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1.
J Biochem Mol Toxicol ; 38(7): e23765, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38967724

RESUMO

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.


Assuntos
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/química
2.
Mar Drugs ; 22(6)2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38921589

RESUMO

Overwhelming evidence points to an aberrant Wnt/ß-catenin signaling as a critical factor in hepatocellular carcinoma (HCC) and cervical cancer (CC) pathogenesis. Dicerandrol C (DD-9), a dimeric tetrahydroxanthenone isolated from the endophytic fungus Phomopsis asparagi DHS-48 obtained from mangrove plant Rhizophora mangle via chemical epigenetic manipulation of the culture, has demonstrated effective anti-tumor properties, with an obscure action mechanism. The objective of the current study was to explore the efficacy of DD-9 on HepG2 and HeLa cancer cells and its functional mechanism amid the Wnt/ß catenin signaling cascade. Isolation of DD-9 was carried out using various column chromatographic methods, and its structure was elucidated with 1D NMR. The cytotoxicity of DD-9 on HepG2 and HeLa cells was observed with respect to the proliferation, clonality, migration, invasion, apoptosis, cell cycle, and Wnt/ß-catenin signaling cascade. We found that DD-9 treatment significantly reduced tumor cell proliferation in dose- and time-dependent manners in HepG2 and HeLa cells. The subsequent experiments in vitro implied that DD-63 could significantly suppress the tumor clonality, metastases, and induced apoptosis, and that it arrested the cell cycle at the G0/G1 phase of HepG2 and HeLa cells. Dual luciferase assay, Western blot, and immunofluorescence assay showed that DD-9 could dose-dependently attenuate the Wnt/ß-catenin signaling by inhibiting ß-catenin transcriptional activity and abrogating ß-catenin translocated to the nucleus; down-regulating the transcription level of ß-catenin-stimulated Wnt target gene and the expression of related proteins including p-GSK3-ß, ß-catenin, LEF1, Axin1, c-Myc, and CyclinD1; and up-regulating GSK3-ß expression, which indicates that DD-9 stabilized the ß-catenin degradation complex, thereby inducing ß-catenin degradation and inactivation of the Wnt/ß-catenin pathway. The possible interaction between DD-9 and ß-catenin and GSK3-ß protein was further confirmed by molecular docking studies. Collectively, DD-9 may suppress proliferation and induce apoptosis of liver and cervical cancer cells, possibly at least in part via GSK3-ß-mediated crosstalk with the Wnt/ß-catenin signaling axis, providing insights into the mechanism for the potency of DD-9 on hepatocellular and cervical cancer.


Assuntos
Apoptose , Proliferação de Células , Via de Sinalização Wnt , Humanos , Células HeLa , Apoptose/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Hep G2 , beta Catenina/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Neoplasias Hepáticas/tratamento farmacológico , Xantonas/farmacologia , Xantonas/química , Xantonas/isolamento & purificação , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Movimento Celular/efeitos dos fármacos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia
3.
Eur J Pharmacol ; 977: 176724, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38851559

RESUMO

INTRODUCTION: Mangiferin is a Chinese herbal extract with multiple biological activities. Mangiferin can penetrate the blood‒brain 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 chromatography‒mass spectrometry and liquid chromatography‒mass 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 fármacos
4.
J Cell Mol Med ; 28(11): e18466, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38847482

