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1.
Protein & Cell ; (12): 877-888, 2021.
Article in English | WPRIM | ID: wpr-922482

ABSTRACT

A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (M


Subject(s)
Antiviral Agents/therapeutic use , Binding Sites , COVID-19/virology , Coronavirus Papain-Like Proteases/metabolism , Crystallography, X-Ray , Drug Evaluation, Preclinical , Drug Repositioning , High-Throughput Screening Assays/methods , Humans , Imidazoles/therapeutic use , Inhibitory Concentration 50 , Molecular Dynamics Simulation , Mutagenesis, Site-Directed , Naphthoquinones/therapeutic use , Protease Inhibitors/therapeutic use , Protein Structure, Tertiary , Recombinant Proteins/isolation & purification , SARS-CoV-2/isolation & purification
2.
Article in Chinese | WPRIM | ID: wpr-828429

ABSTRACT

In this study, based on the transcriptome database of suspension cells of Arnebia euchroma, we explored two candidate cytochrome P450 enzyme genes that might relate to the shikonin biosynthesis downstream pathway when CYP76B74 sequence was referenced. We constructed interference-type hairy roots of candidate genes and cultured them. We measured the fresh weight, dry weight, total naphthoquinone content, shikonin and its derivatives content and expression levels of key enzyme genes involved in shikonin biosynthesis pathway. The effects of candidate genes on the growth and shikonin production of A. euchroma hairy roots were discussed, and the possible regulatory mechanisms that candidate genes affected shikonin synthesis were discussed. Through local Blast and phylogenetic analysis, two candidate CYP450 genes(CYP76B75 and CYP76B100) with high homology to CYP76B74 in A. euchroma were screened, and corresponding interference hairy roots were constructed. Compared with the control(RNAi-control), the fresh weight of CYP76B75 interfered hairy root(RNAi-CYP76B75) and CYP76B100 interfered hairy root(RNAi-CYP76B100) were significantly reduced, while dry weight were not affected, so the dry rate increased significantly. Except for β-acetoxyisovalerylalkannin, which is high in three groups of hairy roots, the contents of shikonin, deoxyshikonin, acetylshikonin, β,β'-dimethacrylicalkannin, β-hydroxyisovalerylshikonin,β-hydroxyisovalerylshikonin, isobutyrylshikonin and total naphthoquinones showed a consistent pattern: RNAi-CYP76B75>RNAi-CYP76B100>RNAi-control. Among them, the synthesis of β-hydroxyisovalerylshikonin was most significantly promoted by interfering with the expression of CYP76B75. The content of β-hydroxyisovalerylshikonin in RNAi-CYP76B75 was 11.7 times that of RNAi-control. RESULTS:: of real-time qPCR analysis showed that compared to RNAi-control, the expression levels of AePGT gene in RNAi-CYP76B75 and RNAi-CYP76B100 were not changed significantly, and the expression levels of CYP76B74 and AeHMGR were up-regulated. In addition, the expression level of CYP76B100 in RNAi-CYP76B75 was down-regulated, whereas in RNAi-CYP76B100, the expression of CYP76B75 was significantly up-regulated. Therefore, this study confirmed that when the expression of CYP76B75 and CYP76B100 were interrupted, the growth of hairy roots were suppressed, but the synthesis of shikonin were promoted. They might increase the shikonin biosynthesis by up-regulating the expression of CYP76B74 in the hairy roots of A. euchroma.


Subject(s)
Boraginaceae , Genetics , Cytochrome P-450 Enzyme System , Naphthoquinones , Phylogeny , Plant Roots , RNA , RNA Interference
3.
Article in Chinese | WPRIM | ID: wpr-879350

ABSTRACT

OBJECTIVE@#To observe the clinical effect of platelet rich plasma (PRP) combined with β tricalcium phosphate bioceramic bone in the treatment of non traumatic necrosis of the femoral head in ARCO stageⅡ.@*METHODS@#From January 2017 to December 2018, 100 patients (160 hips) with ARCO stageⅡnon traumatic necrosis of the femoral head were divided into PRP group and control group. In PRP group, 50 patients (80 hips), 22 males and 28 females, aged from 18 to 65 (43.47± 7.23) years, with a course of 4 to 18 (15.8±2.9) months, underwent core decompression and bone grafting combined with PRP implantation. There were 50 cases (80 hips) in the control group, including 27 males and 23 females, aged 20 to 63 (45.72± 7.43) years, and the course of disease was 6 to 19 (14.9±3.8) months. Hip X-ay film was followed up after operation. Harris score and VAS score were used to evaluate the curative effect, and the survival rate of hip joint was recorded.@*RESULTS@#All patients had good wound healing, no infection, thrombosis and other complications. All patients were followed up for 12 to 14 (12.0±0.4) months. Twelve months after operation, the image expression of PRP group was better than that of control group(@*CONCLUSION@#Platelet-rich plasma(PRP) combined with artificialbone for core decompression and bone grafting can change the situation of simple artificial bone implantation and uncertain curative effect, improve the success rate of this operation, effectively reduce the collapse rate of femoral head necrosis in the early and middle stage, delay or even avoid hip replacement.


