INTRODUCTION:

Garcinia mangostana Linn. (mangosteen) is a family of Clusiaceae, which grows slowly with a height reaching 25 meters or smaller. The stem is cylindrical with a diameter of up to 37 cm. This plant is found in Indonesia, Malay, Myanmar, Thailand, Cambodia, and Vietnam, and has been cultivated in tropical regions such as India, Honduras, Brazil, and Australia for the past two centuries. The aromatic fruit with sweet and soft taste is often consumed by the wider community¹. However, although it is widely known for its fruit, most chemical components are found in the skin of the fruit which is around 70-75%². This exocarp mangosteen is dark purple or reddish and is known as a rich source of red pigment¹.

Mangosteen has 160 aromatic compounds in epicarp and 105 compounds in endocarp, some identified as xanthone compounds consisting of at least 68 types including α-Mangostin, ß-Mangostin, γ-Mangostin, garcinone E, gartanin, 8-Deoxygartanin^3,4.

Whereas in pericarp, α and β-mangostin are the most numerous compounds, in addition to other xantons that have been isolated in the form of mang-mangostin, gartanin, 8-deoxygartanin, garcinones A, B, C, and D, mangostinone, 9-hydroxycalabaxanthone, isomangostin, mangostanin, 8-deoxygartanin trapezifolixanthone, padiaxanthone, tovophilin A, 1,5,8-trihydroxy-3-methoxy-2-xanthone [3-methyl-2-butenyl], 1,3,7-trihydroxy-2,8- di- (3-methylbut2-enyl) xanthones, mangostenone D, 1,7-dihydroxy-2- (3-methylbut-2-enyl) -3-methoxyxanthone, and mangostanaxanthone, I, II, III, IV and VIIII^5,6,7. Because of the many ingredients contained in Garcinia mangostana Linn., This plant is widely used for the treatment of various diseases, including antidiabetic, antihyperlipidemic, antiobesity, antioxidants, analgesic, anti-inflammatory, anticancer, antidepressant, antibacterial, renoprotective, and neuroprotective.

EXPERIMENTAL:

This journal review is referenced from several international journal that related to research conducted on Garcinia mangostana Linn. These journals consist of Research Journal of Pharmacy and Technology, Journal of Natural Medicines, International Journal of Pharmacy and Pharmaceutical Sciences, Oxid Antioxid Med Sci., IJMRHS, Molecules, Indonesian Journal of Chemistry, Iraqi Journal of Veterinary Science, International Journal Med Res Health Sci., Indonesia Journal of Biomedical Science, European Journal of Pharmacology, Nutrients, Journal of Asian Natural Products Research, Asian Journal of Pharmacy and Technology, Journal of Biological Researches, Revista Brasileira de Farmacognosia, Neuroscience Letters, Journal of Toxicology, Walailak Journal, Evidence-Based Complementary and Alternative Medicine, PLoS ONE, Beni-Suef University Journal of Basic and Applied Sciences, Veterinary World, Oxidative Medicine and Cellular Longevity, Food Function, World J. Pharm Sci., Polish Journal of Food and Nutrition Sciences, Food and Chemical Toxicology, International Journal of Pharmacognosy and Phytochemical Research, Frontiers in Microbiology, Iranian Journal of Basic Medical Sciences, Journal of Natural Remedies, BioMed Research International, Frontiers Psychiatry, Metabolic Brain Disease, Asian Journal of Pharmaceutical Research, Pharmacol Biochem Behav., Agro FOOD Industry Hi Tech, International Journal of Advances in Nursing Management, International Conference on Mathematics and Natural Sciences, Journal of Pharmaceutical Sciences and Research, and other publications.

RESULTS AND DISCUSSION:

Antidiabetic:

Mangosteen is a medicinal plant that shows various mechanisms of action as antidiabetic both in vivo, in vitro, and in silico. This can be a reference for its use as an alternative treatment. In addition, pharmacokinetic-pharmacodynamic interaction studies suggest that mangosteen rind extract can increase and accelerate the work of metformin, while α-mangostin can be used as an alternative antidiabetic especially if bioavailability is increased⁸.

Ethanol extract of mangosteen rind sap shows antidiabetic effects such as through work in lowering blood glucose, improving insulin tolerance, biochemical parameters, and liver structure, and as inhibition of glycation in DM-induced mice using Streptozocin^9,10,11,12. In the viability test, mangosteen rind extract at doses of 5 and 20 µg/mL had the highest activity in increasing cell proliferation in glucose-induced mesangial cells¹³.

