M.S. Baliga et al. / Food Research International 44 (2011) 1790–1799 1791Fig. 1. Photograph of Kokum fruits and leaves. a: Plant with raw and ripe fruits; b: Raw fruits and ripe fruit with the inner seed arranged like in orange; c: Raw fruit rind and seed d:dried rinds2. Botanical description The fruits are round, oblong or oval with pointed tips and, are crowned by the four parted stalkless stigma (Fig. 1a and b). When raw Kokum is a slender but very sturdy evergreen tree and does not need they are dark to light green in color and crimson red with a yellowelaborate irrigation or use of fertilizers, pesticides or herbicides. The tinge to dark violet or purple when fully ripe (Fig. 1a and b). The fruitstrees are normally found growing in the riversides, forests, wastelands are initially small and grow up to the size of a lemon. An averageand have been recently cultivated for their fruits. It is a slow growing kokum tree bears hundreds of fruits and each fruits weigh aroundtree and the propagation is usually by sowing the seeds in the plastic 21–85 g. The fruit contains three to eight large seeds and is coveredbags/pots and then transplanting the seedlings into the pits. Plantlets with whitish sweet pulp. The seeds are placed in a pattern similar tocan also be generated by adventitious bud differentiation on mature that in orange (Fig. 1b and c) (Nayak, Rastogi, et al., 2010). The ripeseeds and by in vitro propagation (Nayak, Rastogi, & Raghavarao, 2010). fruits are sour to taste and have a short shelf life of approximately aFrom the time of planting, a seedling requires about six to seven years to week. If left unattended the fully ripe fruits drop to the ground and thegrow and fruit. The maximum yield is mostly observed in a tree that is injured fruits may be easily infested and spoilt by micro organisms20–50 years old (Krishnamurthy, 1984). especially by the yeasts and fungi. The fruits are manually harvested, Kokum tree is dioecious (having separate male and female plants) deseeded and the rinds sun dried. The rinds appear black in color, areand grows up to a height of 12 to 20 m. The tree has branches that are shrunken and hard (Fig. 1d). Drying decreases the water activitydrooping and the canopy is dense with green leaves. The emerging required for the growth of microbes and concomitantly increases theyoung leaves are tender and red-tinged (Chandran, 1996). The leaves shelf life of the rind. This helps in making the rinds availableare simple, opposite, elliptic or oblong and deep green in color in the throughout the year for human consumption.upper side, while pale in the lower side. They are 5 to 8 cm in length The seed amounts to nearly a quarter of the total fruit weight andand 2.5–3.5 cm in breadth and shining (Chandran, 1996). The ﬂowers chemical studies have shown that it contains 23–26% oil. The oilare ﬂeshy, dark pink, solitary or in spreading cluster (Krishnamurthy, remains solid at room temperature and is colloquially known as1984; Nayak, Rastogi, et al., 2010). The mature trees ﬂower annually kokum butter. The extraction of oil is a laborious process and isduring the winter in the months of November–February. The process performed in the extractor. The kokum seeds are ﬁrst decorticatedof fruiting takes approximately ﬁve months to complete and by May, and the kernels are carefully separated. The kernels are then pressedthe ripe fruits are ready for harvesting (Chandran, 1996; Nayak, in expeller to extract oil. The cake left after extraction of the kokumRastogi, et al., 2010). butter may be used as cattle feed and also as an organic manure for
1792 M.S. Baliga et al. / Food Research International 44 (2011) 1790–1799plantation crops. Kokum butter is light gray to yellow in color, greasy Nayak, Rastogi, et al., 2010; Nayak, Srinivas, & Rastogi, 2010). The rindsin texture and is bland to taste (Nayak, Rastogi, et al., 2010). also contain two polyisoprenylated phenolics garcinol and isogarcinol (Rastogi & Mehrotra, 1990). Studies have shown that (−)-hydroxycitric3. Proximate and phytochemical composition of kokum acid (HCA) is the major organic acid in kokum leaves and rinds. It is responsible for the savory taste of kokum and is present to the extent of Studies have shown that the rind contains moisture (80.0 g/100 g), 4.1–4.6 and 10.3–12.7%, respectively in leaves and fruits. The plant alsoprotein (1%), tannin (1.7%), pectin (0.9%), Total sugars (4.1%) and fat contains hydroxycitric acid lactone and citric, but in minor quantities(1.4%) (Krishnamurthy, Lewis, & Ravindranath, 1982; Nayak, Rastogi, (Jayaprakasha & Sakariah, 2002). Some of the important phytochemicalset al., 2010). Kokum leaves are reported to contain 75% moisture, 2.3 g present in kokum are represented in Fig. 2.of protein, 0.5 g of fat, 1.24 g ﬁber, 17.2 g of carbohydrates, 15.14 mgof iron, 250 mg of calcium, 10 mg of ascorbic acid and 18.10 mg of 4. Culinary uses of kokumoxalic acid (Sheela, Nath, Vijayalakshmi, Yankanchi, & Patil, 2004).The seed is very rich in stearic, oleic and stearic triglycerides Kokum is an important culinary agent and is used as an acidulant(Dushyantha, Girish, Suvarna, & Dushyantha, 2010). for curries by people living in Maharashtra, costal Karnataka and Goa, Phytochemical studies have shown that when compared with any India. In summer the ripe rinds are ground in a blender with sugar andother natural sources, kokum rind contains the highest concentration of cardamom and consumed as a cooling drink (Shenoy, 1989; Menezes,anthocyanins (2.4 g/100 g of kokum fruit) (Nayak, Rastogi, et al., 2010; 2000, 2002; Padhye et al., 2009). Addition of kokum is supposed toNayak, Srinivas, et al., 2010). The anthocyanins cyanidin-3-glucoside enhance the taste of coconut-based curries and to remove theand cyanidin-3-sambubioside are the major pigment present in kokum unpleasant smell of mackerel and sardines (Menezes, 2000, 2002).and is reported to occur in the ratio of 4:1 (Krishnamurthy et al., 1982; They are also used in some vegetable dishes and to prepare chutneys Fig. 2. Important phytochemicals of Kokum.
