Medicinal Potential of Garcinia Species and Their Compounds

Garcinia is a genus of Clusiaceae, distributed throughout tropical Asia, Africa, New Caledonia, Polynesia, and Brazil. Garcinia plants contain a broad range of biologically active metabolites which, in the last few decades, have received considerable attention due to the chemical compositions of their extracts, with compounds which have been shown to have beneficial effects in several diseases. Our work had the objective of reviewing the benefits of five Garcinia species (G. brasiliensis, G. gardneriana, G. pedunculata, G. cambogia, and G. mangstana). These species provide a rich natural source of bioactive compounds with relevant therapeutic properties and anti-inflammatory effects, such as for the treatment of skin disorders, wounds, pain, and infections, having demonstrated antinociceptive, antioxidant, antitumoral, antifungal, anticancer, antihistaminic, antiulcerogenic, antimicrobial, antiviral, vasodilator, hypolipidemic, hepatoprotective, nephroprotective, and cardioprotective properties. This demonstrates the relevance of the genus as a rich source of compounds with valuable therapeutic properties, with potential use in the prevention and treatment of nontransmissible chronic diseases.

stress and, consequently, lipidic peroxidation, antioxidant capacity, and removal of free radicals, contributing to a photoprotective effect [47]. Treatment with 7-epiclusianone (12) altered the cell-cycle progression; furthermore, the capacity to form cell colonies was significantly reduced, demonstrating long-term effects. This demonstrated that 7-epiclusianone (12) is a relevant natural benzophenone with antineoplastic activity in a model of glioblastoma-a tumor with chemoresistance, demonstrating influence on growing cells, cell-cycle dynamics, apoptosis, and ability to form colonies [48]. The 7-epiclusianone (12) was isolated from G. brasiliensis for the treatment of schistosomiasis, showing efficacy against Schistosoma mansoni adult worms, cercariae, and schistosomula in vitro [49].
Administration of the ethanolic extract to rats at a concentration of 300 mg/kg produced an increased antioxidant activity through the reduction of inflammation and adiposity in obese rats. The antiobesity effect of the treated group was related to the negative regulation of the lipogenic gene of the lipoprotein lipase (LPL), the proteins of Tumor Necrosis Factor Alpha (TNF-α) and Interleukin 1 (IL-1), diminishing adipogenesis, adipocyte size, and body weight, when compared with the control group [50].
The ethanolic extract of G. brasiliensis, at a concentration of 300 mg/kg, reduced oxidative stress and inflammation in obese rats with cardiac insufficiency, and presented a promising strategy for beneficial microbiota modulation. That demonstrates the potential protective effects of two phenolic compounds, morelloflavone and 7-epiclusianone (12), present in the extract [51].
It is worth noting the method of extraction of the bioactive compounds. The use of the solvent N-hexane has demonstrated to be the most adequate for extracting guttiferone A and/or 7-epiclusianone, whereas the highest levels of fukugetin and norathyriol (17) were detected in the ethyl acetate fraction [37]. Table 1 and Figure 1 summarize the main compounds, plant part from which they were extracted, and their related activities. Table 1. Compounds present in different parts of Garcinia brasiliensis and their related activities.
Evaluation of a hydroalcoholic extract of G. gardneriana revealed that it diminished the quantity of melanin in B16F10 melanoma cells and, specifically, promoted the inhibition of tyrosinase activity [55]. The ethanolic extract conferred an additional beneficial effect to the skin as the plant has a high content of bioflavonoids, which are considered to be able to reduce the potential oxidative damage produced in the skin after exposure to ultraviolet radiation [56]. G. gardneriana presented a potential source of bioactive compounds with a significant antiproliferative effect in breast neoplastic lines in animals [57].
Phytochemical analyses of G. gardneriana detected several classes of compounds, such as steroids, triterpenes, biflavonoids, and xanthones [61]. Several biflavonoids found and identified as volkensiflavone (23), 13-naringenin-II 8-eriodictyol (GB-2a; 24), fukugetin (or morelloflavone; 9), and fukugesid (18) have demonstrated analgesic effects [62]. A new biflavonoid isolated from G. gardneriana leaves, named GB2a-OMe (25), also presented a significant analgesic effect in the formalin test in mice in the neurogenic and inflammatory phases [63]. The compound GB-2a significantly inhibited the melanin content without reducing cell viability, suggesting its great potential for medical use as a hypopigmentation agent, for cosmetic and clinical applications related to skin clearing [64]. The compound fukugetin (or morelloflavone) showed an anti-inflammatory activity in mouse paw edema induced by carrageenin at a concentration of 300 mg/kg, rendering the plant a potential target for the development of new compounds to be explored as alternatives to drugs with anti-inflammatory activity that are already in use [65].
The biflavonoids isolated from G. gardneriana, such as morelloflavone (9), Gb-2a (24), and Gb-2a-7-O-glucose (26) were submitted to an in vitro trial in order to evaluate their modulatory effects on aromatase, utilized for cancer treatment. The results showed that all biflavonoids were able to inhibit the enzyme, with IC 50 values varying from 1.35 to 7.67 µM. This demonstrates that these biflavonoids are a relevant source of new aromatase inhibitors, with focus on the development of new anticancer agents. This reinforces that the species is an important source of bioactive compounds, with applications concentrated mainly in the treatment of estrogen-dependent breast cancers [65]. Table 2 and Figure 2 summarize the main compounds of Garcinia gardneriana, the plant parts from which they were extracted, and their related activities. Table 2. List of compounds presented in different parts of Garcinia gardneriana and related activities.

