|Year : 2019 | Volume
| Issue : 25 | Page : 28-33
The potential of xanthones as a therapeutic option in macrophage-associated inflammatory diseases
Ida May Jen Ng, Caroline Lin Lin Chua
School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Selangor, Malaysia
|Date of Web Publication||3-Apr-2019|
Dr. Caroline Lin Lin Chua
School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya 47500, Selangor
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Xanthones are well known for their significant biological activities and can be found in many herbal medicines. These compounds have the ability to regulate various inflammatory activities and signaling pathways in immune cells, especially macrophages. Macrophages are innate immune cells that can either fuel or dampen an inflammatory response depending on their activation states and play an active role in the development of inflammatory diseases such as atherosclerosis, arthritis, cancer, and diabetes. Many traditional medicines used as a remedy for these diseases contain xanthones, and their bioactivities may be partially attributed to their ability in regulating macrophage responses. In this review, we discuss the in vitro and in vivo findings on the effects of xanthones on different macrophage immune functions including nitric oxide and cytokine production, migration, polarization, and phagocytosis. Their specific modes of action are highlighted whenever known. We also discuss the potential and challenges in using xanthones as a therapeutic option in various inflammatory diseases. It is hoped that this review can pave the way for future research that focuses on developing xanthones as specific macrophage-targeted therapeutics.
Keywords: Anti-inflammatory, inflammation, macrophages, polarization, therapeutics, xanthones
|How to cite this article:|
Ng IM, Chua CL. The potential of xanthones as a therapeutic option in macrophage-associated inflammatory diseases. Phcog Rev 2019;13:28-33
|How to cite this URL:|
Ng IM, Chua CL. The potential of xanthones as a therapeutic option in macrophage-associated inflammatory diseases. Phcog Rev [serial online] 2019 [cited 2019 Apr 23];13:28-33. Available from: http://www.phcogrev.com/text.asp?2019/13/25/28/255390
| Introduction|| |
Xanthones are secondary metabolites that can be isolated from many higher plant, fungi, and lichen families. A previous study reported that from 168 species of herbal medicinal plants investigated between 1988 and 2016, 24 families were shown to contain xanthones. They have been reported to be the main constituent of many traditional medicines, such as Securidaca inappendiculata Hassk, which is used to treat rheumatoid arthritis and the yellow gum-resin secreted from Garcinia hanburyi, which is used to treat infected wound, pain, and edema. Various health supplements containing xanthones are available in the market, and the most common source of xanthones in these products is from either the juice or extract of Garcinia mangostana L., which is also known as the mangosteen fruit in Southeast Asia. A few studies investigating the effects of consuming mangosteen products have reported beneficial effects, including having increased antioxidant capacity and reduced levels of C-reactive protein, which is an inflammatory marker.,,
| Xanthone Research|| |
Each year, discoveries of new xanthones isolated from natural products continue to be reported in journal articles. However, not many of these discoveries have been followed through for drug development, given that there is limited data available on their detailed pharmacological actions, cellular specificity, molecular targets, and bioavailability. Each xanthone molecule has a simple three-ring skeleton. They differ from one another regarding the type and position of substituents present on the core ring, which contribute to their distinct pharmacological properties. A previous study classified xanthones from natural sources into six groups, which are the simple xanthones, xanthone glycosides, prenylated xanthones, xanthonolignoids, bisxanthones, and miscellaneous xanthones, which comprise xanthones with substituents other than the aforementioned ones. Knowledge on xanthone structures has led to the design of a few potential therapeutics that are undergoing clinical trials as cancer treatment, such as 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and gambogic acid. Advances in the field of medicinal chemistry have also enabled structural modifications to be made on xanthones isolated from natural product to create xanthone derivatives with better pharmacological properties such as increased aqueous solubility and cytotoxicity effect against cancer cells.
