RESUMO
BACKGROUND: Treatment of Pancreatic Cancer (PC) is challenging due to its aggressiveness and acquired resistance to conventional chemotherapy and radiotherapy. Therefore, the discovery of new therapeutic agents and strategies is essential. Juglone, a naphthoquinone, is a secondary metabolite produced naturally in walnut-type trees having allelopathic features in its native environment. Juglone was shown to prevent cell proliferation and induce ROS-mediated mitochondrial apoptosis. Ascorbate with both antioxidant and oxidant features, shows selective cytotoxicity in cancer cells. METHODS AND RESULTS: In this study, we evaluated the anticancer effects of Juglone in combination with ascorbate in PANC-1 and BxPC-3 PC cells. The MTT assay was used to determine the IC50 dose of Juglone with 1 mM NaAscorbate (Jug-NaAsc). Subsequently, the cells were treated with 5, 10, 15 and 20 µM Jug-NaAsc for 24 h. Apoptotic effects were evaluated by analyzing the following genes using qPCR; proapoptotic Bax, antiapoptotic Bcl-2 related to the mitochondrial apoptotic pathway and apoptosis inhibitor Birc5 (Survivin). Immunofluorescence analysis was performed using Annexin V-FITC in PC cells. As an antioxidant enzyme, Trx2 protein levels were determined by a commercial ELISA test kit. Jug-NaAsc treatment decreased the expressions of antiapoptotic genes Bcl-2 and Birc5 while the apoptotic gene Bax expression increased at all doses. Additionally, a dose-dependently increase of apoptosis according to immunofluorescence analysis and the decreases of Trx2 enzyme levels at all treatments in both cell lines supported gene expression results. CONCLUSION: Our results suggest that Juglone is a potential anticancer agent especially when combined with ascorbate.
Assuntos
Naftoquinonas , Neoplasias Pancreáticas , Humanos , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Proteína X Associada a bcl-2/metabolismo , Linhagem Celular Tumoral , Apoptose , Ácido Ascórbico/farmacologia , Naftoquinonas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genéticaRESUMO
Walnut trees are cultivated and exploited worldwide for commercial timber and nut production. They are heterografted plants, with the rootstock selected to grow in different soil types and conditions and to provide the best anchorage, vigor, and resistance or tolerance to soil borne pests and diseases. However, no individual rootstock is tolerant of all factors that impact walnut production. In Europe, Juglans regia is mainly used as a rootstock. Like most terrestrial plants, walnut trees form arbuscular mycorrhizal symbioses, improving water and nutrient uptake and providing additional ecosystem services. Effects of arbuscular mycorrhizal symbiosis on root gene regulation, however, has never been assessed. We analyzed the response of one rootstock of J. regia to colonization by the arbuscular mycorrhizal fungus Rhizophagus irregularis DAOM197198. Plant growth as well as the nitrogen and phosphorus concentrations in roots and shoots were significantly increased in mycorrhizal plants versus non-colonized plants. In addition, we have shown that 1,549 genes were differentially expressed, with 832 and 717 genes up- and down-regulated, respectively. The analysis also revealed that some rootstock genes involved in plant nutrition through the mycorrhizal pathway, are regulated similarly as in other mycorrhizal woody species: Vitis vinifera and Populus trichocarpa. In addition, an enrichment analysis performed on GO and KEGG pathways revealed some regulation specific to J. regia (i.e., the juglone pathway). This analysis reinforces the role of arbuscular mycorrhizal symbiosis on root gene regulation and on the need to finely study the effects of diverse arbuscular mycorrhizal fungi on root gene regulation, but also of the scion on the functioning of an arbuscular mycorrhizal fungus in heterografted plants such as walnut tree.
