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European Journal of Pharmacology Mar 2022Acute lung injury (ALI) is a continuum of pulmonary changes caused by various lung insults. Previously, we synthesized a series of nordihydroguaiaretic acid analogs; of...
Acute lung injury (ALI) is a continuum of pulmonary changes caused by various lung insults. Previously, we synthesized a series of nordihydroguaiaretic acid analogs; of these, compound 3a exhibited excellent antioxidant capacity in a murine model of middle cerebral artery occlusion. However, it remains unclear whether compound 3a can modulate lipopolysaccharide (LPS)-induced ALI. ALI was induced via tracheal LPS administration, and the pathological changes were assessed. The level of inflammation was verified by immunofluorescence and immunohistochemical analyses. Apoptosis was measured by terminal deoxynucleotidyl transferase dUTP nick-end labeling assays and Western blotting. Changes in the levels of mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) pathway proteins were assessed by immunofluorescence assays and Western blotting. In vitro, RAW 264.7 cells were treated with compound 3a prior to LPS challenge, and the intracellular level of inflammation was assessed by quantitative PCR (qPCR). Relevant proteins were detected via immunofluorescence assays and Western blotting. Mice developed extensive lung inflammation by 24 h after LPS challenge. Histological examination revealed signs typical of ALI. Preadministration of compound 3a markedly ameliorated the histopathological changes and reduced fluid exudation into the alveolar space. Compound 3a also greatly reduced the levels of inflammation and apoptosis both in vivo and in vitro. Moreover, compound 3a markedly reduced phosphorylation of MAPK/NF-κB pathway-related proteins and p65 translocation, consistent with the in vitro observations. In summary, administration of compound 3a prior to LPS suppressed ALI via inhibition of the MAPK/NF-κB pathway.
Topics: Acute Lung Injury; Animals; Apoptosis; Inflammation; Lipopolysaccharides; Male; Masoprocol; Mice; Mice, Inbred C57BL; Protective Agents; RAW 264.7 Cells
PubMed: 35085517
DOI: 10.1016/j.ejphar.2022.174777 -
The Analyst Feb 2022The concept of a reversible polymer displacement sensor mechanism for electrochemical glucose monitoring is demonstrated. A pyrene-derivatised boronic acid...
Polymer indicator displacement assay: electrochemical glucose monitoring based on boronic acid receptors and graphene foam competitively binding with poly-nordihydroguaiaretic acid.
The concept of a reversible polymer displacement sensor mechanism for electrochemical glucose monitoring is demonstrated. A pyrene-derivatised boronic acid chemo-receptor for glucose is adsorbed onto a graphene foam electrode. Spontaneous oxidative polymerisation of nordihydroguaiaretic acid (NHG) onto the graphene foam electrode leads to a redox active film (poly-NHG) covalently attached to the boronic acid receptors. Oxidation of poly-NHG frees the boronic acid receptors to interact with glucose from the solution phase, which is detected due to competitive binding when reduced poly-NHG re-binds to the boronic acid functional groups. The sensor shows the anticipated boronic acid selectivity of fructose > glucose. The ratio of charges under the voltammetric peaks for poly-NHG unbound and bound is employed for glucose sensing with an approximately linear analytical range from 1 to 50 mM glucose in aqueous pH 7 buffer. The new methodology is shown to give apparent saccharide - boronic acid binding constants and to work in human serum. Therefore, in the future it could be developed further for glucose monitoring.
Topics: Blood Glucose; Blood Glucose Self-Monitoring; Boronic Acids; Glucose; Graphite; Humans; Masoprocol; Polymers
PubMed: 35060574
DOI: 10.1039/d1an01991k -
Journal of Pharmaceutical and... Feb 2022The global transcription inhibitor terameprocol is being evaluated clinically as an oral formulation to treat high-grade glioma. A sensitive, reliable method was...
The global transcription inhibitor terameprocol is being evaluated clinically as an oral formulation to treat high-grade glioma. A sensitive, reliable method was developed to quantitate terameprocol using LC-MS/MS to perform detailed pharmacokinetic studies. Sample preparation involved protein precipitation using acetonitrile. Separation of terameprocol and the internal standard, Sorafenib-methyl-d3, was achieved with a Zorbax XDB C18 column (2.1 × 50 mm, 3.5 µm) and gradient elution over a 2-minute total analytical run time. A SCIEX 4500 or SCIEX 5500 triple quadrupole mass spectrometer operated in positive electrospray ionization mode was used for terameprocol detection. The assay range of 5-1000 ng/mL was demonstrated to be accurate (92.7-107.4%) and precise (CV ≤ 11.3%). A sample diluted 1:10 (v/v) was accurately quantitated. Terameprocol in plasma has been proven stable for at least 20 months when stored at -70 °C. The method was applied to the measurement of total plasma concentrations of terameprocol in a patient with a high-grade glioma receiving a 300 mg oral dose.
Topics: Chromatography, High Pressure Liquid; Chromatography, Liquid; Humans; Masoprocol; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry
PubMed: 34906921
DOI: 10.1016/j.jpba.2021.114525 -
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 -
Canadian Journal of Physiology and... Feb 2022Fingolimod (FTY720) inhibits Ca-permeable, Mg-sensitive channels called transient receptor potential melastatin 7 (TRPM7), but its effects on Ca paradox (CP) - induced...
