Keywords

1 Introduction

Garcinias are important tropical fruits naturally occurring in Asia, Africa, South America, Australia, and Polynesia. Mangosteen (Botanical name; Garcinia mangostana L.), Brindle berry [Botanical name: Garcinia gummigutta (L.) N. Bobson. Syn. G. cambogia (Gaertn.) Desr.], and Kokum (Botanical name: Garcinia indica Choisy) are main fruit yielding trees cultivated in different regions of the world including Australia, Cuba, Dominica, Ecuador, Gabon, Ghana, Guatemala, Honduras, India, Jamaica, Liberia, Myanmar, Nepal, Philippines, Puerto Rico, Singapore, Sri Lanka, Thailand, Trinidad and Tobago, United States of America, Vietnam, and Zanzibar [1]. The fruits of Garcinias with medicinal and neutraceutical properties have been used since ancient times in traditional medicinal practices. The progress and promise in advanced technology for isolation of the bioactive compounds from plants was vital in preferring the synthetic products from the fruits of these plants for pharmacological treatment as it could help in structural modifications of the plant-derived compounds to produce potentially more active and safer drugs and also in improving the economy of pharmaceutical industries. The rind and fruit pulp of mangosteen, brindle berry, and kokum are the rich sources of compounds like xanthones, benzophenones, anthocyanins, and hydroxycitric acid which are proved to be the plant drugs demonstrating a large array of biological activities. Fruit pulp of these plants is rich in nutrients, minerals, vitamins, and dietary fibers. Hence, the Garcinia fruits serve as pools of nutrients as well as medicinal drugs to aid in human health.

2 Fruit Description and Traditional Medicinal Uses of Garcinia Fruits

Mangosteen, brindle berry, and kokum fruits are used in traditional medicine in Asian countries as folk medicine or herbal medicine to treat various ailments. Juice extracted from the entire fruit or extract obtained from the pericarp (rind) along with arils (pulp) or dried powdered rind (Fig. 1) is used in the preparation of drugs in Indian, Chinese, Thai, and Malaysian system of medicine.

Fig. 1
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Fruits, dried pricarp (rind), powdered pericarp and juice of mangosteen, bridle berry, and kokum used as a source of bioactive compounds

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2.1 Fruit Description and Traditional Uses of Mangosteen

Mangosteen fruits are round, red to purplish in color, soft, juicy with sweet flavor, and pleasant aroma, therefore, mangosteen fruits are popularly known as “Queen of fruits” (Fig. 2a) [2]. The pericarp or rind is rich in pigments especially anthocyanins (Fig. 2b). The arils (edible parts) are white, juicy, sweet, and acidic (Fig. 2c) [3].Mangosteen fruit rinds are used in the treatment of dysentery, ulcers, skin infections, wound and as an astringent, antimicrobial, and antiparasitic agent in China, India, and Thailand [4,5,6,7,8,9]. The rind decoction is utilized to relieve diarrhea, cystitis, gonorrhea, and gleet [4, 7, 10].

Fig. 2
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Fruits of Garcinia species. (a) Fruits of mangosteen; (b) Cross section of mangosteen fruit showing aril and pericarp; (c) Arils of mangosteen; (d) Fruits of brindle berry; (e) Cross section of brindle berry fruit showing aril and pericarp; (f) Arils of brindle berry; (g) Fruits of kokum; (h) Cross section of kokum fruit showing aril and pericarp; (i) Arils of kokum

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2.2 Fruit Description and Traditional Uses of Brindle Berry

Brindle berry fruits are small, about 5 cm in diameter with 6–8 grooves yellow or red in color (Fig. 2d, e). Arils are whitish to yellow (Fig. 2f). The fruits are edible, acidic and dried fruit rind is used as condiment. Fruits are also rich source of hydroxycitric acid which is an antiobesity drug [11]. Brindle berry fruits are edible; the rind is dried and used as condiment in India and Sri Lanka [1, 11]. The juice or powdered rind is used in traditional medicine to treat rheumatism and bowel problems. Rind preparations are used as purgative, hydragogue, antihelminthic and emetic [12].

