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Aging Cell Oct 2016The National Institute on Aging Interventions Testing Program (ITP) evaluates agents hypothesized to increase healthy lifespan in genetically heterogeneous mice. Each...
The National Institute on Aging Interventions Testing Program (ITP) evaluates agents hypothesized to increase healthy lifespan in genetically heterogeneous mice. Each compound is tested in parallel at three sites, and all results are published. We report the effects of lifelong treatment of mice with four agents not previously tested: Protandim, fish oil, ursodeoxycholic acid (UDCA) and metformin - the latter with and without rapamycin, and two drugs previously examined: 17-α-estradiol and nordihydroguaiaretic acid (NDGA), at doses greater and less than used previously. 17-α-estradiol at a threefold higher dose robustly extended both median and maximal lifespan, but still only in males. The male-specific extension of median lifespan by NDGA was replicated at the original dose, and using doses threefold lower and higher. The effects of NDGA were dose dependent and male specific but without an effect on maximal lifespan. Protandim, a mixture of botanical extracts that activate Nrf2, extended median lifespan in males only. Metformin alone, at a dose of 0.1% in the diet, did not significantly extend lifespan. Metformin (0.1%) combined with rapamycin (14 ppm) robustly extended lifespan, suggestive of an added benefit, based on historical comparison with earlier studies of rapamycin given alone. The α-glucosidase inhibitor, acarbose, at a concentration previously tested (1000 ppm), significantly increased median longevity in males and 90th percentile lifespan in both sexes, even when treatment was started at 16 months. Neither fish oil nor UDCA extended lifespan. These results underscore the reproducibility of ITP longevity studies and illustrate the importance of identifying optimal doses in lifespan studies.
Topics: Acarbose; Animals; Antioxidants; Drugs, Chinese Herbal; Estradiol; Fish Oils; Glycoside Hydrolase Inhibitors; Hand Strength; Longevity; Male; Masoprocol; Metformin; Mice; NF-E2-Related Factor 2; Rotarod Performance Test; Sirolimus; Survival Analysis; Ursodeoxycholic Acid; alpha-Glucosidases
PubMed: 27312235
DOI: 10.1111/acel.12496 -
Hepatology (Baltimore, Md.) Dec 2011Hepatitis C virus (HCV) relies on host lipid metabolic pathways for its replication, assembly, secretion, and entry. HCV induces de novo lipogenesis, inhibits...
UNLABELLED
Hepatitis C virus (HCV) relies on host lipid metabolic pathways for its replication, assembly, secretion, and entry. HCV induces de novo lipogenesis, inhibits β-oxidation, and lipoprotein export resulting in a lipid-enriched cellular environment critical for its proliferation. We investigated the effects of a hypolipidemic agent, nordihydroguaiaretic acid (NDGA), on host lipid/fatty acid synthesis and HCV life cycle. NDGA negated the HCV-induced alteration of host lipid homeostasis. NDGA decreased sterol regulatory element binding protein (SREBP) activation and enhanced expression of genes involved in β-oxidation. NDGA inhibited very low-density lipoprotein (VLDL) secretion by affecting mediators of VLDL biosynthesis. Lipid droplets (LDs), the neutral lipid storage organelles, play a key role in HCV morphogenesis. HCV induces accumulation and perinuclear distribution of LDs, whereas NDGA most notably reduced the overall number and increased the average size of LDs. The antiviral effects of NDGA resulted in reduced HCV replication and secretion.
CONCLUSION
NDGA-mediated alterations of host lipid metabolism, LD morphology, and VLDL transport appear to negatively influence HCV proliferation.
Topics: Antiviral Agents; Cell Line, Tumor; Hepacivirus; Humans; Hypolipidemic Agents; Lipid Metabolism; Lipogenesis; Lipoproteins, VLDL; Masoprocol; Organelles; Virus Replication
PubMed: 21858850
DOI: 10.1002/hep.24619 -
The Journal of Comparative Neurology Dec 1996Eicosanoids, produced from arachidonic acid by cyclooxygenases (COXs) and lipoxygenases (LIPOXs), are involved in numerous brain processes. To explore if brief and...