Majority of the available literature have so far reviewed the role of xanthones as chemopreventive and chemotherapeutic agents., This is because xanthones have been shown to exert cytotoxic effects on various cancer cell lines without apparent toxicity on non-cancer cells, potentiating their use as cancer drugs. Other studies have reviewed the antioxidant, antimicrobial, and cardiovascular protective effects of xanthones, but so far, none had specifically reviewed on their ability to modulate immune responses. Many related studies on the effects of xanthones on immune responses have been performed using mice and human macrophage models. Specific macrophage subpopulations have been linked to the development of various diseases that are associated with chronic inflammation. In view of this, there is now considerable interest in designing specific therapeutics or compounds that can modulate the functions of macrophages toward desirable clinical outcomes. In this review, we aim to highlight the specific effects of xanthones on various macrophage functions in distinct macrophage models and their underlying mechanisms, based on in vitro and in vivo studies. Their potential use as immunomodulatory agents that specifically target macrophage functions to alter disease outcomes, and potential challenges, will also be discussed.
| Macrophage and Macrophage-Targeted Therapies|| |
Macrophages are heterogeneous in nature, where each organ has its own specialized resident macrophage population with distinct morphology and function. Depending on the stimuli that they receive from the environment, they can be further activated into either pro-inflammatory (M1) or anti-inflammatory (M2) macrophages. The physiological functions of macrophages include recognizing and killing pathogens, initiating and promoting the resolution of an inflammation, presenting antigens to T-cells, and clearing of host apoptotic cells. Due to their major involvement in chronic inflammation that manifests in various diseases, they have become the main target for new anti-inflammatory therapeutics. Various macrophage-targeting approaches have been designed, such as reducing their production of inflammatory mediators, decreasing macrophage recruitment through disrupting chemokine gradient, and changing their polarization status between M1 and M2. Macrophage-targeted therapy is a relatively new field of research and a few limitations to currently available therapies have been identified, including the development of resistance to the drugs and high cost. Thus, it is important to find new sources of therapeutics, such as bioactive compounds from natural sources, which can potentially be developed into macrophage-targeted therapies in the future.
| Molecular Effects of Xanthones on Macrophage Functions|| |
Nitric oxide production
Nitric oxide (NO) is produced by many cell types including endothelial cells and macrophages. Pro-inflammatory stimuli such as cytokines and lipopolysaccharide can significantly enhance the production of this enzyme, thus NO levels are usually upregulated during infection and inflammation. Excessive and sustained NO production has been associated with the development of Alzheimer's disease, inflammatory bowel disease, neurodegeneration, and enhanced tumor growth. Many xanthones and their derivatives were shown to have low-to-intermediate effects in the inhibition of NO production by in different macrophage models, including human J774 macrophages, RAW264.7 murine macrophages, and BV2 human microglia cells (brain macrophages).,,,, These compounds include dulcisxanthone B, 5,9-dihydroxy-8-methoxy-2,2-dimethyl-7-(3-methyl-but-2-enyl)-2H, 6H-pyrano- [3,2b]-xanthone, α-mangostin, cudratricusxanthone A, and 1, 3, 6, 7-tetrahydroxy-8-prenylxanthone (TPX) that were isolated from Cratoxylum, Garcinia, and Cudrania plant genus [Table 1].
Despite their potential as potent NO inhibitors, only few studies have studied the underlying mechanisms of inhibition in detail, mostly in animal cell models. A few naturally occurring xanthones have been reported to suppress inducible NO synthase (iNOS) production, which is one of the main enzymes involved in NO production by macrophages. Mangiferin, α-mangostin, β-mangostin, garcinoxanthone B, and 1, 3, 5, 7-Tetrahydroxy-8-isoprenylxanthone were shown to specifically inhibit iNOS production in RAW 264.7 macrophages.,,,, In addition, it was reported that β-mangostin and 1, 3, 5, 7-Tetrahydroxy-8-isoprenylxanthone can reduce prostaglandin E2 (PGE2) production by macrophages without affecting their viability., PGE2 is an enzyme that can stimulate iNOS activity to promote NO production.
