Novel Carbon Dots Derived from Moutan Cortex Significantly Improve the Solubility and Bioavailability of Mangiferin.

Background: Mangiferin (MA), a bioactive C-glucosyl xanthone with a wide range of interesting therapeutic properties, has recently attracted considerable attention. However, its application in biomedicine is limited by poor solubility and bioavailability. Carbon dots (CDs), novel nanomaterials, have immense promise as carriers for improving the biopharmaceutical properties of active components because of their outstanding characteristics. Methods: In this study, a novel water-soluble carbon dot (MC-CDs) was prepared for the first time from an aqueous extract of Moutan Cortex Carbonisata, and characterized by various spectroscopies, zeta potential and high-resolution transmission electron microscopy (HRTEM). The toxicity effect was investigated using the CCK-8 assay in vitro. In addition, the potential of MC-CDs as carriers for improving the pharmacokinetic parameters was evaluated in vivo. Results: The results indicated that MC-CDs with a uniform spherical particle size of 1-5 nm were successfully prepared, which significantly increased the solubility of MA in water. The MC-CDs exhibited low toxicity in HT-22 cells. Most importantly, the MC-CDs effectively affected the pharmacokinetic parameters of MA in normal rats. UPLC-MS analysis indicated that the area under the maximum blood concentration of MA from mangiferin-MC-CDs (MA-MC-CDs) was 1.6-fold higher than that from the MA suspension liquid (MA control) after oral administration at a dose of 20 mg/kg. Conclusion: Moutan Cortex-derived novel CDs exhibited superior performance in improving the solubility and bioavailability of MA. This study not only opens new possibilities for the future clinical application of MA but also provides evidence for the development of green biological carbon dots as a drug delivery system to improve the biopharmaceutical properties of insoluble drugs.

Design of Nanotechnological Carriers for Ocular Delivery of Mangiferin: Preformulation Study.

(1) Background: Mangiferin (MGN) is a natural compound, showing anti-inflammatory and antioxidant activities for the potential treatment of eye diseases. The poor physicochemical features of MGN (low solubility and high instability) justify its nanoencapsulation into nanostructured lipid carriers (NLC) to improve its ocular bioavailability. (2) Methods: Firstly, MGN-NLC were prepared by the high shear homogenization coupled with the ultrasound (HSH-US) method. Finally, unloaded and MGN-loaded NLC were analyzed in terms of ocular tolerance. (3) Results: MGN-NLC showed good technological parameters suitable for ocular administration (particle size below 200 nm). The ORAC assay was performed to quantify the antioxidant activity of MGN, showing that the antioxidant activity of MGN-NLC (6494 ± 186 µM TE/g) was higher than that of the free compound (3521 ± 271 µM TE/g). This confirmed that the encapsulation of the drug was able to preserve and increase its activity. In ovo studies (HET-CAM) revealed that the formulation can be considered nonirritant. (4) Conclusions: Therefore, NLC systems are a promising approach for the ocular delivery of MGN.

Biotin Transport-Targeting Polysaccharide-Modified PAMAM G3 Dendrimer as System Delivering α-Mangostin into Cancer Cells and C. elegans Worms.

The natural xanthone α-mangostin (αM) exhibits a wide range of pharmacological activities, including antineoplastic and anti-nematode properties, but low water solubility and poor selectivity of the drug prevent its potential clinical use. Therefore, the targeted third-generation poly(amidoamine) dendrimer (PAMAM G3) delivery system was proposed, based on hyperbranched polymer showing good solubility, high biocompatibility and low immunogenicity. A multifunctional nanocarrier was prepared by attaching αM to the surface amine groups of dendrimer via amide bond in the ratio 5 (G32B12gh5M) or 17 (G32B10gh17M) residues per one dendrimer molecule. Twelve or ten remaining amine groups were modified by conjugation with D-glucoheptono-1,4-lactone (gh) to block the amine groups, and two biotin (B) residues as targeting moieties. The biological activity of the obtained conjugates was studied in vitro on glioma U-118 MG and squamous cell carcinoma SCC-15 cancer cells compared to normal fibroblasts (BJ), and in vivo on a model organism Caenorhabditis elegans. Dendrimer vehicle G32B12gh at concentrations up to 20 µM showed no anti-proliferative effect against tested cell lines, with a feeble cytotoxicity of the highest concentration seen only with SCC-15 cells. The attachment of αM to the vehicle significantly increased cytotoxic effect of the drug, even by 4- and 25-fold for G32B12gh5M and G32B10gh17M, respectively. A stronger inhibition of cells viability and influence on other metabolic parameters (proliferation, adhesion, ATP level and Caspase-3/7 activity) was observed for G32B10gh17M than for G32B12gh5M. Both bioconjugates were internalized efficiently into the cells. Similarly, the attachment of αM to the dendrimer vehicle increased its toxicity for C. elegans. Thus, the proposed α-mangostin delivery system allowed the drug to be more effective in the dendrimer-bound as compared to free state against both cultured the cancer cells and model organism, suggesting that this treatment is promising for anticancer as well as anti-nematode chemotherapy.

