RESUMO
OBJECTIVES: This study aims to investigate the primary target and potential mechanism of mangiferin (MF) in treating oral submucous fibrosis (OSF) through Gene Expression Omnibus (GEO) database chip mining, network pharmacology, and molecular docking techniques. METHODS: Potential therapeutic targets for OSF were identified using GEO chip data. The potential targets of MF were predicted, and disease-related targets for OSF were collected from databases. A Venn diagram was created using the EVenn platform to identify overlapping targets. The protein-protein interaction (PPI) network was constructed using the STRING database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the DAVID platform. Cytoscape 3.10.1 software was used to visualize a drug-target-pathway-disease network, while AutoDocktools 1.5.6 software was employed for molecular docking analysis. RESULTS: A total of 356 potential targets for MF and 360 disease-related targets for OSF were obtained from multiple databases. The top 15 key target proteins in the PPI network were selected as significant candidates. GO function and KEGG pathway enrichment analyses revealed that MF treatment primarily involved advanced glycation end products-receptor (AGE-RAGE), epidermal growth factor receptor (EGFR), and other signaling pathways associated with OSF pathogenesis. Molecular docking analysis demonstrated that MF exhibited a strong binding activity toward AKT serine kinase 1 (AKT1), tumor necrosis factor (TNF), and other core targets. CONCLUSIONS: These findings suggest that MF may exert its therapeutic effects on OSF through a multitarget approach involving various signaling pathways.
Assuntos
Simulação de Acoplamento Molecular , Farmacologia em Rede , Fibrose Oral Submucosa , Mapas de Interação de Proteínas , Xantonas , Xantonas/uso terapêutico , Xantonas/farmacologia , Fibrose Oral Submucosa/tratamento farmacológico , Fibrose Oral Submucosa/metabolismo , Humanos , Ontologia Genética , Mineração de Dados , Receptores ErbB/metabolismo , Software , Transdução de SinaisRESUMO
Hypertension affects a large number of individuals globally and is a common cause of nephropathy, stroke, ischaemic heart disease and other vascular diseases. While many anti-hypertensive medications are used safely and effectively in clinic practice, controlling hypertensive complications solely by reducing blood pressure (BP) can be challenging. α-Mangostin, a xanthone molecule extracted from the pericarp of Garcinia mangostana L., has shown various beneficial effects such as anti-tumor, anti-hyperuricemia, and anti-inflammatory properties. However, the effects of α-Mangostin on hypertension remain unknown. In this study, we observed that α-Mangostin significantly decreased systolic and diastolic blood pressure in spontaneously hypertensive rats (SHR), possibly through the down-regulation of angiotensin II (Ang II). We also identified early markers of hypertensive nephropathy, including urinary N-acetyl-ß-D-glucosaminidase (NAG) and ß2-microglobulin (ß2-MG), which were reduced by α-Mangostin treatment. Mechanistic studies suggested that α-Mangostin may inhibit renal tubular epithelial-to-mesenchymal transformation (EMT) by down-regulating the TGF-ß signaling pathway, thus potentially offering a new therapeutic approach for hypertension and hypertensive nephropathy.
Assuntos
Angiotensina II , Pressão Sanguínea , Transição Epitelial-Mesenquimal , Hipertensão , Xantonas , Animais , Humanos , Masculino , Ratos , Angiotensina II/metabolismo , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Linhagem Celular , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose/tratamento farmacológico , Garcinia mangostana/química , Hipertensão/tratamento farmacológico , Hipertensão/patologia , Hipertensão Renal/tratamento farmacológico , Hipertensão Renal/patologia , Nefrite , Ratos Endogâmicos SHR , Transdução de Sinais/efeitos dos fármacos , Xantonas/farmacologia , Xantonas/uso terapêuticoRESUMO
Mangiferin is a naturally occurring glucosylxanthone that has shown promising immunomodulatory effects. It is generally isolated from the leaves, peels, bark, and kernels of Mangifera indica Linn. Mangiferin is like a miraculous natural bioactive molecule that has an immunomodulatory function that makes it a potential therapeutic candidate for the treatment of rheumatoid arthritis (RA) and cancer. The anticancer activity of mangiferin acts by blocking NF-κB, as well as regulating the ß-catenin, EMT, MMP9, MMP2, LDH, ROS, and NO, and also by the activation of macrophages. It has no cytotoxic effect on grown chondrocytes and lowers matrix metalloproteinase levels. Additionally, it has a potent proapoptotic impact on synoviocytes. The precise molecular mechanism of action of mangiferin on RA and malignancies is still unknown. This comprehensive review elaborates on the immunomodulatory effect of mangiferin and its anticancer and anti-RA activity. This also explained the total synthesis of mangiferin and its in vitro and in vivo screening models.
