Xanthones with multiple roles against diabetes: their synthesis, structure-activity relationship, and mechanism studies.

A four-step synthetic process has been developed to prepare 1,3,5,8-tetrahydroxyxanthone (2a) and its isomer 1,3,7,8-tetrahydroxyxanthone (2b). 25 more xanthones were also synthesized by a modified scheme. Xanthone 2a was identified as the most active inhibitor against both α-glucosidase and aldose reductase (ALR2), with IC50 values of 7.8 ± 0.5 µM and 63.2 ± 0.6 nM, respectively, which was far active than acarbose (35.0 ± 0.1 µM), and a little more active than epalrestat (67.0 ± 3.0 nM). 2a was also confirmed as the most active antioxidant in vitro with EC50 value of 8.9 ± 0.1 µM. Any structural modification including methylation, deletion, and position change of hydroxyl group in 2a will cause an activity loss in inhibitory and antioxidation. By applying a H2 O2 -induced oxidative stress nematode model, it was confirmed that xanthone 2a can be absorbed by Caenorhabditis elegans and is bioavailable to attenuate in vivo oxidative stress, including the effects on lifespan, superoxide dismutase, Catalase, and malondialdehyde. 2a was verified with in vivo hypoglycemic effect and mitigation of embryo malformations in high glucose. All our data support that xanthone 2a behaves triple roles and is a potential agent to treat diabetic mellitus, gestational diabetes mellitus, and diabetic complications.

A chemical screen identifies structurally diverse metal chelators with activity against the fungal pathogen Candida albicans.

Candida albicans, one of the most prevalent human fungal pathogens, causes diverse diseases extending from superficial infections to deadly systemic mycoses. Currently, only three major classes of antifungal drugs are available to treat systemic infections: azoles, polyenes, and echinocandins. Alarmingly, the efficacy of these antifungals against C. albicans is hindered both by basal tolerance toward the drugs and the development of resistance mechanisms such as alterations of the drug's target, modulation of stress responses, and overexpression of efflux pumps. Thus, the need to identify novel antifungal strategies is dire. To address this challenge, we screened 3,049 structurally-diverse compounds from the Boston University Center for Molecular Discovery (BU-CMD) chemical library against a C. albicans clinical isolate and identified 17 molecules that inhibited C. albicans growth by >80% relative to controls. Among the most potent compounds were CMLD013360, CMLD012661, and CMLD012693, molecules representing two distinct chemical scaffolds, including 3-hydroxyquinolinones and a xanthone natural product. Based on structural insights, CMLD013360, CMLD012661, and CMLD012693 were hypothesized to exert antifungal activity through metal chelation. Follow-up investigations revealed all three compounds exerted antifungal activity against non-albicans Candida, including Candida auris and Candida glabrata, with the xanthone natural product CMLD013360 also displaying activity against the pathogenic mould Aspergillus fumigatus. Media supplementation with metallonutrients, namely ferric or ferrous iron, rescued C. albicans growth, confirming these compounds act as metal chelators. Thus, this work identifies and characterizes two chemical scaffolds that chelate iron to inhibit the growth of the clinically relevant fungal pathogen C. albicansIMPORTANCEThe worldwide incidence of invasive fungal infections is increasing at an alarming rate. Systemic candidiasis caused by the opportunistic pathogen Candida albicans is the most common cause of life-threatening fungal infection. However, due to the limited number of antifungal drug classes available and the rise of antifungal resistance, an urgent need exists for the identification of novel treatments. By screening a compound collection from the Boston University Center for Molecular Discovery (BU-CMD), we identified three compounds representing two distinct chemical scaffolds that displayed activity against C. albicans. Follow-up analyses confirmed these molecules were also active against other pathogenic fungal species including Candida auris and Aspergillus fumigatus. Finally, we determined that these compounds inhibit the growth of C. albicans in culture through iron chelation. Overall, this observation describes two novel chemical scaffolds with antifungal activity against diverse fungal pathogens.

Unveiling Gambogenic Acid as a Promising Antitumor Compound: A Review.