Macrophages can produce high levels of pro- and anti-inflammatory cytokines through various signaling pathways. Activated kinase proteins in the mitogen-activated protein kinases pathway can trigger a signaling cascade that results in the activation and translocation of nuclear factor-kappa B (NF-κB) into the nucleus to induce the transcription of pro-inflammatory cytokine genes. NF-κB activation is central to the pathogenesis of various chronic diseases, including asthma, rheumatoid arthritis, and atherosclerosis, thus many potential anti-inflammatory compounds were tested for their ability to inhibit its activation.
Many studies have claimed that xanthones are anti-inflammatory because they can decrease pro-inflammatory cytokine production by macrophages [Table 2]. However, the underlying mechanisms of action are only known for a few of these compounds. Mangiferin, which is a natural phenolic xanthonoid, is a potent inhibitor of NF-κB. Mangiferin at 10 μg/mL was shown to completely inhibit tumor necrosis factor-alpha (TNF-α)-induced activation of NF-κB in U-937 human macrophages. Pretreatment of U-937 macrophages with α- and γ-mangostin was reported to inhibit lipopolysaccharide-induced phosphorylation of MEK, c-Jun N-terminal kinases, signal-regulated kinases and p38 and attenuated the activation of their downstream targets. The same study reported that γ-mangostin was able to prevent IκB-α degradation, which is the inhibitory subunit of NF-κB that needs to be degraded before NF-κB activation. Mangiferin was also shown to inactivate NLRP3 inflammasome in RAW264.7 cells, which is a complex required for the pro-inflammatory IL-1 β secretion. Excessive IL-1 β production has been associated with the development of neuroinflammation and autoimmune diseases such as rheumatoid arthritis. Another compound, cudratricusxanthone A, was reported to inhibit the phosphorylation of the inhibitory subunit IκB-α in a microglial cell model.
Apart from directly suppressing the production of pro-inflammatory cytokines, xanthones may also exert indirect effects to mediate an anti-inflammatory response. DMXAA can activate interferon regulatory factor 3 signaling pathway in mice peritoneal macrophages, which promote interferon-beta (IFN-β) production. IFN-β has been used to treat multiple sclerosis because of its ability to dampen an immune response. Cudratricusxanthone A can induce the expression of heme oxygenase-1 in RAW264.7 mice macrophages, which led to the suppression of pro-inflammatory cytokine production. An interesting observation from previous literature was that the effects of xanthones on cytokine production by macrophages are dependent on macrophage type. For example, α-mangostin has also been shown to promote instead of suppressing the production of TNF-α by monocyte-derived human macrophages. In addition, DMXAA promoted the secretion of a plethora of cytokines from tumor-associated macrophages, including the pro-inflammatory IFN-γ and TNF-α.
Macrophages can migrate in response to chemokines and cytokines to the site of tissue damage. While macrophage migration is crucial to allow the clearance of pathogens and initiation of tissue repair, the recruitment of pathological macrophage subpopulations have also been implicated in the development of diseases such as neuroinflammatory diseases, atherosclerosis, and diabetes. Xanthones can prevent the accumulation of macrophages through several mechanisms [Table 3]. TPX from pericarps of G. mangostana was shown to inhibit mRNA expression of monocyte chemoattractant protein-1 (MCP-1), MIP-1α, CXCL10, and CX3CL1 in RAW264.7 macrophages. The aforementioned molecules are chemotactic molecules that can attract lymphocytes, monocytes, and macrophages. TPX and α-mangostin also inhibited migration of macrophages toward adipocyte-conditioned media,, thus has potential in preventing macrophage accumulation in adipose tissues in obesity and diabetes. α-mangostin and γ-mangostin were reported to inhibit expression of CXCL10 in U937 human macrophage model, while DMXAA was shown to inhibit MCP-1 and CXCL10 expression in mice peritoneal and bone marrow-derived macrophages. A few synthesized xanthones have been shown to inhibit the expression of intercellular adhesion molecule-1 (ICAM-1) on endothelial cells, which is a molecule required for transmigration of immune cells across the endothelium. For example, 1,4-dihydroxyxanthone at 65 μg/mL was shown to inhibit up to 86% of ICAM-1 expression. Decreased ICAM-1 expression may block the transmigration of monocytes, which are the precursors of tissue macrophages, thus reduce the number of macrophages in pathological lesions. The authors proposed that the effect on ICAM-1 expression may be mediated by the hydroxy substitution on the xanthone nucleus, potentially because they can be oxidized to form stable quinonoid.
