Botanical characteristics, chemical components, biological activity, and potential applications of mangosteen

Polysaccharides

Mangosteen polysaccharides have a complex molecular structure, consisting of a variety of monosaccharides. They are extensively used in the biomedical field due to their non-toxicity and lack of side effects. These polysaccharides have antioxidant, anticoagulant, anti-tumor, and immune system-supporting effects (Chen et al., 2020; Park & Shin, 2019; Zhang et al., 2020a; Zhang et al., 2020b). They also have unique structural features, such as the presence of specific functional groups, different degrees of branching, and unique conformations and molecular weight distribution. As a main bioactive component in mangosteen peel, polysaccharides are characterized by abundant and powerful bioactivities (Zhang et al., 2020a; Zhang et al., 2020b). The biological activities of polysaccharides depend on their structural features; thus, polysaccharides from the same source exhibit different biological activities.

The polysaccharide content of a mangosteen peel extract was 27.12%. In a study, researchers isolated and identified two kinds of polysaccharides from mangosteen peel, GMP70-1 and GMP90-1, and determined their structure and molecular characteristics. GMP70-1 consisted of four monosaccharides, namely, arabinose, arabinose, rhamnose, and galacturonic acid, with a molar ratio of 16.20:3.29:2.95:1.00, respectively. The repeated unit of GMP70-1 was determined to be (1 → 5)-linked α-L-Araf, (1 → 3, 5)-linked α-L-Araf, (1 → 2, 4)-linked α-L-Rhap, (1 → 4)-linked β-D-Galp, terminating in t- α-L-Araf, t- α-D-GalpA, and t- β-D-Galp (Zhang et al., 2020a; Zhang et al., 2020b). The major components of GMP90-1 were arabinose, galactose, and rhamnose, with a relative abundance of 92.4%, 5.1%, and 2.6%, respectively (Fig. 2). The backbone of GMP90-1 was composed of (1 →5)-linked α-L-Araf, (1 →2,3,5)-linked α-L-Araf, (1 →3,5)-linked α-L-Araf, (1 →6)-linked β-D-Galp, and (1 →2)-linked α-L-Rhap. The two polysaccharides extracted from mangosteen promoted macrophage phagocytosis to neutral red; accelerated the release of tumor necrosis factor- α (TNF- α), interleukin-1 β (IL-1 β), interleukin-6 (IL-6), reactive oxygen species (ROS), and nitric oxide (NO); and showed significant immunomodulatory effects.

These results suggest that the anti-inflammatory effects of polysaccharides in mangosteen peel may be achieved through the regulation of inflammatory cytokines and antioxidant effects.

Plant polysaccharides have become popular research topics in functional chemistry and modern medicine (Lu et al., 2021). Further, polysaccharides from Lentinula edodes have immunomodulatory properties (Roszczyk et al., 2022), whereas those from Ginseng polysaccharides alter the gut microbiota, potentiating the antitumor effect of anti-programmed cell death 1/programmed cell death ligand 1 immunotherapy (Huang et al., 2022). The development and utilization of plant polysaccharides show great potential in the development of functional foods and medicine (Tamang et al., 2022). Currently, research on mangosteen polysaccharides is limited, and there have only been studies on their extraction, preliminary separation, identification, and basic functions (Chitchumroonchokchai et al., 2013; Wathoni et al., 2019; Zou et al., 2021). In the future, research should elucidate the in vivo and in vitro pharmacological effects of these polysaccharides and their mechanisms. It is expected that mangosteen series products can exert superior health effects in comparison to other foods and medical products.