Subject(s)
Adolescent , Adult , Aged , Artemisinins , Bone Transplantation , Decompression, Surgical , Female , Femur Head/surgery , Femur Head Necrosis/surgery , Humans , Male , Middle Aged , Naphthoquinones , Platelet-Rich Plasma , Treatment Outcome , Young Adult
4.
Mem. Inst. Oswaldo Cruz ; 115: e190389, 2020. tab, graf
Article in English | LILACS | ID: biblio-1091236

ABSTRACT

BACKGROUND Chagas disease, which is caused by the protozoan Trypanosoma cruzi, is endemic to Latin America and mainly affects low-income populations. Chemotherapy is based on two nitrocompounds, but their reduced efficacy encourages the continuous search for alternative drugs. Our group has characterised the trypanocidal effect of naphthoquinones and their derivatives, with naphthoimidazoles derived from β-lapachone (N1, N2 and N3) being the most active in vitro. OBJECTIVES In the present work, the effects of N1, N2 and N3 on acutely infected mice were investigated. METHODS in vivo activity of the compounds was assessed by parasitological, biochemical, histopathological, immunophenotypical, electrocardiographic (ECG) and behavioral analyses. FINDINGS Naphthoimidazoles led to a decrease in parasitaemia (8 dpi) by reducing the number of bloodstream trypomastigotes by 25-50% but not by reducing mortality. N1 protected mice from heart injury (15 dpi) by decreasing inflammation. Bradycardia was also partially reversed after treatment with N1 and N2. Furthermore, the three compounds did not reverse hepatic and renal lesions or promote the improvement of other evaluated parameters. MAIN CONCLUSION N1 showed moderate trypanocidal and promising immunomodulatory activities, and its use in combination with benznidazole and/or anti-arrhythmic drugs as well as the efficacy of its alternative formulations must be investigated in the near future.


Subject(s)
Animals , Male , Mice , Trypanocidal Agents/therapeutic use , Naphthoquinones/therapeutic use , Chagas Disease/drug therapy , Nitroimidazoles/therapeutic use , Time Factors , Trypanocidal Agents/chemistry , Acute Disease , Naphthoquinones/chemistry , Parasitemia/drug therapy , Disease Models, Animal , Electrocardiography , Anti-Inflammatory Agents , Nitroimidazoles/chemistry
5.
Pesqui. vet. bras ; 38(12): 2224-2232, dez. 2018. tab, ilus
Article in English | LILACS, VETINDEX | ID: biblio-976429

ABSTRACT

Osteosarcoma is a malignant tumor of primitive bone cells with a high incidence in dogs and humans. The need for more effective drugs with less adverse consequences has pushed the development of chemotherapeutic agents from plants and other natural sources. The aim of this study was to verify the cytotoxic effects of beta-lapachone, a compound present in the sawdust of Tabebuia sp. (popularly known as ipê) wood, on canine osteosarcoma cells subcultured and treated in different concentrations (0.1µm, 0.3µm e 1.0µm) and exposure times (24h, 48h e 72h). Results were obtained through Trypan blue dye exclusion, tetrazolium reducing method, cell survival assay, Annexin V-FITC and Propidium Iodine labeling, JC-1 dye labeling and cell cycle kinetics e analysis. The group treated with 0.3µm beta-lapachone presented higher decrease in cell viability (80.27%, 24h, 47.41%, 48h and 35.19%, 72h) and greater progression of cytotoxicity (19.73%, 24h, 52.59%, 48h and 64.81%, 72h). The lower IC50 (0.180µm) was verified in the group treated for 72 hours. Cell growth after treatment decreased as concentration and time of exposure increased, with 0.50% survival fraction at the concentration of 1.0µm. Initial apoptosis was the most frequent type of cell death in all groups, reaching bottom in the 24-hour group treated with 0.1µm (4.26%) and peaking in the 72-hour group treated with 1.0µm (85.89%). Mitochondrial depolarization demonstrated a dose-dependent phenomenon, indicating the intrinsic apoptosis. Cell growth inhibition by blocking cell cycle in the G0/G1 phase related to the exposure the time. β-lapachone is cytotoxic for canine osteosarcoma cells, induces apoptosis and promotes cell cycle arrest in G0/G1 phase.(AU)


