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1.
J Med Microbiol ; 69(5): 689-696, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32375980

RESUMO

Introduction. Rhein (4, 5-dihydroxyanthraquinone-2-carboxylic acid) has various properties, including anti-inflammatory, antioxidant and anticancer activities. However, the mechanism underlying the role of rhein in antimicrobial activity remains largely unknown.Aim. This study aims to identify potential natural compounds of rhein that are capable of inhibiting Cutibacterium acnes and elucidate the effects of rhein on NADH dehydrogenase-2 activity in C. acnes.Methodology. The anti-C. acnes activity of compounds was analysed using minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), the paper disc diffusion test and the checkerboard dilution test. To check whether rhein was inhibitory, putative type II NADH dehydrogenase (NDH-2) of C. acnes was analysed, cloned and expressed in Escherichia coli, and then NDH-2 purification was assessed with Ni-NTA before rhein inhibition of NADH dehydrogenase-2 activity was checked with ferricyanide [K3Fe(CN)6] as a substrate.Results. The results showed that the MIC of rhein against C. acnes was 6.25 µg ml-1, while the MBC was 12.5 µg ml-1, and there was a 38 mm inhibition zone in the paper disc diffusion test. Rhein showed an additive two- to fourfold reduction of the MIC value with four antibiotics on the checkerboard dilution test. The purified NADH dehydrogenase gene product showed a size of approximately 51 kDa and had a V max of 23 µmol and a K m of 280 µm. The inhibitory effect of rhein against NADH dehydrogenase-2 activity was non-competitive with ferricyanide [K3Fe(CN)6] with a K i value of 3.5-4.5 µm.Conclusion. This study provided evidence of the inhibitory effects of rhein on the growth of C. acnes by blocking of NADH dehydrogenase-2 activity. This mechanism of inhibitory activity in the reduction of ROS formation and ATP productivity should be further tested in C. acnes and the question of whether rhein inhibits the natural growth of C. acnes should be investigated.


Assuntos
Antraquinonas/farmacologia , Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Infecções por Bactérias Gram-Positivas/microbiologia , NADH Desidrogenase/antagonistas & inibidores , Propionibacterium acnes/efeitos dos fármacos , Propionibacterium acnes/enzimologia , Antraquinonas/uso terapêutico , Antibacterianos/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Humanos , Cinética , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Propionibacterium acnes/crescimento & desenvolvimento , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes
2.
Cell Biochem Funct ; 38(1): 47-57, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31710116

RESUMO

Colorectal cancer (CRC) is a common human malignancy that accounts for 600,000 deaths annually worldwide. Chrysophanol, a naturally occurring anthraquinone compound, exhibits anti-neoplastic effects in various cancer cells. The aim of this study was to explore the biological effects of chrysophanol on CRC cells, and determine the underlying mechanism. Chrysophanol inhibited proliferation of and promoted apoptosis in CRC cells by activating the intrinsic mitochondrial apoptotic pathway. In addition, chrysophanol also suppressed tumor growth in vivo and increased the percentage of apoptotic cells in tumor xenografts, without general toxicity. Proteomic iTRAQ analysis revealed decorin (DCN) as the major target of chrysophanol. DCN was upregulated in the tumor tissues following chrysophanol treatment, and ectopic DCN expression markedly augmented the pro-apoptotic effects of chrysophanol in CRC cells. In contrast, DCN knockdown significantly abrogated chrysophanol-induced apoptosis in CRC cells. Taken together, chrysophanol exerts anti-neoplastic effects in vitro and in vivo in CRC cells by modulating DCN, there by highlighting its therapeutic potential in CRC.


Assuntos
Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Decorina/antagonistas & inibidores , Animais , Antraquinonas/química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Decorina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , RNA Interferente Pequeno/farmacologia , Relação Estrutura-Atividade , Células Tumorais Cultivadas
3.
Phytother Res ; 34(2): 270-281, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31680350

RESUMO

Aloe-emodin is a naturally anthraquinone derivative and an active ingredient of Chinese herbs, such as Cassia occidentalis, Rheum palmatum L., Aloe vera, and Polygonum multiflorum Thunb. Emerging evidence suggests that aloe-emodin exhibits many pharmacological effects, including anticancer, antivirus, anti-inflammatory, antibacterial, antiparasitic, neuroprotective, and hepatoprotective activities. These pharmacological properties lay the foundation for the treatment of various diseases, including influenza virus, inflammation, sepsis, Alzheimer's disease, glaucoma, malaria, liver fibrosis, psoriasis, Type 2 diabetes, growth disorders, and several types of cancers. However, an increasing number of published studies have reported adverse effects of aloe-emodin. The primary toxicity among these reports is hepatotoxicity and nephrotoxicity, which are of wide concern worldwide. Pharmacokinetic studies have demonstrated that aloe-emodin has a poor intestinal absorption, short elimination half-life, and low bioavailability. This review aims to provide a comprehensive summary of the pharmacology, toxicity, and pharmacokinetics of aloe-emodin reported to date with an emphasis on its biological properties and mechanisms of action.