Xanthone

Xanthone is the most prevalent phytochemical component in mangosteen and may contribute to its high quality (Ryu et al., 2010). The most representative xanthone isolated from mangosteen peel is α-MG, which has a wide range of biological activities and pharmacological effects. The pharmacological effects of α-MG include antioxidant, anticancer, anti-obesity, antibacterial, and antimalarial properties, in addition to neuroprotective, liver-protective, and heart-protective properties in Alzheimer’s disease (AD) (Abate et al., 2022; Eisvand et al., 2022; Labban et al., 2021; Meepagala & Schrader, 2018; Oh et al., 2021; Wang et al., 2021; Zhu et al., 2021). Because of their poor water solubility, α-MG preparations typically require a high concentration of a solubilizer, limiting their use in certain clinical applications. Therefore, a new, local, α-MG-containing nano-emulsion with an optimal oil phase and surfactant content has been developed. α-MG can be loaded into the nano-emulsion without significant changes to its chemical and physical properties, and its maximum concentration was found to be 0.2% (w/w) (Asasutjarit et al., 2019). Although α-MG has a variety of biological activities, the requirements for the effective use of α-MG remain unclear, and further research is needed.

γ-Mangostin (γ-MG) is another important xanthone, with hydroxyl groups isolated from mangosteen peel through a microwave-assisted extraction and high-speed, counter-current chromatography (Fang et al., 2011). It has anti-cancer, anti-hyperglycemic, and anti-malarial effects. γ-MG provides prolonged free compound exposure and subsequently has high in vivo activities. Other components could influence the metabolism of γ-MG by inhibiting the initial combination and increasing the content of free γ-MG. Only free γ-MG has beneficial biological activities (Li et al., 2013). These findings suggest that food supplements prepared from mangosteen extract are superior to pure compound products. However, further investigations are required to directly compare the in vivo activities of pure compounds and extracts in order to draw a final conclusion.

Procyanidin

Procyanidin is a phenolic compound consisting of epicatechin and catechin (Zheng et al., 2021). The properties of procyanidins, which are water-soluble compounds in mangosteen peel, include anti-inflammatory and antibacterial effects (Oh et al., 2021). The main polyphenols of mangosteen peel are epicatechin and proanthocyanidin B2 (Wang, Chen & Wang, 2017). Epicatechin is a flavanol compound with a molecular formula of C₁₅H₁₄O₆. It has free radical-scavenging, antioxidant, and skin-protective properties (Ngawhirunpat et al., 2010). Proanthocyanidin B2 is an epicatechin dimer with antioxidant, anti-inflammatory, and anti-carcinogenic activities (Liu et al., 2020; Zuriarrain et al., 2015). Uniquely, proanthocyanidin B2 also has a lipopolysaccharide (LPS)-binding capacity, which enables its accurate identification (Zheng et al., 2021).

Benzophenones

Benzophenone synthase (BPS) belongs to the type III polyketide synthase superfamily, and it is an essential enzyme in the biosynthesis of xanthone (Songsiriritthigul et al., 2020). It also catalyzes the biosynthesis of benzophenone (Nualkaew et al., 2012). Therefore, benzophenones are common bioactivators in mangosteen. Many benzophenones with polyisoprenylated benzophenone skeletons, which could be extracted from the Garcinaceae family, have been reported (Choodej et al., 2022). Benzophenones have antioxidant, anti-inflammatory, anti-cancer, cytotoxic, and anti-bacterial activities. Benzophenones exhibit a great structural diversity, having more than 3,000 members. Among of them, 2,3′,4,6-tetrahydroxybenzophenone, 3,4,5,3′-tetrahydroxybenzophenone, 2,4,6,3′,5′-pentahydroxybenzophenone, 1,3,6,7-tetrahydroxyxanthone, 2,3′,4,4′-tetrahydroxy-6-methoxybenzophenone, congestiflorone, 2,3′,4,5′-tetrahydroxy-6-methoxybenzophenone, mangaphenone, and benthamianone have been extracted from mangosteen (Jiang et al., 2010; See et al., 2021).

