Garcinia morella extract confers dopaminergic neuroprotection by mitigating mitochondrial dysfunctions and inflammation in mouse model of Parkinson's disease.

Dopaminergic neuroprotection is the main interest in designing novel therapeutics against Parkinson's disease (PD). In the process of dopaminergic degeneration, mitochondrial dysfunctions and inflammation are significant. While the existing drugs provide symptomatic relief against PD, a therapy conferring total neuroprotection by targeting multiple degenerative pathways is still lacking. Garcinia morella is a common constituent of Ayurvedic medication and has been used for the treatment of inflammatory disorders. The present study investigates whether administration of G. morella fruit extract (GME) in MPTP mouse model of PD protects against dopaminergic neurodegeneration, including the underlying pathophysiologies, and reverses the motor behavioural abnormalities. Administration of GME prevented the loss of dopaminergic cell bodies in the substantia nigra and its terminals in the corpus striatum of PD mice. Subsequently, reversal of parkinsonian behavioural abnormalities, viz. akinesia, catalepsy, and rearing, was observed along with the recovery of striatal dopamine and its metabolites in the experimental model. Furthermore, reduced activity of the mitochondrial complex II in the nigrostriatal pathway of brain of the mice was restored after the administration of GME. Also, MPTP-induced enhanced activation of Glial fibrillary acidic protein (GFAP) and neuronal nitric oxide synthase (nNOS) in the nigrostriatal pathway, which are the markers of inflammatory stress, were found to be ameliorated on GME treatment. Thus, our study presented a novel mode of dopaminergic neuroprotection by G. morella in PD by targeting the mitochondrial dysfunctions and neuroinflammation, which are considered to be intricately associated with the loss of dopaminergic neurons.

Physicochemical Properties and Effects of Fruit Pulps from the Amazon Biome on Physiological Parameters in Rats.

This study aimed to analyze the physicochemical characteristics and the effects of Amazonian pulp fruits consumption, such as araçá-boi (Eugenia stipitata), abiu grande (Pouteria caimito), araticum (Annona crassiflora), biri-biri (Averrhoa bilimbi L.), and yellow mangosteen (Garcinia xanthochymus), on hematologic, metabolic, renal, and hepatic function parameters in Wistar rats (n = 10 rats/group). The pulp of abiu had the highest levels of soluble solids, sugars, and pH. Biri-biri pulp had the highest levels of ascorbic acid and total titratable acidity, and a low pH. The araticum pulp had higher (p ≤ 0.05) ash content, total phenolic compounds, and antioxidant activity than the pulp of other analyzed fruits. No significant increase in hematocrit, nor reduction of blood glucose, plasma cholesterol, and serum levels of glutamic-pyruvic transaminase (TGP), creatinine, and urea was observed in experimental groups relative to the control group of rats after the consumption of fruits pulp. The intake of abiu and araticum pulps promoted a significant reduction (p ≤ 0.05) in total leukocytes of the experimental groups as compared to the control group and only the intake of araticum significantly increased (p ≤ 0.05) triglyceride blood levels in rats (99.50 mg/dL). The regular consumption of biri-biri pulp for 30 days significantly (p ≤ 0.05) increased serum glutamic-oxaloacetic transaminase (TGO) levels in rats (116.83 U/L) compared to the control group (98.00 U/L). More researches are needed to generate knowledge about these promising Amazonian fruits, supporting the native fruit production, in addition to promoting health in the population and sustainability in the Amazon region.

DNA Repair Biosensor-Identified DNA Damage Activities of Endophyte Extracts from Garcinia cowa.