2.3 Fruit Description and Traditional Uses of Kokum

Kokum fruits are round or oval, yellow to purple in color (Fig. 2g–i). The fruits are used in the preparation of juice which is used as a coolant and dried rinds are used as condiment (Fig. 1). Mangosteen, brindle berry, and kokum fruits are rich in nutrients, minerals, vitamins, and dietary fibers [13,14,15]. Kokum fruits are edible, delicious, and have a pleasant flavor and sour taste. Fruits are used in making health beverages or squash and jellies. The dried rinds of Kokum are used as acidulant and preservative in Indian dishes [16]. The fruit juice is used as a coolant, and is beneficial to cure stomach and liver disorders. Kokum is also found to be effective in treatment of dysentery, tumors, and heart complaints [4, 17].

3 Bioactive Compounds Isolated from Garcinia Fruits

3.1 Bioactive Compounds Isolated from Mangosteen Fruits

The major bioactive compounds in mangosteen, brindle berry, and kokum fruits are xanthone derivatives [2, 18]; benzophenone derivatives [4, 19]; and anthocyanins [4]. Xanthones are secondary metabolites which belong to the polyphenolic group consisting of tricyclic aromatic ring. Xanthones are classified into five groups namely simple oxygenated xanthones, xanthone glycosides, prenylated xanthones, xanthonolignoids, and miscellaneous xanthones [20]. Mangosteen fruits consist of xanthones which have substituted isoprene, phenolic, and methoxy groups. α-mangostin was first isolated by Schmid [21] from mangosteen fruits and its chemical nature was elucidated by Dragendorff [22]. More than 54 xanthone derivatives have been isolated from mangosteen fruit till now (Table 1). Major benzophenones isolated are garcimangosone D, maclurin, kolanone [4]. Chrysanthemin, cyanidin-3-O-glucoside, cyanidin-3-O-sophoroside are the anthocyanins extracted from fruits of mangosteen (Table 1) [4].

Table 1 Compounds isolated from fruit of mangosteen
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3.2 Bioactive Compounds Isolated from Brindle Berry Fruits

The important phytochemicals reported from brindle berry fruits are organic acids, xanthones, and benzophenones (Table 2). Hydroxycitric acid (HCA) is the major organic acid isolated from the fruit of brindle berry and the concentration of HCA ranges from 10% to 13% [11, 48]. HCA lactone or Garcinia lactone was also obtained along with HCA from fruits [51]. Major xanthones isolated from fruits of brindle berry are polyisoprenylated xanthones, i.e., oxy-guttiferone I, oxy-guttiferone K, oxy-guttiferone K2, and oxy-guttiferone M (Table 2) [52]. Guttiferone I, guttiferone N, guttiferone J, guttiferone K, and guttiferone M were the polyisoprenylated benzophenones isolated from fruits of brindle berry [52].

Table 2 Compounds isolated from fruit of brindle berry
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3.3 Bioactive Compounds Isolated from Kokum Fruits

The principal phytochemicals isolated from kokum fruits with proven biological activity are hydroxycitric acid, benzophenone derivatives, and anthocyanins (Table 3). Kokum fruit contains polyisoprenylated benzophenone derivatives such as garcinol (camboginol/guttiferone E), isogarcinol (cambogin), xanthochymol, isoxanthochymol [56, 61]. Kokum fruit is also rich in anthocyanin namely cynidin-3-glucoside and cynidin-3-sambubioside [15].

Table 3 Compounds isolated from fruit of kokum
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4 Biological Activities of Compounds Obtained from Garcinia Fruits

4.1 Biological Activities of Xanthones

The most abundant xanthones in the mangosteen fruits are α-mangostin and γ-mangostin, and among these α-mangostin is reported to have antioxidant, anti-inflammatory, anticancer, and antimicrobial activities [62,63,64,65].

4.1.1 Antioxidant Activity

α-mangostin was reported to be a potent antioxidant and it was demonstrated to reduce copper/peroxyl radical induced oxidation of human low density lipoproteins [66, 67]. Jung et al. [2] showed optimal ONOO− scavenging activity of α-mangostin in mouse mammary organ cultures. Sampath and Vijayaraghavan [68] studied the impact of α-mangostin on the antioxidant defiance system and lipid peroxidation against isoproterenol-induced myocardial infarction in rats. Induction of rats with isoproterenol (150 mg kg−1) for 2 days resulted in marked elevation of lipid peroxidation enzymes in the serum namely creatine phosphokinase (CPK), lactate dehydrogenase (LDH), glutamate pyruvate transaminase (GPT), and glutamate oxaloacetate transaminase (GOT) and remarkable decrease in various antioxidant enzymes such as glutathione-S-transferase (GST), glutathione peroxidase (GPX), catalase (CAT), superoxide dismutase (SOD), and glutathione (GSH). Pretreatment of α-mangostin (200 mg kg−1) orally for 6 days prior to isoproterenol administration and 2 days along with isoproterenol administration substantially attenuated such changes.