Eicosanoids, produced from arachidonic acid by cyclooxygenases (COXs) and lipoxygenases (LIPOXs), are involved in numerous brain processes. To explore if brief and noninjurious stimuli chronically alter expression of these enzymes, we examined the induction of COX-2 and LIPOX expression following unilateral neocortical spreading depression (SD). Expression was examined over time and in regions not experiencing SD (hippocampus) but synaptically connected to the site of stimulation (cortex). One hundred six male Wistar rats had SD induced via microinjection of 0.5 M KCl (0.5 M NaCl for sham) into left parietal cortex every 9 minutes for 1 or 3 hours. One hour before SD some animals received dexamethasone (Dex), mepacrine (Mep), indomethacin (Indo), nordihydroguaiaretic acid (Ndga), phenylephrine (Pe), sodium nitroprusside (Snp) with Pe, or N omega-nitro-L-arginine methyl ester (Lnam). Animals survived for 0, 3, or 6 hours, or 1, 2, 3, 7, 14, 21, or 28 days. Brains were processed immunohistochemically for COX-2 and LIPOX, and the optical density (OD) of the left and right cortex, dentate gyrus (DG), CA3, and CA1 immunoreactivity (IR) were measured. Induction was expressed as the log of left divided by right side OD for each region. COX-2 IR in the left cortex was elevated rapidly and was sustained for 21 days following SD. COX-2 IR was also elevated in the ipsilateral hippocampus not experiencing SD, with the rank order of induction as follows: DG > CA3 > CA1. Dex, Snp, and/or Pe significantly reduced the induction of COX-2. No changes in LIPOX IR were observed. These results show that long-term changes in COX-2 expression are induced by SD and these changes decrease with synaptic distance. Benign stimuli increase COX-2 expression and thus may influence brain function for extended periods and at distant locations.
Topics: Adrenergic alpha-Agonists; Animals; Antibody Specificity; Cerebral Cortex; Cortical Spreading Depression; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dexamethasone; Enzyme Inhibitors; Glucocorticoids; Hippocampus; Immunohistochemistry; Indomethacin; Isoenzymes; Lipoxygenase; Lipoxygenase Inhibitors; Male; Masoprocol; Nitroprusside; Phenylephrine; Prostaglandin-Endoperoxide Synthases; Quinacrine; Rats; Rats, Wistar; Synapses; Time Factors; Vasodilator Agents
PubMed: 8956110
DOI: 10.1002/(SICI)1096-9861(19961216)376:3<447::AID-CNE7>3.0.CO;2-2 -
Obesity (Silver Spring, Md.) Oct 2008To determine whether conjugated linoleic acid (CLA)-induced body fat loss is dependent upon metabolism of CLA by Delta6-desaturase, cyclooxygenase, or lipoxygenase.
OBJECTIVE
To determine whether conjugated linoleic acid (CLA)-induced body fat loss is dependent upon metabolism of CLA by Delta6-desaturase, cyclooxygenase, or lipoxygenase.
METHODS AND PROCEDURES
Mice were fed diets with or without CLA and inhibitors to either Delta6-desaturase (SC-26196), cyclooxygenase (aspirin), or lipoxygenase (nordihydroguaiaretic acid (NDGA)) for 2 weeks. Body fat percent, lean mass, fat pad weights, liver weight, and fatty acid concentrations were determined. A Delta6-desaturase index was calculated, and adipose tissue prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) concentrations were determined to confirm enzyme inhibition.
RESULTS
Inhibition of Delta6-desaturase and cyclooxygenase were confirmed. CLA caused a loss of body fat (P < 0.001). The body fat loss was blocked (P = 0.08) by the Delta6-desaturase inhibitor at a dose that decreased (P < 0.05) the calculated index. Aspirin and NDGA had no effect on body fat and did not interact with CLA.
DISCUSSION
Inhibition of Delta6-desaturase prevented CLA from being able to cause a body fat loss. Therefore, a desaturated metabolite of CLA appears to be involved in the CLA antiobesity effect. This effect of CLA does not seem dependent upon cyclooxygenase. Because lipoxygenase activity was not blocked by NDGA, we cannot draw conclusions about its importance in mediating the antiobesity effect of CLA.
Topics: Adipose Tissue; Adiposity; Animals; Aspirin; Cyclooxygenase Inhibitors; Dietary Fats; Dinoprostone; Eating; Enzyme Inhibitors; Leukotriene B4; Linoleic Acids, Conjugated; Linoleoyl-CoA Desaturase; Lipoxygenase; Lipoxygenase Inhibitors; Liver; Male; Masoprocol; Mice; Piperazines; Prostaglandin-Endoperoxide Synthases; Time Factors; Weight Gain
PubMed: 18719641
DOI: 10.1038/oby.2008.338 -
Oncotarget Dec 2016Tumor metastasis is a major cause leading to the deaths of cancer patients. Nordihydroguaiaretic acid (NDGA) is a natural product that has been demonstrated to show...