Assuntos
Antraquinonas/farmacologia , Antraquinonas/farmacocinética , Antraquinonas/toxicidade , Aloe/química , Animais , Cassia/química , Fallopia multiflora/química , Humanos , Rheum/química
4.
Phytochemistry ; 169: 112182, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31669820

RESUMO

The chemical study on the heartwoods extract of Ventilago harmandiana (Rhamnaceae) resulted in the isolation of ten previously undescribed pyranonaphthoquinones (ventilanones A-J), an undescribed anthraquinone (ventilanone K), together with eight known anthraquinone derivatives. Their structures were elucidated by extensive analysis of their spectroscopic data. The absolute configuration of ventilanone A was established from single crystal X-ray crystallographic analysis of its p-bromobenzenesulfonate ester derivative using Cu Kα radiation. The absolute configurations of the other related compounds were identified by comparison of their ECD data with those of ventilanone A and related known compounds. Cytotoxic and anti-inflammatory activities of some of the isolated compounds were evaluated. Ventilanone A and ventilanone C exhibited moderate cytotoxicity against P-388 cell line. Ventilanone D exhibited significant anti-inflammatory activity while ventilanone A and ventilanone C showed moderate activity.


Assuntos
Antraquinonas/farmacologia , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Edema/tratamento farmacológico , Naftoquinonas/farmacologia , Rhamnaceae/química , Animais , Antraquinonas/química , Antraquinonas/isolamento & purificação , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Camundongos , Modelos Moleculares , Estrutura Molecular , Naftoquinonas/química , Naftoquinonas/isolamento & purificação , Ratos , Relação Estrutura-Atividade , Células Tumorais Cultivadas
5.
BMC Complement Altern Med ; 19(1): 364, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31829180

RESUMO

BACKGROUND: The body responds to overnutrition by converting stem cells to adipocytes. In vitro and in vivo studies have shown polyphenols and other natural compounds to be anti-adipogenic, presumably due in part to their antioxidant properties. Purpurin is a highly antioxidative anthraquinone and previous studies on anthraquinones have reported numerous biological activities in cells and animals. Anthraquinones have also been used to stimulate osteoblast differentiation, an inversely-related process to that of adipocyte differentiation. We propose that due to its high antioxidative properties, purpurin administration might attenuate adipogenesis in cells and in mice. METHODS: Our study will test the effect purpurin has on adipogenesis using both in vitro and in vivo models. The in vitro model consists of tracking with various biomarkers, the differentiation of pre-adipocyte to adipocytes in cell culture. The compound will then be tested in mice fed a high-fat diet. Murine 3T3-L1 preadipocyte cells were stimulated to differentiate in the presence or absence of purpurin. The following cellular parameters were measured: intracellular reactive oxygen species (ROS), membrane potential of the mitochondria, ATP production, activation of AMPK (adenosine 5'-monophosphate-activated protein kinase), insulin-induced lipid accumulation, triglyceride accumulation, and expression of PPARγ (peroxisome proliferator activated receptor-γ) and C/EBPα (CCAAT enhancer binding protein α). In vivo, mice were fed high fat diets supplemented with various levels of purpurin. Data collected from the animals included anthropometric data, glucose tolerance test results, and postmortem plasma glucose, lipid levels, and organ examinations. RESULTS: The administration of purpurin at 50 and 100 µM in 3T3-L1 cells, and at 40 and 80 mg/kg in mice proved to be a sensitive range: the lower concentrations affected several measured parameters, whereas at the higher doses purpurin consistently mitigated biomarkers associated with adipogenesis, and weight gain in mice. Purpurin appears to be an effective antiadipogenic compound. CONCLUSION: The anthraquinone purpurin has potent in vitro anti-adipogenic effects in cells and in vivo anti-obesity effects in mice consuming a high-fat diet. Differentiation of 3T3-L1 cells was dose-dependently inhibited by purpurin, apparently by AMPK activation. Mice on a high-fat diet experienced a dose-dependent reduction in induced weight gain of up to 55%.