RESUMO

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by pulmonary and systemic congestion resulting from left ventricular diastolic dysfunction and increased filling pressure. Currently, however, there is no evidence on effective pharmacotherapy for HFpEF. In this study, we aimed to investigate the therapeutic effect of total xanthones extracted from Gentianella acuta (TXG) on HFpEF by establishing an high-fat diet (HFD) + L-NAME-induced mouse model. Echocardiography was employed to assess the impact of TXG on the cardiac function in HFpEF mice. Haematoxylin and eosin staining, wheat germ agglutinin staining, and Masson's trichrome staining were utilized to observe the histopathological changes following TXG treatment. The results demonstrated that TXG alleviated HFpEF by reducing the expressions of genes associated with myocardial hypertrophy, fibrosis and apoptosis. Furthermore, TXG improved cardiomyocyte apoptosis by inhibiting the expression of apoptosis-related proteins. Mechanistic investigations revealed that TXG could activate the inositol-requiring enzyme 1α (IRE1α)/X-box-binding protein 1 (Xbp1s) signalling pathway, but the knockdown of IRE1α using the IRE1α inhibitor STF083010 or siRNA-IRE1α impaired the ability of TXG to ameliorate cardiac remodelling in HFpEF models. In conclusion, TXG alleviates myocardial hypertrophy, fibrosis and apoptosis through the activation of the IRE1α/Xbp1s signalling pathway, suggesting its potential beneficial effects on HFpEF patients.


Assuntos
Apoptose , Endorribonucleases , Insuficiência Cardíaca , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Proteína 1 de Ligação a X-Box , Xantonas , Animais , Endorribonucleases/metabolismo , Endorribonucleases/genética , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Proteína 1 de Ligação a X-Box/metabolismo , Proteína 1 de Ligação a X-Box/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/efeitos dos fármacos , Camundongos , Masculino , Xantonas/farmacologia , Xantonas/isolamento & purificação , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Dieta Hiperlipídica/efeitos adversos , Fibrose , Volume Sistólico/efeitos dos fármacos
5.
J Nat Prod ; 87(6): 1628-1634, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38869194

RESUMO

The unfolded protein response (UPR) is a key component of fungal virulence. The prenylated xanthone γ-mangostin isolated from Garcinia mangostana (Clusiaceae) fruit pericarp, has recently been described to inhibit this fungal adaptative pathway. Considering that Calophyllum caledonicum (Calophyllaceae) is known for its high prenylated xanthone content, its stem bark extract was fractionated using a bioassay-guided procedure based on the cell-based anti-UPR assay. Four previously undescribed xanthone derivatives were isolated, caledonixanthones N-Q (3, 4, 8, and 12), among which compounds 3 and 8 showed promising anti-UPR activities with IC50 values of 11.7 ± 0.9 and 7.9 ± 0.3 µM, respectively.


Assuntos
Calophyllum , Resposta a Proteínas não Dobradas , Xantonas , Xantonas/farmacologia , Xantonas/química , Xantonas/isolamento & purificação , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Calophyllum/química , Estrutura Molecular , Humanos , Casca de Planta/química
6.
J Nanobiotechnology ; 22(1): 324, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858692

RESUMO

Breast cancer remains a malignancy that poses a serious threat to human health worldwide. Chemotherapy is one of the most widely effective cancer treatments in clinical practice, but it has some drawbacks such as poor targeting, high toxicity, numerous side effects, and susceptibility to drug resistance. For auto-amplified tumor therapy, a nanoparticle designated GDTF is prepared by wrapping gambogic acid (GA)-loaded dendritic porous silica nanoparticles (DPSNs) with a tannic acid (TA)-Fe(III) coating layer. GDTF possesses the properties of near-infrared (NIR)-enhanced and pH/glutathione (GSH) dual-responsive drug release, photothermal conversion, GSH depletion and hydroxyl radical (·OH) production. When GDTF is exposed to NIR laser irradiation, it can effectively inhibit cell proliferation and tumor growth both in vitro and in vivo with limited toxicity. This may be due to the synergistic effect of enhanced tumor accumulation, and elevated reactive oxygen species (ROS) production, GSH depletion, and TrxR activity reduction. This study highlights the enormous potential of auto-amplified tumor therapy.