The renoprotective effect of α-mangostin on cisplatin-induced nephrotoxicity in rats was reported by Perez-Rojas et al. [69]. For 10 days 12.5 mg kg−1 day−1 of α-mangostin was administered to experimental rats and on the seventh day the rats were treated with a single dose of cisplatin (7.5 mg kg−1). After 3 days, the rats were killed and studied for the impact of α-mangostin. The attenuation of renal dysfunction, oxidative/nitrosative stress, and structural damages was recorded. The preventive effect of α-mangostin on cisplatin-induced apoptic death is attributed to the inhibition of p53 expression and reactive oxygen species generation. Similarly, the protective effect of α-mangostin on cardiac reperfusion damage was investigated by Buelna-Chontal et al. [70]. Their findings show that α-mangostin could maintain the mechanical work of the heart, decrease the area of infarct, and even prevent the decrease in cardiac ATP and phosphocreatine levels in reperfused myocardium. The defensive effect of α-mangostin was related with reduction in oxidative stress. α-mangostin treatment was found to prevent reperfusion injury-induced protein oxidation, and reduction of glutathione content and lipid peroxidation.

4.1.2 Anti-Inflammatory and Antiallergic Activity

Alpha-mangostin was reported to have potent anti-inflammatory and antiallergic effects [23, 71,72,73]. Chen et al. [23] studied the effect of α-mangostin on the murine macrophage cell line RAW 264.7 and reported the inhibition of nitric oxide (NO) and prostaglandin E2 (PGE2) production. At 3–25 μM α-mangostin, the amount of NO production was measured continuously and the IC50 value was 12.4. The production of PGE2 in lipopolysaccharide-activated RAW 264.7 cell was also significantly reduced by α-mangostin (IC50 value of 11.08 μM). Chen et al. [23] also verified induction of nitric oxide synthase (iNOS) and expression of cyclooxygenase (COX) enzyme to investigate the effect of α-mangostin. α-mangostin concentration was found to reduce iNOS induction in a concentration-dependent manner. 1 μg ml−1 lipopolysaccharide was used to activate the RAW 264.7 cells for 12 h and nitric oxide synthase activity in the activated RAW 264.7 macrophages was inhibited following 24-h treatment of 5 μg ml−1 α-mangostin.

A study conducted by Chae et al. [73] to investigate the effect of α-mangostin and γ-mangostin on the bone marrow-derived mast cell (BMMC) mediated allergy mechanism induced by phorbol 12-myristate 13-acetate (PMA) plus calcimycin A23187. Both α-mangostin and γ-mangostin were shown to inhibit the production of interleukin-6 (IL-6), prostaglandin D2 (PGD2), and leukotriene C4 (LTC4) and degranulation of BMMC induced by PMA plus calcimycin A23187. In addition, both α-mangostin and γ-mangostin were found to repress cyclooxygenase (COX-2) expression as assessed by reverse transcription polymerase chain reaction (RT-PCR) analysis. These results advocate the usefulness of α-mangostin and γ-mangostin in reduction of allergic inflammatory responses.

4.1.3 Anticancer Activity

The α-mangostin (as well as β- and γ-mangostin) was reported to possess inhibition of cell proliferation of human cancer cells [74]. The antiproliferative effects of α-, β-, γ-mangostin were associated with cell-cycle arrest by affecting the expression of cyclins, cdc2, and p27. α- and γ-mangostin were found to induce apoptosis of cancer cells through G1 and S arrest by the activation of intrinsic pathway following the downregulation of signaling pathways involving MAP kinases and serine/threonine kinase activities.

Matsumoto et al. [24] conducted a study on the inhibitory effects of α-mangostin, β-mangostin, γ-mangostin, mangostinone, garcinone E, and 2-isoprenly-1, 7-dihydroxy-3-methoxyxanthone on cell growth of the human leukemia cell line HL60, K562, NB4, and U937. α-mangostin was found to be potent at 10 μM concentration and exhibited the highest inhibitory activity compared to other xanthones. Matsumoto et al. [75] also studied antiproliferative effects of α-, β-, γ-mangostin and methoxy-β-mangostin on human cancer DLD-1 cells. Their results showed that α-mangostin strongly suppressed cell growth at 20 μM, and these effects were associated with cell-cycle arrest by affecting cyclins, cdc2, and p27 expression.

