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1.
Spectrochim Acta A Mol Biomol Spectrosc ; 265: 120382, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34543990

RESUMO

Alkannin is the main coloring matter of Alkanet, a natural red dye extracted from the root of Alkanna tinctoria L. Shikonin, the optical isomer of alkannin, is extracted from Lithospermum erythrorhizon. As both red dyes are only slightly soluble in water, the application of ordinary Raman spectroscopy is limited. Thus, Surface-enhanced Raman spectroscopy (SERS) can be successfully applied to the study of the red dyes solutions. Solid alkannin and shikonin were characterized by ordinary Raman spectroscopy. Density Functional Theory (DFT) methods were used to calculate the Raman spectrum of the dyes and to assign the experimental Raman bands to their vibrational normal modes. Different pH conditions were tested in order to determine the optimal conditions for the SERS detection of alkannin and shikonin. Based on the previous results, a perpendicular orientation of the red dyes on the Ag substrate was deducted. Finally, shikonin was identify by SERS spectroscopy in a dyed paper sample from an 8th century handscroll from Japan.


Assuntos
Corantes , Análise Espectral Raman , Japão , Naftoquinonas
2.
Anticancer Res ; 41(10): 4725-4732, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593421

RESUMO

BACKGROUND/AIM: We investigated the cytotoxic effects of plumbagin on metastatic retinoblastoma, using the highly metastatic cell line Y79. MATERIALS AND METHODS: Effect of plumbagin on cell growth was assessed with water-soluble tetrazolium 1 (WST-1) cell proliferation assay and automated hemocytometry with trypan blue-exclusion assay. Cell death was studied with acridine orange/ethidium bromide live-dead assay and annexin-V-fluorescein isothiocyanate/propidium iodide microscopy. Loss of mitochondrial membrane potential was studied with JC-10 dye and caspase activation was investigated using CellEvent Caspase-3/7 Green detection reagent. RESULTS: Plumbagin highly significantly reduced the growth of Y79 cells treated for 24 h with 2.5 µM or more. Plumbagin also induced significantly high levels of cell death which was associated with loss of mitochondrial membrane potential and caspase activation. CONCLUSION: At very low concentration (2.5 µM), plumbagin potently induced cytotoxicity in metastatic retinoblastoma cells via loss of mitochondrial membrane potential and caspase activation.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Caspases/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Naftoquinonas/farmacologia , Neoplasias da Retina/patologia , Retinoblastoma/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Mitocôndrias , Metástase Neoplásica
3.
Int J Mol Sci ; 22(19)2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34638700

RESUMO

Substitution is well-known to modulate the physico-chemical properties of molecules. In this study, a combined, multifactor approach was employed to determine a plethora of substitution patterns using -Br and -O-H in 1,4-naphthoquinone and its derivatives. On the basis of classical Density Functional Theory (DFT), 25 models divided into three groups were developed. The first group contains 1,4-naphthoquinone and its derivatives substituted only by -Br. The second group consists of compounds substituted by -Br and one -O-H group. As a result of the substitution, an intramolecular hydrogen bond was formed. The third group also contains -Br as a substituent, but two -O-H groups were introduced and two intramolecular hydrogen bonds were established. The simulations were performed at the ωB97XD/6-311++G(2d,2p) level of theory. The presence of substituents influenced the electronic structure of the parent compound and its derivatives by inductive effects, but it also affected the geometry of the 2 and 3 groups, due to the intramolecular hydrogen bonding and the formation of a quasi-ring/rings. The static DFT models were applied to investigate the aromaticity changes in the fused rings based on the Harmonic Oscillator Model of Aromaticity (HOMA). The OH stretching was detected for the compounds from groups 2 and 3 and further used to find correlations with energetic parameters. The evolution of the electronic structure was analyzed using Hirshfeld atomic charges and the Substituent Active Region (cSAR) parameter. The proton reaction path was investigated to provide information on the modulation of hydrogen bridge properties by diverse substitution positions on the donor and acceptor sides. Subsequently, Car-Parrinello Molecular Dynamics (CPMD) was carried out in the double-bridged systems (group 3) to assess the cooperative effects in double -O-H-substituted systems. It was determined that the -O-H influence on the core of the molecule is more significant than that of -Br, but the latter has a major impact on the bridge dynamics. The competitive or synergic effect of two -Br substituents was found to depend on the coupling between the intramolecular hydrogen bridges. Thus, the novel mechanism of a secondary (cooperative) substituent effect was established in the double-bridged systems via DFT and CPMD results comparison, consisting of a mediation of the bromine substitutions' influence by the cooperative proton transfer events in the hydrogen bridges.