Gambogenic acid is a derivative of gambogic acid, a polyprenylated xanthone isolated from Garcinia hanburyi. Compared with the more widely studied gambogic acid, gambogenic acid has demonstrated advantages such as a more potent antitumor effect and less systemic toxicity than gambogic acid according to early investigations. Therefore, the present review summarizes the effectiveness and mechanisms of gambogenic acid in different cancers and highlights the mechanisms of action. In addition, drug delivery systems to improve the bioavailability of gambogenic acid and its pharmacokinetic profile are included. Gambogenic acid has been applied to treat a wide range of cancers, such as lung, liver, colorectal, breast, gastric, bladder, and prostate cancers. Gambogenic acid exerts its antitumor effects as a novel class of enhancer of zeste homolog 2 inhibitors. It prevents cancer cell proliferation by inducing apoptosis, ferroptosis, and necroptosis and controlling the cell cycle as well as autophagy. Gambogenic acid also hinders tumor cell invasion and metastasis by downregulating metastasis-related proteins. Moreover, gambogenic acid increases the sensitivity of cancer cells to chemotherapy and has shown effects on multidrug resistance in malignancy. This review adds insights for the prevention and treatment of cancers using gambogenic acid.

Pharmacological properties of mangiferin: bioavailability, mechanisms of action and clinical perspectives.

This review aims to provide an in-depth analysis of the pharmacological properties of mangiferin, focusing primarily on its bioavailability and mechanisms of action, and its potential therapeutic applications, especially in the context of chronic diseases. We conducted a comprehensive examination of in vitro and in vivo studies, as well as clinical trials involving mangiferin or plant extracts containing mangiferin. The primary source of mangiferin is Mangifera indica, but it's also found in other plant species from the families Anacardiaceae, Gentianaceae, and Iridaceae. Mangiferin has exhibited a myriad of therapeutic properties, presenting itself as a promising candidate for treating various chronic conditions including neurodegenerative disorders, cardiovascular diseases, renal and pulmonary diseases, diabetes, and obesity. Despite the promising results showcased in many in vitro studies and certain animal studies, the application of mangiferin has been limited due to its poor solubility, absorption, and overall bioavailability. Mangiferin offers significant therapeutic potential in treating a spectrum of chronic diseases, as evidenced by both in vitro and clinical trials. However, the challenges concerning its bioavailability necessitate further research, particularly in optimizing its delivery and absorption, to harness its full medicinal potential. This review serves as a comprehensive update on the health-promoting and therapeutic activities of mangiferin.

Mangiferin alleviates 6-OHDA-induced Parkinson's disease by inhibiting AKR1C3 to activate Wnt signaling pathway.

Parkinson's disease (PD) is a neurodegenerative disorder with a lack of effective treatment options. mangiferin, a bioactive compound derived from mango, has been shown to possess strong neuroprotective properties. In this study, we investigated the neuroprotective effects of mangiferin on PD and its underlying mechanisms using both in vitro and in vivo models of 6-OHDA-induced PD. Additionally, we conducted molecular docking experiments to evaluate the interaction between mangiferin and AKR1C3 and ß-catenin. Our results demonstrated that treatment with mangiferin significantly attenuated 6-OHDA-induced cell damage in PC12 cells, reducing intracellular oxidative stress, improving mitochondrial membrane potential, and restoring the expression of tyrosine hydroxylase (TH), a characteristic protein of dopaminergic neurons. Furthermore, mangiferin reduced the accumulation of α-synuclein and inhibited the expression of AKR1C3, thereby activating the Wnt/ß-catenin signaling pathway. In vivo studies revealed that mangiferin improved motor dysfunction in 6-OHDA-induced PD mice. Molecular docking analysis confirmed the interaction between mangiferin and AKR1C3 and ß-catenin. These findings indicate that mangiferin exerts significant neuroprotective effects in 6-OHDA-induced PD by inhibiting AKR1C3 and activating the Wnt/ß-catenin signaling pathway. Therefore, mangiferin may emerge as an innovative therapeutic strategy in the comprehensive treatment regimen of PD patients, providing them with better clinical outcomes and quality of life.

[Regulatory Mechanism of Mangiferin Combined with Bortezomib on Malignant Biological Behavior of Burkitt Lymphoma and Its Effect on Expression of CXC Chemokine Receptors].