Assuntos
Neoplasias da Mama , Glutationa , Nanopartículas , Espécies Reativas de Oxigênio , Dióxido de Silício , Neoplasias da Mama/tratamento farmacológico , Feminino , Nanopartículas/química , Animais , Glutationa/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Dióxido de Silício/química , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Xantonas/química , Xantonas/farmacologia , Taninos/química , Taninos/farmacologia , Proliferação de Células/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Liberação Controlada de Fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química
7.
J Nanobiotechnology ; 22(1): 216, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38698399

RESUMO

The enhanced permeability and retention (EPR) effect has become the guiding principle for nanomedicine against cancer for a long time. However, several biological barriers severely resist therapeutic agents' penetration and retention into the deep tumor tissues, resulting in poor EPR effect and high tumor mortality. Inspired by lava, we proposed a proteolytic enzyme therapy to improve the tumor distribution and penetration of nanomedicine. A trypsin-crosslinked hydrogel (Trypsin@PSA Gel) was developed to maintain trypsin's activity. The hydrogel postponed trypsin's self-degradation and sustained the release. Trypsin promoted the cellular uptake of nanoformulations in breast cancer cells, enhanced the penetration through endothelial cells, and degraded total and membrane proteins. Proteomic analysis reveals that trypsin affected ECM components and down-regulated multiple pathways associated with cancer progression. Intratumoral injection of Trypsin@PSA Gel significantly increased the distribution of liposomes in tumors and reduced tumor vasculature. Combination treatment with intravenous injection of gambogic acid-loaded liposomes and intratumoral injection of Trypsin@PSA Gel inhibited tumor growth. The current study provides one of the first investigations into the enhanced tumor distribution of liposomes induced by a novel proteolytic enzyme therapy.


Assuntos
Hidrogéis , Lipossomos , Polietilenoglicóis , Tripsina , Xantonas , Lipossomos/química , Animais , Polietilenoglicóis/química , Hidrogéis/química , Humanos , Tripsina/metabolismo , Tripsina/química , Feminino , Camundongos , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C , Neoplasias da Mama/tratamento farmacológico , Proteólise
8.
Aging (Albany NY) ; 16(10): 8645-8656, 2024 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-38752883

RESUMO

Mangiferin, a naturally occurring potent glucosylxanthone, is mainly isolated from the Mangifera indica plant and shows potential pharmacological properties, including anti-bacterial, anti-inflammation, and antioxidant in sepsis-induced lung and kidney injury. However, there was a puzzle as to whether mangiferin had a protective effect on sepsis-associated encephalopathy. To answer this question, we established an in vitro cell model of sepsis-associated encephalopathy and investigated the neuroprotective effects of mangiferin in primary cultured hippocampal neurons challenged with lipopolysaccharide (LPS). Neurons treated with 20 µmol/L or 40 µmol/L mangiferin for 48 h can significantly reverse cell injuries induced by LPS treatment, including improved cell viability, decreased inflammatory cytokines secretion, relief of microtubule-associated light chain 3 expression levels and several autophagosomes, as well as attenuated cell apoptosis. Furthermore, mangiferin eliminated pathogenic proteins and elevated neuroprotective factors at both the mRNA and protein levels, showing strong neuroprotective effects of mangiferin, including anti-inflammatory, anti-autophagy, and anti-apoptotic effects on neurons in vitro.


Assuntos
Apoptose , Hipocampo , Lipopolissacarídeos , Neurônios , Fármacos Neuroprotetores , Xantonas , Xantonas/farmacologia , Animais , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Fármacos Neuroprotetores/farmacologia , Células Cultivadas , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Ratos , Citocinas/metabolismo
9.
Eur J Pharm Biopharm ; 200: 114334, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38768764