Tumor metastasis is a major cause leading to the deaths of cancer patients. Nordihydroguaiaretic acid (NDGA) is a natural product that has been demonstrated to show therapeutic values in multiple diseases. In this study, we report that NDGA can inhibit cell migration and tumor metastasis via a novel mechanism. NDGA suppresses NRP1 function by downregulating its expression, which leads to attenuated cell motility, cell adhesion to ECM and FAK signaling in cancer cells. Moreover, due to its cross-cell type activity on NRP1 suppression, NDGA also impairs angiogenesis function of endothelial cells and fibronectin assembly by fibroblasts, both of which are critical to promote metastasis. Based on these comprehensive effects, NDGA effectively suppresses tumor metastasis in nude mice model. Our findings reveal a novel mechanism underlying the anti-metastasis function of NDGA and indicate the potential value of NDGA in NRP1 targeting therapy for selected subtypes of cancer.
Topics: Animals; Cell Adhesion; Cell Line, Tumor; Cell Movement; Endothelial Cells; Fibroblasts; Focal Adhesion Protein-Tyrosine Kinases; Humans; Male; Masoprocol; Mice; Neoplasm Metastasis; Neuropilin-1; Prostatic Neoplasms
PubMed: 27863391
DOI: 10.18632/oncotarget.13368 -
Scientific Reports Feb 2016Agarwood, a highly valuable resinous and fragrant heartwood of Aquilaria plants, is widely used in traditional medicines, incense and perfume. Only when Aquilaria trees...
Agarwood, a highly valuable resinous and fragrant heartwood of Aquilaria plants, is widely used in traditional medicines, incense and perfume. Only when Aquilaria trees are wounded by external stimuli do they form agarwood sesquiterpene defensive compounds. Therefore, understanding the signaling pathway of wound-induced agarwood formation is important. Jasmonic acid (JA) is a well-characterized molecule that mediates a plant's defense response and secondary metabolism. However, little is known about the function of endogenous JA in agarwood sesquiterpene biosynthesis. Here, we report that heat shock can up-regulate the expression of genes in JA signaling pathway, induce JA production and the accumulation of agarwood sesquiterpene in A. sinensis cell suspension cultures. A specific inhibitor of JA, nordihydroguaiaretic acid (NDGA), could block the JA signaling pathway and reduce the accumulation of sesquiterpene compounds. Additionally, compared to SA and H2O2, exogenously supplied methyl jasmonate has the strongest stimulation effect on the production of sesquiterpene compounds. These results clearly demonstrate the central induction role of JA in heat-shock-induced sesquiterpene production in A. sinensis.
Topics: Acetates; Cell Culture Techniques; Cyclopentanes; Gene Expression Regulation, Plant; Heat-Shock Proteins; Heat-Shock Response; Hot Temperature; Masoprocol; Oxylipins; Plant Cells; Plant Proteins; Secondary Metabolism; Sesquiterpenes; Signal Transduction; Thymelaeaceae
PubMed: 26902148
DOI: 10.1038/srep21843 -
Blood Jan 1997The biochemical signaling mechanisms involved in transducing the effects of interferon-gamma (IFN-gamma) on human leukemia-derived HL-60 cell differentiation are not...
