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Talita B Gontijo, Rossimiriam P de Freitas, Guilherme F de Lima, Lucas C D de Rezende, Leandro F Pedrosa, Thaissa L Silva, Marilia O F Goulart, Bruno C Cavalcanti, Claudia Pessoa, Marina P Bruno, José R Corrêa, Flavio S Emery, Eufrânio N da Silva Júnior
For the first time, a fluorescent lapachone-based BODIPY was synthesised and characterised by NMR and mass spectrometry. Computational and electrochemical aspects, as well as cytotoxic activity and subcellular localisation, were studied. Confocal microscopy experiments indicated that the probe was a specific mitochondria-staining agent. These in-detail analyses were useful in understanding the cytotoxic effects and mechanism of action of this novel hybrid compound. This molecule constitutes a promising prototype owing to its potential biological activities and the new strategies aimed at mechanistic investigations in cells and in vivo, and opens up an interesting avenue of research...
October 24, 2016: Chemical Communications: Chem Comm
Danielle Oliveira Dos Anjos, Eliomara Sousa Sobral Alves, Vinicius Tomaz Gonçalves, Sheila Suarez Fontes, Mateus Lima Nogueira, Ana Márcia Suarez-Fontes, João Batista Neves da Costa, Fabricio Rios-Santos, Marcos André Vannier-Santos
Natural products comprise valuable sources for new antiparasitic drugs. Here we tested the effects of a novel β-lapachone derivative on Trypanosoma cruzi parasite survival and proliferation and used microscopy and cytometry techniques to approach the mechanism(s) underlying parasite death. The selectivity index determination indicate that the compound trypanocidal activity was over ten-fold more cytotoxic to epimastigotes than to macrophages or splenocytes. Scanning electron microscopy analysis revealed that the R72 β-lapachone derivative affected the T...
October 12, 2016: International Journal for Parasitology, Drugs and Drug Resistance
Rodney Lacret, Ignacio Pérez-Victoria, Daniel Oves-Costales, Mercedes de la Cruz, Elizabeth Domingo, Jesús Martín, Caridad Díaz, Francisca Vicente, Olga Genilloud, Fernando Reyes
A new napyradiomycin, MDN-0170 (1), was isolated from the culture broth of the marine-derived actinomycete strain CA-271078, together with three known related compounds identified as 4-dehydro-4a-dechloronapyradiomycin A1 (2), napyradiomycin A1 (3) and 3-chloro-6,8-dihydroxy-8-α-lapachone (4). The structure of the new compound was determined using a combination of spectroscopic techniques, including 1D and 2D NMR and electrospray-time of flight mass spectrometry (ESI-TOF MS). The relative configuration of compound 1, which contains two independent stereoclusters, has been established by molecular modelling in combination with nOe and coupling constant analyses...
October 18, 2016: Marine Drugs
Sharyn L Rossi, Casey J Lumpkin, Ashlee W Harris, Jennifer Holbrook, Cinsley Gentillon, Suzanne M McCahan, Wenlan Wang, Matthew E R Butchbach
Topoisomerase 1 (TOP1) poisons like camptothecin (CPT) are currently used in cancer chemotherapy but these compounds can have damaging, off-target effects on neurons leading to cognitive, sensory and motor deficits. To understand the molecular basis for the enhanced sensitivity of neurons to CPT, we examined the effects of compounds that inhibit TOP1-CPT, actinomycin D (ActD) and β-lapachone (β-Lap)-on primary cultured rat motor (MN) and cortical (CN) neurons as well as fibroblasts. Neuronal cells expressed higher levels of Top1 mRNA than fibroblasts but transcript levels are reduced in all cell types after treatment with CPT...