Sato et al. [10] examined the effect of α-mangostin on PC12 rat pheochromocytoma cells and the results showed apoptosis of cells through DNA fragmentation and caspase-3 cleavage. α-mangostin also exhibited features of the mitochondrial apoptotic pathway, including mitochondrial membrane depolarization. Besides, α-mangostin inhibited the endoplasmic reticulum Ca2+-ATPase and activated c-Jun NH2 terminal kinase (JNK) which depicts endoplasmic reticulum stress. These results suggest that α-mangostin inhibits Ca2+-ATPase to accomplish apoptosis of PC12 cells through the mitochondrial pathway.

Suksamrarn et al. [25] studied the effect of 19 xanthones on human breast cancer (BC-1), epidermoid carcinoma of the mouth (KB), and small cell lung cancer (NCI-H187) cell lines and reported that α-mangostin was found to be the most potent biochemical with an IC50 value (0.92 μg ml−1) followed by gacinone E and γ-mangostin. Similarly, Kurose et al. [76] conducted a study on the effect of α-mangostin on the human breast cell line MDA-MB231 and described the apoptosis of these cell lines. They also reported significant cytochrome-c release with α-mangostin treated cell lines which suggested that MDA-MB231 cell line apoptosis occurred through the mitochondrial pathway. Their study also revealed that α-mangostin treatment induces cell cycle arrest though upregulation of the cyclin-dependent kinase (CDK) inhibitor p21cip1 and cell cycle checkpoint regulator CHEK2 [76].

Hung et al. [77] evaluated the antimetastatic effect of α-mangostin against human prostrate carcinoma cell line PC-3 and reported the decreased expression of multiple matrix degrading proteinases including matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and urokinase-plasminogen activator (u-PA). α-mangostin also inhibited the phosphorylation of c-JUN N-terminal kinase 1 and 2 (JNK1/2) as well as activation of nuclear factor kappa B (NF-kB), oncogene c-Fos and c-Jun, which are associated with invasion and metastasis of cancer cells. Similar results were also recorded when human melanoma cell line SK-MEL-28 and squamous cell carcinoma cell line A-431 were treated with α-mangostin [78].

In a study, Aisha et al. [79] verified the effect of α-mangostin and γ-mangostin on colon cancer cell line HCT 116, and their study revealed that these xanthones showed strong cytotoxicity through induction of the mitochondrial apoptosis pathway. In addition, α-mangostin and γ-mangostin was found to inhibit cell migration, invasion, and clonogenicity, which are the major steps in tumor metastasis.

4.1.4 Antimicrobial Activity

Xanthones isolated from fruits of Garcinia species especially α-mangostin and γ-mangostin have been shown to exhibit antimicrobial activity against a range of pathogens including bacteria, fungi, and viral species [26, 80,81,82,83,84]. Sundaram et al. [85] studied the effect of α-mangostin on majority of bacterial and fungal species including Streptococcus aureus, Pseudomonas aeruginosa, Salmonella typhimurium, Bacillus subtilis, Klebsiella sp., Proteus sp., Escherichia coli, Epidermophyton floccosum, Alternaria solani, Mucor sp., Rhizopus sp., Cunninghamella echinulata, Trichophyton mentagrophytes, Microsporum canis, Aspergillus niger, Aspergillus, flavus, Penicillium sp., Fusarium roseum, and Curvularia lunata. The minimum inhibitory concentration of α-mangostin was between 1.25–50 μg ml−1 for bacteria and 1–5 μg ml−1 for fungi, respectively. Various scientists [62, 81] evaluated the effect of α-mangostin against Methicillin-resistant Staphylococus aureus (MRSA) and results revealed that minimum inhibitory values ranging between 1.57–12.5 μg ml−1. Gopalakrishnan et al. [27] demonstrated the potentiality of α-mangostin against phytopathogenic fungi, Fusarium oxysporum vasinfectum, Alternaria tenuis, and Drechslera oryzae.

