RESUMEN
BACKGROUND: Malaria is a major global health concern, particularly in tropical and subtropical countries. With growing resistance to first-line treatment with artemisinin, there is an urgent need to discover novel antimalarial drugs. Mesua ferrea Linn., a plant used in traditional medicine for various purposes, has previously been investigated by our research group for its cytotoxic properties. The objective of this study was to explore the compounds isolated from M. ferrea with regards to their potential antiplasmodial activity, their interaction with Plasmodium falciparum lactate dehydrogenase (PfLDH), a crucial enzyme for parasite survival, and their pharmacokinetic and toxicity profiles. METHODS: The isolated compounds were assessed for in vitro antiplasmodial activity against a multidrug-resistant strain of P. falciparum K1 using a parasite lactate dehydrogenase (pLDH) assay. In vitro cytotoxicity against Vero cells was determined using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The interactions between the isolated compounds and the target enzyme PfLDH were investigated using molecular docking. Additionally, pharmacokinetic and toxicity properties were estimated using online web tools SwissADME and ProTox-II, respectively. RESULTS: Among the seven compounds isolated from M. ferrea roots, rheediachromenoxanthone (5), which belongs to the pyranoxanthone class, demonstrated good in vitro antiplasmodial activity, with the IC50 being 19.93 µM. Additionally, there was no toxicity towards Vero cells (CC50 = 112.34 µM) and a selectivity index (SI) of 5.64. Molecular docking analysis revealed that compound (5) exhibited a strong binding affinity of - 8.6 kcal/mol towards PfLDH and was stabilized by forming hydrogen bonds with key amino acid residues, including ASP53, TYR85, and GLU122. Pharmacokinetic predictions indicated that compound (5) possessed favorable drug-like properties and desired pharmacokinetic characteristics. These include high absorption in the gastrointestinal tract, classification as a non-substrate of permeability glycoprotein (P-gp), non-inhibition of CYP2C19, ease of synthesis, a high predicted LD50 value of 4,000 mg/kg, and importantly, non-hepatotoxic, non-carcinogenic, and non-cytotoxic effects. CONCLUSIONS: This study demonstrated that compounds isolated from M. ferrea exhibit activity against P. falciparum. Rheediachromenoxanthone has significant potential as a scaffold for the development of potent antimalarial drugs.
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Antimaláricos , Simulación del Acoplamiento Molecular , Extractos Vegetales , Raíces de Plantas , Plasmodium falciparum , Xantonas , Antimaláricos/farmacología , Antimaláricos/farmacocinética , Antimaláricos/química , Antimaláricos/toxicidad , Plasmodium falciparum/efectos de los fármacos , Xantonas/farmacología , Xantonas/química , Xantonas/farmacocinética , Animales , Extractos Vegetales/farmacología , Extractos Vegetales/química , Chlorocebus aethiops , Células VeroRESUMEN
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 447.1â271.1 for baicalin m/z and 421.0â301.0 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.
Asunto(s)
Diabetes Mellitus Experimental , Gentiana , Extractos Vegetales , Espectrometría de Masas en Tándem , Xantonas , Animales , Xantonas/farmacocinética , Xantonas/sangre , Xantonas/administración & dosificación , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/tratamiento farmacológico , Espectrometría de Masas en Tándem/métodos , Masculino , Cromatografía Líquida de Alta Presión/métodos , Extractos Vegetales/farmacocinética , Extractos Vegetales/administración & dosificación , Extractos Vegetales/sangre , Administración Oral , Ratas , Gentiana/química , Ratas Sprague-Dawley , Estreptozocina , Reproducibilidad de los Resultados , Cromatografía Líquida con Espectrometría de MasasRESUMEN
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.
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Disponibilidad Biológica , Carbono , Paeonia , Tamaño de la Partícula , Ratas Sprague-Dawley , Solubilidad , Xantonas , Xantonas/farmacocinética , Xantonas/química , Xantonas/administración & dosificación , Animales , Carbono/química , Carbono/farmacocinética , Masculino , Ratas , Paeonia/química , Medicamentos Herbarios Chinos/farmacocinética , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/administración & dosificación , Puntos Cuánticos/química , Puntos Cuánticos/toxicidad , Línea Celular , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Supervivencia Celular/efectos de los fármacosRESUMEN
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.