The biochemical signaling mechanisms involved in transducing the effects of interferon-gamma (IFN-gamma) on human leukemia-derived HL-60 cell differentiation are not completely understood. Recent studies established the existence of a sphingomyelin (SM) cycle that operates in response to the action of IFN-gamma on HL-60 cells, but the mechanisms by which IFN-gamma induces the SM hydrolysis remain unexplored. In this study, biochemical events mediating IFN-gamma effects on SM turnover and their specificity and role in HL-60 differentiation were investigated. The activation of the SM cycle by IFN-gamma occurred rapidly, with a decrease of approximately 20% in the SM level observed after 60 minutes with a concomitant increase in ceramide level. Treatment of HL-60 cells with IFN-gamma did not influence the 1,2-diacylglycerol concentration, intracellular Ca2+ concentration, or phospholipase D activity. IFN-gamma stimulated a rapid release of arachidonic acid (AA) from HL-60 cells; the effect was abolished by the pretreatment of cells with pertussis toxin, suggesting a role for a pertussis-toxin-sensitive G protein in IFN-gamma-mediated activation of phospholipase A2 (PLA2). At 4 to 120 hours after the stimulation of the cells with IFN-gamma, a significant increase in the particulate and soluble PLA2 activity was observed, corresponding to an increase in the level of immunoreactive cPLA2 in both cytosol and membrane fractions. The treatment of cells with tyrosine kinase inhibitor herbimycin A completely abolished the effect of IFN-gamma on PLA2 activity in membrane and cytosolic fractions, but had no effect on IFN-gamma-mediated early AA release suggesting dual mechanism of PLA2 activation. Melittin, potent activator of PLA2, and AA mimicked the effect of IFN-gamma on SM hydrolysis. Pretreatment of HL-60 cells with the PLA2 inhibitor, bromophenacyl bromide (BPB), or pertussis toxin abolished the effect of IFN-gamma on SM hydrolysis; exogenous addition of AA overcame the effects of BPB and pertussis toxin. Long-term exposure (5 days) of HL-60 cells to IFN-gamma caused an increase in nitroblue tetrazolium (NBT)-reducing and nonspecific esterase (NSE) activity and induced expression of Fc gamma RI (CD64) without significant effects on cell number, adherence, or phagocytic activity. The treatment of cells with AA or melittin induced NBT, NSE, and CD64 expression to the level similar to that observed with IFN-gamma, and no further increase was observed with the combination of IFN-gamma and AA or IFN-gamma and melittin. Treatment of HL-60 cells with indomethacin, an inhibitor of cyclo-oxygenase, and nordihydroguaiaretic acid (NDGA), an inhibitor of lipoxygenase, had no effects on IFN-gamma-mediated induction of CD64 expression. These studies indicate a key role for the phospholipase A2/AA pathway, as an early biochemical signal elicited by the occupation of IFN-gamma-receptor, in mediating IFN-gamma induction of the SM cycle and phenotypic changes associated with differentiation of HL-60 along monocytic lineage.
Topics: Antigens, CD; Arachidonic Acid; Benzoquinones; Calcium; Cell Differentiation; Ceramides; Cyclooxygenase Inhibitors; Diglycerides; Enzyme Activation; HL-60 Cells; Humans; Hydrolysis; Indomethacin; Interferon-gamma; Lactams, Macrocyclic; Lipoxygenase Inhibitors; Masoprocol; Melitten; Membrane Lipids; Monocytes; Pertussis Toxin; Phospholipase D; Phospholipases A; Phospholipases A2; Quinones; Receptors, IgG; Receptors, Interferon; Rifabutin; Signal Transduction; Sphingomyelins; Virulence Factors, Bordetella; Interferon gamma Receptor
PubMed: 8978280
DOI: No ID Found -
The Journal of Biological Chemistry Jun 1997Integrin-associated protein (IAP or CD47) is a receptor for the cell/platelet-binding domain (CBD) of thrombospondin-1 (TS1), the most abundant protein of platelet alpha...
Integrin-associated protein (IAP or CD47) is a receptor for the cell/platelet-binding domain (CBD) of thrombospondin-1 (TS1), the most abundant protein of platelet alpha granules. Although it associates with alphaIIbbeta3, IAP has no known function in platelets. TS1, the CBD, and an IAP agonist peptide (4N1K) from the CBD of TS1 activate the platelet integrin alphaIIbbeta3, resulting in platelet spreading on immobilized fibrinogen, stimulation of platelet aggregation, and enhanced tyrosine phosphorylation of focal adhesion kinase. Furthermore, 4N1K peptide selectively stimulates the phosphorylation of LYN and SYK and their association with FAK. The phosphorylation of SYK is blocked by pertussis toxin, implicating a Gi-like heterotrimeric G protein. IAP solublized from membranes of unstimulated platelets binds specifically to an affinity column of 4N1K peptide. Both alphaIIb and beta3 integrin subunits and c-Src bind along with IAP. This complex of proteins is also detected with immunoprecipitation. Activation of platelets with the agonist peptide 4N1K results in the association of FAK with the IAP-alphaIIbbeta3 complex. Thus an important function of TS1 in platelets is that of a secreted costimulator of alphaIIbbeta3 whose unique properties result in its localization to the platelet surface and the fibrin clot.