O osteossarcoma é o tumor maligno das células ósseas primitivas, com alta incidência em cães e humanos. A necessidade de medicamentos mais efetivos, com menor consequência adversa, tem gerado esforços para o desenvolvimento de agentes quimioterápicos compostos por plantas e outras fontes naturais. O objetivo deste estudo foi verificar os efeitos citotóxicos da beta lapachona, um composto presente na serragem da madeira do ipê, sobre células de osteossarcoma canino subcultivadas e submetidas ao tratamento, de acordo com as diferentes concentrações (0.1µm, 0.3µm e 1.0µm) e tempo de exposição (24h, 48h e 72h). Os resultados foram obtidos por meio dos métodos de exclusão do corante azul de Tripan e de redução do tetrazólio, além dos ensaios de sobrevivência celular, de dupla marcação com Anexina V-FITC e Iodeto de Propídio, de marcação com o corante JC-1 e pela análise da cinética do ciclo celular. O grupo tratado com 0.3µm de beta lapachona apresentou melhor regressão da viabilidade celular (80,27%, 24h; 47,41%, 48h e 35,19%, 72h) e maior progressão da citotoxicidade (19,73%, 24h; 52,59%, 48h e 64,81%, 72h). O menor IC50 (0.180µm) ocorreu no grupo tratado por 72 horas. O crescimento celular após o tratamento foi menor, de acordo com o aumento da concentração e tempo de exposição, apresentando 0,50% de fração de sobrevivência na concentração de 1.0µm. A apoptose inicial foi o tipo de morte celular mais frequente em todos os grupos, menor no grupo de 24 horas tratado com 0.1µm (4,26%) e maior no grupo de 72 horas tratado com 1.0µm (85,89%). A despolarização mitocondrial ocorreu de maneira dose dependente, indicando a ocorrência de apoptose intrínseca. A β lapachona possui efeitos citotóxicos em células de osteossarcoma canino, induz apoptose e promove o bloqueio do ciclo celular na fase G0/G1.(AU)


Subject(s)
Animals , Dogs , Osteosarcoma/veterinary , Naphthoquinones , Apoptosis , Tabebuia/chemistry
6.
Int. j. morphol ; 36(3): 1016-1021, Sept. 2018. tab, graf
Article in English | LILACS | ID: biblio-954224

ABSTRACT

To determine the effects of 70 % ethanolic extract of Eleutherine bulbosa (Mill.) L. bulbs contained naphtoquinone in blood pressure and lipids profile level of ovariectomized rats. Thin layer chromatography was performed to analyze the content of the Eleutherine bulbosa (Mill.) bulbs extracts using Chloroform : Methanol (7:1) as eluent. This study used white female Sprague-Dawley rats which were divided into 6 groups: SHAM and OVX, both given 0.5 % carboxymethyl cellulose; the positive control group that was given tamoxifen (0.36 mg/200 g B.W.); the three various of doses of extract namely dose 1, 2, and 3 that were given 8, 12, and 18 mg/200 g BW respectively on day 29 until 50. All groups were ovariectomized on day 1, except sham group. Measurement of blood pressure were performed on the day before ovariectomy using non-invasive tool CODA®; and on the second, third, and fourth weeks post-ovariectomy. Three weeks after treatment of hypoestrogen rats by the dose 18 mg/200 g B.W, Eleutherine bulbosa extracts could decrease the systolic blood pressure level to 28.06 %, the diastolic to 30.47 %. Lipid profile of Dose 3 also showed recovery of Triglyceride, LDL and also Total Cholesterol. Eleutherine bulbosa extracts could improve blood pressure of ovariectomized rats by controlling lipids profile level.


Para determinar los efectos del 70 % de extracto etanólico de Eleutherine bulbosa (Mill.) L. en bulbos que contenían naftoquinona, se analizó la presión arterial de ratas ovariectomizadas. Se realizó un estudio de cromatografía de capa fina para analizar el contenido de los extractos de bulbos de Eleutherine bulbosa (Mill.) usando cloroformo:metanol (7:1) como diluyente. En este estudio se utilizaron ratas blancas Sprague-Dawley hembras, que se dividieron en 6 grupos: SHAM y OVX, ambos grupos fueron administrados con carboximetilcelulosa al 0,5 %; grupo control positivo, recibió tamoxifeno (0,36 mg / 200 g de B.W.); y tres grupos restantes, que recibieron tres dosis diferentes de extracto, es decir, dosis 1, 2 y 3 a las que se les administró 8, 12 y 18 mg / 200 g de por peso, respectivamente el día 29 hasta el día 50. Todos los grupos fueron sometidos a ovariectomía en el día 1, excepto el grupo simulado. La medición de la presión arterial se realizó el día anterior a la ovariectomía con la herramienta no invasiva CODA®, y, posteriormente, en la segunda, tercera y cuarta semanas de realizada la ovariectomía. Tres semanas después del tratamiento aplicado a las ratas hipoestrógenas, con la dosis de 18 mg / 200 g por peso, los extractos de Eleutherine bulbosa podrían disminuir el nivel de presión arterial sistólica al 28,06 %, y la diastólica al 30,47 %. La dosis 3 del perfil lipídico mostró mejoría en los niveles de Triglicéridos, LDL y Colesterol Total. Los extractos de Eleutherine bulbosa podrían mejorar la presión sanguínea de ratas ovariectomizadas controlando el nivel del perfil lipídico.