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Artrite Reumatoide , Neoplasias , Xantonas , Xantonas/farmacologia , Xantonas/uso terapêutico , Xantonas/química , Humanos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Animais , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Agentes de Imunomodulação/farmacologia , Agentes de Imunomodulação/químicaRESUMO
INTRODUCTION: Mangiferin is a Chinese herbal extract with multiple biological activities. Mangiferin can penetrate the bloodâbrain barrier and has potential in the treatment of nervous system diseases. These findings suggest that mangiferin protects the neurological function in ischemic stroke rats by targeting multiple signaling pathways. However, little is known about the effect and mechanism of mangiferin in alleviating poststroke cognitive impairment. METHODS: Cerebral ischemia/reperfusion (I/R) rats were generated via middle cerebral artery occlusion. Laser speckle imaging was used to monitor the cerebral blood flow. The I/R rats were intraperitoneally (i.p.) injected with 40 mg/kg mangiferin for 7 consecutive days. Neurological scoring, and TTC staining were performed to evaluate neurological function. Behavioral experiments, including the open field test, elevated plus maze, sucrose preference test, and novel object recognition test, were performed to evaluate cognitive function. Metabolomic data from brain tissue with multivariate statistics were analyzed by gas chromatographyâmass spectrometry and liquid chromatographyâmass spectrometry. RESULTS: Mangiferin markedly decreased neurological scores, and reduced infarct areas. Mangiferin significantly attenuated anxiety-like and depression-like behaviors and enhanced learning and memory in I/R rats. According to the metabolomics results, 13 metabolites were identified to be potentially regulated by mangiferin, and the differentially abundant metabolites were mainly involved in lipid metabolism. CONCLUSIONS: Mangiferin protected neurological function and relieved poststroke cognitive impairment by improving lipid metabolism abnormalities in I/R rats.
Assuntos
Disfunção Cognitiva , Metabolismo dos Lipídeos , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Xantonas , Animais , Xantonas/farmacologia , Xantonas/uso terapêutico , Masculino , Metabolismo dos Lipídeos/efeitos dos fármacos , Ratos , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/metabolismo , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , Comportamento Animal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Modelos Animais de Doenças , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/complicações , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacosRESUMO
Available online Atopic dermatitis (AD) is a chronic, persistent inflammatory skin disease characterized by eczema-like lesions and itching. Although topical steroids have been reported for treating AD, they are associated with adverse effects. Thus, safer medications are needed for those who cannot tolerate these agents for long periods. Mangiferin (MAN) is a flavonoid widely found in many herbs, with significant anti-inflammatory and immunomodulatory activities. However, the potential modulatory effects and mechanisms of MAN in treating Th2 inflammation in AD are unknown. In the present study, we reported that MAN could reduce inflammatory cell infiltration and scratching at the lesion site by decreasing MC903-induced levels of Th2-type cytokines, Histamine, thymic stromal lymphopoietin, Leukotriene B4, and immunoglobulin E. The mechanism may be related to reductions in MAPK and NF-κB-associated protein phosphorylation by macrophages. The results suggested that MAN may be a promising therapeutic agent for AD.
