NDGA citations are organized into topics. The text after a citation is edited for brevity and relevance. Please consult the originals using the included links. NDGA Topics Aging Amyloid Biofilm Cancer Diabetes Immunity & Auto-Immunity Infection Inflammation Metabolic Syndrome Parkinson’s Disease Obesity Xtra Aging / Longevity Banse SA, et al (2023) - Antioxidants green tea extract and nordihydroguaiaretic acid confer species and strain-specific lifespan and health effects in Caenorhabditis nematodes. Geroscience. 2023 Nov 4. doi: 10.1007/s11357-023-00978-0. [ABS] PMID: 37923874 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. … likely engaging conserved biochemical pathways to exert their effects …lifespan and health can be uncoupled by chemical interventions. Berkel C, et al (2021) - A collective analysis of lifespan-extending compounds in diverse model organisms, and of species whose lifespan can be extended the most by the application of compounds. Biogerontology. 2021 Dec;22(6):639-653. [ABS] PMID: 34687363 We found that, when data from all organisms studied were combined for each compound, aspirin resulted in the highest percent increase in average lifespan (52.01%), followed by minocycline (27.30%), N-acetyl cysteine (17.93%), nordihydroguaiaretic acid (17.65%) and rapamycin (15.66%), in average. Manda G, et al (2020) - Nordihydroguaiaretic Acid: From Herbal Medicine to Clinical Development for Cancer and Chronic Diseases. Front Pharmacol. 2020 Feb 28;11:151. [FULL TEXT] Nordihydroguaiaretic acid (NDGA) is a phenolic lignan obtained from Larrea tridentata, the creosote bush found in Mexico and USA deserts, that has been used in traditional medicine for the treatment of numerous diseases such as cancer, renal, cardiovascular, immunological, and neurological disorders, and even aging. …This review describes the current knowledge on NDGA, its targets and side effects, and its synthetic analogs as promising therapeutic agents, highlighting their mechanism of action and clinical projection towards therapy of neurodegenerative, liver, and kidney disease, as well as cancer. Tezil T, et al (2019) - Lifespan-increasing drug nordihydroguaiaretic acid inhibits p300 and activates autophagy. NPJ Aging Mech Dis. 2019 Oct 2;5:7. [FULL TEXT] Aging is characterized by the progressive loss of physiological function in all organisms. Remarkably, the aging process can be modulated by environmental modifications, including diet and small molecules. The natural compound nordihydroguaiaretic acid (NDGA) robustly increases lifespan in flies and mice, but its mechanism of action remains unclear. Here, we report that NDGA is an inhibitor of the epigenetic regulator p300. …we show that NDGA treatment induces autophagy. These findings identify p300 as a target of NDGA and provide mechanistic insight into its role in longevity. Awasthi S, et al (2019) - Nordihydroguaiaretic acid prevents glycation induced structural alterations and aggregation of albumin. Int J Biol Macromol. 2019 Feb 1;122:479-484. [ABS] 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. … Results suggest that NDGA 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 … due to glycation. Sadagurski M, et al (2017) - Anti-aging drugs reduce hypothalamic inflammation in a sex-specific manner. Aging Cell. 2017 Aug;16(4):652- 660. [FULL TEXT] Aging leads to hypothalamic inflammation, but does so more slowly in mice whose lifespan has been extended by mutations that affect GH/IGF-1 signals. Early-life exposure to GH by injection, or to nutrient restriction in the first 3 weeks of life, also modulate both lifespan and the pace of hypothalamic inflammation. Three drugs extend lifespan of UM-HET3 mice in a sex-specific way: acarbose (ACA), 17-α- estradiol (17αE2), and nordihydroguaiaretic acid (NDGA), with more dramatic longevity increases in males in each case. …the extent of drug-induced changes in hypothalamic inflammatory processes is sexually dimorphic in a pattern that parallels the effects of these agents on mouse longevity and that mimics the changes seen, in both sexes, of long-lived nutrient restricted or mutant mice. Strong R, et al (2016) - Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer. Aging Cell. 2016 Oct;15(5):872-84. [FULL TEXT] 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. Gnabre J, et al (2015) - Creosote bush lignans for human disease treatment and prevention: Perspectives on combination therapy. J Tradit Complement Med. 2015 Mar 12;5(3):119-26. [FULL TEXT] The medicinal properties of the most successful plant in the deserts of the western hemisphere, the creosote bush (Larrea tridentata), are evidenced by the long traditional usage of the plants by the Native Americans Indian tribes in Southwestern North America and the Amerindians from South America. … Only recently have further studies revealed other crucial activities of the same plant molecules as powerful agents against human immunodeficiency virus, human papillomavirus, cancer, neurodegenerative diseases, and symptoms of aging. Molecular mechanisms underlying the antiviral and anticancer activities have been elucidated and involve the inhibition of SP1 dependent gene transcription. Hernández-Damián J, et al (2014) - Paradoxical cellular effects and biological role of the multifaceted compound nordihydroguaiaretic acid. Arch Pharm (Weinheim). 2014 Oct;347(10):685-97. [ABS] Nordihydroguaiaretic acid (NDGA) is a phenolic compound obtained from the leaves of the evergreen desert shrub Larrea tridentata (Creosote bush), which has been used anciently in folk medicine for the treatment of multiple diseases. At the molecular level, NDGA is a potent scavenger of reactive oxygen species. Lipoxygenase inhibition by NDGA has been broadly studied over several cell models; however, NDGA exerts other antioxidant properties and cytoprotective effects in non- tumor cells, which are related with its role as modulator of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) antioxidant pathway. In contrast, in tumor cells NDGA exerts pro-apoptotic activity and anti-tumor effects. Different effects of NDGA have been observed in mitochondria, where NDGA prevents mitochondrial damage in non-tumor cells and induces loss of mitochondrial function in tumor cells. Moreover, NDGA exerts beneficial effects in diverse diseases like cancer, renal damage, Huntington's disease, Alzheimer's disease, and other neurodegenerative pathologies. This work represents a critical review about relevant NDGA mechanisms, cellular effects, and signal pathways involved with possible useful effects. Harrison DE, et al (2014) - Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell. 2014 Apr;13(2):273-82. [FULL TEXT] NDGA increased male median lifespan by 8–10% at three different doses, with P- values ranging from 0.04 to 0.005. Females did not show a lifespan benefit from NDGA, even at a dose that produced blood levels similar to those in males, which did show a strong lifespan benefit. Amyloid, Alzheimer’s Disease, Neurodegeneration Visser JA, et al (2023) - Nordihydroguaiaretic Acid (NDGA) Inhibits CsgA Polymerization, Bacterial Amyloid Biogenesis, and Biofilm Formation. Chembiochem. 2023 Sep 15;24(18):e202300266. [ABS] The natural product nordihydroguaiaretic acid (NDGA) found in the creosote bush is a curlicide. NDGA selectively inhibits in vitro polymerization of the bacterial amyloid protein CsgA and inhibits cellular amyloid biogenesis in E. coli. NDGA's curlicide activity is effective in inhibiting biofilm formation by pathogenic E. coli and Salmonella Typhimurium. Park H, et al (2023) - A three-dimensional spheroid co-culture system of neurons and astrocytes derived from Alzheimer's disease patients for drug efficacy testing. Cell Prolif. 2023 Jun;56(6):e13399. [FULL TEXT] …we describe a three-dimensional (3D) spheroid co-culture system of neurons and astrocytes derived from induced pluripotent stem cells-neural precursor cells (iPSCs- NPCs) of Alzheimer's disease (AD) patients or healthy individuals… patient-derived spheroids showed beta-amyloid (Aβ) accumulation … the neuroprotectants nordihydroguaiaretic acid (NDGA) and curcumin (CU) reduced the the levels of … beta-amyloid (Aβ) accumulation as revealed by thioflavin T (ThT) staining and ELISA. Daniels MJ, et al (2019) - Cyclized NDGA modifies dynamic α-synuclein monomers preventing aggregation and toxicity. Sci Rep. 2019 Feb 27;9(1):2937. [FULL TEXT] 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) … Strikingly, NDGA-pretreated α-synuclein suppressed aggregation of nave untreated aggregation-competent monomeric α-synuclein. Further, cyclized NDGA reduced α- synuclein-driven neurodegeneration in Caenorhabditis elegans. Siddique YH, et al (2017) - Protective effect of nordihydroguaiaretic acid (NDGA) on the transgenic Drosophila model of Alzheimer's disease. Chem Biol Interact. 2017 May 1;269:59-66. [ABS] Nusrat S, et al (2016) - Repositioning nordihydroguaiaretic acid as a potent inhibitor of systemic amyloidosis and associated cellular toxicity. Arch Biochem Biophys. 