HIV-1 protease activity of α-mangostin was demonstrated by Chen et al. [86] by using pepstatin-A as a positive control and α-mangostin exhibited an IC50 value of 5.12 μM. Kaomongkolgit et al. [87] discovered the inhibitory activity of α-mangostin against microorganism involved in oral-candidiasis, Candida albicans. They showed that α-mangostin was effective (at a minimum inhibitory concentration of 1000 μg ml−1) when compared to clotrimazole and nystatin (antifungal medicines). Therefore, α-mangostin could be promising agent for the treatment of oral candidiasis. All the above investigations indicated the antimicrobial properties of α-mangostin.

4.1.5 Antiparasitic and Antihelminthic Activity

Various studies have shown that α-mangostin has insecticidal properties against dipteran, coleopteran, and hemipteran pests [88,89,90]. Ee et al. [88] discovered the inhibitory effect of α-mangostin on Aedes aegypti larval growth [lethal concentration (LC50) was found to be 19.4 μg ml−1 for 24 h]. Kim and Lan [91] studied the larvicidal activities of α-mangostin using larvae and adults of the Colorado potato beetle, Leptinotarsa decemlineata. Their results reveal that α-mangostin had larvicidal activity at LC50 concentration of 63.33, 6.27, and 4.09 mM for 7-, 14-, and 23-day treatment, respectively. In addition, Bullangpoti et al. [92, 93] demonstrated the efficacy of α-mangostin against weevil (Sitophilus oryzae) and the brown plant hopper (Nilaparvata lugens), suggesting that α-mangostin inhibits esterase, acetyl cholinesterase, and glutathione S-transferase activities. Larson et al. [90] also demonstrated the larvicidal activities of α-mangostin in Anopheles stephensi, Anopheles gambiae, and Culex pipiens, Anopheles aegypti (Orlando strain), Anopheles quadrimaculatus Say, and Culex quinquefasciatus Say.

Keiser et al. [94] studied antihelmenthic effects of α-mangostin against trematodes Schistosoma mansoni, Echinostoma caproni, Fasciola hepatica, and the nematodes Heligmosomoides polygyrus, Ancylostoma ceylanicum, and Trichuris muris. Lack of activity of α-mangostin was recorded against Heligmosomoides polygyrus (third-stage larvae), Ancylostoma ceylanicum (third-stage larvae), and Trichuris muris (adults). A low activity was observed against Ancylostoma ceylanicum (adults; IC50 of 91 μg ml−1), whereas promising activities were revealed against Schistosoma mansoni, Echinostoma caproni, Fasciola hepatica in vitro (IC50 value of 2.9–15.6 μg ml−1). Worm burden reductions, ranging from 0% to 38% against Schistosoma mansoni and 11 to 54% against Echinostoma caproni were attained by single oral dose of the drug (400 mg kg−1 and 800 mg kg−1) in vivo. The above investigations suggest that α-mangostin could be used as organic larvicidal and antihelminthic agent.

4.2 Biological Activity of Benzophenones

Natural benzophenones are a class of compounds having phenol-carbonyl-phenol skeleton. The A-ring is benzene ring which is derived from shikimic acid pathway, whereas B-ring is derived from acetate-malonate pathway, and undergoes prenylation and cylization producing a variety of compounds. Various numbers of –OH, OMe, prenyl, and geranyl groups are added as side chains [95]. Various polyisoprenylated benzophenones are reported from fruits of Garcinia species. Garcimangosone D, kolanone, and maclurin were isolated from fruits of mangosteen (Table 1) [4, 19]. Garcinol, guttiferone I, guttiferone J, guttiferone K, guttiferone M, guttiferone N were isolated from fruits of brindle berry (Table 2) [53,54,55]. Whereas fruits of kokum possessed garcinol, isogarcinol, xanthochymol, isoxanthochymol compounds (Table 3) [57, 58]. All the benzophenones isolated from the fruits of mangosteen, brindle berry, and kokum were reported to possess strong biological activities (Tables 2, 3, and 4) and garcinol is a well-known compound in terms of its pharmacological properties (Tables 5 and 6).

