-
Molecules (Basel, Switzerland) Nov 2021Medulloblastoma is a common malignant brain tumor in the pediatric age. The current therapeutics present serious collateral effects. Polyphenols α-mangostin and...
Medulloblastoma is a common malignant brain tumor in the pediatric age. The current therapeutics present serious collateral effects. Polyphenols α-mangostin and nordihydroguaiaretic acid (NDGA) exert potent antitumoral activity in different cancer models, although their antitumoral effects have not been described in medulloblastoma cells yet. This study aimed to examine the proapoptotic effects of these polyphenols on human medulloblastoma cells. Medulloblastoma cell line Daoy was incubated with increasing concentrations of α-mangostin or NDGA for 24 h. The cell viability was analyzed using crystal violet and trypan blue dyes. Determination of the glutathione (GSH)/glutathione disulfide (GSSG) ratio and levels of carbonylated proteins was performed to evaluate the oxidative stress. Cell cycle progression and induction of cell death by fluorochrome-couple and TUNEL assays were evaluated using flow cytometry assays. Individual treatments with α-mangostin or NDGA decreased the viability of Daoy cells in a dose-dependent manner, inducing G2/M and S-G2/M cell cycle arrest, respectively. Both polyphenols induced cell death and increased oxidative stress. Very interestingly, α-mangostin showed more potent effects than NDGA. Our results indicate that α-mangostin and NDGA exert important cytostatic and cytotoxic effects in the Daoy cell line. These data highlight the potential usefulness of these compounds as an alternative strategy in medulloblastoma treatment.
Topics: Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cerebellar Neoplasms; Humans; Masoprocol; Medulloblastoma; Models, Biological; Oxidative Stress; Polyphenols; Xanthones
PubMed: 34885809
DOI: 10.3390/molecules26237230 -
Molecules (Basel, Switzerland) Nov 2021In this study, the antioxidant and antiradical properties of some phyto lignans (nordihydroguaiaretic acid, secoisolariciresinol, secoisolariciresinol diglycoside, and...
In this study, the antioxidant and antiradical properties of some phyto lignans (nordihydroguaiaretic acid, secoisolariciresinol, secoisolariciresinol diglycoside, and α-(-)-conidendrin) and mammalian lignans (enterodiol and enterolactone) were examined by different antioxidant assays. For this purpose, radical scavenging activities of phyto and mammalian lignans were realized by 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) radical (ABTS) scavenging assay and 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) scavenging assay. Additionally, the reducing ability of phyto and mammalian lignans were evaluated by cupric ions (Cu) reducing (CUPRAC) ability, and ferric ions (Fe) and [Fe-(TPTZ)2] complex reducing (FRAP) abilities. Also, half maximal inhibitory concentration (IC) values were determined and reported for DPPH and ABTS scavenging influences of all of the lignan molecules. The absorbances of the lignans were found in the range of 0.150-2.320 for Fe reducing, in the range of 0.040-2.090 for Cu reducing, and in the range of 0.360-1.810 for the FRAP assay. On the other hand, the IC values of phyto and mammalian lignans were determined in the ranges of 6.601-932.167 µg/mL for DPPH scavenging and 13.007-27.829 µg/mL for ABTS scavenging. In all of the used bioanalytical methods, phyto lignans, as secondary metabolites in plants, demonstrated considerably higher antioxidant activity compared to that of mammalian lignans. In addition, it was observed that enterodiol and enterolactone exhibited relatively weaker antioxidant activities when compared to phyto lignans or standard antioxidants, including butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), Trolox, and α-tocopherol.
Topics: Animals; Antioxidants; Benzothiazoles; Biphenyl Compounds; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Butylene Glycols; Chromans; Copper; Free Radical Scavengers; Ions; Iron; Lignans; Lipid Peroxidation; Mammals; Masoprocol; Phytochemicals; Picrates; Sulfonic Acids; Tetrahydronaphthalenes
PubMed: 34885681
DOI: 10.3390/molecules26237099 -
Molecules (Basel, Switzerland) Apr 2021Nordihydroguaiaretic acid (NDGA) is a major lignan metabolite found in spp., which are widely used in South America to treat various diseases. In breast tissue,...
