Quantification of mangiferin in streptozotocin-induced diabetic rat plasma using UPLC-MS/MS: Pharmacokinetic assessment of Gentiana rhodantha extract after oral administration.

Mangiferin, a key bioactive constituent in Gentiana rhodantha, has a favorable impact on reducing blood sugar. A selective and sensitive UPLC MS/MS approach was developed for determining mangiferin in diabetic rats. Employing acetonitrile protein precipitation, chromatographic separation utilized a 2.1×50 mm, 3.5µm C18 column with a mobile phase of 0.1% formic acid aqueous and 5mM ammonium acetate (A, 45%) and acetonitrile (B, 55%) at a 0.5mL min-1 flow rate. Quantification, employing the multiple reaction monitoring (MRM) mode, focused on precursor-to-product ion transitions at m/z 447.1→271.1 for baicalin m/z and 421.0→301.0 for mangiferin. Calibration curves demonstrated linearity in the 1.00~100ng/mL range, with a lower quantification limit for rat plasma set at 1.00ng/mL. Inter- and intra-day accuracies spanned -9.1% to 8.5% and mangiferin mean recovery varied from 82.3% to 86.7%. The adeptly utilized UPLC-MS/MS approach facilitated the exploration of mangiferin pharmacokinetics in diabetic rats.

Development of a manganese complex hyaluronic acid hydrogel encapsulating stimuli-responsive Gambogic acid nanoparticles for targeted Intratumoral delivery.

Gambogic acid is a natural compound with anticancer properties and is effective for many tumors. But its low water solubility and dose-dependent side effects limit its clinical application. This study aims to develop a novel drug delivery system for intratumoral delivery of gambogic acid. In our experimental study, we propose a new method for encapsulating gambogic acid nanoparticles using a manganese composite hyaluronic acid hydrogel as a carrier, designed for targeted drug delivery to tumors. The hydrogel delivery system is synthesized through the coordination of hyaluronic acid-dopamine (HA-DOPA) and manganese ions. The incorporation of manganese ions serves three purposes:1.To form cross-linked hydrogels, thereby improving the mechanical properties of HA-DOPA.2.To monitor the retention of hydrogels in vivo in real-time using magnetic resonance imaging (MRI).3.To activate the body's immune response. The experimental results show that the designed hydrogel has good biosafety, in vivo sustained release effect and imaging tracking ability. In the mouse CT26 model, the hydrogel drug-loaded group can better inhibit tumor growth. Further immunological analysis shows that the drug-loaded hydrogel group can stimulate the body's immune response, thereby better achieving anti-tumor effects. These findings indicate the potential of the developed manganese composite hyaluronic acid hydrogel as an effective and safe platform for intratumoral drug delivery. The amalgamation of biocompatibility, controlled drug release, and imaging prowess positions this system as a promising candidate for tumor treatment.

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.

Integrated anti-vascular and immune-chemotherapy for colorectal carcinoma using a pH-responsive polymeric delivery system.

Colorectal carcinoma (CRC) has become one of the most prevalent malignant tumors and exploring a potential therapeutic strategy with diminished drug-associated adverse effects to combat CRC is urgent. Herein, we designed a pH-responsive polymer to efficiently encapsulate a stimulator of interferon genes (STING) agonist (5,6- dimethylxanthenone-4-acetic acid, termed ASA404) and a common clinically used chemotherapeutic agent (1-hexylcarbamoyl-5-fluorouracil, termed HCFU). Investigations in vitro demonstrated that polymer encapsulation endowed the system with a pH-dependent disassembly behavior (pHt 6.37), which preferentially selected cancerous cells with a favorable dose reduction (dose reduction index (DRI) of HCFU was 4.09). Moreover, the growth of CRC in tumor-bearing mice was effectively suppressed, with tumor suppression rates up to 94.74%, and a combination index (CI) value of less than one (CI = 0.41 for CT26 cell lines), indicating a significant synergistic therapeutic effect. Histological analysis of the tumor micro-vessel density and enzyme-linked immunosorbent assay (ELISA) tests indicated that the system increased TNF-α and IFN-ß levels in serum. Therefore, this research introduces a pH-responsive polymer-based theranostic platform with great potential for immune-chemotherapeutic and anti-vascular combination therapy of CRC.

A differential-targeting core-shell microneedle patch with coordinated and prolonged release of mangiferin and MSC-derived exosomes for scarless skin regeneration.

Microneedles for skin regeneration are conventionally restricted by uncontrollable multi-drug release, limited types of drugs, and poor wound adhesion. Here, a novel core-shell microneedle patch is developed for scarless skin repair, where the shell is composed of hydrophilic gelatin methacryloyl (GelMA) loaded with mangiferin, an anti-inflammatory small molecule, and the core is composed of hydrophobic poly (lactide-co-propylene glycol-co-lactide) dimethacrylates (PGLADMA) loaded with bioactive macromolecule and human mesenchymal stromal cell (hMSC)-derived exosomes. This material choice provides several benefits: the GelMA shell provides a swelling interface for tissue interlocking and rapid release of mangiferin at an early wound healing stage for anti-inflammation, whereas the PGLADMA core offers long-term encapsulation and release of exosomes (30% release in 3 weeks), promoting sustained angiogenesis and anti-inflammation. Our results demonstrate that the core-shell microneedle possesses anti-inflammatory properties and can induce angiogenesis both in vitro in terms of macrophage polarization and tube formation of human umbilical vein endothelial cells (HUVECs), and in vivo in terms of anti-inflammation, re-epithelization, and vessel formation. Importantly, we also observe reduced scar formation in vivo. Altogether, the degradation dynamics of our hydrophilic/hydrophobic materials enable the design of a core-shell microneedle for differential and prolonged release, promoting scarless skin regeneration, with potential for other therapies of long-term exosome release.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.