Assuntos
Simulação de Dinâmica Molecular , Naftoquinonas/química , Ligação de Hidrogênio , Estrutura Molecular
4.
Front Endocrinol (Lausanne) ; 12: 714909, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34712201

RESUMO

Background: Clinically, evidence shows that uterine corpus endometrial carcinoma (UCEC) patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may have a higher death-rate. However, current anti-UCEC/coronavirus disease 2019 (COVID-19) treatment is lacking. Plumbagin (PLB), a pharmacologically active alkaloid, is an emerging anti-cancer inhibitor. Accordingly, the current report was designed to identify and characterize the anti-UCEC function and mechanism of PLB in the treatment of patients infected with SARS-CoV-2 via integrated in silico analysis. Methods: The clinical analyses of UCEC and COVID-19 in patients were conducted using online-accessible tools. Meanwhile, in silico methods including network pharmacology and biological molecular docking aimed to screen and characterize the anti-UCEC/COVID-19 functions, bio targets, and mechanisms of the action of PLB. Results: The bioinformatics data uncovered the clinical characteristics of UCEC patients infected with SARS-CoV-2, including specific genes, health risk, survival rate, and prognostic index. Network pharmacology findings disclosed that PLB-exerted anti-UCEC/COVID-19 effects were achieved through anti-proliferation, inducing cytotoxicity and apoptosis, anti-inflammation, immunomodulation, and modulation of some of the key molecular pathways associated with anti-inflammatory and immunomodulating actions. Following molecular docking analysis, in silico investigation helped identify the anti-UCEC/COVID-19 pharmacological bio targets of PLB, including mitogen-activated protein kinase 3 (MAPK3), tumor necrosis factor (TNF), and urokinase-type plasminogen activator (PLAU). Conclusions: Based on the present bioinformatic and in silico findings, the clinical characterization of UCEC/COVID-19 patients was revealed. The candidate, core bio targets, and molecular pathways of PLB action in the potential treatment of UCEC/COVID-19 were identified accordingly.


Assuntos
COVID-19 , Carcinoma Endometrioide , Neoplasias do Endométrio , Interações Hospedeiro-Patógeno , Naftoquinonas/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/complicações , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , COVID-19/genética , Proteínas de Ligação ao Cálcio/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/metabolismo , Carcinoma Endometrioide/complicações , Carcinoma Endometrioide/diagnóstico , Carcinoma Endometrioide/tratamento farmacológico , Carcinoma Endometrioide/genética , Biologia Computacional , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Neoplasias do Endométrio/complicações , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Estudos de Associação Genética , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Humanos , Proteínas de Membrana/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Proteína Quinase 3 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Simulação de Acoplamento Molecular/métodos , Naftoquinonas/uso terapêutico , Prognóstico , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Útero/efeitos dos fármacos , Útero/metabolismo , Útero/patologia , Útero/virologia
5.
Molecules ; 26(19)2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34641398

RESUMO

Due to the strong drug resistance of Pseudomonas aeruginosa (P. aeruginosa), the inhibition effects of conventional disinfectants and antibiotics are not obvious. Juglone extracted from discarded walnut husk, as a kind of plant-derived antimicrobial agent, has the advantages of naturalness, high efficiency, and low residue, with a potential role in the inhibition of P. aeruginosa. This study elucidated the inhibitory effect of juglone on the growth of plankton and the formation of P. aeruginosa biofilm. The results showed that juglone (35 µg/mL) had an irreversible inhibitory effect on P. aeruginosa colony formation (about 107 CFU/mL). The integrity and permeability of the cell membrane were effectively destroyed, accompanied by disorder of the membrane permeability, mass leakage of the cytoplasm, and ATP consumption. Further studies manifested that juglone could induce the abnormal accumulation of ROS in cells and block the formation of the cell membrane. In addition, RT-qPCR showed that juglone could effectively block the expression of five virulence genes and two genes involved in the production of extracellular polymers, thereby reducing the toxicity and infection of P. aeruginosa and preventing the production of extracellular polymers. This study can provide support for the innovation of antibacterial technology toward P. aeruginosa in food.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Biofilmes/crescimento & desenvolvimento , Membrana Celular/efeitos dos fármacos , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Naftoquinonas/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Proteínas de Bactérias/genética , Biofilmes/efeitos dos fármacos , Membrana Celular/patologia , Citotoxinas/farmacologia , Polímeros/metabolismo , Pseudomonas aeruginosa/crescimento & desenvolvimento , Pseudomonas aeruginosa/metabolismo , Percepção de Quorum , Virulência
6.
PLoS One ; 16(10): e0258235, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34679089