|Table 3: The effects of xanthones on macrophage chemokine production and migration|
Click here to view
Macrophages can be polarized into two different activation states, resulting in either M1 or M2 subpopulations. M1 are generally pro-inflammatory in nature and are involved in infection clearance, while M2 are primarily involved in tissue repair. Apart from performing their homeostasis functions, different macrophage subpopulations have been associated with pathology in various diseases. For example, in atherosclerosis, M1 macrophages were reported to contribute to plaque progression, while M2 macrophages participate in plaque regression. Thus, various therapies to decrease macrophage infiltration and to change their polarization status have been designed, in the hope of altering the course of disease progression.
There are only a few studies which investigated the effects of xanthones on macrophage polarization. A previous study found that treatment of mice with TPX from G. mangostana led to polarization of macrophages in adipose tissue toward M2 phenotype. Increased numbers of M1 macrophages in adipose tissue can promote inflammation, leading to insulin resistance in obesity. They reported increased mRNA levels of ARG1 and CD206 and decreased levels of CD11c, which are characteristics of M2 macrophages. Similarly, α-mangostin was also shown to increase CD206 mRNA levels in macrophages from white adipose tissue of obese mice, with a corresponding decrease in CD11c levels. In another study, mangiferin isolated from leaves of Mangifera indica Linn. at 100 μmol/L was reported to decrease the expression of M1 macrophage markers CD80 and CD86, in addition to reducing expression of interferon regulatory factor 5, which is a transcription factor that can activate pro-inflammatory genes in macrophages [Figure 1]. In contrast, DMXAA, which is an antivascular agent that can prevent tumor development, was reported to polarize macrophage activation status from M2 to M1 phenotype. M2 macrophages are implicated in tumor progression, by promoting growth of tumor and its dissemination. Gambogic acid, which is a xanthonoid, was reported to decrease the expression of IL-6 by RANKL-induced M1 macrophages, which subsequently inhibited their differentiation into osteoclasts. Osteoclasts are involved in bone resorption, leading to the breakdown of bone tissues and causing pathology in diseases such as multiple myeloma.
Macrophage phagocytosis ability
Macrophages are professional phagocytes responsible for eliminating pathogens, tumor cells, and cellular debris. A previous study has reported enhanced phagocytosis of ascitic fibrosarcoma cells by peritoneal macrophages from mangiferin-treated mice. Similarly, in another study, mangiferin was shown to enhance phagocytosis ability of murine peritoneal macrophages when stimulated with various phagocytic targets such as latex beads, red blood cells, and tumor cells. It remains to be investigated if xanthones can enhance the phagocytosis of pathogenic microorganisms. If proven, hence, xanthones have the potential to be developed into antimicrobial agents that are not only cytotoxic against various pathogens, but also have the ability to enhance phagocytosis by macrophages to accelerate infection clearance.
In vivo studies
While xanthones have been shown to possess various bioactive properties in vitro, it is of greater interest to investigate if these effects can be replicated in vivo in various disease settings. In doxorubicin-mediated neuroinflammation model, mangiferin was reported to reduce the brain damage by reducing TNF-α production and oxidative stress. In adjuvant-induced arthritis model, xanthones, particularly 1, 7-dihydroxyl-3-4-dimethoxyl-xanthone, showed good potential as antirheumatic agent due to their potent anti-inflammatory effects in downregulating IL-1, TNF-α, and MCP-1 production. α-mangostin and γ-mangostin were able to inhibit tumor growth in experimental colon cancer and mammary cancer. In experimental gastric ulcer, xanthones such as 7-preniljacareubin and 1, 3, 5, 6-tetrahydroxy xanthone were reported to exert anti-ulcer activity through their ability to promote anti-oxidative effects and prevent TNF-α production. However, in experimental ulcerative colitis, it was reported that xanthones may exacerbate the condition, leading to greater colonic inflammation and injury. Further studies are required to understand if any of these effects can be partly attributed to xanthones' role in modulating macrophage functions.
