-
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 -
Cell Death & Disease May 2017Acyl-CoA thioesterase 7 (ACOT7) is a major isoform of the ACOT family that catalyzes hydrolysis of fatty acyl-CoAs to free fatty acids and CoA-SH. However, canonical and...
Acyl-CoA thioesterase 7 (ACOT7) is a major isoform of the ACOT family that catalyzes hydrolysis of fatty acyl-CoAs to free fatty acids and CoA-SH. However, canonical and non-canonical functions of ACOT7 remain to be discovered. In this study, for the first time, ACOT7 was shown to be responsive to genotoxic stresses such as ionizing radiation (IR) and the anti-cancer drug doxorubicin in time- and dose-dependent manners. ACOT7 knockdown induced cytostasis via activation of the p53-p21 signaling pathway without a DNA damage response. PKCζ was specifically involved in ACOT7 depletion-mediated cell cycle arrest as an upstream molecule of the p53-p21 signaling pathway in MCF7 human breast carcinoma and A549 human lung carcinoma cells. Of the other members of the ACOT family, including ACOT1, 4, 8, 9, 11, 12, and 13 that were expressed in human, ACOT4, 8, and 12 were responsive to genotoxic stresses. However, none of those had a role in cytostasis via activation of the PKCζ-p53-p21 signaling pathway. Analysis of the ACOT7 prognostic value revealed that low ACOT7 levels prolonged overall survival periods in breast and lung cancer patients. Furthermore, ACOT7 mRNA levels were higher in lung cancer patient tissues compared to normal tissues. We also observed a synergistic effect of ACOT7 depletion in combination with either IR or doxorubicin on cell proliferation in breast and lung cancer cells. Together, our data suggest that a low level of ACOT7 may be involved, at least in part, in the prevention of human breast and lung cancer development via regulation of cell cycle progression.
Topics: A549 Cells; Antineoplastic Agents; Cell Cycle; Cell Cycle Checkpoints; Cyclin-Dependent Kinase Inhibitor p21; DNA Damage; Down-Regulation; Doxorubicin; Drug Synergism; Humans; MCF-7 Cells; Masoprocol; Protein Kinase C; Radiation, Ionizing; Signal Transduction; Thiolester Hydrolases; Tumor Suppressor Protein p53
PubMed: 28518146
DOI: 10.1038/cddis.2017.202 -
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 -
Scientific Reports Feb 2019Growing evidence implicates α-synuclein aggregation as a key driver of neurodegeneration in Parkinson's disease (PD) and other neurodegenerative disorders. Herein, the...
Growing evidence implicates α-synuclein aggregation as a key driver of neurodegeneration in Parkinson's disease (PD) and other neurodegenerative disorders. Herein, the molecular and structural mechanisms of inhibiting α-synuclein aggregation by novel analogs of nordihydroguaiaretic acid (NDGA), a phenolic dibenzenediol lignan, were explored using an array of biochemical and biophysical methodologies. NDGA analogs induced modest, progressive compaction of monomeric α-synuclein, preventing aggregation into amyloid-like fibrils. This conformational remodeling preserved the dynamic adoption of α-helical conformations, which are essential for physiological membrane interactions. Oxidation-dependent NDGA cyclization was required for the interaction with monomeric α-synuclein. NDGA analog-pretreated α-synuclein did not aggregate even without NDGA-analogs in the aggregation mixture. Strikingly, NDGA-pretreated α-synuclein suppressed aggregation of naïve untreated aggregation-competent monomeric α-synuclein. Further, cyclized NDGA reduced α-synuclein-driven neurodegeneration in Caenorhabditis elegans. The cyclized NDGA analogs may serve as a platform for the development of small molecules that stabilize aggregation-resistant α-synuclein monomers without interfering with functional conformations yielding potential therapies for PD and related disorders.
Topics: Amyloid; Animals; Caenorhabditis elegans; Cell Membrane; Humans; Masoprocol; Parkinson Disease; Phospholipids; Protein Aggregation, Pathological; alpha-Synuclein
PubMed: 30814575
DOI: 10.1038/s41598-019-39480-z -
BMC Cancer Apr 2015Fibroblast growth factor receptor 1 (FGFR1) is correlated closely with the occurrence and development of lung cancer. FGFR1 kinase inhibitors have exhibited significant...
BACKGROUND
Fibroblast growth factor receptor 1 (FGFR1) is correlated closely with the occurrence and development of lung cancer. FGFR1 kinase inhibitors have exhibited significant therapeutic effects against non-small-cell lung cancer. Recently, non-ATP competitive FGFR1 inhibitors have attracted extensive attention due to their low side effects.
METHODS
Caliper Mobility Shift Assay was used for FGFR1 inhibition test and kinase inhibitory mode study. Hoechst staining and Annexin V/PI staining were used to evaluate the cell apoptosis induction. Western blot were then performed to confirm the intracellular FGFR1 inhibition and apoptotic protein expression. Finally, the anti-tumor effect and mechanism of Af23 and Ad23 was evaluated in vivo.