OBJECTIVE: To analyze the effects of mangiferin combined with bortezomib on the proliferation, invasion, apoptosis and autophagy of human Burkitt lymphoma Raji cells, as well as the expression of CXC chemokine receptors (CXCRs) family, and explore the molecular mechanism between them to provide scientific basis for basic research and clinical work of Burkitt lymphoma. METHODS: Raji cells were intervened with different concentrations of mangiferin and bortezomib alone or in combination, then cell proliferation was detected by CCK-8 assay, cell invasion ability was detected by Transwell chamber method, cell apoptosis was detected by Annexin V/PI double-staining flow cytometry, apoptosis, autophagy and Akt/mTOR pathway protein expression were detected by Western blot, and the expression changes of CXCR family was detected by real-time quantitative PCR (RT-qPCR). RESULTS: Different concentrations of mangiferin intervened Raji cells for different time could inhibit cell viability in a concentration- and time-dependent manner (r =-0.682, r =-0.836). When Raji cells were intervened by combination of mangiferin and bortezomib, compared with single drug group, the proliferation and invasion abilities were significantly decreased, while the apoptosis level was significantly increased (P <0.01). Mangiferin combined with bortezomib could significantly up-regulate the expression of pro-apoptotic protein Bax and down-regulate the expression of anti-apoptotic protein Bcl-2 after intervention in Raji cells. Caspase-3 was also hydrolyzed and activated, and then induced the apoptosis of Raji cells. Mangiferin combined with bortezomib could up-regulate the expression of LC3Ⅱ protein in Raji cells, and the ratio of LC3Ⅱ/LC3Ⅰ in cells was significantly up-regulated compared with single drug or control group (P <0.01). Mangiferin combined with bortezomib could significantly inhibit the phosphorylation levels of Akt and mTOR, inhibit the proliferation and invasion of Raji cells by inhibiting Akt/mTOR pathway, and induce cell autophagy and apoptosis. Mangiferin and bortezomib could down-regulate the expressions of CXCR4 and CXCR7 mRNA after single-agent intervention in Raji cells, and the down-regulations of CXCR4 and CXCR7 mRNA expression were more significant when the two drugs were combined (P <0.01). Mangiferin alone or combined with bortezomib had no significant effect on CXCR5 mRNA expression in Raji cells (P >0.05), while the combination of the two drugs could down-regulate the expression of CXCR3 (P <0.05). CONCLUSION: Mangiferin combined with bortezomib can synergistically inhibit the proliferation and invasion of Raji cells, and induce autophagy and apoptosis. The mechanism may be related to the inhibition of Akt/mTOR signaling pathway, down-regulation of anti-apoptotic protein Bcl-2 and up-regulation of pro-apoptotic protein Bax, and the inhibition of the expression of CXCR family.

Carrier-Free Gambogic Acid Dimer Self-Assembly Nanomedicines for Rheumatoid Arthritis Treatment.

Introduction: The insufficient targeting delivery of therapeutic agents greatly impeded the treatment outcomes of rheumatoid arthritis (RA). Despite the recognized therapeutic advantages of gambogic acid (GBA) in inflammatory diseases, its high delivery efficiency to inflammatory site still limits its clinical application. Self-assembly of drug dimers into carrier-free nanoparticles (NPs) has become a straightforward and attractive approach to develop nanomedicines for RA treatment. Herein, homodimers of GBA were designed to form the carrier-free NPs by self-assembly for RA treatment. Methods: The synthetic gambogic acid dimers (GBA2) were self-assembled into NPs using a one-step solvent evaporation method. The size distribution, morphology, drug-loading efficiency (DLE) and storage stability were evaluated. A molecular dynamic simulation was conducted to gain further insight into the self-assembly mechanisms of GBA2/NPs. Besides, we investigated the cytotoxicity, apoptosis and cellular uptake profiles of GBA2/NPs in macrophages and osteoclasts. Finally, the specific biodistribution on the ankles of adjuvant-induced arthritis (AIA) mice, and the anti-RA efficacy of the AIA rat model were assessed. Results: GBA2/NPs exhibited the uniform spherical structure, possessing excellent colloidal stability, high self-assembly stability, high drug loading and low hemolytic activity. Comparing with GBA, GBA2/NPs showed higher cytotoxicity, cellular uptake and apoptosis rate against osteoclasts. In addition, GBA2/NPs exhibited much higher accumulation in ankle joints in vivo. As expected, the systematic administration of GBA2/NPs resulted in the greater alleviation of arthritic symptoms, cartilage protection, and inflammation, notably the reduced systemic toxicity compared to free GBA. Conclusion: GBA2/NPs formed GBA dimers exhibited the superior accumulation in the inflamed joint and anti-RA activity, potentially attributing to the similar extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration ("ELVIS") effects in inflamed joint and the enhanced cellular uptake in macrophages and osteoclasts. Our findings provide substantial evidence that self-assembly of GBA2/NPs would be a promising therapeutic alternative for RA treatment.