Compounds
Plant Part Activity

Garcinia Pedunculata
Garcinia pedunculata Roxb. (Clusiaceae) is a tree endemic to some Asian regions-namely to parts of Myanmar and oriental parts of India. The fruit is known as "taikor" in Bangladesh and

Garcinia Pedunculata
Garcinia pedunculata Roxb. (Clusiaceae) is a tree endemic to some Asian regions-namely to parts of Myanmar and oriental parts of India. The fruit is known as "taikor" in Bangladesh and "amlavetasa" in India [66]. It also is an indigenous medicinal plant. Traditionally, the fruit has been utilized by people to treat several gastrointestinal disorders [67], as a cardiotonic, and as an emollient. It is also utilized in the treatment of asthma, cough, bronchitis, diarrhea, and fever [68].
Among the reported benefits of G. pedunculata fruit are antioxidant [70][71][72][73][74][75], antimicrobial [76], anti-inflammatory [71], hypolipidemic [77], hepatoprotective [66], and nephroprotective effects [71], as well as cardioprotective properties [77]. The peel and the pericarp of dry fruits have been shown to contain benzophenones, pedunculol (27), garcinol (28), cambogin (29), and hydroxycitric acid (HCA; 30) [70], some of which are potent antioxidants. Some research has suggested that benzophenones and garcinol present protective effects against the toxicity of carbon tetrachloride in hepatocytes of Molecules 2020, 25, 4513 9 of 30 rats [70] and anti-inflammatory effects in hepatocytes of mice [78]. An ethanolic extract of the fruit showed significant hepatoprotective, cardioprotective, and hypoglycemic activities in the treatment of Long Evans rats with a daily dose of 1000 mg/kg for 21 days [79]. The nephroprotective effect detected with the administration of a water extract of the fruit peel at concentrations of 200 and 400 mg/kg of weight was attributed to its general cytoprotective effect, which promptly impeded the ischemic damage caused by acute toxicity by cisplatin, a cytotoxic agent that has effects on the kidneys, liver, and neural tissues [80].
Administration of the extract of G. pedunculata fruit significantly reduced blood glucose levels, demonstrating the possibility of reduction of hyperglycemia, diabetes, diabetic comorbidities, and protection against damages induced by oxidative stress [81]. Administration of methanolic extract at a concentration of 200 mg/kg attenuated hyperlipidemia and oxidative stress in the studied animals [77]. Evaluation of a methanolic extract of the fruit showed antioxidant activity, having free-radical scavengers and the capacity to protect cells from lipidic peroxidation, which is associated with the treatment of degenerative diseases and diabetes [77,82].
A recent study on an aqueous extract of fruits of G. pedunculata given to rats at 200 and 400 mg/kg of body weight observed a significant reduction in damage caused by colitis, preventing oxidative peroxidation. At the dose of 400 mg/kg, the lipidic peroxidation was reverted significantly, and in several parameters of inflammation generated in the colon showed improvement (i.e., the punctuation of macroscopic damage, lipidic peroxidation, and histopathological exam of the colon tissue), demonstrating its therapeutical potential for the treatment of colitis [83].

Garcinia Cambogia
Garcinia cambogia L., known as Malabar tamarind, is a plant native to Southeast Asia. The fruit is used as a food preservative, carminative, and flavoring agent [82]. The fruit contains hydroxycitric acid (HCA; 30) and is a popular ingredient utilized for weight reduction [85,86]. Semwal [85] presented a revision of the species, citing the presence of organic acids, such as HCA, in the fruits, as well as the xanthones oxy-guttiferone-I (40) [87]. In that same study, the presence of the xanthone garbogiol was reported in the roots. In the peel, the presence of rheediaxanthone-A [86], benzophenonesgarcinol (28), and isogarcinol (29) was also reported.

