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1.
Phytomedicine ; 94: 153805, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34749177

RESUMO

BACKGROUND: Shikonin is one of the major phytochemical components of Lithospermum erythrorhizon (Purple Cromwell), which is a type of medicinal herb broadly utilized in traditional Chinese medicine. It is well established that shikonin possesses remarkable therapeutic actions on various diseases, with the underlying mechanisms, pharmacokinetics and toxicological effects elusive. Also, the clinical trial and pharmaceutical study of shikonin remain to be comprehensively delineated. PURPOSE: The present review aimed to systematically summarize the updated knowledge regarding the therapeutic actions, pharmacokinetics, toxicological effects, clinical trial and pharmaceutical study of shikonin. METHODS: The information contained in this review article were retrieved from some authoritative databases including Web of Science, PubMed, Google scholar, Chinese National Knowledge Infrastructure (CNKI), Wanfang Database and so on, till August 2021. RESULTS: Shikonin exerts multiple therapeutic efficacies, such as anti-inflammation, anti-cancer, cardiovascular protection, anti-microbiomes, analgesia, anti-obesity, brain protection, and so on, mainly by regulating the NF-κB, PI3K/Akt/MAPKs, Akt/mTOR, TGF-ß, GSK3ß, TLR4/Akt signaling pathways, NLRP3 inflammasome, reactive oxygen stress, Bax/Bcl-2, etc. In terms of pharmacokinetics, shikonin has an unfavorable oral bioavailability, 64.6% of the binding rate of plasma protein, and enhances some metabolic enzymes, particularly including cytochrome P450. In regard to the toxicological effects, shikonin may potentially cause nephrotoxicity and skin allergy. The above pharmacodynamics and pharmacokinetics of shikonin have been validated by few clinical trials. In addition, pharmaceutical innovation of shikonin with novel drug delivery system such as nanoparticles, liposomes, microemulsions, nanogel, cyclodextrin complexes, micelles and polymers are beneficial to the development of shikonin-based drugs. CONCLUSIONS: Shikonin is a promising phytochemical for drug candidates. Extensive and intensive explorations on shikonin are warranted to expedite the utilization of shikonin-based drugs in the clinical setting.


Assuntos
Naftoquinonas , Preparações Farmacêuticas , NF-kappa B , Naftoquinonas/farmacologia , Fosfatidilinositol 3-Quinases
2.
Am J Chin Med ; 49(8): 1871-1895, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34961421

RESUMO

Shikonin is one of the primary active components extracted from the dried root ofZicao (Lithospermum erythrorhizon, Onosma paniculata, or Arnebia euchroma), a traditional Chinese herbal medicine. Shikonin is known to not only exert anti-proliferative, anti-inflammatory, and anti-angiogenic activities, but also play a crucial role in triggering the production of reactive oxygen species, suppressing the release of exosomes, and inducing apoptosis. Increasing evidence suggests that shikonin has a protective effect against skin diseases, including psoriasis, melanoma, and hypertrophic scars. In order to evaluate the application potential of shikonin in the treatment of skin diseases, this review is the first of its kind to provide comprehensive and up-to-date information regarding the uses of shikonin and its derivatives on skin diseases and its underlying mechanisms. In this review, we have focused on the signaling pathways and cellular targets involved in the anti-dermatosis effects of shikonin to bridge the gaps in the literature, thereby providing scientific support for the research and development of new drugs from a traditional medicinal plant.


Assuntos
Lithospermum , Naftoquinonas , Dermatopatias , Humanos , Inflamação , Naftoquinonas/farmacologia , Naftoquinonas/uso terapêutico , Dermatopatias/tratamento farmacológico
3.
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
4.
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
5.
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
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.
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
8.
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
9.
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
10.
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
11.
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
12.
Biochem J ; 478(13): 2465-2479, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34198324

RESUMO

SARS-CoV-2 is responsible for COVID-19, a human disease that has caused over 2 million deaths, stretched health systems to near-breaking point and endangered economies of countries and families around the world. Antiviral treatments to combat COVID-19 are currently lacking. Remdesivir, the only antiviral drug approved for the treatment of COVID-19, can affect disease severity, but better treatments are needed. SARS-CoV-2 encodes 16 non-structural proteins (nsp) that possess different enzymatic activities with important roles in viral genome replication, transcription and host immune evasion. One key aspect of host immune evasion is performed by the uridine-directed endoribonuclease activity of nsp15. Here we describe the expression and purification of nsp15 recombinant protein. We have developed biochemical assays to follow its activity, and we have found evidence for allosteric behaviour. We screened a custom chemical library of over 5000 compounds to identify nsp15 endoribonuclease inhibitors, and we identified and validated NSC95397 as an inhibitor of nsp15 endoribonuclease in vitro. Although NSC95397 did not inhibit SARS-CoV-2 growth in VERO E6 cells, further studies will be required to determine the effect of nsp15 inhibition on host immune evasion.