In line with this, α-mangostin contained in mangosteen peel shows an effect in improving insulin resistance by looking at the expression of glucose transporter-4 (GLUT-4) and PPAR-γ, inhibiting the action of α-glucosidase, and increasing the regeneration of Langerhans islands¹⁴. Some current treatment targets include through this mechanism and complications related to synthetic drugs leading to the use of herbal medicines^15,16including Garcinia mangostana L. In addition, tolerance glucose and insulin were significantly increased in obese rats given α-mangostin¹⁷. The α-mangostin dose of 100mg/kg is the dose that shows the best results in several antidiabetic testing parameters in rats¹⁸ while efficiently inhibiting the enzyme α-glucosidase and α-amylase in vitro depending on the dose¹⁹.

Other compounds such as mangostanaxanthones III and IV, β-mangostin, garcinone E, rubraxanthone, garcinone C, and 9-hydroxycalabaxanthone which are isolated significantly inhibit both sugar (ribose) and dicarbonyl (methylglyoxal) compounds²⁰. The activity of α-amylase is also hampered by the administration of mangosteen peel extract²¹ which is suspected by the working content of mangostanaxanthones I, II, and VIIII⁷. Even one of the pancreatic cholesterol esterase enzymes which are enzymes related to the DM process through hypercholesterolemia can be inhibited by the mangosteen content of 1,3,5,6-tetrahydroxyxanthone, euxanthone, and epicatechin²².

Antihyperlipidemic:

α-Mangostin content contained in mangosteen peel can be developed into one of the antihyperlipidemic agents in both combination and monotherapy forms¹⁰. Reduction in blood cholesterol levels was observed as a result of inhibition of cholesterol formation in the administration of mangosteen peel extract through inhibition of cholesterol synthesis²³. Whereas the polar fraction of mangosteen rind given for 14 days showed an effect on decreasing fasting blood cholesterol levels in mice and reducing serum MDA (malondialdehyde) levels in mice with type 2 diabetes¹². If mangosteen peel extract is combined with curcumin, it will have the effect of increasing HDL content and reducing total cholesterol, triglyceride, LDL and abdominal fat levels²⁴, with this effect related to the inhibition of the atherosclerotic state²⁵. A similar effect was also shown by ethanol, methanol, and ethyl acetate extracts from mangosteen rind²⁶.

Antiobesity:

Obesity is an overweight condition associated with various factors, including demographic conditions, gender, eating habits, duration of watching television, family socioeconomic status, prior knowledge about obesity, and family history of obesity²⁷. To handle this situation, good treatment is needed among the alternatives by using Garcinia mangostana L. This plant has several mechanisms including, weight loss²⁸, which the ethanol extract of mangosteen pericarp (MPEE) at doses of 200 and 500mg/kg body weight mice can reduce weight gain and fat storage, as well as lipid droplets in the liver²⁹.

Antiadepogenesis activity is shown by MPEE by inhibiting the synthesis of triglycerides and cholesterol whose effects are better than those shown by α-mangostin, γ-mangostin, garcinone-C, and garcinone-D³⁰. In addition to inhibition of the two parameters, MPEE at a concentration of 50 μg/mL can also inhibit the activity of Glucose-6-Phosphate Dehydrogenase (G6PDH), and lipid droplets observed in 3T3-L1 cells³¹.

Antioxidant:

Oxidative stress is a state of imbalance in the production of free radicals or reactive oxygen species (ROS) is higher than the presence of antioxidants. One cause of the situation is the maximum physical activity. Based on the results of research showed that physical training with mangosteen peel extract reduces oxidative stress through reducing MDA, as well as increasing Superoxide dismutase (SOD) and Glutathione Peroxidase (GPx)³².

Several other studies have also shown that mangosteen rind is a potent antioxidant. Ethanol, hexane, ethyl acetate, butanol, and water fraction extracts have a good DPPH (2,2-diphenyl-1-picrylhydrazyl) radical trapping activity³³This ability shows the level of evaluation of the activity of cleaning free radicals from plant extracts^34,35. The highest SOD (superoxide dismutase) level was found after administration of the mangosteen rind water fraction, while the highest TAS (total antioxidant status) level was in the ethyl acetate fraction³³. Results from clinical trials show that the administration of polar fractions from mangosteen peel extracts to humans for 24 weeks can act as an antioxidant without any significant side effects³⁶.