Subject(s)
Animals , Female , Rats , Blood Pressure/drug effects , Plant Extracts/pharmacology , Naphthoquinones/pharmacology , Iridaceae/chemistry , Plant Extracts/chemistry , Ovariectomy , Chromatography, Thin Layer , Naphthoquinones/analysis , Rats, Sprague-Dawley , Estrogens/deficiency , Lipids/analysis
7.
Article in Chinese | WPRIM | ID: wpr-775320

ABSTRACT

Fourteen compounds, including rubiprasin D (1), rubiprasin B (2), rubiprasin C (3), oleanolic acid (4), methyl-5-hydroxy-dinaphtho[1, 2-2'3']furan-7, 12-dione-6-carboxylate (5), rubioncolin C (6), mollugin (7), furomollugin (8), 3-amino-2-methoxycarbonyl-1, 4-naphthoquinone (9), 1-hydroxy-2-methyl-9, 10-anthraquinone (10), 2-hydroxy-6-methyl-9, 10-anthraquinone (11), 1, 4-dihydroxy-2-hydroxymethyl-9, 10-anthraquinone (12), 2-hydroxy-1-methoxy-9, 10-anthraquinone (13), and 1-hydroxy-2-methoxy-6-methyl-9, 10-anthraquinone(14), were isolated from the methanol extract of the roots and rhizomes of Rubia oncotricha using various column chromatographies. Their structures were mainly determined on basis of NMR and MS spectroscopic data analyses. Among them, 1 is a new oleanane triterpene, and compounds 2-5, 9 and 11-13 were obtained from this plant for the first time. Cytotoxic and nematicidal activities of all these compounds were evaluated, and the results showed that only 4, 6, 11 and 12 exhibited cytotoxicities against A549, SGC-7901 and HeLa cancer cell lines. The IC₅₀ of 6 were 19.42, 2.74, 8.07 μmol·L⁻¹, respectively.


Subject(s)
Molecular Structure , Naphthoquinones , Plant Extracts , Plant Roots , Rhizome , Rubia
8.
Article in English | WPRIM | ID: wpr-773587

ABSTRACT

The present study was designed to identify and characterize the major constituents in Juglans mandshurica Maxim. A simple, efficient and sensitive ultra performance liquid chromatography coupled with time-of-flight mass spectrometry (UPLC-ESI-Q-TOF/MS) method was established and validated under positive and negative ion modes. The separation was performed on a Waters ACQUITY UPLC BEH C column (2.1 mm × 100 mm, 1.7 μm) by gradient elution with a mobile phase (Phase A: 0.1% aqueous formic acid solution, Phase B: 0.1% formic acid acetonitrile solution). A total of 165 compounds were rapidly selected by Targeted and Non-Targeted Peak Finding approaches, and then tentatively identifled by comparing with reference substances or inferred through mass spectrometry fragment ion analysis and literature data. These compounds included 68 naphthalenequinones, 20 diarylheptanoids, 29 flavonoids, 20 triterpenes, and 28 phenolic acids. In conclusion, the present study provided an effective approach to identifying components in complex matrices of herbal medicines such as Juglans mandshurica Maxim.


Subject(s)
Chromatography, High Pressure Liquid , Databases, Factual , Diarylheptanoids , Chemistry , Drugs, Chinese Herbal , Chemistry , Flavonoids , Chemistry , Fruit , Chemistry , Hydroxybenzoates , Chemistry , Juglans , Chemistry , Molecular Structure , Naphthoquinones , Chemistry , Reproducibility of Results , Tandem Mass Spectrometry , Triterpenes , Chemistry
9.
Article in English | WPRIM | ID: wpr-812376

ABSTRACT

The present study was designed to identify and characterize the major constituents in Juglans mandshurica Maxim. A simple, efficient and sensitive ultra performance liquid chromatography coupled with time-of-flight mass spectrometry (UPLC-ESI-Q-TOF/MS) method was established and validated under positive and negative ion modes. The separation was performed on a Waters ACQUITY UPLC BEH C column (2.1 mm × 100 mm, 1.7 μm) by gradient elution with a mobile phase (Phase A: 0.1% aqueous formic acid solution, Phase B: 0.1% formic acid acetonitrile solution). A total of 165 compounds were rapidly selected by Targeted and Non-Targeted Peak Finding approaches, and then tentatively identifled by comparing with reference substances or inferred through mass spectrometry fragment ion analysis and literature data. These compounds included 68 naphthalenequinones, 20 diarylheptanoids, 29 flavonoids, 20 triterpenes, and 28 phenolic acids. In conclusion, the present study provided an effective approach to identifying components in complex matrices of herbal medicines such as Juglans mandshurica Maxim.