| Conclusion|| |
Xanthones are a class of compounds with extensive and promising pharmacological properties. Their ability to modulate macrophage functions suggest that they may be useful in treating various diseases where macrophages have been implicated in causing pathology. In addition, xanthones with proven bioactivities such as anti-inflammatory effects may be useful as a therapeutic option in more than one inflammatory disease due to their general effects on macrophage function. However, to fully harness the therapeutic potential of xanthones, there are several areas of future research that require attention. Apart from screening xanthones for their potential bioactivities, studies should also focus on unraveling the exact biological targets of different xanthone compounds and mechanisms underlying these bioactivities. The functional groups on the xanthone skeleton that contribute to their functional activity should be compared and studied in detail. For example, it was proposed that the position of hydroxyl group within the xanthones from Cudrania tricuspidata and the presence of a catechol moiety may determine its ability to inhibit NO production. In addition, there is a need to investigate the bioavailability of specific xanthones in vivo given their poor aqueous solubility and to find ways to delivery xanthones to target host cells. For example, nanoencapsulation of xanthone and 3-methoxyxanthone in poly (DL-lactide-co-glycolide) significantly enhanced the inhibition of NO production by macrophages, with approximately 74% increase in inhibition. Finally, because macrophages exist in different activation states and there are clear differences between human and mice macrophages, there is a need to carefully select and justify the use of each macrophage model when studying the effects of xanthones on macrophages.
The authors would like to acknowledge funding support by Ministry of Higher Education Malaysia (MoHE) Fundamental Research Grant Scheme (FRGS/1/2015/SKK08/TAYLOR/03/2) and Taylor's University Research Grant Scheme (TRGS/MFS/1/2014/SBS/007).
Financial support and sponsorship
Ministry of Higher Education (MoHE) Malaysia Fundamental Research Grant Scheme (FRGS/1/2015/SKK08/TAYLOR/03/2) and Taylor's University Research Grant Scheme (TRGS/MFS/1/2014/SBS/007).
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ruan J, Zheng C, Liu Y, Qu L, Yu H, Han L, et al.
Chemical and biological research on herbal medicines rich in xanthones. Molecules 2017;22. pii: E1698.
Zuo J, Xia Y, Mao KJ, Li X, Chen JW. Xanthone-rich dichloromethane fraction of Securidaca inappendiculata
, the possible antirheumatic material base with anti-inflammatory, analgesic, and immunodepressive effects. Pharm Biol 2014;52:1367-73.
Jia B, Li S, Hu X, Zhu G, Chen W. Recent research on bioactive xanthones from natural medicine: Garcinia hanburyi
. AAPS PharmSciTech 2015;16:742-58.
Xie Z, Sintara M, Chang T, Ou B. Daily consumption of a mangosteen-based drink improves in vivo
antioxidant and anti-inflammatory biomarkers in healthy adults: A randomized, double-blind, placebo-controlled clinical trial. Food Sci Nutr 2015;3:342-8.
Xie Z, Sintara M, Chang T, Ou B. Functional beverage of Garcinia mangostana
(mangosteen) enhances plasma antioxidant capacity in healthy adults. Food Sci Nutr 2015;3:32-8.
Udani JK, Singh BB, Barrett ML, Singh VJ. Evaluation of mangosteen juice blend on biomarkers of inflammation in obese subjects: A pilot, dose finding study. Nutr J 2009;8:48.
Negi JS, Bisht VK, Singh P, Rawat MS, Joshi GP. Naturally occurring xanthones: Chemistry and biology. J Appl Chem 2013;2013:1-9.
Daei Farshchi Adli A, Jahanban-Esfahlan R, Seidi K, Samandari-Rad S, Zarghami N. An overview on Vadimezan (DMXAA): The vascular disrupting agent. Chem Biol Drug Des 2018;91:996-1006.
Yang LJ, Chen Y. New targets for the antitumor activity of gambogic acid in hematologic malignancies. Acta Pharmacol Sin 2013;34:191-8.