Assuntos
Juglans , Micorrizas , Raízes de Plantas , Simbiose , Transcriptoma , Juglans/microbiologia , Juglans/genética , Micorrizas/fisiologia , Raízes de Plantas/microbiologia , Regulação da Expressão Gênica de Plantas , Árvores/microbiologia , FungosRESUMO
The aim of our study was the detailed polyphenol profiling of Juglans nigra and the characterization of the membrane permeability and antiproliferative properties of its main phenolics. A total of 161 compounds were tentatively identified in J. nigra bark, leaf, and pericarp extracts by ultrahigh-performance liquid chromatography-high-resolution tandem mass spectrometry (UHPLC-HR-MS/MS). Eight compounds including myricetin-3-O-rhamnoside (86), quercetin-3-O-rhamnoside (106), quercetin-3-O-xyloside (74), juglone (141), 1,2,3,4-tetrahydro-7,8-dihydroxy-4-oxonaphthalen-1-yl-6-O-galloyl-glucoside (92), ellagic acid (143), gallic acid (14), and ethyl gallate (58) were isolated from J. nigra pericarp. The in vitro antiproliferative activity of the isolated compounds was investigated against three human cancer cell lines, confirming that juglone (141) inhibits cell proliferation in all of them, and has similar activity as the clinical standards. The permeability of the isolated compounds across biological membranes was evaluated by the parallel artificial membrane permeability assay (PAMPA). Both juglone (141) and ethyl-gallate (58) showed positive results in the blood-brain-barrier-specific PAMPA-BBB study. Juglone (141) also possesses logPe values which indicates that it may be able to cross both the GI and BBB membranes via passive diffusion.
Assuntos
Permeabilidade da Membrana Celular , Proliferação de Células , Juglans , Compostos Fitoquímicos , Polifenóis , Juglans/química , Humanos , Polifenóis/farmacologia , Polifenóis/química , Permeabilidade da Membrana Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/química , Linhagem Celular Tumoral , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas em Tandem/métodosRESUMO
Juglone, a quinonic compound present in walnut extracts, was proposed as a restoring agent for hair keratin treated with permanent or discoloration processes. The proposed mechanism of restoration by juglone involves the formation of a Michael adduct between the quinone and the thiol moieties of cysteine residues. To this purpose, the first part of the present paper involved the spectroscopic study of the product of the reaction between juglone and N-acetyl-L-cysteine as a model compound. IR spectroscopy and Scanning Electron Microscopy (SEM) monitored the chemical and morphological variations induced by applying juglone to hair keratin. In order to simulate the most common hair treatments (i.e., permanent and discoloration), juglone was applied to hair that had been previously treated with a reducing agent, i.e., methyl thioglycolate (MT) or with bleaching agents (based on hydrogen peroxide and persulfates) followed by sodium hydrogen sulfite. IR spectroscopy allowed us to monitor the formation of Michael adducts between juglone and cysteine residues: the Michael adducts' content was related to the cysteine content of the samples. In fact, MT and sodium hydrogen sulfite favored the reduction of the disulfide bonds and increased the content of free cysteine residues, which can react with juglone. SEM analyses confirmed the trend observed by IR spectroscopy since hair samples treated with juglone adopted a more regular hair surface and more imbricated scales, thus supporting the possible use of juglone as a restoring agent for damaged hair keratins.
Assuntos
Acetilcisteína , Queratinas Específicas do Cabelo , Naftoquinonas , Sulfitos , Microscopia Eletrônica de Varredura , CabeloRESUMO
BACKGROUND: Arbuscular mycorrhizal fungi (AMF) have a positive effect on drought tolerance of plants after establishing reciprocal resymbiosis with roots, while the underlying mechanism is not deciphered. Metabolomics can explain the mechanism of plant response to environmental stress by analyzing the changes of all small molecular weight metabolites. The purpose of this study was to use Ultra High Performance Liquid Chromatography Q Exactive Mass Spectrometer to analyze changes in root metabolites of walnut (Juglans regia) after inoculation with an arbuscular mycorrhizal fungus Diversispora spurca under well-watered (WW) and drought stress (DS). RESULTS: Sixty days of soil drought significantly inhibited root mycorrhizal colonization rate, shoot and root biomass production, and leaf water potential in walnut, while AMF inoculation significantly increased biomass production and leaf water potential, accompanied by a higher increase magnitude under DS versus under WW. A total of 3278 metabolites were identified. Under WW, AMF inoculation up-regulated 172 metabolites and down-regulated 61 metabolites, along with no changes in 1104 metabolites. However, under DS, AMF inoculation up-regulated 49 metabolites and down-regulated 116 metabolites, coupled with no changes in 1172 metabolites. Among them, juglone (a quinone found in walnuts) as the first ranked differential metabolite was up-regulated by AMF under WW but not under DS; 2,3,5-trihydroxy-5-7-dimethoxyflavanone as the first ranked differential metabolite was increased by AMF under DS but not under WW. The KEGG annotation showed a large number of metabolic pathways triggered by AMF, accompanied by different metabolic pathways under WW and DS. Among them, oxidative phosphorylation and phenylalanine metabolism and biosynthesis were triggered by AMF in response to WW and DS, where N-acetyl-L-phenylalanine was induced by AMF to increase under DS, while decreasing under WW. CONCLUSION: This study provides new insights into the metabolic mechanisms of mycorrhiza-enhanced drought tolerance in walnuts.