Assuntos
Adipogenia/efeitos dos fármacos , Antraquinonas/farmacologia , Fármacos Antiobesidade/farmacologia , Dieta Hiperlipídica , Células 3T3-L1 , Tecido Adiposo/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Peso Corporal/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo
6.
J BUON ; 24(5): 2062-2067, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31786876

RESUMO

PURPOSE: Oral cancer causes considerable mortality across the globe, mainly due development of chemoresistance and lack of efficient chemotherapeutic agents. In the current study the anticancer potential of Acetylshikonin was examined against KB-R cisplatin-resistant oral cancer cells along with evaluation of in vitro and in vivo modes of action. METHODS: The proliferation rate of the oral cancer cells was checked by MTT assay. Autophagy was detected by electron microscopy. Apoptotic cell death was assessed by DAPI and annexin V/propidium iodide (PI) staining. Protein expression was determined by immunoblotting. Xenografted mice models were used for in vivo evaluation of Acetylshikonin. RESULTS: The results revealed that Acetylshikonin could significantly inhibit the proliferation of all the oral cancer cells with lower cytoxicity compared with the normal cells. The anticancer activity of Acetylshikonin against the KB-R cisplatin-resistant cells was found to be due to induction of autophagy and apoptosis. The Acetylshikonin prompted apoptosis and autophagy was also associated with alteration in the apoptosis and autophagy-related protein expression. Furthermore, it was observed that Acetylshikonin could inhibit the mTOR/PI3K/AKT signalling pathway in the cisplatin-resistant KB-R oral cancer cells. The effects of the Acetylshikonin were also examined in vivo in xenografted mice models and it was observed that Acetylshikonin inhibited the growth of xenografted tumors. CONCLUSIONS: These results suggest that Acetylshikonin considerably suppresses the growth of cisplatin-resistant oral cancer in vitro and in vivo and may prove beneficial in the treatment of drug-resistant oral cancer.


Assuntos
Antraquinonas/farmacologia , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Bucais/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Cisplatino/efeitos adversos , Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Proteína Oncogênica v-akt/genética , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Chem Commun (Camb) ; 55(100): 15129-15132, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31788680

RESUMO

Here, a reaction-based indicator displacement hydrogel assay (RIA) was developed for the detection of hydrogen peroxide (H2O2) via the oxidative release of the optical reporter Alizarin Red S (ARS). In the presence of H2O2, the RIA system displayed potent biofilm inhibition for Methicillin-resistant Staphylococcus aureus (MRSA), as shown through an in vitro assay quantifying antimicrobial efficacy. This work demonstrated the potential of H2O2-responsive hydrogels containing a covalently bound diol-based drug for controlled drug release.


Assuntos
Antraquinonas/química , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Peróxido de Hidrogênio/química , Staphylococcus aureus Resistente à Meticilina/fisiologia , Antraquinonas/farmacologia , Antibacterianos/química , Escherichia coli/efeitos dos fármacos , Hidrogéis/química , Hidrogéis/farmacologia , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/efeitos dos fármacos , Solubilidade
8.
Mol Med Rep ; 20(5): 4576-4586, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702038

RESUMO

Quinalizarin has been demonstrated to exhibit potent antitumor activities in lung cancer and gastric cancer cells, but currently, little is known regarding its anticancer mechanisms in human breast cancer cells. The aim of the present study was to investigate the apoptotic effects of quinalizarin in MCF­7 cells and to analyze its molecular mechanisms. The MTT assay was used to evaluate the viability of human breast cancer cells that had been treated with quinalizarin and 5­fluorouracil. Flow cytometric analyses and western blotting were used to investigate the effects of quinalizarin on apoptosis and cycle arrest in MCF­7 cells with focus on reactive oxygen species (ROS) production. The results demonstrated that quinalizarin exhibited significant cytotoxic effects on human breast cancer cells in a dose­dependent manner. Accompanying ROS, quinalizarin induced MCF­7 cell mitochondrial­associated apoptosis by regulating mitochondrial­associated apoptosis, and caused cell cycle arrest at the G2/M phase in a time­dependent manner. Furthermore, quinalizarin can activate p38 kinase and JNK, and inhibit the extracellular signal­regulated kinase, signal transducer and activator of transcription 3 (STAT3) and NF­κB signaling pathways. These effects were blocked by mitogen­activated protein kinase (MAPK) inhibitor and N­acetyl­L­cysteine. The results from the present study suggested that quinalizarin induced G2/M phase cell cycle arrest and apoptosis in MCF­7 cells through ROS­mediated MAPK, STAT3 and NF­κB signaling pathways. Thus, quinalizarin may be useful for human breast cancer treatment, as well as the treatment of other cancer types.