Asunto(s)
Garcinia mangostana , Redes y Vías Metabólicas/fisiología , Fitoquímicos , Xantonas , Administración Oral , Animales , Vías de Eliminación de Fármacos/fisiología , Hidrogenación , Tasa de Depuración Metabólica/fisiología , Fitoquímicos/administración & dosificación , Fitoquímicos/farmacocinética , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Ratas Sprague-Dawley , Xantonas/administración & dosificación , Xantonas/farmacocinéticaRESUMEN
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.
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Materiales Biocompatibles/síntesis química , Quitosano/química , Dióxido de Silicio/química , Andamios del Tejido/química , Xantonas/administración & dosificación , Animales , Materiales Biocompatibles/química , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Materiales Biocompatibles Revestidos/síntesis química , Materiales Biocompatibles Revestidos/química , Ensayo de Materiales , Ratones , Nanocompuestos/química , Porosidad , Xantonas/farmacocinéticaRESUMEN
Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive memory loss, declining language skills and other cognitive disorders. AD has brought great mental and economic burden to patients, families and society. However due to the complexity of AD's pathology, drugs developed for the treatment of AD often fail in clinical or experimental trials. The main problems of current anti-AD drugs are low efficacy due to mono-target method or side effects, especially high hepatotoxicity. To tackle these two main problems, multi-target-directed ligand (MTDL) based on "one molecule, multiple targets" has been studied. MTDLs can regulate multiple biological targets at the same time, so it has shown higher efficacy, better safety. As a natural active small molecule, α-mangostin (α-M) has shown potential multi-factor anti-AD activities in a series of studies, furthermore it also has a certain hepatoprotective effect. The good availability of α-M also provides support for its application in clinical research. In this work, multiple activities of α-M related to AD therapy were reviewed, which included anti-cholinesterase, anti-amyloid-cascade, anti-inflammation, anti-oxidative stress, low toxicity, hepatoprotective effects and drug formulation. It shows that α-M is a promising candidate for the treatment of AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Xantonas/uso terapéutico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/psicología , Animales , Encéfalo/metabolismo , Encéfalo/fisiopatología , Composición de Medicamentos , Humanos , Terapia Molecular Dirigida , Fármacos Neuroprotectores/efectos adversos , Fármacos Neuroprotectores/farmacocinética , Transducción de Señal , Xantonas/efectos adversos , Xantonas/farmacocinéticaRESUMEN
Nowadays, the research of photothermal-chemical co-therapy provides new ideas for the treatment of cancer. However, the harsh photothermal temperature hinders the clinical development of photothermal therapy. To ensure low-temperature photothermal-chemical combined therapy, a safe and feasible drug delivery system is highly desirable. Herein, through one step co-precipitation method, ginsenoside Rb1-based nanovehicles composed of the hydrophobic drug doxorubicin, the photochemical reagent Cypate and the heat shock protein inhibitor gambogic acid was prepared, resulting from the amphiphilicity and membrane permeability of Rb1. Encouragingly, this platform exhibited excellent biocompatibility and rapid cellular uptake, both of which led to significant and irreversible death of breast cancer cells under the trigger of short-term near-infrared light.
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Antineoplásicos , Portadores de Fármacos , Ginsenósidos/química , Nanopartículas , Fotoquimioterapia/métodos , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Portadores de Fármacos/química , Portadores de Fármacos/toxicidad , Humanos , Indoles/química , Indoles/farmacocinética , Ratones , Nanopartículas/química , Nanopartículas/toxicidad , Propionatos/química , Propionatos/farmacocinética , Xantonas/química , Xantonas/farmacocinéticaRESUMEN
Fibrosis is the end stage of many chronic diseases, which results in organ function failure and high mortality. Mangiferin is a major constituent in mango and other 16 plants, and has been shown a variety of pharmacological effects, such as antioxidant, antibacterial, anti-tumor, anti-inflammation. The emerging evidence has shown that mangiferin can improve renal interstitial fibrosis, pulmonary fibrosis, myocardial fibrosis and hepatic fibrosis through the inhibition of inflammation, oxidative stress and fibrogenesis effects, indicating that mangiferin is promising therapeutic choice for organ fibrosis. The aim of this review is to summarize the therapeutic effects of mangiferin on fibrosis of various organs and the underlying mechanisms.