RESUMO

Carnivorous plants feed on animal prey, mainly insects, to get additional nutrients. This carnivorous syndrome is widely investigated and reported. In contrast, reports on herbivores feeding on carnivorous plants and related defenses of the plants under attack are rare. Here, we studied the interaction of a pitcher plant, Nepenthes x ventrata, with a generalist lepidopteran herbivore, Spodoptera littoralis, using a combination of LC/MS-based chemical analytics, choice and feeding assays. Chemical defenses in N. x ventrata leaves were analyzed upon S. littoralis feeding. A naphthoquinone, plumbagin, was identified in Nepenthes defense against herbivores and as the compound mainly responsible for the finding that S. littoralis larvae gained almost no weight when feeding on Nepenthes leaves. Plumbagin is constitutively present but further 3-fold increased upon long-term (> 1 day) feeding. Moreover, in parallel de novo induced trypsin protease inhibitor (TI) activity was identified. In contrast to TI activity, enhanced plumbagin levels were not phytohormone inducible, not even by defense-related jasmonates although upon herbivory their level increased more than 50-fold in the case of the bioactive jasmonic acid-isoleucine. We conclude that Nepenthes is efficiently protected against insect herbivores by naphthoquinones acting as phytoanticipins, which is supported by additional inducible defenses. The regulation of these defenses remains to be investigated.


Assuntos
Planta Carnívora/fisiologia , Herbivoria/fisiologia , Naftoquinonas/farmacologia , Compostos Fitoquímicos/farmacologia , Sarraceniaceae/fisiologia , Ácido Abscísico/farmacologia , Animais , Planta Carnívora/efeitos dos fármacos , Ciclopentanos/farmacologia , Dieta , Herbivoria/efeitos dos fármacos , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Oxilipinas/farmacologia , Reguladores de Crescimento de Plantas/análise , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/fisiologia , Inibidores de Proteases/farmacologia , Ácido Salicílico/farmacologia , Sarraceniaceae/efeitos dos fármacos , Spodoptera/efeitos dos fármacos , Spodoptera/fisiologia
7.
Parasitol Res ; 120(11): 3783-3794, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34549347

RESUMO

Cysticercosis is a disease caused by the metacestode of the parasite Taenia solium (T. solium). In humans, the most severe complication of the disease is neurocysticercosis. The drug of choice to treat this disease is albendazole; however, the bioavailability and efficacy of the drug are variable. Therefore, new molecules with therapeutic effects against this and other parasitic infections caused by helminths must be developed. Naphthoquinones are naphthalene-derived compounds that possess antibacterial, antifungal, antitumoral, and antiparasitic properties. The aim of this work was to evaluate the in vitro anti-helminthic effect of 2-[(3-chlorophenylamino)phenylmethyl]-3-hydroxy-1,4-naphthoquinone, isolated from a natural source and then synthesized (naphthoquinone 4a), using an experimental model of murine cysticercosis caused by Taenia crassiceps (T. crassiceps). This compound causes paralysis in the cysticerci membrane from day 3 of the in vitro treatment. Additionally, it induces changes in the shape, size, and appearance of the cysticerci and a decrease in the reproduction rate. In conclusion, naphthoquinone 4a has in vitro cysticidal activity on T. crassiceps cysticerci depending on the duration of the treatment and the concentration of the compound. Therefore, it is a promising drug candidate to be used in T. crassiceps and possibly T. solium infections.


