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The Journals of Gerontology. Series A,... Dec 2015Mesonordihydroguaiaretic acid (NDGA) extends murine lifespan. The studies reported here describe its dose dependence, effects on body weight, toxicity-related clinical...
Nordihydroguaiaretic Acid Extends the Lifespan of Drosophila and Mice, Increases Mortality-Related Tumors and Hemorrhagic Diathesis, and Alters Energy Homeostasis in Mice.
Mesonordihydroguaiaretic acid (NDGA) extends murine lifespan. The studies reported here describe its dose dependence, effects on body weight, toxicity-related clinical chemistries, and mortality-related pathologies. In flies, we characterized its effects on lifespan, food consumption, body weight, and locomotion. B6C3F1 mice were fed AIN-93M diet supplemented with 1.5, 2.5, 3.5, or 4.5 g NDGA/kg diet (1.59, 2.65, 3.71 and 4.77 mg/kg body weight/day) beginning at 12 months of age. Only the 3.5 mg/kg diet produced a highly significant increase in lifespan, as judged by either the Mantel-Cox log-rank test (p = .008) or the Gehan-Breslow-Wilcoxon test (p = .009). NDGA did not alter food intake, but dose-responsively reduced weight, suggesting it decreased the absorption or increased the utilization of calories. NDGA significantly increased the incidence of liver, lung, and thymus tumors, and peritoneal hemorrhagic diathesis found at necropsy. However, clinical chemistries found little evidence for overt toxicity. While NDGA was not overtly toxic at its therapeutic dosage, its association with severe end of life pathologies does not support the idea that NDGA consumption will increase human lifespan or health-span. The less toxic derivatives of NDGA which are under development should be explored as anti-aging therapeutics.
Topics: Animals; Antioxidants; Body Weight; Dose-Response Relationship, Drug; Drosophila; Eating; Energy Metabolism; Hemorrhagic Disorders; Homeostasis; Longevity; Male; Masoprocol; Mice; Neoplasms
PubMed: 25380600
DOI: 10.1093/gerona/glu190 -
Molecular and Cellular Endocrinology Dec 2019Creosote bush (Larrea tridentata)-derived nordihydroguaiaretic acid (NDGA) was shown to have profound effects on the core components of metabolic syndrome. This study...
Creosote bush (Larrea tridentata)-derived nordihydroguaiaretic acid (NDGA) was shown to have profound effects on the core components of metabolic syndrome. This study investigated the in vivo potential of NDGA for prevention or attenuation of the pathophysiologic abnormalities of NASH. A novel dietary NASH model with feeding C57BL/6J mice with a high trans-fat, high cholesterol and high fructose (HTF) diet, was used. The HTF diet fed mice exhibited obesity, insulin resistance, hepatic steatosis, fibrosis, inflammation, ER stress, oxidative stress, and liver injury. NDGA attenuated these metabolic abnormalities as well as hepatic steatosis and fibrosis together with attenuated expression of genes encoding fibrosis, progenitor and macrophage markers with no effect on the levels of mRNAs for lipogenic enzymes. NDGA increased expression of fatty acid oxidation genes. In conclusion, NDGA exerts anti-NASH/anti-fibrotic actions and raises the therapeutic potential of NDGA for treatment of NASH patients with fibrosis and other associated complications.
Topics: Animals; Antioxidants; Diet, High-Fat; Disease Models, Animal; Hyperlipidemias; Inflammation; Insulin Resistance; Larrea; Lipogenesis; Male; Masoprocol; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress
PubMed: 31415794
DOI: 10.1016/j.mce.2019.110538 -
Journal of Microbiology and... Sep 2022This study investigated the contribution of lipoxygenase (LOX) inhibitors, nordihydroguaiaretic acid (NDGA), tetra--methyl nordihydroguaiaretic acid (MN) and zileuton...
This study investigated the contribution of lipoxygenase (LOX) inhibitors, nordihydroguaiaretic acid (NDGA), tetra--methyl nordihydroguaiaretic acid (MN) and zileuton (ZIL), and thromboxane A2 (TXA) inhibitor 4,5-diphenylimidazole (DPI) in the proliferation of infection. None of the compounds affected the uptake of into the macrophages. We determined the effect of neutralizing leukotriene B4 (LTB4) receptor and showed that the uptake of the bacteria was inhibited at 30 min post-infection. MN treatment attenuated intracellular survival of at 2 h post-incubation but it was not observed in the succeeding time points. DPI treatment showed reduced survival of at 24 h post-incubation while blocking LTB4 receptor was observed to have a lower intracellular growth at 48 h post-incubation suggesting different action of the inhibitors in the course of the survival of within the cells. Reduced proliferation of the bacteria in the spleens of mice was observed in animals treated with ZIL or DPI. Increased serum cytokine level of TNF-α and MCP-1 was observed in mice treated with MN or ZIL while a lower IFN-γ level in ZIL-treated mice and a higher IL-12 serum level in DPI-treated mice were observed at 7 d post-infection. At 14 d post-infection, ZIL-treated mice displayed reduced serum level of IL-12 and IL-10. Overall, inhibition of 5-LOX or TXA or a combination therapy promises a potential alternative therapy against infection. Furthermore, strong ligands for LTB4 receptor could also be a good candidate for the control of infection.