Characterization of Metabolites of α-mangostin in Bio-samples from SD Rats by UHPLC-Q-exactive Orbitrap MS.

BACKGROUND: α-mangostin, a typical xanthone, often exists in Garcinia mangostana L. (Clusiaceae). α-mangostin was found to have a wide range of pharmacological properties. However, its specific metabolic route in vivo remains unclear, while these metabolites may accumulate to exert pharmacological effects, too. OBJECTIVE: This study aimed to clarify the metabolic pathways of α-mangostin after oral administration to the rats. METHODS: Here, an UHPLC-Q-Exactive Orbitrap MS was used for the detection of potential metabolites formed in vivo. A new strategy for the identification of unknown metabolites based on typical fragmentation routes was implemented. RESULTS: A total of 42 metabolites were detected, and their structures were tentatively identified in this study. The results showed that major in vivo metabolic pathways of α-mangostin in rats included methylation, demethylation, methoxylation, hydrogenation, dehydrogenation, hydroxylation, dehydroxylation, glucuronidation, and sulfation. CONCLUSIONS: This study is significant to expand our knowledge of the in vivo metabolism of α-mangostin and to understand the mechanism of action of α-mangostin in rats in vivo.

Gambogic amide inhibits angiogenesis by suppressing VEGF/VEGFR2 in endothelial cells in a TrkA-independent manner.

CONTEXT: Gambogic amide (GA-amide) is a non-peptide molecule that has high affinity for tropomyosin receptor kinase A (TrkA) and possesses robust neurotrophic activity, but its effect on angiogenesis is unclear. OBJECTIVE: The study investigates the antiangiogenic effect of GA-amide on endothelial cells (ECs). MATERIALS AND METHODS: The viability of endothelial cells (ECs) treated with 0.1, 0.15, 0.2, 0.3, 0.4, and 0.5 µM GA-amide for 48 h was detected by MTS assay. Wound healing and angiogenesis assays were performed on cells treated with 0.2 µM GA-amide. Chicken eggs at day 7 post-fertilization were divided into the dimethyl sulfoxide (DMSO), bevacizumab (40 µg), and GA-amide (18.8 and 62.8 ng) groups to assess the antiangiogenic effect for 3 days. mRNA and protein expression in cells treated with 0.1, 0.2, 0.4, 0.8, and 1.2 µM GA-amide for 6 h was detected by qRT-PCR and Western blots, respectively. RESULTS: GA-amide inhibited HUVEC (IC50 = 0.1269 µM) and NhEC (IC50 = 0.1740 µM) proliferation, induced cell apoptosis, and inhibited the migration and angiogenesis at a relatively safe dose (0.2 µM) in vitro. GA-amide reduced the number of capillaries from 56 ± 14.67 (DMSO) to 20.3 ± 5.12 (62.8 ng) in chick chorioallantoic membrane (CAM) assay. However, inactivation of TrkA couldn't reverse the antiangiogenic effect of GA-amide. Moreover, GA-amide suppressed the expression of VEGF and VEGFR2, and decreased activation of the AKT/mTOR and PLCγ/Erk1/2 pathways. CONCLUSIONS: Considering the antiangiogenic effect of GA-amide, it might be developed as a useful agent for use in clinical combination therapies.

Mangiferin and Hesperidin Transdermal Distribution and Permeability through the Skin from Solutions and Honeybush Extracts (Cyclopia sp.)-A Comparison Ex Vivo Study.