The xanthone content has a renoprotective effect and reduces oxidative stress in rats induced by type 2 diabetes mellitus¹⁰. The xanton compound in question is thought to be α-mangostin with the help of tannin compounds such as epicatechin⁹. α-mangostin significantly withstand the oxidative stress caused by APAP³⁷.

Analgesic:

Pain is a sensory and emotionally unpleasant state associated with tissue damage. Handling in this situation can be tested using several test methods³⁸. Based on research that has been done, the α-mangostin and γ-mangostin compounds in Garcinia mangostana L. shows analgesic effects at doses of 25 and 50mg/kg tested on mice³⁹ this test has been carried out using two tests namely the hot-plate and formalin test. In a clinical investigation, this compounds also show significantly reduce soft tissue pain in volunteers⁴⁰.

Anti-inflammatory:

Garcinia mangsotana L. works as an anti-inflammatory through various mechanisms of action so that it can provide safe and effective treatment options for a variety of inflammatory mediated diseases. Isogarcinol compounds from mangosteen peel extract can act as an anti-inflammatory by improving CD4 T-cell suppression in murine models²⁸.

Research revealed that the ethanol extract of mangosteen rind, α-mangostin, and γ-mangostin had anti-inflammatory effects by reducing COX-2, IL-6, IL-1β, NO production³⁷and tumor necrosis factor-α (TNF-α)⁴⁰. This extract is thought to have therapeutic potential for the modulation and regulation of macrophage activation. The greatest activity against COX-2 and IL-6 inhibition was given by the extract of mangosteen peel ethanol 20µg/mL and 75µM mangostin. In addition, the anti-inflammatory properties of α-mangostin, which are mediated by the NF-κB and MAPK (Mitogen-activated protein kinase) signaling pathways, also contribute to their hepatoprotective effects³⁷.

This extract provides an anti-inflammatory effect at a concentration of 12.5% after 2 hours of administration. This is presumed by its flavonoid content which acts to inhibit the irreversible release of the enzyme cyclooxygenase⁴¹.

Anticancer:

Garcinia mangostana acts as an anticancer agent in various ways. Ethanol extract, n-hexane fraction, ethyl acetate fraction, I-A isolate, and II5B isolate had cytotoxic activity against HeLa cervical cancer cells, and compound I-A showed the highest cytotoxicity⁴². Giving ethanol extract of Garcinia mangostana 22.5 μg/mL increases the cytotoxic effect of doxorubicin on MCF-7 cells. The in silico test showed that the α-mangostin content had an affinity for the Pgp (P-glycoprotein) receptor, which is one of the destination receptors of anticancer agents with a binding energy of -6.13 kcal/mol⁴³.

Alpha-mangostin also significantly shows the inhibitory effect of HepG2 cell survival by inducing caspase-9, caspase-8 and caspase-3 activity, increasing levels of pro-apoptotic proteins (Bax, Bim, t-Bid), and decreasing anti-apoptotic levels protein (c-FLIP, Mcl-1). In addition, this content can also reduce cell re-adhesion and migration, matrix metalloproteinases-2 (MMP-2) and MMP-9 secretion, and expression of proteins involved in EMT (N-cadherin, VV, β1 integrin, and vimentin). The AKT and ERK signaling pathways are drastically suppressed, which shows that α-mangostin inhibits anoikis resistance by inhibiting this pathway in HepG2. These findings support the development of α-mangostin for use in the treatment of anoikis-resistant liver cancer³¹. Furthermore, α-mangostin has also been shown to be potentially used as an adjunctive adjuvant therapy or supplementary alternative drug for the management of pancreatic cancer through threatening the suppression of PI3K/Akt pathway activity in pancreatic cancer cells, thereby significantly inhibiting the growth of mouse xenografts in BxPc-3 tumors⁴⁴.

OSCC (Oral Squamous Cell Carcinoma) is one of the most common forms of oral cancer that can be a risk factor for other diseases. In a study showed that α-mangostin specifically induces cell death and inhibits proliferation in OSCC cells through intrinsic apoptosis pathways and cell cycle arrest in the G1 phase, so that it can be used for OSCC treatment⁴⁵.

