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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 -
GeroScience Apr 2024The Caenorhabditis Intervention Testing Program (CITP) is an NIH-funded research consortium of investigators who conduct analyses at three independent sites to identify...
The Caenorhabditis Intervention Testing Program (CITP) is an NIH-funded research consortium of investigators who conduct analyses at three independent sites to identify chemical interventions that reproducibly promote health and lifespan in a robust manner. The founding principle of the CITP is that compounds with positive effects across a genetically diverse panel of Caenorhabditis species and strains are likely engaging conserved biochemical pathways to exert their effects. As such, interventions that are broadly efficacious might be considered prominent compounds for translation for pre-clinical research and human clinical applications. Here, we report results generated using a recently streamlined pipeline approach for the evaluation of the effects of chemical compounds on lifespan and health. We studied five compounds previously shown to extend C. elegans lifespan or thought to promote mammalian health: 17α-estradiol, acarbose, green tea extract, nordihydroguaiaretic acid, and rapamycin. We found that green tea extract and nordihydroguaiaretic acid extend Caenorhabditis lifespan in a species-specific manner. Additionally, these two antioxidants conferred assay-specific effects in some studies-for example, decreasing survival for certain genetic backgrounds in manual survival assays in contrast with extended lifespan as assayed using automated C. elegans Lifespan Machines. We also observed that GTE and NDGA impact on older adult mobility capacity is dependent on genetic background, and that GTE reduces oxidative stress resistance in some Caenorhabditis strains. Overall, our analysis of the five compounds supports the general idea that genetic background and assay type can influence lifespan and health effects of compounds, and underscores that lifespan and health can be uncoupled by chemical interventions.
Topics: Animals; Humans; Aged; Antioxidants; Masoprocol; Caenorhabditis elegans; Caenorhabditis; Longevity; Health Promotion; Plant Extracts; Tea; Mammals
PubMed: 37923874
DOI: 10.1007/s11357-023-00978-0 -
Molecules (Basel, Switzerland) Oct 2022Fish by-product oil and lemon oil have potential applications as active ingredients in many industries, including cosmetics, pharmaceuticals and food. However, the...
Fish by-product oil and lemon oil have potential applications as active ingredients in many industries, including cosmetics, pharmaceuticals and food. However, the physicochemical properties, especially the poor stability, compromised the usage. Generally, nanoemulsions were used as an approach to stabilize the oils. This study employed an ultrasonication method to form oil-in-water nanoemulsion of lemon and fish by-product oils (NE-FLO). The formulation is produced at a fixed amount of 2 wt% fish by-product oil, 8 wt% lemon oil, 10 wt% surfactant, 27.7 wt% co-surfactants and 42 min of ultrasonication time. The size, polydispersity index (PDI) and zeta potential obtained were 44.40 nm, 0.077, and -5.02 mV, respectively. The biological properties, including antioxidant, antibacterial, cell cytotoxicity, and anti-inflammatory, showed outstanding performance. The antioxidant activity is comparable without any significant difference with ascorbic acid as standard and is superior to pure lemon oil. NE-FLO successfully inhibits seven Gram-positive and seven Gram-negative bacterial strains. NE-FLO's anti-inflammatory activity is 99.72%, comparable to nordihydroguaiaretic acid (NDGA) as the standard. At a high concentration of 10,000 µg·mL, NE-FLO is non-toxic to normal skin cells. These findings demonstrate that the NE-FLO produced in this study has significant potential for usage in various industries.
Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Emulsions; Fish Oils; Masoprocol; Plant Oils; Surface-Active Agents; Water
PubMed: 36235261
DOI: 10.3390/molecules27196725 -
Phytomedicine : International Journal... Nov 2022Dengue virus (DENV) is considered one of the most important pathogens in the world causing 390 million infections each year. Currently, the development of vaccines...
BACKGROUND
Dengue virus (DENV) is considered one of the most important pathogens in the world causing 390 million infections each year. Currently, the development of vaccines against DENV presents some shortcomings and there is no antiviral therapy available for its infection. An important challenge is that both treatments and vaccines must be effective against all four DENV serotypes. Nordihydroguaiaretic acid (NDGA), isolated from Larrea divaricata Cav. (Zygophyllaceae) has shown a significant inhibitory effect on a broad spectrum of viruses, including DENV serotypes 2 and 4.
PURPOSE
We evaluated the in vitro virucidal and antiviral activity of NDGA on DENV serotype 1 (DENV1), including the study of its mechanism of action, to provide more evidence on its antiviral activity.