Polyphenolic compounds-mangiferin and hesperidin-are, among others, the most important secondary metabolites of African shrub Cyclopia sp. (honeybush). The aim of this study was to compare the percutaneous absorption of mangiferin and hesperidin from solutions (water, ethanol 50%, (v/v)) and extracts obtained from green and fermented honeybush (water, ethanol 50%, (v/v)). Research was performed with the Bronaugh cells, on human dorsal skin. The mangiferin and hesperidin distributions in skin layers (stratum corneum, epidermis, and dermis) and in acceptor fluid (in every 2, 4, 6, and 24 h) were evaluated by HPLC-Photodiode Array Coulometric and Coulometric Electrochemical Array Detection. The transdermal distribution of hesperidin was also demonstrated by fluorescence microscopy. Results indicated that mangiferin and hesperidin were able to cross the stratum corneum and penetrate into the epidermis and dermis. An advantage of hesperidin penetration into the skin from the water over ethanol solution was observed (451.02 ± 14.50 vs. 357.39 ± 4.51 ng/cm2), as well as in the mangiferin study (127.56 ± 9.49 vs. 97.23 ± 2.92 ng/cm2). Furthermore, mangiferin penetration was more evident from nonfermented honeybush ethanol extract (189.85 ± 4.11 ng/cm2) than from solutions. The permeation of mangiferin and hesperidin through the skin to the acceptor fluid was observed regardless of whether the solution or the honeybush extract was applied. The highest ability to permeate the skin was demonstrated for the water solution of hesperidin (250.92 ± 16.01 ng/cm2), while the hesperidin occurring in the extracts permeated in a very low capacity. Mangiferin from nonfermented honeybush ethanol extract had the highest ability to permeate to the acceptor fluid within 24 h (152.36 ± 8.57 ng/cm2).

Cudraxanthone D Ameliorates Psoriasis-like Skin Inflammation in an Imiquimod-Induced Mouse Model via Inhibiting the Inflammatory Signaling Pathways.

Psoriasis is a chronic inflammatory skin disease accompanied by excessive keratinocyte proliferation. Corticosteroids, vitamin D3 analogs, and calcineurin inhibitors, which are used to treat psoriasis, have diverse adverse effects, whereas natural products are popular due to their high efficiency and relatively low toxicity. The roots of the Cudrania tricuspidata (C. tricuspidata) are known to have diverse pharmacological effects, among which the anti-inflammatory effect is reported as a potential therapeutic agent in skin cells. Nevertheless, its effectiveness against skin diseases, especially psoriasis, is not fully elucidated. Here, we investigated the effect of cudraxanthone D (CD), extracted from the roots the C. tricuspidata Bureau, on psoriasis using an imiquimod (IMQ)-induced mouse model and the tumor necrosis factor (TNF)-α/interferon (IFN)-γ-activated keratinocytes. IMQ was topically applied to the back skin of C57BL/6 mice for seven consecutive days, and the mice were orally administered with CD. This resulted in reduced psoriatic characteristics, such as the skin thickness and Psoriasis Area Severity Index score, and the infiltration of neutrophils in IMQ-induced skin. CD inhibited the serum levels of TNF-α, immunoglobulin G2a, and myeloperoxidase, and the expression of Th1/Th17 cells in splenocytes. In TNF-α/IFN-γ-activated keratinocytes, CD reduced the expressions of CCL17, IL-1ß, IL-6, and IL-8 by inhibiting the phosphorylation of STAT1 and the nuclear translocation of NF-kB. Taken together, these results suggest that CD could be a potential drug candidate for the treatment of psoriasis.

Synergistic effects of α-Mangostin and sorafenib in hepatocellular carcinoma: New insights into α-mangostin cytotoxicity.

Sorafenib remains the standard first-line treatment for advanced hepatocellular carcinoma (HCC), although other clinical trials are currently underway for treatments that show better curative effects. However, some patients are not sensitive to sorafenib. α-Mangostin, extracted from the pericarp of the mangosteen, which is widely used as a traditional medicine, has anticancer and anti-proliferative properties in various types of cancers, including HCC. In the present study, we found that combining sorafenib and α-Mangostin could be synergistically toxic to HCC both in vitro and in vivo. We then demonstrated that the combination of sorafenib and α-Mangostin enhances the inhibition of cell proliferation in HCC cell lines. Combination therapy leads directly to apoptosis. In xenograft mouse models, the in vivo safety and effectivity was confirmed by a reduction in tumor size after combination treatment. RNA sequencing and protein testing showed that the expression of LRRC8A and RNF181 genes and mTOR and MAPK pathways may be associated with the synergistic effect of the two drugs. In conclusion, our results highlight the synergistic effect of the combination of sorafenib and α-Mangostin, which indicates a potential treatment for advanced HCC for patients that are not sensitive to sorafenib therapy.