Asunto(s)
Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Fibrosis/tratamiento farmacológico , Xantonas/uso terapéutico , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Antioxidantes/química , Antioxidantes/farmacocinética , Antioxidantes/farmacología , Fibrosis/etiología , Humanos , Riñón/patología , Cirrosis Hepática/tratamiento farmacológico , Ratones , Miocardio/patología , Fibrosis Pulmonar/tratamiento farmacológico , Ratas , Xantonas/química , Xantonas/farmacocinética , Xantonas/farmacologíaRESUMEN
BACKGROUND: Mangosteen, Garciniam angostana L., is a juicy fruit commonly found in Thailand. The rinds of Garciniam angostana L.have been used as a traditional medicine for the treatment of trauma, diarrhea and skin infection. It is also used in dermatological product such as in cosmetics. The mangosteen pericarp can be used to extract valuable bioactive xanthone compounds such as α-mangostin and gartanin. This study is aimed to predict the metabolism of α-mangostin and gartanin using in silico and in vitro skin permeation strategies. METHODS: Based on their 2D molecular structures, metabolites of those compounds were predicted in silico using ADMET Predictor™. The Km and Vmax, for 5 important recombinant CYP isozymes 1A2, 2C9, 2C19, 2D6 and 3A4 were predicted. Moreover, the in vitro investigation of metabolites produced during skin permeation using human epidermal keratinocyte cells, neonatal (HEKn cells) was performed by LC-MS/MS. RESULTS: It was found that the results derived from in silico were in excellent alignment with those obtained from in vitro studies for both compounds. The prediction referred that gartanin and α-mangostin were the substrate of CYP1A2, 2C9, 2C19 and 3A. In the investigation of α-mangostin metabolites by LC-MS/MS system, the MW of the parent compound was increased from 411.200 to 459.185 Da. Therefore, α-mangostin might be metabolized via tri-oxidation process. The increased molecular weight of parent compound (397.200 to 477.157 Da) illustrated that gartanin might be conjugated to sulfated derivatives. CONCLUSIONS: In all the studies, α-mangostin and gartanin were predicted to be. metabolized via phase I and phase II metabolism (sulfation), respectively.
Asunto(s)
Extractos Vegetales/farmacocinética , Absorción Cutánea/efectos de los fármacos , Xantonas/farmacocinética , Línea Celular , Simulación por Computador , Humanos , Técnicas In Vitro , Estructura Molecular , Permeabilidad , Extractos Vegetales/química , Tailandia , Xantonas/químicaRESUMEN
PURPOSE: Therapy for triple-negative breast cancer (TNBC) is a global problem due to lack of specific targets for treatment selection. Cancer stem cells (CSCs) are responsible for tumor formation and recurrence but also offer a promising target for TNBC-targeted therapy. Here, zirconium-89 (89Zr)-labelled multifunctional liposomes (MLPs) surface-decorated with chitosan (CS) were fabricated to specifically target and trace cluster of differentiation 44+ (CD44+) TNBC CSCs specifically. PATIENTS AND METHODS: The biological basis of CS targeting CD44 for cancer therapy was investigated by detecting the expression of CD44 in TNBC CSCs and TNBC tissues. Molecular docking and dynamics simulations were performed to investigate the molecular basis of CS targeting CD44 for cancer therapy. Gambogic acid (GA)-loaded, 89Zr@CS-MLPs (89Zr-CS-GA-MLPs) were prepared, and their uptake and biodistribution were observed. The anti-tumor efficacy of 89Zr@CS-GA-MLPs was investigated in vivo. RESULTS: CD44 is overexpressed in TNBC CSCs and tissues. Molecular docking and dynamics simulations showed that CS could be stably docked into the active site of CD44 in a reasonable conformation. Furthermore, 89Zr@CS-GA-MLPs were able to bind specifically to CD44+ TNBC stem-like cells and accumulated in tumors of xenograft-bearing mice with excellent radiochemical stability. 89Zr@CS-GA-MLPs loaded with GA showed remarkable anti-tumor efficacy in vivo. CONCLUSION: The GA-loaded, 89Zr-labelled, CS-decorated MLPs developed in this study represent a novel strategy for TNBC imaging and therapy.