Assuntos
Cisticercose , Naftoquinonas , Taenia solium , Taenia , Teníase , Animais , Cisticercose/tratamento farmacológico , Cisticercose/veterinária , Cysticercus , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Naftoquinonas/farmacologia
8.
Int J Mol Sci ; 22(18)2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34576094

RESUMO

Targeted screening using the MTT cell viability test with a mini-library of natural and synthetic 1,4-naphthoquinones and their derivatives was performed in order to increase the survival of Neuro-2a neuroblastoma cells in in vitro paraquat and 6-hydroxydopamine models of Parkinson's disease. As a result, 10 compounds were selected that could protect neuronal cells from the cytotoxic effects of both paraquat and 6-hydroxydopamine. The five most active compounds at low concentrations were found to significantly protect the activity of nonspecific esterase from the inhibitory effects of neurotoxins, defend cell biomembranes from lytic destruction in the presence of paraquat and 6-hydroxydopamine, and normalize the cell cycle. The protective effects of these compounds are associated with the suppression of oxidative stress, decreased expression of reactive oxygen species and nitric oxide formation in cells and normalization of mitochondrial function, and restoration of the mitochondrial membrane potential altered by neurotoxins. It was suggested that the neuroprotective activity of the studied 1,4-NQs is attributable to their pronounced antioxidant and free radical scavenging activity and their ability to reduce the amount of reactive oxygen species formed by paraquat and 6-hydroxydopamine action on neuronal cells. The significant correlation between the neuroprotective properties of 1,4-naphthoquinones and Quantitative Structure-Activity Relationship descriptors describing the physicochemical properties of these compounds means that the hydrophobicity, polarity, charge, and shape of the molecules can be of decisive importance in determining the biological activity of studied substances.


Assuntos
Modelos Biológicos , Naftoquinonas/farmacologia , Neuroproteção , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/toxicidade , Oxidopamina/toxicidade , Paraquat/toxicidade , Animais , Compostos de Bifenilo/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sequestradores de Radicais Livres/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Neuroproteção/efeitos dos fármacos , Óxido Nítrico/biossíntese , Picratos/química , Relação Quantitativa Estrutura-Atividade , Espécies Reativas de Oxigênio/metabolismo , Reprodutibilidade dos Testes
9.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(4): 415-418, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34374263

RESUMO

Objective: To investigate the effects and molecular mechanisms of shikonin on liver cancer SMMC-772 cells. Methods: SMMC-7721 cells were treated with shikonin at the concentrations of 0, 5, 20, 80 and 320 ng/ml for 0, 24, 48 and 72 h respectively. The proliferative activity of the cells was detected by CCK8 assay. The nuclear type changes of cells was observed after hoechst 33342 staining. Flow cytometry was used to analyze cell apoptosis and death rate. The expressions of proteins in cells were determined by Western blot, and the tumor inhibitive effects were observed through anti-tumor experiment on the BALB/c mice. Results: In vitro experiments, shikonin could inhibit the proliferation of SMMC-7721 cells and induce their apoptosis(P<0.01), up-regulate the expression of p53 gene, down-regulate the phosphorylation levels of AKT and PI3K protein. In vivo study also confirmed that shikonin could significantly inhibit the growth of tumor in tumor-bearing mice(P<0.01)in dose-dependent and time-dependent manners. Conclusion: Shikonin can inhibit the proliferation activitity and induce apoptosis of SMMC-7721 cells by affecting the PI3K/AKT signal pathway and has potential anti-liver cancer functions.


Assuntos
Neoplasias Hepáticas , Fosfatidilinositol 3-Quinases , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Naftoquinonas , Proteínas Proto-Oncogênicas c-akt
10.
Biomacromolecules ; 22(9): 3692-3703, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34375099

RESUMO

The biological consequences associated with the conversion of soluble proteins into insoluble toxic amyloids are not only limited to the onset of neurodegenerative diseases but also to the potential health risks associated with supplements of protein therapeutic agents as well. Hence, finding inhibitors against amyloid formation is important, and natural product-based anti-amyloid compounds have gained much interest because of their higher efficacy and biocompatibility. Plumbagin has been identified as a potential natural product with multiple medical benefits; however, it remains largely unclear whether plumbagin can act against amyloid formation of proteins. Here, we show that plumbagin can effectively inhibit the temperature-induced amyloid aggregation of important proteins (insulin and serum albumin). Both experimental and computational data revealed that the presence of plumbagin in protein solutions, under aggregating conditions, promotes a direct protein-plumbagin interaction, which is predominantly stabilized by stronger H-bonds and hydrophobic interactions. Plumbagin-mediated retention of the native structures of proteins appears to play a crucial role in preventing their conversion into insoluble ß-sheet-rich amyloid aggregates. More importantly, the addition of plumbagin into a suspension of protein fibrils triggered their spontaneous disassembly, promoting the release of soluble proteins. The results highlight that a possible synergistic effect via both the stabilization of protein structures and the restriction of the monomer recruitment at the fibril growth sites could be important for the mechanism of plumbagin's anti-aggregation effect. These findings may inspire the development of plumbagin-based formulations to benefit both the prevention and treatment of amyloid-related health complications.


