Stem Extract from Momordica cochinchinensis Induces Apoptosis in Chemoresistant Human Prostate Cancer Cells (PC-3).

Natural compounds have been recognized as valuable sources for anticancer drug development. In this work, different parts from Momordica cochinchinensis Spreng were selected to perform cytotoxic screening against human prostate cancer (PC-3) cells. Chromatographic separation and purification were performed for the main constituents of the most effective extract. The content of the fatty acids was determined by Gas Chromatography-Flame Ionization Detector (GC-FID). Chemical structural elucidation was performed by spectroscopic means. For the mechanism of the apoptotic induction of the most effective extract, the characteristics were evaluated by Hoechst 33342 staining, sub-G1 peak analysis, JC-1 staining, and Western blotting. As a result, extracts from different parts of M. cochinchinensis significantly inhibited cancer cell viability. The most effective stem extract induced apoptosis in PC-3 cells by causing nuclear fragmentation, increasing the sub-G1 peak, and changing the mitochondrial membrane potential. Additionally, the stem extract increased the pro-apoptotic (caspase-3 and Noxa) mediators while decreasing the anti-apoptotic (Bcl-xL and Mcl-1) mediators. The main constituents of the stem extract are α-spinasterol and ligballinol, as well as some fatty acids. Our results demonstrated that the stem extract of M. cochinchinensis has cytotoxic and apoptotic effects in PC-3 cells. These results provide basic knowledge for developing antiproliferative agents for prostate cancer in the future.

HDAC inhibitor cowanin extracted from G. fusca induces apoptosis and autophagy via inhibition of the PI3K/Akt/mTOR pathways in Jurkat cells.

Cowanin, a xanthone derivative extracted from the Garcinia fusca plant, has been recognized for various biological activities including, antimicrobial, anti-inflammatory, and anticancer activities. However, the mechanism to induce cancer cell death in cancer cells remains to be fully elucidated. Our previous report showed that other xanthones from these plants could act as histone deacetylase inhibitors (HDACi), so we deeply analyzed the role of cowanin, a major compound of G.fusca, and investigated through the mode of cell death both apoptosis and autophagy that have never been reported. As a result, it was demonstrated that cowanin indicated the role of HDACi as other xanthones. The molecular docking analysis showed that cowanin could interact within the catalytic pocket region of HDAC class I (HDAC2, 8) and II (HDAC4, 7) proteins and inhibit their activity. Also, the level of protein expression of HDAC2, 4, 7, and 8 was distinctly decreased, and the level of histone H3 and H4 acetylation increased in cowanin treated cells. For the mode of cell death, cowanin demonstrated both apoptosis and autophagy activation in Jurkat cells. Besides, cowanin significantly suppressed phosphorylation of PI3K, Akt, and mTOR signaling. Therefore, these findings revealed that cowanin represents a new promising candidate for development as an anticancer agent by inducing apoptosis and autophagy via PI3K/AKT/mTOR pathway and effectively inhibiting HDAC activity.

Highly potent cholinesterase inhibition of geranylated xanthones from Garcinia fusca and molecular docking studies.

Three new oxygenated xanthones, fuscaxanthones L-N (1-3), and 14 known xanthones 4-17, together with the other known metabolites 18-20 were isolated from the stem barks of Garcinia fusca Pierre. Their chemical structures were determined based on NMR and MS spectroscopic data analysis, as well as single X-ray crystallography. The geranylated compounds, cowanin (13), cowagarcinone E (15), norcowanin (16) and cowanol (17) exhibited potent inhibitions against acetylcholinesterase (AChE) (IC50 0.33-1.09 µM) and butyrylcholinesterase (BChE) (IC50 0.048-1.84 µM), which were more active than the reference drug, galanthamine. Compound 15 was highly potent BChE inhibitor (IC50 0.048 µM) and was 76-fold more potent than the drug. Structure-activity relationship studies indicated that the C-2 prenyl and C-8 geranyl substituents in the tetraoxygenated scaffold are important for high activity. Molecular docking studies revealed that the leads 13 and 15-17 showed similar binding orientations on both enzymes and very well-fitted at the double binding active sites of PAS and CAS with strong hydrophobic interactions from both isoprenyl side chains.

Effects of Long-Term Alpha-mangostin Supplementation on Hyperglycemia and Insulin Resistance in Type 2 Diabetic Rats Induced by High Fat Diet and Low Dose Streptozotocin.