Potency of Xanthone Derivatives from Garcinia mangostana L. for COVID-19 Treatment through Angiotensin-Converting Enzyme 2 and Main Protease Blockade: A Computational Study.

ACE2 and Mpro in the pathology of SARS-CoV-2 show great potential in developing COVID-19 drugs as therapeutic targets, due to their roles as the "gate" of viral entry and viral reproduction. Of the many potential compounds for ACE2 and Mpro inhibition, α-mangostin is a promising candidate. Unfortunately, the potential of α-mangostin as a secondary metabolite with the anti-SARS-CoV-2 activity is hindered due to its low solubility in water. Other xanthone isolates, which also possess the xanthone core structure like α-mangostin, are predicted to be potential alternatives to α-mangostin in COVID-19 treatment, addressing the low drug-likeness of α-mangostin. This study aims to assess the potential of xanthone derivative compounds in the pericarp of mangosteen (Garcinia mangostana L.) through computational study. The study was conducted through screening activity using molecular docking study, drug-likeness prediction using Lipinski's rule of five filtration, pharmacokinetic and toxicity prediction to evaluate the safety profile, and molecular dynamic study to evaluate the stability of formed interactions. The research results showed that there were 11 compounds with high potential to inhibit ACE2 and 12 compounds to inhibit Mpro. However, only garcinone B, in addition to being indicated as active, also possesses a drug-likeness, pharmacokinetic, and toxicity profile that was suitable. The molecular dynamic study exhibited proper stability interaction between garcinone B with ACE2 and Mpro. Therefore, garcinone B, as a xanthone derivative isolate compound, has promising potential for further study as a COVID-19 treatment as an ACE2 and Mpro inhibitor.

Potential Antitumor Effect of α-Mangostin against Rat Mammary Gland Tumors Induced by LA7 Cells.

In this study, the chemotherapeutic effect of α-mangostin (AM) was assessed in rats injected with LA7 cells. Rats received AM orally at 30 and 60 mg/kg twice a week for 4 weeks. Cancer biomarkers such as CEA and CA 15-3 were significantly lower in AM-treated rats. Histopathological evaluations showed that AM protects the rat mammary gland from the carcinogenic effects of LA7 cells. Interestingly, AM decreased lipid peroxidation and increased antioxidant enzymes when compared to the control. Immunohistochemistry results of the untreated rats showed abundant PCNA and fewer p53-positive cells than AM-treated rats. Using the TUNEL test, AM-treated animals had higher apoptotic cell numbers than those untreated. This report revealed that that AM lessened oxidative stress, suppressed proliferation, and minimized LA7-induced mammary carcinogenesis. Therefore, the current study suggests that AM has significant potential for breast cancer treatment.

Biochemical features and therapeutic potential of α-Mangostin: Mechanism of action, medicinal values, and health benefits.

α-Mangostin (α-MG) is a natural xanthone obtained from the pericarps of mangosteen. It exhibits excellent potential, including anti-cancer, neuroprotective, antimicrobial, antioxidant, and anti-inflammatory properties, and induces apoptosis. α-MG controls cell proliferation by modulating signaling molecules, thus implicated in cancer therapy. It possesses incredible pharmacological features and modulates crucial cellular and molecular factors. Due to its lesser water solubility and pitiable target selectivity, α-MG has limited clinical application. As a known antioxidant, α-MG has gained significant attention from the scientific community, increasing interest in extensive technical and biomedical applications. Nanoparticle-based drug delivery systems were designed to improve the pharmacological features and efficiency of α-MG. This review is focused on recent developments on the therapeutic potential of α-MG in managing cancer and neurological diseases, with a special focus on its mechanism of action. In addition, we highlighted biochemical and pharmacological features, metabolism, functions, anti-inflammatory, antioxidant effects and pre-clinical applications of α-MG.

Lipidomics of the erythrocyte membrane and network pharmacology to explore the mechanism of mangiferin from Anemarrhenae rhizoma in treating type 2 diabetes mellitus rats.