Assuntos
Citocinas , Dermatite Atópica , Macrófagos , NF-kappa B , Células Th2 , Xantonas , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/imunologia , Xantonas/farmacologia , Xantonas/uso terapêutico , Animais , NF-kappa B/metabolismo , Células Th2/imunologia , Células Th2/efeitos dos fármacos , Citocinas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos , Humanos , Masculino , Linfopoietina do Estroma do Timo , Imunoglobulina E/metabolismo , Pele/efeitos dos fármacos , Pele/patologia , Pele/imunologia , Pele/metabolismoRESUMO
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.
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Neoplasias Colorretais , Fluoruracila , Camundongos Endogâmicos BALB C , Animais , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Concentração de Íons de Hidrogênio , Fluoruracila/administração & dosagem , Linhagem Celular Tumoral , Xantonas/administração & dosagem , Xantonas/uso terapêutico , Polímeros/química , Polímeros/administração & dosagem , Sistemas de Liberação de Medicamentos , Humanos , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Camundongos , Imunoterapia/métodos , Feminino , Fator de Necrose Tumoral alfaRESUMO
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.
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Complicações do Diabetes , Diabetes Mellitus , Xantonas , Humanos , Relação Estrutura-Atividade , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/química , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo , Complicações do Diabetes/tratamento farmacológico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Xantonas/farmacologia , Xantonas/uso terapêutico , Simulação de Acoplamento Molecular , Diabetes Mellitus/tratamento farmacológicoRESUMO
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.
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Produtos Biológicos , Micoses , Xantonas , Humanos , Candida albicans , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Micoses/tratamento farmacológico , Farmacorresistência Fúngica , Quelantes/farmacologia , Quelantes/uso terapêutico , Aspergillus fumigatus , Ferro , Xantonas/uso terapêutico , Testes de Sensibilidade MicrobianaRESUMO
Diabetes mellitus results in numerous complications. Diabetic pulmonary fibrosis (DPF), a late pulmonary complication of diabetes, has not attracted as much attention as diabetic nephropathy and cardiomyopathy. Mangiferin (MF) is a natural small molecular compound that exhibits a variety of pharmacological effects including anti-inflammatory, anti-cancer, anti-diabetes, and anti-fibrosis effects. In this study, we investigated whether long-term diabetes shock induces DPF, and explored whether MF had a protective effect against DPF. We first examined the lung tissues and sections of 20 diabetic patients obtained from discarded lung surgical resection specimens and found that pulmonary fibrosis mainly accumulated around the pulmonary vessels, accompanied by significantly enhanced endothelial-mesenchymal transition (EndMT). We established a mouse model of DPF by STZ injections. Ten days after the final STZ injection, the mice were administered MF (20, 60 mg/kg, i.g.) every 3 days for 4 weeks, and kept feeding until 16 weeks and euthanized. We showed that pulmonary fibrotic lesions were developed in the diabetic mice, which began around the pulmonary vessels, while MF administration did not affect long-term blood glucose levels, but dose-dependently alleviated diabetes-induced pulmonary fibrosis. In human umbilical vein endothelial cells (HUVECs), exposure to high glucose (33.3 mM) induced EndMT, which was dose-dependently inhibited by treatment with MF (10, 50 µM). Furthermore, MF treatment promoted SIRT3 expression in high glucose-exposed HUVECs by directly binding to AMPK to enhance the activity of FoxO3, which finally reversed diabetes-induced EndMT. We conclude that MF attenuates DPF by inhibiting EndMT through the AMPK/FoxO3/SIRT3 axis. MF could be a potential candidate for the early prevention and treatment of DPF.
Assuntos
Proteínas Quinases Ativadas por AMP , Diabetes Mellitus Experimental , Proteína Forkhead Box O3 , Camundongos Endogâmicos C57BL , Fibrose Pulmonar , Sirtuína 3 , Xantonas , Animais , Xantonas/farmacologia , Xantonas/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Sirtuína 3/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Proteína Forkhead Box O3/metabolismo , Masculino , Humanos , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Estreptozocina , Transdução de Sinais/efeitos dos fármacos , Transição Endotélio-MesênquimaRESUMO
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.