Table 4 Structure and biological activity of compounds obtained from mangosteen fruit
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Table 5 Structure and biological activity of compounds obtained from brindle berry fruit
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Table 6 Structure and biological activity of compounds obtained from kokum fruit
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4.2.1 Antioxidant Activity

Garcinol exhibited a strong antioxidant activity against superoxide anion, hydroxyl radical, and methyl radicals. Yamaguchi et al. [96, 97] studied antioxidative, chelating, and free radical scavenging activities of garcinol and reported a moderate antioxidative activity in the micellar linoleic acid peroxidation system, while it exhibits nearly three times greater free radical scavenging activity against 2, 2, diphenyl-1-picrylhydrazyl (DPPH) radicals than the DL-α tocopherol (used standard chemical) by weight. These authors also recorded superoxide anion scavenging activity of garcinol and suppression of protein glycation in bovine serum/fructose system. Hong et al. [98] investigated a possible mechanism of antioxidant action of garcinol and its derivatives (cambogin, gracim-1, and gracim-2) on arachidonic acid metabolism and nitric oxide (NO) synthesis in lipoploysaccharide (LPS)-stimulated RAW264.7 cells. Results of this evaluation revealed that there was a significant inhibition to the release of arachidonic acid and it metabolizes in macrophages with the treatment of 1 mM garcinol and its derivatives to cell cultures after 1 h of LPS stimulation. Similar inhibitory activity of garcinol was also recorded by Hong et al. [98] in intestinal cell lines (HT-29, HCT-116, and IEC-6). Garcinol remarkably decreased inducible nitric oxide synthase (iNOS) express and nitric oxide (NO)release from LPS-stimulated macrophages. In another study, Sang et al. [99, 100] assessed the mechanism of antioxidant reactions of garcinol with a stable radical DPPH and characterized the reaction products. Depending on the position of hydroxyl group (C-3 or C-5) which initiates the reaction, different reaction products were formed (GDPPH-1 and GDPPH-2). Their study revealed that garcinol reacts with peroxyl radicals by a single electron transfer followed by deprotonation of the hydroxyl group from the enolized 1,3-diketone to form a resonance pair. The above investigations suggested that garcinol has potentiality as a free radical scavenger. Similar to garcinol, other benzophenones like xanthochymol, isoxanthchymol, guttiferone K, and maclurin are reported to possess excellent antioxidant activities [95].

4.2.2 Anti-Inflammatory Activity

Aberrant arachidonic acid metabolism and generation of nitric oxide were reported in lipopolysaccharide (LPS)-induced/stimulated inflammation in rat neuron cultures [98]. Archidonic acid is released by phospholipase A2 (cPLA2) from membrane phospholipids and is further metabolized by cyclooxygenase (COX), lipooxygenase (LOX) enzymes, and cytochrome P450 pathways. Cell cultures treated with garcinol (5 μM) showed modulation of archidonic acid metabolism through suppression of cytosolic PLA2 (cPLA2) and inhibition of extracellular ERK1/2 kinase activation and suppression of iNOS expression through modulation of the janus kinase (JAK) pathway [98], and the results suggested the potent anti-inflammatory effects of garcinol. Similarly, Hung et al. [101] demonstrated the inhibitory effect of garcinol against 12–0-tetradecanoylphorbol 13-acetate (TPA)-induced skin inflammation in mice. Topical pre-treatment of mouse skin with garcinol remarkably reduced TPA-induced expression of inducible nitric oxide synthase and cyclooxygenase-2. In addition, garcinol markedly reduced TPA-induced activation of extracellular signal-regulated kinases (ERK), c-Jun-N-terminal kinases (JNK), p38 mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K)/Akt, which are upstream of NF-κB. In addition, Koeberle et al. [102] demonstrated the significant effect of garcinol and its interference with two enzymes that play crucial role in inflammation, namely, 5-lipoxygense and microsomal prostaglandin PGE2 synthase (mPGES)-1. Garcinol was found to suppress 5-lipoxygense product formations in intact human neutrophils and reduced PGE2 formation of interleukin-1β-stimulated A549 human lung carcinoma cells and in human whole blood stimulated by lipopolysaccharide. Garcinol also hindered with isolated COX-1 enzyme (IC50 of 12 μM) and with formation of COX-1-derived 12(S)-hydroxy-5-cis-8, 10-trans-heptadecatrienoic acid and thromoxane B2 in human platelets [102].

