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Andrologia Apr 2018Nordihydroguaiaretic acid (NDGA) is a naturally occurring lignan with potent antioxidant activity. Currently, it is in clinical trials as anticancer agent. As there is...
Nordihydroguaiaretic acid (NDGA) is a naturally occurring lignan with potent antioxidant activity. Currently, it is in clinical trials as anticancer agent. As there is no earlier report on the effect of NDGA on spermatogenesis and fertility, this study was designed to investigate this aspect. Administration of NDGA to rats for 60 days produced degenerative changes in testis but had no effect on sperm DNA integrity test and androgen receptor expression. Ultrastructural studies revealed loss of integrity of cells in seminiferous tubules, vacuolation and presence of apoptotic bodies. Derangement of the outer dense fibres was noted in some sperm flagella. Acrosome formation appears to be normal. About 13.7% of epididymal spermatozoa had deformations like short tail or rounded head. This may explain the lower fertility index in NDGA-treated group. No external deformations in newborns were noted. In conclusion, NDGA may have adverse effects on spermatogenesis.
Topics: Animals; DNA Damage; Epididymis; Fertility; Male; Masoprocol; Rats; Rats, Wistar; Receptors, Androgen; Seminiferous Tubules; Sperm Count; Spermatogenesis; Spermatozoa; Testis
PubMed: 29110321
DOI: 10.1111/and.12916 -
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 -
IUBMB Life May 2018Multiple sclerosis (MS) is a poorly understood disease mechanistically. MOG35-55 peptide induced experimental autoimmune encephalomyelitis (EAE) is a broadly used model...
Multiple sclerosis (MS) is a poorly understood disease mechanistically. MOG35-55 peptide induced experimental autoimmune encephalomyelitis (EAE) is a broadly used model to study MS. Using this model we have earlier shown that the antioxidant tempol or the small molecule inhibitor of p38 SB203580 can effectively prevent EAE progression. This effect was mediated by means of regulating immune inflammation, signaling by the p38MAPK-SGK1 pathway, and oxidative stress. However, there is a need to test drugs that can be used in pharmacological intervention of EAE. Given that nordihydroguaiaretic Acid (NDGA) has been shown to possess anti-oxidant activity and capacity of antagonizing autoimmune inflammation, we tested the effect of NDGA in ameliorating EAE in the current study. NDGA showed significant beneficial effect against EAE with both anti-inflammation and antioxidant activity. NDGA could weaken the immune inflammation at least partly by inhibiting the oxidant stress-p38MAPK-SGK1 pathway representing a target for putative pharmacological intervention. © 2018 IUBMB Life, 70(5):432-436, 2018.
Topics: Animals; Demyelinating Diseases; Disease Progression; Encephalomyelitis, Autoimmune, Experimental; Female; Gene Expression Regulation; Heme Oxygenase-1; Immediate-Early Proteins; Immunologic Factors; Injections, Intraperitoneal; Masoprocol; Mice; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; Neuroprotective Agents; Oxidation-Reduction; Oxidative Stress; Peptide Fragments; Protein Serine-Threonine Kinases; p38 Mitogen-Activated Protein Kinases
PubMed: 29637686
DOI: 10.1002/iub.1739 -
American Journal of Physiology. Lung... Sep 2015Pulmonary arterial hypertension (PAH) is a disease characterized by thickening of pulmonary artery walls, elevated pulmonary vascular resistance, pulmonary vascular...
Pulmonary arterial hypertension (PAH) is a disease characterized by thickening of pulmonary artery walls, elevated pulmonary vascular resistance, pulmonary vascular thrombotic lesions, and right heart failure. Recent studies suggest that 15-lipoxygenase (15-LO)/15-hydroxyeicosatetraenoic acid (15-HETE) play an important role in PAH, acting on arterial walls. Here, we show evidence for the action of the 15-LO/15-HETE signaling in the pulmonary vascular thrombotic lesions in the experimental PAH models. Platelet deposition was augmented in rats exposed to hypoxia and Sugen 5416, which were both prevented by nordihydroguaiaretic acid (NDGA), a 15-LO inhibitor. Chronic hypoxic resulted in the platelet deposition specifically in pulmonary vasculature, which was reversed by 15-LO inhibitor. The 15-LO pathway mediated in the endothelial dysfunction induced by hypoxia in vivo. Meanwhile, 15-HETE positively regulated the generation of IL-6 and monocyte chemoattractant protein-1 (MCP-1). The coagulation and platelet activation induced by hypoxia were reversed by 15-LO inhibitor NDGA or the MCP-1 inhibitor synthesis inhibitor bindarit in rats. The 15-LO/15-HETE signaling promoted the coagulation and platelet activation, which was suppressed by MCP-1 inhibition. These results therefore suggest that 15-LO/15-HETE signaling plays a role in platelet activation and pulmonary vascular thrombosis in PAH, involving MCP-1.