2016 Dec 15;612:78-90. [ABS] Nordihydroguaiaretic acid (NA) interferes in the amyloid fibrillogenesis process by interacting hydrophobically with the amino acid residues found in highly prone amyloid fibril forming region of HEWL as explicated by molecular docking results. The results recommend NA as a probable neuroprotective and promising inhibitor for the therapeutic advancement prospective against amyloid related diseases. Szwajgier D (2015) - Anticholinesterase activity of selected phenolic acids and flavonoids - interaction testing in model solutions. Ann Agric Environ Med. 2015;22(4):690-4. [ABS] Alzheimer's disease is a progressively developing neurodegenerative disorder of the central nervous system. The only present treatment of this disease is the use of acetyl- and butyrylcholinesterase inhibitors. … The anti-acetylcholinesterase activity of phenolic acids was as follows: homogentisic acid > 4-hydroxyphenylpyruvic acid > nordihydroguaiaretic acid > rosmarinic acid > caffeic acid > … Gnabre J, et al (2015) - Creosote bush lignans for human disease treatment and prevention: Perspectives on combination therapy. J Tradit Complement Med. 2015 Mar 12;5(3):119-26. [FULL TEXT] The medicinal properties of the most successful plant in the deserts of the western hemisphere, the creosote bush (Larrea tridentata), are evidenced by the long traditional usage of the plants by the Native Americans Indian tribes in Southwestern North America and the Amerindians from South America. … Only recently have further studies revealed other crucial activities of the same plant molecules as powerful agents against human immunodeficiency virus, human papillomavirus, cancer, neurodegenerative diseases, and symptoms of aging. Molecular mechanisms underlying the antiviral and anticancer activities have been elucidated and involve the inhibition of SP1 dependent gene transcription. Yamada M, et al (2015) - Natural Phenolic Compounds as Therapeutic and Preventive Agents for Cerebral Amyloidosis. Adv Exp Med Biol. 2015;863:79-94. [ABS] We investigated the effects of natural phenolic compounds, such as myricetin (Myr), rosmarinic acid (RA), ferulic acid (FA), curcumin (Cur) and nordihydroguaiaretic acid (NDGA) on the aggregation of amyloid β-protein (Aβ), using in vitro and in vivo models of cerebral Aβ amyloidosis. The in vitro studies revealed that these phenolic compounds efficiently inhibit oligomerization as well as fibril formation of Aβ through differential binding, whilst reducing Aβ oligomer-induced synaptic and neuronal toxicity. Furthermore, a transgenic mouse model fed orally with such phenolic compounds showed significant reduction of soluble Aβ oligomers as well as of insoluble Aβ deposition in the brain. …These data, together with an updated review of the literature, indicate that natural phenolic compounds have anti-amyloidogenic effects on Aβ in addition to well-known anti-oxidative and anti-inflammatory effects, hence suggesting their potential as therapeutic and/or preventive agents for cerebral Aβ amyloidosis, including AD and cerebral amyloid angiopathy (CAA). Ferreira N, et al (2012) - Natural polyphenols as modulators of TTR amyloidogenesis: in vitro and in vivo evidences towards therapy. Amyloid. 2012 Jun;19 Suppl 1:39-42. [ABS] Several natural polyphenols have been reported to act on different amyloidogenic proteins inhibiting amyloid formation therefore we decided to test their effect on transthyretin (TTR) amyloid formation. We found that epigallocatechin-3-gallate (EGCG), curcumin and nordihydroguaiaretic acid (NDGA) bind to TTR and modulate its amyloidogenicity, in vitro, although through different mechanisms of action. Ferreira N, et al (2011) - Natural polyphenols inhibit different steps of the process of transthyretin (TTR) amyloid fibril formation. FEBS Lett. 2011 Aug 4;585(15):2424-30. [ABS] Several natural polyphenols with potent inhibitory effects on amyloid fibril formation have been reported. Herein, we studied modulation of transthyretin (TTR) fibrillogenesis by selected polyphenols. We demonstrate that both curcumin and nordihydroguaiaretic acid (NDGA) bind to TTR and stabilize the TTR tetramer. However, while NDGA slightly reduced TTR aggregation, curcumin strongly suppressed TTR amyloid fibril formation by generating small "off-pathway" oligomers and EGCG maintained most of the protein in a non-aggregated soluble form. This indicates alternative mechanisms of action supported by the occurrence of different non-toxic intermediates. Moreover, EGCG and curcumin efficiently disaggregated pre-formed TTR amyloid fibrils. Our studies, together with the safe toxicological profile of these phytochemicals may guide a novel pharmacotherapy for TTR-related amyloidosis targeting different steps in fibrillogenesis. Biofilm Visser JA, et al (2023) - Nordihydroguaiaretic Acid (NDGA) Inhibits CsgA Polymerization, Bacterial Amyloid Biogenesis, and Biofilm Formation. Chembiochem. 2023 Sep 15;24(18):e202300266. [ABS] The natural product nordihydroguaiaretic acid (NDGA) found in the creosote bush is a curlicide. NDGA selectively inhibits in vitro polymerization of the bacterial amyloid protein CsgA and inhibits cellular amyloid biogenesis in E. coli. NDGA's curlicide activity is effective in inhibiting biofilm formation by pathogenic E. coli and Salmonella Typhimurium. Fourie R, et al (2017) - Pseudomonas aeruginosa produces aspirin insensitive eicosanoids and contributes to the eicosanoid profile of polymicrobial biofilms with Candida albicans. Prostaglandins Leukot Essent Fatty Acids. 2017 Feb;117:36-46. [ABS] Nordihydroguaiaretic acid inhibited biofilm formation by P. aeruginosa… and this previously uncharacterized facet of interaction could facilitate novel therapeutic intervention against polymicrobial infection. Ooi N, et al (2015) - Redox-active compounds with a history of human use: antistaphylococcal action and potential for repurposing as topical antibiofilm agents. J Antimicrob Chemother. 2015 Feb;70(2):479-88. [FULL TEXT] The two most promising agents [celastrol and nordihydroguaiaretic acid (NDGA)] in respect of antibacterial potency and selective toxicity against bacterial membranes acted synergistically with gentamicin against biofilms, did not damage artificial skin following topical application and exhibited low resistance potential. … celastrol and NDGA represent particularly attractive candidates for development as topical antistaphylococcal biofilm treatments. Cancer and growth regulation Kimura K, et al (2023) - Tetra-O-methyl-nordihydroguaiaretic acid inhibits energy metabolism and synergistically induces anticancer effects with temozolomide on LN229 glioblastoma tumors implanted in mice while preventing obesity in normal mice that consume high-fat diets. PLoS One. 2023 May 25;18(5):e0285536. [FULL TEXT] Tetra-O-methyl-nordihydroguaiaretic acid (terameprocol; M4N), a global transcription inhibitor, in combination with a second anticancer drug induces strong tumoricidal activity and has the ability to suppress energy metabolism in cultured cancer cells. …. The dual ability of combination treatment with M4N to suppress both energy metabolism and oncometabolites shows that it is potentially an effective therapy for cancer. Manciu FS, et al (2022) - Assessing Nordihydroguaiaretic Acid Therapeutic Effect for Glioblastoma Multiforme. Sensors (Basel). 2022 Mar 30;22(7):2643. [FULL TEXT] NDGA phenolic lignan was selected as a potential therapeutic agent because of its reported beneficial effects in alleviating and inhibiting the formation of multi-organ malignant tumors. …The current analysis of NDGA's impact on GBM human cells demonstrates a reduction in the quantity of altered protein content and of reactive oxygen species (ROS)-damaged phenylalanine; results that correlate with the ROS scavenger and anti-oxidant properties of NDGA. …A very high dose results in cell structural and membrane damage that favors transformed protein overexpression. The information gained through this work is of substantial value for understanding NDGA's beneficial as well as detrimental bio-effects as a potential therapeutic drug for brain cancer. Gonçalves C, et al (2021) - Lipid Nanoparticles Containing Mixtures of Antioxidants to Improve Skin Care and Cancer Prevention. Pharmaceutics. 2021 Nov 30;13(12):2042. [FULL TEXT] In this work, three natural compounds, naringenin, nordihydroguaiaretic acid (NDGA), and kaempferol, were encapsulated into nanostructured lipid carriers (NLCs) aiming for the development of a formulation for cutaneous application with antioxidant properties. …Interestingly, the NDGA and kaempferol mixture provided an antioxidant synergic effect. The NLC formulations' cytotoxicity was tested in vitro in immortalized human keratinocytes (HaCaT). In addition, putative antioxidant effects of the developed NLC formulations against tert-butyl hydroperoxide (t-BHP)-induced oxidative stress were studied, and the NDGA-loaded NLC was revealed to be the one with the most protective effect. Therefore, we concluded that the naringenin, NDGA, and kaempferol incorporation into NLCs constitutes a promising strategy to increase their bioavailability and delivery to the skin. Rojas-Ochoa A, et al (2021) - The Polyphenols α-Mangostin and Nordihydroguaiaretic Acid Induce Oxidative Stress, Cell Cycle Arrest, and Apoptosis in a Cellular Model of Medulloblastoma. Molecules. 