METHODS
The viability of viral particles was quantified by the plaque-forming unit reduction method. NDGA effects on DENV1 genome and viral proteins were evaluated by qPCR and immunofluorescence, respectively. Lysosomotropic activity was assayed using acridine orange and neutral red dyes.
RESULTS
NDGA showed in vitro virucidal and antiviral activity against DENV1. The antiviral effect would be effective within the first 2 h after viral internalization, when the uncoating process takes place. In addition, we determined by qPCR that NDGA decreases the amount of intracellular RNA of DENV1 and, by immunofluorescence, the number of cells infected. These results indicate that the antiviral effect of NDGA would have an intracellular mechanism of action, which is consistent with its ability to be incorporated into host cells. Considering the inhibitory activity of NDGA on the cellular lipid metabolism, we compared the antiviral effect of two inhibitors acting on two different pathways of this type of metabolism: 1) resveratrol that inhibits the sterol regulatory element of binding proteins, and 2) caffeic acid that inhibits the 5-lipoxygenase (5-LOX) enzyme. Only caffeic acid produced an inhibitory effect on DENV1 infection. We studied the lysosomotropic activity of NDGA on host cells and found, for the first time, that this compound inhibited the acidification of cell vesicles which would prevent DENV1 uncoating process.
CONCLUSION
The present work contributes to the knowledge of NDGA activity on DENV. We describe its activity on DENV1, a serotype different to those that have been already reported. Moreover, we provide evidence on which stage/s of the viral replication cycle NDGA exerts its effects. We suggest that the mechanism of action of NDGA on DENV1 is related to its lysosomotropic effect, which inhibits the viral uncoating process.
Topics: Acridine Orange; Antiviral Agents; Arachidonate 5-Lipoxygenase; Caffeic Acids; Coloring Agents; Dengue Virus; Masoprocol; Neutral Red; RNA; Resveratrol; Serogroup; Sterols; Viral Proteins; Virus Replication
PubMed: 36126544
DOI: 10.1016/j.phymed.2022.154424 -
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 -
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 -
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 -
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 -
Pediatric Rheumatology Online Journal Mar 2024Chronic non-bacterial osteomyelitis (CNO) is a rare, non-infection- related inflammatory disorder that affects children and teens. Clinical manifestations of CNO range...
INTRODUCTION
Chronic non-bacterial osteomyelitis (CNO) is a rare, non-infection- related inflammatory disorder that affects children and teens. Clinical manifestations of CNO range widely from moderate, time-limited, monofocal inflammation of the bone to extreme multifocal or chronically active inflammation of the bone.
OBJECTIVES
The main aim of this study was to explore the correlation between musculoskeletal (MSK) symptoms and health-related quality of life (HRQoL) in patients with CNO.
METHODS
Children and adults with CNO and their parents were asked to answer a web-based survey. The survey consisted of multiple questions centered around demographic, clinical and therapeutic data, MSK discomfort form based on the Nordic MSK Questionnaire and HRQoL based on Pediatric Quality of Life Inventory-4 (PedsQL-4) and PedsQL rheumatology module. The inclusion criteria included diagnosis of CNO before the age of 18. Patients who had malignancies or any chronic rheumatic, MSK, neurological disease prior to CNO onset were excluded.
RESULTS
There was a total of 68 participants, mostly females (66.2%), with median age 14 years and median disease duration 4.75 years. The median number of bones affected by CNO was 5 and ranged from 1 to 24 bones. Among the studied patients, 45 patients (66.2%) had MSK manifestations at the last month. The most commonly affected part was ankle and feet (26.5%). Regarding HRQoL, patients with MSK manifestations had lower scores than did patients without in PedsQL-4 (p < 0.001) including domains of physical functioning (p < 0.001), emotional functioning (p = 0.033), social functioning (p < 0.001) and school functioning (p = 0.007) in addition to lower scores in PedsQL rheumatology module (p < 0.001) including domains of pain and hurt (p < 0.001), daily activities (p < 0.001), treatment (p = 0.035), worry (p = 0.001) and communication (p < 0.001).
CONCLUSION
MSK manifestations have a negative impact on HRQoL in CNO patients. So, early identification and treatment are highly recommended.
Topics: Adult; Child; Female; Adolescent; Humans; Male; Quality of Life; Osteomyelitis; Foot; Musculoskeletal Diseases; Inflammation; Masoprocol
PubMed: 38448884
DOI: 10.1186/s12969-024-00971-7 -
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