Phenolic acid

Zadernowski, Czaplicki & Naczk (2009) identified 10 phenolic acids from a mangosteen fruit extract. Phenolic acids, which are aromatic secondary plant metabolites, account for about one-third of the total phenol content in mangosteen fruits. They are widely found in plants in the free and bound forms (Robbins, 2003). Bound phenolics could bind to a variety of plant components through acetal, ester, or ether bonds (Chalas et al., 2001). In mangosteen, the major phenolic acids in the aril, peel, and rind are p-hydroxybenzoic acid and protocatechuic acid. m-Hydroxybenzoic acid was only found in the peel, while 3,4-dihydroxymandelic was only present in the rind. Phenolic acids have antimicrobial and antioxidant properties, and they bind specifically to human serum albumin (Table 1).

Antioxidant properties

The incidence of degenerative diseases can be reduced via the incorporation of fruits and vegetables in the diet (Abate et al., 2022; Zhang et al., 2020a; Zhang et al., 2020b). Various antioxidants found in fruits and vegetables, such as tea polyphenols and vitamin E, are regarded as their key active compounds (Chandran & Abrahamse, 2020; Petruk et al., 2018; Urquiaga & Leighton, 2000). Antioxidants are known to mitigate harmful oxidative reactions. Many studies have shown that lipids, proteins, and nucleic acids undergo oxidative damage caused by free radicals (Di Meo & Venditti, 2020; Pisoschi & Pop, 2015). Oxidative stress induces lipid peroxidation, which is the key process of many pathological events (Guéraud et al., 2010). Malondialdehyde (MDA), the decomposition product of unsaturated lipid oxidation, destroys membrane lipids and is known to have mutagenic and carcinogenic effects (Ayala, Muñoz & Argüelles, 2014). Antioxidants are very important in preventing these diseases, as the production of oxidizable substrates could be inhibited or delayed by the activity of antioxidant compounds.

Tjahjani (2017) found that various mangosteen rind (GMR) fractions had a high 1,1-diphenyl-2-picrylhydrazyl (DPPH) capture activity, indicating mangosteen’s good antioxidant activity. Hassan et al. (2021) found that GMR could significantly reduce the redox imbalance and toxicity of liver tissue caused by a long-term γ-ray irradiation. It also improved the function, MDA content, antioxidant enzyme activity, and NO level of damaged liver. Oh et al. (2021) demonstrated that an aqueous extract of mangosteen peel powder reduced lipid peroxidation and eliminated DPPH free radicals in cultures of primary rat cortical cells, confirming its antioxidant properties. The extract also inhibited the activities of β-secretase and acetylcholinesterase, leading to antioxidant and neuroprotective effects. Antioxidants are very important in preventing these diseases, as the production of oxidizable substrates could be inhibited or delayed by the activity of antioxidant compounds (Chang et al., 2020).

Anti-inflammatory properties

Inflammation is a natural defense response of an organism to a stimulation involving pathogens, toxic agents, or a tissue injury. Many inflammatory cells and mediators participate in inflammatory responses. In most cases, the inflammatory response plays an advantageous role for organisms, but sometimes it leads to cellular damage. Many vegetables and fruits, including mangosteen, have anti-inflammatory effects (Li et al., 2018; Tatiya-aphiradee, Chatuphonprasert & Jarukamjorn, 2021). Park et al. (2021) showed that mangosteen pericarp extract (GME) decreased mRNA levels, restored the expression of genes to normal levels, and downregulated the expression of pro-inflammatory cytokines. These changes supported the therapeutic action of GME on an MRSA-induced superficial skin infection in mice. Hassan et al. (2021) found that GMR significantly reduced inflammatory markers, such as TNF- α, IL-6, and C reactive protein (CRP), and downregulated the transcription factors NF- κB/TGF-B1 in liver tissue after long-term γ-ray irradiation. At the same time, GME has also shown good therapeutic effects on gingivitis and early periodontitis. Moreover, an oral mangosteen and propolis extracted complex has the clinical and immunological potential to reduce gingivitis (Zhang et al., 2022). These are important examples of the anti-inflammatory effects of mangosteen, and further studies should explore the specific bioactive compounds and mechanisms involved (Fig. 2).