RESUMO

Functional polymer-lipid hybrid nanoparticles (H-NPs) are a promising class of nanocarriers that combine the benefits of polymer and lipid nanoparticles, offering biocompatibility, structural stability, high loading capacity, and, most importantly, superior surface functionalization. Here, we report the synthesis and design of highly functional H-NPs with specificity toward the transferrin receptor (TfR), using a small molecule ligand, gambogic acid (GA). A fluorescence study revealed the molecular orientation of H-NPs, where the lipid-dense core is surrounded by a polymer exterior, functionalized with GA. Urolithin A, an immunomodulator and anti-inflammatory agent, served as a model drug-like compound to prepare H-NPs via traditional emulsion-based techniques, where H-NPs led to smaller particles (132 nm) and superior entrapment efficiencies (70 % at 10 % drug loading) compared to GA-conjugated polymeric nanoparticles (P-NPs) (157 nm and 52 % entrapment efficiency) and solid lipid nanoparticles (L-NPs) (186 nm and 29 % entrapment efficiency). H-NPs showed superior intracellular accumulation compared to individual NPs using human small intestinal epithelial (FHs 74) cells. The in vitro efficacy was demonstrated by flow cytometry analysis, in which UA-laden H-NPs showed excellent anti-inflammatory properties in cisplatin-induced injury in healthy human proximal tubular cell (HK2) model by decreasing the TLR4, NF-κß, and IL-ß expression. This preliminary work highlights the potential of H-NPs as a novel functional polymer-lipid drug delivery system, establishing the foundation for future research on its therapeutic potential in addressing chemotherapy-induced acute kidney injury in cancer patients.


Assuntos
Cisplatino , Nanopartículas , Polímeros , Humanos , Cisplatino/farmacologia , Nanopartículas/química , Polímeros/química , Lipídeos/química , Portadores de Fármacos/química , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Xantonas/farmacologia , Xantonas/química , Xantonas/administração & dosagem , Linhagem Celular , Cumarínicos/química , Cumarínicos/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Lipossomos
10.
J Mater Chem B ; 12(24): 5940-5949, 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38804636

RESUMO

Gambogic acid (GA) as a naturally derived chemotherapeutic agent is of increasing interest for antitumor therapy. However, current research mainly focuses on improving the pharmacological properties to overcome the shortcomings in clinical applications or as a synergistic anticancer agent in combination with chemotherapy and chemophototherapy. Yet, the material properties of GA (e.g., self-assembly) are often neglected. Herein, we validated the self-assembly function of GA and its huge potential as a single-component active carrier for synergistic delivery using pyropheophorbide-a (PPa) as a drug model. The results showed that self-assembled GA drives the formation of nano-GA/PPa mainly through noncovalent interactions such as π-π stacking, hydrophobic interactions, and hydrogen bonding. Additionally, although no significant differences in cytotoxicity were found between the individual in vitro chemotherapy and combined chemophototherapy, the as-prepared nano-GA/PPa exhibits remarkably improved water solubility and multiple favorable therapeutic features, leading to a prominent in vivo photochemotherapy efficiency of 89.3% inhibition rate with reduced hepatotoxicity of GA. This work highlights the potential of self-assembled GA as a drug delivery carrier for synergistic biomedical applications.


Assuntos
Antineoplásicos , Neoplasias da Mama , Xantonas , Xantonas/química , Xantonas/farmacologia , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Camundongos , Ensaios de Seleção de Medicamentos Antitumorais , Clorofila/química , Clorofila/análogos & derivados , Clorofila/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Nanopartículas/química , Proliferação de Células/efeitos dos fármacos , Fotoquimioterapia , Tamanho da Partícula , Camundongos Endogâmicos BALB C , Portadores de Fármacos/química , Estrutura Molecular
11.
J Food Sci ; 89(6): 3455-3468, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38700315

RESUMO

Excessive accumulation of advanced glycation end products (AGEs) in the body is associated with diabetes and its complications. In this study, we aimed to explore the potential and mechanism of coffee leaf extract (CLE) in inhibiting the generation of AGEs and their precursors in an in vitro glycation model using bovine serum albumin and glucose (BSA-Glu) for the first time. High-performance liquid chromatography analysis revealed that CLE prepared with ultrasound pretreatment (CLE-U) contained higher levels of trigonelline, mangiferin, 3,5-dicaffeoylquinic acid, and γ-aminobutyric acid than CLE without ultrasound pretreatment (CLE-NU). The concentrations of these components, along with caffeine and rutin, were dramatically decreased when CLE-U or CLE-NU was incubated with BSA-Glu reaction mixture. Both CLE-U and CLE-NU exhibited a dose-dependent inhibition of fluorescent AGEs, carboxymethyllysine, fructosamine, 5-hydroxymethylfurfural, 3-deoxyglucosone, glyoxal, as well as protein oxidation products. Notably, CLE-U exhibited a higher inhibitory capacity compared to CLE-NU. CLE-U effectively quenched fluorescence intensity and increased the α-helix structure of the BSA-Glu complex. Molecular docking results suggested that the key bioactive compounds present in CLE-U interacted with the arginine residues of BSA, thereby preventing its glycation. Overall, this research sheds light on the possible application of CLE as a functional ingredient in combating diabetes by inhibiting the generation of AGEs.