Assuntos
Amiloidose , Agregados Proteicos , Amiloide , Proteínas Amiloidogênicas , Humanos , Naftoquinonas
11.
Fish Shellfish Immunol ; 117: 311-319, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34418558

RESUMO

Echinoid pigments have various biological properties such as antioxidant, cytotoxic, and antibacterial activities. We aimed to evaluate the extraction of cell-free coelomic fluid (CFCF) and coelomocyte lysate (CL) as well as qualitatively and quantitatively identify the coelomic fluid of Echinometra mathaei as a new source of polyhydroxylatednaphthoquinone (PHNQ) antioxidant pigments. Based on the High Performance liquid chromatography-electrospray mass spectrometry (HPLC-MS) analysis in negative mode, the main quinonoid (PHNQ) pigments were identified and quantified. This study also illustrated the total ion current chromatograms and related mass spectra of Spinochrome A, Spinochrome B, Spinochrome C, and Echinochrome A in CL and SpinochromeC in CFCF samples. The ions at 221, 279, 265 and 263 m/z correspond to the pseudo-molecular [M - H] ions of Spinochrome B, Spinochrome C, Echinochrome A, and Spinochrome A, respectively. These components have previously been noted from the shells and spines of sea urchins but identification of PHNQs pigments in CL and CFCF of E. mathaei using LC-MS was introduced for the first time. The results also showed that, the highest DPPH radical scavenging activity of CFCF (88.12 DPPH% scavenging at 70 µg/mL, IC50 = <10 µg/mL). The findings clearly suggest that the coelomic fluid of E. mathaei could be served as the promising as well as potential natural antioxidants in the medical and pharmaceutical industries and could replace the increasing prices of the commercial antioxidants products.


Assuntos
Antioxidantes , Naftoquinonas , Pigmentos Biológicos , Ouriços-do-Mar , Animais , Antioxidantes/química , Compostos de Bifenilo/química , Naftoquinonas/química , Picratos/química , Pigmentos Biológicos/química
12.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360798

RESUMO

Non-covalent interactions responsible for molecular features and self-assembly in Naphthazarin C polymorph were investigated on the basis of diverse theoretical approaches: Density Functional Theory (DFT), Diffusion Quantum Monte Carlo (DQMC), Symmetry-Adapted Perturbation Theory (SAPT) and Car-Parrinello Molecular Dynamics (CPMD). The proton reaction paths in the intramolecular hydrogen bridges were studied. Two potential energy minima were found indicating that the proton transfer phenomena occur in the electronic ground state. Diffusion Quantum Monte Carlo (DQMC) and other levels of theory including Coupled Cluster (CC) employment enabled an accurate inspection of Potential Energy Surface (PES) and revealed the energy barrier for the proton transfer. The structure and reactivity evolution associated with the proton transfer were investigated using Harmonic Oscillator Model of Aromaticity - HOMA index, Fukui functions and Atoms In Molecules (AIM) theory. The energy partitioning in the studied dimers was carried out based on Symmetry-Adapted Perturbation Theory (SAPT) indicating that dispersive forces are dominant in the structure stabilization. The CPMD simulations were performed at 60 K and 300 K in vacuo and in the crystalline phase. The temperature influence on the bridged protons dynamics was studied and showed that the proton transfer phenomena were not observed at 60 K, but the frequent events were noticed at 300 K in both studied phases. The spectroscopic signatures derived from the CPMD were computed using Fourier transformation of autocorrelation function of atomic velocity for the whole molecule and bridged protons. The computed gas-phase IR spectra showed two regions with OH absorption that covers frequencies from 2500 cm-1 to 2800 cm-1 at 60 K and from 2350 cm-1 to 3250 cm-1 at 300 K for both bridged protons. In comparison, the solid state computed IR spectra revealed the environmental influence on the vibrational features. For each of them absorption regions were found between 2700-3100 cm-1 and 2400-2850 cm-1 at 60 K and 2300-3300 cm-1 and 2300-3200 cm-1 at 300 K respectively. Therefore, the CPMD study results indicated that there is a cooperation of intramolecular hydrogen bonds in Naphthazarin molecule.