2021 Nov 29;26(23):7230. [FULL TEXT] 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, …These data highlight the potential usefulness of these compounds as an alternative strategy in medulloblastoma treatment Manda G, et al (2020) - Nordihydroguaiaretic Acid: From Herbal Medicine to Clinical Development for Cancer and Chronic Diseases. Front Pharmacol. 2020 Feb 28;11:151. [FULL TEXT] Nordihydroguaiaretic acid (NDGA) is a phenolic lignan obtained from Larrea tridentata, the creosote bush found in Mexico and USA deserts, that has been used in traditional medicine for the treatment of numerous diseases such as cancer, renal, cardiovascular, immunological, and neurological disorders, and even aging. …This review describes the current knowledge on NDGA, its targets and side effects, and its synthetic analogs as promising therapeutic agents, highlighting their mechanism of action and clinical projection towards therapy of neurodegenerative, liver, and kidney disease, as well as cancer. Mundhe N, et al (2019) - Differential effect of NDGA on cisplatin-induced nephrotoxicity in Spargue-Dawley rats. Immunopharmacol Immunotoxicol. 2019 Feb;41(1):68-75. [ABS] …pretreatment did not lead to significantly rise in oxidative stress, nitrosative stress, and inflammation along with restored the level of IL-10 in the kidney and preserved renal function. Moreover, NDGA post-treatment also presented nephroprotective effects, but the effects were not as positive as compared to NDGA pretreatment. In conclusion, these results indicate that NDGA pretreatment is renoprotective while on the other hand NDGA post-treatment is not so effective in cisplatin-induced nephrotoxicity. Bibikova MV, et al (2017) - Lipoxygenase Inhibitors Nordihydroguaiaretic Acid and Fungus Lecanicillum lecanii Extract Induce Death of Lymphoid Leukemia Cells. Bull Exp Biol Med. 2017 Jul;163(3):330-333. [ABS] Riaz M, et al (2017) - Screening of medicinal plant phytochemicals as natural antagonists of p53-MDM2 interaction to reactivate p53 functioning. Anticancer Drugs. 2017 Oct;28(9):1032-1038. [ABS] In most types of cancer, overexpression of murine double minute 2 (MDM2) often leads to inactivation of p53. …four phytochemicals including epigallocatechin gallate, alvaradoin M, alvaradoin E and nordihydroguaiaretic acid were found to be potential inhibitors of p53-MDM2 interaction. The screened phytochemicals, derived from natural extracts, may have negligible side effects and can be explored as potent antagonists of p53-MDM2 interactions, resulting in reactivation of the normal transcription of p53. Zhao QW, et al (2017) - NDGA-P21, a novel derivative of nordihydroguaiaretic acid, inhibits glioma cell proliferation and stemness. Lab Invest. 2017 Oct;97(10):1180-1187. [ABS] 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. … the novel NDGA-based compound NDGA-P21 exhibits potential therapeutic implications through inhibiting proliferation of glioma cells and self-renewal capability of GSLCs. Sjöstedt N, et al (2017) - Inhibition of Breast Cancer Resistance Protein and Multidrug Resistance Associated Protein 2 by Natural Compounds and Their Derivatives. Mol Pharm. 2017 Jan 3;14(1):135-146. [ABS] … three novel inhibitors, gossypin, nordihydroguaiaretic acid, and octyl gallate, were identified. Our results confirm that flavonoids are avid inhibitors of BCRP, and flavones and flavonols appear to be important subclasses of flavonoids for this inhibition. The strong inhibition of BCRP transport by some compounds suggests that their presence at high levels in the diet could cause food-drug interactions, but this seems to be a minor cause of concern for MRP2. Li X, et al (2016) - Nordihydroguaiaretic acid impairs prostate cancer cell migration and tumor metastasis by suppressing neuropilin 1. Oncotarget. 2016 Dec 27;7(52):86225-86238. [FULL TEXT] 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…. 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. Leon D, et al (2016) - Effect of nordihydroguaiaretic acid on cell viability and glucose transport in human leukemic cell lines. FEBS Open Bio. 2016 Aug 23;6(10):1000-1007. [FULL TEXT] The polyphenol nordihydroguaiaretic acid (NDGA) has antineoplastic properties, hence it is critical to understand its action at the molecular level. Here, we establish that NDGA inhibits glucose uptake and cell viability in leukemic HL-60 and U-937 cell lines. …. Our study shows for the first time that NDGA can act as inhibitor of the glucose transporter GLUT1. Kim SA, et al (2016) - Estrogenic compound attenuates angiotensin II- induced vascular smooth muscle cell proliferation through interaction between LKB1 and estrogen receptor α. J Pharmacol Sci. 2016 Sep;132(1):78-85. [ABS] The prevalence rate of cardiovascular disease is higher for males than females, and estradiol (E2) induces AMP-activated protein kinase (AMPK) activation, which is known to regulate proliferation of VSMC. We identified the estrogenic properties of nordihydroguaiaretic acid (NDGA, a lignan phytoestrogen) that inhibit VSMC proliferation and explored the underlying mechanisms. Both the phosphorylation and expression of LKB1 were increased by NDGA. In addition, NDGA significantly attenuated angiotensin II (Ang II)-induced VSMC proliferation. … Taken together, the beneficial effects of estrogenic compound (E2 and NDGA) on inhibition of VSMC proliferation are mediated by interaction between LKB1 and ERα, suggesting a potential mechanism for females having less cardiovascular disease. Note: LKB1 regulates cell polarity and scaffolding interactions. It is a tumor suppressor gene also known as serine/threonine protein kinase. It also regulates cell cycle and apoptosis. A germ line mutation leads to Peutz-Jeghers syndrome. Lu F, et al (2016) - Virtual Screening for Potential Allosteric Inhibitors of Cyclin-Dependent Kinase 2 from Traditional Chinese Medicine. Molecules. 2016 Sep 21;21(9):1259. [FULL TEXT] Cyclin-dependent kinase 2 (CDK2), a member of Cyclin-dependent kinases (CDKs), plays an important role in cell division and DNA replication. It is regarded as a desired target to treat cancer and tumor by interrupting aberrant cell proliferation. … Prostaglandin E1 and NDGA could be regarded as promising candidates for CDK2 allosteric inhibitors. Nusrat S, et al (2016) - A Comprehensive Spectroscopic and Computational Investigation to Probe the Interaction of Antineoplastic Drug Nordihydroguaiaretic Acid with Serum Albumins. PLoS One. 2016 Jul 8;11(7):e0158833. [FULL TEXT] Kimura K, et al (2016) - Tetra-O-Methyl Nordihydroguaiaretic Acid Broadly Suppresses Cancer Metabolism and Synergistically Induces Strong Anticancer Activity in Combination with Etoposide, Rapamycin and UCN-01. PLoS One. 2016 Feb 17;11(2):e0148685. [FULL TEXT] The ability of Tetra-O-methyl nordihydroguaiaretic acid (M4N) to induce rapid cell death in combination with Etoposide, Rapamycin, or UCN-01 was examined in LNCaP cells, both in cell culture and animal experiments. … The data overall indicate that M4N has profound specific negative impacts on a wide range of cancer metabolisms supporting the use of M4N combination for cancer treatments. Yarla NS, et al (2016) - Targeting arachidonic acid pathway by natural products for cancer prevention and therapy. Semin Cancer Biol. 2016 Oct;40-41:48-81. [ABS] Nordihydroguaiaretic acid and baicalein can be chemopreventive molecules against various cancers by inhibiting LOXs. …Arachidonic acid (AA) pathway, a metabolic process, plays a key role in carcinogenesis. Hence, AA pathway metabolic enzymes phospholipase A2s (PLA2s), cyclooxygenases (COXs) and lipoxygenases (LOXs) and their metabolic products, such as prostaglandins and leukotrienes, have been considered novel preventive and therapeutic targets in cancer. …Bioactive natural products are a good source for development of novel cancer preventive and therapeutic drugs, which have been widely used in clinical practice due to their safety profiles. Hua X, et al (2016) - Anti-tumor effect of ultrasound-induced Nordy- loaded microbubbles destruction. J Drug Target. 2016 Sep;24(8):703-8. [ABS] Synthesized dl-Nordihydroguaiaretic acid (dl-NGDA or "Nordy") can inhibit the growth of malignant human tumors, especially the tumor angiogenesis. However, its liposoluble nature limits its in vivo efficacy in the hydrosoluble circulation of human. … Ultrasonic microbubbles can be used as the carrier of Nordy and achieve its targeted release with improved anti-tumor efficacy in the condition of ultrasound-induced microbubbles destruction. Mundhe NA, et al (2015) - Nordihydroguaiaretic acid ameliorates cisplatin induced nephrotoxicity and potentiates its anti-tumor activity in DMBA induced breast cancer in female Sprague-Dawley rats. Int Immunopharmacol. 