4.2.3 Anticancer Activity

Various studies have examined the potential of benzophenones, especially garcinol, against different cancer types including breast cancer, colon cancer, pancreatic cancer, prostate cancer, lung cancer, leukemia, hepatocellular carcinoma. Tanaka et al. [103] carried out studies on the effect of garcinol on the development of azoxymethane (AOM)-induced colinic aberrant crypt foci (ACF) in F344 rats. In addition, this group also studied the effect of garcinol on proliferating cell nuclear antigen (PCNA) index in ACF and activities of detoxifying enzymes namely glutathione S-transferase (GST) and quinone reductase (QR) in liver. It was noticed that garcinol administration significantly reduced PCNA index in ACF and considerably elevated liver GST and QR activities. Further, garcinol was also found to suppress superoxide anion (O2−) and nitric oxide (NO) generation and expression of inducible nitric oxide synthase and cyclooxygenase-2 proteins. Liao et al. [104] studied the effects of garcinol in human colorectal cancer cell line HT-29 and showed the beneficial effects of tumor prevention. The cell lines treated with 10 μM garcinol inhibited cell invasion and decreased the tyrosine phosphorylation of focal adhesion kinase (FAK). Western blot analysis revealed that garcinol inhibits activation of the Src, MAPK/ERK, and P13K/Akt signaling pathways. In addition, the study also indicated that decreased metalloproteinase-7 (MMP-7) protein levels in HT-29 cells result in sensitization to garcinol and that the compound significantly inhibits the expression of metalloproteinase-7 (MMP-7) in IL-beta-induced HT-29 cells. Hong et al. [105] conducted a study to examine the effects of garcinol and its derivatives, cambogin, gracim-1, gracim-2, on the growth of HT-29 and HCT-116 colon cancer cells, as well as IEC-6 and INT-407 which are the normal immortalized intestinal cells. Garcinol and its derivatives showed strong growth-inhibitory effects on all intestinal cells, with IC50 values in the range of 3.2–21.4 μM after 72-h treatment. Garcinol was found to be more effective in inhibiting growth of cancer cells than normal immortalized cells. These observations suggest the possible chemopreventive role of garcinol.

Garcinol reported to possess a strong growth inhibitory activity in human leukemia HL-60 cells (IC50 of 9.42 μM) through the induction caspase-3 activity in a dose- and time-dependent manner and including degradation of poly (ADP-ribose) polymerase (PARP) protein [106]. Matsumoto et al. [24] examined the effects of garcinol, isogarcinol, and xanthochymol on cell growth in human leukemia cell lines, U937, K562, NB4, and HL60 and all the compounds exhibited strong growth suppression due to apoptosis mediated by the activation of capsase-3. Ahmad et al. [107, 108] has demonstrated beneficial effects of garcinol in suppression of breast, prostate, and pancreatic cancer cell growth by induction of apoptosis which was mediated by caspase-3 followed by downregulation of the NFkB pathway.

4.2.4 Antibacterial and Antiulcer Activity

Iinuma et al. [81] evaluated garcinol, isogarcinol, and xanthochymol for their antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and results revealed high efficacy of all the compounds with minimum inhibitory concentration values ranging between 3.1 and 12.5 μg ml−1. Various physical and psychological stresses cause gastric ulceration in human and experimental animals [109]. Recently oxygen-derived free radicals have been shown to play a role in experimental gastric damage induced by ischemia and reperfusion [110]. Yamaguchi et al. [96] have reported a significant free radical scavenging activity against hydroxyl radicals and it was vigorous than that of α-tocopherol. Therefore, garcinol is expected to be useful for preventing gastric ulcers. Yamguchi et al. [97] demonstrated that garcinol suppressed the gastric injury in rats induced by indomethacin and water immersion stress. These investigations suggest that garcinol may have potential as an antiulcer drug.