Assuntos
Simulação de Dinâmica Molecular , Naftoquinonas/química , Ligação de Hidrogênio , Teoria Quântica
13.
DNA Res ; 28(5)2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34424327

RESUMO

Increasing genome data are coming out. Genome size estimation plays an essential role in guiding genome assembly. Several months ago, other researchers were the first to publish a draft genome of the red gromwell (i.e. Lithospermum erythrorhizon). However, we considered that the genome size they estimated and assembled was incorrect. This study meticulously estimated the L. erythrorhizon genome size to should be ∼708.74 Mb and further provided a reliable genome version (size ≈ 693.34 Mb; contigN50 length ≈ 238.08 Kb) to support our objection. Furthermore, according to our genome, we identified a gene family of the alkannin/shikonin O-acyltransferases (i.e. AAT/SAT) that catalysed enantiomer-specific acylations in the alkannin/shikonin biosynthesis (a characteristic metabolic pathway in L. erythrorhizon's roots) and further explored its evolutionary process. The results indicated that the existing AAT/SAT were not generated from only one round of gene duplication but three rounds; after different rounds of gene duplication, the existing AAT/SAT and their recent ancestors were under positive selection at different amino acid sites. These suggested that a combined power from gene duplication plus positive selection plausibly propelled AAT/SAT's functional differentiation in evolution.


Assuntos
Lithospermum , Naftoquinonas , Aciltransferases , Lithospermum/genética
14.
Biofouling ; 37(7): 724-739, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34396840

RESUMO

The global rise in antimicrobial resistance and lack of discovery of new antimicrobials have created serious concerns. Targeting quorum sensing (QS) and biofilms of pathogenic bacteria is considered a promising approach in antimicrobial drug discovery. This study explored the inhibitory effect of plumbagin against biofilms and QS of Chromobacterium violaceum, Serratia marcescens and Pseudomonas aeruginosa. Violacein production in C. violaceum 12472 was reduced by >80%. The virulent traits of P. aeruginosa PAO1 such as pyocyanin, rhamnolipid and proteases were also inhibited at sub-minimum inhibitory concentrations. Moreover, the biofilms of the test bacteria were reduced by 56-70%. Plumbagin reduced the bacterial adherence and colonization on solid surface. Computational studies gave closer insights regarding the possible modes of action. Molecular dynamics simulations revealed that the protein complexes were quite stable under physiological conditions. This study provides both experimental and computational evidence regarding the efficacy of plumbagin against biofilms and the QS-controlled virulence factors of Gram-negative bacteria.


Assuntos
Chromobacterium , Percepção de Quorum , Antibacterianos/farmacologia , Biofilmes , Simulação por Computador , Bactérias Gram-Negativas , Naftoquinonas , Pseudomonas aeruginosa , Virulência , Fatores de Virulência
15.
Front Immunol ; 12: 674341, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34421890

RESUMO

Juglone (JUG), a natural product found in walnut trees and other plants, shows potent antioxidant, antimicrobial, and immunoregulatory activities. However, it remains unknown whether JUG can alleviate ulcerative colitis. This study aims to explore the effect of JUG on dextran sulfate sodium (DSS)-induced colitis in mice. The mice were randomly assigned into three groups: the vehicle group, the DSS group, and the JUG group. The experiments lasted for 17 days; during the experiment, all mice received dimethyl sulfoxide (DMSO, 0.03% v/v)-containing water, while the mice in the JUG group received DMSO-containing water supplemented with JUG (0.04 w/v). Colitis was induced by administering DSS (3% w/v) orally for 10 consecutive days. The results showed that the JUG treatment significantly ameliorated body weight loss and disease activity index and improved the survival probability, colon length, and tissue damage. JUG reversed the DSS-induced up-regulation of proinflammatory cytokines, including interleukin (IL)-6, 12, 21, and 23, and tumor necrosis factor-alpha, and anti-inflammatory cytokines, such as IL-10 and transforming growth factor-beta, in the serum of the colitis mice. Additionally, the activation of mitochondrial uncoupling protein 2 and phospho-Nuclear Factor-kappa B p65 and the inhibition of the kelch-like ECH-associated protein 1 and NF-E2-related factor 2 induced by DSS were also reversed under JUG administration. Although the JUG group possessed a similar microbial community structure as the DSS group, JUG enriched potential beneficial microbes such as Lachnospiraceae_NK4A136_group but not pathogens such as Escherichia Shigella, which was dominative in DSS group, at the genus level. In conclusion, our results demonstrated that JUG could be a promising agent for UC prevention to regulate inflammatory cytokines and oxidative stress.