Assuntos
Antraquinonas/farmacologia , Apoptose/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Células MCF-7
9.
Artigo em Inglês | MEDLINE | ID: mdl-31678841

RESUMO

Leishmania is the aethiological agent responsible for the visceral leishmaniasis, a serious parasite-borne disease widely spread all over the World. The emergence of resistant strains makes classical treatments less effective; therefore, new and better drugs are necessary. Naphthoquinones are interesting compounds for which many pharmacological properties have been described, including leishmanicidal activity. This work shows the antileishmanial effect of two series of terpenyl-1,4-naphthoquinones (NQ) and 1,4-anthraquinones (AQ) obtained from natural terpenoids, such as myrcene and myrceocommunic acid. They were evaluated both in vitro and ex vivo against the transgenic iRFP-Leishmania infantum strain and also tested on liver HepG2 cells to determine their selectivity indexes. The results indicated that NQ derivatives showed better antileishmanial activity than AQ analogues, and among them, compounds with a diacetylated hydroquinone moiety provided better results than their corresponding quinones. Regarding the terpenic precursor, compounds obtained from the monoterpenoid myrcene displayed good antiparasitic efficiency and low cytotoxicity for mammalian cells, whereas those derived from the diterpenoid showed better antileishmanial activity without selectivity. In order to explore their mechanism of action, all the compounds have been tested as potential inhibitors of Leishmania type IB DNA topoisomerases, but only some compounds that displayed the quinone ring were able to inhibit the recombinant enzyme in vitro. This fact together with the docking studies performed on LTopIB suggested the existence of another mechanism of action, alternative or complementary to LTopIB inhibition. In silico druglikeness and ADME evaluation of the best leishmanicidal compounds has shown good predictable druggability.


Assuntos
Antiprotozoários/farmacologia , DNA Topoisomerases/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Leishmania infantum/enzimologia , Quinonas/farmacologia , Animais , Antraquinonas/farmacologia , Camptotecina/química , Camptotecina/farmacologia , DNA Topoisomerases/química , DNA Topoisomerases/genética , Resistência a Medicamentos , Feminino , Células Hep G2/parasitologia , Humanos , Leishmaniose Visceral/tratamento farmacológico , Macrófagos/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Naftoquinonas/farmacologia , Quinonas/química , Baço/citologia , Inibidores da Topoisomerase/química , Inibidores da Topoisomerase/farmacologia
10.
Fish Shellfish Immunol ; 95: 117-127, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31629810

RESUMO

Anthracenedione is a derivative of anthraquinone aromatic organic natural pigments found in senna, aloe latex, rhubarb, cascara, lichens, and fungi having broad range of bioactivity, including anti-cancer, anti-inflammatory, anti-microbial, anti-fungal, anti-oxidant, anti-viral activities suggesting potential for clinical purpose of many diseases. The effect of anthracenedione enriched diet on growth, hematology, innate and adaptive immune parameters as well as protection from Aeromonas hydrophila in Mystus vittatus was reported. The weight gain, feed intake, specific growth rate (SGR), and feed conversion ratio (FCR) were significantly increased in uninfected groups fed with 5 mg kg-1 diet. The red blood cells (RBC) and white blood cells (WBC) count and the percentage of lymphocytes were significantly augmented in both infected and uninfected groups feeding with any diet. The percentage of monocytes, eosinophils, neutrophils and the biochemical profile such as total protein, albumin, and globulin also were significantly increased in the infected and uninfected groups fed with 5 mg kg-1 enriched diet. The innate and adaptive immune parameters such as phagocytic activity, immunoglobulin M (IgM), respiratory burst activity, complement activity, and lysozyme activity were significantly increased in uninfected and infected groups fed with 5 or 10 mg kg-1 diets but not with 1 mg kg-1 diet. The serum superoxide dismutase (SOD) activity is significantly increased in the uninfected and infected fish fed with 5 mg kg-1 diet but the increase was not significantly observed in 1 or 10 mg kg-1 diets. The nitric oxide (NO) production is significantly elevated in both uninfected and infected groups fed with 5 mg kg-1 diet. On the other hand, the lymphocyte proliferation and myeloperoxidase (MPO) activity were significantly increased the infected and uninfected groups fed with 5 and 10 mg kg-1 diets. The cumulative mortality was found 5% with 1 and 5 mg kg-1 diet groups while it was observed 10% mortality with 10 mg kg-1 diet group. Based on the results, it is observed that feeding the uninfected and infected groups with 5 mg kg-1 anthracenedione diet resulted in better improvement of growth, hematological, biochemical, and innate as well as adaptive immune parameters in M. vittatus against A. hydrophila.