Assuntos
Juglans , Micorrizas , Secas , Metabolômica , Resistência à SecaRESUMO
IMPORTANCE: Nitrification, the microbial conversion of ammonia to nitrate via nitrite, plays a pivotal role in the global nitrogen cycle. However, the excessive use of ammonium-based fertilizers in agriculture has disrupted this cycle, leading to groundwater pollution and greenhouse gas emissions. In this study, we have demonstrated the inhibitory effects of plant-derived juglone and related 1,4-naphthoquinones on the nitrification process in Nitrosomonas europaea. Notably, the inhibition mechanism is elucidated in which 1,4-naphthoquinones interact with hydroxylamine oxidoreductase, disrupting the electron transfer to cytochrome c554, a physiological electron acceptor. These findings support the notion that phytochemicals can impede nitrification by interfering with the essential electron transfer process in ammonia oxidation. The findings presented in this article offer valuable insights for the development of strategies aimed at the management of nitrification, reduction of fertilizer utilization, and mitigation of greenhouse gas emissions.
Assuntos
Gases de Efeito Estufa , Naftoquinonas , Citocromos c/metabolismo , Amônia/metabolismo , Elétrons , Naftoquinonas/farmacologia , Fertilizantes , Oxirredução , Hidroxilamina/farmacologia , NitrificaçãoRESUMO
The treatments currently used for prostate cancer (PC) do not meet clinical needs, and thus, new therapies with greater effectiveness are urgently required. Metabolic reprogramming of tumor cells is emerging as an exciting field for cancer therapy. Although the Warburg effect is a common feature of glucose metabolism in many cancers, PC cells have a unique metabolic phenotype. Non-neoplastic prostate cells show reduced oxidative phosphorylation (OXPHOS) because large, accumulated zinc inhibits citrate oxidation. During transformation, there are low levels of zinc in PC cells, and the tricarboxylic acid (TCA) cycle is reactivated. However, metastatic PC exhibits the Warburg effect. Due to metabolic differences in prostate tissue, targeting metabolic alterations in PC cells is an attractive therapeutic strategy. In this study, we investigated the effect of juglone on energy metabolism in PC cells. We found that juglone inhibited cell proliferation and induced apoptosis. Mechanistically, we demonstrated that juglone suppressed OXPHOS and glycolysis due to its inhibition of hexokinase (HK), phosphofructokinase (PFK), and pyruvate kinase (PK) activity. Furthermore, downregulation of PFK and PK, but not HK contributed to the inhibition of these enzyme activities. The current study indicates that further development of juglone for PC treatment would be beneficial.
Assuntos
Fosforilação Oxidativa , Neoplasias da Próstata , Humanos , Masculino , Glicólise/fisiologia , Metabolismo Energético , Neoplasias da Próstata/tratamento farmacológico , Hexoquinase/metabolismo , Linhagem Celular TumoralRESUMO
Bioderived molecules have been identified as viable anodes for organic potassium-ion batteries (OPIBs) due to the abundance of the necessary natural resources, their high capacity, and their sustainability. However, the high solubility and the inherent nonconductivity cause serious capacity decay and large voltage hysteresis. Here, the biomass molecule juglone was cross-linked with a carbon nanotube network, coupling and cooperating with sodium alginate binder (J@CNT-SA), and was proposed to inhibit small molecule dissolution via weak intermolecular interactions. The synergistic effect of hydrogen bonding and π-π stacking is proven for its outstanding reversible high capacities (262 mA h g-1 at 0.05 A g-1), and a remarkable long life span with capacity retention of 77% over 5000 cycles. Further in situ Fourier transform infrared spectroscopy (FTIR) was performed to reveal the electrochemical mechanism. The feasibility of juglone as an anode for PIBs paves the way for other natural organic small molecules to be investigated as potential energy storage materials.