Mangiferin, a natural C-glucoside xanthone, is one of the major bioactive ingredients derived from the dry rhizome of Anemarrhenae rhizome, which has been reported to exhibit various pharmacological effects, including anti-oxidant, anti-inflammatory, anti-fatty liver, anti-metabolic syndrome, and anti-diabetic. However, the precise molecular mechanisms underlying its impact on phospholipid metabolism in the erythrocyte membrane of type 2 diabetes mellitus (T2DM) remain unclear. The present research aimed to evaluate the effects of mangiferin on glucose and lipid metabolism in T2DM model rats and discuss the relationship between lipid metabolites and potential targets involved in the hypoglycemic effects by integrating lipidomics and network pharmacology method. After 8 consecutive weeks of treatment with mangiferin, the T2DM model rats exhibited significant improvements in several biochemical indices and cytokines, including fasting blood glucose (FBG) levels after 12 h of fasting, fasting insulin level (FINS), total cholesterol (T-CHO), triacylglycerols (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), homeostasis model assessment of insulin resistance (HMOA-IR), TNF-α and IL-6. A total of 22 differential lipid metabolites were selected from erythrocyte membrane phospholipids, which were closely associated with the processes of T2DM. These metabolites mainly belonged to glycerophospholipid metabolism and sphingolipid metabolism. Based on network pharmacology analysis, 22 genes were recognized as the potential targets of mangiferin against diabetes. Moreover, molecular docking analysis revealed that the targets of TNF, CASP3, PTGS2, MMP9, RELA, PLA2G2A, PPARA, and NOS3 could be involved in the modulation of inflammatory signaling pathways and arachidonic acid (AA) metabolism to improve IR and hyperglycemia. The combination of immunohistochemical staining and PCR showed that mangiferin could treat T2DM by regulating the expression of PPARγ protein and NF-κB mRNA expression to impact glycerophospholipids (GPs) and AA metabolism. The present study showed that mangiferin might alleviate IR and hyperglycemia of T2DM model rats via multiple targets and multiple pathways to adjust their phospholipid metabolism, which may be the underlying mechanism for mangiferin in the treatment of T2DM.

Discovery of phenylcarbamoyl xanthone derivatives as potent neuroprotective agents for treating ischemic stroke.

Compounds of natural sources are widespread discovered in the treatment of ischemic stroke. Alpha-mangostin, a natural prenylated xanthone, has been found to display a therapeutic potential to treat ischemic stroke. However, the direct application of α-mangostin is limited due to its cytotoxicity and relatively low efficacy. Herein, structural modification of α-mangostin was necessary to improve its drug-ability. Currently, 34 α-mangostin phenylcarbamoyl derivatives were synthesized and evaluated for their neuroprotective activities by glutamate-induced excitotoxicity and H2O2-induced oxidative damage models in vitro. The results showed that compound 2 had the most therapeutic potential in both models. Whereafter, 2 has been proved to have powerful therapeutic effects by the MCAO ischemic stroke model in rats, which might be due to inhibition of inflammatory reaction and free radical accumulation. Besides, acute toxicity assay in rats showed that compound 2 had excellent safety. Overall, 2 could be a promising neuroprotective agent for the treatment of ischemic stroke deserving further investigations.

Flavonoid derivative DMXAA attenuates cisplatin-induced acute kidney injury independent of STING signaling.

Cisplatin-induced nephrotoxicity is the main adverse effect of cisplatin-based chemotherapy and highly limits its clinical use. DMXAA, a flavonoid derivative, is a promising vascular disrupting agent and known as an agonist of STING. Although cGAS-STING activation has been demonstrated to mediate cisplatin-induced acute kidney injury (AKI), the role of DMXAA in this condition is unclear. Here, we defined an unexpected and critical role of DMXAA in improving renal function, ameliorating renal tubular injury and cell apoptosis, and suppressing inflammation in cisplatin-induced AKI. Moreover, we confirmed that DMXAA combated AKI in a STING-independent manner, as evidenced by its protective effect in STING global knockout mice subjected to cisplatin. Furthermore, we compared the role of DMXAA with another STING agonist SR717 in cisplatin-treated mice and found that DMXAA but not SR717 protected animals against AKI. To better evaluate the role of DMXAA, we performed transcriptome analyses and observed that both inflammatory and metabolic pathways were altered by DMXAA treatment. Due to the established role of metabolic disorders in AKI, which contributes to kidney injury and recovery, we also performed metabolomics using kidney tissues from cisplatin-induced AKI mice with or without DMXAA treatment. Strikingly, our results revealed that DMXAA improved the metabolic disorders in kidneys of AKI mice, especially regulated the tryptophan metabolism. Collectively, therapeutic administration of DMXAA ameliorates cisplatin-induced AKI independent of STING, suggesting a promising potential for preventing nephrotoxicity induced by cisplatin-based chemotherapy.