Assuntos
Aeromonas hydrophila/efeitos dos fármacos , Antraquinonas/farmacologia , Peixes-Gato/imunologia , Doenças dos Peixes/imunologia , Infecções por Bactérias Gram-Negativas/veterinária , Imunomodulação , Imunidade Adaptativa/efeitos dos fármacos , Aeromonas hydrophila/patogenicidade , Ração Animal , Animais , Peixes-Gato/crescimento & desenvolvimento , Suplementos Nutricionais , Doenças dos Peixes/microbiologia , Infecções por Bactérias Gram-Negativas/imunologia , Imunidade Inata/efeitos dos fármacos
11.
J Biosci ; 44(4)2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31502566

RESUMO

4,5-Dihydroxyanthraquinone-2-carboxylic acid (Rhein) has been shown to have various physiological and pharmacological properties including anticancer activity and modulatory effects on bioenergetics. In this study, we explored the impact of rhein on protein profiling of undifferentiated (UC) and differentiated (DC) SH-SY5Y cells. Besides that, the cellular morphology and expression of differentiation markers were investigated to determine the effect of rhein on retinoic acidinduced neuronal cell differentiation. Using two-dimensional gel electrophoresis and matrix-assisted laser desorption/ ionization-time-of-flight mass spectrometry we evaluated the changes in the proteome of both UC and DC SH-SY5Y cells after 24 h treatment with rhein. Validation of selected differentially expressed proteins and the assessment of neuronal differentiation markers were performed by western blotting. Proteomic analysis revealed significant changes in the abundance of 15 proteins linked to specific cellular processes such as cytoskeleton structure and regulation, mitochondrial function, energy metabolism, protein synthesis and neuronal plasticity. We also observed that the addition of rhein to the cultured cells during differentiation resulted in a significantly reduced neurite outgrowth and decreased expression of neuronal markers. These results indicate that rhein may strongly interfere with the differentiation process of SH-SY5Y neuroblastoma cells and is capable of inducing marked proteomic changes in these cells.


Assuntos
Antraquinonas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Neuroblastoma/tratamento farmacológico , Proteômica , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células-Tronco Neurais/efeitos dos fármacos , Neuritos/efeitos dos fármacos , Neuritos/patologia , Neuroblastoma/genética , Neuroblastoma/patologia , Crescimento Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos
12.
mBio ; 10(4)2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31431545

RESUMO

Extracellular electron exchange in Methanosarcina species and closely related Archaea plays an important role in the global carbon cycle and enhances the speed and stability of anaerobic digestion by facilitating efficient syntrophic interactions. Here, we grew Methanosarcina acetivorans with methanol provided as the electron donor and the humic analogue, anthraquione-2,6-disulfonate (AQDS), provided as the electron acceptor when methane production was inhibited with bromoethanesulfonate. AQDS was reduced with simultaneous methane production in the absence of bromoethanesulfonate. Transcriptomics revealed that expression of the gene for the transmembrane, multiheme, c-type cytochrome MmcA was higher in AQDS-respiring cells than in cells performing methylotrophic methanogenesis. A strain in which the gene for MmcA was deleted failed to grow via AQDS reduction but grew with the conversion of methanol or acetate to methane, suggesting that MmcA has a specialized role as a conduit for extracellular electron transfer. Enhanced expression of genes for methanol conversion to methyl-coenzyme M and the Rnf complex suggested that methanol is oxidized to carbon dioxide in AQDS-respiring cells through a pathway that is similar to methyl-coenzyme M oxidation in methanogenic cells. However, during AQDS respiration the Rnf complex and reduced methanophenazine probably transfer electrons to MmcA, which functions as the terminal reductase for AQDS reduction. Extracellular electron transfer may enable the survival of methanogens in dynamic environments in which oxidized humic substances and Fe(III) oxides are intermittently available. The availability of tools for genetic manipulation of M. acetivorans makes it an excellent model microbe for evaluating c-type cytochrome-dependent extracellular electron transfer in Archaea IMPORTANCE The discovery of a methanogen that can conserve energy to support growth solely from the oxidation of organic carbon coupled to the reduction of an extracellular electron acceptor expands the possible environments in which methanogens might thrive. The potential importance of c-type cytochromes for extracellular electron transfer to syntrophic bacterial partners and/or Fe(III) minerals in some Archaea was previously proposed, but these studies with Methanosarcina acetivorans provide the first genetic evidence for cytochrome-based extracellular electron transfer in Archaea The results suggest parallels with Gram-negative bacteria, such as Shewanella and Geobacter species, in which multiheme outer-surface c-type cytochromes are an essential component for electrical communication with the extracellular environment. M. acetivorans offers an unprecedented opportunity to study mechanisms for energy conservation from the anaerobic oxidation of one-carbon organic compounds coupled to extracellular electron transfer in Archaea with implications not only for methanogens but possibly also for Archaea that anaerobically oxidize methane.