October 14, 2016: Biochemical and Biophysical Research Communications
Scott B Vafai, Emily Mevers, Kathleen W Higgins, Yevgenia Fomina, Jianming Zhang, Anna Mandinova, David Newman, Stanley Y Shaw, Jon Clardy, Vamsi K Mootha
Deficiency of mitochondrial complex I is encountered in both rare and common diseases, but we have limited therapeutic options to treat this lesion to the oxidative phosphorylation system (OXPHOS). Idebenone and menadione are redox-active molecules capable of rescuing OXPHOS activity by engaging complex I-independent pathways of entry, often referred to as "complex I bypass." In the present study, we created a cellular model of complex I deficiency by using CRISPR genome editing to knock out Ndufa9 in mouse myoblasts, and utilized this cell line to develop a high-throughput screening platform for novel complex I bypass factors...
2016: PloS One
Hui-Ying Liu, Qing-Ran Li, Xue-Fang Cheng, Guang-Ji Wang, Hai-Ping Hao
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...
August 2016: Chinese Journal of Natural Medicines
Giselle Villa Flor Brunoro, Vitor Marcel Faça, Marcelle Almeida Caminha, André Teixeira da Silva Ferreira, Monique Trugilho, Kelly Cristina Gallan de Moura, Jonas Perales, Richard Hemmi Valente, Rubem Figueiredo Sadok Menna-Barreto
BACKGROUND: The obligate intracellular protozoan Trypanosoma cruzi is the causative agent of Chagas disease, a neglected illness affecting millions of people in Latin America that recently entered non-endemic countries through immigration, as a consequence of globalization. The chemotherapy for this disease is based mainly on benznidazole and nifurtimox, which are very efficient nitroderivatives against the acute stage but present limited efficacy during the chronic phase. Our group has been studying the trypanocidal effects of naturally occurring quinones and their derivatives, and naphthoimidazoles derived from β-lapachone N1, N2 and N3 were the most active...
August 2016: PLoS Neglected Tropical Diseases
Marival Bermejo, Victor Mangas-Sanjuan, Isabel Gonzalez-Alvarez, Marta Gonzalez-Alvarez
β-Lapachone is a naphthoquinone with high and diverse biological activity. It is useful to treat several pathologies, in particular cancer due to its ability to induce selective apoptosis in tumoral cells. Despite its advantages, β-lapachone's clinical applications are limited by its low solubility in biological fluids and its low specific distribution pattern. In the last decade various formulation strategies have been designed and developed in order to overcome these limitations and to make feasible its wide therapeutic use...
August 18, 2016: European Journal of Drug Metabolism and Pharmacokinetics
Raimunda Sâmia Nogueira Brilhante, Érica Pacheco Caetano, Rita Amanda Chaves de Lima, Francisca Jakelyne de Farias Marques, Débora de Souza Collares Maia Castelo-Branco, Charlline Vládia Silva de Melo, Glaucia Morgana de Melo Guedes, Jonathas Sales de Oliveira, Zoilo Pires de Camargo, José Luciano Bezerra Moreira, André Jalles Monteiro, Tereza de Jesus Pinheiro Gomes Bandeira, Rossana de Aguiar Cordeiro, Marcos Fábio Gadelha Rocha, José Júlio Costa Sidrim
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...
October 2016: Brazilian Journal of Microbiology: [publication of the Brazilian Society for Microbiology]
Marcilia P Costa, Anderson C S Feitosa, Fátima C E Oliveira, Bruno C Cavalcanti, Eufrânio N da Silva, Gleiston G Dias, Francisco A M Sales, Bruno L Sousa, Ito L Barroso-Neto, Cláudia Pessoa, Ewerton W S Caetano, Stefano Di Fiore, Rainer Fischer, Luiz O Ladeira, Valder N Freire
Prostate cancer is one of the most common malignant tumors in males and it has become a major worldwide public health problem. This study characterizes the encapsulation of Nor-β-lapachone (NβL) in poly(d,l-lactide-co-glycolide) (PLGA) microcapsules and evaluates the cytotoxicity of the resulting drug-loaded system against metastatic prostate cancer cells. The microcapsules presented appropriate morphological features and the presence of drug molecules in the microcapsules was confirmed by different methods...