Assuntos
Antivirais/química , Antivirais/farmacologia , Avaliação Pré-Clínica de Medicamentos , Endorribonucleases/antagonistas & inibidores , SARS-CoV-2/enzimologia , Bibliotecas de Moléculas Pequenas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica , Animais , Chlorocebus aethiops , Endorribonucleases/isolamento & purificação , Endorribonucleases/metabolismo , Ensaios Enzimáticos , Fluorescência , Ensaios de Triagem em Larga Escala , Técnicas In Vitro , Cinética , Naftoquinonas/farmacologia , Reprodutibilidade dos Testes , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/crescimento & desenvolvimento , Bibliotecas de Moléculas Pequenas/química , Soluções , Células Vero , Proteínas não Estruturais Virais/isolamento & purificação , Proteínas não Estruturais Virais/metabolismo
13.
Chem Biol Interact ; 347: 109582, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34302802

RESUMO

Different aspects of reproductive functions are regulated by mitochondrial-controlled events. This study investigated the effect of plumbagin (PL) on testicular mitochondria with a view to unravelling the mechanism of the antifertility potential of plumbagin in testis of healthy rats. Thirty-two male Wistar strain albino rats were randomly allocated into four groups of eight animals each. The control or healthy group received orally 0.1 % DMSO while animals in the remaining three groups received 2.5 mg PL/kg bdwt, 5.0 mg PL/kg bdwt and 10 mg PL/kg bdwt, respectively, for 14 days. In study two, twenty-four male Wistar rats were randomly divided into three (3) groups and were orally administered 0.1% DMSO (control), 30 and 100 mg/kg PL, respectively once daily for 72 h. Rat testis mitochondria were isolated using differential centrifugation. The mitochondrial Permeability Transition (mPT) pore, mitochondrial ATPase (mATPase) activity and mitochondrial lipid peroxidation were assessed spectrophotometrically. Expression of apoptotic proteins (p53, Bax, Bcl-2) and the release of cytochrome c were determined by immunochemical technique. Reproductive receptors (FSH, PR), the expression of aromatase, Testis Specific Kinase-1 {TESK-1} were quantified by RT-PCR. The various doses of plumbagin (2.5, 5.0 and 10 mg/kg bdwt) induced opening of the testicular mPT pore by 2, 5 and 8 folds, respectively, after 14 days of oral administration. These doses of plumbagin also caused enhancement of mATPase activity, elevated generation of mLPO as well as increases in the concentrations of caspases 9 and 3. Sperm analysis revealed that these doses of PL also caused significant decreases in sperm count and motility and increased sperm abnormalities compared to control. Interestingly, these effects were accompanied by dose-dependent expressions of the Bak, p53 and cytochrome c release. Conversely, the abundance of anti-apoptotic Bcl-2 protein decreased relative to control. The levels of transcripts of FSH and progesterone receptors as well as TESK-1 and aromatase decreased significantly relative to control. Furthermore, PL strongly inhibited p53-MDM2 compared to control. Altogether, these findings show that plumbagin damages testicular cells through the activation of mitochondrial pathway involving the p53 protein network.


Assuntos
Morte Celular/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Naftoquinonas/farmacologia , Testículo/efeitos dos fármacos , Adenosina Trifosfatases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Caspase 9/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Mitocôndrias/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Testículo/metabolismo , Proteína Supressora de Tumor p53/metabolismo
14.
Chem Pharm Bull (Tokyo) ; 69(7): 661-673, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34193715

RESUMO

In this study, based on our previous study, derivatives of naphtho[2,3-b]furan-4,9-diones were synthesized and their antimicrobial activities were evaluated. The screening of these naphthoquinones revealed that the fluorine-containing NQ008 compound exhibited potent and broad antimicrobial activities against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), Gram-negative bacteria, and fungi. The results of the ratio of the minimum bactericidal concentration (MBC) to the minimum inhibitory concentrations (MICs) and time-kill assays suggest that the mode of action of NQ008 is bactericidal. Additionally, the results of a drug resistance study revealed that NQ008 exhibited potent antibacterial activity and may delay the development of bacteria resistance. Furthermore, NQ008 exhibited preliminary antiviral activity against the swine influenza virus and Feline calicivirus.