Topics: Amino Acid Sequence; Antigens, CD; Blood Platelets; CD47 Antigen; Carrier Proteins; Cell Adhesion Molecules; Chromatography, Affinity; Enzyme Precursors; Fibrinogen; Humans; Indomethacin; Intracellular Signaling Peptides and Proteins; Macromolecular Substances; Masoprocol; Membrane Glycoproteins; Peptide Fragments; Pertussis Toxin; Platelet Activation; Platelet Aggregation; Platelet Glycoprotein GPIIb-IIIa Complex; Protein-Tyrosine Kinases; Syk Kinase; Thrombospondins; Virulence Factors, Bordetella
PubMed: 9169439
DOI: 10.1074/jbc.272.23.14740 -
Proceedings of the National Academy of... May 1996Arachidonic acid (AA) metabolites derived from both cyclooxygenase (COX) and lipoxygenase (LOX) pathways transduce a variety of signals related to cell growth. Here, we...
Arachidonic acid (AA) metabolites derived from both cyclooxygenase (COX) and lipoxygenase (LOX) pathways transduce a variety of signals related to cell growth. Here, we report that the AA LOX pathway also functions as a critical regulator of cell survival and apoptosis. Rat Walker 256 (W256) carcinosarcoma cells express 12-LOX and synthesize 12(S)- and 15(S)-hydroxyeicosatetraenoic acids as their major LOX metabolites. W256 cells transfected with 12-LOX-specific antisense oligonucleotide or antisense oligonucleotides directed to conserved regions of LOXs underwent time- and dose-dependent apoptosis. Likewise, treatment of W256 cells with various LOX but not COX inhibitors induced apoptotic cell death, which could be partially inhibited by exogenous 12(S)- or 15(S)-hydroxyeicosatetraenoic acids. The W256 cell apoptosis induced by antisense oligos and LOX inhibitors was followed by a rapid downregulation of bcl-2 protein, a dramatic decrease in the bcl-2/bax ratio, and could be suppressed by bcl-2 overexpression. In contrast, p53, which is wild type in W256 cells, did not undergo alterations during apoptosis induction. The results suggest that the LOX pathway plays an important physiological role in regulating apoptosis.
Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Apoptosis; Arachidonate 12-Lipoxygenase; Base Sequence; Cell Division; Cell Line; Cell Survival; Female; Homeostasis; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Leukotriene C4; Leukotrienes; Lipid Peroxides; Lipoxins; Masoprocol; Molecular Sequence Data; Oligonucleotides, Antisense; Plasmids; Rats; Transfection
PubMed: 8643560
DOI: 10.1073/pnas.93.11.5241 -
Biochimica Et Biophysica Acta Nov 2004Inhibition of the accumulation of amyloid beta-peptide (Abeta) and the formation of beta-amyloid fibrils (fAbeta) from Abeta, as well as the destabilization of preformed...
Inhibition of the accumulation of amyloid beta-peptide (Abeta) and the formation of beta-amyloid fibrils (fAbeta) from Abeta, as well as the destabilization of preformed fAbeta in the CNS would be attractive therapeutic targets for the treatment of Alzheimer's disease (AD). We previously reported that nordihydroguaiaretic acid (NDGA) and wine-related polyphenols inhibit fAbeta formation from Abeta(1-40) and Abeta(1-42) as well as destabilizing preformed fAbeta(1-40) and fAbeta(1-42) dose-dependently in vitro. Using fluorescence spectroscopic analysis with thioflavin T and electron microscopic studies, we examined the effects of polymeric polyphenol, tannic acid (TA) on the formation, extension, and destabilization of fAbeta(1-40) and fAbeta(1-42) at pH 7.5 at 37 degrees C in vitro. We next compared the anti-amyloidogenic activities of TA with myricetin, rifampicin, tetracycline, and NDGA. TA dose-dependently inhibited fAbeta formation from Abeta(1-40) and Abeta(1-42), as well as their extension. Moreover, it dose-dependently destabilized preformed fAbetas. The effective concentrations (EC50) of TA for the formation, extension and destabilization of fAbetas were in the order of 0-0.1 microM. Although the mechanism by which TA inhibits fAbeta formation from Abeta as well as destabilizes preformed fAbeta in vitro is still unclear, it could be a key molecule for the development of therapeutics for AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Flavonoids; Kinetics; Masoprocol; Microscopy, Electron; Rifamycins; Tannins; Tetracycline; Thermodynamics
PubMed: 15511626
DOI: 10.1016/j.bbadis.2004.06.008