M.S. Baliga et al. / Food Research International 44 (2011) 1790–1799 1793and pickles (especially with prawns and cartilaginous ﬁshes like 7.1. Antibacterial effectssharks, ray ﬁsh and other cartilagenous ﬁsh) (Menezes, 2000, 2002).The Konkani community of Goa and Karnataka, India make a simple Since its discovery, antibiotics have been an important chemo-soup like item known as birindi saar from the rinds (Shenoy, 1989). therapeutic agent for controlling pathogenic bacteria. However theThe Goans regularly prepare kokum kadi or birinda sol kadi by mincing recent development and spread of microbes that are resistant to thethe kokum rinds and coconut milk together and seasoning it with existing antibiotics are a major problem. These bacteria fail to respondgarlic, green chillies, coriander leaves and curry leaves. This curry is to treatment, which will then result in prolonged illness and increaseused with rice or like an aftermeal digestive drink. Both birindi saar the risk of death (Negi & Jayaprakasha, 2006). The aqueous extract ofand kokum kadi are supposed to be digestive and to relieve gastric the kokum rind is reported to inhibit growth of Escherichia coli,problems (Shenoy, 1989; Menezes, 2000, 2002). Bacillus subtilis, Enterobacter aerogenes and Staphylococcus aureus. The highest effect was observed in B. subtilis and the least on S. aureus.5. Industrial use Moderate inhibition was shown in other bacteria (1.5 mm). Minimum inhibition concentration studies showed that 0.5 mg/ml of the extract The kokum rinds are commercially used to prepare concentrated concentration was required for inhibiting E. coli, while 5 mg/ml for B.syrups which on appropriate dilution gives the ready to use cool subtilis and E. aerogenes and 50 mg/ml was required to inhibit S.health drinks especially during the off season periods. The local Aureus (Varalakshmi, Sangeetha, Shabeena, Sunitha, & Vapika, 2010).community of Goa also use the rinds to prepare wine. Dried rinds are The organic extract (hexane and benzene) of the spent rinds ofpowdered and marketed to be used as acidulant for traditional curries kokum and the active principle garcinol are also reported to possess(Nayak, Rastogi, et al., 2010). Kokum butter isolated from the seeds is antibacterial action (Negi & Jayaprakasha, 2006). However garcinol isin great demand in confectionery, medicines and cosmetic industries. reported to be ineffective on gram-negative enteric bacilli (BakanaKokum butter has fatty acid and triacylglycerol compositions, et al., 1987). The kokum leaf extract also possesses antibacterial effecttolerance toward milk fat and solidiﬁcation properties similar to against the pathogenic Salmonella typhi, Salmonella paratyphi A, andthose of cocoa butter (Reddy & Prabhakar, 1994). These properties are Salmonella typhimurium (Pasha, Sayeed, Ali, & Khan, 2009). Theconsidered ideal in confectionary industry and kokum is used as a phytochemicals of kokum garcinol, isogarcinol and xanthochymolreplacement to cocoa butter in the preparation of chocolates (Reddy & inhibits growth of methicillin-resistant S. aureus with lowestPrabhakar, 1994). Studies have also shown that kokum butter when minimum inhibitory concentration being observed in the range ofused along with cocoa butter increases the heat-resistance property of 3.1–12.5 μg/ml and equal to that of vancomycin (Iinuma et al., 1996).cocoa butter and chocolate and is helpful in preventing the heat- Garcinol has also been observed to be effective and to enhance theinduced softening and loss of consistency of chocolates (Maheshwari antibacterial effects of clarithromycin on H. pylori (Sang et al., 2001;& Reddy, 2005; Reddy & Prabhakar, 1994). The kokum butter is also of Sang et al., 2002). Together, these observations suggest the usefulnessuse in the production of soaps and candle (Bhat, Kamat, & Shirodkar, of kokum and its phytochemicals as antibacterial agents and suggest2005; Nayak, Rastogi, et al., 2010). the requirement for detail investigations. 7.2. Antifungal effects6. Traditional medicinal uses Increase in the incidence of invasive fungal infections coupled with Kokum has a long history of use in the Indian traditional system of limited potency, drug related toxicity, non-optimal pharmacokineticsmedicine, the Ayurveda. The leaves and fruits are sour, astringent, and development of resistence to some agents by certain fungalthermogenic, constipating and digestive. The herbal preparations made strains have necessitated the need for newer effective agents fromfrom kokum rinds are used in the treatment of inﬂammatory ailments, natural products (Perlin, 2009). With regard to kokum the aqueousfor rheumatic pains and bowel complaints. The fruit is considered to be extract was tested on Candida albicans, Aspergillus niger, Fusaruum sp.antihelmintic and cardiotonic (CHEMEXCIL, 1992). The juice (sherbet) and Penicillium sp. The extract was effective only against C. albicansmade out of the rind is used for piles, hemorrhoids, colic problems, and Penicillium sp and the minimum inhibition concentration wasulcers, inﬂammations, treat sores, dermatitis, diarrhea, dysentery, ear observed to be 0.5 mg/ml (Varalakshmi et al., 2010). Studies have alsoinfection, to facilitate digestion and to prevent over perspiration or shown that the chloroform extract prepared from the rinds inhibit thehyper perspiration (CHEMEXCIL, 1992). Kokum is a natural antacid and growth of Aspergillus ﬂavus and production of aﬂatoxin (Selvi, Joseph,the preparation rind, yogurt and salt is supposed to relieve gastric & Jayaprakasha, 2003). Together these observations clearly suggestulcerations and burning sensation (CHEMEXCIL, 1992). The Kokum the usefulness of kokum in the prevention of fungal infections andbutter is useful in dysentery, diarrhea, phthisis pulmonalis and scorbutic possibly to increase the shelf life of grains.diseases. Application of kokum butter on the skin is known to possesswound healing property and to be useful in ameliorating ulcerations, 7.3. Free radical scavenging propertiesﬁssures of the lips, hands, chapped skin and inﬂammatory sores. Theyoung leaves are useful in preventing dysentery. The leaves are also used Free radicals, consisting of ROS and RNS when generated in excessto treat skin ulcers inﬂammations, hemorrhoids, diarrhea, dysentery, cause damage to DNA, lipids, proteins, and other biomolecules.ﬂatulent colic, dyspepsia and hyperplasia (CHEMEXCIL, 1992). Accordingly, antioxidants are needed to prevent the formation/ nullify the deleterious effects of the ROS and RNS. Many medicinal plants and7. Validated studies fruits rich in polyphenols like anthocyanins, ﬂavanoids, terpens, etc. have been reported to be effective at scavenging these free radicals Being an indigenous tree and localized to selected geographical and to prevent the ensuing damage (Sánchez-Moreno, Larrauri, &pockets of India, the scientiﬁc studies, especially on the pharmaco- Saura-Calixto, 1999; Alia et al., 2008; Leopoldini, Rondinelli, Russo, &logical properties of kokum have been minimal. However some of the Toscano, 2010; Ruﬁno, Alves, Fernandes, & Brito, in press).phytochemicals like cyanidin-3-glucoside, garcinol and (−)-hydro- With regard to kokum, Selvi et al. (2003) showed that thexycitric acid, which are present in other species of the family and chloroform extract prepared from the rinds of kokum possessplants have been studied in detailed (Padhye et al., 2009). Some of the antioxidant properties. The authors used the standard β-carotene-relevant pharmacological properties of these compounds have also linoleate and 1, DPPH assays and observed the extract was effective inbeen addressed in the following sections (Table 1). scavenging the free radicals. The extract exhibited 53% and 73%
