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1.
Food Chem ; 399: 133962, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36007440

RESUMO

Recently, intelligent packaging has emerged for monitoring food quality in food industry. This study aimed to develop the electrospun HACC/PCL/SKN nanofibrous films with improved antimicrobial and antioxidant activity as intelligent packaging to monitor food freshness. The SKN loading resulted in nanoscale uniform fibers (approximately 55.0 nm), and the HACC/PCL/SKN nanofibrous films presented improved hydrophobicity, barrier properties and mechanical properties. Release kinetics study demonstrated that the loading effect led to a sustained release of SKN from fibers. The HACC/PCL film containing 2 wt% SKN showed good antibacterial effect during 24 h, suggesting enhanced antimicrobial activity. Moreover, the SKN-based solutions and films exhibited pH-responsive color changes from red (pH 2) to blue-purple (pH 12). Finally, the HACC/PCL/SKN film effectively provided a spoilage indication for shrimp stored at different temperatures for 3 days by color changes. This work provides a promising strategy for developing multi-functional film as an intelligent packaging in food industry.


Assuntos
Anti-Infecciosos , Quitosana , Nanofibras , Antocianinas/química , Anti-Infecciosos/farmacologia , Quitosana/química , Embalagem de Alimentos/métodos , Concentração de Íons de Hidrogênio , Naftoquinonas , Poliésteres
2.
Future Med Chem ; 14(22): 1611-1620, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36349868

RESUMO

Background: In 1948, the synthesis and Plasmodium lophurae activity of 2-hydroxy-1,4-naphthoquinones containing 3-alkyldiarylether side chains was reported. Method/results: The synthesis of five related compounds, designed to be more metabolically stable, was pursued. The compounds were synthesized using a radical alkylation reaction with naphthoquinones. One compound had a lower IC50 value against various strains of Plasmodium falciparum and assay data indicate that it binds to the Qo site of cytochrome bc1. With a low yield for the radical alkylation of the most active compound, a reductive alkylation method with used to improve reaction yields. Conclusion: Further synthetic knowledge was obtained, and the assay data indicate that there are sensitivity differences between avian and human malarial parasites for these molecules.


Malaria is a disease caused by a parasite that affects millions of people each year and results in many deaths. In 1948, 300 structurally related compounds were made and tested for antimalarial activity with the goal of finding a drug to treat the disease. From this work, promising compounds were identified and this work has served as a starting point for further investigations. Based on recent discoveries, this study made variations of promising 1948 compounds to investigate whether antimalarial activity could be improved. These compounds were made using two different methods. One derivative was found to be more potent than the original compound but was not the one expected based on the 1948 work.


Assuntos
Antimaláricos , Naftoquinonas , Humanos , Plasmodium falciparum , Antimaláricos/química
3.
Int J Mol Sci ; 23(21)2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36362080

RESUMO

1,4-Napththoquinones (NQs) are clinically relevant therapeutics that affect cell function through production of reactive oxygen species (ROS) and formation of adducts with regulatory protein thiols. Reactive sulfur species (RSS) are chemically and biologically similar to ROS and here we examine RSS production by NQ oxidation of hydrogen sulfide (H2S) using RSS-specific fluorophores, liquid chromatography-mass spectrometry, UV-Vis absorption spectrometry, oxygen-sensitive optodes, thiosulfate-specific nanoparticles, HPLC-monobromobimane derivatization, and ion chromatographic assays. We show that NQs, catalytically oxidize H2S to per- and polysulfides (H2Sn, n = 2-6), thiosulfate, sulfite and sulfate in reactions that consume oxygen and are accelerated by superoxide dismutase (SOD) and inhibited by catalase. The approximate efficacy of NQs (in decreasing order) is, 1,4-NQ ≈ juglone ≈ plumbagin > 2-methoxy-1,4-NQ ≈ menadione >> phylloquinone ≈ anthraquinone ≈ menaquinone ≈ lawsone. We propose that the most probable reactions are an initial two-electron oxidation of H2S to S0 and reduction of NQ to NQH2. S0 may react with H2S or elongate H2Sn in variety of reactions. Reoxidation of NQH2 likely involves a semiquinone radical (NQ·-) intermediate via several mechanisms involving oxygen and comproportionation to produce NQ and superoxide. Dismutation of the latter forms hydrogen peroxide which then further oxidizes RSS to sulfoxides. These findings provide the chemical background for novel sulfur-based approaches to naphthoquinone-directed therapies.