Assuntos
Citocromos/metabolismo , Transporte de Elétrons/fisiologia , Membranas/metabolismo , Methanosarcina/metabolismo , Acetatos/metabolismo , Antraquinonas/farmacologia , Citocromos/genética , Transporte de Elétrons/genética , Elétrons , Compostos Férricos/metabolismo , Regulação da Expressão Gênica em Archaea , Bactérias Gram-Negativas/metabolismo , Mesna/análogos & derivados , Metano/metabolismo , Metanol/metabolismo , Methanosarcina/efeitos dos fármacos , Methanosarcina/genética , Methanosarcina/crescimento & desenvolvimento , Oxirredução , Oxirredutases/metabolismo , Transcriptoma
13.
Phytother Res ; 33(11): 2960-2970, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31410907

RESUMO

Although the approved hepatitis B virus (HBV)-polymerase inhibitors (e.g., lamivudine) often lead to drug-resistance, several natural products have shown promising efficacies. Though Aloe vera (AV) gel and its constituents are shown inhibitors of many viruses, their anti-HBV activity still remains elusive. We therefore, tested the anti-HBV potential of AV extract and its anthraquinones in hepatoma cells, including molecular docking, high-performance thin layer chromatography (HPTLC), and cytochrome P450 (CYP3A4) activation analyses. Our anti-HBV assays (HBsAg/HBeAg Elisa) showed maximal inhibition of viral antigens production by aloe-emodin (~83%) > chrysophanol (~62%) > aloin B (~61%) > AV extract (~37%) in HepG2.2.15 cells. Interestingly, the effect of aloe-emodin was comparable with lamivudine (~86%). Moreover, sequential treatment with lamivudine (pulse) followed by aloe-emodin (chase) enhanced the efficacy of monotherapy by ~12%. Docking (AutoDock Vina) of the anthraquinones indicated strong interactions with HBV-polymerase residues that formed stable complexes with high Gibbs's free energy. Further, identification of aloe-emodin and aloin B by validated HPTLC in AV extract strongly endorsed its anti-HBV potential. In addition, our luciferase-reporter gene assay of transfected HepG2 cells showed moderate induction of CYP3A4 by aloe-emodin. In conclusion, this is the first report on anti-HBV potential of AV-derived anthraquinones, possibly via HBV-polymerase inhibition. Of these, although aloin B exhibits novel antiviral effect, aloe-emodin appears as the most promising anti-HBV natural drug with CYP3A4 activating property towards its enhanced therapeutic efficacy.


Assuntos
Aloe/química , Antraquinonas/uso terapêutico , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Antraquinonas/farmacologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Linhagem Celular , Emodina/análogos & derivados , Emodina/farmacologia , Emodina/uso terapêutico , Células Hep G2 , Humanos , Fitoterapia/métodos , Extratos Vegetais/farmacologia
14.
Molecules ; 24(16)2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31434258

RESUMO

Herein, a direct strategy to synthesize 3-(2-hydroxybenzoyl)-1-aza-anthraquinones with excellent efficiency, mild conditions, and benign functional group compatibility was reported. A variety of 3-formylchromone compounds were employed as compatible substrates and this protocol gave the 3-(2-hydroxybenzoyl)-1-aza-anthraquinone derivatives in good to excellent yields without inert gas and expensive transition metal catalysts. Some compounds displayed good anti-proliferative activities.


Assuntos
Antraquinonas/síntese química , Antineoplásicos/síntese química , Antraquinonas/química , Antraquinonas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células , Técnicas de Química Sintética , Ensaios de Seleção de Medicamentos Antitumorais , Células HT29 , Células HeLa , Humanos , Metais , Estrutura Molecular
15.
Drug Dev Res ; 80(8): 1040-1050, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31432559