Development of mangiferin loaded chitosan-silica hybrid scaffolds: Physicochemical and bioactivity characterization.

Development of hybrid materials with molecular structure of organic-inorganic co-network is a promising method to enhance the stability and mechanical properties of biopolymers. Chitosan-silica hybrid nanocomposite scaffolds loaded with mangiferin, a plant-derived active compound possessing several bioactivities, were fabricated using the sol-gel synthesis and the freeze-drying processes. Investigation on the physicochemical and mechanical properties of the fabricated scaffolds showed that their properties can be improved and tailored by the formation of 3-dimensional crosslinked network and the addition of ZnO nanoparticles. The scaffolds possessed porosity, fluid uptake, morphology, thermal properties and mechanical strength suitable for bone tissue engineering application. Investigation on the biomineralization and cell viability indicated that the inclusion of bioactive mangiferin further promote potential use of the hybrid nanocomposite scaffolds in guided bone regeneration application.

Oral administration of mangiferin ameliorates diabetes in animal models: a meta-analysis and systematic review.

Although mangiferin has a number of documented beneficial effects, there are no systematic reviews or meta-analyses of its effects in diabetic animal models. To investigate the effects of oral administration of mangiferin on blood glucose levels, body weight, and total cholesterol and triglycerides levels in diabetic animal models, a meta-analysis was conducted and the underlying mechanisms were reviewed. Studies from 6 databases (PubMed, Web of Science, Embase, Cochrane Library, and CNKI (China National Knowledge Infrastructure), and Wanfang Med) were searched from inception to April 2020. After article screening, a total of 19 articles were included in this meta-analysis. The meta-analysis was performed using RevMan 5.3 and STATA 14.0 software. The overall pooled estimate of standardized mean difference (SMD) of mangiferin's effect on blood glucose was -1.27 (95% confidence interval [CI]: -1.71, -0.82, P < .00001). Body weight increased in lean diabetic animals with an SMD of 1.41 (95% CI: 0.57, 2.25; P = .001), while it decreased in obese diabetic animals with an SMD of -0.92 (95% CI: -1.69, -0.14; P = .02). Mangiferin intake reduced serum total cholesterol and triglycerides levels with SMDs of -1.02 (95% CI: -1.43, -0.61; P < .001) and -1.24 (95% CI: -1.70, -0.79; P < .001), respectively. The meta-analysis suggests that oral intake of mangiferin has a significant antidiabetic effect in animal models, and the systematic review suggested that this function might be attributed to its anti-inflammatory and antioxidative properties, as well as to its function of improving glycolipid metabolism and enhancing insulin signaling.

Mucoadhesive chitosan and thiolated chitosan nanoparticles containing alpha mangostin for possible Colon-targeted delivery.

α-Mangostin-loaded mucoadhesive nanoparticles (NPs) were prepared for colon-targeted drug delivery against colorectal cancer cells using pH-dependent composite mucoadhesive NPs. Chitosan (CS) and thiolated chitosan (TCS) were used to form the NPs, following by genipin (GP) crosslinking and the surface modification by Eudragit® L100 (L100). The particle size, morphologies and characteristics of NPs were observed. The α-mangostin loading and release patterns were investigated. In vitro mucoadhesive properties were examined by the wash-off method. In addition, the anti-tumour activity was tested on colorectal cancer cells. The results showed that NPs were slightly oblong in shape with particle size ranging between 300 and 900 nm. The small size of NPs was found with TCS and larger NPs were observed by GP and L100 process. However, GP and L100 provided an increase in α-mangostin loading, limited the release of α-mangostin in the upper gastrointestinal tract, and enhanced α-mangostin delivery to the colon. The TCS-based NPs with GP and L100 exhibited strong mucoadhesion to colon mucosa, more than uncoated-NPs and CS-based NPs. Moreover, NPs exhibited the anti-tumour activity. Therefore, the mucoadhesive TCS-based NPs could be a promising candidate for a controlled-release drug delivery system of α-mangostin to the colon.

Cashew apple pectin as a carrier matrix for mangiferin: Physicochemical characterization, in vitro release and biological evaluation in human neutrophils.