Topics: Animals; Brucella abortus; Brucellosis; Cytokines; Interleukin-10; Interleukin-12; Leukotriene B4; Lipoxygenase Inhibitors; Lipoxygenases; Masoprocol; Mice; Receptors, Leukotriene B4; Thromboxane A2; Tumor Necrosis Factor-alpha
PubMed: 36039381
DOI: 10.4014/jmb.2207.07026 -
The Tohoku Journal of Experimental... Sep 2008Acoustic injury is a common cause of hearing loss for people in industrial societies. Cyclooxygenase (COX) and lipoxygenase (LOX) are two important enzymes involved in...
Acoustic injury is a common cause of hearing loss for people in industrial societies. Cyclooxygenase (COX) and lipoxygenase (LOX) are two important enzymes involved in arachidonic acid metabolism. Two COX isozymes are characterized, COX-1 and COX-2, that differ in terms of regulatory mechanisms of expression. Although COX-1, COX-2, and LOX are expressed in cochlea, their roles played in cochlear acoustic injury have not fully been evaluated. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit either COX or LOX, or both. This study evaluated the effects of NSAIDs on the functional recovery of the cochlea after acoustic injury. Mice were exposed to a 4-kHz pure tone of 128 dB SPL (sound pressure level) for 4 hours and received one of the following drugs for two weeks after acoustic overexposure: indomethacin (COX-1 inhibitor), meloxicam, SC58125, and CAY10404 (COX-2 inhibitors), and nordihydroguaiaretic acid (LOX inhibitor). The hearing ability was evaluated using an auditory brainstem response (ABR) before and after overexposure. The ABR threshold shifts, defined as subtraction between ABR thresholds before and after overexposure, were compared among the control and the medication groups at one and two weeks after acoustic overexposure. Treatment of mice with either indomethacin or nordihydroguaiaretic acid decreased the ABR threshold shifts after overexposure, indicating that COX-1 and LOX inhibitors exhibited protective effects against acoustic injury. In contrast, COX-2 inhibitors, meloxicam, SC58125, and CAY10404, showed no noticeable effects on the ABR threshold shifts. These findings suggest that COX-1 and LOX are involved in the pathogenesis of acoustic injury in cochlea.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Auditory Threshold; Cochlea; Cyclooxygenase 1; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Evoked Potentials, Auditory, Brain Stem; Hair Cells, Auditory; Hearing Loss, Noise-Induced; Indomethacin; Isoxazoles; Lipoxygenase Inhibitors; Masoprocol; Meloxicam; Mice; Mice, Inbred Strains; Neuroprotective Agents; Pyrazoles; Sulfones; Thiazines; Thiazoles
PubMed: 18719338
DOI: 10.1620/tjem.216.53 -
BMC Complementary and Alternative... Aug 2019Oxidative stress is an imbalance between the levels of reactive oxygen species (ROS), reactive nitrogen species (RNS) and endogenous antioxidants. The aetiology and...
BACKGROUND
Oxidative stress is an imbalance between the levels of reactive oxygen species (ROS), reactive nitrogen species (RNS) and endogenous antioxidants. The aetiology and pathogenesis of several oral diseases are attributed to this process. The antioxidant enzymes secreted in the saliva by submandibular glands maintain oral health through the scavenging of ROS. The objective of this work was to study the capacity of an aqueous extract of L. divaricata (AE), and its majority compound, nordihydroguariaretic acid (NDGA), to modulate the pro-oxidant/antioxidant status in submandibular glands in a model of oxidative stress induced by streptozotocin (STZ) in rats.
METHODS
To induce oxidative stress with STZ, a group of animals was treated i.p. with 1 X PBS (control group) and other group was injected i.p. once with STZ (60 mg/kg). Ten days after the treatment, blood samples were taken from the tail vain to determine the glucose levels. Animals with glucose values ≥300 mg/ml were selected. The submandibular glands of control and STZ treated animals were incubated with either the AE (500 μg/ml) or with NDGA (1.5 μg/ml), and the content of malondialdehyde (MDA), protein carbonyl groups, ROS and RNS, and the activity and expression of peroxidase (Px), superoxide dismutase (SOD) and inducible nitric oxide synthase (iNOS) were assayed.