1794 M.S. Baliga et al. / Food Research International 44 (2011) 1790–1799Table 1Effect of kokum and its phytochemicals in exerting the various pharmacological properties in experimental systems of study. Pharmacological properties Observations and references Antioxidant effects 1. Chloroform extract of rinds possess antioxidant properties in β-carotene-linoleate and DPPH assays in vitro (Selvi et al., 2003). 2. The marketed concentrated syrup, cold aqueous and hot (boiled) aqueous extract of kokum also possesses antioxidant effects (Mishra et al., 2006). 3. Garcinol chelates iron (Yamaguchi et al., 2000), scavenges DPPH (Yamaguchi et al., 2000), superoxide anion (Yamaguchi et al., 2000), hydroxyl radical (Yamaguchi et al., 2000) and inhibits activity of xanthine oxidase (Liao et al., 2004). 4. Garcinol reduces the levels of LPS-induced intracellular reactive oxygen species (Liao et al., 2004). 5. Garcinol inhibited TPA-induced superoxide generation in differentiated human promyelocytic HL-60 cells and LPS and IFN-γ-induced nitric oxide generation in the mouse macrophage RAW 264.7 cells (Tanaka et al., 2000). 6. Cyanidin-3-glucoside scavenges UVB-induced hydroxyl and superoxide radicals in the cultured JB6 cells (Ding et al., 2006), protected Caco-2 colon cancer cells against the peroxyl radical (AAPH)-induced oxidative damage (Elisia & Kitts, 2008). Inhibition of lipid peroxidation 1. The marketed concentrated syrup, cold aqueous and hot (boiled) aqueous extract of kokum inhibited the ascorbate — Fe2+-induced lipid peroxidation in the rat liver mitochondrial fraction (Mishra et al., 2006). 2. Garcinol ineffective in inhibiting lipid peroxidation in the micellar system (Yamaguchi et al., 2000), but was effective in inhibiting peroxynitrite-induced lipid peroxidation in blood platelets and plasma (Kolodziejczyk et al., 2009). Inhibition of carbonyl content 1. Garcinol reduces the peroxynitrite-induced carbonylation in the blood platelets and plasma (Kolodziejczyk et al., 2009). Anticlastogenic effects 1. Garcinol scavenged the hydroxyl radical and prevented DNA damage to the pUC-19 plasmid (Liao et al., 2004). Anti-glycation activities 1. Garcinol suppresses protein glycation in the bovine serum albumin/fructose system (Yamaguchi et al., 2000). Inhibitory effects on elastase and 1. Methanolic extract of kokum rind as well as the ethyl acetate and water fraction possess anti-hyaluronidase and anti-elastase hyaluronidase activities in vitro (Sahasrabudhe & Deodhar, 2010). Antibacterial 1. Aqueous extract of kokum rind possess antibacterial effects (Varalakshmi et al., 2010). 2. The organic extract (hexane and benzene) of spent rinds and garcinol are also reported to possess antibacterial action (Negi & Jayaprakasha, 2006). 3. Kokum leaf possesses antibacterial effects (Pasha et al., 2009). 4. The phytochemicals garcinol, isogarcinol and xanthochymol possess antibacterial activity against methicillin-resistant Staphylococcus aureus (Iinuma et al., 1996). 5. Garcinol effective alone and in combination with clarithromycin on the H. pylori (Sang et al., 2001; Sang et al., 2002) but is ineffective on gram-negative enteric bacilli (Bakana et al., 1987). Antifungal activity 1. Aqueous extract possess antifungal action on Candida albicans and Penicillium sp (Varalakshmi et al., 2010). 2. The chloroform extract from spent rinds inhibits the growth of and production of aﬂatoxin by Aspergillus ﬂavus (Selvi et al., 2003). Gastroprotective effects 1. Garcinol reduced indomethacin-induced and water immersion stress-induced gastric ulceration in rats (Yamaguchi et al., 2000). 2. Garcinol alone (Chatterjee et al., 2003) and in combination with clarithromycin (Chatterjee et al., 2005) inhibits the growth of H. Pylori. Neuroprotection 1. Garcinol prevented the nitric oxide accumulation in LPS-treated astrocytes and reduced expression of LPS-induced inﬂammatory mediators, iNOS and COX-2 (Liao et al., 2005). 2. Garcinol possesses anti-cholinesterase (Lenta et al., 2007). 3. Cyanidin-3-glucoside decreased ethanol-mediated activation of GSK3β, blocked ethanol-induced intracellular accumulation of reactive oxygen species, the neurite outgrowth and expression of neuroﬁlament proteins (Chen et al., 2009). Anti-obesity activity 1. Hydroxycitric acid reported to possess anti-obesity effects by suppressing fatty acid synthesis, lipogenesis, food intake, and induced weight loss (Jena et al., 2002). 2. Feeding cyanidin 3-glucoside-rich corn suppressed high fat diet-induced increase in body weight gain, and white and brown adipose tissue weights in mice (Tsuda et al., 2003). Antidiabetic activities 1. Aqueous extract of the kokum rind decreases streptozotocin-induced hyperglycemia (Kirana & Srinivasan, 2010). 2. Feeding cyanidin 3-glucoside caused a reduction in the blood glucose levels and enhanced insulin sensitivity, upregulated the glucose transporter 4 (Glut4) and down regulated RBP4 in the white adipose tissue (Sasaki et al., 2007). Cardioprotective effects 1. Cyanidin-3-glucoside causes a concentration and time dependent enhancement in the levels of endothelial nitric oxide synthase on bovine artery endothelial cells (Xu et al., 2004). Antineoplastic and Chemopreventive effects 1. The aqueous extract of kokum rind possesses inhibitory effect on cultured 3 T3 mouse ﬁbroblasts (Varalakshmi et al., 2010). 2. The phytochemicals garcinol and isogarcinol affected the growth and proliferation of human leukemia cell lines (Matsumoto et al., 2003). 3. Garcinol decrease the cell viability, increased cell death and apoptosis in human leukemia HL-60 cells (Pan et al., 2001), HeLa cells (Balasubramanyam et al., 2004), human colorectal cancer cell line HT-29 (Liao et al., 2005) and human breast cancer cells the ER-positive MCF-7 and ER-negative MDA-MB-231 cells (Ahmad et al., 2010). 4. Garcinol enhances TRAIL-induced apoptosis of cancer cells including the TRAIL-resistant cells (Prasad et al., 2010). 5. Garcinol inhibited Nic-induced human breast cancer (MDA-MB-231) cell proliferation (Chen et al., 2011). 6. Garcinol inhibited cell invasion reduced the levels of MMP-7 in HT-29 cells (Liao et al., 2005). 7. Cyanidin-3-glucoside also caused a dose-dependent inhibitory effect on the migration and invasion of metastatic A549 human lung carcinoma cells (Chen et al., 2006). 8. Feeding garcinol shown to prevent 4-NQO-induced oral carcinogenesis in rats (Yoshida et al., 2005). 9. Garcinol prevented AOM-induced colonic aberrant crypt foci in rats (Tanaka et al., 2000). 10. Cyanidin-3-glucoside decreased the number of non-malignant and malignant skin tumors in the two staged skin carcinogenesis, reduced the size of A549 tumor xenograft growth and signiﬁcantly inhibited metastasis in nude mice by inhibiting migration and invasion of A549 tumor cells (Ding et al., 2006). 11. Feeding cyanidin-3-glucoside containing diet to the Apc (Min) mouse also decreased the intestinal adenomas (Cooke et al., 2006).antioxidant effects at 50 and 100 ppm concentrations, in the β- effective in scavenging the free radicals (Mishra, Bapat, Tilak, &carotene-linoleate assay. In the DPPH assay it was observed that the Devasagayam, 2006). In the FRAP assay, the hot aqueous kokumextract was very effective and caused 60 and 78% free radical extract was best followed by the syrup and the aqueous extract. In thescavenging activity at 25 and 50 ppm concentrations respectively ABTS assay, the kokum syrup was most effective followed by the cold(Selvi et al., 2003). aqueous extract and the hot aqueous extract radical formation. In the Studies have also shown that the marketed concentrated syrup, ORAC assay, the cold aqueous extract was better than the hot aqueouscold aqueous and hot (boiled) aqueous extract of kokum are also and kokum syrup (Mishra et al., 2006).
M.S. Baliga et al. / Food Research International 44 (2011) 1790–1799 1795 The phytochemical garcinol is also reported to chelate iron wrinkled (Sahasrabudhe & Deodhar, 2010). Exposure of skin to sun(Yamaguchi, Ariga, Yoshimura, & Nakazawa, 2000), scavenge DPPH and detrimental chemicals also hasten the process of aging andfree radical (Yamaguchi et al., 2000), superoxide anion (Yamaguchi wrinkling and application of antioxidant rich cosmaceuticals is knownet al., 2000), hydroxyl radical (Yamaguchi et al., 2000) and inhibit to retard the process (Baliga & Katiyar, 2006).xanthine oxidase activity (Liao, Sang, Liang, Ho, & Lin, 2004). Studies Recently, Sahasrabudhe and Deodhar (2010) have observed that thewith cultured primary neuron/astrocyte have shown that garcinol whole methanolic extract as well as the ethyl acetate and water fraction(5 μM) treatment for 7 days promotes neuronal attachment and of the methanolic extract prepared from the rind possess anti--causes neurite extension. It also prevented the LPS-induced formation hyaluronidase and anti-elastase activities in vitro. The authors observedand accumulation of nitric oxide by reducing the expression of that the ethyl acetate fraction showed signiﬁcant hyaluronidaseinﬂammatory mediators, such as iNOS and COX-2 in the macrophages inhibition and at a low concentration (25 μg/ml), while the aqueous(Liao et al., 2004) and rat astrocytes (Liao, Ho, & Lin, 2005). fraction was effective against both elastase and hyaluronidase (90 μg/ Garcinol reduced the levels of LPS-induced