In this work, cashew apple pectin (CP) of the species Anacardium occidentale L. was used as an encapsulation matrix for hydrophobic drugs. The model drug chosen was mangiferin (Mf), a glycosylated C-xanthone which has antioxidant properties but low solubility in aqueous medium. CP (1-100 µg mL-1) was not toxic to human neutrophils and also did not significantly interfere with the pro-inflammatory mechanism of these cells in the concentration range of 12.5 and 100 µg mL-1. The results are promising because they show that pectin encapsulated mangiferin after spray drying presented an efficiency of 82.02%. The results obtained in the dissolution test, simulating the release of mangiferin in the gastrointestinal tract (pH 1.2, 4.6 and 6.8) and using Franz diffusion cells (pH 7.4), showed that cashew pectin may be a promising vehicle in prolonged drug delivery systems for both oral and dermal applications.

Mangiferin enhances the antifungal activities of caspofungin by destroying polyamine accumulation.

The incidence of fungal infections has increased continuously in recent years. Caspofungin (CAS) is one of the first-line drugs for the treatment of systemic fungal infection. However, the emerging CAS-resistant clinical isolates and high economic cost for CAS administration hamper the wide application of this drug. Thus, the combined administration of CAS with other compounds that can enhance the antifungal activity and reduce the dose of CAS has gained more and more attention. In this study, we investigated the effect of mangiferin (MG) on the antifungal activities of CAS. Our results showed that MG acted synergistically with CAS against various Candida spp., including CAS-resistant C. albicans. Moreover, MG could enhance the activity of CAS against biofilm. The in vivo synergism of MG and CAS was further confirmed in a mouse model of disseminated candidiasis. To explore the mechanisms, we found that SPE1-mediated polyamine biosynthesis pathway was involved in the fungal cell stress to caspofungin. Treatment of CAS alone could stimulate SPE1 expression and accumulation of polyamines, while combined treatment of MG and CAS inhibited SPE1 expression and destroyed polyamine accumulation, which might contribute to increased oxidative damage and cell death. These results provided a promising strategy for high efficient antifungal therapies and revealed novel mechanisms for CAS resistance.

Mangiferin loaded magnetic PCEC microspheres: preparation, characterization and antitumor activity studies in vitro.

Mangiferin is a promising effective chemopreventive agent against various tumors. However, its clinical use is limited by poor water solubility and low bioavailability. In this article, mangiferin loaded magnetic PCEC microspheres (MG-MS) were designed, characterized and the antitumor activity of MG-MS was evaluated in vitro. The magnetic nanoparticles (MNP) were synthesized via the high-temperature reaction of iron acetylacetonate in phenyl ether in the presence of oleic acid and oleylamine. Poly (ε-caprolactone)-poly (ethyleneglycol)-poly (ε-caprolactone) (PCL-PEG-PCL, PCEC) copolymers were formed by ring-opening copolymerization of ε-CL initiated by PEG-diol using Sn(Oct)2 as a catalyst and MG-MS were prepared by solvent diffusion method. MNP, PCEC copolymer, and MG-MS were characterized by GPC, TEM, XRD, FT-IR, 1H-NMP and Malvern Laser Particle Sizer. Meanwhile, the antiproliferative activity in vitro and in vitro release behavior of this microspheres were studied in detail. The results indicate that the obtained magnetic microspheres might have great potential as an effective carrier for mangiferin used in cancer chemotherapy.

Garciesculenxanthone B induces PINK1-Parkin-mediated mitophagy and prevents ischemia-reperfusion brain injury in mice.

Mitophagy is a selective form of autophagy involving the removal of damaged mitochondria via the autophagy-lysosome pathway. PINK1-Parkin-mediated mitophagy is one of the most important mechanisms in cardiovascular disease, cerebral ischemia-reperfusion (I/R) injury, and neurodegenerative diseases. In this study we conducted an image-based screening in YFP-Parkin HeLa cells to discover new mitophagy regulators from natural xanthone compounds. We found that garciesculenxanthone B (GeB), a new xanthone compound from Garcinia esculenta, induced the formation of YFP-Parkin puncta, a well known mitophagy marker. Furthermore, treatment with GeB dose-dependently promoted the degradation of mitochondrial proteins Tom20, Tim23, and MFN1 in YFP-Parkin HeLa cells and SH-SY5Y cells. We revealed that GeB stabilized PINK1 and triggered Parkin translocation to the impaired mitochondria to induce mitophagy, and these effects were abolished by knockdown of PINK1. Finally, in vivo experiments demonstrated that GeB partially rescued ischemia-reperfusion-induced brain injury in mice. Taken together, our findings demonstrate that the natural compound GeB can promote the PINK1-Parkin-mediated mitophagy pathway, which may be implicated in protection against I/R brain injury.