Antidepressant:

Depression occurs as a result of a chemical imbalance in the brain that may occur hereditary or due to certain diseases⁴⁶. Therefore, the treatment can also affect several factors. Garcinia mangostana Linn. (mangosteen) pericarp can be used as an alternative treatment for bipolar disorder and schizophrenia because it has antioxidant, putative, anti-inflammatory, and mitochondrial antioxidant properties that have been tested on experimental animals⁴⁷. Preclinical data on Mangosteen pericarp also show positive results on the treatment of schizophrenia through mechanisms related to biological factors such as replenishes glutathione (GSH), reduces oxidative and inflammatory stress, impacts apoptosis, and enhances neurogenesis⁴⁸. In fact, administration of Garcinia mangostana rind can show an antidepressant-like and pro-cognitive effect similar to the effect given by imipramine⁴⁹.

Antibacterial:

Garcinia mangostana has several activities in inhibiting the growth of both gram positive and gram-negative bacteria. Ethanol and chloroform extracts of Garcinia mangostana can inhibit the growth of E. coli, Streptococcus, and Lactobacillus^5,3.

α-mangostin through various mechanisms especially eliminating cell membrane integrity shows inhibition of the growth of the bacterium Staphylococcus epidermidis⁵⁰. In addition, the compound which can be isolated from the stem sap of Garcinia mangostana has also been shown to inhibit the growth of the bacteria Bacillus subtilis, Enterococcus faecalis, Vibrio cholera, Candida albicans, Escherichia coli, Pseudomonas aeruginosa, Mycobacterium smegmatis, M. cheleneoi, M. xenopi and M. intraculellare^51,52. While other compounds namely β and γ-mangostin are only active against a few bacteria⁵¹.

Renoprotective:

One parameter of kidney disorders is increased levels of KI (kidney hypertrophy), BUN (plasma blood urea nitrogen), and CREA (creatinine). The levels of these three parameters can be reduced by administering xanton compounds obtained from Garcinia mangostana. Xanton at doses of 100, 200, and 400mg/kg BW significantly reduced levels of KI, BUN, and CREA in rats induced by DM¹⁰.

Ethanol extract 96% from mangosteen rind at a dose of 100mg/kg body weight showed effective results to reduce plasma creatinine levels and improve the histological structure of the kidney of diabetic rats. This was suspected by the antioxidant mechanism of its xanthone compound⁵³.

Neuroprotective:

Parkinson's is a neurodegenerative disease associated with mitochondrial dysfunction, oxidative stress, and activation of the apoptotic cascade. Through its antioxidant mechanism and modulating the process of apoptosis α-mangostin can be said to have a neuroprotective effect in the cellular Parkinson model⁵⁴. This result is supported by research that shows that α-Mangostin treatment can reduce the potential of the mitochondrial membrane and cellular ATP levels by its ability to stop reactive oxygen overproduction, activation of caspases (−8 and −3) and mitochondrial dysfunction⁵⁵.

In addition to α-mangosteen, mang-mangostin is also an effective xanthone to prevent nerve degeneration in Parkinson's disease caused by oxidative stress. This is proven by the activity of γ-mangostin which can prevent the death of nerve cells induced by 6-OHDA. The protective effect of mang-mangostin is related to its antioxidant potential and through modulation of the apoptotic signaling pathway⁵⁶.

Oral administration of γ-mangostin at doses of 10 and 30 mg/kg can significantly increase memory impairment in scopolamine-induced mice. Both in vitro and in vivo mang-mangostin provide a protective effect on nerves and memory. This indicates its ability to deal with neurodegenerative diseases related to oxidative stress including Alzheimer's disease⁵⁷.

CONCLUSION:

Mangosteen has 160 aromatic compounds in epicarp and 105 compounds in endocarp, some identified as xanthone compounds. Based on these contents, according to the results of research conducted in 2013 to 2019, Garcinia mangostana Linn., Can be used as an alternative in dealing with several types of diseases, including antidiabetec, antihyperlipidemia, antiobesity, antioxidants, analgesic, anti-inflammatory, anticancer, antidepressant, antibacterial, renoprotective, and neuroprotective.

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Received on 26.02.2020 Modified on 12.04.2020

Research J. Pharm. and Tech. 2020; 13(11):5471-5476.

DOI: 10.5958/0974-360X.2020.00955.5