intracellular ROS, ml) (Sahasrabudhe & Deodhar, 2010). Kokum pigments are alsoblocked the activation of NF-kB, inhibited NF-kB-dependent tran- reported to possess UV light absorbing properties, suggesting itsscriptional activity and suppressed phosphorylation of IkBa and p38- usefulness in skin care (Bhat et al., 2005; Nayak, Rastogi, et al., 2010).MAPK (Liao et al., 2004). Garcinol inhibited TPA-induced superoxidegeneration in differentiated human promyelocytic HL-60 cells and LPS 7.6. Neuroprotective effectsand IFN-γ -induced nitric oxide generation in the mouse macrophageRAW 264.7 cells (Tanaka et al., 2000). Together all these observations Neurodegenerative diseases as diverse as Alzheimers, Parkinsons,suggest the utility of garcinol as an antioxidant. and Creutzfeldt–Jakob disease are a major global health burden and Studies have also shown that cyanidin-3-glucoside, the anthocyanins considerably affect the aging population (Aruoma, Bahorun, & Jena,present in the rind of kokum also possess antioxidant activity. Cyanidin- 2003). Imbalanced metabolism and excess generation of ROS and RNS3-glucoside scavenged ultraviolet B-induced hydroxyl and superoxide are known to initiate/fasten Neurodegeneration and antioxidants areradicals in the cultured JB6 cells (Ding et al., 2006). The anthocyanins rich proven to prevent/reduce the ensuing damage to the neuronal systemin cyanidin-3-glucoside is also shown to protect the Caco-2 colon cancer (Uttara, Singh, Zamboni, & Mahajan, 2009). In vitro studies have showncells against the peroxyl radical (AAPH)-induced oxidative damage and that pretreatment of primary neuron/astrocyte with garcinol (5 μM forto reduce its cytotoxicity (Elisia & Kitts, 2008). These observations clearly 7 days) promotes neuronal attachment and neurite extension. Garcinolsuggest that kokum and some of its phytochemicals possess good free prevented the nitric oxide accumulation in LPS-treated astrocytes andradical scavenging and antioxidant effects and to be of immense use in this was due to reduction in the expression of LPS-induced inﬂamma-ameliorating the various pathological ailments. tory mediators, iNOS and COX-2 (Liao et al., 2005). Garcinol is also reported to possess anti-cholinesterase properties and the observed IC507.4. Anti Lipid peroxidation and anti-carbonyl activities of 0.66 μM was comparable to that of the standard Galanthamine (0.50 μM) (Lenta et al., 2007). Excess generation of free radicals damages the lipid membranes and Studies with mouse Neuro2a (N2a) neuroblastoma cells have alsocauses loss of cell functioning and cell death. The process of lipid shown that cyanidin-3-glucoside possess neuroprotective effects.peroxidation gives rise to a number of secondary products and one of the Cyanidin-3-glucoside blocked ethanol-induced intracellular accumula-products, malondialdehyde is reported to be mutagenic, atherogenic and tion of ROS, reversed the ethanol-mediated activation of GSK3β,is implicated in the pathogenesis of various diseases (Del Rio, Stewart, & inhibited the neurite outgrowth and the expression of neuroﬁlamentPellegrini, 2005). Therefore, prevention of lipid peroxidation is extremely proteins (Chen et al., 2009). Together these observations clearly suggestimportant for the optimal functioning of the cell. Studies by Mishra et al. that cyanidin-3-glucoside and garcinol possess neuroprtotective effects(2006) have shown that that kokum extracts and syrup inhibited the and warranty detail studies in relevant animal models.ascorbate — Fe2+-induced lipid peroxidation in the rat liver assay invitro. The kokum syrup was the most effective followed by the cold 7.7. Gastroprotective effectsaqueous and hot aqueous extracts (Mishra et al., 2006). With regard togarcinol, the observations on its anti-lipid peroxidative properties are Peptic ulcer is a multifactorial disease and affects a signiﬁcantcontradictory. Garcinol is also reported to be effective in inhibiting number of the global population. Studies have shown that the oralperoxynitrite-induced lipid peroxidation in blood platelets and plasma administration of garcinol (40–200 mg/kg) reduced the indometha-(Kolodziejczyk, Masullo, Olas, Piacente, & Wachowicz, 2009). cin — induced gastric ulcerations in rats. The optimal effects were The ROS and RNS also have deleterious effects on proteins and may observed at 200 mg/kg and the protective effects were better thancontribute to tissue inﬂammation and cell death. The glutamic that of cetraxate-HCl used as a positive control (Yamaguchi et al.,semialdehyde (arginine and proline oxidation), and aminoadipic 2000). Garcinol was also effective in reducing water (23 °C)semialdehyde (oxidation of lysine) are the main carbonyl products immersion-induced gastric ulceration and the effects were similarand affect the cell functioning (Requena, Levine, & Stadtman, 2003). In to that of cetraxate-HCl used as positive control (Yamaguchi et al.,vitro studies have shown that garcinol reduces the peroxynitrite- 2000). In vitro studies have also shown that garcinol was effective oninduced formation of carbonyl groups in the blood platelets and plasma H. Pylori, a causative agent of gastric ulcerations and cancer, both(Kolodziejczyk et al., 2009). Together these observations suggest the alone (Chatterjee, Yasmin, Bagchi, & Stohs, 2003) and in combinationusefulness of kokum and garcinol in the prevention of diseases where with clarithromycin (Chatterjee, Bagchi, Yasmin, & Stohs, 2005).lipid peroxidation and protein modiﬁcation by ROS and RNS plays a vital Isogarcinol has also been claimed to possess antiulcer propertiesrole in the pathogenesis. (Sang et al., 2001). Together these observations clearly suggest the usefulness of garcinol in the prevention of gastric ulcerogenesis and7.5. Antiaging activities merit detail investigations. Aging is a natural process and one of the conspicuous features is 7.8. Anti-obesity activitythe development of wrinkles and sagging of the skin. With age, due tothe action of the enzyme elastase the elasticity of the skin decreases Recent reports from the WHO suggest that globally the number ofand this gradually causes sagging. Concomitantly the levels of obese people is increasing and with it the incidence of cardiovascularhyaluronic acid also decrease and this makes the skin dry and diseases, diabetes, digestive diseases and cancer (Nguyen & El-Serag,
1796 M.S. Baliga et al. / Food Research International 44 (2011) 1790–17992010). In the Ayurvedic system of medicine, kokum is used to treat healers of Goa and Maharastra state, India have been using the kokumillness related to obesity and multiple studies have shown that rind decoction in the treatment of diabetes and recent studies havehydroxycitric acid (also known as garcinia acid) a component of validated its antidiabetic effects (Kirana & Srinivasan, 2010). Oralkokum is reported to possess anti-obesity effects. Studies have shown administration of the aqueous extract of the kokum rind (100 mg/kgthat consumption of hydroxycitric acid reduces appetite, inhibits fat and 200 mg/kg) for a period of 4 weeks to streptozotocin-inducedsynthesis, lipogenesis, decreases food intake and reduces body weight type 2 diabetic rats is shown to be effective in decreasing both fasting(Preussa et al., 2004; Jena, Jayaprakasha, Singh, & Sakariah, 2002). and postprandial blood glucose. Kokum also restored the levels of Mechanistic studies have shown that it is a competitive inhibitor of erythrocyte GSH, an intracellular antioxidant proved to be effective inthe extra-mitochondrial enzyme ATP-citrate lyase that catalyzes the preventing the risk of developing secondary complications and theseextramitochondrial cleavage of citrate to oxaloacetate and acetyl-CoA, observations suggest the usefulness of kokum in treating bothan important precursor involved in the initial steps of de novo hyperglycemia and other complications. To corroborate these obser-lipogenesis in the liver (Jena et al., 2002). Hydroxycitric acid also vations, in vitro studies have also shown that garcinol suppressed theinhibits pancreatic α-amylase and intestinal α-glucosidase, leading to protein glycation in the bovine serum albumin/fructose systema reduction in carbohydrate metabolism (Yamada, Hida, & Yamada, (Yamaguchi et al., 2000). However detail studies are warranted to2007). It also inhibits synthesis of fatty acid and lipogenesis from establish the usefulness of kokum in treating diabetes.various precursors (Jena et al., 2002). Concomitantly, it also increasesthe synthesis of hepatic glycogen