Nordihydroguaiaretic acid (NDGA) is a major lignan metabolite found in spp., which are widely used in South America to treat various diseases. In breast tissue, estradiol is metabolized to the catechol estrogens such as 4-hydroxyestradiol (4-OHE), which have been proposed to be cancer initiators potentially involved in mammary carcinogenesis. Catechol--methyltransferase (COMT) catalyzes the methylation of catechol estrogens to their less toxic methoxy derivatives, such as 4--methylestradiol (4-MeOE). The present study investigated the novel biological activities of NDGA in relation to COMT and the effects of COMT inhibition by NDGA on 4-OHE-induced cyto- and genotoxicity in MCF-7 human breast cancer cells. Two methoxylated metabolites of NDGA, 3--methylNDGA (3-MNDGA) and 4-methyl NDGA (4-MNDGA), were identified in the reaction mixture containing human recombinant COMT, NDGA, and cofactors. values for the COMT-catalyzed metabolism of NDGA were 2.6 µM and 2.2 µM for 3-MNDGA and 4-MNDGA, respectively. The COMT-catalyzed methylation of 4-OHE was inhibited by NDGA at an IC of 22.4 µM in a mixed-type mode of inhibition by double reciprocal plot analysis. Molecular docking studies predicted that NDGA would adopt a stable conformation at the COMT active site, mainly owing to the hydrogen bond network. NDGA is likely both a substrate for and an inhibitor of COMT. Comet and apurinic/apyrimidinic site quantitation assays, cell death, and apoptosis in MCF-7 cells showed that NDGA decreased COMT-mediated formation of 4-MeOE and increased 4-OHE-induced DNA damage and cytotoxicity. Thus, NDGA has the potential to reduce COMT activity in mammary tissues and prevent the inactivation of mutagenic estradiol metabolites, thereby increasing catechol estrogen-induced genotoxicities.
Topics: Binding Sites; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Cell Death; DNA Damage; Estrogens, Catechol; Humans; MCF-7 Cells; Masoprocol; Methylation; Molecular Docking Simulation; Mutagens; Recombinant Proteins; Substrate Specificity
PubMed: 33916785
DOI: 10.3390/molecules26072060 -
Computers in Biology and Medicine Apr 2021Papain-Like Protease (PLpro) is a key protein for SARS-CoV-2 viral replication which is the cause of the emerging COVID-19 pandemic. Targeting PLpro can suppress viral...
Papain-Like Protease (PLpro) is a key protein for SARS-CoV-2 viral replication which is the cause of the emerging COVID-19 pandemic. Targeting PLpro can suppress viral replication and provide treatment options for COVID-19. Due to the dynamic nature of its binding site loop, PLpro multiple conformations were generated through a long-range 1 micro-second molecular dynamics (MD) simulation. Clustering the MD trajectory enabled us to extract representative structures for the conformational space generated. Adding to the MD representative structures, X-ray structures were involved in an ensemble docking approach to screen the FDA approved drugs for a drug repositioning endeavor. Guided by our recent benchmarking study of SARS-CoV-2 PLpro, FRED docking software was selected for such a virtual screening task. The results highlighted potential consensus binders to many of the MD clusters as well as the newly introduced X-ray structure of PLpro complexed with a small molecule. For instance, three drugs Benserazide, Dobutamine and Masoprocol showed a superior consensus enrichment against the PLpro conformations. Further MD simulations for these drugs complexed with PLpro suggested the superior stability and binding of dobutamine and masoprocol inside the binding site compared to Benserazide. Generally, this approach can facilitate identifying drugs for repositioning via targeting multiple conformations of a crucial target for the rapidly emerging COVID-19 pandemic.
Topics: Binding Sites; Coronavirus 3C Proteases; Crystallography, X-Ray; Cysteine Proteinase Inhibitors; Drug Repositioning; Enzyme Stability; Humans; Molecular Dynamics Simulation; SARS-CoV-2
PubMed: 33662683
DOI: 10.1016/j.compbiomed.2021.104295 -
PloS One 2020Nordihydroguaiaretic acid (NDGA) is a plant extract that has been shown to act as a free radical scavenger and pluripotent inhibitor of pro-inflammatory cytokines, two...
BACKGROUND
Nordihydroguaiaretic acid (NDGA) is a plant extract that has been shown to act as a free radical scavenger and pluripotent inhibitor of pro-inflammatory cytokines, two major cellular processes involved in the pathophysiology of sepsis. We investigated whether NDGA would improve markers of organ injury as well as survival in a rodent model of sepsis.
METHODS
Abdominal sepsis was induced by cecal ligation and double puncture (CLP) in male Sprague-Dawley rats. NDGA was administered either at the time of injury (pre-) or 6 hours later (post-treatment). A sham surgery group and a vehicle only group were also followed as controls. Blood and lung tissue were collected 24 h after CLP. Lung tissue was used for histopathologic analysis and to measure pulmonary edema. Arterial oxygenation was measured directly to generate PaO2/FiO2, and markers of renal injury (blood urea nitrogen), liver injury (alanine aminotransferase), and tissue hypoxia (lactate) were measured. In a separate set of animals consisting of the same treatment groups, animals were followed for up to 36 hours for survival.