2015 Sep;28(1):634-42. [ABS] Cisplatin is a widely used antineoplastic drug, but its clinical usefulness is limited due to dose dependent nephrotoxicity. Nordihydroguaiaretic acid (NDGA) is a natural compound with broad pharmacological properties like antioxidant, anti-inflammatory and anticancer activity. … NDGA induced amelioration of cisplatin nephrotoxicity was clearly visible from significant reductions in serum blood urea nitrogen (86.51 g/dl) and creatinine (5.30 g/dl) levels and significant improvement in body weight change (- 10.34 g) and kidney weight (728 mg/kg). The protective effect of NDGA against cisplatin induced nephrotoxicity in the rats was further confirmed by significant restoration of antioxidant enzymes like SOD (86.28% inhibition), inflammatory markers like TNF-α (34.6 pg/ml) and histopathological examination. Moreover, our results showed that NDGA potentiated anti-breast cancer activity of cisplatin through an increment in the expression of antioxidant enzymes like SOD (85.35% inhibition) in breast cancer tissue. These results indicated that NDGA potentiated the anti-breast cancer activity of cisplatin, which was clearly evident from the tumor volume and % tumor inhibition in breast cancer rats. breast cancer in female Sprague-Dawley rats. Rahman S, et al (2015) - Nordihydroguiaretic acid attenuates skin tumorigenesis in Swiss albino mice with the condition of topical co- administration of an immunosuppressant. Chem Biol Interact. 2015 May 25;233:106-14. [ABS] … NDGA has the potential to inhibit or delay the onset of tumor development during immunosuppressive regimen. Yang X, et al (2014) - A synthetic dl-nordihydroguaiaretic acid (Nordy), inhibits angiogenesis, invasion and proliferation of glioma stem cells within a zebrafish xenotransplantation model. PLoS One. 2014 Jan 15;9(1):e85759. [FULL TEXT] …We next evaluated the effects of a synthetic dl-nordihydroguaiaretic acid compound (dl-NDGA or "Nordy"), which revealed anti-tumor activity against glioma stem cells (GSCs) in vitro by establishing parameters through studying its ability to suppress angiogenesis, tumor invasion, and proliferation. Furthermore, our results indicated that Nordy might inhibit GSCs invasion and proliferation through regulation of the arachidonate 5-lipoxygenase (Alox-5) pathway. Moreover, the combination of Nordy and a VEGF inhibitor exhibited an enhanced ability to suppress angiogenesis that was induced by GSCs. By contrast, even following treatment with 50 µM Nordy, there was no discernible effect on zebrafish embryonic development. Castro-Gamero AM, et al (2013) - Tetra-O-methyl nordihydroguaiaretic acid, an inhibitor of Sp1-mediated survivin transcription, induces apoptosis and acts synergistically with chemo-radiotherapy in glioblastoma cells. Invest New Drugs. 2013 Aug;31(4):858-70. [ABS] Glioblastoma (GBM), one of the most malignant human neoplasias, responds poorly to current treatment modalities, with temozolomide (TMZ) being the drug most frequently used for its treatment. Tetra-O-methyl Nordihydroguaiaretic Acid (M4N) is a global transcriptional repressor of genes dependent on the Sp1 transcription factor, such as Survivin and Cdk1. …M4N decreased the glioblastoma cell proliferation separately and synergistically with TMZ, and enhanced the effects of radiation, mainly when associated with TMZ. M4N also induced apoptotic cell death, decreased the mitotic index and arrested the cell cycle mainly in the G2/M phase. Our results suggest a potential clinical application of M4N in combination with TMZ and radiation for GB treatment. Gerhauser C, et al (2013) - Cancer chemoprevention and nutriepigenetics: state of the art and future challenges. Top Curr Chem. 2013;329:73-132. [ABS] The present review will summarize the potential of natural chemopreventive agents to counteract these cancer-related epigenetic alterations by influencing the activity or expression of DNA methyltransferases and histone modifying enzymes. Chemopreventive agents that target the epigenome include micronutrients (folate, retinoic acid, and selenium compounds), butyrate, polyphenols from green tea, apples, coffee, black raspberries, and other dietary sources, genistein and soy isoflavones, curcumin, resveratrol, dihydrocoumarin, nordihydroguaiaretic acid (NDGA), lycopene, anacardic acid, garcinol, constituents of Allium species and cruciferous vegetables, … Zhang Y, et al (2012) - mTORC1 is a target of nordihydroguaiaretic acid to prevent breast tumor growth in vitro and in vivo. Breast Cancer Res Treat. 2012 Nov;136(2):379-88. [ABS] Nordihydroguaiaretic acid (NDGA) is a natural phenolic compound isolated from the creosote bush Larrea divaricata, which has anti-tumor activities both in vitro and in vivo. Its analogs are in clinical development for use in refractory solid tumors. … Our data also raise the possibility that NDGA, as an mTORC1 inhibitor, may have a broad spectrum of action on breast cancers. Grossman SA, et al (2012) - Phase I study of terameprocol in patients with recurrent high-grade glioma. Neuro Oncol. 2012 Apr;14(4):511-7. [FULL TEXT] Terameprocol (meso-tetra-O-methylnordihydroguaiaretic acid) is a global transcription inhibitor that affects cell division apoptosis, drug resistance, hypoxia responsive genes, and radiation resistance in hypoxia….Preclinical and human data suggest that this novel transcription inhibitor is worthy of further study. The long-term stability noted in some patients and the lack of associated myelosuppression suggest that terameprocol could be safely combined with radiation and temozolomide in newly diagnosed high-grade gliomas. Kim BJ, et al (2012) - The role of transient receptor potential channel blockers in human gastric cancer cell viability. Can J Physiol Pharmacol. 2012 Feb;90(2):175-86. [ABS] Transient receptor potential cation channel, subfamily M, receptor 7 (TRPM7) is a ubiquitous divalent-selective ion channel with its own kinase domain. Human gastric cancer cells express the TRPM7 channel, and the presence of this channel is essential for cell survival. …Recent studies have suggested that 5-lipoxygenase (5- LOX) inhibitors are potent blockers of the TRPM7 channels. The aim of this study was to show the effects of 5-LOX inhibitors on the growth and survival of gastric cancer cells. Among 5-LOX inhibitors, nordihydroguaiaretic acid (NDGA), … were potent blockers of TRPM7-like currents in gastric cancer cells and also induced cell death. Friedlander TW, et al (2012) - A phase II study of insulin-like growth factor receptor inhibition with nordihydroguaiaretic acid in men with non-metastatic hormone-sensitive prostate cancer. Oncol Rep. 2012 Jan;27(1):3-9. [ABS] Insulin-like growth factor (IGF)-mediated signaling is a newly recognized clinical target in prostate cancer, and it is hypothesized that blockade of the IGF receptor (IGF1R) will impair downstream signaling and slow tumor growth. In this study the efficacy of nordihydroguaiaretic acid (NDGA), a small molecule inhibitor of the IGF- 1R, was prospectively evaluated in patients with non-metastatic hormone-sensitive prostate cancer (HSPC). …. NDGA therapy lengthens median PSADT but does not induce significant PSA declines. Further study may require a placebo-control to determine if changes in PSADT are drug related. Park S, et al (2011) - Inhibitory effect of nordihydroguaiaretic acid on β- catenin/Tcf signalling in β-catenin-activated cells. Cell Biochem Funct. 2011 Jan-Feb;29(1):22-9. [ABS] Activated β-catenin/T-cell factor (Tcf) signalling plays a role in human carcinogenesis. We identified the inhibitory effect of nordihydroguaiaretic acid (NDGA) against β- catenin/Tcf signalling in β-catenin activated cells… these results suggest that the NDGA acts as a negative regulator of β-catenin/Tcf signalling and its inhibitory mechanism is related to the decreased binding of β-catenin/Tcf complexes to consensus DNA. Gao P, et al (2011) - Nordihydroguaiaretic acid inhibits growth of cervical cancer SiHa cells by up-regulating p21. Oncol Lett. 2011 Jan;2(1):123-128. [FULL TEXT] Nordihydroguaiaretic acid (NDGA) and its derivatives possess anti-cancer effects on various types of cancer via the induction of apoptosis or cell cycle arrest. This study proved that NDGA inhibited cervical cancer SiHa cell growth and induced cell cycle arrest at the G(1) phase, which may be a consequence of cell cycle kinase inhibitor p21 induction. NDGA promoted acetylation of histone H3 in total and p21 gene- associated chromatin. This effect is gene selective, since NDGA has no impact on the p27 gene. NDGA also inhibited HPV-16 E6 gene transcription, which in turn resulted in the restoration of p53 protein levels. The silencing mediator for retinoid and thyroid hormone receptors (SMRT) is a key component of the HDAC3-HDAC4-N-CoR/SMRT complex. We found that NDGA significantly inhibited the transcription of SMRT, which, together with p53, may aid in the detection of the increase of histone H3 acetylation within the p21 gene. Our results suggest that NDGA induces p21 transcription by selectively elevating histone H3 acetylation associated with p21 gene and p53 protein levels via the inhibition of HPV-16 E6 expression. Huang J, et al (2011) - Cancer chemoprevention by targeting the epigenome. Curr Drug Targets. 