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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 -
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 -
PloS One 2016Exogenous drugs that are used as antidote against chemotheray, inflammation or viral infection, gets absorbed and interacts reversibly to the major serum transport...
Exogenous drugs that are used as antidote against chemotheray, inflammation or viral infection, gets absorbed and interacts reversibly to the major serum transport protein i.e. albumins, upon entering the circulatory system. To have a structural guideline in the rational drug designing and in the synthesis of drugs with greater efficacy, the binding mechanism of an antineoplastic and anti-inflammatory drug Nordihydroguaiaretic acid (NDGA) with human and bovine serum albumins (HSA & BSA) were examined by spectroscopic and computational methods. NDGA binds to site II of HSA with binding constant (Kb) ~105 M-1 and free energy (ΔG) ~ -7.5 kcal.mol-1. It also binds at site II of BSA but with lesser binding affinity (Kb) ~105 M-1 and ΔG ~ -6.5 kcal.mol-1. The negative value of ΔG, ΔH and ΔS for both the albumins at three different temperatures confirmed that the complex formation process between albumins and NDGA is spontaneous and exothermic. Furthermore, hydrogen bonds and hydrophobic interactions are the main forces involved in complex formation of NDGA with both the albumins as evaluated from fluorescence and molecular docking results. Binding of NDGA to both the albumins alter the conformation and causes minor change in the secondary structure of proteins as indicated by the CD spectra.
Topics: Animals; Antineoplastic Agents; Cattle; Computer Simulation; Humans; Masoprocol; Models, Chemical; Protein Binding; Serum Albumin, Bovine; Spectrophotometry, Ultraviolet
PubMed: 27391941
DOI: 10.1371/journal.pone.0158833 -
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 -
Journal of Translational Medicine Apr 2010NSC-741909 is a novel anticancer agent that can effectively suppress the growth of several cell lines derived from lung, colon, breast, ovarian, and kidney cancers. We...
BACKGROUND
NSC-741909 is a novel anticancer agent that can effectively suppress the growth of several cell lines derived from lung, colon, breast, ovarian, and kidney cancers. We recently showed that NSC-741909-induced antitumor activity is associated with sustained Jun N-terminal kinase (JNK) activation, resulting from suppression of JNK dephosphorylation associated with decreased protein levels of MAPK phosphatase-1. However, the mechanisms of NSC-741909-induced antitumor activity remain unclear. Because JNK is frequently activated by oxidative stress in cells, we hypothesized that reactive oxygen species (ROS) may be involved in the suppression of JNK dephosphorylation and the cytotoxicity of NSC-741909.
METHODS
The generation of ROS was measured by using the cell-permeable nonfluorescent compound H2DCF-DA and flow cytometry analysis. Cell viability was determined by sulforhodamine B assay. Western blot analysis, immunofluorescent staining and flow cytometry assays were used to determine apoptosis and molecular changes induced by NSC-741909.
RESULTS
Treatment with NSC-741909 induced robust ROS generation and marked MAPK phosphatase-1 and -7 clustering in NSC-741909-sensitive, but not resistant cell lines, in a dose- and time-dependent manner. The generation of ROS was detectable as early as 30 min and ROS levels were as high as 6- to 8-fold above basal levels after treatment. Moreover, the NSC-741909-induced ROS generation could be blocked by pretreatment with antioxidants, such as nordihydroguaiaretic acid, aesculetin, baicalein, and caffeic acid, which in turn, inhibited the NSC-741909-induced JNK activation and apoptosis.
CONCLUSION
Our results demonstrate that the increased ROS production was associated with NSC-741909-induced antitumor activity and that ROS generation and subsequent JNK activation is one of the primary mechanisms of NSC-741909-mediated antitumor cell activity.
Topics: Antioxidants; Apoptosis; Caspase 8; Cell Line, Tumor; Cell Proliferation; Cluster Analysis; Drug Screening Assays, Antitumor; Dual-Specificity Phosphatases; Enzyme Activation; Humans; Indoles; Inhibitory Concentration 50; JNK Mitogen-Activated Protein Kinases; Lung Neoplasms; Masoprocol; Mitogen-Activated Protein Kinase Phosphatases; Oxidative Stress; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-jun; RNA, Small Interfering; Reactive Oxygen Species
PubMed: 20398386
DOI: 10.1186/1479-5876-8-37 -
Cellular Physiology and Biochemistry :... 2012We investigated the unknown molecular mechanisms of Interleukin-1 (IL-1β)-induced cartilage aggrecan degeneration by aggrecanase (ADAMTS-A Disintegrin And...
BACKGROUND/AIMS
We investigated the unknown molecular mechanisms of Interleukin-1 (IL-1β)-induced cartilage aggrecan degeneration by aggrecanase (ADAMTS-A Disintegrin And Metalloproteinase with ThromboSpondin motifs) in human articular chondrocytes, a model mimicking human arthritis.
METHODS
Chondrocytes were pretreated with various pharmacological inhibitors and then stimulated with IL-1β for 24 h. ADAMTS-4 expression or activity was studied by RT-PCR or ELISA and other proteins measured by Western blotting.