RESULTS
AE decreased the levels of MDA (P < 0.01) and protein carbonyl groups (P < 0.05), and modulated the levels of ROS such as hydrogen peroxide (HO)(P < 0.01), superoxide anion (O) (P < 0.05) and nitric oxide (NO) (P < 0.05) in relation to the modulation of Px and iNOS expression. NDGA was found to be involved in these effects.
CONCLUSIONS
The antioxidant activity of the AE in the submandibular glands would allow the maintenance of the antioxidant pool to prevent oral oxidative diseases.
Topics: Animals; Antioxidants; Diabetes Mellitus, Experimental; Female; Larrea; Malondialdehyde; Masoprocol; Oxidative Stress; Oxidoreductases; Plant Extracts; Rats; Rats, Wistar; Submandibular Gland
PubMed: 31438933
DOI: 10.1186/s12906-019-2636-z -
Suppression of heat- and polyglutamine-induced cytotoxicity by nonsteroidal anti-inflammatory drugs.European Journal of Biochemistry Nov 2004We have shown that sodium salicylate activates the heat shock promoter and induces the expression of heat shock proteins (hsps), with a concomitant increase in the...
We have shown that sodium salicylate activates the heat shock promoter and induces the expression of heat shock proteins (hsps), with a concomitant increase in the thermotolerance of cells. To determine whether these effects are generally displayed by nonsteroidal anti-inflammatory drugs (NSAIDs), we examined the effects of a cyclooxygenase inhibitor, indomethacin, and a lipoxygenase inhibitor, nordihydroguaiaretic acid. Both inhibitors up-regulated the hsp promoter at 37 degrees C through the activation of heat shock factors, and increased cellular levels of hsps in mammalian cells, although the degree of the expression of hsps and thermotolerance of cells differed depending on the drugs. Furthermore, NSAIDs such as sodium salicylate and indomethacin suppressed the protein aggregation and apoptosis caused by an expanded polyglutamine tract in a cellular model of polyglutamine disease. These findings suggest that NSAIDs generally induce the expression of hsps in mammalian cells and may be used for the protection of cells against deleterious stressors and neurodegenerative diseases.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; COS Cells; Cell Line; Cell Survival; Chlorocebus aethiops; Chromatin; Cyclooxygenase Inhibitors; Gene Expression; Heat-Shock Proteins; Hot Temperature; Indomethacin; Lipoxygenase Inhibitors; Masoprocol; Mice; Mice, Inbred C3H; Microscopy, Confocal; Peptides; Promoter Regions, Genetic; Sodium Salicylate
PubMed: 15560796
DOI: 10.1111/j.1432-1033.2004.04419.x -
The Journal of Clinical Investigation Aug 1995Previous studies from other laboratories suggest that linoleic acid and its metabolites, hydroperoxyoctadecadienoic acids, play an important role in modulating the...
Linoleic acid and its metabolites, hydroperoxyoctadecadienoic acids, stimulate c-Fos, c-Jun, and c-Myc mRNA expression, mitogen-activated protein kinase activation, and growth in rat aortic smooth muscle cells.
Previous studies from other laboratories suggest that linoleic acid and its metabolites, hydroperoxyoctadecadienoic acids, play an important role in modulating the growth of some cells. A correlation has been demonstrated between hydroperoxyoctadecadienoic acids and conditions characterized by abnormal cell growth such as atherosclerosis and psoriasis. To determine if linoleic acid and its metabolites modulate cell growth in atherosclerosis, we measured DNA synthesis, protooncogene mRNA expression, and mitogen-activated protein kinase (MAPK) activation in vascular smooth muscle cells (VSMC). Linoleic acid induces DNA synthesis, c-fos, c-jun, and c-myc mRNA expression and MAPK activation in VSMC. Furthermore, nordihydroguaiaretic acid, a potent inhibitor of the lipoxygenase system, significantly reduced the growth-response effects of linoleic acid in VSMC, suggesting that conversion of linoleic acid to hydroperoxyoctadecadienoic acids (HPODEs) is required for these effects. HPODEs also caused significant induction of DNA synthesis, protooncogene mRNA expression, and MAPK activation in growth-arrested VSMC, suggesting that linoleic acid and its metabolic products, HPODEs, are potential mitogens in VSMC, and that conditions such as oxidative stress and lipid peroxidation which provoke the production of these substances may alter VSMC growth.