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Liposomas/química , Células Madre Neoplásicas/efectos de los fármacos , Radioisótopos/química , Neoplasias de la Mama Triple Negativas/diagnóstico por imagen , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Circonio/química , Adulto , Anciano , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Quitosano/química , Femenino , Humanos , Receptores de Hialuranos/química , Receptores de Hialuranos/metabolismo , Liposomas/farmacocinética , Ratones Desnudos , Persona de Mediana Edad , Simulación del Acoplamiento Molecular , Terapia Molecular Dirigida/métodos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Tomografía de Emisión de Positrones/métodos , Distribución Tisular , Neoplasias de la Mama Triple Negativas/patología , Xantonas/farmacocinética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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.
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Antidepresivos/farmacología , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Xantonas/farmacología , beta-Arrestinas/efectos de los fármacos , Animales , Antidepresivos/administración & dosificación , Antidepresivos/farmacocinética , Conducta Animal/efectos de los fármacos , Masculino , Ratones , Xantonas/administración & dosificación , Xantonas/farmacocinéticaRESUMEN
Garcinia mangostana L. (mangosteen) is a famous tropical fruit that contains a large number of xanthones. Regular consumption of mangosteen may confer health benefits and prevent some diseases, such as malaria. Quinone reductase 2 (QR-2) is a cytosolic enzyme found in human red blood cells, and it is becoming a target for chemoprevention because it is involved in the mechanisms of several diseases, including malaria. To understand whether the xanthones present in mangosteen might inhibit the activity of QR-2, blood samples were collected from rat following the oral administration of mangosteen extract and then incubated with QR-2 followed by UF-HPLC-QTOF/MS analysis to rapidly screen for and identify the QR-2-inhibiting xanthones. A total of 16 xanthones were identified, and six of these (α-mangostin, γ-mangostin, 8-deoxyartanin, 1,3,7-trihydroxy-2,8-di(3-methylbut-2-enyl)xanthone, garcinone E, and 9-hydroxycalabaxanthone) were subjected to QR-2 inhibition assay. γ-Mangostin exhibited the strongest inhibition, achieving an IC50 value of 3.82 ± 0.51 µM. Its interaction with QR-2 was found to involve hydrogen bond and arene-arene interaction as revealed by molecular docking. The present study could provide new insight into the potential application of mangosteen as functional food ingredients for inhibiting the activity of QR-2. However, the extent of daily intake of mangosteen required and the exact contribution of mangosteen to the prevention and treatment of malaria remain subjects of further study.
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Inhibidores Enzimáticos/farmacocinética , Garcinia mangostana/química , Extractos Vegetales/farmacocinética , Quinona Reductasas/antagonistas & inhibidores , Administración Oral , Animales , Cromatografía Liquida , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Frutas/química , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Extractos Vegetales/administración & dosificación , Extractos Vegetales/química , Quinona Reductasas/química , Quinona Reductasas/metabolismo , Ratas , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem , Xantonas/administración & dosificación , Xantonas/química , Xantonas/farmacocinéticaRESUMEN
Alzheimer's disease (AD), Parkinson's disease (PD), and depression are growing burdens for society globally, partly due to a lack of effective treatments. Mangosteen (Garcinia mangostana L.,) pericarp (MP) and its xanthones may provide therapeutic advantages for these disorders. In this review, we discuss potential therapeutic value of MP-derived agents in AD, PD, and depression with their pharmacokinetic and safety profiles. MP-derived agents have shown multifunctional effects including neuroprotective, antioxidant, and anti-neuroinflammatory actions. In addition, they target specific disease pathologies, such as amyloid beta production and deposition as well as cholinergic dysfunction in AD; α-synuclein aggregation in PD; and modulation of monoamine disturbance in depression. Particularly, the xanthone derivatives, including α-mangostin and γ-mangostin, exhibit potent pharmacological actions. However, low oral bioavailability and poor brain penetration may limit their therapeutic applications. These challenges can be overcome in part by administering as a form of MP extract (MPE) or using specific carrier systems. MPE and α-mangostin are generally safe and well-tolerated in animals. Furthermore, mangosteen-based products are safe for humans. Therefore, MPE and its bioactive xanthones are promising candidates for the treatment of AD, PD, and depression. Further studies including clinical trials are essential to decipher their efficacy, and pharmacokinetic and safety profiles in these disorders.