Shagufta IA. Recent insight into the biological activities of synthetic xanthone derivatives. Eur J Med Chem 2016;116:267-80.
Na Y. Recent cancer drug development with xanthone structures. J Pharm Pharmacol 2009;61:707-12.
Shan T, Ma Q, Guo K, Liu J, Li W, Wang F, et al.
Xanthones from mangosteen extracts as natural chemopreventive agents: Potential anticancer drugs. Curr Mol Med 2011;11:666-77.
Panda SS, Chand M, Sakhuja R, Jain SC. Xanthones as potential antioxidants. Curr Med Chem 2013;20:4481-507.
Riscoe M, Kelly JX, Winter R. Xanthones as antimalarial agents: Discovery, mode of action, and optimization. Curr Med Chem 2005;12:2539-49.
Jiang DJ, Dai Z, Li YJ. Pharmacological effects of xanthones as cardiovascular protective agents. Cardiovasc Drug Rev 2004;22:91-102.
Parisi L, Gini E, Baci D, Tremolati M, Fanuli M, Bassani B, et al.
Macrophage polarization in chronic inflammatory diseases: Killers or builders? J Immunol Res 2018;2018:8917804.
Mantovani A, Vecchi A, Allavena P. Pharmacological modulation of monocytes and macrophages. Curr Opin Pharmacol 2014;17:38-44.
Quail DF, Joyce JA. Molecular pathways: Deciphering mechanisms of resistance to macrophage-targeted therapies. Clin Cancer Res 2017;23:876-84.
Aliev G, Palacios HH, Lipsitt AE, Fischbach K, Lamb BT, Obrenovich ME, et al.
Nitric oxide as an initiator of brain lesions during the development of Alzheimer disease. Neurotox Res 2009;16:293-305.
Kolios G, Valatas V, Ward SG. Nitric oxide in inflammatory bowel disease: A universal messenger in an unsolved puzzle. Immunology 2004;113:427-37.
Liu B, Gao HM, Wang JY, Jeohn GH, Cooper CL, Hong JS, et al.
Role of nitric oxide in inflammation-mediated neurodegeneration. Ann N Y Acad Sci 2002;962:318-31.
Coulter JA, McCarthy HO, Xiang J, Roedl W, Wagner E, Robson T, et al.
Nitric oxide – A novel therapeutic for cancer. Nitric Oxide 2008;19:192-8.
Boonnak N, Karalai C, Chantrapromma S, Ponglimanont C, Fun HK, Kanjana-Opas A, et al
. Bioactive prenylated xanthones and anthraquinones from Cratoxylum formosum
ssp. pruniflorum. Tetrahedron 2006;62:8850-9.
Wahyuni FS, Ali DA, Lajis NH, Dachriyanus. Anti-inflammatory activity of isolated compounds from the stem bark of Garcinia cowa
Roxb. Pharmacogn J 2017;9:55-7.
Yoon CS, Kim DC, Quang TH, Seo J, Kang DG, Lee HS, et al.
Aprenylated xanthone, cudratricusxanthone A, isolated from Cudrania tricuspidata
inhibits lipopolysaccharide-induced neuroinflammation through inhibition of NF-κB and p38 MAPK pathways in BV2 microglia. Molecules 2016;21. pii: E1240.
Li D, Liu Q, Sun W, Chen X, Wang Y, Sun Y, et al.
1,3,6,7-tetrahydroxy-8-prenylxanthone ameliorates inflammatory responses resulting from the paracrine interaction of adipocytes and macrophages. Br J Pharmacol 2018;175:1590-606.
Zhang DD, Zhang H, Lao YZ, Wu R, Xu JW, Murad F, et al.
Anti-inflammatory effect of 1,3,5,7-tetrahydroxy-8-isoprenylxanthone isolated from twigs of Garcinia esculenta
on stimulated macrophage. Mediators Inflamm 2015;2015:350564.
Tewtrakul S, Wattanapiromsakul C, Mahabusarakam W. Effects of compounds from Garcinia mangostana
on inflammatory mediators in RAW264.7 macrophage cells. J Ethnopharmacol 2009;121:379-82.