4.3 Biological Activity of Hydroxycitric Acid

Hydroxycitric acid (HCA) is the major organic acid found in the fruits of brindle berry and kokum. HCA exist in free form as well as in the lactone form, and HCA in free form is reported to possess potent biological activities [111]. HCA is an antiobesity drug and its activity is through regulation of serotonin and food intake suppression, decreased de novo lipogenesis, and enhanced fat oxidation [112]. Various in vivo studies have been carried out to understand these effects of HCA. HCA has been shown to be a strong inhibitor of ATP citrate lyase (EC 4.1.3.8) which catalyzes the cleavage of citrate to oxaloacetate and acetyl-Co-A, results in limitation of acetyl-Co-A required for fatty acid biosynthesis [113, 114]. As a consequence of this, the consumed carbon source is diverted to glycogen synthesis in liver, which results in signaling brain cells and increased production of serotonin and concomitant with a reduced appetite. Preuss et al. [115] reported that HCA generated a significant reduction in appetite, weight loss, and plasma leptin level, accompanying with an increase in the serum serotonin level and a favorable lipid profile in human clinical trials. Asghar et al. [116] conducted experiments in obese Zucker rats which were fed with HCA and recorded decrease in body weight combined with increased serotonin levels. Another possible consequence of HCA effect is the depletion of the acetyl-Co-A which is the precursor of fatty acid and cholesterol biosynthesis. Various in vitro and in vivo studies conducted in rodent models by Sullivan et al. [113, 114, 117, 118] established the inhibition of lopogenesis by HCA. Several experimental evidences suggest that HCA intake is also responsible for increased fat oxidation. Ishihara et al. [119] carried out a study on acute and chronic effects of HCA on energy metabolism. Acute administrations of HCA (10 mg μl−1) per mice significantly increased serum free fatty acid levels and levels of glycogen in the muscle; however, respiratory exchange was normal. In contrast, chronic administration of HCA (10 mg μl−1 twice a day) significantly lowered the respiratory quotient during resting and exercised conditions in mice. Lim et al. [120, 121] also reported that short-term administration of HCA led to fat oxidation in human volunteers.

4.4 Biological Activity of Anthocyanins

Chrysanthemin, cynidin-3-O-glucoside, and cynidin-3-O-sophoroside are the major anthocyanins isolated from fruits of mangosteen (Table 1) [4], whereas, kokum fruits were rich in anthocyanins namely cynidin-3-O-glucoside and cynidin-3-sambubioside [15]. The anthocyanins from kokum has a high prospective as a natural colorant and they are used in the production of confectionery, jellies, jams, health beverages, and deserts [59, 122]. Anthocyanins are having become more important in the food industry because of their bright and attractive shades and water solubility, which allows their incorporation into aqueous food systems [59, 123]. Various studies have also proved that anthocyanins are having possible health benefits as antioxidant, anti-inflammatory, anticancer, antidiabetic, cardio-protective, and neuroprotective agents [124,125,126]. In a study Min et al. [127] demonstrated neuroprotective effects cynidin-3-O-glucoside in a mouse model of permanent middle cerebral artery occlusion (pMCAO) even when delivered 3 h after the onset of ischemia, which is a clinically relevant time point in stroke. Cynidin-3-O-glucoside decreased cerebral superoxide levels, inhibited apoptosis-inducing (AIF) release from mitochondria, but did not influence the cytochrome-c related cell death pathway. Wang et al. [128] conducted a study to examine the role of cynidin-3-O-glucoside in the prevention of triple-negative breast cancer (TNBC). It was discovered that cynidin-3-O-glucoside preferentially promotes the apoptosis of TNBC cells, which co-express the estrogen receptor alpha 36 (ERα36) and the epidermal growth factor receptor (EGFR). Cynidin-3-O-glucoside binds to the legend-binding receptor of ERα36, inhibited EGFR/AKT signaling, and promotes EGFR degradation. In summary, all of the above, results indicate that cynidin-3-O-glucoside is an important anthocyanin possessing potent biological activities, and mangosteen and kokum fruits are rich in cynidin-3-O-glucoside; therefore, these fruits could be used as a potential source of cynidin-3-O-glucoside and other anthocyanins.

5 Conclusion

Latterly, Garcinia fruits especially mangosteen, brindle berry, and kokum are used in the preparation of nutraceuticals, dietary supplements, and other health foods because of their nutrient richness and chemical compounds with potential health promoting properties. All the three fruits are rich in bioactive phytochemicals such as xanthone derivatives and benzophenone derivatives. Brindle berry and kokum are abundant with hydroxycitric acid. While, mangosteen and kokum fruits are rich in anthocyanin derivatives. Various in vitro and in vivo studies have shown that xanthone derivatives, benzophenone derivatives, and anthocyanins obtained from mangosteen, brindle berry, and kokum fruits possess antioxidant, anti-inflammatory, anticancer, antimicrobial, antiallergy, antiobesity, antiulcer, antiparasitic, and antihelminthic properties. At the same time, hydroxycitric acid has been recognized as a potential antiobesity drug. In addition, various studies have suggested the safety of these natural compounds for human consumption and utilization [65, 112, 129,130,131,132]. Nevertheless, further preclinical and post-clinical studies are warranted to prove the efficacy and safety of these natural phytochemicals.