Assuntos
Sulfeto de Hidrogênio , Naftoquinonas , Tiossulfatos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Oxirredução , Naftoquinonas/farmacologia , Naftoquinonas/metabolismo , Sulfeto de Hidrogênio/metabolismo , Enxofre/metabolismo , Oxigênio/metabolismo
4.
Molecules ; 27(21)2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36364402

RESUMO

A series of 11-substituted 3,5,10,11-tetrahydro-2H-benzo[6,7]thiochromeno[2,3-d][1,3]thiazole-2,5,10-triones were obtained via hetero-Diels-Alder reaction of 5-alkyl/arylallylidene/-4-thioxo-2-thiazolidinones and 1,4-naphthoquinones. The structures of newly synthesized compounds were established by spectral data and a single-crystal X-ray diffraction analysis. According to U.S. NCI protocols, compounds 3.5 and 3.6 were screened for their anticancer activity; 11-Phenethyl-3,11-dihydro-2H-benzo[6,7]thiochromeno[2,3-d]thiazole-2,5,10-trione (3.6) showed pronounced cytotoxic effect on leukemia (Jurkat, THP-1), epidermoid (KB3-1, KBC-1), and colon (HCT116wt, HCT116 p53-/-) cell lines. The cytotoxic action of 3.6 on p53-deficient colon carcinoma cells was two times weaker than on HCT116wt, and it may be an interesting feature of the mechanism action.


Assuntos
Antineoplásicos , Naftoquinonas , Tiazóis/química , Proteína Supressora de Tumor p53 , Naftoquinonas/química , Antineoplásicos/química , Ensaios de Seleção de Medicamentos Antitumorais
5.
Sci Rep ; 12(1): 17093, 2022 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-36224205

RESUMO

Alkannin/shikonin and their derivatives are specialised metabolites of high pharmaceutical and ecological importance exclusively produced in the periderm of members of the plant family Boraginaceae. Previous studies have shown that their biosynthesis is induced in response to methyl jasmonate but not salicylic acid, two phytohormones that play important roles in plant defence. However, mechanistic understanding of induction and non-induction remains largely unknown. In the present study, we generated the first comprehensive transcriptomic dataset and metabolite profiles of Lithospermum officinale plants treated with methyl jasmonate and salicylic acid to shed light on the underlying mechanisms. Our results highlight the diverse biological processes activated by both phytohormones and reveal the important regulatory role of the mevalonate pathway in alkannin/shikonin biosynthesis in L. officinale. Furthermore, by modelling a coexpression network, we uncovered structural and novel regulatory candidate genes connected to alkannin/shikonin biosynthesis. Besides providing new mechanistic insights into alkannin/shikonin biosynthesis, the generated methyl jasmonate and salicylic acid elicited expression profiles together with the coexpression networks serve as important functional genomic resources for the scientific community aiming at deepening the understanding of alkannin/shikonin biosynthesis.


Assuntos
Lithospermum , Naftoquinonas , Acetatos , Ciclopentanos , Lithospermum/genética , Ácido Mevalônico/metabolismo , Naftoquinonas/metabolismo , Oxilipinas , Preparações Farmacêuticas/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Reguladores de Crescimento de Plantas/farmacologia , Ácido Salicílico/metabolismo , Ácido Salicílico/farmacologia
6.
Drug Des Devel Ther ; 16: 3385-3394, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36199632

RESUMO

Objective: A sensitive and rapid UPLC-MS/MS method for determination of tazemetostat in rat plasma was developed, and the pharmacokinetics of herb-drug interactions (HDIs) of plumbagin (PLB) and tazemetostat was investigated. Methods: After the rat plasma samples were precipitated by acetonitrile, tazemetostat and verubecestat (ISTD) were detected. Gradient elution was performed with 0.1% formic acid and acetonitrile as mobile phases. The multi-reaction monitoring was used with ESI+ source, and the ion pairs for tazemetostat and ISTD were m/z 573.12→135.99 and m/z 410.10→124.00, respectively. 12 SD rats were randomly divided into the control group and the experimental group, 6 rats in each group. The rats in the experimental group were given PLB 100 mg/kg by gavage once a day for 7 consecutive days. The rats in the control group were given the same amount of 0.1% sodium carboxymethyl cellulose solution by gavage once a day for 7 consecutive days. At the seventh day, tazemetostat (80 mg/kg) was given and the blood was collected at different time points. The main parameters of pharmacokinetics were calculated and the herb-drug interactions (HDIs) were evaluated. Results: In the calibrated range of 1-1000 ng/mL, tazemetostat had a good linearity. The extraction recovery was more than 84%, and the RSD of intra-batch and inter-batch precision were both less than 15%. The Cmax of tazemetostat in the experimental group was 32.48% higher than that in the control group, and the AUC(0-t) and AUC(0-∞) of tazemetostat in the experimental group were 46.24% and 46.67% higher than that in the control group, respectively, and the t1/2 was prolonged from 10.56 h to 11.73 h. Conclusion: A simple, rapid and sensitive UPLC-MS/MS method for the determination of tazemetostat in rat plasma was established. PLB can inhibit the metabolism of tazemetostat and increase the plasma exposure of tazemetostat in rats.