Assuntos
Potássio , EletrodosRESUMO
A serious problem currently facing the field of wound healing is bacterial infection, especially Staphylococcus aureus (S. aureus) infection. Although the application of antibiotics has achieved good effects, their irregular use has resulted in the emergence of drug-resistant strains. It is thus the purpose of this study to analyze whether the naturally extracted phenolic compound, juglone, can inhibit S. aureus in wound infection. The results show that the minimum inhibitory concentration (MIC) of juglone against S. aureus was 1000 µg/mL. Juglone inhibited the growth of S. aureus by inhibiting membrane integrity and causing protein leakage. At sub-inhibitory concentrations, juglone inhibited biofilm formation, the expression of α-hemolysin, the hemolytic activity, and the production of proteases and lipases of S. aureus. When applied to infected wounds in Kunming mice, juglone (50 µL juglone with a concentration of 1000 µg/mL) significantly inhibited the number of S. aureus and had a significant inhibitory effect on the expression of inflammatory mediators (TNF-α, IL-6 and IL-1ß). Moreover, the juglone-treated group promoted wound healing. At the same time, in animal toxicity experiments, juglone had no obvious toxic effects on the main tissues and organs of mice, indicating that juglone has good biocompatibility and has the potential to be used in the treatment of wounds infected with S. aureus.
Assuntos
Antibacterianos , Naftoquinonas , Infecções Estafilocócicas , Infecção dos Ferimentos , Animais , Camundongos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Infecção dos Ferimentos/tratamento farmacológico , Infecção dos Ferimentos/microbiologia , Naftoquinonas/farmacologia , Naftoquinonas/uso terapêuticoRESUMO
Glioblastoma (GBM) is the most common and aggressive primary brain tumor and one of the human malignancies with the highest mortality. Standard approaches for GBM, including gross total resection, radiotherapy, and chemotherapy, cannot destroy all the cancer cells, and despite advances in its treatment, the prognosis for GBM remains poor. The problem is that we still do not understand what triggers GBM. Until now, the most successful chemotherapy with temozolomide for brain gliomas is not effective, and therefore new therapeutic strategies for GBM are needed. We found that juglone (J), which exhibits cytotoxic, anti-proliferative, and anti-invasive effects on various cells, could be a promising agent for GBM therapy. In this paper, we present the effects of juglone alone and in combination with temozolomide on glioblastoma cells. In addition to the analysis of cell viability and the cell cycle, we looked at the epigenetics effects of these compounds on cancer cells. We showed that juglone induces strong oxidative stress, as identified by a high increase in the amount of 8-oxo-dG, and decreases m5C in the DNA of cancer cells. In combination with TMZ, juglone modulates the level of both marker compounds. Our results strongly suggest that a combination of juglone and temozolomide can be applied for better GBM treatment.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Linhagem Celular Tumoral , Epigênese Genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Antineoplásicos Alquilantes/farmacologiaRESUMO
Plant diseases and insect pests seriously affect the yield and quality of crops and are difficult to control. Natural products are an important source for the discovery of new pesticides. In this work, naphthoquinones plumbagin and juglone were selected as parent structures, and a series of their derivatives were designed, synthesized and evaluated for their fungicidal activities, antiviral activities and insecticidal activities. We found that the naphthoquinones have broad-spectrum anti-fungal activities against 14 types of fungus for the first time. Some of the naphthoquinones showed higher fungicidal activities than pyrimethanil. Compounds I, I-1e and II-1a emerged as new anti-fungal lead compounds with excellent fungicidal activities (EC50 values: 11.35-17.70 µg/mL) against Cercospora, arachidicola Hori. Some compounds also displayed good to excellent antiviral activities against the tobacco mosaic virus (TMV). Compounds I-1f and II-1f showed similar level of anti-TMV activities with ribavirin, and could be used as new antiviral candidates. These compound also exhibited good to excellent insecticidal activities. Compounds II-1d and III-1c displayed a similar level of insecticidal activities with matrine, hexaflumuron and rotenone against Plutella xylostella. In current study, plumbagin and juglone were discovered as parent structures, which lays a foundation for their application in plant protection.