Asunto(s)
Depresión/metabolismo , Garcinia mangostana/química , Enfermedades Neurodegenerativas/metabolismo , Xantonas/farmacocinética , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Aminas/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Depresión/tratamiento farmacológico , Humanos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Extractos Vegetales/química , Xantonas/química , Xantonas/uso terapéutico , alfa-Sinucleína/metabolismoRESUMEN
BACKGROUND: Non-alcoholic fatty liver is one of the most common comorbidities of diabetes. It can cause disturbance of glucose and lipid metabolism in the body, gradually develop into liver fibrosis, and even cause liver cirrhosis. Mangiferin has a variety of pharmacological activities, especially for the improvement of glycolipid metabolism and liver injury. However, its poor oral absorption and low bioavailability limit its further clinical development and application. The modification of mangiferin derivatives is the current research hotspot to solve this problem. METHODS: The plasma pharmacokinetic of mangiferin calcium salt (MCS) and mangiferin were monitored by HPLC. The urine metabolomics of MCS were conducted by UPLC-Q-TOF-MS. RESULTS: The pharmacokinetic parameters of MCS have been varied, and the oral absorption effect of MCS was better than mangiferin. Also MCS had a good therapeutic effect on type 2 diabetes and NAFLD rats by regulating glucose and lipid metabolism. Sixteen potential biomarkers had been identified based on metabolomics which were related to the corresponding pathways including Pantothenate and CoA biosynthesis, fatty acid biosynthesis, citric acid cycle, arginine biosynthesis, tryptophan metabolism, etc. CONCLUSIONS: The present study validated the favorable pharmacokinetic profiles of MCS and the biochemical mechanisms of MCS in treating type 2 diabetes and NAFLD.
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Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Xantonas/farmacocinética , Animales , Biomarcadores/metabolismo , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/orina , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/orina , Femenino , Masculino , Metabolómica , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/orina , Ratas Sprague-Dawley , Sales (Química)/sangre , Sales (Química)/farmacocinética , Sales (Química)/orina , Xantonas/sangre , Xantonas/orinaRESUMEN
Natural products are increasing used in preventing and treating various diseases. Mangiferin belongs to the xanthone family, and has potential antiangiogenic, anticancer, immunomodulatory and anti-inflammatory activity along with the antioxidant activity. It is also used in the treatment of cardiac problem, diabetes and neurodegenerative disease. Finding of various researchers proves that mangiferin has a broad spectrum therapeutic application. Motive of this review is to describe the various studies performed on mangiferin for its different pharmacological activities. It also discusses various challenges associated with mangiferin such as stability and bioavailability. Strategies and approaches to improve bioavailability of mangiferin have also been discussed. Both research and review articles were used to write the manuscript. They were collected from various search engines like Pub Med, Science Direct and Google Scholar, using keywords like mangiferin, polyphenol, bioavailability enhancement, solubility enhancement, and antioxidant. Mangiferin being a potent antioxidant is effective in the treatment of various diseases. With novel drug delivery approaches we can overcome poor solubility and bioavailability problem which eventually can result to better utilisation of mangiferin in treating a variety of diseases and make mangiferin a revolutionary drug.
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Antioxidantes/farmacocinética , Xantonas/farmacocinética , Animales , Disponibilidad Biológica , Diabetes Mellitus/tratamiento farmacológico , Cardiopatías/tratamiento farmacológico , Humanos , Enfermedades Neurodegenerativas/tratamiento farmacológicoRESUMEN
To validate PDE4 inhibitors as novel therapeutic agents against vascular dementia (VaD), 25 derivatives were discovered from the natural inhibitor α-mangostin (IC50 = 1.31 µM). Hit-to-lead optimization identified a novel and selective PDE4 inhibitor 4e (IC50 = 17 nM), which adopted a different binding pattern from PDE4 inhibitors roflumilast and rolipram. Oral administration of 4e at a dose of 10 mg/kg exhibited remarkable therapeutic effects in a VaD model and did not cause emesis to beagle dogs, indicating its potential as a novel anti-VaD agent.