RESULTS
MAP kinase kinase-specific inhibitor, U0126 inhibited IL-1-induced phosphorylation of ERK1/2 and down-regulated ADAMTS-4 expression and activity. Protein 38 inhibitor, SB203580 down-regulated the phosphorylation of p38 and its target, activating transcription factor-2 (ATF-2), ADAMTS-4 mRNA and activity. C-Jun N-terminal kinase (JNK) inhibitor, SP600125 diminished IL-1-stimulated JNK phosphorylation, ADAMTS-4 mRNA expression and enzyme activity. A c-fos/lipoxygenase pathway inhibitor and antioxidant, nordihydroguaiaretic acid (NDGA) significantly suppressed ADAMTS-4 mRNA induction and activity. Activating protein (AP-1) and nuclear factor kappa B (NF-ĸB) transcription factor inhibitors, curcumin and pyrrolidine dithiocarbamate (PDTC) partially inhibited ADAMTS-4 induction and activity.
CONCLUSION
These results suggest partial involvement of ERK-, p38-and JNK-MAPKs as well as AP-1, ATF-2 and NF-ĸB transcription factors in IL-1-induced ADAMTS-4 in chondrocytes. Inhibition of these targets by the specific pharmacological agents could be useful for reducing aggrecanase-driven cartilage resorption in arthritis.
Topics: Anthracenes; Butadienes; Cartilage, Articular; Cells, Cultured; Chondrocytes; Curcumin; Endopeptidases; Gene Expression Regulation; Humans; Imidazoles; Interleukin-1beta; JNK Mitogen-Activated Protein Kinases; Lipoxygenases; Masoprocol; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; NF-kappa B; Nitriles; Phosphorylation; Pyridines; Pyrrolidines; RNA, Messenger; Thiocarbamates; Transcription Factor AP-1; p38 Mitogen-Activated Protein Kinases
PubMed: 22832115
DOI: 10.1159/000341438 -
Clinical Cancer Research : An Official... Oct 2011The transcription factor specificity protein 1 (Sp1) controls number of cellular processes by regulating the expression of critical cell cycle, differentiation, and...
PURPOSE
The transcription factor specificity protein 1 (Sp1) controls number of cellular processes by regulating the expression of critical cell cycle, differentiation, and apoptosis-related genes containing proximal GC/GT-rich promoter elements. We here provide experimental and clinical evidence that Sp1 plays an important regulatory role in multiple myeloma (MM) cell growth and survival.
EXPERIMENTAL DESIGN
We have investigated the functional Sp1 activity in MM cells using a plasmid with Firefly luciferase reporter gene driven by Sp1-responsive promoter. We have also used both siRNA- and short hairpin RNA-mediated Sp1 knockdown to investigate the growth and survival effects of Sp1 on MM cells and further investigated the anti-MM activity of terameprocol (TMP), a small molecule that specifically competes with Sp1-DNA binding in vitro and in vivo.
RESULTS
We have confirmed high Sp1 activity in MM cells that is further induced by adhesion to bone marrow stromal cells (BMSC). Sp1 knockdown decreases MM cell proliferation and induces apoptosis. Sp1-DNA binding inhibition by TMP inhibits MM cell growth both in vitro and in vivo, inducing caspase-9-dependent apoptosis and overcoming the protective effects of BMSCs.
CONCLUSIONS
Our results show Sp1 as an important transcription factor in myeloma that can be therapeutically targeted for clinical application by TMP.
Topics: Animals; Apoptosis; Bone Marrow Cells; Cell Cycle; Cell Proliferation; Cell Survival; Gene Knockdown Techniques; Humans; Male; Masoprocol; Melanoma, Experimental; Mice; Mice, SCID; Multiple Myeloma; RNA Interference; Sp1 Transcription Factor; Transcriptional Activation; Tumor Cells, Cultured
PubMed: 21856768
DOI: 10.1158/1078-0432.CCR-11-1036 -
Acta Neuropathologica Apr 2011Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. Oxidative damage has been associated with pathological neuronal loss in HD. The...
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. Oxidative damage has been associated with pathological neuronal loss in HD. The therapeutic modulation of oxidative stress and mitochondrial function using low molecular weight compounds may be an important strategy for delaying the onset and slowing the progression of HD. In the present study, we found a marked increase of 4-hydroxy-2-nonenal (4-HNE) adducts, a lipid peroxidation marker, in the caudate and putamen of HD brains and in the striatum of HD mice. Notably, 4-HNE immunoreactivity was colocalized with mutant huntingtin inclusions in the striatal neurons of R6/2 HD mice. Administration of nordihydroguaiaretic acid (NDGA), an antioxidant that functions by inhibiting lipid peroxidation, markedly reduced 4-HNE adduct formation in the nuclear inclusions of R6/2 striatal neurons. NDGA also protected cultured neurons against oxidative stress-induced cell death by improving ATP generation and mitochondrial morphology and function. In addition, NDGA restored mitochondrial membrane potential, mitochondrial structure, and synapse structure in the striatum of R6/2 mice and increased their lifespan. The present findings suggest that further therapeutic studies using NDGA are warranted in HD and other neurodegenerative diseases characterized by increased oxidative stress and altered mitochondrial function.
Topics: Adenosine Triphosphate; Age Factors; Aldehydes; Analysis of Variance; Animals; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Embryo, Mammalian; Glutamic Acid; Humans; Huntingtin Protein; Huntington Disease; Imaging, Three-Dimensional; In Situ Nick-End Labeling; Indoles; Lipid Peroxidation; Lipoxygenase Inhibitors; Male; Masoprocol; Membrane Potential, Mitochondrial; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Mitochondria; Neostriatum; Nerve Tissue Proteins; Neurons; Nuclear Proteins; Oxidative Stress; Synapses; Tetrazolium Salts; Thiazoles; Trinucleotide Repeat Expansion
PubMed: 21161248
DOI: 10.1007/s00401-010-0788-5