Assuntos
Produtos Biológicos , Fungicidas Industriais , Inseticidas , Naftoquinonas , Praguicidas , Vírus do Mosaico do Tabaco , Estrutura Molecular , Relação Estrutura-Atividade , Fungicidas Industriais/farmacologia , Produtos Biológicos/química , Naftoquinonas/farmacologia , Antivirais/farmacologia , Antivirais/química , Inseticidas/farmacologia , Inseticidas/químicaRESUMO
There is strong scientific evidence that the electric field is harmful to life. Exposure to an electric field (EF) can cause lung toxicity and respiratory disorders. In addition, the electric field has been shown to cause tissue damage through inflammation and apoptosis. Juglone (JUG) is one of the powerful antioxidants with anti-apoptotic and anti-inflammatory, various pharmacological properties in the biological system. In this study, we evaluated the efficacy of JUG against the potential adverse effects of electric field on the lung. Twenty-four Wistar albino rats were randomly divided into three groups; control group (Cont), EF group, and EF exposure+JUG-treated group (EJUG). After routine histological procedures, sections stained with hematoxylin-eosin (H&E) showed significant changes in lung tissues in the EF group compared to the Cont group. Significant protective effects were observed in the building volumes and histopathology in the EJUG group. Our immunohistochemical and gene expression results increased the expression of caspase-3 and tumor necrosis factor alpha (TNF-α) in the EF group (p < 0.05). Juglon increased cytokine signal suppressor (SOCS) expression (p < 0.001). These findings were consistent with the antioxidant effect of JUG treatment. We reasoned that exposure to EF damaged rat lung tissues and administration of JUG alleviated the complications caused by 50 Hz EF.
Depending on technological developments, the use of electric devices and equipment is increasing day by day. During the transmission and use of electrical energy, electric and magnetic fields occurs. This forces can affect the environment and people. 50 Hz electric fields damage the cells and tissues of exposed living things in many ways. In our study, we examined the hypothesis that juglone, a natural antioxidant, can reduce the damage caused by the 50 Hz electric field that we are exposed to for a long time in our daily lives. In our study, it was shown by histological and genetic approaches that juglone, which has antioxidant and anti-apoptotic effects, may be protective against lung damage due to electric field exposure on experimental animals. According to our study results, for increased electric field exposure as a consequence of developing technology, juglone could be an important supportive treatment option.
Assuntos
Pulmão , Naftoquinonas , Ratos , Animais , Ratos Wistar , Naftoquinonas/farmacologia , Eletricidade , Antioxidantes/farmacologia , Antioxidantes/metabolismoRESUMO
Therapeutic and/or preventive interventions using phytochemical constituents for ischemic heart disease have gained considerable attention worldwide, mainly due to their antioxidant activity. This study investigated the cardioprotective effect and possible mechanism of juglone, a major constituent of the walnut tree, using an isoproterenol (ISO)-induced myocardial infarction (MI) model in rats. Rats were pretreated for five (5) days with juglone (1, 3 mg/kg, i.p) and atenolol (1 mg/kg, i.p) in separate experiments before inducing myocardial injury by administration of ISO (80 mg/kg, s.c) at an interval of 24 h for 2 consecutive days (4th and 5th day). The cardioprotective effect of juglone was confirmed through a lead II electrocardiograph (ECG), cardiac biomarkers (cTnI, CPK, CK-MB, LDH, ALT and AST) and histopathological study. The results of our present study suggest that prior administration of juglone (1 and 3 mg/kg) proved to be effective as a cardioprotective therapeutic agent in reducing the extent of myocardial damage (induced by ISO) by fortifying the myocardial cell membrane, preventing elevated T-waves, deep Q-waves in the ECG, heart to body weight ratio, infarction and also by normalizing cardiac marker enzymes (cTnI, CPK, CK-MB, LDH, ALT and AST) and histopathological changes, such as inflammation, edema and necrosis. In conclusion, this study has identified phytochemical constituents, in particular juglone, as a potential cardioprotective agent.