Garcinia Cambogia
Garcinia cambogia L., known as Malabar tamarind, is a plant native to Southeast Asia. The fruit is used as a food preservative, carminative, and flavoring agent [82]. The fruit contains hydroxycitric acid (HCA; 30) and is a popular ingredient utilized for weight reduction [85,86]. Semwal [85] presented a revision of the species, citing the presence of organic acids, such as HCA, in the fruits, as well as the xanthones oxy-guttiferone-I (40) [87]. In that same study, the presence of the xanthone garbogiol was reported in the roots. In the peel, the presence of rheediaxanthone-A [86], benzophenonesgarcinol (28), and isogarcinol (29) was also reported.
The hypolipidemic effect of the G. cambogia extract has been attributed to its high content of flavonoids [100]. The generated anti-inflammatory effects resulted in the improvement of some parameters analyzed in experimental colitis, where 2,4,6-Trinitrobenzenesulfonic acid (TNBS)/ethanol caused lesions characterized by severe necrosis of the mucosa, hyperemia, and focal adhesion to adjacent organs. Administration of the extract by oral gavage at a dose of 1.0 The hypolipidemic effect of the G. cambogia extract has been attributed to its high content of flavonoids [100]. The generated anti-inflammatory effects resulted in the improvement of some parameters analyzed in experimental colitis, where 2,4,6-Trinitrobenzenesulfonic acid (TNBS)/ethanol caused lesions characterized by severe necrosis of the mucosa, hyperemia, and focal adhesion to adjacent organs. Administration of the extract by oral gavage at a dose of 1.0 g/kg reduced the length of the lesions observed macroscopically; thus, it may provide a source to search for new anti-inflammatory compounds useful in the treatment of intestinal inflammatory diseases [101].
Garcinia cambogia showed an antiobesity effect and a significant reduction in the values of triacylglycerol (TAG) of the adipose tissue and liver of the tested groups; however, it significantly increased the TAG pool of the gastrointestinal system [95,102,103]. The plant also reduced the serum levels of total cholesterol, triglycerides, and insulin, as well as the intolerance of glucose and levels of alpha-TNF associated with hyperlipidic diets [95,[102][103][104][105]. G. cambogia extracts have also been shown to trigger the myotubes and skeleton cells to absorb glucose and to equilibrate the glucose levels in the blood [106].
This species also has already shown favorable results in tests in humans-either healthy or bearing some nontransmissible chronic disease-for 6 months. Treatment with 500 mg of HCA, twice a day, promoted weight loss and reduction of fatty mass, visceral fat, total cholesterol, and glycemic profile. Furthermore, an increase of the basal metabolic rate was perceived, independent of sex, age, or bearing hypertension, diabetes mellitus type 2, or dyslipidemia [107].
The HCA (30) present in G. cambogia is a potent and competent inhibitor of adenosinetriphosphate (ATP) citrate lyase, which is a key enzyme in the synthesis of fatty acids, cholesterol, and triglycerides [85,108]. It also regulates the level of serotonin, which has been associated with satiety, increased oxidation of fat, and decreased gluconeogenesis [85,109]. This explains how the compound exerts weight-loss activity, with reduced food ingestion and reduction of accumulated gain of body fat [85,[108][109][110]. HCA (30) presents a chemical structure similar to citric acid and, therefore, inhibits the action of adenosine triphosphate (ATP) citrate lyase in the citric acid cycle. This action inhibits the conversion of citric acidinacetyl-coenzyme A (CoA) and suppresses the synthesis of fatty acids. The increased quantity of citric acid that is not converted into acetyl-CoA leads to acceleration of the production of glycogen from glucose. Thus, the ingestion of HCA (30) stabilizes glucose levels in the blood, resulting in the suppression of feelings of hunger. Therefore, it is also expected to show a preventive effect against hyperphagia [111][112][113][114][115]. Earlier studies showed that HCA (30) reduced the build-up of lipidic droplets and accelerated the energy metabolism, besides protecting cells from oxidative stress, as well as increasing the antioxidant status and mitochondrial functions [116,117].
Despite the benefits present in the species, some studies have shown that its consumption can cause adverse effects, such as headache, dizziness, dry mouth, nausea, and diarrhea [118]. Recent studies have described (hypo)mania and/or psychosis after the consumption of G. cambogia [87,[119][120][121]. Some liver complications have also been reported, such as hepatotoxicity, with acute hepatic lesions, acute hepatitis, and hepatic insufficiency requiring transplant [122][123][124][125]. The complications from G. cambogia include mania or hypomania, mania with psychosis, and serotonin syndrome [10,126]. When taken over the recommended dose, individuals should be aware that the extract of G. cambogia can also lead to ocular complications [127].
HCA (30), the main active ingredient of G. cambogia extracts, presents effects of inhibiting the recapture of serotonin, inhibiting acetylcholinesterase, increasing the oxidation of fatty acids, and reducing lipogenesis [85]. The serotoninergic effects of HCA (30) are worrisome and can contribute to serotonin syndrome when combined with serotonin recapture inhibitors [109].
Some cases have been reported of acute pancreatitis secondary to the use of G. cambogia [128,129]. The pathogenesis of how such an increased risk of acute pancreatitis may occur is not clear; however, there is evidence that active oxygen species may play a central role in this pathogenesis. Garcinia cambogia increases lipidic peroxidation and positively regulates the expression of superoxide dismutase and glutathione peroxidase messenger ribonucleic acid (RNA) [130]. Lipidic peroxidation also increases oxidative stresss and can increase the risk of acute pancreatitis in patients using the species [131]. G. cambogia can cause other severe adverse events, including hepatoxicity and secondary acute hepatic insufficiency [124,132]. Other studies have also shown acute necrotizing eosinophilic myocarditis, rhabdomyolysis, serotonin toxicity, and nephropathy secondary to the use of G. cambogia [87,121,122,[128][129][130][131][132][133][134][135][136]. Table 4 and Figure 4 describe the main compounds, the plant parts they have been extracted from, and their related activities.