RESULTS
NDGA pre-treatment resulted in improved oxygenation, less lung edema, lower lactate, lower BUN, and reduced histologic lung injury. NDGA post-treatment resulted in less lung edema, lower lactate, lower BUN, and less histologic lung injury, but did not significantly change oxygenation. None of the NDGA treatment groups statistically affected ALT or creatinine. NDGA pre-treatment showed improved survival compared with control CLP animals at 36 hours, while post-treatment did not.
CONCLUSIONS
NDGA represents a novel pleiotropic anti-inflammatory agent with potential clinical utility for modulation of organ injury secondary to sepsis.
Topics: Animals; Antioxidants; Cecum; Ligation; Lung Diseases; Male; Masoprocol; Punctures; Rats; Rats, Sprague-Dawley; Sepsis
PubMed: 32790786
DOI: 10.1371/journal.pone.0237613 -
Journal of Nanobiotechnology May 2020Nordihydroguaiaretic acid (NDGA) is a plant lignan obtained from creosote bush, known to possess anti-oxidant, anti-cancer and anti-viral activities and is being used in...
BACKGROUND
Nordihydroguaiaretic acid (NDGA) is a plant lignan obtained from creosote bush, known to possess anti-oxidant, anti-cancer and anti-viral activities and is being used in traditional medicine. However, toxicity studies indicated liver and kidney damage despite its immense medicinal properties. There has been a recent increase of curiosity in the chemical synthesis of NDGA derivatives for therapeutic applications. NDGA derivatives have been developed as better alternatives to NDGA and for targeted delivery to the site of tissue by chemical derivatives. In this regard, an analog of NDGA, Acetyl NDGA (Ac-NDGA), has been synthesized based on a previous procedure and formulated as a nanostructured complex with Polycaprolactone/Polyethylene glycol polymer matrices, by o/w solvent evaporation method.
RESULTS
The drug-incorporated polymeric nanospheres exhibited a drug load of 10.0 ± 0.5 µg drug per mg of nanospheres in acetonitrile solvent with 49.95 ± 10% encapsulation efficiency and 33-41% drug loading capacity with different batches of nanospheres preparation. The in vitro drug release characteristics indicated 82 ± 0.25% drug release at 6 h in methanol. Further, the nanospheres have been characterized extensively to evaluate their suitability for therapeutic delivery.
CONCLUSIONS
The present studies indicate a new and efficient formulation of the nanostructured AcNDGA with good therapeutic potential.
Topics: Antioxidants; Cell Survival; Hep G2 Cells; Humans; Masoprocol; Materials Testing; Nanostructures; Particle Size; Polymers
PubMed: 32410712
DOI: 10.1186/s12951-020-00628-z -
Nature Chemical Biology Jul 2020Leukotrienes (LT) are lipid mediators of the inflammatory response that are linked to asthma and atherosclerosis. LT biosynthesis is initiated by 5-lipoxygenase (5-LOX)...
Leukotrienes (LT) are lipid mediators of the inflammatory response that are linked to asthma and atherosclerosis. LT biosynthesis is initiated by 5-lipoxygenase (5-LOX) with the assistance of the substrate-binding 5-LOX-activating protein at the nuclear membrane. Here, we contrast the structural and functional consequences of the binding of two natural product inhibitors of 5-LOX. The redox-type inhibitor nordihydroguaiaretic acid (NDGA) is lodged in the 5-LOX active site, now fully exposed by disordering of the helix that caps it in the apo-enzyme. In contrast, the allosteric inhibitor 3-acetyl-11-keto-beta-boswellic acid (AKBA) from frankincense wedges between the membrane-binding and catalytic domains of 5-LOX, some 30 Å from the catalytic iron. While enzyme inhibition by NDGA is robust, AKBA promotes a shift in the regiospecificity, evident in human embryonic kidney 293 cells and in primary immune cells expressing 5-LOX. Our results suggest a new approach to isoform-specific 5-LOX inhibitor development through exploitation of an allosteric site in 5-LOX.
Topics: Allosteric Site; Arachidonate 5-Lipoxygenase; Biological Products; Catalytic Domain; Cloning, Molecular; Crystallography, X-Ray; Escherichia coli; Gene Expression; Genetic Vectors; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase Inhibitors; Masoprocol; Models, Molecular; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Protein Multimerization; Recombinant Proteins; Substrate Specificity; Triterpenes
PubMed: 32393899
DOI: 10.1038/s41589-020-0544-7 -
Marine Drugs Apr 2020Several biochemical mechanisms, including the arachidonic acid cascade and activation of nicotinic acetylcholine receptors (nAChRs), are involved in increased tumor...
α-Conotoxins Enhance both the In Vivo Suppression of Ehrlich carcinoma Growth and In Vitro Reduction in Cell Viability Elicited by Cyclooxygenase and Lipoxygenase Inhibitors.