RESUMO
Ovarian cancer is the deadliest gynecological cancer which rarely causes symptoms, and goes undetected until reaching the advanced stage of drug-resistant metastases. The cationic porphyrin meso-tetra(4-N-methylpyridyl)porphine (TMPyP) is a well-known photosensitizer (PS) used in photodyamic therapy (PDT) for curing cancer due to its strong affinity for DNA and high yield of reactive oxygen species (ROS) upon light activation. The practicality to irradiate tumor cells alone in the physiological system being slim (due to the close proximity of healthy cells and tumors), we looked for a variation in the PDT using a mixture of TMPyP with 1,5-dihydroxynapthalene (DHN) and Fe(III) ions at a mole ratio of 1:20:17 (drug combo) respectively in aqueous solution. The drug combo needs no photoactivation in H2O2 rich environment (mimicking the microenvironment of cancer/tumor), where it generates ȮH and juglone, the latter being a known potent anticancer agent. In vitro studies of the drug combo in drug resistant and sensitive ovarian cancer cell lines showed drastic growth inhibition and cell death compared to normal epithelial cells. The drug combo provides an effective and non-invasive alternative to conventional PDT, exploiting the cytosolic carcinogenic H2O2 to produce an efficient anticancer treatment. The unique action of cancer-specific cytotoxicity arises from the redox chemistry involving activation of Fe(III) as the oxidizing agent to generate juglone, which utilizes the cytosolic ROS in cancer cells against itself.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Ácidos/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Camundongos , Naftóis/farmacologia , Naftoquinonas/farmacologia , Oxirredução , Porfirinas/farmacologia , Espectrometria de FluorescênciaRESUMO
NAD(P)H:quinone oxidoreductases (NQOs) play an essential protective role as antioxidants in the detoxification of quinones in both Prokaryotes and Eukaryotes. NQO from Pseudomonas aeruginosa PAO1 uses FMN to catalyze the two-electron reduction of various quinones with NADH. In this study, steady-state kinetics, kinetic solvent viscosity effects, and rapid reaction kinetics were used to determine which kinetic steps control the overall turnover of the enzyme with benzoquinone or juglone. The rate constant for flavin reduction (kred) at pH 6.0 was 12.9 ± 0.3 s-1, and the Kd for NADH was at least an order of magnitude lower than 90 µM. With benzoquinone, the kcat value was 11.7 ± 0.3 s-1, consistent with flavin reduction being almost entirely rate-limiting for overall turnover. With juglone, a kcat value of 10.0 ± 0.5 s-1 was recorded. The normalized plot of the relative solvent viscosity effects on the kcat values established that hydride transfer from NADH to the FMN and quinol product release, with a calculated rate constant (kP-rel) of 52 s-1, are partially rate-limiting for the overall turnover of NQO. Kinetic solvent viscosity effects with glucose or sucrose revealed a hyperbolic dependence on the kcat and kcat/Km values with benzoquinone or juglone, respectively, consistent with the presence of a solvent-sensitive internal isomerization of the enzyme-substrate complex (ES). The data demonstrate opposing effects of benzoquinone and juglone on the equilibrium of the NQO ES isomerization with glucose or sucrose. Thus, our study demonstrates how quinol substrate properties alter the equilibrium of NQO ES isomerization.