OBJECTIVE: The present study investigated the effects of long-term supplementation of alpha-mangostin (MG; a xanthone isolated from mangosteen fruit) on hyperglycemia, and insulin resistance in type 2 diabetic rats. MATERIAL AND METHOD: Type 2 diabetes (DM2) was induced in male Sprague-Dawley rats by feeding high fat diet for three weeks followed by an IP injection of low dose streptozotocin. The rats were divided into four groups: control and diabetes without or with alpha-MG supplementation (CON, DM2, CON-MG and DM2-MG group, respectively). Alpha-MG was administered by gavage feeding in the amount of 200 mg/kg BW/day for 8 or 40 weeks. Fasting blood glucose, plasma HbA1c, cholesterol, and triglyceride were determined in all groups of rats. Serum insulin, calculated HOMA-IR and Oral glucose tolerance test were also carried out. RESULTS: The results showed that both 8 and 40 weeks DM2 groups had a significant increase in fasting blood glucose, HbA1c, plasma cholesterol and triglyceride compared with their aged-match control groups. Furthermore, the serum insulin and HOMA-IR were significantly elevated in 8 weeks DM2 whereas these two parameters were significantly decreased in 40 weeks DM2 group compared with their aged-match CON groups (p < 0.001). The OGTT showed impaired glucose tolerance in DM2 groups. Interestingly, alpha-MG supplemented DM2-MG group had significantly decreased levels of fasting blood glucose, HbA1c, plasma cholesterol, triglyceride when compared with the untreated DM2 groups. Supplementation of alpha-MG for 40 weeks in DM2-MG group showed significantly increase serum insulin levels compared with that of DM2 group (p < 0.001). Moreover alpha-MG supplemented DM-MG group demonstrated a better glucose tolerance pattern which was different from that of DM2 group at both 8 weeks and 40 weeks experimental periods. CONCLUSION: Long-term alpha-mangostin supplementation has anti-hyperglycemic, anti-hyperlipidemic effects and increase insulin sensitivity by improving beta-cell functions in type 2 diabetes mellitus.

Dietary α-mangostin, a xanthone from mangosteen fruit, exacerbates experimental colitis and promotes dysbiosis in mice.

SCOPE: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. α-Mangostin (α-MG), the most abundant xanthone in mangosteen fruit, exerts anti-inflammatory and antibacterial activities in vitro. We evaluated the impact of dietary α-MG on murine experimental colitis and on the gut microbiota of healthy mice. METHODS AND RESULTS: Colitis was induced in C57BL/6J mice by administration of dextran sulfate sodium (DSS). Mice were fed control diet or diet with α-MG (0.1%). α-MG exacerbated the pathology of DSS-induced colitis. Mice fed diet with α-MG had greater colonic inflammation and injury, as well as greater infiltration of CD3(+) and F4/80(+) cells, and colonic myeloperoxidase, than controls. Serum levels of granulocyte colony-stimulating factor, IL-6, and serum amyloid A were also greater in α-MG-fed animals than in controls. The colonic and cecal microbiota of healthy mice fed α-MG but no DSS shifted to an increased abundance of Proteobacteria and decreased abundance of Firmicutes and Bacteroidetes, a profile similar to that found in human UC. CONCLUSION: α-MG exacerbated colonic pathology during DSS-induced colitis. These effects may be associated with an induction of intestinal dysbiosis by α-MG. Our results suggest that the use of α-MG-containing supplements by patients with UC may have unintentional risk.

Combating Helicobacter pylori infections with mucoadhesive nanoparticles loaded with Garcinia mangostana extract.

AIM: To combat the resistance of Helicobacter pylori to antibiotics through the use of Garcinia mangostana extract (GME) in the form that can be localized at stomach mucosa. MATERIALS & METHODS: GME and its major active component, α-mangostin, are encapsulated into the moderately acid stable mucoadhesive nanocarriers, and tested for anti-H. pylori and antiadhesion activities in vitro and their ability to eradicate H. pylori in infected mice. RESULTS: The two in vitro activities are observed and are enhanced when the materials are encapsulated into nanocarriers. Preliminary in vivo tests revealed the ability to combat H. pylori in mice following oral administration of the encapsulated GME, but not the unencapsulated GME. CONCLUSION: Nanoencapsulated GME is a potential anti-H. pylori agent.

Antileptospiral activity of xanthones from Garcinia mangostana and synergy of gamma-mangostin with penicillin G.