Anti-tumor properties

Cancer is a great threat to human health and life. Currently, chemical therapy is still one of the most important cancer treatment methods. Molecules of unmodified natural products, their semi-synthetic derivatives, or synthetic biosimilars account for about 50% of the more than 200 new chemical entities approved for anti-cancer use in the past 50 years (Butler, Robertson & Cooper, 2014; Newman & Cragg, 2016). Several natural, plant-derived products have demonstrated good anti-tumor properties (Zou et al., 2021). According to current studies, mangosteen and its bioactivators have potential applications in cancer therapy (Agarwal et al., 2020; Taokaew et al., 2021).

Zhu et al. (2021) found that the migration and invasion of breast cancer cells was inhibited by α-MG due to the cleavage of poly ADP-ribose polymerase (PARP) and apoptosis via the PI3K/protein kinase B (AKT) signaling pathway targeting RXR α. In addition, the proliferation of multiple breast cancer cells was inhibited by α-MG via a reduction in cancer compounds (Herdiana et al., 2021). Fatty acid synthase (FAS) is a target of breast cancer treatment due to its overexpression in human breast cancer cells. Li, Tian & Ma (2014) demonstrated that α-MG decreased the accumulation of intracellular fatty acids via the inhibition of the intracellular activity and expression of FAS.

α-MG has also exhibited anti-cancer and anti-proliferative properties in various digestive cancers, such as advanced hepatocellular carcinoma (HCC) and colorectal cancer (CRC) (Chitchumroonchokchai et al., 2013). Wang et al. (2021) found that the combination of α-MG and sorafenib could inhibit the proliferation of HCC cells and induce apoptosis. Moreover, the authors demonstrated the safety and effectiveness of this combined therapy in a mouse model. Mohamed et al. (2017) extracted 14 new mangosteen peel compounds and found that carnation flavone E showed considerable anti-proliferative effects/cytotoxicity, which induced a significant cell cycle stagnation in the G0/G1 phase. Ultimately, it demonstrated a cytotoxic effect, leading to the necrosis and apoptosis of human CRC and HCC cells. However, mangostanone IV (MX-IV) only induced necrosis and apoptosis in CRC cells. Further, Wu et al. showed that γ-MG downregulated GSK3 β-related signals. In addition, it overcame 5-fluorouracil-induced resistance in cancer-related fibroblasts and hindered the production of cancer stem cells in CRC (Wu et al., 2022).

The potential of mangosteen-derived compounds as emerging cancer therapies is worthy of further study. Bioactive substances isolated from mangosteen fruits have shown their effectiveness as natural cytotoxic agents against certain cancers (Akao, Nakagawa & Nozawa, 2008; Li et al., 2017). These studies provide important scientific evidence for the potential application of mangosteen in cancer treatment. In fact, compared with Cancer medicines available in the present-day pharmaceutical industries such as Methotrexate, Fluorouracil and Alkeran, potential natural candidates with anti-cancer properties (flavonoids, ganoderma lucidum polysaccharide, lentinus edodes polysaccharide, etc.) have fewer adverse reactions, and originated from natural food or Chinese herbal medicine, which are easy to obtain, economic, easy to be accepted by patients (Uddin et al., 2020; Man et al., 2012).

Diabetes prevention and treatment

Diabetes mellitus (DM) is marked by high blood glucose resulting from the body’s insensitivity to the actions of insulin (Dennery, 2006). Chen et al. (2021) found that γ-MG inhibited α-amylase/ α-glucosidase through insulin sensitization, promoted glucose intake, and reduced sugar digestion, thus exerting an anti-hyperglycemic activity. Protein tyrosine phosphatase 1B (PTP1B) is an action site for diabetes medicines. Hu et al. (2021) reported that garcinone E, a xanthone of mangosteen, effectively inhibited the activity of PTP1B. Moreover, Watanabe et al. (2018) found that a mangosteen extract significantly improved the insulin sensitivity of insulin-resistant obese female patients without side effects. In conclusion, mangosteen has multiple bioactivities toward DM, providing new strategies for the discovery and development of diabetes drugs. However, the therapeutic effect of mangosteen on type 1 diabetes has not been thoroughly studied.