Subject(s)
Chromatography, High Pressure Liquid , Databases, Factual , Diarylheptanoids , Chemistry , Drugs, Chinese Herbal , Chemistry , Flavonoids , Chemistry , Fruit , Chemistry , Hydroxybenzoates , Chemistry , Juglans , Chemistry , Molecular Structure , Naphthoquinones , Chemistry , Reproducibility of Results , Tandem Mass Spectrometry , Triterpenes , Chemistry
10.
Mem. Inst. Oswaldo Cruz ; 112(4): 299-308, Apr. 2017. tab, graf
Article in English | LILACS | ID: biblio-841780

ABSTRACT

BACKGROUND Malaria persists as a major public health problem. Atovaquone is a drug that inhibits the respiratory chain of Plasmodium falciparum, but with serious limitations like known resistance, low bioavailability and high plasma protein binding. OBJECTIVES The aim of this work was to perform molecular modelling studies of 2-hydroxy-1,4-naphthoquinones analogues of atovaquone on the Qo site of P. falciparum cytochrome bc1 complex (Pfbc1) to suggest structural modifications that could improve their antimalarial activity. METHODS We have built the homology model of the cytochrome b (CYB) and Rieske iron-sulfur protein (ISP) subunits from Pfbc1 and performed the molecular docking of 41 2-hydroxy-1,4-naphthoquinones with known in vitro antimalarial activity and predicted to act on this target. FINDINGS Results suggest that large hydrophobic R2 substituents may be important for filling the deep hydrophobic Qo site pocket. Moreover, our analysis indicates that the H-donor 2-hydroxyl group may not be crucial for efficient binding and inhibition of Pfbc1 by these atovaquone analogues. The C1 carbonyl group (H-acceptor) is more frequently involved in the important hydrogen bonding interaction with His152 of the Rieske ISP subunit. MAIN CONCLUSIONS Additional interactions involving residues such as Ile258 and residues required for efficient catalysis (e.g., Glu261) could be explored in drug design to avoid development of drug resistance by the parasite.


Subject(s)
Plasmodium falciparum/drug effects , Electron Transport Complex III/chemistry , Antimalarials/pharmacology , Antimalarials/chemistry , Naphthoquinones/chemistry , Sequence Analysis, Protein
11.
Article in English | WPRIM | ID: wpr-812047

ABSTRACT

Two new dimeric naphthoquinones, 5',8'-dihydroxy-6,6'-dimethyl-7,3'-binaphthyl-1,4,1',4'-tetraone (1; Di-naphthodiospyrol D) and 5',8'-dihydroxy-5,8-dimethoxy-6,6'-dimethyl-7,3'-binaphthyl-1,4,1',4'-tetraone (2; Di-naphthodiospyrol E), along with known naphthoquinones diospyrin (3) and 8-hydroxy diospyrin (4) were isolated from the chloroform fraction of extract of Diospyros lotus roots. Their structures were elucidated by advanced spectroscopic analyses, including HSQC, HMBC, NOESY, and J-resolved NMR experiments. The fractions and compounds 1-4 were evaluated for urease activity and phosphodiesterase-I, carbonic anhydrase-II and α-chymotrypsin enzyme inhibitory activities. Compounds 1 and 2 and their corresponding fractions showed significant and selective inhibitory effects on urease activities. The IC values of 1 and 2 were 260.4 ± 6.37 and 381.4 ± 4.80 µmol·L, respectively, using thiourea (IC = 21 ± 0.11 µmol·L) as the standard inhibitor. This was the first report demonstrating that the naphthoquinones class showed urease inhibition.


Subject(s)
Biological Assay , Diospyros , Chemistry , Enzyme Inhibitors , Chemistry , Pharmacology , Molecular Structure , Naphthoquinones , Chemistry , Pharmacology , Plant Extracts , Chemistry , Pharmacology , Plant Roots , Urease
12.
Braz. j. med. biol. res ; 50(10): e6586, 2017. tab, graf
Article in English | LILACS | ID: biblio-888930

ABSTRACT

Human enterovirus 71 (EV71) is the major causative agent of hand, foot, and mouth disease (HFMD), particularly in infants and children below 4 years of age. Shikonin is a bioactive compound with anti-inflammatory, antiviral, and antibacterial activities derived from the roots of the Chinese medicinal herb Lithospermum erythrorhizon. This study aimed to examine the antiviral activity of PMM-034, a shikonin ester derivative, against EV71 in rhabdomyosarcoma (RD) cells. Cytotoxicity of PMM-034 on RD cells was determined using WST-1 assay. Dose- and time-dependent effects of PMM-034 on EV71 replication in RD cells were determined using plaque reduction assay. mRNA expression levels of EV71/VP1 and pro-inflammatory cytokines (IL-1β, IL-6, IL-8, and TNF-α) were determined by real-time RT-PCR, and EV71/VP1 and phospho-p65 protein expressions were determined by western blot analysis. PMM-034 exhibited only weak cytotoxicity against RD cells. However, PMM-034 exhibited significant antiviral activity against EV71 in RD cells with 50% inhibitory concentration of 2.31 μg/mL. The VP1 mRNA and protein levels were significantly reduced in cells treated with PMM-034. Furthermore, relative mRNA expression levels of IL-1β, IL-6, IL-8, and TNF-α significantly decreased in the cells treated with PMM-034, while the phospho-p65 protein expression was also significantly lower in the treated cells. These results indicated that PMM-034 suppressed the expressions of pro-inflammatory cytokines in RD cells, exhibiting antiviral activity against EV71, as evidenced by the reduced VP1 mRNA and protein levels in PMM-034-treated cells. Thus, PMM-034 is a promising candidate for further development as an EV71 inhibitor.