Ethanolic Garcinia mangostana extract and α-mangostin improve dextran sulfate sodium-induced ulcerative colitis via the suppression of inflammatory and oxidative responses in ICR mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is an inflammatory disorder of the colon. Garcinia mangostana Linn. (GM) has been traditionally used for its anti-inflammatory and antioxidant activities. AIM OF THE STUDY: The effects of GM and its bioactive constituent α-mangostin on dextran sulfate sodium (DSS)-induced UC in mice were investigated. MATERIALS AND METHODS: Adult ICR mice (n = 63) were pretreated with ethanolic GM extract at 40, 200, and 1000 mg/kg/day (GM40, GM200, and GM1000), α-mangostin at 30 mg/kg/day, or sulfasalazine at 100 mg/kg/day (SA) for 7 consecutive days. On days 4-7, UC was induced in the mice by the oral administration of DSS (40 kDa, 6 g/kg/day), while control mice received distilled water. The UC disease activity index (DAI) and histological changes were recorded. The activities of myeloperoxidase, catalase, and superoxide dismutase, and the levels of reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA) were determined. The mRNA expression of inflammatory related genes including proinflammatory cytokine Tnf-α, Toll-like receptor (Tlr-2), adhesion molecules (Icam-1 and Vcam-1), and monocyte chemoattractant protein (Mcp-1) were evaluated. RESULTS: Treatment with GM or α-mangostin decreased the UC DAI and protected against colon shortening and spleen and kidney enlargement. GM and α-mangostin prevented histological damage, reduced mast cell infiltration in the colon, and decreased myeloperoxidase activity. GM and α-mangostin increased catalase and superoxide dismutase activity and decreased ROS, NO, and MDA production. GM downregulated mRNA expression of Tnf-α, Tlr-2, Icam-1, Vcam-1, and Mcp-1. CONCLUSIONS: GM and α-mangostin attenuated the severity of DSS-induced UC via anti-inflammatory and antioxidant effects. Therefore, GM is a promising candidate for development into a novel therapeutic agent for UC.

Development of ROS-responsive amino acid-based poly(ester amide) nanoparticle for anticancer drug delivery.

Reactive oxygen species (ROS) play an important role in cellular metabolism and many oxidative stress related diseases. Oxidative stress results from toxic effects of ROS and plays a critical role in the pathogenesis of a variety of diseases like cancers and many important biological processes. It is known that the unique feature of high intracellular ROS level in cancer cells can be considered as target and utilized as a useful cancer-related stimulus to mediate intracellular drug delivery. Therefore, biomaterials responsive to excess level of ROS are of great importance in biomedical applications. In this study, a novel ROS-responsive polymer based on L-methionine poly(ester amide) (Met-PEA-PEG) was designed, synthesized, characterized and self-assembled into nano-micellar-type nanoparticles (NP). The Met-PEA-PEG NP exhibited responsiveness to an oxidative environment. The size and morphology of the nanoparticle changed rapidly in the presence of H2 O2 . The Nile Red dye was loaded into the Met-PEA-PEG NP to demonstrate a H2 O2 concentration induced time-dependent release behavior. The Met-PEA-PEG NP was sensitive to high intracellular ROS level of PC3 prostate cancer cells. Furthermore, the Met-PEA-PEG NP was investigated as a carrier of a Chinese medicine-based anticancer component, gambogic acid (GA). Compared to free GA, the GA-loaded nanocomplex (GA-NP) showed enhanced cytotoxicity toward PC3 and HeLa cells. The GA-NP also induced a higher level of apoptosis and mitochondrial depolarization in PC3 cells than free GA. The Met-PEA-PEG NP improved the therapeutic effect of GA and may serve as a potential carrier for anticancer drug delivery.

Gambogic Acid as a Candidate for Cancer Therapy: A Review.