2011 Dec;12(13):1925-56. [ABS] Given the fact that epigenetic modifications occur early in carcinogenesis and represent potentially initiating events in cancer development, they have been identified as promising new targets for prevention strategies. The present review will give a comprehensive overview of the current literature on chemopreventive agents and their influence on major epigenetic mechanisms, that is DNA methylation, histone acetylation and methylation, and microRNAs … Chemopreventive agents with reported mechanisms targeting the epigenome include micronutrients (folate, selenium, retinoic acid, Vit. E), butyrate, polyphenols (from green tea, apples, coffee, and other dietary sources), genistein and soy isoflavones, parthenolide, curcumin, ellagitannin, indol-3-carbinol (I3C) and diindolylmethane (DIM), mahanine, nordihydroguaiaretic acid (NDGA), lycopene, sulfur-containing compounds from Allium and cruciferous vegetables … Their effects on global DNA methylation, tumor suppressor genes silenced by promoter methylation, histone modifications, and miRNAs deregulated during carcinogenesis have potential impact on multiple mechanisms relevant for chemoprevention, including signal transduction mediated by nuclear receptors and transcription factors such as NF-B, cell cycle progression, cellular differentiation, apoptosis induction, senescence and others. Diabetes Peralta I, et al (2022) - Anti-hyperglycaemic effect and nutritional properties of an aqueous extract of Larrea divaricata Cav. (jarilla) in streptozotocin-induced diabetes in mice. J Ethnopharmacol. 2022 Oct 5;296:115429. [ABS] …These results support the hypothesis that AE could be used as a therapeutic adjuvant or as a nutritional supplement to control glucose levels and lipid metabolism in metabolic syndrome-associated diseases. Moreover, these results scientifically reinforce the popular use of the plant. Peralta I, et al (2022) - Larrea divaricata: anti-inflammatory and antioxidant effects of on macrophages and low density lipoproteins. BMC Complement Med Ther. 2022 Mar 23;22(1):84. [FULL TEXT] The aim of this work was to study the antioxidant and anti-inflammatory effects of the aqueous extract (AE) of L. divaricata on macrophages under glucose stimulation and on human LDL and HDL particles under free radical generators. …These results suggest a potential usefulness of AE as an adjuvant phytotherapy in patients with diabetes mellitus and atherosclerosis. Peralta I, et al (2019) - Larrea divaricata Cav. aqueous extract and nordihydroguariaretic acid modulate oxidative stress in submandibular glands of diabetic rats: a buccal protective in diabetes. BMC Complement Altern Med. 2019 Aug 22;19(1):227. [FULL TEXT] 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. …The antioxidant activity of the AE in the submandibular glands would allow the maintenance of the antioxidant pool to prevent oral oxidative diseases. Daz-Gerevini GT, et al (2019) - Diabetic encephalopathy: beneficial effects of supplementation with fatty acids ω3 and nordihydroguaiaretic acid in a spontaneous diabetes rat model. Lipids Health Dis. 2019 Feb 8;18(1):43. [FULL TEXT] Diabetic encephalopathy is a chronic complications of diabetes mellitus that affects the central nervous system. We evaluated the effect of ω3 and ω6 polyunsaturated fatty acids (PUFAs) supplementation plus the antioxidant agent nordihydroguaiaretic acid (NDGA) on the etiopathology of diabetic encephalopathy in eSS rats, a spontaneous model of type 2 diabetes. …The treatments tested with ω3 or ω3 plus NDGA showed improvement in the values of the studied parameters in eSS diabetic rats. These observations may form the basis to help in prevent and manage the diabetic encephalopathy. Awasthi S, et al (2019) - Nordihydroguaiaretic acid prevents glycation induced structural alterations and aggregation of albumin. Int J Biol Macromol. 2019 Feb 1;122:479-484. [ABS] 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. … Results suggest that NDGA 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 … due to glycation. Dain A, et al (2016) - 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). Lipids Health Dis. 2016 Nov 25;15(1):205. [FULL TEXT] ω-3 + NDGA supplementation, at the doses tested, ameliorated inflammatory, metabolic and oxidative stress markers studied. Roskar I, et al (2016) - Screening of Phenolic Compounds Reveals Inhibitory Activity of Nordihydroguaiaretic Acid Against Three Enzymes Involved in the Regulation of Blood Glucose Level. Plant Foods Hum Nutr. 2016 Mar;71(1):88-9. [ABS] Nordihydroguaiaretic acid, a phenolic compound abundant in Creosote bush Larrea tridentata, possessed inhibitory activity for all tested enzymes. This in vitro mechanism of action supports traditional use of Creosote bush in diabetes treatment. Immunity Allergy and Auto-Immunity see also Infection and Inflammation. Birga AM, et al (2022) - Prediction of New Risk Genes and Potential Drugs for Rheumatoid Arthritis from Multiomics Data. Comput Math Methods Med. 2022 Jan 31;2022:6783659. [FULL TEXT] …four drugs (trastuzumab, lapatinib, masoprocol, and arsenic trioxide) have been reported to have a high potential to ameliorate RA. Note – Masoprocol is also known as meso-nordihydroguaiaretic acid. Bergren DR, et al (2016) - Anti-anaphylactic action of nordihydroguaiaretic acid in antigen sensitized guinea pigs. Respir Physiol Neurobiol. 2016 Dec;234:26-31. [ABS] The anti-antigenic action of the plant alkaloid nordihydroguaiaretic acid (NDGA) was studied in ovalbumin (OA)-sensitized guinea pigs. … This study demonstrates that NDGA is an effective antigenic agent when given by aerosol or intravenous injection in either conscious or anesthetized guinea pigs, respectively. The mechanism of action of NDGA is presumed primarily be due to the blockage of 5-lipoxygenase and therefore the synthesis of leukotrienes. Infection – Viral, Fungal, Parasitic Villalobos-Sánchez E, et al (2023) - In Vitro Antiviral Activity of Nordihydroguaiaretic Acid against SARS-CoV-2. Viruses. 2023 May 11;15(5):1155. [FULL TEXT] …nordihydroguaiaretic acid (NDGA), a molecule found in Creosote bush (Larrea tridentata) leaves was not toxic to Vero cells (monkey kidney) and exhibited a remarkable inhibitory effect on the SARS-CoV-2 cytopathic effect, viral plaque formation, RNA replication, and expression of the SARS-CoV-2 spike glycoprotein. The 50% effective concentration for NDGA was as low as 16.97 µM. Our results show that NDGA could be a promising therapeutic candidate against SARS-CoV-2. Li B, et al (2023) - Effects of diarylbutane lignans from Schisandra chinensis fruit on SARS-CoV-2 3CL(pro) and PL(pro) and their in vitro anti-inflammatory properties. Phytomed Plus. 2023 May;3(2):100432. [FULL TEXT] Two components of Schizandra, Nordihydroguaiaretic acid and meso- dihydroguaiaretic acid (NDGA), inhibit SARS-CoV-2 and reduce inflammation. Martinez F, et al (2022) - New insights into the antiviral activity of nordihydroguaiaretic acid: Inhibition of dengue virus serotype 1 replication. Phytomedicine. 2022 Nov;106:154424. [ABS] Nordihydroguaiaretic acid (NDGA), isolated from Larrea divaricata Cav. (Zygophyllaceae) has shown a significant inhibitory effect on a broad spectrum of viruses, including DENV serotypes 2 and 4. …The viability of viral particles was quantified by the plaque-forming unit reduction method… NDGA decreases the amount of intracellular RNA of DENV1 and, by immunofluorescence, the number of cells infected. These results indicate that the antiviral effect of NDGA would have an intracellular mechanism of action, which is consistent with its ability to be incorporated into host cells. Mohiuddin SG, et al (2022) - Proton Motive Force Inhibitors Are Detrimental to Methicillin-Resistant Staphylococcus aureus Strains. Microbiol Spectr. 2022 Aug 31;10(4):e0202422. [FULL TEXT] …we identified a subset of chemicals (including nordihydroguaiaretic acid…) that strongly disrupted proton motive force (PMF) in MRSA cells by dissipating either the transmembrane electric potential (ΔΨ) or the proton gradient (ΔpH). These drugs robustly permeabilized cell membranes and reduced MRSA cell levels below the limit of detection. Overall, our study further highlights the importance of cellular PMF as a target for designing new bactericidal therapeutics for pathogens. Reyes AWB, et al (2022) - The In Vitro and In Vivo Effect of Lipoxygenase Pathway Inhibitors Nordihydroguaiaretic Acid and Its Derivative Tetra-O-methyl Nordihydroguaiaretic Acid against Brucella abortus 544. J Microbiol Biotechnol. 