Assuntos
Produtos Finais de Glicação Avançada , Extratos Vegetais , Folhas de Planta , Soroalbumina Bovina , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Folhas de Planta/química , Soroalbumina Bovina/química , Coffea/química , Alcaloides/farmacologia , Furaldeído/análogos & derivados , Furaldeído/farmacologia , Frutosamina , Cromatografia Líquida de Alta Pressão , Glioxal , Glucose/metabolismo , Simulação de Acoplamento Molecular , Glicosilação/efeitos dos fármacos , Ácido Quínico/análogos & derivados , Ácido Quínico/farmacologia , Rutina/farmacologia , Lisina/análogos & derivados , Cafeína/farmacologia , Desoxiglucose/análogos & derivados , Desoxiglucose/farmacologia , Xantonas
12.
Microb Genom ; 10(5)2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38785231

RESUMO

The genus Catenibacillus (family Lachnospiraceae, phylum Bacillota) includes only one cultivated species so far, Catenibacillus scindens, isolated from human faeces and capable of deglycosylating dietary polyphenols and degrading flavonoid aglycones. Another human intestinal Catenibacillus strain not taxonomically resolved at that time was recently genome-sequenced. We analysed the genome of this novel isolate, designated Catenibacillus decagia, and showed its ability to deglycosylate C-coupled flavone and xanthone glucosides and O-coupled flavonoid glycosides. Most of the resulting aglycones were further degraded to the corresponding phenolic acids. Including the recently sequenced genome of C. scindens and ten faecal metagenome-assembled genomes assigned to the genus Catenibacillus, we performed a comparative genome analysis and searched for genes encoding potential C-glycosidases and other polyphenol-converting enzymes. According to genome data and physiological characterization, the core metabolism of Catenibacillus strains is based on a fermentative lifestyle with butyrate production and hydrogen evolution. Both C. scindens and C. decagia encode a flavonoid O-glycosidase, a flavone reductase, a flavanone/flavanonol-cleaving reductase and a phloretin hydrolase. Several gene clusters encode enzymes similar to those of the flavonoid C-deglycosylation system of Dorea strain PUE (DgpBC), while separately located genes encode putative polyphenol-glucoside oxidases (DgpA) required for C-deglycosylation. The diversity of dgpA and dgpBC gene clusters might explain the broad C-glycoside substrate spectrum of C. scindens and C. decagia. The other Catenibacillus genomes encode only a few potential flavonoid-converting enzymes. Our results indicate that several Catenibacillus species are well-equipped to deglycosylate and degrade dietary plant polyphenols and might inhabit a corresponding, specific niche in the gut.


Assuntos
Flavonoides , Microbioma Gastrointestinal , Polifenóis , Humanos , Polifenóis/metabolismo , Flavonoides/metabolismo , Genoma Bacteriano , Genômica , Flavonas/metabolismo , Glicosídeos/metabolismo , Filogenia , Fezes/microbiologia , Glicosilação , Xantonas/metabolismo
13.
ACS Appl Mater Interfaces ; 16(19): 24221-24234, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38709623