Gambogic acid (GA), a kind of dry resin secreted by the Garcinia hanburyi tree, is a natural active ingredient with various biological activities, such as anti-cancer, anti-inflammatory, antioxidant, anti-bacterial effects, etc. An increasing amount of evidence indicates that GA has obvious anti-cancer effects via various molecular mechanisms, including the induction of apoptosis, autophagy, cell cycle arrest and the inhibition of invasion, metastasis, angiogenesis. In order to improve the efficacy in cancer treatment, nanometer drug delivery systems have been employed to load GA and form micelles, nanoparticles, nanofibers, and so on. In this review, we aim to offer a summary of chemical structure and properties, anti-cancer activities, drug delivery systems and combination therapy of GA, which might provide a reference to promote the development and clinical application of GA.

The antidepressant-like activity of chiral xanthone derivatives may be mediated by 5-HT1A receptor and ß-arrestin signalling.

BACKGROUND: Our previous studies showed that xanthone derivatives with N-(2-methoxyphenyl)piperazine fragment have an affinity to the 5-HT1A receptor and show antidepressant-like properties in rodents. In this study, we tested three xanthone derivatives, HBK-1 (R, S) and its enantiomers, in which we increased the distance between the piperazine and xanthone fragments by using a hydroxypropoxy linker. We hypothesized that this would increase the binding to the 5-HT1A receptor and consequently, pharmacological activity. AIMS: We aimed to assess the in vitro and in vivo pharmacological activity of the xanthone derivatives. METHODS: We evaluated the in vitro affinity for serotonin 5-HT1A and 5-HT2A receptors and serotonin transporter. We also determined the intrinsic activity at the 5-HT1A receptor. We investigated the antidepressant-like properties and safety after acute administration (dose range: 1.25-20 mg/kg) using the forced swim, tail suspension, locomotor activity, rotarod and chimney tests in mice. We also evaluated the basic pharmacokinetic parameters. RESULTS: Our results indicated that the compounds showed a high affinity for the 5-HT1A receptor but very weak antagonistic properties in the Ca2+ mobilization assay; however, they showed significant agonistic properties in the ß-arrestin recruitment assay. In both behavioural tests the studied xanthone derivatives showed antidepressant-like activity. Pre-treatment with p-chlorophenylalanine or WAY-100635 abolished their antidepressant-like activity. None of the compounds caused motor impairments at antidepressant-like doses. The racemate penetrated the blood-brain barrier and had a relatively high bioavailability after intraperitoneal administration. CONCLUSIONS: Xanthone derivatives with N-(2-methoxyphenyl)piperazine fragment and hydroxypropoxy linker show increased binding to the 5-HT1A receptor and may represent an attractive putative treatment candidate for depression.

Mangiferin ameliorates intracerebroventricular-quinolinic acid-induced cognitive deficits, oxidative stress, and neuroinflammation in Wistar rats.

INTRODUCTION: Mangiferin (MGF), a xanthonoid polyphenol, confers neuroprotection via combating oxidative stress and inflammation. The current investigation aimed to assess the neuroprotective potential of MGF on behavioral and neurochemical anomalies evoked by administration of quinolinic acid (QA) through intrastriatal injection in male Wistar rats and to reveal the associated mechanisms. MATERIALS AND METHODS: QA (300 nm/4 µl saline) was administered intracerebroventricular in the striatum (unilaterally) once. Thereafter, MGF 20 and 40 mg/kg (peroral) was administered to the animals for 21 days. RESULTS: QA administration caused marked alteration in motor activity (rotatod), footprint analysis, and cognitive function (Morris water maze test, and novel object recognition test). Furthermore, oxido-nitrosative stress (increased nitrite content, lipid peroxidation, with reduction of GSH), cholinergic dysfunction, and mitochondrial complex (I, II, and IV) dysfunction were observed in hippocampus and striatal region of QA-treated rats in comparison to normal control. Pro inflammatory mediators (tumor necrosis factor-alpha TNF-α and interleukin-1ß) were noted to increase in the hippocampus and striatum of QA-treated rats. In addition, we observed BDNF depletion in both the hippocampus and striatum of QA-treated animals. MGF treatment significantly ameliorated memory and motor deficits in QA-administered rats. Moreover, MGF treatment (40 mg/kg) restored the GSH level and reduced the MDA, nitrite level, and pro-inflammatory cytokines in striatum and hippocampus. Furthermore, QA-induced cholinergic dysfunction (AChE), BDNF depletion and mitochondrial impairment were found to be ameliorated by MGF treatment. CONCLUSION: The results suggest that MGF offers the neuroprotective potential that may be a promising pharmacological approach to ameliorate cognitive deficits associated with neurodegeneration.