Assuntos
Anti-Infecciosos/química , Naftoquinonas/química , Tabebuia/química , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Relação Estrutura-Atividade , Tabebuia/metabolismo
15.
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
16.
Environ Toxicol ; 36(9): 1775-1784, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34089293

RESUMO

Pneumonia is an inflammatory disease induced by infection with different pathogens. Currently, multiple preclinical studies have revealed that shikonin, a natural naphthoquinone, can mitigate lipopolysaccharide (LPS)-induced inflammation, but its underlying mechanism in pneumonia remains unknown. This research was designed to explore the function and regulatory mechanism of shikonin in LPS-induced cell injury and inflammation in WI-38 cells. In-vitro model of pneumonia was constructed by treating WI-38 cells with LPS. Expression of miR-489-3p and MAP2K1 was tested by RT-qPCR and (or) Western blot analysis. Cell viability was examined by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide assay. The productions of pro-inflammatory cytokines were determined by enzyme-linked immunosorbent assays. Cell apoptosis was detected by Western blot and flow cytometry analysis. In the current study, LPS induced WI-38 cell damage by inhibiting cell viability and promoting cell apoptosis and inflammation. Shikonin ameliorated LPS-induced cell injury and elevated miR-489-3p expression. LPS-induced inflammatory injury was further mitigated by upregulation of miR-489-3p. In addition, MAP2K1, the target of miR-489-3p, was upregulated by LPS. Furthermore, upregulation of MAP2K1 reversed the influence of shikonin and miR-489-3p mimics on LPS-induced cell injury and inflammation. This study revealed that shikonin protected WI-38 cells against LPS-induced cell injury and inflammatory response by regulating the miR-489-3p/MAP2K1 axis, thus affecting the progression of pneumonia.


Assuntos
MicroRNAs , Naftoquinonas , Apoptose , Lipopolissacarídeos/toxicidade , MicroRNAs/genética , Naftoquinonas/farmacologia
17.
BMC Cancer ; 21(1): 662, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078316

RESUMO

BACKGROUND: Melanoma is a malignant cancer that affects melanocytes and is considered the most aggressive skin-type cancer. The prevalence for melanoma cancer for the last five year is about one million cases. The impact caused of this and other types of cancer, revel the importance of research into potential active compounds. The natural products are an important source of compounds with biological activity and research with natural products may enable the discovery of compounds with potential activity in tumor cells. METHODS: The Sulforhodamine B was used to determine cell density after treatment with lawsone derivatives. Apoptosis and necrosis were analyzed by flow cytometer. Morphological changes were observed by fluorescence using the Phalloidin/FITC and DAPI stains. The clonogenic and wound healing assays were used to analyze reduction of colonies formation and migratory capacity of melanoma cells, respectability. RESULTS: In pharmacological screening, seven compounds derived from lawsone were considered to have high cytotoxic activity (GI > 75%). Three compounds were selected to assess the inhibitory concentration for 50% of cells (IC50), and the compound 9, that has IC50 5.3 µM in melanoma cells, was selected for further analyses in this cell line. The clonogenic assay showed that the compound is capable of reducing the formation of melanoma colonies at 10.6 µM concentration. The compound induced apoptotic morphological changes in melanoma cells and increased by 50% the cells dying from apoptosis. Also, this compound reduced the migratory capacity of melanoma cells. CONCLUSIONS: The results of this study showed that the evaluated lawsone derivatives have potential activity on tumor cells. The compound 9 is capable of inducing cell death by apoptosis in melanoma cells (B16F10).