Assuntos
Colite Ulcerativa/patologia , Naftoquinonas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
16.
Eur J Med Chem ; 225: 113789, 2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34438124

RESUMO

SARS-CoV-2 as a positive-sense single-stranded RNA coronavirus caused the global outbreak of COVID-19. The main protease (Mpro) of the virus as the major enzyme processing viral polyproteins contributed to the replication and transcription of SARS-CoV-2 in host cells, and has been characterized as an attractive target in drug discovery. Herein, a set of 1,4-naphthoquinones with juglone skeleton were prepared and evaluated for the inhibitory efficacy against SARS-CoV-2 Mpro. More than half of the tested naphthoquinones could effectively inhibit the target enzyme with an inhibition rate of more than 90% at the concentration of 10 µM. In the structure-activity relationships (SARs) analysis, the characteristics of substituents and their position on juglone core scaffold were recognized as key ingredients for enzyme inhibitory activity. The most active compound, 2-acetyl-8-methoxy-1,4-naphthoquinone (15), which exhibited much higher potency in enzyme inhibitions than shikonin as the positive control, displayed an IC50 value of 72.07 ± 4.84 nM towards Mpro-mediated hydrolysis of the fluorescently labeled peptide. It fit well into the active site cavity of the enzyme by forming hydrogen bonds with adjacent amino acid residues in molecular docking studies. The results from in vitro antiviral activity evaluation demonstrated that the most potent Mpro inhibitor could significantly suppress the replication of SARS-CoV-2 in Vero E6 cells within the low micromolar concentrations, with its EC50 value of about 4.55 µM. It was non-toxic towards the host Vero E6 cells under tested concentrations. The present research work implied that juglone skeleton could be a primary template for the development of potent Mpro inhibitors.


Assuntos
COVID-19/tratamento farmacológico , Naftoquinonas/química , Inibidores de Proteases/uso terapêutico , SARS-CoV-2/enzimologia , Proteínas da Matriz Viral/antagonistas & inibidores , Animais , Sítios de Ligação , COVID-19/patologia , COVID-19/virologia , Domínio Catalítico , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Naftoquinonas/metabolismo , Naftoquinonas/farmacologia , Naftoquinonas/uso terapêutico , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacologia , SARS-CoV-2/isolamento & purificação , Relação Estrutura-Atividade , Células Vero , Proteínas da Matriz Viral/metabolismo
17.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202294

RESUMO

Dihydroorotase (DHOase) is the third enzyme in the de novo biosynthesis pathway for pyrimidine nucleotides, and an attractive target for potential anticancer chemotherapy. By screening plant extracts and performing GC-MS analysis, we identified and characterized that the potent anticancer drug plumbagin (PLU), isolated from the carnivorous plant Nepenthes miranda, was a competitive inhibitor of DHOase. We also solved the complexed crystal structure of yeast DHOase with PLU (PDB entry 7CA1), to determine the binding interactions and investigate the binding modes. Mutational and structural analyses indicated the binding of PLU to DHOase through loop-in mode, and this dynamic loop may serve as a drug target. PLU exhibited cytotoxicity on the survival, migration, and proliferation of 4T1 cells and induced apoptosis. These results provide structural insights that may facilitate the development of new inhibitors targeting DHOase, for further clinical anticancer chemotherapies.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Produtos Biológicos/farmacologia , Vias Biossintéticas/efeitos dos fármacos , Di-Hidro-Orotase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Naftoquinonas/farmacologia , Pirimidinas/biossíntese , Antineoplásicos Fitogênicos/química , Sítios de Ligação , Produtos Biológicos/química , Domínio Catalítico , Di-Hidro-Orotase/química , Di-Hidro-Orotase/genética , Inibidores Enzimáticos/química , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Mutação , Naftoquinonas/química , Ligação Proteica , Relação Estrutura-Atividade
18.
Biosensors (Basel) ; 11(6)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201174

RESUMO

The development of in situ analytical devices has gained outstanding scientific interest. A solid sensing membrane composed of 1,2-naphthoquinone-4-sulfonate (NQS) derivatizing reagent embedded into a polymeric polydimethylsiloxane (PDMS) composite was proposed for in situ ammonium (NH4+) and urea (NH2CONH2) analysis in water and urine samples, respectively. Satisfactory strategies were also applied for urease-catalyzed hydrolysis of urea, either in solution or glass-supported urease immobilization. Using diffuse reflectance measurements combined with digital image processing of color intensity (RGB coordinates), qualitative and quantitative analyte detection was assessed after the colorimetric reaction took place inside the sensing membrane. A suitable linear relationship was found between the sensor response and analyte concentration, and the results were validated by a thymol-PDMS-based sensor based on the Berthelot reaction. The suggested sensing device offers advantages such as rapidity, versatility, portability, and employment of non-toxic reagents that facilitate in situ analysis in an energy-efficient manner.