Assuntos
Interações Ervas-Drogas , Espectrometria de Massas em Tandem , Acetonitrilas , Animais , Benzamidas , Compostos de Bifenilo , Carboximetilcelulose Sódica , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida , Morfolinas , Naftoquinonas , Piridonas , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sódio , Espectrometria de Massas em Tandem/métodos
7.
Int J Mol Sci ; 23(19)2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-36233004

RESUMO

The anti-inflammatory effects of the CRG/Ech complex in LPS-induced endotoxemia were investigated in vivo in mice and in vitro in LPS-stimulated RAW 264.7 cells and peritoneal macrophages. The results indicated that the CRG/Ech complex suppressed the LPS-induced inflammatory response by reducing the production of ROS and NO in the macrophages. Furthermore, the in vivo experiment indicated that the CRG/Ech complex minimized disorders of the physiological and metabolic processes in mice subjected to LPS intoxication and reduced the levels of proinflammatory cytokines in the mouse serum. The preventive administration of the CRG/Ech complex to mice prevented endotoxin-induced damage in the mouse model of endotoxemia, increased the mice's resistance to LPS, and prevented increases in the levels of proinflammatory cytokines (TNFα). In this work, we showed by the molecular docking that Ech interacted with carrageenan, and that H-donor and H-acceptor bonds are involved in the formation of the complex.


Assuntos
Endotoxemia , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Carragenina/química , Citocinas/metabolismo , Endotoxemia/induzido quimicamente , Endotoxemia/tratamento farmacológico , Endotoxemia/metabolismo , Endotoxinas , Lipopolissacarídeos/toxicidade , Camundongos , Simulação de Acoplamento Molecular , Naftoquinonas , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
8.
Planta ; 256(6): 102, 2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36282353

RESUMO

MAIN CONCLUSION: Novel cytochrome P450s, CYP81B140 and CYP81B141 from Plumbago zeylanica were functionally characterized to understand their involvement in polyketide plumbagin biosynthesis. Further, we propose 3-methyl-1-8-naphthalenediol and isoshinanolone as intermediates for plumbagin biosynthesis. Plumbago zeylanica L. (P. zeylanica) is a medicinally important plant belonging to the family Plumbaginaceae. It comprises the most abundant naphthoquinone plumbagin having anti-cancer activity. Only the polyketide synthase (PKS) enzyme has been identified from the biosynthetic pathway which catalyzes iterative condensation of acetyl-CoA and malonyl-CoA molecules. The plumbagin biosynthesis involves hydroxylation, oxidation, hydration and dehydration of intermediate compounds which are expected to be catalyzed by cytochrome P450s (CYPs). To identify the CYPs, co-expression analysis was carried out using PKS as a candidate gene. Out of the eight identified CYPs, CYP81B140 and CYP81B141 have similar expression with PKS and belong to the CYP81 family. Phylogenetic analysis suggested that CYP81B140 and CYP81B141 cluster with CYPs from CYP81B, CYP81D, CYP81E and CYP81AA subfamilies which are known to be involved in the hydroxylation and oxidation reactions. Moreover, artificial microRNA-mediated transient individual silencing and co-silencing of CYP81B140 and CYP81B141 significantly reduced plumbagin and increased the 3-methyl-1-8-naphthalenediol and isoshinanolone content. Based on metabolite analysis, we proposed that 3-methyl-1-8-naphthalenediol and isoshinanolone function as intermediates for plumbagin biosynthesis. Transient silencing, over-expression and docking analysis revealed that CYP81B140 is involved in C-1 oxidation, C-4 hydroxylation and [C2-C3] hydration of 3-methyl-1-8-naphthalenediol to form isoshinanolone, whereas CYP81B141 is catalyzing [C2-C3] dehydration and C-4 oxidation of isoshinanolone to form plumbagin. Our results indicated that both CYP81B140 and CYP81B141 are promiscuous and necessary for plumbagin biosynthesis. This is the first report of identification and functional characterization of P. zeylanica-specific CYPs involved in plumbagin biosynthetic pathway and in general hexaketide synthesis in plants.