2022 Sep 28;32(9):1126-1133. [FULL TEXT] This study investigated the contribution of lipoxygenase (LOX) inhibitors, nordihydroguaiaretic acid (NDGA), tetra-O-methyl nordihydroguaiaretic acid (M4N) and zileuton (ZIL), and thromboxane A2 (TXA2) inhibitor 4,5-diphenylimidazole (DPI) in the proliferation of Brucella abortus infection. Reyes-Melo KY, et al (2021) - Larrea tridentata and its Biological Activities. In Current Topics in Medicinal Chemistry Vol 21, Issue 26, 2021. [ABS] Larrea tridentata is a dominant shrub in the deserts of North America and is recognized for its various traditional uses. More than 50 traditional uses have been recorded. Regarding its chemical composition, the products of the mevalonate, shikimate, and malonate pathways are predominant. L. tridentata has nordihydroguaiaretic acid (NDGA) … reported to exhibit antibacterial, antiprotozoal, anthelmintic, antifungal, antiviral, anticancer, and antioxidant activities Martinez F, et al (2021) - First report of antiviral activity of nordihydroguaiaretic acid against Fort Sherman virus (Orthobunyavirus). Antiviral Res. 2021 Mar;187:104976. [ABS] A characteristic of these viruses is their lack of antiviral treatment or vaccine for its prevention. The objective of this work was to study the in vitro antiviral activity of nordihydroguaiaretic acid (NDGA), the most important active compound of Larrea divaricata Cav. (Zigophyllaceae), against Fort Sherman virus (FSV) as a model of Orthobunyavirus genus. Zubrow ME, et al (2020) - Nordihydroguaiaretic acid reduces secondary organ injury in septic rats after cecal ligation and puncture. PLoS One. 2020 Aug 13;15(8):e0237613[FULL TEXT] 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. … NDGA pre- treatment showed improved survival compared with control CLP animals at 36 hours, while post-treatment did not. …NDGA represents a novel pleiotropic anti- inflammatory agent with potential clinical utility for modulation of organ injury secondary to sepsis. Moreno MA, et al (2020) - Antifungal, anti-inflammatory and antioxidant activity of bi-herbal mixtures with medicinal plants from Argentinean highlands. J Ethnopharmacol. 2020 May 10;253:112642. [ABS] Argentinean medicinal plants such as Larrea divaricata Cav., Larrea cuneifolia Cav., Larrea nitida Cav., Zuccagnia punctata Cav. and Tetraglochin andina Ciald. are used alone and in combination in traditional medicine by inhabitants from northwestern Argentina to solve mycosis, vaginal infections, gastrointestinal, respiratory, and inflammatory processes. …Our results indicated that the most active combinations of these species extracts could be useful in the treatment of vaginal infectious diseases caused by Saccharomyces cerevisiae and Candida spp. strains and in associated oxidative and inflammatory processes, supporting its traditional use. Cui Q, et al (2020) - Lignans and Their Derivatives from Plants as Antivirals. Molecules. 2020 Jan 1;25(1):183. [FULL TEXT] Lignans are widely produced by various plant species; they are a class of natural products that share structural similarity… Lignans possess diverse pharmacological properties, including their antiviral activities that have been reported in recent years. This review discusses the distribution of lignans in nature according to their structural classification, and it provides a comprehensive summary of their antiviral activities. Mori M, et al (2018) - Structure-Based Identification of HIV-1 Nucleocapsid Protein Inhibitors Active against Wild-Type and Drug- Resistant HIV-1 Strains. ACS Chem Biol. 2018 Jan 19;13(1):253-266. [ABS] The authors identified nordihydroguaiaretic acid as a novel natural product inhibitor of nucleocapsid protein (NC) of HIV-1. Bashyal B, et al (2017) - Larrea tridentata: A novel source for anti- parasitic agents active against Entamoeba histolytica, Giardia lamblia and Naegleria fowleri. PLoS Negl Trop Dis. 2017 Aug 9;11(8):e0005832. [FULL TEXT] … we report Larrea tridentata, known as creosote bush, as a novel source for secondary metabolites that display antiparasitic activity against all three pathogens. This report also characterizes the lignan compound classes, nordihydroguairetic acid and demethoxyisoguaiacin, as novel antiparasitic lead agents to further develop more effective drug therapy options for millions of people worldwide. Merino-Ramos T, et al (2017) - Antiviral Activity of Nordihydroguaiaretic Acid and Its Derivative Tetra-O-Methyl Nordihydroguaiaretic Acid against West Nile Virus and Zika Virus. Antimicrob Agents Chemother. 2017 Jul 25;61(8):e00376-17. [FULL TEXT] … treatment with NDGA, M4N, PF-429242, and fatostatin also inhibited the multiplication of the mosquito-borne flavivirus Zika virus (ZIKV), which has been recently associated with birth defects (microcephaly) and neurological disorders. Our results point to SREBP inhibitors, such as NDGA and M4N, as potential candidates for further antiviral development against medically relevant flaviviruses. Guzmán-Beltrán S, et al (2016) - Nordihydroguaiaretic acid (NDGA) and α-mangostin inhibit the growth of Mycobacterium tuberculosis by inducing autophagy. Int Immunopharmacol. 2016 Feb;31:149-57. [ABS] 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. …both compounds directly inhibit M. tuberculosis growth in liquid medium with Minimal Inhibitory Concentrations (MIC) of 250 and 62 g/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 g/mL, respectively) and contributed to the elimination of intracellular bacteria. Cunningham-Oakes E, et al (2015) - Nordihydroguaiaretic acid enhances the activities of aminoglycosides against methicillin- sensitive and resistant Staphylococcus aureus in vitro and in vivo. Front Microbiol. 2015 Oct 27;6:1195. [FULL TEXT] Nordihydroguaiaretic acid (NDGA) is an antioxidant compound found in extracts from plant Larrea Tridentata. It exhibits antimicrobial activity and may target bacterial cell membrane. …The enhanced activity of NDGA resides on its ability to damage bacterial cell membrane leading to accumulation of the antibiotics inside bacterial cells. We demonstrated that NDGA strongly revived the therapeutic potencies of aminoglycosides in vitro and in vivo. This combinational strategy could contribute major clinical implications to treat antibiotic resistant bacterial infections. Tsugawa H, et al (2015) - Nordihydroguaiaretic Acid Disrupts the Antioxidant Ability of Helicobacter pylori through the Repression of SodB Activity In Vitro. Biomed Res Int. 2015;2015:734548. [FULL TEXT] Specifically, we demonstrated that nordihydroguaiaretic acid (NDGA) is a predicted FecA1-binding compound. NDGA reduced intracellular Fe(2+) levels in H. pylori and reduced superoxide dismutase SodB activity. Additionally, NDGA increased H2O2 sensitivity of H. pylori and increased the metronidazole (Mtz) sensitivity. The present study demonstrated that NDGA repressed SodB activity associated with the gastric mucosal-colonization via inhibition of intracellular Fe(2+) uptake by FecA1, suggesting that NDGA might be effective for the development of a novel eradication therapy. Batallán G, et al (2013) - Larvicidal activity of crude extracts from Larrea cuneifolia (Zygophyllaceae) and of its metabolite nordihydroguaiaretic acid against the vector Culex quinquefasciatus (Diptera: Culicidae). Rev Soc Bras Med Trop. 2013 Jan-Feb;46(1):84-7. [ABS] These results indicate that the chloroform extract of L. cuneifolia and NDGA are promising insecticides of botanical origin that could be useful for controlling Cx. quinquefasciatus. Syed GH, et al (2011) - Effects of hypolipidemic agent nordihydroguaiaretic acid on lipid droplets and hepatitis C virus. Hepatology. 2011 Dec;54(6):1936-46. [FULL TEXT] Hepatitis C virus (HCV) relies on host lipid metabolic pathways for its replication, assembly, secretion, and entry. … NDGA-mediated alterations of host lipid metabolism, LD morphology, and VLDL transport appear to negatively influence HCV proliferation. Aguero MB, et al (2011) - Argentinean Andean propolis associated with the medicinal plant Larrea nitida Cav. (Zygophyllaceae). HPLC-MS and GC-MS characterization and antifungal activity. Food Chem Toxicol. 2011 Sep;49(9):1970-8. [ABS] The chemical profile and botanical origin of Andean Argentinian propolis were studied by HPLC-ESI-MS/MS and GC-MS techniques as well as the antifungal activity according to CLSI protocols. Dermatophytes and yeasts tested were strongly inhibited by propolis extracts (MICs between 31.25 and 125 g/mL). The main antifungal compounds were: 3'methyl-nordihydroguaiaretic acid (MNDGA) 1, nordihydroguaiaretic acid (NDGA) 2 and a NDGA derivative 3, showing strong activity against Trichophyton mentagrophytes, T. rubrum and Microsporum gypseum (MICs between 15.6 and 31.25 g/mL). The lignans 1 and 2 showed activities against clinical isolates of Candidas spp., Cryptococcus spp., T. rubrum and T. mentagrophytes (MICs and MFCs between 31.25 and 62.5 g/mL). The lignan and volatile organic compounds (VOCs) profiles from propolis matched with those of exudates of Larrea nitida providing strong evidences on its botanical origin. These results support that Argentinian Andean propolis are a valuable natural product with potential to improve human health. Inflammation Kahnt AS, et al (2022) - Inhibitors of Human 5-Lipoxygenase Potently Interfere With Prostaglandin Transport. Front Pharmacol. 