Garcinia Mangostana
Garcinia mangostana L. is a tropical evergreen fruit tree native to Southeast Asia, with the popular name of mangosteen, known for containing several constituents including xanthones, flavonoids, triterpenoids, and benzophenones [64]. In many Asian countries, the peel of G. mangostana has been used in traditional medicine to cure various diseases, such as diarrhea, dysentery, skin infections, mycosis, inflammation, cholera, and fever [139,140]. Fruit extracts have exhibited antioxidant [141,142], anti-inflammatory [143,144], antibacterial [145], and antidepressive effects [146]. In particular, α-mangostin (AM; 49), a primary component of G. mangostana, has presented substantial pharmacological properties [147,148], including antioxidant activity in the treatment of age-related macular degeneration and protecting the retina from light damage [149].
Its pharmacological properties have been attributed to the presence of polyphenols such as xanthones, anthocyanins, phenolic acids, and flavonoids [142,150]. It has demonstrated antioxidant, anti-inflammatory, antitumoral, antibacterial, antifungal, antiviral, and anti-allergic properties [150,151]. Alfa-mangostin (49) is one of the most abundant xanthones in G. mangostana. The presented anti-inflammatory effects have been evidenced by reduced levels of TNF-α and IL-6 [152,153]. It has also shown antihyperglycemic, antioxidant, and anti-inflammatory effects, as well as improved blood flux and integrity of the retina [153,154]. The fruit has also produced improved results in terms of adiposity, hyperlipidemia, insulin resistance, and hepatic lesion related to ageing [155].