Assuntos
MicroRNAs , Naftoquinonas , Plumbaginaceae , Policetídeos , Plumbaginaceae/genética , Plumbaginaceae/metabolismo , Policetídeo Sintases/genética , Filogenia , Acetilcoenzima A , Desidratação , Raízes de Plantas/metabolismo , Naftoquinonas/metabolismo , Genômica , Citocromos
9.
Parasit Vectors ; 15(1): 356, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-36199104

RESUMO

BACKGROUND: When Theileria annulata infects host cells, it undertakes unlimited proliferation as tumor cells. Although the transformed cells will recover their limited reproductive characteristics and enter the apoptosis process after treatment with buparvaquone (BW720c), the metabolites and metabolic pathways involved are not clear. METHODS: The transformed cells of T. annulata were used as experimental materials, and the buparvaquone treatment group and DMSO control group were used. Qualitative and quantitative analysis was undertaken of 36 cell samples based on the LC-QTOF platform in positive and negative ion modes. The metabolites of the cell samples after 72 h of drug treatment were analyzed, as were the different metabolites and metabolic pathways involved in the BW720c treatment. Finally, the differential metabolites and metabolic pathways in the transformed cells were found. RESULTS: A total of 1425 metabolites were detected in the negative ion mode and 1298 metabolites were detected in the positive ion mode. After drug treatment for 24 h, 48 h, and 72 h, there were 56, 162, and 243 differential metabolites in negative ion mode, and 35, 121, and 177 differential metabolites in positive ion mode, respectively. These differential metabolites are mainly concentrated on various essential amino acids. CONCLUSION: BW720c treatment induces metabolic disturbances in T. annulata-infected cells by regulating the metabolism of leucine, arginine, and L-carnitine, and induces host cell apoptosis.


Assuntos
Theileria annulata , Theileria , Theileriose , Animais , Arginina/uso terapêutico , Carnitina/uso terapêutico , Bovinos , Dimetil Sulfóxido/uso terapêutico , Leucina/uso terapêutico , Naftoquinonas , Theileriose/tratamento farmacológico
10.
Mar Drugs ; 20(10)2022 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-36286435

RESUMO

This review presents literature data: the history of the discovery of quinoid compounds, their biosynthesis and biological activity. Special attention is paid to the description of the quinoid pigments of the sea urchins Scaphechinus mirabilis (from the family Scutellidae) and Strongylocentrotus intermedius (from the family Strongylocentrotidae). The marine environment is considered one of the most important sources of natural bioactive compounds with extremely rich biodiversity. Primary- and some secondary-mouthed animals contain very high concentrations of new biologically active substances, many of which are of significant potential interest for medical purposes. The quinone pigments are products of the secondary metabolism of marine animals, can have complex structures and become the basis for the development of new natural products in echinoids that are modulators of chemical interactions and possible active ingredients in medicinal preparations. More than 5000 chemical compounds with high pharmacological potential have been isolated and described from marine organisms. There are three well known ways of naphthoquinone biosynthesis-polyketide, shikimate and mevalonate. The polyketide pathway is the biosynthesis pathway of various quinones. The shikimate pathway is the main pathway in the biosynthesis of naphthoquinones. It should be noted that all quinoid compounds in plants and animals can be synthesized by various ways of biosynthesis.