2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Eduardo H G da Cruz, Molly A Silvers, Guilherme A M Jardim, Jarbas M Resende, Bruno C Cavalcanti, Igor S Bomfim, Claudia Pessoa, Carlos A de Simone, Giancarlo V Botteselle, Antonio L Braga, Divya K Nair, Irishi N N Namboothiri, David A Boothman, Eufrânio N da Silva Júnior
UNLABELLED: Selenium-containing quinone-based 1,2,3-triazoles were synthesized using click chemistry, the copper catalyzed azide-alkyne 1,3-dipolar cycloaddition, and evaluated against six types of cancer cell lines: HL-60 (human promyelocytic leukemia cells), HCT-116 (human colon carcinoma cells), PC3 (human prostate cells), SF295 (human glioblastoma cells), MDA-MB-435 (melanoma cells) and OVCAR-8 (human ovarian carcinoma cells). Some compounds showed IC50 values < 0.3 μM. The cytotoxic potential of the quinones evaluated was also assayed using non-tumor cells, exemplified by peripheral blood mononuclear (PBMC), V79 and L929 cells...
October 21, 2016: European Journal of Medicinal Chemistry
Vitor Francisco Ferreira
Quinones are among the most studied natural and synthetic products in the literature because they have considerable biological potential. These compounds exhibit activity against many microorganisms and are able to eliminate tumor cells through several mechanisms of action. Some of these compounds have become drugs that are used clinically. However, they also have problems with respect to solubility, stability and toxicity. The alternative of using controlled-release systems has been applied to quinones, with good results in some cases, indicating that these formulations may be a strategy for improving the pharmacological profile of this class of compounds...
June 10, 2016: Current Pharmaceutical Design
Won Hee Choi, Jiyun Ahn, Chang Hwa Jung, Young Jin Jang, Tae Youl Ha
There has been great interest in the browning of fat for the treatment of obesity. Although β-lapachone (BLC) has potential therapeutic effects on obesity, the fat-browning effect and thermogenic capacity of BLC on obesity have never been demonstrated. Here, we showed that BLC stimulated the browning of white adipose tissue (WAT), increased the expression of brown adipocyte-specific genes (e.g., uncoupling protein 1 [UCP1]), decreased body weight gain, and ameliorated metabolic parameters in mice fed a high-fat diet...
September 2016: Diabetes
Jin-Sun Park, Yu-Young Lee, Jisun Kim, Hyemyung Seo, Hee-Sun Kim
β-Lapachone (β-LAP) is a naturally occurring quinine that exerts a number of pharmacological actions including antibacterial, antifungal, antimalarial, and antitumor activities. In the present study, we investigated whether β-LAP has an antioxidant effect in rat primary astrocytes. β-LAP suppressed intracellular reactive oxygen species (ROS) production induced by hydrogen peroxide and inhibited astroglial cell death. It also increased astrocytic expression of phase II antioxidant enzymes such as heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), manganese superoxide dismutase (MnSOD), and catalase...
August 2016: Free Radical Biology & Medicine
Long-Shan Li, Srilakshmi Reddy, Zhen-Hua Lin, Shuangping Liu, Hyunsil Park, Stephen G Chun, William G Bornmann, Joel Thibodeaux, Jingsheng Yan, Gaurab Chakrabarti, Xian-Jin Xie, Baran D Sumer, David A Boothman, John S Yordy
Ionizing radiation (IR) is a key therapeutic regimen for many head and neck cancers (HNC). However, the 5-year overall survival rate for locally advanced HNCs is approximately 50% and better therapeutic efficacy is needed. NAD(P)H:quinone oxidoreductase 1 (NQO1) is overexpressed in many cancers, and β-lapachone (β-lap), a unique NQO1 bioactivatable drug, exploits this enzyme to release massive reactive oxygen species (ROS) that synergize with IR to kill by programmed necrosis. β-Lap represents a novel therapeutic opportunity in HNC leading to tumor-selective lethality that will enhance the efficacy of IR...