Assuntos
NAD , Pseudomonas aeruginosa , Benzoquinonas , Mononucleotídeo de Flavina , Flavinas/metabolismo , Glucose , Hidroquinonas , Isomerismo , Cinética , NAD/metabolismo , Oxirredução , Quinonas , Solventes , Sacarose , ViscosidadeRESUMO
The development of tumor therapeutic resistance is one of the important reasons for the failure of antitumor therapy. Starting with multiple targets and multiple signaling pathways is helpful in understanding the mechanism of tumor resistance. The overexpression of prolyl isomerase Pin1 is highly correlated with the malignancy of cancer, since Pin1 controls many oncogenes and tumor suppressors, as well as a variety of cancer-driving signaling pathways. Strikingly, numerous studies have shown that Pin1 is directly involved in therapeutic resistance. In this review, we mainly summarize the functions and mechanisms of Pin1 in therapeutic resistance of multifarious cancers, such as breast, liver, and pancreatic carcinomas. Furtherly, from the perspective of Pin1-driven cancer signaling pathways including Raf/MEK/ERK, PI3K/Akt, Wnt/ß-catenin, NF-κB, as well as Pin1 inhibitors containing juglone, epigallocatechin-3-gallate (EGCG), all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), it is better to demonstrate the important potential role and mechanism of Pin1 in resistance and sensitization to cancer therapies. It will provide new therapeutic approaches for clinical reversal and prevention of tumor resistance by employing synergistic administration of Pin1 inhibitors and chemotherapeutics, implementing combination therapy of Pin1-related cancer signaling pathway inhibitors and Pin1 inhibitors, and exploiting novel Pin1-specific inhibitors.
Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Trióxido de Arsênio/uso terapêutico , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno , NF-kappa B , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Peptidilprolil Isomerase/metabolismo , Peptidilprolil Isomerase/uso terapêutico , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Tretinoína/uso terapêutico , beta CateninaRESUMO
Tephritid fruit flies in the genus Rhagoletis bridge between predictable periods of fruit availability by becoming dormant. To cope with acyclic unpredictable events (e.g., frost, mast seeding, etc), a proportion of the population can undergo prolonged dormancy. In the case of walnut infesting Rhagoletis, host plant-derived cues such as juglone soil concentration vary seasonally in predictable patterns. Here, we examined the effects of host plant parts and derived compounds on emergence rates and dormancy duration of Rhagoletis completa (Cresson), Rhagoletis zoqui (Bush) (Diptera: Tephritidae), and associated parasitoids. Pupae of both species were exposed to walnut leaves, fruit, or fruit and leaves and compared to a control. In a second experiment, R. zoqui were exposed to 10 mg l-1 of juglone applied to pupation medium during four consecutive 4-week time periods under variable combinations of temperature and frequency of exposure. Overall, the presence of fruit resulted in greater overwintering survival of R. completa but had no effect on the duration of dormancy of either fly species. Application of juglone over two consecutive periods produced greater mortality of R. zoqui than the control. Three parasitoid species emerged from R. completa and one from R. zoqui. Duration of dormancy for parasitoids was longer than that of fly hosts. Regardless of treatment, 13.3-18.4% of R. completa pupae and 1.3-2.8% R. zoqui engaged in prolonged (>year) dormancy. Our results indicate that host plant derived cues have little or no effect on survival and duration of dormancy of walnut infesting Rhagoletis, and at the tested concentration juglone is toxic to R. zoqui pupae. Testing the effect of juglone at lower concentrations is necessary to rule out its role as an environmental cue for regulation of dormancy. So far, host plant fruiting phenology appears to play a greater role than host plant derived cues in selecting for fly eclosion times.
RESUMO
5-hydroxy-1,4-naphthoquinone (5NQ) or juglone is a bioactive molecule found in walnuts and has shown therapeutic effects in various disease models. Limited information is available regarding the toxicity of 5NQ, thereby limiting the clinical development of this drug. In the present study, oral acute (50, 300 and 2000 mg/kg) and sub-acute toxicity (5, 15 and 50 mg/kg) was assessed in mice to evaluate the safety of 5NQ. The acute toxicity study identified 118 mg/kg as the point-of-departure dose (POD) for single oral administration of 5NQ using benchmark dose modeling (BMD). Repeated administration of 5NQ at doses of 15 and 50 mg/kg/day caused reduction in food consumption and body weight of mice along with alterations in liver and renal function. Histopathological assessment revealed significant damage to hepatic and renal tissues at all doses in the acute toxicity study, and at higher doses of 15 and 50 mg/kg in the sub-acute toxicity study. We observed dose dependent mortality in sub-acute toxicity study and the no observed adverse effect level (NOAEL) was established as < 5 mg/kg/day. Modeling the survival response in sub-acute toxicity study identified 1.74 mg/kg/day as the POD for repeated administration of 5NQ. Serum levels of aspartate aminotransferase (AST) were most sensitive to 5NQ administration with a lower limit of BMD interval (BMDL) of 1.1 × 10-3 mg/kg/day. The benchmark doses reported in the study can be further used to determine a reference dose of 5NQ for human risk assessment.