Several biochemical mechanisms, including the arachidonic acid cascade and activation of nicotinic acetylcholine receptors (nAChRs), are involved in increased tumor survival. Combined application of inhibitors acting on these two pathways may result in a more pronounced antitumor effect. Here, we show that baicalein (selective 12-lipoxygenase inhibitor), nordihydroguaiaretic acid (non-selective lipoxygenase inhibitor), and indomethacin (non-selective cyclooxygenase inhibitor) are cytotoxic to Ehrlich carcinoma cells in vitro. Marine snail α-conotoxins PnIA, RgIA and ArIB11L16D, blockers of α3β2/α6β2, α9α10 and α7 nAChR subtypes, respectively, as well as α-cobratoxin, a blocker of α7 and muscle subtype nAChRs, exhibit low cytotoxicity, but enhance the antitumor effect of baicalein 1.4-fold after 24 h and that of nordihydroguaiaretic acid 1.8-3.9-fold after 48 h of cell cultivation. α-Conotoxin MII, a blocker of α6-containing and α3β2 nAChR subtypes, increases the cytotoxic effect of indomethacin 1.9-fold after 48 h of cultivation. In vivo, baicalein, α-conotoxins MII and PnIA inhibit Ehrlich carcinoma growth and increase mouse survival; these effects are greatly enhanced by the combined application of α-conotoxin MII with indomethacin or conotoxin PnIA with baicalein. Thus, we show, for the first time, antitumor synergism of α-conotoxins and arachidonic acid cascade inhibitors.
Topics: Animals; Arachidonic Acid; Carcinoma; Carcinoma, Ehrlich Tumor; Cell Survival; Cobra Neurotoxin Proteins; Conotoxins; Cyclooxygenase Inhibitors; Drug Synergism; Flavanones; Indomethacin; Lipoxygenase Inhibitors; Masoprocol; Mice; Nicotinic Antagonists; Receptors, Nicotinic
PubMed: 32272633
DOI: 10.3390/md18040193 -
Molecules (Basel, Switzerland) Jan 2020Lignans are widely produced by various plant species; they are a class of natural products that share structural similarity. They usually contain a core scaffold that is... (Review)
Review
Lignans are widely produced by various plant species; they are a class of natural products that share structural similarity. They usually contain a core scaffold that is formed by two or more phenylpropanoid units. Lignans possess diverse pharmacological properties, including their antiviral activities that have been reported in recent years. This review discusses the distribution of lignans in nature according to their structural classification, and it provides a comprehensive summary of their antiviral activities. Among them, two types of antiviral lignans-podophyllotoxin and bicyclol, which are used to treat venereal warts and chronic hepatitis B (CHB) in clinical, serve as examples of using lignans for antivirals-are discussed in some detail. Prospects of lignans in antiviral drug discovery are also discussed.
Topics: Antiviral Agents; Benzodioxoles; Biological Products; Biphenyl Compounds; Drug Development; Furans; Lignans; Masoprocol; Plants; Podophyllotoxin
PubMed: 31906391
DOI: 10.3390/molecules25010183 -
Physiological Research Feb 2020Autologous and allogenic human pericardia used as biomaterials for cardiovascular surgery are traditionally crosslinked with glutaraldehyde. In this work, we have... (Comparative Study)
Comparative Study
Autologous and allogenic human pericardia used as biomaterials for cardiovascular surgery are traditionally crosslinked with glutaraldehyde. In this work, we have evaluated the resistivity to collagenase digestion and the cytotoxicity of human pericardium crosslinked with various concentrations of glutaraldehyde in comparison with pericardium crosslinked by genipin, nordihydroguaiaretic acid, tannic acid, and in comparison with unmodified pericardium. Crosslinking retained the wavy-like morphology of native pericardium visualized by second harmonic generation microscopy. The collagenase digestion products were analyzed using SDS-PAGE, capillary electrophoresis, and a hydroxyproline assay. Glutaraldehyde and genipin crosslinking protected the native pericardium efficiently against digestion with collagenase III. Only low protection was provided by the other crosslinking agents. The cytotoxicity of crosslinked pericardium was evaluated using xCELLigence by monitoring the viability of porcine valve interstitial cells cultured in eluates from crosslinked pericardium. The highest cell index, reflecting both the number and the shape of the monitored cells was observed in eluates from genipin. Crosslinking pericardium grafts with genipin therefore seems to be a promising alternative procedure to the traditional crosslinking with glutaraldehyde, because it provides similarly high protection against degradation with collagenase, without cytotoxic effects.
Topics: Biocompatible Materials; Cross-Linking Reagents; Glutaral; Humans; Iridoids; Masoprocol; Pericardium; Tannins; Transplants
PubMed: 31852209
DOI: 10.33549/physiolres.934335