Asunto(s)
Demencia Vascular/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Xantonas/uso terapéutico , Aminopiridinas/metabolismo , Animales , Benzamidas/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Ciclopropanos/metabolismo , Perros , Diseño de Fármacos , Humanos , Masculino , Ratones Endogámicos C57BL , Estructura Molecular , Inhibidores de Fosfodiesterasa 4/síntesis química , Inhibidores de Fosfodiesterasa 4/metabolismo , Inhibidores de Fosfodiesterasa 4/farmacocinética , Unión Proteica , Rolipram/metabolismo , Rolipram/uso terapéutico , Relación Estructura-Actividad , Vómitos/prevención & control , Xantonas/síntesis química , Xantonas/metabolismo , Xantonas/farmacocinéticaRESUMEN
Mangiferin, a natural compound isolated from Mangifera indica L, was incorporated in glycerosomes, ethosomes and alternatively in glycerol-ethanol phospholipid vesicles (glycethosomes). Actually, only glycethosomes were able to stably incorporate the mangiferin that was loaded at increasing concentrations (2, 4, 6, 8 mg/mL). The morphology, size distribution, rheological properties, surface charge and entrapment efficiency of prepared vesicles were deeply measured. All vesicles were mainly spherical, oligolamellar, small in size (~145 nm) and negatively charged (~-40 mV), as confirmed by cryo-TEM observation and dynamic laser light scattering measurements. The higher concentration of mangiferin (8 mg/mL) allowed an increase of vesicle mean diameter up to ~288 nm. The entrapment efficiency was inversely proportional to the amount of loaded mangiferin. In vitro studies performed by using human abdominal skin, underlined that, the dose-dependent ability of vesicles to promote mangiferin retention in epidermis. In addition, glycethosomes were highly biocompatible and showed a strong ability to protect in vitro the fibroblasts against damages induced by hydrogen peroxide. In vivo results underlined the superior ability of mangiferin loaded glycethosomes respect to the mangiferin dispersion to promote the heal of the wound induced by TPA, confirming their potential application for the treatment of psoriasis or other skin disorders.
Asunto(s)
Adyuvantes Farmacéuticos/administración & dosificación , Portadores de Fármacos/química , Mangifera/química , Psoriasis/tratamiento farmacológico , Xantonas/administración & dosificación , Células 3T3 , Adyuvantes Farmacéuticos/farmacocinética , Administración Cutánea , Animales , Modelos Animales de Enfermedad , Composición de Medicamentos/métodos , Epidermis/efectos de los fármacos , Epidermis/metabolismo , Etanol/química , Femenino , Glicerol/química , Humanos , Peróxido de Hidrógeno/toxicidad , Ratones , Fosfolípidos/química , Psoriasis/inducido químicamente , Acetato de Tetradecanoilforbol/toxicidad , Distribución Tisular , Cicatrización de Heridas/efectos de los fármacos , Xantonas/farmacocinéticaRESUMEN
Gambogic acid (GA) is a natural anti-tumor drug whose application is restricted by its poor aqueous solubility and inefficient bioavailability. Developing nanomaterials with excellent biocompatibility can amplify the therapeutic effects of GA. In this study, a tumor-targeted redox controllable self-assembled nano-system with magnetic enhanced EPR effects (mPEG-HA/CSO-SS-Hex/SPION/GA) was developed to improve the anticancer efficacy of GA. The nano-system is constituted by three layers: the outer layer is mono-aminated poly(ethylene glycol) grafted hyaluronic acid (mPEG-HA), which can target the CD44 receptor in breast cancer cells; the middle layer consists of disulfide linked hexadecanol (Hex) and chitosan oligosaccharide (CSO) to control the drug release by reduction response; the core layer is superparamagnetic iron oxide nanoparticles (SPION), which can enhance the EPR effect by magnetic guidance and contribute to GA entrapment. Different experiments were performed to characterize the complex self-assembly, and the cytotoxicity, pharmacokinetics, and in vivo antitumor activity of the self-assembly were investigated to evaluate its anti-tumor effects. The results revealed that mPEG-HA/CSO-SS-Hex/SPION/GA is an excellent nanosystem with appropriate size and sensitive responsiveness; it can accumulate in tumor sites and achieve excellent therapeutic effects on triple-negative breast cancer (TNBC). In summary, a CD44-targeted redox-triggered self-assembly nanosystem with magnetic enhanced EPR effects was developed for effective amplification of GA; it has potential to act as an effective carrier in drug delivery for chemotherapy of TNBC.