Topics: Animals; Arachidonate 15-Lipoxygenase; Blood Platelets; Cells, Cultured; Chemokine CCL2; Cytokines; Humans; Hydroxyeicosatetraenoic Acids; Hypertension, Pulmonary; Hypoxia; Indazoles; Lipoxygenase Inhibitors; Male; Masoprocol; Platelet Activation; Propionates; Pulmonary Artery; RNA Interference; RNA, Small Interfering; Random Allocation; Rats; Rats, Wistar; Signal Transduction; Thrombosis; Vascular Resistance
PubMed: 26092993
DOI: 10.1152/ajplung.00004.2015 -
Laboratory Investigation; a Journal of... Oct 2017Nordihydroguaiaretic acid (NDGA) and its synthetic chiral analog dl-nordihydroguaiaretic acid (Nordy) show collective benefits in anti-tumor, and defending against viral...
Nordihydroguaiaretic acid (NDGA) and its synthetic chiral analog dl-nordihydroguaiaretic acid (Nordy) show collective benefits in anti-tumor, and defending against viral and bacterial infections. Here, we synthetized a new derivative-NDGA-P21 based on NDGA structure. Regardless of the structural similarity, NDGA-P21 exhibited stronger capability in suppression of glioblastoma (GBM) cell growth as compared to Nordy. Mechanically, NDGA-P21 is able to arrest cell cycle of GBM cells in G0/G1 phase, and to block cell proliferation sequentially. It is important to note that NDGA-P21 is able to impair the stemness of glioma stem-like cells (GSLCs) via measurement of colony formation and sphere formation. Taken together, the novel NDGA-based compound NDGA-P21 exhibits potential therty -20 apeutic implications through inhibiting proliferation of glioma cells and self-renewal capability of GSLCs.
Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Glioma; Humans; Masoprocol
PubMed: 28504686
DOI: 10.1038/labinvest.2017.46 -
European Journal of Medicinal Chemistry Jan 2018Exogenous supplementation of antioxidants with ROS scavenging activity would be a potential therapy to cerebral ischemia-reperfusion injury in stroke. In the present...
Exogenous supplementation of antioxidants with ROS scavenging activity would be a potential therapy to cerebral ischemia-reperfusion injury in stroke. In the present study, a series of NDGA analogues with attenuation oxidative stress by directly scavenging ROS and indirectly through keap1/Nrf2/ARE pathway activation were designed and synthesized. All analogues were found to effectively remove ROS directly by DPPH radical scavenging assay, and compound 3a conferred potent protection from the oxidative injury in PC12 cells via promoting Nrf2 to translocate into nucleus and increasing expression of heme oxygenase-1(HO-1), where strongly reduced intracellular ROS level indirectly. More importantly, 3a significantly reduced brain infarction after cerebral ischemia-reperfusion injury in rats subjected to transient middle cerebral artery occlusion (MCAO). Overall, our findings shown compound 3a could serve as a promising compound for the treatment of stroke.
Topics: Animals; Brain Ischemia; Cell Survival; Dose-Response Relationship, Drug; Drug Design; Hydrogen Peroxide; Male; Masoprocol; Molecular Structure; Neuroprotective Agents; PC12 Cells; Rats; Rats, Sprague-Dawley; Stroke; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 29126723
DOI: 10.1016/j.ejmech.2017.09.028 -
International Journal of Biological... Feb 2019This study demonstrates the antiglycation activity of Nordihydroguaiaretic acid, a lignin from the creosote bush (Larrea tridentate), which has also been proven to...
This study demonstrates the antiglycation activity of Nordihydroguaiaretic acid, a lignin from the creosote bush (Larrea tridentate), which has also been proven to assist in the treatment of cancer, neurological disorders, and cardiovascular complications. We determined the antiglycation activity of NDG based on spectroscopic analysis, molecular interactions and circular dichroism studies with albumin. It was also seen that NDG inhibits the aggregation of albumin, after glycation, using Thioflavin T binding and confocal imaging. Results suggest that NDG is a potent inhibitor of advanced glycation end products formation. NDG was found to impart protective effects on albumin by preventing glycation modification of lysine residues (Lys20, Phe36, Lys41, Lys131, and Lys132) due to glycation.
Topics: Animals; Cattle; Glycosylation; Masoprocol; Molecular Docking Simulation; Protein Aggregates; Protein Conformation; Serum Albumin, Bovine
PubMed: 30416092
DOI: 10.1016/j.ijbiomac.2018.10.173 -
Journal of Neurochemistry Sep 2015Lewy bodies, mainly composed of α-synuclein (αS), are pathological hallmarks of Parkinson's disease and dementia with Lewy bodies. Epidemiological studies showed that...