Subject(s)
Humans , Antiviral Agents/pharmacology , Enterovirus A, Human/drug effects , Naphthoquinones/pharmacology , Rhabdomyosarcoma/virology , Blotting, Western , Cell Line, Tumor , Cytokines/analysis , Dose-Response Relationship, Drug , Real-Time Polymerase Chain Reaction , Toxicity Tests , Viral Plaque Assay , Virus Replication/drug effects
13.
Braz. j. microbiol ; 47(4): 917-924, Oct.-Dec. 2016. tab, graf
Article in English | LILACS | ID: biblio-828189

ABSTRACT

Abstract This study aimed to evaluate the in vitro antifungal activity of terpinen-4-ol, tyrosol, and β-lapachone against strains of Coccidioides posadasii in filamentous phase (n = 22) and Histoplasma capsulatum in both filamentous (n = 40) and yeast phases (n = 13), using the broth dilution methods as described by the Clinical and Laboratory Standards Institute, to determine the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of these compounds. The mechanisms of action of these compounds were also investigated by analyzing their effect on cell membrane permeability and ergosterol synthesis. The MIC and MFCf these compounds against C. posadasii, mycelial H. capsulatum, and yeast-like H. capsulatum, were in the following ranges: 350-5720 µg/mL, 20-2860 µg/mL, and 40-1420 µg/mL, respectively for terpinen-4-ol; 250-4000 µg/mL, 30-2000 µg/mL, and 10-1000 µg/mL, respectively, for tyrosol; and 0.48-7.8 µg/mL, 0.25-16 µg/mL, and 0.125-4 µg/mL, respectively for β-lapachone. These compounds showed a decrease in MIC when the samples were subjected to osmotic stress, suggesting that the compounds acted on the fungal membrane. All the compounds were able to reduce the ergosterol content of the fungal strains. Finally, tyrosol was able to cause a leakage of intracellular molecules.


Subject(s)
Phenylethyl Alcohol/analogs & derivatives , Terpenes/pharmacology , Naphthoquinones/pharmacology , Fungi/drug effects , Antifungal Agents/pharmacology , Osmotic Pressure , Phenylethyl Alcohol/pharmacology , Microbial Sensitivity Tests , Cell Membrane Permeability/drug effects , Ergosterol/metabolism , Fungi/classification , Fungi/metabolism
14.
Article in English | WPRIM | ID: wpr-812589

ABSTRACT

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first rate-limiting step in converting nicotinamide to NAD(+), essential for a number of enzymes and regulatory proteins involved in a variety of cellular processes, including deacetylation enzyme SIRT1 which modulates several tumor suppressors such as p53 and FOXO. Herein we report that NQO1 substrates Tanshione IIA (TSA) and β-lapachone (β-lap) induced a rapid depletion of NAD(+) pool but adaptively a significant upregulation of NAMPT. NAMPT inhibition by FK866 at a nontoxic dose significantly enhanced NQO1-targeting agent-induced apoptotic cell death. Compared with TSA or β-lap treatment alone, co-treatment with FK866 induced a more dramatic depletion of NAD(+), repression of SIRT1 activity, and thereby the increased accumulation of acetylated FOXO1 and the activation of apoptotic pathway. In conclusion, the results from the present study support that NAMPT inhibition can synergize with NQO1 activation to induce apoptotic cell death, thereby providing a new rationale for the development of combinative therapeutic drugs in combating non-small lung cancer.


Subject(s)
Abietanes , Pharmacology , Apoptosis , Carcinoma, Non-Small-Cell Lung , Drug Therapy , Genetics , Cell Line, Tumor , Cytokines , Genetics , Metabolism , Enzyme Inhibitors , Pharmacology , Humans , NAD , Metabolism , NAD(P)H Dehydrogenase (Quinone) , Genetics , Metabolism , Naphthoquinones , Pharmacology , Nicotinamide Phosphoribosyltransferase , Genetics , Metabolism
15.
Rev. Inst. Med. Trop. Säo Paulo ; 57(3): 197-204, May-Jun/2015. tab
Article in English | LILACS | ID: lil-752593

ABSTRACT

Anthelmintics used for intestinal helminthiasis treatment are generally effective; however, their effectiveness in tissue parasitosis (i.e. visceral toxocariasis) is moderate. The aim of this study was to evaluate the in vitro activity of lapachol, β-lapachone and phenazines in relation to the viability of Toxocara canis larvae. A concentration of 2 mg/mL (in duplicate) of the compounds was tested using microculture plates containing Toxocara canis larvae in an RPMI-1640 environment, incubated at 37 °C in 5% CO2 tension for 48 hours. In the 2 mg/mL concentration, four phenazines, lapachol and three of its derivatives presented a larvicide/larvistatic activity of 100%. Then, the minimum larvicide/larvistatic concentration (MLC) test was conducted. The compounds that presented the best results were nor-lapachol (MLC, 1 mg/mL), lapachol (MLC 0.5 mg/mL), β-lapachone, and β-C-allyl-lawsone (MLC, 0.25 mg/mL). The larvae exposed to the compounds, at best MLC with 100% in vitro activity larvicide, were inoculated into healthy BALB/c mice and were not capable of causing infection, confirming the larvicide potential in vitro of these compounds.