thereby activating the glucorecep- 7.10. Cardioprotective effectstors and causing a sensation of reduced appetite and fullness(Lowenstein, 1971; Preussa et al., 2004). Despite incredible improvements in the diagnosis and treatment, Hydroxycitric acid is non toxic as experimental studies have CVD account for one-third of annual global mortality. Additionally,shown that by oral route it did not cause death or systemic or with approximately 80% of all cardiovascular-related deaths occurringbehavioral toxicity even at high dose of 5 g/kg b. wt. When in the low- and middle-income countries having limited health careextrapolated to human dose, 5 g/kg b. wt. amounts to about 350 g, resources the impact of CVD is catastrophic (Gersh, Sliwa, Mayosi, &which is nearly 233 times more than the recommended dose of 1.5 g/ Yusuf, 2010). In vitro studies with the bovine artery endothelial cellsday (Jena et al., 2002). Hydroxycitric acid is also reported to be devoid have shown that cyanidin-3-glucoside enhanced the levels of eNOS,of toxic effects like nervousness, rapid heart rate, high blood pressure, an enzyme important in maintaining blood pressure homeostasis andor insomnia symptoms in humans, thereby suggesting its non toxic vascular integrity, and concomitantly increased the nitric oxidenature (Preussa et al., 2004). output. At molecular level cyanidin-3-glucoside stimulated the Preclinical studies have also shown that feeding cyanidin 3- phosphorylation of Src and ERK1/2. It also enhanced the bindingglucoside-rich purple corn suppressed the high fat diet-induced activity of the transcription factor Sp1 to the GC box in the proximalincrease in body weight gain, and synthesis/accumulation white and eNOS promoter of bovine artery endothelial cells. Together thesebrown adipose tissue in mice. Dietary feeding of cyanidin 3-glucoside observations suggest that cyanidin-3-glucoside induced eNOSrich corn decreased the sterol regulatory element binding protein-1 expression and increased the NO production, may be of help inmRNA level in white adipose tissue. It also reduced the high fat induced improving endothelial dysfunction, harmonize blood pressure andincrease in hypertrophy of the adipocytes in epididymal white adipose. may possibly prevent atherosclerosis (Xu, Ikeda, & Yamori, 2004).Cyanidin 3-glucoside feeding decreased hyperglycemia, hyperinsuline-mia and hyperleptinemia and concomitantly suppressed the transcrip- 7.11. Antineoplastic and chemopreventive effectstion of TNF-α and enzymes involved in the fatty acid and triacylglycerolsynthesis (Tsuda, Horio, Uchida, Aoki, & Osawa, 2003). Cyanidin 3- Chemotherapy is an important modality of treatment in cancerglucoside also caused a reduction in the blood glucose levels and especially when metastasis has occurred and the prognosis is poorenhanced insulin sensitivity, upregulated the Glut4 and downregulated (Dorr & Fritz, 1980). Unfortunately, most of the chemotherapeuticRBP4 in the white adipose tissue. A concomitant downregulation of the agents used in cancer treatment possess inherent toxic effects andinﬂammatory adipocytokines (monocyte chemoattractant protein-1 compromise the therapeutic beneﬁt and quality of life. Additionally,and tumor necrosis factor-alpha) in the white adipose tissue was also many of the clinically used drugs are exorbitant to people living in theobserved (Sasaki et al., 2007). developing countries where primary care itself is expensive. Therefore In vitro studies have also shown that treatment of rat adipocytes efforts are on to discover substitutes that are non toxic at effectivewith cyanidin 3-glucoside enhanced adipocytokine (adiponectin and concentrations and are inexpensive (Arora, 2010).leptin) secretion and up-regulated the adipocyte speciﬁc gene With regard to Kokum studies have shown that the phytochem-expression without activation of PPARγ. Feeding cyanidin 3-glucoside icals garcinol, isogarcinol, and xanthochymol affected the growth andto mice also enhanced the gene expression of adiponectin in the white proliferation of four human leukemia cell lines. The growth inhibitoryadipose tissue conﬁrming that the in vitro mechanisms extended in to effects of isogarcinol and xanthochymol were more potent than thatthe live system (Tsuda et al., 2004). Isogarcinol is also reported to of garcinol. These compounds induce apoptosis in the neoplastic cellspossess lipase inhibitory effect and antiobesity properties (Sang et al., through the activation of caspase-3. Detail studies also showed that2001). Together all these observations suggest that the presence of apoptosis induction by garcinol and isogarcinol was mediatedhydroxycitric acid and cyanidin 3-glucoside in the kokum rind might through the loss of mitochondrial membrane potential, while thathave contributed towards the observed antiobesity effects and by xanthochymol was independent of it (Matsumoto et al., 2003).suggest the need for translational studies. Multiple studies have also shown that garcinol possess antipro- liferative effects on various neoplastic cells like in HeLa cells7.9. Antidiabetic effects (Balasubramanyam et al., 2004), human colorectal cancer cell line HT-29 (Liao et al., 2005), human leukemia HL-60 cells (Pan, Chang, Diabetes characterized by chronic hyperglycaemia, is a disease as Lin-Shiau, Ho, & Lin, 2001) and human breast cancer cells theold as mankind. Current reports suggest it to be the worlds leading ER-positive MCF-7 and ER-negative MDA-MB-231 cells (Ahmad et al.,endocrine disorder and affects nearly 5% of the global population. 2010). Additionally, studies have also shown that at equivalentChronic hyperglycemia leads to secondary complications that are concentrations garcinol did not affect the proliferation of the non-more dangerous than hyperglycemia and meriting constant medical tumorigenic MCF-10A cells thereby suggesting it to be selectivelyattention and care (King & Loeken, 2004). Since antiquity, the herbal cytotoxic only to the neoplastic cells (Ahmad et al., 2010).
M.S. Baliga et al. / Food Research International 44 (2011) 1790–1799 1797 Studies planned at understanding the mechanistic actions have Studies have also shown that garcinol prevented AOM-inducedshown that garcinol-mediated apoptosis in HL 60 cells was triggered colonic aberrant crypt foci in rats. Feeding garcinol (0.01 or 0.05%) forby the release of cytochrome C into the cytosol, decrease in Bcl-2 and 5 weeks, one week before the ﬁrst of the three weekly subcutaneousincrease in Bad and Bax, procaspase-9 processing, activation of injections of AOM (15 mg/kg body wt), caused a concentrationcaspase-3 and caspase-2, degradation of PARP, and DNA fragmenta- dependent decrease in the PCNA index in aberrant crypt foci. Garcinoltion caused by the caspase-activated deoxyribonuclease through the increased the activities of detoxifying enzymes GST and QR in the liverdigestion of DFF-45 (Pan et al., 2001). suggesting that garcinol enhanced the detoxiﬁcation mechanisms Studies with the human breast cancer cells have shown that (Tanaka et al., 2000).garcinol-induced apoptosis in highly metastatic MDA-MB-231 cells To corroborate the animal studies, in vitro studies with pUC-19and that the effect was mediated through the induction of caspase. plasmid have shown that garcinol provides a concentration-depen-Garcinol inhibited constitutive NF-kB activity and, concomitantly dent protection against the Fenton reaction-induced clastogenesis.down-regulated the NF-kB-regulated genes (Ahmad et al., 2010). These results clearly show that garcinol scavenged the hydroxylGarcinol also inhibited activation of Src, MAPK/ERK, and PI3K/Akt radical and prevented the DNA damage considered to be the initiatorsignaling pathways, changed the ratio of the anti-apoptotic Bcl-2 and for carcinogenesis (Liao et al., 2004). Additionally, garcinol and itsproapoptotic BAX proteins concurrently triggered the release of oxidative derivatives, cambogin, garcim-1, and garcim-2 possesscytochrome C from the mitochondria to the cytosol (Liao et al., 2005). potent growth-inhibitory effects on the neoplastic HT-29 and HCT-Garcinol is a potent inhibitor of histone acetyltransferases p300 in 116 colon cancer cells, as well as in IEC-6 and INT-407 normalboth in vitro and in vivo systems (Arif et al., 2009; Mantelingu et al., immortalized intestinal cells (Hong et al., 2007).2007). It strongly inhibited the histone acetyltransferases activity- Treatment of garcinol and its derivatives (1 μM), 1 h after LPSdependent chromatin transcription, without affecting the