Mangiferin: the miraculous xanthone with diverse pharmacological properties.

Mangiferin (1,3,6,7-tetrahydroxy-2-[3,4,5-trihydroxy-6-(hydroxymethyl) oxan-2-yl] xanthen-9-one) is a bioactive component derived primarily from the mango tree. Belonging to the Xanthone family, its structure allows it to engage with a variety of pharmacological targets. The symmetric linked core of xanthones has a heterogeneous biogenetic background. The carbon atoms are designated in a biochemical order, which reveals the reason of ring A (C1-C4) being referred to as acetate originated, and ring B (C5-C8) is referred to as shikimate originated. The antibacterial, hypocholesterolemic, antiallergic, cardiotonic, antidiabetic, anti-neoplastic, neuroprotective, antioxidant and immunomodulatory properties have all been demonstrated for the secondary metabolite. This study assessed and explained the important medical properties of mangiferin available in published literature, as well as its natural source, biosynthesis, absorption and bioavailability; multiple administration routes; metabolism; nanotechnology for enhanced efficacy of mangiferin and its toxicity, to aid the anticipated on-going potential of mangiferin as a novel diagnostic treatment.

Use of photoacoustic imaging for monitoring vascular disrupting cancer treatments.

Vascular disrupting agents disrupt tumor vessels, blocking the nutritional and oxygen supply tumors need to thrive. This is achieved by damaging the endothelium lining of blood vessels, resulting in red blood cells (RBCs) entering the tumor parenchyma. RBCs present in the extracellular matrix are exposed to external stressors resulting in biochemical and physiological changes. The detection of these changes can be used to monitor the efficacy of cancer treatments. Spectroscopic photoacoustic (PA) imaging is an ideal candidate for probing RBCs due to their high optical absorption relative to surrounding tissue. The goal of this work is to use PA imaging to monitor the efficacy of the vascular disrupting agent 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) through quantitative analysis. Then, 4T1 breast cancer cells were injected subcutaneously into the left hind leg of eight BALB/c mice. After 10 days, half of the mice were treated with 15 mg/kg of DMXAA and the other half were injected with saline. All mice were imaged using the VevoLAZR X PA system before treatment, 24 and 72 hours after treatment. The imaging was done at six wavelengths and linear spectral unmixing was applied to the PA images to quantify three forms of hemoglobin (oxy, deoxy and met-hemoglobin). After imaging, tumors were histologically processed and H&E and TUNEL staining were used to detect the tissue damage induced by the DMXAA treatment. The total hemoglobin concentration remained unchanged after treatment for the saline treated mice. For DMXAA treated mice, a 10% increase of deoxyhemoglobin concentration was detected 24 hours after treatment and a 22.6% decrease in total hemoglobin concentration was observed by 72 hours. A decrease in the PA spectral slope parameters was measured 24 hours after treatment. This suggests that DMXAA induces vascular damage, causing red blood cells to extravasate. Furthermore, H&E staining of the tumor showed areas of bleeding with erythrocyte deposition. These observations are further supported by the increase in TUNEL staining in DMXAA treated tumors, revealing increased cell death due to vascular disruption. This study demonstrates the capability of PA imaging to monitor tumor vessel disruption by the vascular disrupting agent DMXAA.

Promising anticonvulsant and/or analgesic compounds among 5-chloro-2- or 5-chloro-4-methyl derivatives of xanthone coupled to aminoalkanol moieties-Design, synthesis and pharmacological evaluation.