Assuntos
Produtos Biológicos , Mirabilis , Naftoquinonas , Policetídeos , Strongylocentrotus , Animais , Strongylocentrotus/metabolismo , Mirabilis/metabolismo , Ácido Mevalônico/metabolismo , Ouriços-do-Mar/química , Naftoquinonas/química , Policetídeos/metabolismo , Produtos Biológicos/farmacologia , Produtos Biológicos/metabolismo , Pigmentos Biológicos/farmacologia , Pigmentos Biológicos/metabolismo
11.
Molecules ; 27(19)2022 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-36235096

RESUMO

Quinones and quinols are secondary metabolites of higher plants that are associated with many biological activities. The oxidative dearomatization of phenols induced by hypervalent iodine(III) reagents has proven to be a very useful synthetic approach for the preparation of these compounds, which are also widely used in organic synthesis and medicinal chemistry. Starting from several substituted phenols and naphthols, a series of cyclohexadienone and naphthoquinone derivatives were synthesized using different hypervalent iodine(III) reagents and evaluated for their in vitro antiprotozoal activity. Antiprotozoal activity was assessed against Plasmodium falciparum NF54 and Trypanosoma brucei rhodesiense STIB900. Cytotoxicity of all compounds towards L6 cells was evaluated and the respective selectivity indices (SI) were calculated. We found that benzyl naphthoquinone 5c was the most active and selective molecule against T. brucei rhodesiense (IC50 = 0.08 µM, SI = 275). Furthermore, the antiprotozoal assays revealed no specific effects. In addition, some key physicochemical parameters of the synthesised compounds were calculated.


Assuntos
Antiprotozoários , Iodo , Malária Falciparum , Naftoquinonas , Antiprotozoários/química , Antiprotozoários/farmacologia , Cicloexenos , Humanos , Hidroquinonas/farmacologia , Indicadores e Reagentes , Naftóis/farmacologia , Naftoquinonas/farmacologia , Estresse Oxidativo , Testes de Sensibilidade Parasitária , Fenóis/farmacologia , Plasmodium falciparum , Trypanosoma brucei rhodesiense
12.
J Phys Chem Lett ; 13(40): 9510-9516, 2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36200782

RESUMO

Non-covalent interactions between aromatic molecules and water are fundamental in many chemical and biological processes, and their accurate description is essential to understand molecular relative configurations. Here we present the rotational spectroscopy study of the water complexes of the polycyclic aromatic hydrocarbon 1,4-naphthoquinone (1,4-NQ). In 1,4-NQ-(H2O)1,2, water molecules bind through O-H···O and C-H···O hydrogen bonds and are located on the plane of 1,4-NQ. For 1,4-NQ-(H2O)3, in-plane and above-plane water configurations are observed exhibiting O-H···O, C-H···O, and lone pair···π-hole interactions. The observation of different water arrangements for 1,4-NQ-(H2O)3 allows benchmarking theoretical methods and shows that they have great difficulty in predicting energy orderings due to the strong competition of C-H···O binding with π and π-hole interactions. This study provides important insight into water interactions with aromatic systems and the challenges in their modeling.


Assuntos
Naftoquinonas , Água , Ligação de Hidrogênio , Conformação Molecular , Água/química
13.
Cells ; 11(20)2022 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-36291055

RESUMO

Shikonin is a naphthoquinone compound extracted from Chinese comfrey for treating cancer. However, there are few reports on its research on vertebrate tissue regeneration. Zebrafish is an ideal model for studying organ regeneration. In this study, we found that 3-dpf of zebrafish larvae exposed to shikonin at concentrations of 0.2, 0.3, and 0.4 mg/L showed increasingly inhibited regeneration of the tail fin. Immunohistochemical staining showed that shikonin exposure from 6 to 12 hpa increased the number of apoptotic cells in the caudal fin wound of larvae and decreased the number of proliferating cells. Shikonin exposure was found to up-regulate oxidative stress, increase ROS levels, and reduce neutrophil recruitment in the early stage of wound repair. Moreover, shikonin exposure caused disordered expression of fin regeneration blastemal-related genes. The use of astaxanthin to down-regulate oxidative stress was found to significantly reduce the inhibition of caudal fin regeneration. Mixed exposure of AMPK inhibitors or fullerenes (C60) with shikonin also showed the similar rescue effect. Collectively, our study showed that shikonin inhibited fin regeneration in zebrafish larvae by the upregulation of oxidative stress level and AMPK signaling pathway. This research provides valuable information on the mechanism of action of shikonin for its safe application.