transcrip- stimulation also inhibited the release of arachidonic acid and itstion from DNA template (Balasubramanyam et al., 2004). metabolites in macrophages and the intestinal (HT-29, HCT-116 and In addition to the observed cytotoxic effects, studies also suggest that IEC-6) cells. Garcinol inhibited the phosphorylation of cPLA2 withoutgarcinol potentiated TRAIL (a cytokine currently in phase II clinical altering its protein level, and the effect was due to the inhibition oftrial)-induced apoptosis of cancer cells including the TRAIL-resistant ERK1/2 phosphorylation. It also inhibited NFkB activation and COX-2cells. Mechanistic studies showed that the observed process was expression but only when it was added to the cells before LPSmediated through the generation of reactive oxygen species, upregula- stimulation. Garcinol also decreased the iNOS expression and NOtion of both TRAIL receptors and the death receptor 4 (DR4) and DR5, release from LPS-stimulated macrophages, possibly by inhibiting thedownregulation of antiapoptotic proteins (survivin, bcl-2, XIAP, and STAT-1, an upstream event in the activation of iNOS synthesis (HongcFLIP) and concomitant induction of proapototic process like bid et al., 2006).cleavage, bax, and cytochrome C release. However it did not affect the Cell free assays have also showed that garcinol interferes with 5-LOnormal cells suggesting its usefulness in cancer treatment (Prasad, and mPGES-1, enzymes important in the process of inﬂammation andRavindran, Sung, Pandey, & Aggarwal, 2010). Studies have also shown carcinogenesis (Koeberle, Northoff, & Werz, 2009). Garcinol inhibitedthat garcinol inhibited Nic-induced human breast cancer (MDA-MB- the activity of puriﬁed 5-lipoxygenase (IC50 of 0.1 μM) and blocked the231) cell proliferation and that this was mediated through the down- mPGES-1-mediated conversion of PGH2 to PGE2 (IC50 of 0.3 μM). Studiesregulation of α9-nAChR and cyclin D3 expression (Chen et al., 2011). with intact human neutrophils have shown that garcinol was effective in Invasiveness and metastasis are the dangerous and unique suppressing the 5-lipoxygenase products. Garcinol reduced the forma-property of cancer and their inhibition is thought of as an attractive tion in of PGE2 in A549 human lung carcinoma cells and in human wholetarget for inhibiting spreading of cancer. Preclinical studies have also blood stimulated by IL-1β-stimulated and lipopolysaccharide, respec-shown that garcinol inhibited cell invasion and decreased the tyrosine tively. Garcinol interfered with isolated COX-1 enzyme (IC50 of 12 μM)phosphorylation of the focal adhesion kinase, the major signaling and inhibited the formation of COX-1-derived 12(S)-hydroxy-5-cis-8,mediator of integrin-mediated cell-matrix contact-regulated cellular 10-trans-heptadecatrienoic acid as well as thromboxane B2 in humanproliferation, migration, and apoptosis of HT-29. Garcinol also platelets (Koeberle et al., 2009).reduced the levels of MMP-7 protein level and inhibited expression The anthocyanins rich in cyanidin-3-glucoside is also reported toof MMP-7 in IL-1beta-induced HT-29 cells, suggesting its usefulness protect the Caco-2 colon cancer cells against peroxyl radical (AAPH)-(Liao et al., 2005). induced oxidative damage and associated cytotoxicity, thereby The anthocyanins cyanidin-3-glucoside is also reported to be suggesting its potential role as an antioxidant and in preventingeffective in causing a dose-dependent inhibitory effect on the migration mutagenesis and carcinogenesis (Elisia & Kitts, 2008). Pretreatment ofand invasion, of highly metastatic A549 human lung carcinoma cells. JB6 cells with cyanidin-3-glucoside inhibited both UVB- and TPA-Cyanidin 3-glucoside caused a dose-dependent decrease in the induced transactivation of NF-kB and AP-1 and expression of COX-2expressions of MMP-2 and u-PA, and concomitantly enhances the and TNF-α. It also blocked TPA-induced neoplastic transformation inexpression of the TIMP-2 and PAI. Treatment with cyanidin 3-glucoside JB6 cells and inhibited proliferation of a human lung carcinoma cellalso inhibited the activation of c-Jun and NF-kB that are crucial in line A549 (Ding et al., 2006). Animal studies showed that Cyanidin-3-carcinogenesis (Chen et al., 2006). glucoside decreased the number of non-malignant and malignant skin Chemoprevention, the use of drugs or natural substances to retard tumors per mouse induced by TPA in DMBA-initiated mouse skinor reverse the process of carcinogenesis, represents a promising carcinogenesis model. It also reduced the size of A549 tumorstrategy to reduce the development of cancer (Ding et al., 2006). xenograft growth and inhibited metastasis by inhibiting the migrationPreclinical studies have shown that when compared to cohorts on and invasion of A549 tumor cells (Ding et al., 2006). Feeding cyanidin-control diet, feeding garcinol prevented the development of 4-NQO- 3-glucoside for 12 weeks in diet to the Apc (Min) mouse, a geneticinduced oral carcinogenesis in rats. Feeding garcinol (100 or model of human familial adenomatous polyposis decreased the500 ppm) either during (for 10 weeks) or after (for 22 weeks) the intestinal adenomas, thus conﬁrming its chemopreventive effectscarcinogen decreased the incidence and multiplicity of 4-NQO- (Cooke et al., 2006).induced tongue neoplasms and/or preneoplasms at the end of thestudy (week 32). Immunohistochemical studies conﬁrmed that the 8. Conclusionsobserved preventive effects were due to the decrease in the cellproliferation (BrdU-labeling index and cyclin D1-positive cell ratio) Studies carried out in the past one decade indicate that kokumand reduction in the levels of cyclooxygenase-2 (Yoshida et al., 2005). possess diverse health beneﬁts and that the phytochemicals garcinol,
1798 M.S. Baliga et al. / Food Research International 44 (2011) 1790–1799isogarcinol, cyanidin-3-glucoside and (−)-hydroxycitric acid are Ding, M., Feng, R., Wang, S. Y., Bowman, L., Lu, Y., Qian, Y., et al. (2006). Cyanidin-3- glucoside, a natural product derived from blackberry, exhibits chemopreventive anduseful in various medical conditions. Future studies should be on chemotherapeutic activity. The Journal of Biological Chemistry, 281, 17359−17368.understanding the mechanism of action/s responsible for the various Dorr, R. T., & Fritz, W. (1980). Cancer chemotherapy handbook. New York and Oxford:beneﬁcial effects. This will enhance our knowledge and appreciation Elsevier. Dushyantha, D. K., Girish, D. N., Suvarna, V. C., & Dushyantha, D. K. (2010). Native lacticfor the use of kokum in our daily diet. Kokum plantation does not need acid bacterial isolates of kokum for preparation of fermented beverage. E Journals ofelaborate care and as these can grow in any harsh condition farmers Academic Research & Reviews, 2, 21−24. http://www.ejarr.com/Volumes/Vol2/should be encouraged to take up large scale cultivation. The juice of EJBS_2_04.pdf Elisia, I., & Kitts, D. D. (2008). Anthocyanins inhibit peroxyl radical-induced apoptosis inkokum is a delicacy and will have immense commercial beneﬁt if Caco-2 cells. Molecular & Cellular Biochemistry, 312, 139−145.marketed by emphasizing on the beneﬁcial effects. Studies should be Gersh, B. J., Sliwa, K., Mayosi, B. M., & Yusuf, S. (2010). Novel therapeutic concepts: Theplanned on optimizing the products from the fruits and the resulting epidemic of cardiovascular disease in the developing world: Global implications. European Heart Journal, 31, 642−648.observations should be implemented in industrial scale to cater to Hong, J., Kwon, S. J., Sang, S., Ju, J., Zhou, J. N., Ho, C. T., et al. (2007). Effects of garcinol and itsboth national and international consumers of kokum. derivatives on intestinal cell growth: Inhibitory effects and autoxidation-dependent growth-stimulatory effects. Free Radical Biology and Medicine, 42, 1211−1221. Hong, J., Sang, S., Park, H. J., Kwon, S. J., Suh, N., Huang, M. T., et al. (2006). Modulation ofAcknowledgments arachidonic acid metabolism and nitric oxide synthesis by garcinol and its derivatives. Carcinogenesis, 27, 278−286. Iinuma, M., Tosa, H., Tanaka, T., Kanamaru, S., Asai, F., Kobayashi, Y., et al. (1996). The authors MSB, RJP, RB and PLP are grateful to Rev. Fr. Patrick Antibacterial activity of some Garcinia benzophenone derivatives against methicillin-Rodrigus (Director), Rev. Fr. Denis DSa (Administrator) and Dr. resistant Staphylococcus aureus. Biological Pharmaceutical Bulletin, 19, 311−314.Jayaprakash Alva (Dean) of Father Muller Charitable Institutions