RESUMO
1,4-Napththoquinones (NQs) are clinically relevant therapeutics that affect cell function through production of reactive oxygen species (ROS) and formation of adducts with regulatory protein thiols. Reactive sulfur species (RSS) are chemically and biologically similar to ROS and here we examine RSS production by NQ oxidation of hydrogen sulfide (H2S) using RSS-specific fluorophores, liquid chromatography-mass spectrometry, UV-Vis absorption spectrometry, oxygen-sensitive optodes, thiosulfate-specific nanoparticles, HPLC-monobromobimane derivatization, and ion chromatographic assays. We show that NQs, catalytically oxidize H2S to per- and polysulfides (H2Sn, n = 2−6), thiosulfate, sulfite and sulfate in reactions that consume oxygen and are accelerated by superoxide dismutase (SOD) and inhibited by catalase. The approximate efficacy of NQs (in decreasing order) is, 1,4-NQ ≈ juglone ≈ plumbagin > 2-methoxy-1,4-NQ ≈ menadione >> phylloquinone ≈ anthraquinone ≈ menaquinone ≈ lawsone. We propose that the most probable reactions are an initial two-electron oxidation of H2S to S0 and reduction of NQ to NQH2. S0 may react with H2S or elongate H2Sn in variety of reactions. Reoxidation of NQH2 likely involves a semiquinone radical (NQ·−) intermediate via several mechanisms involving oxygen and comproportionation to produce NQ and superoxide. Dismutation of the latter forms hydrogen peroxide which then further oxidizes RSS to sulfoxides. These findings provide the chemical background for novel sulfur-based approaches to naphthoquinone-directed therapies.
Assuntos
Sulfeto de Hidrogênio , Naftoquinonas , Tiossulfatos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Oxirredução , Naftoquinonas/farmacologia , Naftoquinonas/metabolismo , Sulfeto de Hidrogênio/metabolismo , Enxofre/metabolismo , Oxigênio/metabolismoRESUMO
A series of naphthoquinones, namely, 1,4-naphthoquinone, menadione, plumbagin, juglone, naphthazarin, and lawsone, were reacted with N-acetyl-L-cysteine, and except for lawsone, which did not react, the related adducts were obtained. After the tuning of the solvent and reaction conditions, the reaction products were isolated as almost pure from the complex reaction mixture via simple filtration and were fully characterized. Therefore, the aim of this work was to evaluate whether the antitumor activity of new compounds of 1,4-naphthoquinone derivatives leads to an increase in ROS in tumor cell lines of cervical carcinoma (HeLa), neuroblastoma (SH-SY5Y), and osteosarcoma (SaOS2, U2OS) and in normal dermal fibroblast (HDFa). The MTT assay was used to assay cell viability, the DCF-DA fluorescent probe to evaluate ROS induction, and cell-cycle analysis to measure the antiproliferative effect. Compounds 8, 9, and 12 showed a certain degree of cytotoxicity towards all the malignant cell lines tested, while compound 11 showed biological activity at higher IC50 values. Compounds 8 and 11 induced increases in ROS generation after 1 h of exposure, while after 48 h of treatment, only 8 induced an increase in ROS formation in HeLa cells. Cell-cycle analysis showed that compound 8 caused an increase in the number of G0/G1-phase cells in the HeLa experiment, while for the U2OS and SH-SY5Y cell lines, it led to an accumulation of S-phase cells. Therefore, these novel 1,4-naphthoquinone derivatives may be useful as antitumoral agents in the treatment of different cancers.