RESULTS
In this study, we designed, synthesized and discovered two novel non-ATP competitive FGFR1 inhibitors, Af23 and Ad23, using NDGA as a leading compound. They had IC50 values of 0.6 μM and 1.4 μM against FGFR1 kinase, respectively. The kinase inhibitory assay carried at different ATP concentrations showed that the FGFR1 inhibition mode of both Ad23 and Af23 was non-ATP-competitive. Further, Af23 and Ad23 significantly suppressed FGFR1 phosphorylation and cell proliferation in non-small-cell lung cancer (NSLCLC) H460 cells and induced cell apoptosis. Af23 and Ad23 also showed significant anti-tumor activity in the H460 xenograft mouse model, accompanied with the inhibition of FGFR1, ERK, and AKT phosphorylation without exhibiting toxicity.
CONCLUSIONS
These results indicate that Ad23 and Af23 are potential agents for the treatment of non-small-cell lung cancer. This work also provides a structural lead for the design of new non-ATP-competitive FGFR1 inhibitors.
Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Drug Discovery; Humans; Lung Neoplasms; Masoprocol; Mice; Phosphorylation; Protein Kinase Inhibitors; Receptor, Fibroblast Growth Factor, Type 1; Xenograft Model Antitumor Assays
PubMed: 25880284
DOI: 10.1186/s12885-015-1307-9 -
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 -
Veterinary Immunology and... May 2010Mast cells play an important role in both innate and acquired immunity as well as several pathological conditions including allergy, arthritis and neoplasia. They...
Mast cells play an important role in both innate and acquired immunity as well as several pathological conditions including allergy, arthritis and neoplasia. They influence these processes by producing a variety of mediators including cytokines, chemokines and eicosanoids. Very little is currently known about the spectrum of inflammatory mediators, particularly eicosanoids (prostaglandins and leukotrienes), produced by canine mast cells. This is important since modulating mast cell derived eicosanoids may help in the treatment of autoimmune and inflammatory disorders. The purpose of this study was to investigate the spectrum of eicosanoids produced by normal canine mast cells and to evaluate the effects of cytokines and non-steroidal anti-inflammatory mediators (NSAIDS) on eicosanoid production and release. Canine bone marrow derived cultured mast cells (cBMCMCs) expressed COX-1, COX-2, and 5-LOX and synthesized and released PGD2, PGE2, LTB4, and LTC4 following activation by a variety of stimuli. The selective COX-2 NSAIDs carprofen (Rimadyl) and deracoxib (Deramaxx) inhibited PGD2 and PGE2 production but only slightly inhibited LTB4 and LTC4. The mixed COX-1/COX-2 inhibitor piroxicam blocked PGD2 and PGE2 production, but upregulated LTC4 following treatment while tepoxilan (Zubrin), a pan COX/LOX inhibitor, markedly reduced the production of all eicosanoids. The LOX inhibitor nordihydroguaiaretic acid (NDGA) prevented LTB4/LTC4 release and BMBMC degranulation. Pre-incubation of cBMCMCs with IL-4 and SCF sensitized these cells to degranulation in response to substance P. In conclusion, canine BMCMCs produce an array of eicosanoids similar to those produced by mast cells from other species. Tepoxilan appeared to be the most effective NSAID for blocking eicosanoid production and thus may be useful for modulating mast cell mediated responses in dogs.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 5-Lipoxygenase; Carbazoles; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Dogs; Leukotriene Antagonists; Leukotriene B4; Leukotriene C4; Leukotrienes; Masoprocol; Mast Cells; Piroxicam; Prostaglandin Antagonists; Prostaglandin D2; Prostaglandins; Pyrazoles; Sulfonamides
PubMed: 20036014
DOI: 10.1016/j.vetimm.2009.11.010 -
The Journal of Experimental Medicine Dec 1985Fragments of human lung parenchyma or bronchi were studied by high performance liquid chromatography, gas chromatography-mass spectrometry, and bioassay for the...
Studies on the release of leukotrienes and histamine by human lung parenchymal and bronchial fragments upon immunologic and nonimmunologic stimulation. Effects of nordihydroguaiaretic acid, aspirin, and sodium cromoglycate.