RESUMO

Clinical studies have continually referred to the involvement of drug carrier having dramatic negative influences on the biocompatibility, biodegradability, and loading efficacy of hydrogel. To overcome this deficiency, researchers have proposed to directly self-assemble natural herbal small molecules into a hydrogel without any structural modification. However, it is still a formidable challenge due to the high requirements on the structure of natural molecules, leading to a rarity of this type of hydrogel. Mangiferin (MF) is a natural polyphenol of C-glucoside xanthone with various positive health benefits, including the treatment of diabetic wounds, but its poor hydrosolubility and low bioavailability significantly restrict the clinical application. Inspired by these, with heating/cooling treatment, a carrier-free hydrogel (MF-gel) is developed by assembling the natural herbal molecule mangiferin, which is mainly governed through hydrogen bonds and intermolecular π-π stacking interactions. The as-prepared hydrogel has injectable and self-healing properties and shows excellent biocompatibility, continuous release ability, and reversible stimuli-responsive performances. All of the superiorities enable the MF-based hydrogel to serve as a potential wound dressing for treating diabetic wounds, which was further confirmed by both the vitro and vivo studies. In vitro, the MF-gel could promote the migration of healing-related cells from peripheral as well as the angiogenesis and displays the capacity of mediating inflammation response by scavenging the intracellular ROS. In vivo, the MF-gel accelerates wound contraction and healing via inflammatory adjustment, collagen deposition, and angiogenesis. This study provides a facile and effective method for diabetic wound management and emphasizes the direct self-assembly hydrogel from natural herbal small molecule.


Assuntos
Hidrogéis , Cicatrização , Xantonas , Xantonas/química , Xantonas/farmacologia , Hidrogéis/química , Hidrogéis/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Humanos , Camundongos , Diabetes Mellitus Experimental/tratamento farmacológico , Ratos , Masculino
14.
Biomed Pharmacother ; 175: 116736, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38739992

RESUMO

AIMS: The xanthone dimer 12-O-deacetyl-phomoxanthone A (12-ODPXA) was extracted from the secondary metabolites of the endophytic fungus Diaporthe goulteri. The 12-ODPXA compound exhibited anticancer properties in murine lymphoma; however, the anti-ovarian cancer (OC) mechanism has not yet been explored. Therefore, the present study evaluated whether 12-ODPXA reduces OC cell proliferation, metastasis, and invasion by downregulating pyruvate dehydrogenase kinase (PDK)4 expression. METHODS: Cell counting kit-8, colony formation, flow cytometry, wound healing, and transwell assays were performed to examine the effects of 12-ODPXA on OC cell proliferation, apoptosis, migration, and invasion. Transcriptome analysis was used to predict the changes in gene expression. Protein expression was determined using western blotting. Glucose, lactate, and adenosine triphosphate (ATP) test kits were used to measure glucose consumption and lactate and ATP production, respectively. Zebrafish xenograft models were constructed to elucidate the anti-OC effects of 12-ODPXA. RESULTS: The 12-ODPXA compound inhibited OC cell proliferation, migration, invasion, and glycolysis while inducing cell apoptosis via downregulation of PDK4. In vivo experiments showed that 12-ODPXA suppressed tumor growth and migration in zebrafish. CONCLUSION: Our data demonstrate that 12-ODPXA inhibits ovarian tumor growth and metastasis by downregulating PDK4, revealing the underlying mechanisms of action of 12-ODPXA in OC.


Assuntos
Apoptose , Movimento Celular , Proliferação de Células , Regulação para Baixo , Neoplasias Ovarianas , Piruvato Desidrogenase Quinase de Transferência de Acetil , Xantonas , Peixe-Zebra , Animais , Feminino , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Humanos , Xantonas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Metástase Neoplásica , Invasividade Neoplásica
15.
Pak J Pharm Sci ; 37(2): 291-296, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38767095