Recent developments in chemotherapy focus on target-specific mechanisms, which occur only in cancer cells and minimize the effects on normal cells. DNA damage and repair pathways are a promising target in the treatment of cancer. In order to identify novel compounds targeting DNA repair pathways, two key proteins, 53BP1 and RAD54L, were tagged with fluorescent proteins as indicators for two major double strand break (DSB) repair pathways: non-homologous end-joining (NHEJ) and homologous recombination (HR). The engineered biosensor cells exhibited the same DNA repair properties as the wild type. The biosensor cells were further used to investigate the DNA repair activities of natural biological compounds. An extract from Phyllosticta sp., the endophyte isolated from the medicinal plant Garcinia cowa Roxb. ex Choisy, was tested. The results showed that the crude extract induced DSB, as demonstrated by the increase in the DNA DSB marker γH2AX. The damaged DNA appeared to be repaired through NHEJ, as the 53BP1 focus formation in the treated fraction was higher than in the control group. In conclusion, DNA repair-based biosensors are useful for the preliminary screening of crude extracts and biological compounds for the identification of potential targeted therapeutic drugs.

Efficient Semi-Synthesis of Natural δ-( R)-Tocotrienols from a Renewable Vegetal Source.

Recent studies have highlighted the biological potential of tocotrienols, a vitamin E subfamily. The major natural sources of tocotrienols are complex mixtures requiring particularly challenging purification processes. The present study describes efficient semi-synthetic strategies toward relevant δ-( R)-tocotrienol derivatives, using as a starting material δ-( R)-garcinoic acid, the major vitamin E derivative isolated from Garcinia kola nuts, a renewable vegetal source.

Gambogic acid prevents angiotensin II­induced abdominal aortic aneurysm through inflammatory and oxidative stress dependent targeting the PI3K/Akt/mTOR and NF­κB signaling pathways.

Gamboge is the dry resin secreted by Garcinia hanbaryi Hook.f, with the function of promoting blood circulation and anti­cancer effects, detoxification, hemostasis and killing insects. It is also used for the treatment of cancer, brain edema and other diseases. Gambogic acid is the main effective constituent of Gamboge. The present study tested the hypothesis that the effect of Gambogic acid prevents angiotensin II­induced abdominal aortic aneurysm (AAA), and explored its underlying mechanism. It was demonstrated that gambogic acid significantly inhibited AAA incidence rate, and reduced edge leading aortic diameter and aortic wall thickness in AAA mice. Gambogic acid treatment markedly decreased the levels of proinflammatory cytokines and oxidative stress factors, and transforming growth factor­ß (TGF­ß) and matrix metalloproteinase (MMP)­2 and MMP­9 protein expression in AAA mice. Furthermore, Gambogic acid decreased expression of phosphatidylinositol 3­kinase (PI3K), and phosphorylation of protein kinase B (Akt), mechanistic target of rapamycin (mTOR) and p70­S6 kinase 1. It also suppressed nuclear factor (NF)­κB protein expression in AAA mice. The findings of the present study indicated that Gambogic acid prevents angiotensin II­induced AAA through inflammatory and oxidative stress­dependent targeting of the PI3K/Akt/mTOR and NF­κB signaling pathways.

Polyprenylated polycyclic acylphloroglucinol: Angiogenesis inhibitor from Garcinia multiflora.

A new polyprenylated polycyclic acylphloroglucinol, garcimultiflorone K (1), has been isolated from the stems of Garcinia multiflora, together with two known compounds, garcimultiflorone A (2) and garcimultiflorone B (3). The structure of new compound 1 was determined through spectroscopic methods including 1D and 2D NMR and MS analyses. The anti-angiogenic and anti-cancer effects of compounds 1-3 were evaluated in human endothelial progenitor cells (EPCs) and cancer cells. Of these, garcimultiflorone K (1) displayed the most potent anti-angiogenic property by suppressing cell growth and tube formation of EPCs. Compound 1 also exhibited growth-inhibitory activities against human hepatocellular carcinoma cell line SK-Hep-1 and hormone refractory prostate cancer cell line PC-3 with GI50 values of 4.3 ±â€¯1.6 and 6.6 ±â€¯0.4 µM, respectively.

Biofabrication of silver nanoparticles and their combined effect with low intensity ultrasound for treatment of lung cancer.