Assuntos
Naftoquinonas/química , Ureia/metabolismo , Urease/metabolismo , Colorimetria , Dimetilpolisiloxanos , Polímeros , Urease/análise , Água/química
19.
Molecules ; 26(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200517

RESUMO

Epoxy-α-lapachone (Lap) and Epoxymethyl-lawsone (Law) are oxiranes derived from Lapachol and have been shown to be promising drugs for Leishmaniases treatment. Although, it is known the action spectrum of both compounds affect the Leishmania spp. multiplication, there are gaps in the molecular binding details of target enzymes related to the parasite's physiology. Molecular docking assays simulations were performed using DockThor server to predict the preferred orientation of both compounds to form stable complexes with key enzymes of metabolic pathway, electron transport chain, and lipids metabolism of Leishmania spp. This study showed the hit rates of both compounds interacting with lanosterol C-14 demethylase (-8.4 kcal/mol to -7.4 kcal/mol), cytochrome c (-10.2 kcal/mol to -8.8 kcal/mol), and glyceraldehyde-3-phosphate dehydrogenase (-8.5 kcal/mol to -7.5 kcal/mol) according to Leishmania spp. and assessed compounds. The set of molecular evidence reinforces the potential of both compounds as multi-target drugs for interrupt the network interactions between parasite enzymes, which can lead to a better efficacy of drugs for the treatment of leishmaniases.


Assuntos
Leishmania/efeitos dos fármacos , Naftoquinonas/farmacologia , Simulação por Computador , Citocromos c/metabolismo , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Compostos de Epóxi/farmacologia , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Leishmaniose/tratamento farmacológico , Leishmaniose/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Redes e Vias Metabólicas/efeitos dos fármacos , Simulação de Acoplamento Molecular
20.
Molecules ; 26(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34208908

RESUMO

Diabetes mellitus is a multifactorial disease that affects both developing and developed countries and is a major public health concern. Many synthetic drugs are available in the market, which counteracts the associated pathologies. However, due to the propensity of side effects, there is an unmet need for the investigation of safe and effective drugs. This research aims to find a novel phytoconstituent having diminished action on blood glucose levels with the least side effects. Shikonin is a naturally occurring naphthoquinone dying pigment obtained by the roots of the Boraginaceae family. Besides its use as pigments, it can be used as an antimicrobial, anti-inflammatory, and anti-tumor agent. This research aimed to hypothesize the physicochemical and phytochemical properties of Shikonin's in silico interaction with protein tyrosine phosphate 1B, as well as it's in vitro studies, in order to determine its potential anti-diabetic impact. To do so, molecular docking experiments with target proteins were conducted to assess their anti-diabetic ability. Analyzing associations with corresponding amino acids revealed the significant molecular interactions between Shikonin and diabetes-related target proteins. In silico pharmacokinetics and toxicity profile of Shikonin using ADMET Descriptor, Toxicity Prediction, and Calculate Molecular Properties tools from Biovia Discovery Studio v4.5. Filter by Lipinski and Veber Rule's module from Biovia Discovery Studio v4.5 was applied to assess the drug-likeness of Shikonin. The in vitro studies exposed that Shikonin shows an inhibitory potential against the PTP1B with an IC50 value of 15.51 µM. The kinetics studies revealed that it has a competitive inhibitory effect (Ki = 7.5 M) on the enzyme system, which could be useful in the production of preventive and therapeutic agents. The findings of this research suggested that the Shikonin could be used as an anti-diabetic agent and can be used as a novel source for drug delivery.


Assuntos
Inibidores Enzimáticos/química , Hipoglicemiantes/química , Simulação de Acoplamento Molecular , Naftoquinonas/química , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Regulação Alostérica , Humanos , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/química , Relação Estrutura-Atividade
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