2022 Jan 21;12:782584. [FULL TEXT] Further, experiments showed that the PG exporter ATP-binding cassette transporter multidrug resistance protein 4 (MRP-4) is targeted by the inhibitors and may be involved in the 5-LO inhibitor-mediated PGE2 inhibition. … In addition, 5-LO inhibitors may serve as new scaffolds for the development of potent prostaglandin export inhibitors. Lin Y, et al (2022) - A novel nordihydroguaiaretic acid analog, compound 3a, alleviates acute lung injury by exerting antiapoptotic and antiinflammatory effects. Eur J Pharmacol. 2022 Mar 15;919:174777. [ABS] Previously, we synthesized a series of nordihydroguaiaretic acid analogs; of these, compound 3a exhibited excellent antioxidant capacity in a murine model of middle cerebral artery occlusion. …Mice developed extensive lung inflammation by 24 h after LPS [lipopolysaccharide] challenge. …Preadministration of compound 3a markedly ameliorated the histopathological changes and reduced fluid exudation into the alveolar space. Compound 3a also greatly reduced the levels of inflammation and apoptosis both in vivo and in vitro. …In summary, administration of compound 3a prior to LPS suppressed ALI [acute lung injury] via inhibition of the MAPK/NF-B pathway. Guvenc-Bayram G, et al (2020) - Modulation of arachidonic acid-evoked cardiorespiratory effects by the central lipoxygenase pathway. Respir Physiol Neurobiol. 2020 Jul;278:103441. [ABS] Central pretreatment with different doses of a non-selective LOX inhibitor, nordihydroguaiaretic acid (NDGA) (500 and 1000 g; ICV) partially blocked the AA (0.5 mol; ICV)-evoked pressor and bradycardic cardiovascular responses in male anesthetized Sprague Dawley rats. Pretreatment with different doses of NDGA (500 and 1000 g; ICV) also reduced AA-induced hyperventilation responses, with an increase in tidal volume, respiratory rate and minute ventilation… Sadagurski M, et al (2017) - Anti-aging drugs reduce hypothalamic inflammation in a sex-specific manner. Aging Cell. 2017 Aug;16(4):652- 660. [FULL TEXT] Aging leads to hypothalamic inflammation, but does so more slowly in mice whose lifespan has been extended by mutations that affect GH/IGF-1 signals. Early-life exposure to GH by injection, or to nutrient restriction in the first 3 weeks of life, also modulate both lifespan and the pace of hypothalamic inflammation. Three drugs extend lifespan of UM-HET3 mice in a sex-specific way: acarbose (ACA), 17-α- estradiol (17αE2), and nordihydroguaiaretic acid (NDGA), with more dramatic longevity increases in males in each case. …the extent of drug-induced changes in hypothalamic inflammatory processes is sexually dimorphic in a pattern that parallels the effects of these agents on mouse longevity and that mimics the changes seen, in both sexes, of long-lived nutrient restricted or mutant mice. Shen T, et al (2015) - 15-Lipoxygenase and 15-hydroxyeicosatetraenoic acid regulate intravascular thrombosis in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2015 Sep 1;309(5):L449-62. [ABS] 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. Guzmán-Beltrán S, et al (2013) - Nordihydroguaiaretic acid attenuates the oxidative stress-induced decrease of CD33 expression in human monocytes. Oxid Med Cell Longev. 2013;2013:375893. [FULL TEXT] NDGA attenuates toxicity, reactive oxygen species (ROS) production and the oxidative stress-induced decrease of CD33 expression secondary to iodoacetate or hydrogen peroxide in human monocytes. … These results suggest that NDGA has a protective effect on CD33 expression, which is associated with its antioxidant activity in human monocytes. Li YJ, et al (2012) - Nordihydroguaiaretic acid inhibition of NFATc1 suppresses osteoclastogenesis and arthritis bone destruction in rats. Lab Invest. 2012 Dec;92(12):1777-87. [ABS] …in vivo studies demonstrated that administration of NDGA significantly reduced severe bone destruction and osteoclast recruitment in the ankle joint of rats with adjuvant-induced arthritis. These results indicate the potential utility of NDGA as a therapeutic agent for ameliorating inflammatory bone destruction in rheumatoid arthritis. Czapski GA, et al (2012) - Evaluation of the antioxidative properties of lipoxygenase inhibitors. Pharmacol Rep. 2012;64(5):1179-88. [ABS] Oxidative stress is a component of many pathological conditions including neurodegenerative diseases and inflammation. An important source of reactive oxygen species (ROS) are lipoxygenases (LOX) - enzymes responsible for the metabolism of arachidonic acid and other polyunsaturated fatty acids. LOX inhibitors have a protective effect in inflammatory diseases and in neurodegenerative disorders because of their anti-inflammatory activity. … Our data showed that the inhibitor of all LOXs, i.e., NDGA, 5-LOX inhibitor BWB70C and the inhibitor of 12/15-LOX, baicalein, significantly decreased the level of lipid and protein oxidation. The free radical scavenging activity of these inhibitors was comparable to known ROS scavengers, i.e., resveratrol and trolox. Mori T, et al (2012) - Involvement of the arachidonic acid cascade in the hypersusceptibility to pentylenetetrazole-induced seizure during diazepam withdrawal. Biol Pharm Bull. 2012;35(12):2243-6. [ABS] The decrease in the seizure threshold for pentylenetetrazole during diazepam withdrawal was significantly suppressed by intracerebroventricular (i.c.v.) pretreatment with the phospholipase A(2) inhibitor quinacrine (30, 100 nmol) and the lipoxygenase inhibitor nordihydroguaiaretic acid (10, 30 nmol). …These findings suggest that enhancement of the arachidonic acid cascade may contribute to the hypersusceptibility to pentylenetetrazole-induced seizure during diazepam withdrawal. Kim HY, et al (2012) - Impact on inflammation and recovery of skin barrier by nordihydroguaiaretic Acid as a protease-activated receptor 2 antagonist. Biomol Ther (Seoul). 2012 Sep;20(5):463-9. [FULL TEXT] Atopic dermatitis is a chronic, inflammatory disease of the skin with increased transepidermal water loss. … we show that nordihydroguaiaretic acid (NDGA) inhibits the PAR2-mediated signal pathway and plays a role in skin barrier recovery in atopic dermatitis. Specifically, NDGA reduces the mobilization of intracellular Ca(2+) … by down-regulating inflammatory mediators, such as interleukin-8, thymus and activation-regulated chemokine and intercellular cell adhesion molecule-1 in HaCaT keratinocytes. Also, NDGA decreases the protein expression of involucrin, a differentiation maker of keratinocyte, in both HaCaT keratinocytes and normal human epidermal keratinocytes. ... Topical application of NDGA produced an increase in transepidermal water loss recovery and a decrease in serum IgE level, without weight loss. Accordingly, we suggest that NDGA acts as a PAR2 antagonist and may be a possible therapeutic agent for atopic dermatitis. Liu Y, et al (2012) - The protective effect of nordihydroguaiaretic acid on cerebral ischemia/reperfusion injury is mediated by the JNK pathway. Brain Res. 2012 Mar 22;1445:73-81. [ABS] Nordihydroguaiaretic acid (NDGA) is a powerful antioxidant and/or lipoxygenase (LOX) inhibitor which is isolated from Larrea tridentate. NDGA has been shown to have neuroprotective effects both in vitro and in vivo experiments. However, little is known regarding NDGA's protective mechanism in ischemia/reperfusion (I/R) injury. We therefore investigated the potential protective effects of NDGA and explored the underlying mechanisms. Oxygen-glucose deprivation (OGD) was performed in cultured rat cortical neurons for 60min. … The results showed that NDGA increased cell viability and inhibited apoptosis after OGD in neurons… NDGA improved neurological deficit, reduced infarct volumes, and downregulated the overexpression of p-c-jun and p-JNK after MCAO and reperfusion. In conclusion, these results suggest that NDGA's protective effect against I/R injury is mediated by the suppression of JNK pathway. This effect is probably due to its 12/15-LOX inhibitor property. Natera-Naranjo O, et al (2012) - Local translation of ATP synthase subunit 9 mRNA alters ATP levels and the production of ROS in the axon. Mol Cell Neurosci. 