Garcinia Mangostana
Garcinia mangostana L. is a tropical evergreen fruit tree native to Southeast Asia, with the popular name of mangosteen, known for containing several constituents including xanthones, flavonoids, triterpenoids, and benzophenones [64]. In many Asian countries, the peel of G. mangostana has been used in traditional medicine to cure various diseases, such as diarrhea, Mangosteen is used, in the form of an infusion, as a tonic for fatigue and as a digestive [139]. It can also be utilized for its medicinal properties in hemorrhoids, flood allergies, arthritis, tuberculosis, mycosis, mouth sores, fever, candidiasis, abdominal pain, suppuration, leucorrhea, and convulsions [140].
A hepatoprotective effect, which has previously been shown as one of the actions of α-mangostin [159], and renoprotective action were also found in streptozotocin-induced diabetic mice [160]. Some authors have cited the compound α-mangostin (49) as having anticancer activities, being capable of inducing cell death via apoptosis of human colorectal carcinomas [161,162]. This compound has presented antioxidant activity and evidences the benefits of the fruit in improving the kidney structure and function in diabetic rats [157]. In human melanoma, breast cancer, and epidermoid carcinoma, the compound α-mangostin had a cytotoxic effect, inducing the death of the cited cells [163,164].
One study on the mangosteen pericarp demonstrated a wide range of activities, including antifungal, antioxidant, antiobesity, and antidiabetic properties [139]. Its hypoglycemic power is due to the inhibition of the activity of α-glucosidase and α-amylase, enzymes responsible for the digestion of carbohydrates [158].
Some studies have presented satisfactory results with respect to the endogenous antioxidant system, demonstrating a high level of antioxidant enzymes in the organisms of the tested animals. Such effects suggest the capacity of the fruit to eliminate free radicals from the biological system [165]. Human adipocytes treated with α-mangostin (49) showed a decrease in the expression of inflammatory genes, as well as reducing insulin resistance [166]. Indeed, the daily consumption of a mangosteen drink for 30 days in healthy adults resulted in reduction of the inflammatory markers and increased the antioxidant capacity of human blood, due to reduction of the inflammatory marker C-reactive protein, reducing the risk of inflammation and chronic diseases related to immunity [167]. Thus, it has been proven that the mangosteen is a plant which can provide benefits in the development of drugs for the prevention and treatment of numerous diseases, mainly as it is a rich source of xanthones and other bioactive substances [159].
A study on rats fed daily with an aqueous extract of mangosteen pericarp (100 and 200 mg/kg, 38 days) showed that they exhibited significant improvements in memory loss. The extract, rich in xanthones, was also capable of restoring acetylcholinesterase activity in the dysfunction induced by lead in red blood cells and brain tissue. The presence of the xanthones αand γ-mangostin (55), 3-isomangostin (57), gartanin (54), garciniafuran (62), 9-hydroxycalabaxanthone (63), and garcinone -C (64) and -d (65) was verified [134]. Table 5 and Figure 5 list the main compounds of Garcinia mangostana, the plant part where they have been extracted from, and their related ativities. Table 5. List of compounds presented in different parts of Garcinia mangostana and their related activities.

Compounds
Plant Part Activity

Conclusions
Plant species of the genus Garcinia are a relevant source of bioactive compounds. This review compiled the bioactive compounds found in five species of the genus Garcinia, as well as the effects of several types of extracts of different plant parts. Plants from genus Garcinia exhibits healing properties with anti-inflammatory effects, for the treatment of such ailments as skin disorders, wounds, pain, and infections, as well as presenting antinociceptive, antioxidant, antitumoral, antifungal, anticancer, antihistaminic, antiulcerogenic, antimicrobial, antiviral, vasodilatory, hypolipemic, hepatoprotective, nephroprotective, and cardioprotective properties. It was possible to observe that, across all the species mentioned in the present review, most of the studies carried out were in vitro experiments. Some tests have already been started in in vivo models; however, these are recent studies evaluating the effectiveness of the plant in treating diseases in animal models. These studies are promising and open up new perspectives on the use of the compounds present in these species, offering new perspectives on the possibility of developing new drugs. For this to be effective, it is necessary to initiate plant-use tests in humans, in order to analyze their effectiveness in treating diseases. Therefore, considering the high number of compounds found in plants of the genus and their beneficial effects, additional studies are required to support the development of new products with therapeutic properties for the prevention and treatment of various diseases; most importantly, non-transmissible chronic diseases. Therefore, these plants provide a promising potential source of natural biomolecules for pharmaceutical and medicinal applications.

Conclusions
Plant species of the genus Garcinia are a relevant source of bioactive compounds. This review compiled the bioactive compounds found in five species of the genus Garcinia, as well as the effects of several types of extracts of different plant parts. Plants from genus Garcinia exhibits healing properties with anti-inflammatory effects, for the treatment of such ailments as skin disorders, wounds, pain, and infections, as well as presenting antinociceptive, antioxidant, antitumoral, antifungal, anticancer, antihistaminic, antiulcerogenic, antimicrobial, antiviral, vasodilatory, hypolipemic, hepatoprotective, nephroprotective, and cardioprotective properties. It was possible to observe that, across all the species mentioned in the present review, most of the studies carried out were in vitro experiments. Some tests have already been started in in vivo models; however, these are recent studies evaluating the effectiveness of the plant in treating diseases in animal models. These studies are promising and open up new perspectives on the use of the compounds present in these species, offering new perspectives on the possibility of developing new drugs. For this to be effective, it is necessary to initiate plant-use tests in humans, in order to analyze their effectiveness in treating diseases. Therefore, considering the high number of compounds found in plants of the genus and their beneficial effects, additional studies are required to support the development of new products with therapeutic properties for the prevention and treatment of various diseases; most importantly, non-transmissible chronic diseases. Therefore, these plants provide a promising potential source of natural biomolecules for pharmaceutical and medicinal applications.