Ablation treatments are the minimally invasive surgical procedures that are used to treat early stage cancers. High intensity ultrasonic treatments that are used to treat solid cancers are not much successful in differentiating between healthy and cancerous cells. In this study, a method of combining ultrasound treatment with Garcinia mangostana bark extract mediated silver nanoparticles (AgNPs) was extended by making use of human lung epithelial cells, that could preferentially destruct the cancerous cells. Flow cytometry analysis is used to study the effect of ultrasound and AgNPs on cancerous (A549) cell lines and healthy (BEAS-2B) lung cells by means of counting viable cells (Q4). These experimental data showed a minor decline in the percentage of living cells from (66.8 ±â€¯3.2) to (56 ±â€¯6.2) % after the addition of bark extract synthesized AgNPs to the US-treated normal BEAS- 2B cell lines. However, the percentage of live A549 cancer cells presented a significant reduction from (61.4 ±â€¯4.2) % for US-treated cells to (28.7 ±â€¯6.4) % for the combination treatment of US with AgNPs. This study conducted against various cell lines denoted that nanoparticle-assisted ultrasound therapy (NAUT) could serve as an effective novel means for targeted destruction of cancer cells.

The Notch inhibitor cowanin accelerates nicastrin degradation.

Aberrant activation of Notch signaling contributes to the pathogenesis of several different types of cancer, and Notch pathway inhibitors may have significant therapeutic potential. Using a unique cell-based assay system, we isolated twelve compounds, including one new natural product from Garcinia speciosa, that inhibit the Notch signaling pathway. HES1 and HES5 are target genes of the Notch cascade, and compound 2, referred to as cowanin, decreased the protein levels of HES1 and HES5 in assay cells. Furthermore, cowanin (2) showed potent cytotoxicity against human leukemic HPB-ALL cells. The Notch signaling inhibitory activity of cowanin (2) is linked to the increased degradation of nicastrin, which is one of the components of the γ-secretase complex. To the best of our knowledge, this is the first example of a compound with Notch pathway inhibitory activity mediated by nicastrin degradation.

Anti­inflammatory effects of gambogic acid in murine collagen­induced arthritis through PI3K/Akt signaling pathway.

Garcinia angustifolia is a dry resin secreted by Garcinia cambogia, which has the functions of breaking blood, detoxifying, stopping bleeding and killing insects. It is used for the treatment of cancer and brain edema. Gambogic acid is the primary active ingredient. The present study aimed to investigate the anti­inflammatory and antiproliferative effects of gambogic acid on arthritis and the possible mechanisms. It was demonstrated that gambogic acid decreased arthritic scores in murine collagen­induced arthritic mice. The tumor necrosis factor (TNF)­α, interleukin (IL)­1ß, IL­6 and IL­18 concentrations, and caspase­3 and caspase­9 were significantly inhibited by gambogic acid in arthritic mice. Gambogic acid decreased matrix metalloproteinases (MMP)­2, MMP­9, nuclear factor (NF)­κB and phosphorylated­p38 protein expression, and increased tissue inhibitors of matrix metalloproteases­1 (TIMP­1) protein expression in arthritic mice. Furthermore, the phosphoinositide 3­kinase (PI3K)/AKT serine/threonine kinase (Akt) signaling pathway was induced in arthritic mice treated with gambogic acid. The results suggested that gambogic acid induced anti­inflammatory effects in murine collagen­induced arthritis, through the PI3K/Akt signaling pathway, and offers future potential for application in arthritis patients.

Separation and preparation of xanthochymol and guttiferone E by high performance liquid chromatography and high speed counter-current chromatography combined with silver nitrate coordination reaction.