July 2016: Molecular Cancer Therapeutics
Ki Hyun Kim, So-Hyun Park, Pratik Adhikary, Jin Hun Cho, Nae-Gyu Kang, Seong Hoon Jeong
Even though β-lapachone is a promising compound with antitumor, antiinflammatory, antineoplastic, and wound-healing effects, there are still issues concerning its chemical stability and degradation mechanisms. The objective of this study was to obtain degradation profiles of β-lapachone and evaluate its chemical stability under various stress conditions. Moreover, the correlation between stability and efficacy was evaluated. The degradation study of β-lapachone was performed using heat, acid, base, oxidation, and light conditions...
2016: Chemical & Pharmaceutical Bulletin
Camila Raquel Paludo, Eduardo Afonso da Silva-Junior, Eliane de Oliveira Silva, Ricardo Vessecchi, Norberto Peporine Lopes, Mônica Tallarico Pupo, Flavio da Silva Emery, Natália Dos Santos Gonçalves, Raquel Alves Dos Santos, Niege Araçari Jacometti Cardoso Furtado
BACKGROUND AND OBJECTIVES: β-Lapachone is a drug candidate in phase II clinical trials for treatment of solid tumors. The therapeutic efficacy of β-lapachone is closely related to its metabolism, since this o-naphthoquinone produces cytotoxic effect after intracellular bioreduction by reactive oxygen species formation. The aim of this study was to produce β-lapachone human blood phase I metabolites to evaluate their cytotoxic activities. METHODS: The biotransformation of β-lapachone was performed using Mucor rouxii NRRL 1894 and Papulaspora immersa SS13...
April 8, 2016: European Journal of Drug Metabolism and Pharmacokinetics
Yougen Wu, Xue Wang, Siyu Chang, Weiqiang Lu, Mingyao Liu, Xiufeng Pang
UNLABELLED: β-Lapachone [β-lap; 3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione] is a novel anticancer drug currently under investigation in phase I/II clinical trials. However, the mechanism underlying its clinical efficacy remains unclear. In this study, we found that β-lap provoked the cleavage of heat shock protein 90 (Hsp90) in NAD(P)H: quinone oxidoreductase-1 (NQO1)-expressing lung and prostate cancer cells as well as in primary human umbilical vein endothelial cells (HUVECs)...
June 2016: Journal of Pharmacology and Experimental Therapeutics
Eliane O Silva, Antonio Ruano-González, Raquel A dos Santos, Rosario Sánchez-Maestre, Niege A J C Furtado, Isidro G Collado, Josefina Aleu
In the screening for biological active compounds, the biotransformation processes catalyzed by filamentous fungi are useful because they can provide information about the possible appearance of toxic metabolites after oral administration and also generate new leads. In this paper, biotransformation of lapachol (1) by three fungal strains, Mucor circinelloides NRRL3631, Botrytis cinerea UCA992 and Botrytis cinerea 2100, has been investigated for the first time. Lapachol (1) was biotransformed into avicequinone-A (2) by M circinelloides, 3'-hydroxylapachol (3) by B...
January 2016: Natural Product Communications
Souichi Nukuzuma, Kazuo Nakamichi, Masanori Kameoka, Shigeki Sugiura, Chiyoko Nukuzuma, Takafumi Tasaki, Tsutomu Takegami
JC polyomavirus (JCPyV) causes progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease of the central nervous system, in immunocompromised patients. Because no drugs have been approved for treating PML, many antiviral agents are currently being investigated for this purpose. The inhibitory effects of the topoisomerase I inhibitors topotecan and β-lapachone were assessed by investigating viral replication, propagation and viral protein 1 (VP1) production in cultured cells. JCPyV replication was assayed using the human neuroblastoma cell line IMR-32 transfected with the JCPyV plasmid and RT- PCR combined with Dpn I treatment...
April 2016: Microbiology and Immunology
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