Topics: Animals; Aorta, Thoracic; Calcium-Calmodulin-Dependent Protein Kinases; Cell Division; Enzyme Activation; Gene Expression Regulation; Genes, fos; Genes, jun; Genes, myc; Linoleic Acid; Linoleic Acids; Lipid Peroxidation; Lipid Peroxides; Lipoxygenase; Male; Masoprocol; Muscle Development; Muscle, Smooth, Vascular; Oxidative Stress; Rats; Rats, Sprague-Dawley
PubMed: 7635978
DOI: 10.1172/JCI118130 -
Yakugaku Zasshi : Journal of the... Apr 2010The conversion of soluble, nontoxic amyloid beta-peptide (Abeta) to aggregated, toxic Abeta rich in beta-sheet structures by seeded polymerization is considered to be... (Review)
Review
The conversion of soluble, nontoxic amyloid beta-peptide (Abeta) to aggregated, toxic Abeta rich in beta-sheet structures by seeded polymerization is considered to be the key step in the development of Alzheimer's disease. Accumulated evidence suggests that lipid rafts (microdomains) in membranes mainly composed of sphingolipids (gangliosides and sphingomyelin) and cholesterol play a pivotal role in this process. Our model membrane studies revealed the following mechanism of Abeta aggregation in membranes. Soluble Abeta with unordered structures specifically binds to raft-like membranes containing a ganglioside cluster, the formation of which is facilitated by cholesterol. The membrane-bound Abeta forms an alpha-helix-rich structure at lower densities. At higher densities, Abeta undergoes a conformational transition to a beta-sheet-rich structure that can serve as a seed for amyloid fibril formation. This model was confirmed at a cellar level using rat pheochromocytoma PC12 cells. Amyloid fibrils formed in lipid rafts were cytotoxic, whereas fibrils formed in solution were almost nontoxic and had different morphologies. Thus, the role of membranes in Abeta fibrillization is not merely the acceleration of Abeta aggregation but the generation of toxic fibrils. Furthermore, nordihydroguaiaretic acid was found to effectively inhibit the ganglioside-induced amyloidogenesis by preventing the binding of Abeta to the membrane.
Topics: Agglutination; Alzheimer Disease; Amyloid beta-Peptides; Animals; Depression, Chemical; Gangliosides; Humans; Masoprocol; Membrane Microdomains; Protein Binding; Protein Conformation; Rats
PubMed: 20371994
DOI: 10.1248/yakushi.130.511 -
European Journal of Biochemistry Nov 2002Although the role of arachidonic acid (AA) in the regulation of steroidogenesis is well documented, the mechanism for AA release is not clear. Therefore, the aim of this...
Although the role of arachidonic acid (AA) in the regulation of steroidogenesis is well documented, the mechanism for AA release is not clear. Therefore, the aim of this study was to characterize the role of an acyl-CoA thioesterase (ARTISt) and an acyl-CoA synthetase as members of an alternative pathway in the regulation of the intracellular levels of AA in steroidogenesis. Purified recombinant ARTISt releases AA from arachidonoyl-CoA (AA-CoA) with a Km of 2 micro m. Antibodies raised against recombinant acyl-CoA thioesterase recognize the endogenous protein in both adrenal tissue and Y1 adrenal tumor cells by immunohistochemistry and immunocytochemistry and Western blot. Stimulation of Y1 cells with ACTH significantly stimulated endogenous mitochondrial thioesterases activity (1.8-fold). Nordihydroguaiaretic acid (NDGA), an inhibitor of AA release known to affect steroidogenesis, affects the in vitro activity of recombinant ARTISt and also the endogenous mitochondrial acyl-CoA thioesterases. ACTH-stimulated steroid synthesis in Y1 cells was significantly inhibited by a synergistic effect of NDGA and triacsin C an inhibitor of the AA-CoA synthetase. The apparent IC50 for NDGA was reduced from 50 micro m to 25, 7.5 and 4.5 micro m in the presence of 0.1, 0.5 and 2 micro m triacsin C, respectively. Our results strongly support the existence of a new pathway of AA release that operates in the regulation of steroid synthesis in adrenal cells.
Topics: Acyltransferases; Adrenal Glands; Animals; Arachidonic Acid; Blotting, Western; Cholesterol; Coenzyme A Ligases; Dose-Response Relationship, Drug; Escherichia coli; Escherichia coli Proteins; Hormones; Immunohistochemistry; Kinetics; Masoprocol; Mice; Mitochondria; Recombinant Proteins; Thiolester Hydrolases; Triazenes
PubMed: 12423359
DOI: 10.1046/j.1432-1033.2002.03267.x -
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