Fragments of human lung parenchyma or bronchi were studied by high performance liquid chromatography, gas chromatography-mass spectrometry, and bioassay for the biosynthesis of 5-lipoxygenase metabolites of arachidonic acid, and by radioenzymatic assay for the release of histamine, upon immunologic and nonimmunologic stimulation. Human lung parenchyma were passively sensitized with serum from timothy-positive allergic patients (radioallergosorbent test, 30-40%) and challenged with 0.5 microgram/ml of timothy allergen. Analysis of the incubation media showed the presence of LTB4, LTC4, LTD4, LTE4, and histamine. Maximum release of LTB4 and LTD4 was observed after 15 min of challenge (92.8 +/- 21, and 67.8 +/- 14 pmol/g tissue wet weight, respectively; mean +/- SEM) whereas maximum release of LTC4 was observed after 5 min of challenge (25 +/- 7.1 pmol). In parallel to leukotriene formation, histamine was released rapidly and reached a maximum after approximately 15 min of challenge (2.85 +/- 0.76 nmol/g tissue). When fragments of human lung parenchyma were stimulated with ionophore A23187 (4 microM), we observed a profile of leukotriene and histamine release similar to that seen in response to the allergen. Ionophore A23187 stimulated the release of two- to fivefold greater amounts of leukotrienes and histamine than did the allergen. Release of LTC4 and histamine was maximal after 5 min of stimulation (83 +/- 22.2 and 5.2 +/- 0.95 nmol/g tissue, respectively), whereas LTB4 and LTD4 release reached a maximum after 15 min (438 +/- 66.6 and 205 +/- 68 nmol/g tissue, respectively). In addition, human lung parenchyma metabolized LTB4 into omega-OH-LTB4 and omega-COOH-LTB4. This tissue also released 5-hydroxy-eicosatetraenoic acid (5-Hete), 12-Hete, and 15-Hete. Fragments of human lung bronchi also released a similar profile of leukotrienes (except LTC4) and histamine when challenged with the allergen or ionophore A23187. Maximum release of LTB4 and LTD4 by allergen or ionophore stimulation was observed after approximately 15 min (40 +/- 7.5 and 21 +/- 8 pmol/g tissue, respectively, upon allergen challenge; 100 +/- 13 and 47 +/- 10.6 pmol/g tissue, respectively, upon ionophore stimulation). The maximum release of histamine by bronchi was observed after approximately 15 min of allergen challenge and 5 min of ionophore stimulation (2.25 +/- 0.65 and 3.15 +/- 0.9 nmol/g tissue, respectively). The release of leukotrienes but not of histamine by human lung parenchyma upon both allergen and ionophore challenge was inhibited by nordihydroguaiaretic acid (NDGA) (ID50, 2 X 10(-6)M).(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Adjuvants, Immunologic; Arachidonate Lipoxygenases; Arachidonic Acid; Arachidonic Acids; Aspirin; Bronchi; Catechols; Cromolyn Sodium; Histamine Release; Humans; Kinetics; Leukotriene B4; Lipoxygenase; Lipoxygenase Inhibitors; Lung; Masoprocol; SRS-A
PubMed: 2415659
DOI: 10.1084/jem.162.6.1904 -
FEBS Letters Nov 1985Purified 5-lipoxygenase from potato tubers was inhibited strongly by vitamin E and its analogs. The inhibition by d-alpha-tocopherol was found to be irreversible and...
Purified 5-lipoxygenase from potato tubers was inhibited strongly by vitamin E and its analogs. The inhibition by d-alpha-tocopherol was found to be irreversible and non-competitive with respect to arachidonic acid. An IC50 of 5 microM was calculated for d-alpha-tocopherol. The inhibition appears to be unrelated to its antioxidant function. Binding studies with 14C-labelled d-alpha-tocopherol revealed that there is a strong interaction between vitamin E and 5-lipoxygenase. Tryptic digestion and peptide mapping of 5-lipoxygenase-vitamin E complex indicate that vitamin E binds strongly to a single peptide. These studies suggest that cellular vitamin E levels may have profound influence on the formation of leukotrienes.
Topics: Antioxidants; Butylated Hydroxytoluene; Catechols; Chromatography, Gel; Lipoxygenase; Lipoxygenase Inhibitors; Masoprocol; Solanum tuberosum; Vitamin E
PubMed: 3934003
DOI: 10.1016/0014-5793(85)80075-2 -
International Immunopharmacology Feb 2016Tuberculosis (TB) remains as a global health problem. The prevalence of this infection is related to the association with other diseases, such as HIV, neglect treatment...
Tuberculosis (TB) remains as a global health problem. The prevalence of this infection is related to the association with other diseases, such as HIV, neglect treatment and misuse of antibiotics. Hence, the identification of new drugs is required to eradicate TB. Possible alternatives to existing antibiotics include pure compounds extracted from medicinal plants, which are an important source of antimicrobial agents. The aim of this study was to evaluate the effect of nordihydroguaiaretic acid (NDGA) and α-mangostin on Mycobacterium tuberculosis growth and bacterial survival in infected macrophages derived from the human THP-1 cell line and monocytes. Our results show that both compounds directly inhibit M. tuberculosis growth in liquid medium with Minimal Inhibitory Concentrations (MIC) of 250 and 62 μg/mL respectively, likely through preventing bacterial replication. In addition, NDGA and α-mangostin were able to induce autophagy in human cells at lower concentrations (7 and 6 μg/mL, respectively) and contributed to the elimination of intracellular bacteria. NDGA and α-mangostin could be candidates for coadjuvant therapy in cases of drug-resistant TB, and their ability to enhance the immune response by promoting autophagy might contribute to TB treatment.
Topics: Autophagy; Cell Line; Humans; Macrophages; Masoprocol; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Tuberculosis, Pulmonary; Xanthones
PubMed: 26735610
DOI: 10.1016/j.intimp.2015.12.027