Assuntos
Fulerenos , Naftoquinonas , Animais , Peixe-Zebra/genética , Larva , Fulerenos/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Naftoquinonas/farmacologia
14.
Int J Nanomedicine ; 17: 4497-4508, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36186533

RESUMO

Introduction: Shikonin is well known for its anti-inflammatory activity in cardiovascular diseases. However, the application of shikonin is limited by its low water solubility and poor bioavailability. Methoxy poly (ethylene glycol)-b-poly (ε-caprolactone) (MPEG-PCL) is considered a promising delivery system for hydrophobic drugs. Therefore, in this study, we prepared shikonin-loaded MPEG-PCL micelles and investigated their effect on endothelial-to-mesenchymal transition (EndMT) induced by inflammatory cytokines. Methods: Shikonin was encapsulated in MPEG-PCL micelles using an anti-solvent method and the physiochemical characteristics of the micelles (particle size, zeta potential, morphology, critical micelle concentration (CMC), drug loading and encapsulation efficiency) were investigated. Cellular uptake of micelles in human umbilical vein endothelial cells (HUVECs) was evaluated using fluorescence microscopy. In vitro EndMT inhibition was explored in HUVECs by quantitative real-time PCR analysis. Results: The average particle size of shikonin-loaded MPEG-PCL micelles was 54.57±0.13 nm and 60 nm determined by dynamic light scattering and transmission electron microscopy, respectively. The zeta potential was -6.23±0.02 mV. The CMC of the micelles was 6.31×10-7mol/L. The drug loading and encapsulation efficiency were 0.88±0.08% and 43.08±3.77%, respectively. The MPEG-PCL micelles significantly improved the cellular uptake of cargo with low water solubility. Real-time PCR analysis showed that co-treatment with TNF-α and IL-1ß successfully induced EndMT in HUVECs, whereas this process was significantly inhibited by shikonin and shikonin-loaded MPEG-PCL micelles, with greater inhibition mediated by the shikonin-loaded MPEG-PCL micelles. Conclusion: Shikonin-loaded MPEG-PCL micelles significantly improved the EndMT-inhibiting effect of the free shikonin. MPEG-PCL is suitable for use more generally as a lipophilic drug carrier.


Assuntos
Células Endoteliais , Micelas , Anti-Inflamatórios/uso terapêutico , Portadores de Fármacos/química , Humanos , Naftoquinonas , Poliésteres/química , Polietilenoglicóis/química , Fator de Necrose Tumoral alfa , Água
15.
Fitoterapia ; 162: 105288, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36058473

RESUMO

A new pentacyclic triterpenoid, 2-hydroxy-1-ene-hydroxyhopanone (19), and a new benzoxepin-5-one, 3-(4-methyl-3-penten-1-yl)-6-hydroxy-9-methoxy-2H-1-benzoxepin-5-one (25), along with 26 known compounds (1-18, 20-24, 26-28), were isolated from the roots of Arnebia euchroma (Royle) Johnst. The structures of the new compounds were elucidated by extensive spectroscopic analyses. The absolute configurations of shikonofurans 9-13 were determined by quantum chemical ECD calculations and CD spectra comparison for the first time. Pharmacological study revealed that naphthoquinones 1-5, 7, and 8 had obvious cytotoxicity toward human lung adenocarcinoma A549 cell line. Meanwhile, the hypoglycemic and lipid-lowering effects of isolated compounds were assessed by checking their inhibitory effects on key enzymes regulating glucose and lipid metabolism. Results showed that compounds 1, 3, 5, 6, 8, 18, and 19 could inhibit the activity of ATP-citrate lyase (ACL); compound 7 could inhibit the activity of acetyl-CoA carboxylase (ACC1); while compounds 8 and 19 showed inhibitory effects on protein tyrosine phosphatase 1B (PTP1B). Among them, the naphthoquinone 6, steroid 18, and triterpenoid 19 showed moderate inhibitory effects on ACL and PTP1B, but didn't exhibit obvious cytotoxicity. This study demonstrated that compounds 6, 18, and 19 show great promising for the development of new agents for the treatment of metabolic diseases.