Fingolimod (FTY720) inhibits Ca-permeable, Mg-sensitive channels called transient receptor potential melastatin 7 (TRPM7), but its effects on Ca paradox (CP) - induced myocardial damage has not been evaluated. We studied the effect of FTY720 on CP-induced myocardial damage and used other TRPM7 channel inhibitors nordihydroguaiaretic acid (NDGA) and Mg to test if any effect of FTY720 was via TRPM7 inhibition. Langendorff-perfused Wistar rat hearts were treated with FTY720 or NDGA and subjected to a CP protocol consisting of Ca depletion followed by Ca repletion. Hearts of rats pre-treated with MgSO were also subjected to CP. Hemodynamic parameters were measured using an intraventricular balloon, and myocardial infarct size was quantified using triphenyltetrazolium chloride stain. TRPM7 proteins in ventricular tissue were detected using immunoblot analysis. FTY720, but not NDGA, decreased CP-induced infarct size. Both FTY720 and NDGA minimized the CP-induced elevation of left ventricular end-diastolic pressure, but only FTY720 ultimately improved ventricular developed pressure. Mg pre-treatment had no effect on CP-induced infarct size, nor hemodynamic parameters during CP, nor the level of TRPM7 protein expression in ventricular tissue. Overall, FTY720 attenuated CP-induced myocardial damage, with potential therapeutic implications on Ca-mediated cardiotoxicity; however, the cardioprotective mechanism of FTY720 seems to be unrelated to TRPM7 channel modulation.
Topics: Animals; Calcium; Cardiotonic Agents; Fingolimod Hydrochloride; In Vitro Techniques; Magnesium; Male; Masoprocol; Myocardial Infarction; Rats, Wistar; TRPM Cation Channels; Rats
PubMed: 34559972
DOI: 10.1139/cjpp-2021-0381 -
Prostaglandins, Leukotrienes, and... Aug 2021Cytoplasmic availability of leukocyte lipid bodies is controlled by a highly regulated cycle of opposing biogenesis- and catabolism-related events. While leukocyte...
Cytoplasmic availability of leukocyte lipid bodies is controlled by a highly regulated cycle of opposing biogenesis- and catabolism-related events. While leukocyte biogenic machinery is well-characterized, lipid body catabolic mechanisms are yet mostly unknown. Here, we demonstrated that nordihydroguaiaretic acid (NDGA) very rapidly decreases the numbers of pre-formed lipid bodies within lipid body-enriched cytoplasm of mouse leukocytes - macrophages, neutrophils and eosinophils. NDGA mechanisms driving leukocyte lipid body disappearance were not related to loss of cell viability, 5-lipoxygenase inhibition, ATP autocrine/paracrine activity, or biogenesis inhibition. Proteasomal-dependent breakdown of lipid bodies appears to control NDGA-driven leukocyte lipid body reduction, since it was Bortezomib-sensitive in macrophages, neutrophils and eosinophils. Our findings unveil an acute NDGA-triggered lipid body catabolic event - a novel experimental model for the still neglected research area on leukocyte lipid body catabolism, additionally favoring further insights on proteasomal contribution to lipid body breakdown.
Topics: Animals; Eosinophils; Leukocytes; Lipid Droplets; Lipoxygenase Inhibitors; Macrophages; Masoprocol; Mice; Neutrophils; Proteasome Endopeptidase Complex
PubMed: 34303171
DOI: 10.1016/j.plefa.2021.102320 -
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 -
Antiviral Research Mar 2021The genus Orthobunyavirus are a group of viruses within arbovirus, with a zoonotic cycle, some of which could lead to human infection. A characteristic of these viruses...
The genus Orthobunyavirus are a group of viruses within arbovirus, with a zoonotic cycle, some of which could lead to human infection. A characteristic of these viruses is their lack of antiviral treatment or vaccine for its prevention. The objective of this work was to study the in vitro antiviral activity of nordihydroguaiaretic acid (NDGA), the most important active compound of Larrea divaricata Cav. (Zigophyllaceae), against Fort Sherman virus (FSV) as a model of Orthobunyavirus genus. At the same time, the effect of NDGA as a lipolytic agent on the cell cycle of this viral model was assessed. The method of reducing plaque forming units on LLC-MK2 cells was used to detect the action of NDGA on CbaAr426 and SFCrEq231 isolates of FSV. NDGA did not show virucidal effect, but it had antiviral activity with a similar inhibition in both isolates, which was dose dependent. It was established that the NDGA has a better inhibition 1-h post-internalization (p.i.), showing a different behavior in each isolate, which was dependent upon the time p.i. Since virus multiplication is dependent on host cell lipid metabolism, the antiviral effect of NDGA has been previously related to its ability to disturb the lipid metabolism, probably by interfering with the 5-lipoxigenase (5-LOX) and the sterol regulatory element-binding proteins (SREBP) pathway. We determined by using caffeic acid, a 5-LOX inhibitor, that the inhibition of this enzyme negatively affected the FSV replication; and by means of resveratrol, a SREBP1 inhibitor, it was showed that the negative regulation of this pathway only had action on the SFCrEq231 reduction. In addition, it was proved that the NDGA acts intracellularly, since it showed the ability to incorporate into LLC-MK2 cells. The information provided in this work converts the NDGA into a compound with antiviral activity in vitro against FSV (Orthobunyavirus), which can be subjected to structural modifications in the future to improve the activity.
Topics: Animals; Antiviral Agents; Arachidonate 5-Lipoxygenase; Dose-Response Relationship, Drug; Haplorhini; Lipid Metabolism; Masoprocol; Microbial Viability; Orthobunyavirus; Sterol Regulatory Element Binding Protein 1; Time Factors; Virus Replication
PubMed: 33444704
DOI: 10.1016/j.antiviral.2020.104976