Xanthochymol (XCM) and guttiferone E (GFE), a pair of π bond benzophenone isomers from Garcinia xanthochymus, were once reported to be difficult or impossible to separate. The present study reports the successful separation of these two isomers through high performance liquid chromatography (HPLC), as well as their effective isolation using high speed counter-current chromatography (HSCCC) based on the silver nitrate (AgNO3) coordination reaction. First, an effective HPLC separation system was developed, achieving a successful baseline separation with resolution of 2.0. Based on the partition coefficient (K) resolved by HPLC, the two-phase solvent system was determined as n-hexane, methanol and water with the uncommon volume ratio of 4:6:1. A crude extract of Garcinia xanthochymus (0.2g) was purified by normal HSCCC and refined with AgNO3-HSCCC. Monomers of XCM and GFE were identified by HPLC, mass spectrometry (MS) and nuclear magnetic resonance (NMR). The results demonstrate the separation and isolation of π bond benzophenone isomers using ordinary octadecyl silane (C18) columns and HSCCC.

UPLC-ESI-TOF MS-Based Metabolite Profiling of the Antioxidative Food Supplement Garcinia buchananii.

Comparative antioxidative analyses of aqueous ethanolic extracts from leaf, root, and stem of Garcinia buchananii revealed high activity of all three organs. To investigate the metabolite composition of the different parts of G. buchananii, an untargeted metabolomics approach using UPLC-ESI-TOF MS with simultaneous acquisition of low- and high-collision energy mass spectra (MS(e)) was performed. Unsupervised statistics (PCA) highlighted clear differences in the metabolomes of the three organs. OPLS-DA revealed (2R,3S,2″R,3″R)-GB-1, (2R,3S)-morelloflavone, and (2R,3S)-volkensiflavone as the most decisive marker compounds discriminating leaf from root and stem extract. Leaves represent the best source to isolate GB-1, morelloflavone, and volkensiflavone. Root extract is the best organ to isolate xanthones and stem bark extract the best source to isolate (2R,3S,2″R,3″R)-manniflavanone; the identified polyisoprenylated benzophenones are characteristic compounds for the leaf organ. Morelloflavone, volkensiflavone, and garcicowin C were isolated for the first time from G. buchananii, identified via MS, NMR, and CD spectroscopy, and showed in H2O2 scavenging, H/L-TEAC, and H/L-ORAC assays moderate to strong in vitro antioxidative activities.

Novel natural-product-like caged xanthones with improved druglike properties and in vivo antitumor potency.

DDO-6101, a natural-product-like caged xanthone discovered previously in our laboratory based on the pharmacophoric scaffold of Garcinia natural product gambogic acid (GA), shows potent cytotoxicity in vitro but poor efficacy in vivo due to its poor druglike properties. In order to improve the druglike properties and in vivo cytotoxic potency, a novel series of 19 prenyl group-modified derivatives of DDO-6101 was synthesized and evaluated for their in vitro antitumor activity and druglike properties. The SAR and SPR information of these compounds was also obtained. In the light of the in vitro antitumor activity and druglike properties such as aqueous solubility and permeability, compound 6f (named as DDO-6306) was advanced into in vivo efficacy experiment. The results showed that DDO-6306 is more potent than DDO-6101 in vivo and is a promising antitumor candidate for further evaluation.

Oblongifolin C inhibits metastasis by up-regulating keratin 18 and tubulins.

Tumor metastasis is the main cause of cancer-related patient death. In this study, we performed a wound healing migration screen to search for a metastatic inhibitor within our library of natural compounds. We found that oblongifolin C (OC), a natural compound extracted from Garcinia yunnanensis Hu, is an effective inhibitor of metastasis in human esophageal squamous carcinoma Eca109 cells. The transwell migration and matrigel invasion assay results also showed that OC inhibits the migration of Eca109 cells and HepG2 cells. OC can increase the expression of tubulin, indicating that OC inhibits metastasis via tubulin aggregation. In addition, the Western blotting, real-time PCR, and immunostaining results indicated that OC increases the expression of keratin18. Furthermore, the knockdown of keratin 18 by small interfering RNAs inhibited the expression of tubulin and increased the metastasis of cancer cells, suggesting that keratin 18 is the upstream signal of tubulin and plays a vital role in metastasis. A subsequent study in a tail vein injection metastasis model showed that OC can significantly inhibit pulmonary metastasis, as revealed by immunohistochemistry staining. Taken together, our results suggest that OC inhibits metastasis through the induction of the expression of keratin 18 and may be useful in cancer therapy.