Assuntos
Benzoxepinas , Boraginaceae , Naftoquinonas , Triterpenos , Acetil-CoA Carboxilase/metabolismo , Trifosfato de Adenosina/metabolismo , Benzoxepinas/metabolismo , Boraginaceae/química , Glucose/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Lipídeos , Estrutura Molecular , Naftoquinonas/química , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Triterpenos/metabolismo
16.
In Vivo ; 36(5): 2105-2115, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36099094

RESUMO

BACKGROUND/AIM: Few studies have examined the correlation between pyruvate kinase M2 (PKM2) overexpression and triple-negative breast cancer (TNBC). TNBC is considered incurable with the currently available treatments, highlighting the need for alternative therapeutic targets. MATERIALS AND METHODS: PKM2 expression was examined immunohistochemically in human breast tumor samples. Furthermore, we studied the effect of three PKM2 inhibitors (gliotoxin, shikonin, and compound 3K) in the MDA-MB-231 TNBC cell line. RESULTS: PKM2 overexpression correlates with TNBC. Interestingly, most TNBC tissues showed increased levels of PKM2 compared to those of receptor-positive breast cancer tissues. This suggests that PKM2 overexpression is an important factor in the development of TNBC. MDA-MB-231 TNBC cells are resistant to anticancer drugs, such as vincristine (VIC) compared to other cancer cells. We found that the recently developed PKM2 inhibitor gliotoxin sensitized MDA-MB-231 cells at a relatively low dose to the same extent as the known PKM2 inhibitor shikonin, suggesting that PKM2 inhibitors could be an effective treatment for TNBC. Detailed sensitization mechanisms were also analyzed. Both gliotoxin and shikonin highly increased late apoptosis in MDA-MB-231 cells, as revealed by annexin V staining. However, MDA-MB-231 cells with high cellular density inhibited the sensitizing effect of PKM2 inhibitors; therefore, we investigated ways to overcome this inhibitory effect. We found that gliotoxin+shikonin co-treatment highly increased toxicity in MDA-MB-231 cells with high density, whereas either VIC+gliotoxin or VIC+shikonin were not effective. Thus, combination therapy with various PKM2 inhibitors may be more effective than combination therapy with anticancer drugs. Gliotoxin+shikonin co-treatment did not increase S or G2 arrest in cells, suggesting that the co-treatment showed a high increase in apoptosis without S or G2 arrest. We confirmed that another recently developed PKM2 inhibitor compound 3K had similar mechanisms of sensitizing MDA-MB-231 cells, suggesting that PKM2 inhibitors have similar sensitization mechanisms in TNBC. CONCLUSION: PKM2 is a regulator of the oncogenic function of TNBC, and combination therapy with various PKM2 inhibitors may be effective for high-density TNBC. Targeting PKM2 in TNBC lays the foundation for the development of PKM2 inhibitors as promising anti-TNBC agents.


Assuntos
Antineoplásicos , Gliotoxina , Neoplasias de Mama Triplo Negativas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Gliotoxina/uso terapêutico , Humanos , Naftoquinonas , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piruvato Quinase/genética , Piruvato Quinase/metabolismo , Ácido Pirúvico/uso terapêutico , Neoplasias de Mama Triplo Negativas/patologia
17.
Med Oncol ; 39(12): 234, 2022 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-36175806

RESUMO

SMARCB1/INI1 deficiency is seen in several malignant tumors including malignant rhabdoid tumor (MRT), a highly aggressive pediatric malignancy. Loss of SMARCB1/INI1 function alters diverse oncogenic cellular signals, making it difficult to discover effective targeting therapy. By utilizing an in vitro drug screening system, effective therapeutic agents against SMARCB1/INI1-deficient tumors were explored in this study. In the in vitro drug sensitivity test, 80 agents with various actions were screened for their cytotoxicity in a panel of five SMARCB1/INI1-deficient tumor cell lines. The combination effect was screened based on the Bliss independent model. The growth-inhibitory effect was determined in both the conventional two-dimensional culture and the collagen-embedded three-dimensional culture system. Survivin expression after agent exposure was determined by Western blot analysis. All five cell lines were found to be sensitive to YM155, a selective survivin inhibitor. In the drug combination screening, YM155 showed additive to synergistic effects with various agents including chrysin. Chrysin enhanced YM155-induced apoptosis, but not mitochondrial depolarization upon exposure of SMARCB1/INI1-deficient tumor cells to the two agents for 6 h. YM155 and chrysin synergistically suppressed survivin expression, especially in TTN45 cells in which such suppression was observed as early as 6 h after exposure to the two agents. Survivin is suggested to be a therapeutic target in MRT and other SMARCB1/INI1-deficient tumors. Chrysin, a flavone that is widely distributed in plants, cooperatively suppressed survivin expression and enhanced the cytotoxicity of YM155.