for Jayaprakasha, G. K., & Sakariah, K. K. (2002). Determination of organic acids in leavestheir unstinted support. MSB and HPB are also grateful to Prof. TL and rinds of Garcinia indica (Desr.) by LC. Journal of Pharmaceutical and Biomedical Analysis, 28, 379−384.Shantha, director and Prof MB Nagaveni, Maharani Lakshmi Ammani Jena, B. S., Jayaprakasha, G. K., Singh, R. P., & Sakariah, K. K. (2002). Journal of agriculturalWomens College, for their help and support. and food chemistry, 50, 10−22. King, G. L., & Loeken, M. R. (2004). Hyperglycemia-induced oxidative stress in diabetic complications. Histochemistry and Cell Biology, 122, 333−338.References Kirana, H., & Srinivasan, B. (2010). Aqueous extract of Garcinia indica choisy restores glutathione in type 2 diabetic rats. Journal of Young Pharmacists, 2, 265−268.Ahmad, A., Wang, Z., Ali, R., Maitah, M. Y., Kong, D., Banerjee, S., et al. (2010). Apoptosis- Koeberle, A., Northoff, H., & Werz, O. (2009). Identiﬁcation of 5-lipoxygenase and inducing effect of garcinol is mediated by NF-kappaB signaling in breast cancer microsomal prostaglandin E2 synthase-1 as functional targets of the anti- cells. Journal of Cellular Biochemistry, 109, 1134−1141. inﬂammatory and anti-carcinogenic garcinol. Biochemical Pharmacology, 77,Alia, S. S., Kasojua, N., Luthraa, A., Singha, A., Sharanabasavaa, H., Sahua, A., et al. (2008). 1513−1521. Indian medicinal herbs as sources of antioxidants. Food Research International, 41, Kolodziejczyk, J., Masullo, M., Olas, B., Piacente, S., & Wachowicz, B. (2009). Effects of 1−15. garcinol and guttiferone K isolated from Garcinia cambogia on oxidative/nitrativeArif, M., Pradhan, S. K., Thanuja, G. R., Vedamurthy, B. M., Agrawal, S., Dasgupta, D., et al. modiﬁcations in blood platelets and plasma. Platelets, 20, 487−492. (2009). Mechanism of p300 speciﬁc histone acetyltransferase inhibition by small Krishnamurthy, N. (1984). Chemical and technological studies on coloring matters molecules. Journal of Medicinal Chemistry, 52, 267−277. from natural sources for use in foods, PhD Thesis, Mysore University, Mysore,Arora, R. (Ed.). (2010). Herbal drugs: A cancer chemopreventive and therapeutic Karnataka, India. perspective. New Delhi, India: Jaypee Brothers Medical Publishers (P) Ltd. Krishnamurthy, N., Lewis, Y. S., & Ravindranath, B. (1982). Chemical constituents ofAruoma, O. I., Bahorun, T., & Jena, L. S. (2003). Neuroprotection by bioactive Kokum fruit rind. Journal of Food Science and Technology, 19(3), 97−100. components in medicinal and food plant extracts. Mutation Research/Reviews in Lenta, B. N., Vonthron-Senecheau, C., Weniger, B., Devkota, K. P., Ngoupayo, J., Kaiser, Mutation Research, 544, 203−215. M., et al. (2007). Leishmanicidal and cholinesterase inhibiting activities of phenolicBakana, P., Claeys, M., Totte, J., Pieters, L. A., Van, H. L., Tamba, V., et al. (1987). Structure compounds from Allanblackia monticola and Symphonia globulifera. Molecules, 12, and chemotherapeutical activity of a polyisoprenylated benzophenone from the 1548−1557. stem bark of Garcinia huillensis. Journal of Ethnopharmacology, 21, 75−84. Leopoldini, M., Rondinelli, F., Russo, N., & Toscano, M. (2010). Pyranoanthocyanins: ABalasubramanyam, K., Altaf, M., Varier, R. A., Swaminathan, V., Ravindran, A., Sadhale, P. P., theoretical investigation on their antioxidant activity. Journal of Agricultural & Food et al. (2004). Polyisoprenylated benzophenone, garcinol, a natural histone acetyl- Chemistry, 58, 8862−8871. transferase inhibitor, represses chromatin transcription and alters global gene Liao, C. H., Ho, C. T., & Lin, J. K. (2005). Effects of garcinol on free radical generation and expression. The Journal of Biological Chemistry, 279, 33716−33726. NO production in embryonic rat cortical neurons and astrocytes. Biochemical &Baliga, M. S., & Katiyar, S. K. (2006). Chemoprevention of photocarcinogenesis by Biophysical Research Communication, 329, 1306−1314. selected dietary botanicals. Photochemistry Photobiological Sciences, 5, 243−253. Liao, C. H., Sang, S., Liang, Y. C., Ho, C. T., & Lin, J. K. (2004). Suppression of inducibleBhat, J. D., Kamat, N., & Shirodkar, A. (2005). Compendium and proceedings of 2nd nitric oxide synthase and cyclooxygenase-2 in downregulating nuclear factor- national seminar on KOKUM (Garcinia indica Choisy). Goa University March, 4–5, kappa B pathway by Garcinol. Molecular Carcinogensis, 41, 140−149. 2005. Lowenstein, J. M. (1971). Effect of (−)-hydroxycitrate on fatty acid synthesis by ratChandran, M. D. S. (1996). Nature watch: The Kokum tree. Resonance, 1, 86−89. liver in vivo. The Journal of Biological Chemistry, 246, 629−632.Chatterjee, A., Bagchi, D., Yasmin, T., & Stohs, S. J. (2005). Antimicrobial effects of Maheshwari, B., & Reddy, S. Y. (2005). Application of kokum (Garcinia indica) fat as antioxidants with and without clarithromycin on Helicobacter pylori. Molecular & cocoa butter improver in chocolate. Journal of the Science of Food and Agriculture, 85, Cellular Biochemistry, 270, 125−130. 135−140.Chatterjee, A., Yasmin, T., Bagchi, D., & Stohs, S. J. (2003). The bactericidal effects of Mantelingu, K., Reddy, B. A., Swaminathan, V., Kishore, A. H., Siddappa, N. B., Kumar, G. V., Lactobacillus acidophilus, garcinol and Protykin compared to clarithromycin, on et al. (2007). Speciﬁc inhibition of p300-HAT alters global gene expression and Helicobacter pylori. Molecular & Cellular Biochemistry, 243, 29−35. represses HIV replication. Chemical Biology, 14, 645−657.CHEMEXCIL (1992). Selected medicinal plants of India. Basic Chemicals, Pharmaceutical Matsumoto, K., Akao, Y., Kobayashi, E., Ito, T., Ohguchi, K., Tanaka, T., et al. (2003). and Cosmetic Export Promotion Council, Bombay 400 039, India. Cytotoxic benzophenone derivatives from Garcinia species display a strongChen, G., Bower, K. A., Xu, M., Ding, M., Shi, X., Ke, Z. J., et al. (2009). Cyanidin-3- apoptosis-inducing effect against human leukemia cell lines. Biological Pharma- glucoside reverses ethanol-induced inhibition of neurite outgrowth: Role of ceutical Bulletin, 26, 569−571. glycogen synthase kinase 3 Beta. Neurotoxicity Research, 15, 321−331. Menezes, M. T. (2000). The essential Goa cookbook. India: Penguin Books.Chen, P. N., Chu, S. C., Chiou, H. L., Kuo, W. H., Chiang, C. L., & Hsieh, Y. S. (2006). Menezes, M. T. (2002). Great Goan cooking: 100 easy recipes. India: Penguin Books. Mulberry anthocyanins, cyanidin 3-rutinoside and cyanidin 3-glucoside, exhibited Mishra, A., Bapat, M. M., Tilak, J. C., & Devasagayam, T. P. A. (2006). Antioxidant activity an inhibitory effect on the migration and invasion of a human lung cancer cell line. of Garcinia indica (kokam) and its syrup. Current Science, 91, 90−93. Cancer Letters, 235, 248−259. Nayak, C. A., Rastogi, N. K., & Raghavarao, K. S. M. S. (2010). Bioactive constituentsChen, C. S., Lee, C. H., Hsieh, C. D., Ho, C. T., Pan, M. H., Huang, C. S., et al. (2011). present in Garcinia indica Choisy and its potential food applications: A review. Nicotine-induced human breast cancer cell proliferation attenuated by garcinol International Journal of Food Properties, 13, 441−453. through down-regulation of the nicotinic receptor and cyclin D3 proteins. Breast Nayak, C. A., Srinivas, P., & Rastogi, N. K. (2010). Characterization of anthocyanin from Cancer Research and Treatment, 125, 73−87. Garcinia indica choisy. Food Chemistry, 118, 719−724.Cooke, D., Schwarz, M., Boocock, D., Winterhalter, P., Steward, W. P., Gescher, A. J., et al. Negi, P. S., & Jayaprakasha, G. K. (2006). Control of foodborne pathogenic and spoilage (2006). Effect of cyanidin-3-glucoside and an anthocyanin mixture from bilberry on bacteria by Garcinol and Garcinia indica extracts and their antioxidant activity. adenoma development in the ApcMin mouse model of intestinal carcinogenesis — Journal of Food Science Education, 69, 61−65. Relationship with tissue anthocyanin levels. International Journal of Cancer, 119, Nguyen, D. M., & El-Serag, H. B. (2010). The epidemiology of obesity. Gastroenterology 2213−2220. Clinics of North America, 39, 1−7.Del Rio, D., Stewart, A. J., & Pellegrini, N. (2005). A review of recent studies on Padhye, S., Ahmad, A., Oswal, N., & Sarkar, F. H. (2009). Emerging role of Garcinol, the malondialdehyde as toxic molecule and biological marker of oxidative stress. antioxidant chalcone from Garcinia indica Choisy and its synthetic analogs. Journal Nutrition, Metabolism and Cardiovascular Disease, 15, 316−328. of Hematology and Oncology, 2, 38−49.