Os anti-helmínticos empregados no tratamento das helmintoses intestinais, de modo geral, são eficazes, porém nas parasitoses teciduais, como é o caso da toxocaríase visceral, a eficácia é moderada. Este estudo teve como objetivo avaliar in vitro a atividade do lapachol, β-lapachona e fenazinas derivadas da β-lapachona sobre a viabilidade de larvas de Toxocara canis. Os compostos foram testados na concentração de 2 mg/mL (em duplicata) em placas de microcultivo, contendo larvas de T. canis em meio RPMI-1640, sendo incubados, a 37 °C, em tensão de CO2 de 5%, por 48 horas. Na concentração de 2 mg/mL, quatro fenazinas, o lapachol e três derivados, apresentaram atividade larvicida/larvostática de 100%. A seguir, foi realizado o teste de concentração larvicida/larvostártica mínima (CLM). Os compostos que apresentaram os melhores resultados foram o nor-lapachol (CLM, 1 mg/mL), lapachol (CLM, 0,5 mg/mL), a β-lapachona e a β-C-alil-lausona (CLM, 0,25 mg/mL). As larvas expostas aos compostos, na melhor CLM 100% in vitro foram inoculadas em camundongos BALB/c saudáveis não sendo capazes de causar infecção, confirmando o potencial larvicida in vitro desses compostos.


Subject(s)
Animals , Female , Mice , Anthelmintics/pharmacology , Naphthoquinones/pharmacology , Toxocara canis/drug effects , Larva/drug effects , Larva/growth & development , Mice, Inbred BALB C , Parasitic Sensitivity Tests
16.
Article in English | WPRIM | ID: wpr-250383

ABSTRACT

This study aimed to evaluate the effects of Pin1 inhibitor Juglone on proliferation, migration and the angiogenic ability of breast cancer cell line MCF7Adr. MCF7Adr cells were cultured and separately treated with Pin1 inhibitor Juglone (treatment group) and DMEM without drug (control group). The cell cycle was examined by flow cytometry. Cell migration was measured by wound-healing assay. Cyclin E protein content was detected by Western blotting. The angiogenesis factor vascular endothelial growth factor (VEGF) in cell media was determined by enzyme linked immunosorbent assay. The results showed that the percentage of cells in G2/M phase in treatment group was significantly higher than that in control group (25.5% vs. 10.1%, P<0.05), and that in G0/G1 phase and S stage in treatment group was significantly lower than that in control group (40.5% vs. 48.2%, and 33.7% vs. 41.7%, P<0.05). Cyclin E protein content in treatment group was significantly lower than that in control group (39.2 ± 7.4 vs. 100 ± 23.1, P<0.05). (A0-A24)/A0 value in treatment group was significantly lower than that in control group (23.9 ± 3.8 vs. 100 ± 14.4, P<0.05). VEGF-A, -B, and -C contents in cell media of treatment group were significantly lower than those in control group (P<0.05). It was suggested that Pin1 inhibitor Juglone can effectively inhibit the proliferation, migration and the angiogenic ability of MCF7Adr cells, and can be used as an alternative drug therapy for breast cancer.


Subject(s)
Antineoplastic Agents , Pharmacology , Breast Neoplasms , Drug Therapy , Metabolism , Cell Cycle , Cell Movement , Cell Proliferation , Cyclin E , Metabolism , Female , Gene Expression Regulation, Neoplastic , Humans , MCF-7 Cells , NIMA-Interacting Peptidylprolyl Isomerase , Naphthoquinones , Pharmacology , Peptidylprolyl Isomerase , Vascular Endothelial Growth Factor A , Metabolism
17.
Article in English | WPRIM | ID: wpr-258874

ABSTRACT

Recently, a wide range of food-derived phytochemical compounds and their synthetic derivatives have been proposed for cancer treatment. Unfortunately, data available in related literature focus on the anti-cancer properties of compounds derived from edible plants, while very little is known about those derived from non-edible plants. And thus, the underlying mechanisms of their anti-cancer effects are yet to be elucidated. This review collates the available data on the anti-cancer activities of six phytochemical-derived compounds from edible and non-edible plants, i.e. rottlerin, berbamine, sparstolonin B, sulforaphane, plumbagin and 6-shogaol. These compounds are used as bioactive markers for cytotoxicity against tumors. As such, understanding their mode of action will provide the rationale for the combination strategies of these compounds with other drugs in the battle against cancer.