Shin JS, Noh YS, Kim DH, Cho YW, Lee KT. Mangiferin isolated from the rhizome of Anemarrhena asphodeloides
inhibits the LPS-induced nitric oxide and prostagladin E2 via the NF-κB inactivation in inflammatory macrophages. Nat Prod Sci 2008;14:206-13.
Syam S, Bustamam A, Abdullah R, Sukari MA, Hashim NM, Mohan S, et al.
b mangostin suppress LPS-induced inflammatory response in RAW 264.7 macrophages in vitro
and carrageenan-induced peritonitis in vivo
. J Ethnopharmacol 2014;153:435-45.
Liu Q, Li D, Wang A, Dong Z, Yin S, Zhang Q, et al.
Nitric oxide inhibitory xanthones from the pericarps of Garcinia mangostana
. Phytochemistry 2016;131:115-23.
Lawrence T. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 2009;1:a001651.
Gutierrez-Orozco F, Chitchumroonchokchai C, Lesinski GB, Suksamrarn S, Failla ML. A-mangostin: Anti-inflammatory activity and metabolism by human cells. J Agric Food Chem 2013;61:3891-900.
Jeong GS, Lee DS, Kim YC. Cudratricusxanthone A from Cudrania tricuspidata
suppresses pro-inflammatory mediators through expression of anti-inflammatory heme oxygenase-1 in RAW264.7 macrophages. Int Immunopharmacol 2009;9:241-6.
Bumrungpert A, Kalpravidh RW, Chuang CC, Overman A, Martinez K, Kennedy A, et al.
Xanthones from mangosteen inhibit inflammation in human macrophages and in human adipocytes exposed to macrophage-conditioned media. J Nutr 2010;140:842-7.
Kim HM, Kim YM, Huh JH, Lee ES, Kwon MH, Lee BR, et al.
A-mangostin ameliorates hepatic steatosis and insulin resistance by inhibition C-C chemokine receptor 2. PLoS One 2017;12:e0179204.
Sahoo BK, Zaidi AH, Gupta P, Mokhamatam RB, Raviprakash N, Mahali SK, et al.
Anatural xanthone increases catalase activity but decreases NF-kappa B and lipid peroxidation in U-937 and hepG2 cell lines. Eur J Pharmacol 2015;764:520-8.
Bulugonda RK, Kumar KA, Gangappa D, Beeda H, Philip GH, Muralidhara Rao D, et al.
Mangiferin from Pueraria tuberosa
reduces inflammation via inactivation of NLRP3 inflammasome. Sci Rep 2017;7:42683.
Roberts ZJ, Goutagny N, Perera PY, Kato H, Kumar H, Kawai T, et al.
The chemotherapeutic agent DMXAA potently and specifically activates the TBK1-IRF-3 signaling axis. J Exp Med 2007;204:1559-69.
Kasper LH, Reder AT. Immunomodulatory activity of interferon-beta. Ann Clin Transl Neurol 2014;1:622-31.
Jassar AS, Suzuki E, Kapoor V, Sun J, Silverberg MB, Cheung L, et al.
Activation of tumor-associated macrophages by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid induces an effective CD8+ T-cell-mediated antitumor immune response in murine models of lung cancer and mesothelioma. Cancer Res 2005;65:11752-61.
Yu Z, Predina JD, Cheng G. Refractoriness of interferon-beta signaling through NOD1 pathway in mouse respiratory epithelial cells using the anticancer xanthone compound. World J Biol Chem 2013;4:18-29.
Madan B, Singh I, Kumar A, Prasad AK, Raj HG, Parmar VS, et al.
Xanthones as inhibitors of microsomal lipid peroxidation and TNF-alpha induced ICAM-1 expression on human umbilical vein endothelial cells (HUVECs). Bioorg Med Chem 2002;10:3431-6.
Sica A, Erreni M, Allavena P, Porta C. Macrophage polarization in pathology. Cell Mol Life Sci 2015;72:4111-26.
Aras S, Zaidi MR. TAMeless traitors: Macrophages in cancer progression and metastasis. Br J Cancer 2017;117:1583-91.