RESUMO

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


Assuntos
Diabetes Mellitus Experimental , Gentiana , Extratos Vegetais , Espectrometria de Massas em Tandem , Xantonas , Animais , Xantonas/farmacocinética , Xantonas/sangue , Xantonas/administração & dosagem , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Espectrometria de Massas em Tandem/métodos , Masculino , Cromatografia Líquida de Alta Pressão/métodos , Extratos Vegetais/farmacocinética , Extratos Vegetais/administração & dosagem , Extratos Vegetais/sangue , Administração Oral , Ratos , Gentiana/química , Ratos Sprague-Dawley , Estreptozocina , Reprodutibilidade dos Testes , Espectrometria de Massa com Cromatografia Líquida
16.
Int J Biol Macromol ; 270(Pt 2): 132348, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38750838

RESUMO

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


Assuntos
Ácido Hialurônico , Hidrogéis , Manganês , Nanopartículas , Xantonas , Ácido Hialurônico/química , Animais , Manganês/química , Xantonas/química , Xantonas/farmacologia , Xantonas/administração & dosagem , Camundongos , Nanopartículas/química , Hidrogéis/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Imageamento por Ressonância Magnética
17.
ACS Appl Mater Interfaces ; 16(20): 25788-25798, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38716694

RESUMO

Phototherapy, represented by photodynamic therapy (PDT) and photothermal therapy (PTT), has great potential in tumor treatment. However, the presence of antioxidant glutathione (GSH) and the heat shock proteins (HSPs) expression caused by high temperature can weaken the effects of PDT and PTT. Here, a multifunctional nanocomplex BT&GA@CL is constructed to realize enhanced synergistic PDT/PTT. Cinnamaldehyde liposomes (CLs) formed by cinnamaldehyde dimer self-assembly were loaded with in gambogic acid (GA) and an aggregation-induced emission molecule BT to obtain BT&GA@CL. As a drug carrier, CL can consume glutathione (GSH) and release drugs responsively. The released BT aggregates can simultaneously act as both a photothermal agent and photosensitizer to achieve PDT and PTT under 660 nm laser irradiation. Specifically, GA as an HSP90 inhibitor can attenuate PTT-induced HSP90 protein expression, thereby weakening the tolerance of tumor cells to high temperatures and enhancing PTT. Such a multifunctional nanocomplex simultaneously modulates the content of GSH and HSP90 in tumor cells, thus enhancing both PDT and PTT, ultimately achieving the goal of efficient combined tumor suppression.


Assuntos
Glutationa , Lipossomos , Fotoquimioterapia , Fármacos Fotossensibilizantes , Xantonas , Lipossomos/química , Glutationa/metabolismo , Glutationa/química , Humanos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Xantonas/química , Xantonas/farmacologia , Animais , Camundongos , Terapia Fototérmica , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Neoplasias/patologia , Neoplasias/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/química , Antineoplásicos/química , Antineoplásicos/farmacologia
18.
Phytomedicine ; 129: 155657, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38692076

RESUMO

BACKGROUND: The pentose phosphate pathway (PPP) plays a crucial role in the material and energy metabolism in cancer cells. Targeting 6-phosphogluconate dehydrogenase (6PGD), the rate-limiting enzyme in the PPP metabolic process, to inhibit cellular metabolism is an effective anticancer strategy. In our previous study, we have preliminarily demonstrated that gambogic acid (GA) induced cancer cell death by inhibiting 6PGD and suppressing PPP at the cellular level. However, it is unclear whether GA could suppress cancer cell growth by inhibiting PPP pathway in mouse model. PURPOSE: This study aimed to confirm that GA as a covalent inhibitor of 6PGD protein and to validate that GA suppresses cancer cell growth by inhibiting the PPP pathway in a mouse model. METHODS: Cell viability was detected by CCK-8 assays as well as flow cytometry. The protein targets of GA were identified using a chemical probe and activity-based protein profiling (ABPP) technology. The target validation was performed by in-gel fluorescence assay, the Cellular Thermal Shift Assay (CETSA). A lung cancer mouse model was constructed to test the anticancer activity of GA. RNA sequencing was performed to analyze the global effect of GA on gene expression. RESULTS: The chemical probe of GA exhibited high biological activity in vitro. 6PGD was identified as one of the binding proteins of GA by ABPP. Our findings revealed a direct interaction between GA and 6PGD. We also found that the anti-cancer activity of GA depended on reactive oxygen species (ROS), as evidenced by experiments on cells with 6PGD knocked down. More importantly, GA could effectively reduce the production of the two major metabolites of the PPP in lung tissue and inhibit cancer cell growth in the mouse model. Finally, RNA sequencing data suggested that GA treatment significantly regulated apoptosis and hypoxia-related physiological processes. CONCLUSION: These results demonstrated that GA was a covalent inhibitor of 6PGD protein. GA effectively suppressed cancer cell growth by inhibiting the PPP pathway without causing significant side effects in the mouse model. Our study provides in vivo evidence that elucidates the anticancer mechanism of GA, which involves the inhibition of 6PGD and modulation of cellular metabolic processes.