Lewy bodies, mainly composed of α-synuclein (αS), are pathological hallmarks of Parkinson's disease and dementia with Lewy bodies. Epidemiological studies showed that green tea consumption or habitual intake of phenolic compounds reduced Parkinson's disease risk. We previously reported that phenolic compounds inhibited αS fibrillation and destabilized preformed αS fibrils. Cumulative evidence suggests that low-order αS oligomers are neurotoxic and critical species in the pathogenesis of α-synucleinopathies. To develop disease modifying therapies for α-synucleinopathies, we examined effects of phenolic compounds (myricetin (Myr), curcumin, rosmarinic acid (RA), nordihydroguaiaretic acid, and ferulic acid) on αS oligomerization. Using methods such as photo-induced cross-linking of unmodified proteins, circular dichroism spectroscopy, the electron microscope, and the atomic force microscope, we showed that Myr and RA inhibited αS oligomerization and secondary structure conversion. The nuclear magnetic resonance analysis revealed that Myr directly bound to the N-terminal region of αS, whereas direct binding of RA to monomeric αS was not detected. Electrophysiological assays for long-term potentiation in mouse hippocampal slices revealed that Myr and RA ameliorated αS synaptic toxicity by inhibition of αS oligomerization. These results suggest that Myr and RA prevent the αS aggregation process, reducing the neurotoxicity of αS oligomers. To develop disease modifying therapies for α-synucleinopathies, we examined effects of phenolic compounds on α-synuclein (αS) oligomerization. Phenolic compounds, especially Myricetin (Myr) and Rosmarinic acid (RA), inhibited αS oligomerization and secondary structure conversion. Myr and RA ameliorated αS synaptic toxicity on the experiment of long-term potentiation. Our results suggest that Myr and RA prevent αS aggregation process and reduce the neurotoxicity of αS oligomers. Phenolic compounds are good candidates of disease modifying drugs for α-synucleinopathies.
Topics: Amyloid; Animals; Antioxidants; Cinnamates; Circular Dichroism; Coumaric Acids; Curcumin; Depsides; Drug Evaluation, Preclinical; Flavonoids; Hippocampus; Long-Term Potentiation; Masoprocol; Mice; Microscopy, Atomic Force; Models, Molecular; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Phenols; Polymerization; Protein Structure, Secondary; alpha-Synuclein; Rosmarinic Acid
PubMed: 26016728
DOI: 10.1111/jnc.13180 -
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 -
Lipids in Health and Disease Nov 2016Diabetes mellitus (DM) is a complex disease with alterations in metabolic and inflammatory markers. Stillman Salgado rats (eSS) spontaneously develop type 2 DM by middle...
Long chain polyunsaturated fatty acids (LCPUFAs) and nordihydroguaiaretic acid (NDGA) modulate metabolic and inflammatory markers in a spontaneous type 2 diabetes mellitus model (Stillman Salgado rats).
BACKGROUND
Diabetes mellitus (DM) is a complex disease with alterations in metabolic and inflammatory markers. Stillman Salgado rats (eSS) spontaneously develop type 2 DM by middle age showing progressive impairment of glucose tolerance with hyperglycemia, hypertriglyceridemia and hyperinsulinemia. We analyzed the effects of supplementation of ω-3 and ω-6 polyunsaturated fatty acids (PUFAs) with or without nordihydroguaiaretic acid (NDGA) added, an antioxidant and lipoxygenase inhibitor, on metabolic and inflammatory parameters in eSS rats to evaluate whether they can delay development and/or prevent progression of DM.
METHODS
After weaning, eSS rats received, intraperitoneally, once a month ω-3 (EPA 35% and DHA 40%-6.25 mg/Kg) or ω-6 (90% arachidonic acid- 6. 25 mg/Kg) for twelve months. Two additional groups of rats received 1.9 mg/kg NDGA added to ω-3 and ω-6 fatty acids. Blood samples were collected at day 40, and at the end of the 6th month and 12th month of age to determine plasma triglycerides (TGs), total plasma fatty acids (FA), A1C hemoglobin (HbA1C), C-reactive protein (CRP), gamma glutamyl transpeptidase (GGT), lipo and hydro peroxides, nitrites and IL-6 (in plasma and liver, kidney, and pancreas) and underwent oral glucose tolerance test (OGTT) as well. Wistar and eSS rats that received saline solution were used as controls.
RESULTS
Plasma lipids profile, TG, fasting and post-prandial blood glucose levels, and glycosylated HbA1C showed significant improvements in ω-3 and ω-3 + NDGA treated animals compared to eSS control group. ω-3 and ω-3 + NDGA groups showed an inverse correlation with fasting blood glucose and showed lower plasma levels of GGT, TG, and CRP. eSS rats treated with ω-3 LCPUFAs showed reduced level of inflammatory and oxidative indices in plasma and liver, kidney and pancreas tissues in comparison with eSS control (non-treated) and ω-6 treated groups.
CONCLUSIONS
eSS rats are a useful model to study type 2 DM pathophysiology and related inflammatory indices. ω-3 + NDGA supplementation, at the doses tested, ameliorated inflammatory, metabolic and oxidative stress markers studied.
Topics: Animals; Arachidonic Acid; Biomarkers; C-Reactive Protein; Diabetes Mellitus, Type 2; Dietary Supplements; Disease Models, Animal; Fatty Acids, Omega-3; Glycated Hemoglobin; Inflammation; Interleukin-6; Male; Masoprocol; Rats; Rats, Wistar; Triglycerides; gamma-Glutamyltransferase
PubMed: 27884155
DOI: 10.1186/s12944-016-0363-8