M.S. Baliga et al. / Food Research International 44 (2011) 1790–1799 1799Pan, M. H., Chang, W. L., Lin-Shiau, S. Y., Ho, C. T., & Lin, J. K. (2001). Induction of of retinol binding protein 4 expression in diabetic mice. Biochemical Pharmacology, 74, apoptosis by garcinol and curcumin through cytochrome Crelease and activation of 1619−1627. caspases in human leukemia HL-60 cells. Journal of Agricultural & Food Chemistry, Selvi, A. T., Joseph, G. S., & Jayaprakasha, G. K. (2003). Inhibition of growth and aﬂatoxin 49, 1464−1474. production in Aspergillus ﬂavus by Garcinia indica extract and its anti-oxidantPasha, C., Sayeed, S., Ali, M. S., & Khan, M. Z. (2009). Antisalmonella activity of selected activity. Food Microbiology, 20, 455−460. medicinal plants. Turkish Journal of Biology, 33, 59−64. Sheela, K., Nath, Kamal G., Vijayalakshmi, D., Yankanchi, Geeta M., & Patil, Roopa B.Perlin, D. S. (2009). Antifungal drug resistance: Do molecular methods provide a way (2004). Proximate composition of underutilized green leafy vegetables in Southern forward? Current Opinion in Infectious Diseases, 22, 568−573. Karnataka. Journal of Human Ecology, 15, 227−229.Prasad, S., Ravindran, J., Sung, B., Pandey, M. K., & Aggarwal, B. B. (2010). Garcinol Shenoy, J. V. (1989). Dakshin Bharat dishes: Indian vegetarian cookbook. D.K., India: potentiates TRAIL-induced apoptosis through modulation of death receptors and Saraswatha Prakashana in Udupi. antiapoptotic proteins. Molecular Cancer Therapeutics, 9, 856−868. Tanaka, T., Kohno, H., Shimada, R., Kagami, S., Yamaguchi, F., Kataoka, S., et al. (2000).Preussa, H. G., Bagchi, D., Bagchi, M., Rao, C. V. S., Satyanarayana, S., & Deye, D. K. (2004). Prevention of colonic aberrant crypt foci by dietary feeding of garcinol in male F344 Efﬁcacy of a novel, natural extract of (−)-hydroxycitric acid (HCA-SX) and a rats. Carcinogenesis, 21, 1183−1189. combination of HCA-SX, niacin bound chromium and Gymnema sylvestre extract in Tsuda, T., Horio, F., Uchida, K., Aoki, H., & Osawa, T. (2003). Dietary cyanidin 3-O-beta-D- weight management in human volunteers: A pilot study. Nutrition Research, 24, 45−58. glucoside-rich purple corn color prevents obesity and ameliorates hyperglycemiaRastogi, R. M., & Mehrotra, B. N. (1990). Compendium of Indian medicinal plants. in mice. The Journal of Nutrition, 133, 2125−2130. Lucknow, India: Central drug research Institute. Tsuda, T., Ueno, Y., Aoki, H., Koda, T., Horio, F., Takahashi, N., et al. (2004). AnthocyaninReddy, S. Y., & Prabhakar, J. V. (1994). Cocoa butter extenders from Kokum (Garcinia enhances adipocytokine secretion and adipocyte-speciﬁc gene expression in indica) and Phulwara (Madhuca butyracea) butter. Journal of the American Oil isolated rat adipocytes. Biochemical & Biophysical Research Communication, 316, Chemists Society, 7, 217−219. 149−157.Requena, J. R., Levine, R. L., & Stadtman, E. R. (2003). Recent advances in the analysis of Uttara, B., Singh, A. V., Zamboni, P., & Mahajan, R. T. (2009). Oxidative stress and oxidized proteins. Amino Acids, 25, 221−226. neurodegenerative diseases: A review of upstream and downstream antioxidantRuﬁno, M. S. M., Alves, R. E., Fernandes, F. A. N., Brito, E. S. (in press). Free radical scavenging therapeutic options. Current Neuropharmacology, 7, 65−74. behavior of ten exotic tropical fruits extracts. Food Research International. Varalakshmi, K. N., Sangeetha, C. G., Shabeena, A. N., Sunitha, S. R., & Vapika, J. (2010).Sahasrabudhe, A., & Deodhar, M. (2010). Anti-hyaluronidase, anti-elastase activity of Antimicrobial and cytotoxic effects of Garcinia indica fruit rind extract. American- Garcinia indica. International Journal of Botany, 6, 1−10. Eurasian Journal of Agricultural & Environmental Sciences, 7, 652−656.Sánchez-Moreno, C., Larrauri, J. A., & Saura-Calixto, F. (1999). Free radical scavenging Xu, J. W., Ikeda, K., & Yamori, Y. (2004). Upregulation of endothelial nitric oxide capacity and inhibition of lipid oxidation of wines, grape juices and related synthase by cyanidin-3-glucoside, a typical anthocyanin pigment. Hypertension, 44 polyphenolic constituents. Food Research International, 32, 407−412. (2), 217−222.Sang, S., Liao, C. H., Pan, M. H., Rosen, R. T., Lin-Shiau, S. Y., Lin, J. K., et al. (2002). Yamada, T., Hida, H., & Yamada, Y. (2007). Chemistry, physiological properties, and Chemical studies on antioxidant mechanism of garcinol: Analysis of radical microbial production of hydroxycitric acid. Applied Microbiology and Biotechnology, reaction products of garcinol with peroxyl radicals and their antitumor activities. 75, 977−982. Tetrahedron, 58, 10095−10102. Yamaguchi, F., Ariga, T., Yoshimura, Y., & Nakazawa, H. (2000). Antioxidative and anti-Sang, S., Pan, M. H., Cheng, X., Bai, N., Stark, R. E., Rosen, R. T., et al. (2001). Chemical glycation activity of garcinol from Garcinia indica fruit rind. Journal of Agricultural & studies on antioxidant mechanism of garcinol: Analysis of radical reaction products Food Chemistry, 48, 180−185. of garcinol and their antitumor activities. Tetrahedron, 57, 9931−9938. Yoshida, K., Tanaka, T., Hirose, Y., Yamaguchi, F., Kohno, H., Toida, M., et al. (2005).Sasaki, R., Nishimura, N., Hoshino, H., Isa, Y., Kadowaki, M., Ichi, T., et al. (2007). Cyanidin Dietary garcinol inhibits 4-nitroquinoline 1-oxide-induced tongue carcinogenesis 3-glucoside ameliorates hyperglycemia and insulin sensitivity due to downregulation in rats. Cancer Letters, 221, 29−39.