A series of 10 aminoalkanol derivatives of 5-chloro-2- or 5-chloro-4-methylxanthone was synthetized and evaluated for anticonvulsant properties (MES test, mice, intraperitoneal) and compared with neurotoxicity rotarod test (NT, mice, i.p.). The best results both in terms of anticonvulsant activity and protective index value were obtained for 3: 5-chloro-2-([4-hydroxypiperidin-1-yl]methyl)-9H-xanthen-9-one hydrochloride. Compounds: 1-3, 7 and 10 revealed ED50 values in MES test: 42.78, 31.64, 25.76, 46.19 and 52.50 mg/kg b.w., respectively. 3 showed 70% and 72% of inhibition control specific binding of sigma-1 (σ1) and sigma-2 (σ2) receptor, respectively. 3 exhibited also antinociceptive activity at dose 2 mg/kg b.w. after chronic constriction injury in mice. 1, 3, 7 and 10 were evaluated on gastrointestinal flora and proved safe. In genotoxicity test (UMU-Chromotest) compounds 1, 7 and 10 proved safe at dose 150-300 µg/ml. The pharmacokinetic analysis showed rapid absorption of all studied molecules from the digestive tract (tmax  = 5-30 min). The bioavailability of the compounds ranged from 6.6% (1) to 16% (10). All studied compounds penetrate the blood-brain barrier with brain to plasma ratios varied from 4.15 (3) to 7.6 (compound 7), after i.v. administration, and from 1 (7) to 5.72 (3) after i.g. administration.

Mangosteen for malignancy prevention and intervention: Current evidence, molecular mechanisms, and future perspectives.

Mangosteen (Garcinia mangostana L.), also known as the "queen of fruits", is a tropical fruit of the Clusiacea family. While native to Southeast Asian countries, such as Thailand, Indonesia, Malaysia, Myanmar, Sri Lanka, India, and the Philippines, the fruit has gained popularity in the United States due to its health-promoting attributes. In traditional medicine, mangosteen has been used to treat a variety of illnesses, ranging from dysentery to wound healing. Mangosteen has been shown to exhibit numerous biological and pharmacological activities, such as antioxidant, anti-inflammatory, antibacterial, antifungal, antimalarial, antidiabetic, and anticancer properties. Disease-preventative and therapeutic properties of mangosteen have been ascribed to secondary metabolites called xanthones, present in several parts of the tree, including the pericarp, fruit rind, peel, stem bark, root bark, and leaf. Of the 68 mangosteen xanthones identified so far, the most widely-studied are α-mangostin and γ-mangostin. Emerging studies have found that mangosteen constituents and phytochemicals exert encouraging antineoplastic effects against a myriad of human malignancies. While there are a growing number of individual research papers on the anticancer properties of mangosteen, a complete and critical evaluation of published experimental findings has not been accomplished. Accordingly, the objective of this work is to present an in-depth analysis of the cancer preventive and anticancer potential of mangosteen constituents, with a special emphasis on the associated cellular and molecular mechanisms. Moreover, the bioavailability, pharmacokinetics, and safety of mangosteen-derived agents together with current challenges and future research avenues are also discussed.

Alpha-mangostin Protects PC12 Cells Against Neurotoxicity Induced by Cadmium and Arsenic.

Arsenic and cadmium are nonessential elements that are of importance in public health due to their high toxicity. Contact with these toxic elements, even in very small amounts, can induce various side effects, including neurotoxicity. Oxidative stress and apoptosis are part of the main mechanisms of arsenic- and cadmium-induced toxicity. Alpha-mangostin is the main xanthone derived from mangosteen, Garcinia mangostana, with anti-oxidative properties.In this study, PC12 cells were selected as a nerve cell model, and the protective effects of alpha-mangostin against neurotoxicity induced by arsenic and cadmium were investigated. PC12 cells were exposed to cadmium (5-80 µM) and arsenic (2.5-180 µM) for 24 h. Cytotoxicity, reactive oxygen species (ROS) production, and the protein expression of Bax, Bcl2, and cleaved caspase 3 were determined using MTT assay, fluorimetry, and western blot, respectively.Arsenic (10-180 µM) and cadmium (50-80 µM) significantly reduced cell viability. IC50 values were 10.3 ± 1.09 and 45 ± 4.63 µM, respectively. Significant increases in ROS, Bax/Bcl-2 ratio, and cleaved caspase-3 were observed after arsenic and cadmium exposures. Cell viability increased and ROS production decreased when cells were pretreated with alpha-mangostin for 2 h. Alpha-mangostin reduced the increased level of cleaved caspase-3 induced by cadmium and decreased the elevated level of the Bax/Bcl-2 ratio after arsenic exposure.Alpha-mangostin significantly increased cell viability and reduced oxidative stress caused by cadmium and arsenic in PC12 cells. Moreover, alpha-mangostin reduced cadmium-induced apoptosis through the reduction in the level of cleaved caspase 3. Further studies are required to determine the different mechanisms of alpha-mangostin against neurotoxicity induced by these elements.

