanium Research Institute Co., Ltd. Suzuranoka 3-131, Hakodate 042-0958, Hokkaido, Japan
| | - Hisashi Aso
- Asai Germanium Research Institute Co., Ltd. Suzuranoka 3-131, Hakodate 042-0958, Hokkaido, Japan
- Laboratory of Animal Health Science, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Miyagi, Japan
| | - Takashi Nakamura
- Asai Germanium Research Institute Co., Ltd. Suzuranoka 3-131, Hakodate 042-0958, Hokkaido, Japan
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Exploring the Action Mechanism of the Active Ingredient of Quercetin in Ligustrum lucidum on the Mouse Mastitis Model Based on Network Pharmacology and Molecular Biology Validation. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:4236222. [PMID: 35722145 PMCID: PMC9205729 DOI: 10.1155/2022/4236222] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 04/26/2022] [Indexed: 11/17/2022]
Abstract
Aim The aim of this study is to explore the mechanism of action of quercetin, the main active anti-inflammatory component of Ligustrum lucidum, in the prevention and treatment of mastitis. Methods Prediction of the main active ingredients and key anti-inflammatory targets of Ligustrum lucidum using a network pharmacology platform and molecular biology validation of the results. Observation of histopathological changes in the mouse mammary gland by hematoxylin-eosin staining(H&E) method, quantitative real-time PCR(qPCR), and Western blot (WB) to detect the expression levels of relevant inflammatory factors mRNA and protein. Results A total of 7 active ingredients and 42 key targets were obtained from the network pharmacological analysis of Ligustrum lucidum, with quercetin as the main core ingredient and tumor necrosis factor(TNF), serine threonine protein kinase1(AKT1), and interleukin6(IL6) as the core targets; H&E results showed that pathological changes were reduced to different degrees in the dose group compared to the model group. The qPCR results showed that the relative expression of TNF and IL6 mRNA in the high dose group on day 3 and the high and medium dose groups on day 7 were not significantly different compared with the blank group (P > 0.05), and the difference between the dose groups on day 5 was significant (P < 0.05). WB results showed that the difference in nuclear factor kappa-B(NF-κB) protein expression in the medium and low dose groups on day 7 was significant compared with the blank group (P < 0.05), the difference in 5 and 7 days, significant differences in AKT1 protein expression between the middle and low dose groups (P < 0.05), nonsignificant differences in the TNF protein expression between the high dose groups on day 7 (P > 0.05), and significant differences in the IL6 protein expression between the middle and low dose groups on days 3 and 7 (P < 0.05). Conclusion Quercetin, the main active ingredient of Ligustrum lucidum, may act in the prevention and treatment of mastitis by inhibiting the expression of inflammatory factors in phosphoinositol 3-kinase(PI3K)-AKT and NF-κB signaling pathways and showa a significant dose-dependent effect. This study provides theoretical basis and clues for the control of mastitis in dairy cows.
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Kostoff RN, Briggs MB, Shores DR. Treatment repurposing for inflammatory bowel disease using literature-related discovery and innovation. World J Gastroenterol 2020; 26:4889-4899. [PMID: 32952337 PMCID: PMC7476176 DOI: 10.3748/wjg.v26.i33.4889] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 05/21/2020] [Accepted: 08/27/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) incidence has been increasing steadily, most dramatically in the Western developed countries. Treatment often includes lifelong immunosuppressive therapy and surgery. There is a critical need to reduce the burden of IBD and to discover medical therapies with better efficacy and fewer potential side-effects. Repurposing of treatments originally studied in other diseases with similar pathogenesis is less costly and time intensive than de novo drug discovery. This study used a treatment repurposing methodology, the literature-related discovery and innovation (LRDI) text mining system, to identify potential treatments (developed for non-IBD diseases) with sufficient promise for extrapolation to treatment of IBD. By searching for desirable patterns of twenty key biomarkers relevant to IBD (e.g., inflammation, reactive oxygen species, autophagy, barrier function), the LRDI-based query retrieved approximately 9500 records from Medline. The most recent 350 records were further analyzed for proof-of-concept. Approximately 18% (64/350) met the criteria for discovery (not previously studied in IBD human or animal models) and relevance for application to IBD treatment. Many of the treatments were compounds derived from herbal remedies, and the majority of treatments were being studied in cancer, diabetes, and central nervous system disease, such as depression and dementia. As further validation of the search strategy, the query identified ten treatments that have just recently begun testing in IBD models in the last three years. Literature-related discovery and innovation text mining contains a unique search strategy with tremendous potential to identify treatments for repurposing. A more comprehensive query with additional key biomarkers would have retrieved many thousands more records, further increasing the yield of IBD treatment repurposing discovery.
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Affiliation(s)
- Ronald Neil Kostoff
- School of Public Policy, Georgia Institute of Technology, Gainesville, VA 20155, United States
| | | | - Darla Roye Shores
- The Hopkins Resource for Intestinal Vitality and Enhancement, the Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
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