Assuntos
Melanoma/tratamento farmacológico , Naftoquinonas/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Glicosídeos/química , Humanos , Melanoma/patologia , Camundongos , Naftoquinonas/química , Naftoquinonas/uso terapêutico , Neoplasias Cutâneas/patologia , Ensaio Tumoral de Célula-Tronco
18.
Mol Cell Biochem ; 476(10): 3701-3709, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34081254

RESUMO

Hyaluronic acid (HA)-CD44 pathway showed association with several malignancies. The natural polyphenols Plumbagin, Pongapin and Karanjin showed anti-cancer activities in different tumors including cervical carcinoma. To understand their mechanism of anti-cancer activity, the effect of the compounds on HA-CD44 pathway was analyzed in cervical cancer cell line HeLa. The mRNA expression of three different isoforms of CD44 i.e., CD44s, CD44v3, and CD44v6, was differentially downregulated by the compounds. This was validated by Western blot and immunocytochemical analysis of CD44s.The low molecular weight HA (LMW-HA) showed growth promoting activity in HeLa at low concentration, whereas high molecular weight HA (HMW-HA) had no such effect. The compounds could preferentially downregulate the LMW-HA level in HeLa, as evident in the cell as well as in the cell-free conditioned medium. Concentration-dependent upregulation of HA synthase-2 (HAS2) was seen in the cell by the compounds, whereas differential downregulation of hyalurinidases 1-4 (HYAL 1-4), predominantly HYAL1, were seen. The compounds could also downregulate the downstream target of the pathway p-AKT (T-308) in concentration-dependent manner. Thus, the compounds could attenuate the HA-CD44 pathway in HeLa cell to restrict the tumor growth.


Assuntos
Benzopiranos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Flavonas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Receptores de Hialuronatos/biossíntese , Ácido Hialurônico/metabolismo , Naftoquinonas/farmacologia , Proteínas de Neoplasias/biossíntese , Transdução de Sinais/efeitos dos fármacos , Neoplasias do Colo do Útero/metabolismo , Feminino , Células HeLa , Humanos , Receptores de Hialuronatos/genética , Ácido Hialurônico/genética , Proteínas de Neoplasias/genética , Transdução de Sinais/genética , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
19.
Food Funct ; 12(11): 4947-4959, 2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34100505

RESUMO

Ferroptosis is a novel iron-dependent cell death pathway mainly caused by an abnormal redox state and associated with various diseases including cancer. Recently, much attention has been paid to natural compounds that are involved in its activation and inhibition. This is the first ever study to demonstrate the role of juglone isolated from Carya cathayensis green peel in inducing autophagy and inhibiting endometrial cancer (EC) cell migration. Subsequently, Fe2+ accumulation, lipid peroxidation, GSH depletion, the upregulation of HMOX1, and heme degradation to Fe2+ were reported. Juglone was involved in inducing autophagy and inhibiting cell migration and endoplasmic reticulum stress, which are the new hallmarks of cancer treatment. Collectively, our data indicate that juglone as a functional food ingredient induces the programmed cell death of EC cells by activating oxidative stress and suggest a novel therapeutic approach for the treatment and prevention of EC.


Assuntos
Morte Celular/efeitos dos fármacos , Neoplasias do Endométrio/tratamento farmacológico , Ferroptose/efeitos dos fármacos , Naftoquinonas/metabolismo , Naftoquinonas/farmacologia , Apoptose , Autofagia/efeitos dos fármacos , Carya/química , Linhagem Celular Tumoral , Movimento Celular , Neoplasias do Endométrio/patologia , Feminino , Humanos , Ferro/metabolismo , Peroxidação de Lipídeos , Oxirredução , Estresse Oxidativo , Fagocitose
20.
Inorg Chem ; 60(13): 9805-9819, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34115482

RESUMO

A series of nine RuII arene complexes bearing tridentate naphthoquinone-based N,O,O-ligands was synthesized and characterized. Aqueous stability and their hydrolysis mechanism were investigated via UV/vis photometry, HPLC-MS, and density functional theory calculations. Substituents with a positive inductive effect improved their stability at physiological pH (7.4) intensely, whereas substituents such as halogens accelerated hydrolysis and formation of dimeric pyrazolate and hydroxido bridged dimers. The observed cytotoxic profile is unusual, as complexes exhibited much higher cytotoxicity in SW480 colon cancer cells than in the broadly chemo- (incl. platinum-) sensitive CH1/PA-1 teratocarcinoma cells. This activity pattern as well as reduced or slightly enhanced ROS generation and the lack of DNA interactions indicate a mode of action different from established or previously investigated classes of metallodrugs.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Naftoquinonas/farmacologia , Rutênio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Naftoquinonas/química , Rutênio/química , Água/química
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