Assuntos
Neoplasias Pulmonares , Via de Pentose Fosfato , Xantonas , Xantonas/farmacologia , Animais , Via de Pentose Fosfato/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Humanos , Fosfogluconato Desidrogenase/metabolismo , Linhagem Celular Tumoral , Antineoplásicos Fitogênicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças
19.
J Org Chem ; 89(11): 7692-7704, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38768258

RESUMO

A MS/MS-based molecular networking approach compared to the Global Natural Product Social Molecular Networking library, in association with genomic annotation of natural product biosynthetic gene clusters within a marine-derived fungus, Aspergillus sydowii, identified a suite of xanthone metabolites. Chromatographic techniques applied to the cultured fungus led to the isolation of 11 xanthone-based alkaloids, dubbed sydoxanthones F-M. The structures of these alkaloids were elucidated using extensive spectroscopic data, including electronic circular dichroism and single-crystal X-ray diffraction data for configurational assignments. Among these analogues, sydoxanthones F-K exhibit structure features typical of nucleobase-coupled xanthones, with sydoxanthone H being an N-bonded xanthone dimer. Notably, (±)sydoxanthones F (1a/1b), (±)sydoxanthones H (3b/3a), and (±)sydoxanthones J (5b/5a) are enantiomeric pairs, while sydoxanthones G (2), I (4), and K (6) are stereoisomers of 1, 3, and 5, respectively. Furthermore, (+)sydoxanthone H (3a) demonstrated significant rescue of cell viability in H2O2-injuried SH-SY5Y cells by inhibiting reactive oxygen species production, suggesting its potential for neuroprotection.


Assuntos
Aspergillus , Espécies Reativas de Oxigênio , Xantonas , Xantonas/química , Xantonas/farmacologia , Xantonas/isolamento & purificação , Aspergillus/química , Humanos , Espécies Reativas de Oxigênio/metabolismo , Estrutura Molecular , Linhagem Celular Tumoral
20.
Adv Colloid Interface Sci ; 329: 103188, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38761602

RESUMO

With the target of fabricating healthier products, food manufacturing companies look for natural-based nutraceuticals that can potentially improve the physicochemical properties of food systems while being nutritive to the consumer and providing additional health benefits (biological activities). In this regard, Mangiferin joins all these requirements as a potential nutraceutical, which is typically contained in Mangifera indica products and its by-products. Unfortunately, knowing the complex chemical composition of Mango and its by-products, the extraction and purification of Mangiferin remains a challenge. Therefore, this comprehensive review revises the main strategies proposed by scientists for the extraction and purification of Mangiferin. Importantly, this review identifies that there is no report reviewing and criticizing the literature in this field so far. Our attention has been targeted on the timely findings on the primary extraction techniques and the relevant insights into isolation and purification. Our discussion has emphasized the advantages and limitations of the proposed strategies, including solvents, extracting conditions and key interactions with the target xanthone. Additionally, we report the current research gaps in the field after analyzing the literature, as well as some examples of functional food products containing Mangiferin.


Assuntos
Mangifera , Xantonas , Xantonas/isolamento & purificação , Xantonas/química , Mangifera/química , Suplementos Nutricionais/análise , Humanos , Solventes/química
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