Plant homeostasis of foliar manganese sinks: specific variation in hyperaccumulators.

Plant manganese (Mn) hyperaccumulation provides unusual insight into homeostasis of this essential micronutrient, in particular its excessive storage in shoot tissues. The compartmentation of hyperaccumulated foliar Mn appears exceptional among metal hyperaccumulators, since it occurs via specific microdistribution patterns. Here, three associated Mn hyperaccumulators, Virotia neurophylla, Maytenus fournieri, and Garcinia amplexicaulis exhibiting distinctly different Mn detoxification strategies were examined. Non-invasive sample preparation in conjunction with cryo scanning electron microscopy (SEM) was used to obtain in vivo quantitative microprobe X-ray and anatomical data from fully hydrated cells. Highly vacuolated large palisade mesophyll cells in V. neurophylla leaves were found to contain around 650 mM Mn. The large non-photosynthetic hypodermal cells of M. fournieri leaves, also with high vacuolar content, and the main site for Mn disposal, had an estimated mean vacuolar Mn concentration of around 600 mM. Previous qualitative X-ray mapping had shown Mn to be almost evenly sequestered across the entire leaf cross section of G. amplexicaulis. However, quantitative data obtained here showed a marked variation in localised concentrations that ranged between ~15 and >800 mM. Notable among these were mean values of >600 mM in spongy mesophyll cells, and ~800 mM within cells of a narrow sub epidermal layer preceding the palisade mesophyll. This study demonstrated the extraordinary Mn carrying capacities of different types of leaf cell vacuoles.

Garcina cambogia leaf and seawater for tannase production by marine Aspergillus awamori BTMFW032 under slurry state fermentation.

Garcinia gummi-gutta (syn. G. cambogia, G. quaesita), known to have medicinal properties, was evaluated as a substrate and inducer for tannase production by a marine Aspergillus awamori BTMFW032, under slurry state fermentation using Czapekdox-minimal medium and sea water as the cultivation medium. Among the various natural tannin substrates evaluated, Garcinia leaf supported maximal tannase production. The cultivation conditions and components of the cultivation medium were optimized employing response surface methodology. The experimental results were fitted to a second-order polynomial model at a 92.2% level of significance (p < 0.0001). The maximal tannase activity was obtained in a slurry state medium containing 26.6%, w/v, Garcinia leaf, supplemented with 0.1% tannic acid as inducer. The optimum values of pH, temperature and inoculum concentration obtained were 5.0, 40 degrees C and 3%, respectively. A Box-Behnken model study of the fermentation conditions was carried out, and the best production of tannase was registered at 40 degrees C without agitation. Optimization strategy employing response surface methodology led to nearly 3-fold increase in the enzyme production from 26.2 U/mL obtained in unoptimized medium to 75.2 Units/mL in Box Behnken design, within 18 h of fermentation. It was observed that sea water could support maximal tannase production by A. awamori compared with other media suggesting that the sea water salts could have played an inducer role in expression of tannase encoding genes. To the best of our knowledge, this is the first report on production of tannase, an industrially important enzyme, utilizing Garcinia leaf as substrate under slurry state fermentation by marine A. awamori and sea water as the cultivation medium.

Inhibition of acidic sphingomyelinase by xanthone compounds isolated from Garcinia speciosa.

Sphingomyelinase is considered to be involved in the regulation of apoptosis and cell growth. In the course of our screening for acidic sphingomyelinase inhibitors we isolated three xanthone compounds, alpha-mangostin, cowanin, and cowanol, from the bark of Garcinia speciosa. These compounds competitively inhibited bovine brain-derived acidic sphingomyelinase with IC(50) values of 14.1, 19.2, and 10.9 microM, respectively and inhibited the acidic sphingomyelinase more effectively than the neutral sphingomyelinase of bovine brain. alpha-Mangostin inhibited the acidic sphingomyelinase in the most selective manner. alpha-Mangostin was chemically modified and its structure-activity relationships are discussed.