Assuntos
Flavonas , Naftoquinonas , Criança , Flavonoides , Humanos , Imidazóis , Naftoquinonas/farmacologia , Proteína SMARCB1/genética , Survivina/genética
18.
Mar Drugs ; 20(9)2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36135744

RESUMO

Excessive increase in melanin pigment in the skin can be caused by a variety of environmental factors, including UV radiation, and can result in spots, freckles, and skin cancer. Therefore, it is important to develop functional whitening cosmetic reagents that regulate melanogenesis. In this study, we investigated the effects of echinochrome A (Ech A) on melanogenesis in the B16F10 murine melanoma cell line. We triggered B16F10 cells using α-MSH under Ech A treatment to observe melanin synthesis and analyze expression changes in melanogenesis-related enzymes (tyrosinase, tyrosinase-related protein 1 (TYRP1), and tyrosinase-related protein 2 (TYRP2)) at the mRNA and protein levels. Furthermore, we measured expression changes in the microphthalmia-associated transcription factor (MITF), CREB, and pCREB proteins. Melanin synthesis in the cells stimulated by α-MSH was significantly reduced by Ech A. The expression of the tyrosinase, TYRP1, and TYRP2 mRNA and proteins was significantly decreased by Ech A, as was that of the MITF, CREB, and pCREB proteins. These results show that Ech A suppresses melanin synthesis by regulating melanogenesis-related enzymes through the CREB signaling pathway and suggest the potential of Ech A as a functional agent to prevent pigmentation and promote skin whitening.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Melanoma Experimental , Naftoquinonas , Animais , Linhagem Celular Tumoral , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Melaninas , Camundongos , Fator de Transcrição Associado à Microftalmia/genética , Fator de Transcrição Associado à Microftalmia/metabolismo , Monofenol Mono-Oxigenase/metabolismo , Naftoquinonas/farmacologia , RNA Mensageiro , Transdução de Sinais , alfa-MSH/farmacologia
19.
Arch Oral Biol ; 143: 105546, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36162339

RESUMO

OBJECTIVE: This study aimed (i) to evaluate the antibacterial and cytotoxic activities of the crude extract and fractions obtained from Euclea natalensis A.D.C. roots against bacteria that cause periodontal disease and caries and (ii) to identify the isolated compounds. DESIGN: The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of the extract and fractions were determined by the microplate dilution assay. The cytotoxicity of the extract and fractions was evaluated by using the XTT colorimetric assay and normal human fibroblast cells (GM07492A, lung fibroblasts). The compounds present in the most promising fraction were determined by qualitative analysis through liquid chromatography coupled to mass spectrometry (HPLC-MS-ESI). RESULTS: The MIC results ranged from 25 to > 400 µg/mL for the extract and from 1.56 to > 400 µg/mL for the fractions. To evaluate cytotoxicity, the tested concentrations of the extract and fractions ranged from 19.5 to 2500 µg/mL; IC50 values between 625 and 1250 µg/mL were obtained. Analysis of the main bioactive fraction by HPLC-MS-ESI identified phenolic acids, coumarins, naphthoquinones, lignans, and fatty acids. CONCLUSIONS: The E. natalensis root extract and fractions displayed good antibacterial activity against periodontal pathogenic and cariogenic bacteria. The antibacterial activity may be due to compounds present in the extract and fractions, which also showed low cytotoxicity to normal human cells. These data are relevant and encourage further research into this plant species, which may contribute to the discovery of new herbal medicines that will help to mitigate the problems caused by oral pathogenic bacteria.


Assuntos
Ebenaceae , Lignanas , Naftoquinonas , Antibacterianos/química , Bactérias , Cumarínicos , Ácidos Graxos , Humanos , Testes de Sensibilidade Microbiana , Naftoquinonas/farmacologia , Extratos Vegetais/química
20.
Chem Commun (Camb) ; 58(80): 11312-11315, 2022 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-36125353

RESUMO

A catalytic oxidative addition of sulfoximines to naphthoquinones via C-H functionalization has been achieved using an iron catalytic system, which exhibits good reactivity and high regioselectivity in the presence of visible light. This is the first report offering an efficient protocol for obtaining (naphtho)quinone-sulfoximine hybrid analogs in moderate to good yields with wide scope for both the substrates. This protocol has also been applied on natural products for their modification, including vitamin K3, Juglone and some other modified natural scaffolds as well.


Assuntos
Produtos Biológicos , Naftoquinonas , Catálise , Ferro , Luz , Acoplamento Oxidativo , Quinonas , Vitamina K 3
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