RESUMO

Quinalizarin, a bioactive and highly selective compound, is known to promote apoptosis in colon and lung cancer cells. However, studies evaluating quinalizarin-induced apoptosis in melanoma cells have not been conducted. In the present study, we investigated the underlying mechanisms of antimelanoma activity of quinalizarin in human melanoma A375 cells. The MTT assay and Trypan blue staining were used to evaluate the cell viability. The flow cytometry was used to detect cell cycle, apoptosis and reactive oxygen species (ROS). Western blot was used to detect the expression of cell cycle and apoptosis-related proteins, MAPK, and STAT3. The results revealed a significant dose and time dependent effect of quinalizarin on inhibiting proliferation in three kinds of human melanoma cells, and had no significant toxic effects on normal cells. Moreover, quinalizarin triggered G2/M phase cell arrest by modulating the protein expression levels of CDK 1/2, cyclin A, cyclin B, p21 and p27, and induced apoptosis by down-regulating the antiapoptotic protein Bcl-2 and upregulating the proapoptotic protein BAD, leading to the activation of caspase-3 and PARP in the caspase cascade in A375 cells. Quinalizarin treatment led to apoptosis of A375 cells via activation of MAPK and inhibition of STAT3 signaling pathways. In addition, quinalizarin increased the level of ROS, but ROS scavenger NAC inhibited quinalizarin-induced apoptosis by regulating MAPK and STAT3 signaling pathways. In summary, quinalizarin induces cell cycle arrest and apoptosis via ROS-mediated MAPK and STAT3 signaling pathways in human melanoma A375 cells, and quinalizarin may be used as a novel and effective antimelanoma therapeutic.


Assuntos
Antraquinonas/farmacologia , Melanoma/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Melanoma/tratamento farmacológico , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Transdução de Sinais/efeitos dos fármacos
16.
J Pharm Pharmacol ; 71(10): 1475-1487, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31373015

RESUMO

OBJECTIVE: Chrysophanol is a natural anthraquinone, also known as chrysophanic acid and 1,8-dihydroxy-3-methyl-anthraquinone. It has been widely used in the food and pharmaceutical fields. This review is intended to provide a comprehensive overview of the pharmacology, toxicity and pharmacokinetic researches of chrysophanol. KEY FINDING: Information on chrysophanol was collected from the Internet database PubMed, Elsevier, ResearchGate, Web of Science, Wiley Online Library and Europe PM using a combination of keywords including 'pharmacology', 'toxicology' and 'pharmacokinetics'. The literature we collected included from January 2010 to June 2019. Chrysophanol has a wide spectrum of pharmacological effects, including anticancer, antioxidation, neuroprotection, antibacterial and antiviral, and regulating blood lipids. However, chrysophanol has obvious hepatotoxicity and nephrotoxicity, and pharmacokinetics indicate that the use of chrysophanol in combination with other drugs can reduce toxicity and enhance efficacy. SUMMARY: Chrysophanol can be used in many diseases. Future research directions include how the concentration of chrysophanol affects pharmacological effects and toxicity; the mechanism of synergy between chrysophanol and other drugs.


Assuntos
Antraquinonas/efeitos adversos , Antraquinonas/farmacologia , Animais , Antraquinonas/agonistas , Antraquinonas/farmacocinética , Humanos
17.
Int Immunopharmacol ; 75: 105780, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31376624

RESUMO

Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disorder, which may lead to joint disabilities. So far the pathogenesis of RA remains largely undetermined, and there are still no potent drugs for clinical treatment. Rhein, a natural bioactive anthraquinone derivative, exhibited significant anti-inflammatory activities demonstrated by previous studies. Here we aimed to investigate the effects of rhein on ATP-induced inflammation responses in fibroblast-like synoviocytes isolated from a rat model of collagen induced arthritis (CIA). Our results showed that ATP triggered rapid cytosolic calcium concentration ([Ca2+]c) increase depending on extracellular Ca2+ entry. Given the major P2 subtypes expressed in rat synoviocytes were P2X4 and P2Y2 receptors, ATP-elicited calcium entry should be mainly resulted from activating P2X4. Interestingly, rhein could effectively block the ATP-induced [Ca2+]c increases in a dose-dependent manner. Besides, rhein also suppressed the production of intracellular reactive oxygen species (ROS) induced by ATP in synoviocytes that was resulted from P2X4-mediated Ca2+ entry. Brilliant blue G (BBG), which can block P2X4 receptor at high concentration, showed similar suppressive effects on above responses. Furthermore, in lipopolysaccharide-primed cells, application of ATP synergistically promoted the gene expression of cyclooxygenase-2, interleukin-6 and matrix metalloproteinase-9. Both rhein and BBG attenuated these inflammatory gene expressions enhanced by ATP. Above data together suggested a potential anti-arthritic role of rhein by inhibiting ATP-induced [Ca2+]c increase, ROS production and inflammatory gene expression targeting P2X4 in CIA rat synoviocytes, which will provide a novel insight in the therapy of RA.