Asunto(s)
Receptores de Hialuranos/antagonistas & inhibidores , Ácido Hialurónico/química , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Xantonas/administración & dosificación , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Portadores de Fármacos , Femenino , Humanos , Células MCF-7 , Nanopartículas de Magnetita , Ratones , Oxidación-Reducción , Polietilenglicoles , Células RAW 264.7 , Distribución Tisular , Neoplasias de la Mama Triple Negativas/metabolismo , Xantonas/química , Xantonas/farmacocinética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Precision medicine has increased the demand for stage-specific cancer chemotherapy. Drugs with different properties are needed for different stages of tumor development, which is, inducing rapid destruction in the early stage and facilitating deep penetration in the advanced stage. Herein, we report a novel reduction-activated charge-conversional core-shell nanoparticle (CS NP) formula based on ring-closing metathesis of the thiamine disulfide system (TDS) to deliver the chemotherapeutic agent-gambogic acid (GA). Methods: The shell consisted of hyaluronic acid-all-trans retinoid acid with a disulfide bond as the linker (HA-SS-ATRA). The core was selected from poly (γ-glutamic acid) with different grafting rates of the functional group (Fx%) of TDS. GA/CF100%S NPs, with the strongest reduction-responsive drug release, and GA/CF60%S NPs with the strongest penetration have been finally screened. On this basis, a stage-specific administration strategy against a two-stage hepatocellular carcinoma was proposed. Results: The developed CS NPs have been confirmed as inducing reduction-activated charge conversion from about -25 to +30 mV with up to 95% drug release within 48 h. The administration strategy, GA/CF100%S NPs for the early-stage tumor, and sequential administration of GA/CF60%S NPs followed by GA/CF100%S NPs for the advanced-stage tumor, achieved excellent tumor inhibition rates of 93.86±2.94% and 90.76±6.43%, respectively. Conclusions: Our CS NPs provide a novel platform for charge conversion activated by reduction. The stage-specific administration strategy showed great promise for cancer therapy.
Asunto(s)
Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/administración & dosificación , Nanopartículas/química , Xantonas/administración & dosificación , Animales , Antineoplásicos/farmacocinética , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Liberación de Fármacos , Células Hep G2 , Humanos , Ácido Hialurónico/química , Inyecciones Intravenosas , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Masculino , Ratones Endogámicos ICR , Oxidación-Reducción , Esferoides Celulares/efectos de los fármacos , Tiamina/análogos & derivados , Tiamina/química , Tretinoina/química , Xantonas/farmacocinética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Searching for CNS active cyclic amines derivatives containing heterocyclic xanthone core we designed and synthesized a set of fourteen novel 2- or 4-methylxanthone substituted by alkyl- or aryl-piperazine moieties. The compounds were evaluated in vivo for their potential antidepressant-like activity (in the forced swim test) and anxiolytic-like activity (four-plate test) and their inhibitory effect against rat 5-HT2 receptor was checked. The pharmacokinetic analysis of active compounds done by a non-compartmental approach have shown a rapid absorption of all studied molecules from intraperitoneal cavity and good penetration the blood-brain barrier after i.p. administration with brain to plasma ratios varied from 2.8 to 31.6. Genotoxicity and biotransformation of active compounds were studied. Compound 19 interactions with major classes of GPCRs, uptake systems and ion channels were tested and results indicated that it binds to 5-HT2A, 5-HT2B receptors and sodium channels.