Subject(s)
Acetophenones , Pharmacology , Therapeutic Uses , Antineoplastic Agents, Phytogenic , Pharmacology , Therapeutic Uses , Benzopyrans , Pharmacology , Therapeutic Uses , Benzylisoquinolines , Pharmacology , Therapeutic Uses , Catechols , Pharmacology , Therapeutic Uses , Heterocyclic Compounds, 4 or More Rings , Pharmacology , Therapeutic Uses , Humans , Isothiocyanates , Pharmacology , Therapeutic Uses , Naphthoquinones , Pharmacology , Therapeutic Uses , Neoplasms , Drug Therapy , Phytotherapy , Plant Extracts , Pharmacology , Therapeutic Uses , Signal Transduction
18.
Article in Chinese | WPRIM | ID: wpr-279219

ABSTRACT

A method for simultaneous determination of the shikonin, acetyl shikonin and β, β'-dimethylpropene shikonin in Onosma hookeri and the chromatographic fingerprint was estabished by HPLC-DAD on an Agilent Zorbax SB-column with a gradient elution of acetonitrile and water at 0.8 mL x min(-1), 30 degrees C. The quality assessment was conducted by comparing the content difference of three naphthoquinone constituents, in combination with chromatographic fingerprint analysis and systems cluster analysis among 7 batches of radix O. hookeri. The content of the three naphthoquinone constituents showed wide variations in 7 bathces. The similarity value of the fingerprints of sample 5, 6 and 7 was above 0.99, sample 2 and 3 above 0.97, sample 3 and 4 above 0.90, and other samples larger than 0.8, which was in concert with the content of three naphthoquinone constituents. The 7 samples were roughly divided into 4 categories. The results above indicated that the using of this medicine is complex and rather spotty. The established HPLC fingerprints and the quantitative analysis method can be used efficiently for quality assessment of O. hookeri.


Subject(s)
Boraginaceae , Chemistry , Chromatography, High Pressure Liquid , Methods , Drugs, Chinese Herbal , Naphthoquinones , Plant Roots , Chemistry
19.
Article in Chinese | WPRIM | ID: wpr-259582

ABSTRACT

<p><b>OBJECTIVE</b>This study was purposed to investigate the effect of YM155, a survivin inhibitor, on the apoptosis and autophagy of K562 cells.</p><p><b>METHODS</b>K562 cells were treated with YM155 at different concentration. Cell survival was analyzed by CCK-8 assay, the cell apoptosis was detected by flow cytometry. Survivin, BCL-2 and beclin1 mRNA expressions were determined by RT-PCR. Survivin, BCL-2, caspase-3, PARP and LC-3 protein expressions were assayed by Western blot.</p><p><b>RESULTS</b>YM155 inhibited the proliferation of K562 cells in a time- and dose-dependent manners. With the increasing of YM155 concentration and prolonging of action time, the expression levels of mRNA and protein of survivin and BCL-2 decreased, while the expression levels of caspase-3, PARP, beclin1 and LC-3 increased. Compared with the YM155 group, the protein levels of LC-3 and caspase-3 were lower in YM155 combined with 3-MA group.</p><p><b>CONCLUSION</b>YM155 can inhibit K562 cell proliferation by inducing apoptosis and autophagy, while autophagy induction effect can enhance its cytotoxic effect.</p>


Subject(s)
Apoptosis , Autophagy , Cell Proliferation , Flow Cytometry , Humans , Imidazoles , K562 Cells , Naphthoquinones
20.
Article in English | WPRIM | ID: wpr-264607

ABSTRACT

Radiation encephalopathy is the main complication of cranial radiotherapy. It can cause necrosis of brain tissue and cognitive dysfunction. Our previous work had proved that a natural antioxidant shikonin possessed protective effect on cerebral ischemic injury. Here we investigated the effects of shikonin on carbon ion beam induced radiation brain injury in mice. Pretreatment with shikonin significantly increased the SOD and CAT activities and the ratio of GSH/GSSG in mouse brain tissues compared with irradiated group (P<0.01), while obviously reduced the MDA and PCO contents and the ROS levels derived from of the brain mitochondria. The shikonin also noticeably improved the spatial memory deficits caused by carbon ion beam irradiation. All results demonstrated that shikonin could improve the irradiated brain injury which might resulted from its modulation effects on the oxidative stress induced by the 12C6+ ion beam.


Subject(s)
Animals , Antioxidants , Pharmacology , Brain Injuries , Catalase , Metabolism , Heavy Ion Radiotherapy , Male , Malondialdehyde , Metabolism , Mice , Naphthoquinones , Pharmacology , Protein Carbonylation , Radiation Injuries, Experimental , Radiation-Protective Agents , Pharmacology , Random Allocation , Specific Pathogen-Free Organisms , Superoxide Dismutase , Metabolism
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