Assuntos
Antraquinonas/farmacologia , Anti-Inflamatórios/farmacologia , Sinoviócitos/efeitos dos fármacos , Trifosfato de Adenosina , Animais , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Cálcio/metabolismo , Células Cultivadas , Ciclo-Oxigenase 2/genética , Fibroblastos , Interleucina-6/genética , Masculino , Metaloproteinase 9 da Matriz/genética , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Receptores Purinérgicos P2X4/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Sinoviócitos/metabolismo
18.
Chem Biodivers ; 16(9): e1900353, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31329336

RESUMO

Five known secondary metabolites, chrysophanol (1), 7,7'-biphyscion (2), secalonic acid D (3), mannitol (4) and trehalose (5) were isolated for the first time from the extracts of the fungus Phialomyces macrosporus. Their structures were elucidated by NMR methods (1D and 2D NMR analysis), optical activity and ESI-MS. Complete 1 H and 13 C assignments were performed for compound 2. The antimicrobial activity was evaluated by serial microdilution assay for compounds 2 and 3 and results showed that compound 3 exhibited a significant growth inhibition at concentrations of 15.6 mg/ml (S. aureus and S. choleraesius) and 0.97 mg/mL (B. subtilis), comparable to the positive control.


Assuntos
Antibacterianos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Salmonella/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Antraquinonas/química , Antraquinonas/isolamento & purificação , Antraquinonas/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Bacillus subtilis/crescimento & desenvolvimento , Relação Dose-Resposta a Droga , Espectroscopia de Ressonância Magnética , Manitol/química , Manitol/isolamento & purificação , Manitol/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Salmonella/crescimento & desenvolvimento , Staphylococcus aureus/crescimento & desenvolvimento , Trealose/química , Trealose/isolamento & purificação , Trealose/farmacologia , Xantonas/química , Xantonas/isolamento & purificação , Xantonas/farmacologia
19.
Phytother Res ; 33(10): 2702-2713, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31313371

RESUMO

Chrysophanol (CHR), a purified active constituent extracted from Rheum palmatum L., possesses anti-inflammatory activity. This study aimed to evaluate its effects on asthma-associated airway inflammation and remodeling. BALB/c mice were sensitized and challenged by ovalbumin (OVA) and administrated with different doses of CHR. We found that CHR decreased OVA-induced pulmonary inflammation: the levels of interleukin (IL)-4, IL-5, and IL-13, tumor necrosis factor (TNF)-α, and inducible nitric oxide synthase were downregulated. CHR also attenuated airway remodeling induced by OVA challenge-CHR inhibited pulmonary α-smooth muscle actin expression. Moreover, both the nuclear translocation and activity of NF-κB p65 were inhibited by CHR in the asthmatic lung. Enhanced autophagy was initiated in the lung by OVA challenge as evidenced by upregulated light chain 3 beta, autophagy-related protein 5, and Beclin 1. CHR suppressed OVA-induced alterations in these autophagy-related molecules. In vitro, CHR (2 or 20 µM) was used to treat human pulmonary epithelial BEAS-2B cells in the presence of 10 ng/ml recombinant TNF-α. CHR not only exhibited the antiproliferation effect but also inhibited the activation of nuclear factor-kappa B (NF-kB) signaling pathway in TNF-α-treated BEAS-2B cells. In conclusion, our study indicates that CHR has the potential to ameliorate asthma.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Antraquinonas/farmacologia , Asma/tratamento farmacológico , NF-kappa B/fisiologia , Animais , Antraquinonas/uso terapêutico , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos
20.
Free Radic Res ; 53(8): 922-931, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31357895

RESUMO

Prediction of the antioxidant activity of three Aloe vera components (aloesone, aloe-emodin, and isoeleutheol) was performed based on density functional theory calculations using the B3LYP hybrid functional and the 6-311++ G** basis set. Calculation of highest occupied molecular orbital (HOMO), lowest occupied molecular orbital (LUMO), and Egap revealed that aloe-emodin has the lowest Egap value, indicating good antioxidant activity. Also in terms of electron affinity, softness, electrophilicity, and chemical potential, aloe-emodin is a potent structure with potential high radical scavenging activity. Calculation of the ionisation potential revealed that isoeleutherol likely also possesses a high degree of antiradical scavenging. To study the conjugating system of the radicals, density plots of HOMO, natural bond orbital analyses, and spin density plots were used. According to calculations, the isoeleutherol radical is more delocalised and the most stable radical. Calculated proton affinity values revealed that the most probable antioxidant mechanism is sequential proton loss-electron transfer. Our results were compared with available experimental data. Published experimental data were found to correlate well with our theoretical predictions. These results support the usefulness of theoretical calculations not only for identifying potentially useful structures of studied compounds but also for predicting their relative activity.


Assuntos
Aloe/química , Antraquinonas/farmacologia , Antioxidantes/farmacologia , Benzopiranos/farmacologia , Antraquinonas/química , Antioxidantes/química , Benzopiranos/química , Oxirredução , Extratos Vegetais/química , Plantas Medicinais/química
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