Castoldi A, Naffah de Souza C, Câmara NO, Moraes-Vieira PM. The macrophage switch in obesity development. Front Immunol 2015;6:637.
Wei Z, Yan L, Chen Y, Bao C, Deng J, Deng J, et al.
Mangiferin inhibits macrophage classical activation via downregulating interferon regulatory factor 5 expression. Mol Med Rep 2016;14:1091-8.
Downey CM, Aghaei M, Schwendener RA, Jirik FR. DMXAA causes tumor site-specific vascular disruption in murine non-small cell lung cancer, and like the endogenous non-canonical cyclic dinucleotide STING agonist, 2'3'-cGAMP, induces M2 macrophage repolarization. PLoS One 2014;9:e99988.
Pandey MK, Kale VP, Song C, Sung SS, Sharma AK, Talamo G, et al.
Gambogic acid inhibits multiple myeloma mediated osteoclastogenesis through suppression of chemokine receptor CXCR4 signaling pathways. Exp Hematol 2014;42:883-96.
Guha S, Chattopadhyay U, Ghosal S. Activation of peritoneal macrophages by mangiferin, a naturally occurring xanthone. Phyther Res 1993;7:107-10.
De A, Chattopadhyay S. The variation in cytoplasmic distribution of mouse peritoneal macrophage during phagocytosis modulated by mangiferin, an immunomodulator. Immunobiology 2009;214:367-76.
Seesom W, Jaratrungtawee A, Suksamrarn S, Mekseepralard C, Ratananukul P, Sukhumsirichart W, et al.
Antileptospiral activity of xanthones from Garcinia mangostana
and synergy of gamma-mangostin with penicillin G. BMC Complement Altern Med 2013;13:182.
Dua VK, Verma G, Dash AP.In vitro
antiprotozoal activity of some xanthones isolated from the roots of Andrographis paniculata
. Phytother Res 2009;23:126-8.
Siswanto S, Arozal W, Juniantito V, Grace A, Agustini FD, Nafrialdi. The effect of mangiferin against brain damage caused by oxidative stress and inflammation induced by doxorubicin. HAYATI J Biosci 2016;23:51-5.
Zuo J, Xia Y, Li X, Chen JW. Xanthones from Securidaca inappendiculata
exert significant therapeutic efficacy on adjuvant-induced arthritis in mice. Inflammation 2014;37:908-16.
Aisha AF, Abu-Salah KM, Ismail Z, Majid AM.In vitro
and in vivo
anti-colon cancer effects of Garcinia mangostana
xanthones extract. BMC Complement Altern Med 2012;12:104.
Doi H, Shibata MA, Shibata E, Morimoto J, Akao Y, Iinuma M, et al.
Panaxanthone isolated from pericarp of Garcinia mangostana
L. suppresses tumor growth and metastasis of a mouse model of mammary cancer. Anticancer Res 2009;29:2485-95.
Mariano LN, da Silva LM, de Souza P, Boeing T, Somensi LB, Bonomini TJ, et al.
Gastroprotective xanthones isolated from Garcinia achachairu
: Study on mucosal defensive factors and H(+), K(+)-ATPase activity. Chem Biol Interact 2016;258:30-9.
Gutierrez-Orozco F, Thomas-Ahner JM, Berman-Booty LD, Galley JD, Chitchumroonchokchai C, Mace T, et al.
Dietary α-mangostin, a xanthone from mangosteen fruit, exacerbates experimental colitis and promotes dysbiosis in mice. Mol Nutr Food Res 2014;58:1226-38.
Jo YH, Kim SB, Liu Q, Hwang BY, Lee MK. Prenylated xanthones from the roots of Cudrania tricuspidata as inhibitors of lipopolysaccharide-stimulated nitric oxide production. Arch Pharm (Weinheim) 2017;350 (1):e1600263.
Teixeira M, Cerqueira F, Barbosa CM, Nascimento MS, Pinto M. Improvement of the inhibitory effect of xanthones on NO production by encapsulation in PLGA nanocapsules. J Drug Target 2005;13:129-35.
[Table 1], [Table 2], [Table 3]