α-Crystallin chaperone mimetic drugs inhibit lens γ-crystallin aggregation: Potential role for cataract prevention.

Γ-Crystallins play a major role in age-related lens transparency. Their destabilization by mutations and physical chemical insults are associated with cataract formation. Therefore, drugs that increase their stability should have anticataract properties. To this end, we screened 2560 Federal Drug Agency-approved drugs and natural compounds for their ability to suppress or worsen H2O2 and/or heat-mediated aggregation of bovine γ-crystallins. The top two drugs, closantel (C), an antihelminthic drug, and gambogic acid (G), a xanthonoid, attenuated thermal-induced protein unfolding and aggregation as shown by turbidimetry fluorescence spectroscopy dynamic light scattering and electron microscopy of human or mouse recombinant crystallins. Furthermore, binding studies using fluorescence inhibition and hydrophobic pocket-binding molecule bis-8-anilino-1-naphthalene sulfonic acid revealed static binding of C and G to hydrophobic sites with medium-to-low affinity. Molecular docking to HγD and other γ-crystallins revealed two binding sites, one in the "NC pocket" (residues 50-150) of HγD and one spanning the "NC tail" (residues 56-61 to 168-174 in the C-terminal domain). Multiple binding sites overlap with those of the protective mini αA-crystallin chaperone MAC peptide. Mechanistic studies using bis-8-anilino-1-naphthalene sulfonic acid as a proxy drug showed that it bound to MAC sites, improved Tm of both H2O2 oxidized and native human gamma D, and suppressed turbidity of oxidized HγD, most likely by trapping exposed hydrophobic sites. The extent to which these drugs act as α-crystallin mimetics and reduce cataract progression remains to be demonstrated. This study provides initial insights into binding properties of C and G to γ-crystallins.

Xanthones from Securidaca inappendiculata Hassk. attenuate collagen-induced arthritis in rats by inhibiting the nicotinamide phosphoribosyltransferase/glycolysis pathway and macrophage polarization.

Securidaca inappendiculata (SI) Hassk. is a traditional medicine used to treat rheumatoid arthritis. Recent studies have reported that macrophages are the primary regulators of joint homeostasis and their polarization is closely related to their metabolic mode. Here, we aimed to investigate the relationship between the joint protective effect of SI's xanthone-rich fraction (XRF) on collagen-induced arthritis (CIA) in rats and the nicotinamide phosphoribosyltransferase (NAMPT)-glycolysis-polarization axis of macrophages. CIA model rats were treated with oral XRF and therapeutic efficacy was assessed based on arthritis score, degree of paw swelling, histological examination, and immunohistochemical analysis. Serum levels of cytokines, cellular metabolite concentrations, and protein and mRNA expression were determined by enzyme-linked immunosorbent assay (ELISA), western blotting (WB), and quantitative real-time PCR (RT-qPCR), respectively. The effects of dihydroxy-3,4-dimethoxyxanthone (XAN), a representative SI-derived compound, on RAW264.7 macrophages was analyzed in vitro using confocal laser scanning and flow cytometry. We found that XRF treatment significantly alleviated disease severity in CIA model rats. Levels of pro-inflammatory cytokines in the serum and M1 markers in synovium were reduced after XRF treatment, accompanied by an increase in the levels of anti-inflammatory cytokines and M2 markers. Further, XRF significantly suppressed synovial glycolysis by regulating NAMPT. In vitro studies further showed that XAN induced repolarization of lipopolysaccharide (LPS)-induced RAW264.7 macrophages with M1-M2 phenotype. Moreover, XAN negatively regulated glycolysis in the LPS-induced RAW264.7 macrophages in correlation with changes in NAMPT expression. Overall, the findings of this study suggest that the joint protective effects of XRF are achieved by inhibiting the NAMPT/glycolysis pathway and thereby regulating macrophage polarization.