BACKGROUND: Leptospirosis, one of the most widespread zoonotic infectious diseases worldwide, is caused by spirochetes bacteria of the genus Leptospira. The present study examined inhibitory activity of purified xanthones and crude extracts from Garcinia mangostana against both non-pathogenic and pathogenic leptospira. Synergy between γ-mangostin and penicillin G against leptospires was also determined. METHODS: Minimal inhibitory concentrations (MIC) of crude extracts and purified xanthones from G. mangostana and penicillin G for a non-pathogenic (L. biflexa serovar Patoc) and pathogenic (L. interrogans serovar Bataviae, Autumnalis, Javanica and Saigon) leptospires were determined by using broth microdilution method and alamar blue. The synergy was evaluated by calculating the fractional inhibitory concentration (FIC) index. RESULTS: The results of broth microdilution test demonstrated that the crude extract and purified xanthones from mangosteen possessed antileptospiral activities. The crude extracts were active against all five serovars of test leptospira with MICs ranging from 200 to ≥ 800 µg/ml. Among the crude extracts and purified xanthones, garcinone C was the most active compound against both of pathogenic (MIC =100 µg/ml) and non-pathogenic leptospira (MIC = 200 µg/ml). However, these MIC values were higher than those of traditional antibiotics. Combinations of γ-mangostin with penicillin G generated synergistic effect against L. interrogans serovars Bataviae, Autumnalis and Javanica (FIC = 0.52, 0.50, and 0.04, respectively) and no interaction against L. biflexa serovar Patoc (FIC =0.75). However, antagonistic activity (FIC = 4.03) was observed in L. interrogans serovar Saigon. CONCLUSIONS: Crude extracts and purified xanthones from fruit pericarp of G. mangostana with significant antibacterial activity may be used to control leptospirosis. The combination of xanthone with antibiotic enhances the antileptospiral efficacy.

Potential of xanthones from tropical fruit mangosteen as anti-cancer agents: caspase-dependent apoptosis induction in vitro and in mice.

The pericarp of mangosteen (Garcinia mangostana L.) is rich in various xanthones that are known to possess unique biological activities. In this work, we characterized the anti-proliferative and cytotoxic activities of mangosteen xanthones both in vitro and in mice. In vitro analysis with a human colorectal adenocarcinoma cell line, COLO 205, showed that mangosteen xanthones not only inhibit the proliferation of target cells but also induce their death by apoptosis that involves the activation of the caspase cascade. In vivo analysis using a mouse subcutaneous tumor model with COLO 205 cells showed that, at relatively low doses, the growth of tumors was repressed upon intratumoral administration of mangosteen xanthones. When a higher dose of mangosteen xanthones was administered, the size of tumors was reduced gradually, and, in some mice, the disappearance of tumors was seen. Histopathological evaluation and biochemical analysis of tumors that received mangosteen xanthones indicate the induction of apoptosis in tumors, which resulted in the repression of their growth and the reduction of their sizes. These results demonstrate the potential of mangosteen xanthones to serve as anti-cancer agents for the chemotherapy of cancer.

Iridoid glucosides from the flowers of Barleria lupulina.

A new iridoid diglucoside, lupulinoside, and eight known iridoid glucosides, acetylbarlerin, ipolamiidoside ( 3), 6-O-acetylshanzhiside methyl ester, barlerin, shanzhiside methyl ester, mussaenosidic acid, 8-O-acetylshanzhiside, and shanzhiside have been isolated from the flowers of Barleria lupulina. The structure of the new compound was established as 8-O-acetyl-2'- O-(beta-glucopyranosyl)mussaenoside by spectroscopic, especially 2D NMR, techniques. When tested for anti-herpes simplex type 1 activity, only compound 3 exhibited antiviral properties. None of the compounds showed cytotoxic effects to the vero cells and none of them inhibited cyclooxygenase-2 enzyme.

Antimycobacterial and antioxidant flavones from Limnophila geoffrayi.

The chloroform extract of the aerial part of Limnophila geoffrayi showed antimycobacterial and antioxidant activities. Bioassay-guided fractionation has led to the isolation of the flavones nevadensin (5,7-dihydroxy-6,8,4'-trimethoxyflavone, 1) and isothymusin (6,7-dimethoxy-5,8,4'-trihydroxyflavone, 2). Both compounds 1 and 2 exhibited inhibition activity against Mycobacterium tuberculosis, with equal MIC value of 200 microg/mL. Only compound 2 exhibited antioxidant activity against the radical scavenging ability of DPPH, with the IC50 value of 7.7 microg/mL. The crude hexane, chloroform and methanol extracts as well as the pure compounds 1 and 2 did not exhibit mutagenic activity in the Bacillus subtilis recassay.

Xanthones from the green fruit hulls of Garcinia mangostana.

Three new xanthones, mangostenol (1), mangostenone A (2), and mangostenone B (3), were isolated from the green fruit hulls of Garcinia mangostana, along with the known xanthones, trapezifolixanthone, tovophyllin B (4), alpha- and beta-mangostins, garcinone B, mangostinone, mangostanol, and the flavonoid epicatechin. The structures of the new xanthones were elucidated by analysis of their spectroscopic data.