Therapy for central nervous system (CNS) diseases

CNS diseases include Parkinson’s disease (PD), AD, depression, stroke, and sleep disorders (Sharma et al., 2019). The major pathologies of these diseases involve oxidative stress, neuroinflammation, reduction of neurotrophic factors, and mitochondrial dysfunction (Do & Cho, 2020). Recently, many researchers reported the anti-inflammatory, anti-oxidative, and neuroprotective effects of mangosteen (Oh et al., 2021; Weecharangsan et al., 2006). Herein, we summarize its bioactivities and clinical application in these diseases.

Anti-parasitic properties

Parasitic diseases prevail widely around the world, especially in developing countries located in the subtropical and tropical regions (Momčilović et al., 2019). In 2000, the World Health Organization listed 11 parasitic infectious diseases as neglected tropical diseases, as they threaten the health of millions of people and disproportionately affect the poor. Recent studies have demonstrated the potential of mangosteen in the prevention and treatment of parasitic diseases.

Malaria remains an important public health issue worldwide (Brock et al., 2015). Quinone reductase 2 (QR-2), a cytoplasmic enzyme in human erythrocytes, has been related to the pathogenesis of malaria and other diseases. Another study reported that γ-MG has a strong inhibitory effect on QR-2. Its interaction with QR-2 includes hydrogen bonding and aromatic-aromatic interactions. In a study by Tjahjani (2017), GMR exhibited an antimalarial activity that was similar and synergistic to artemisinin. Upegui et al. (2015) showed that the activity of α-MG against chloroquine-resistant strains of Plasmodium falciparum was higher than that of δ-MG. In summary, mangosteen extract has a good antimalarial activity and could be used in the treatment of parasitic diseases.

In humans, Acanthamoeba spp. is the main pathogen implicated in acanthamoeba keratitis (AK) and granulomatous amoebic encephalitis (Loufouma Mbouaka et al., 2021). AK is a serious corneal infection that can sometimes lead to blindness if not diagnosed and treated in a timely manner (de Lacerda & Lira, 2021). In recent years, the number of patients with AK caused by Acanthamoeba spp. has increased significantly worldwide, and the infection has been associated to the increase in contact lens users (Sifaoui et al., 2017). Sangkanu et al. (2022) found that a mangosteen extract and α-MG showed an anti-Acanthamoeba activity to trypanosome trophozoites and cysts and inhibited the growth of amoebas (Tatiya-aphiradee, Chatuphonprasert & Jarukamjorn, 2019). Furthermore, α-MG eliminated the possibility of triangular adhesions from contact lenses. Further, (Sangkanu et al., 2022) demonstrated that crude mangosteen extracts and α-Mg could be incorporated into contact lens solutions to effectively eliminate triangular adhesions within 24 h. Thus, mangosteen extracts and α-MG are promising candidates for the treatment of Acanthamoeba infections (Fig. 3).

Additional biological functions

In addition to the properties discussed above, mangosteen has an immunological activity, cardiovascular protective effects, and therapeutic effects in the treatment of gingivitis and early periodontitis. α-MG has been shown to improve the cardiotoxicity of doxorubicin in chemotherapy without decreasing its anticancer effect (Eisvand et al., 2022). Also, researchers found that α-MG can inhibit the formation of osteoclasts (Zhang et al., 2022). In summary, mangosteen is a valuable functional food with the potential to treat many systemic diseases. Thus, the extraction and effective utilization of the bioactive components from mangosteen peel need further investigation (Fig. 4; Table 2).