2012 Mar;49(3):263-70. [ABS] To date, it has been demonstrated that axonal mRNA populations contain a large number of nuclear-encoded mRNAs for mitochondrial proteins. Here, we report that the mRNA encoding ATP synthase subunit 9 (ATP5G1), a key component of Complex V of the oxidative phosphorylation chain, is present in the axons of rat primary sympathetic neurons, … Exposure of the distal axons to nordihydroguaiaretic acid (NDGA), a ROS scavenger, mitigated the reduction in the rate of axon elongation observed after knock-down of ATP5G1. Taken together, these data call attention to the key regulatory role that local translation of nuclear-encoded mitochondrial mRNAs plays in energy metabolism and growth of the axon. Mahajan UM, et al (2011) - Alteration in inflammatory/apoptotic pathway and histone modifications by nordihydroguaiaretic acid prevents acute pancreatitis in Swiss albino mice. Apoptosis. 2011 Nov;16(11):1138-49. [ABS] Reactive oxygen radicals, pro-inflammatory mediators and cytokines have been implicated in caerulein induced acute pancreatitis. Nordihydroguaiaretic acid (NDGA), a plant lignin, has marked anti-inflammatory properties. T…NDGA was administered after 9 h of acute pancreatitis induction. … NDGA attenuated the oxidative stress, led to increased plasma α-amylase and decreased IGF-1 in AP mice. It modulated the mRNA and protein levels of heat shock proteins and reduced the expression of NF-B, TNF-α and p-p38. … this is the first report which suggests that NDGA prevents the progression of acute pancreatitis by involving alteration of histone H3 modifications and modulating the expression of genes involved in inflammatory/apoptotic cascade, which may be responsible for decreased necrosis and increased apoptosis in this model of acute pancreatitis. Smirnova NA, et al (2011) - Development of Neh2-luciferase reporter and its application for high throughput screening and real-time monitoring of Nrf2 activators. Chem Biol. 2011 Jun 24;18(6):752-65. [FULL TEXT] The NF-E2-related factor 2 (Nrf2) is a key transcriptional regulator of antioxidant defense and detoxification. The most robust and yet nontoxic Nrf2 activators found-- nordihydroguaiaretic acid, fisetin, and gedunin--induced astrocyte-dependent neuroprotection from oxidative stress via an Nrf2-dependent mechanism. Czubowicz K, et al (2010) - Lipoxygenase inhibitors protect brain cortex macromolecules against oxidation evoked by nitrosative stress. Folia Neuropathol. 2010;48(4):283-92. [ABS] Lipoxygenases (LOX) are a family of enzymes that are responsible for the metabolism of arachidonic and docosahexaenoic acid and for the formation of several eicosanoids and docosanoids, including leukotrienes, lipoxins and neuroprotectins. Depending on cells' redox state and other milieu conditions, these enzymes are engaged in oxidative stress and cell death mechanisms or in cell protection. In this study the antioxidative properties of several inhibitors of LOX isoforms were evaluated. … Inhibitor of all LOXs nordihydroguaiaretic acid …significantly reduced, in a concentration dependent manner (1-10 M), the level of lipid and protein oxidation. Lee J, et al (2011) - Modulation of lipid peroxidation and mitochondrial function improves neuropathology in Huntington's disease mice. Acta Neuropathol. 2011 Apr;121(4):487-98. [FULL TEXT] 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. Oyegunwa AO, et al (2010) - Tetra-O-methyl nordihydroguaiaretic acid (Terameprocol) inhibits the NF-B-dependent transcription of TNF-α and MCP-1/CCL2 genes by preventing RelA from binding its cognate sites on DNA. J Inflamm (Lond). 2010 Dec 7;7:59. [FULL TEXT] Tetra-O-methyl nordihydroguaiaretic acid, also known as terameprocol (TMP), is a naturally occurring phenolic compound found in the resin of the creosote bush. We have shown previously that TMP will suppress production of certain inflammatory cytokines, chemokines and lipids from macrophages following stimulation with LPS or infection with H1N1 influenza virus. In this study our goal was to elucidate the mechanism underlying TMP-mediated suppression of cytokine and chemokine production. … TMP acts indirectly as an inhibitor of NF-B-dependent transcription by preventing RelA from binding the promoters of certain key cytokine and chemokine genes. Metabolic Syndrome Peralta I, et al (2022) - Anti-hyperglycaemic effect and nutritional properties of an aqueous extract of Larrea divaricata Cav. (jarilla) in streptozotocin-induced diabetes in mice. J Ethnopharmacol. 2022 Oct 5;296:115429. [ABS] …These results support the hypothesis that AE could be used as a therapeutic adjuvant or as a nutritional supplement to control glucose levels and lipid metabolism in metabolic syndrome-associated diseases. Moreover, these results scientifically reinforce the popular use of the plant. Han L, et al (2019) - Creosote bush-derived NDGA attenuates molecular and pathological changes in a novel mouse model of non-alcoholic steatohepatitis (NASH). Mol Cell Endocrinol. 2019 Dec 1;498:110538. [FULL TEXT] Creosote bush (Larrea tridentata)-derived nordihydroguaiaretic acid (NDGA) was shown to have profound effects on the core components of metabolic syndrome. … 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. Singh M, et al (2019) - Anti-hyperlipidaemic effects of synthetic analogues of nordihydroguaiaretic acid in dyslipidaemic rats. Br J Pharmacol. 2019 Feb;176(3):369-385. [FULL TEXT] Previous studies have shown that Creosote bush-derived nordihydroguaiaretic acid (NDGA) exerts beneficial actions on the key components of metabolic syndrome including dyslipidaemia, insulin resistance and hypertension in several relevant rodent models. Here, we synthesized and screened a total of 6 anti-hyperlipidaemic analogues of NDGA and tested their efficacy against hepatic lipid metabolism in a high-fructose diet (HFrD) fed dyslipidaemic rat model. …Our data suggest that NDGA analogues … exert their anti-hyperlipidaemic actions by negatively targeting genes of key enzymes and transcription Chan JKW, et al (2018) - Nordihydroguaiaretic Acid, a Lignan from Larrea tridentata (Creosote Bush), Protects Against American Lifestyle- Induced Obesity Syndrome Diet-Induced Metabolic Dysfunction in Mice. J Pharmacol Exp Ther. 2018 May;365(2):281-290. [FULL TEXT] … we provide evidence that NDGA improves metabolic dysregulation by simultaneously modulating the PPARα transcription factor and key genes involved in fatty acid oxidation, key antioxidant and lipogenic enzymes, and apoptosis and ER stress signaling pathways. Zhang H, et al (2016) - Microarray analysis of gene expression in liver, adipose tissue and skeletal muscle in response to chronic dietary administration of NDGA to high-fructose fed dyslipidemic rats. Nutr Metab (Lond). 2016 Sep 29;13:63. [FULL TEXT] Nordihydroguaiaretic acid (NDGA), the main metabolite of Creosote Bush, has been shown to have profound effects on the core components of metabolic syndrome, including lowering of blood glucose, free fatty acids and triglyceride levels, attenuating elevated blood pressure in several rodent models of dyslipidemia, and improving body weight, insulin resistance, diabetes and hypertension. In the present study, a high-fructose diet fed rat model of hypertriglyceridemia, dyslipidemia, insulin resistance and hepatic steatosis was employed to investigate the global transcriptional changes in the lipid metabolizing pathways in three insulin sensitive tissues: liver, skeletal muscle and adipose tissue in response to chronic dietary administration of NDGA. … These findings suggest that NDGA ameliorates hypertriglyceridemia and steatosis primarily by inhibiting lipogenesis and enhancing fatty acid catabolism in three major insulin responsive tissues by altering the expression of key enzyme genes and transcription factors involved in de novo lipogenesis and fatty acid oxidation. Zhang H, et al (2015) - Effect of Creosote Bush-Derived NDGA on Expression of Genes Involved in Lipid Metabolism in Liver of High- Fructose Fed Rats: Relevance to NDGA Amelioration of Hypertriglyceridemia and Hepatic Steatosis. PLoS One. 2015 Sep 22;10(9):e0138203. [FULL TEXT] These findings suggest that NDGA ameliorates hypertriglyceridemia and hepatic steatosis primarily by interfering with lipogenesis and promoting increased channeling of fatty acids towards their oxidation. Zhang H, et al (2013) - Nordihydroguaiaretic acid improves metabolic dysregulation and aberrant hepatic lipid metabolism in mice by both PPARα-dependent and -independent pathways. Am J Physiol Gastrointest Liver Physiol. 2013 Jan 1;304(1):G72-86. [FULL TEXT] Creosote bush-derived nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, possesses antioxidant properties and functions as a potent antihyperlipidemic agent in rodent models. Here, we examined the effect of chronic NDGA treatment of ob/ob mice on plasma dyslipidemia, hepatic steatosis, and changes in hepatic gene expression. … In conclusion, the beneficial actions of NDGA on dyslipidemia and hepatic steatosis in ob/ob mice are exerted primarily through enhanced fatty acid oxidation via PPARα-dependent pathways. However, PPARα-independent pathways also contribute to NDGA's action to ameliorate hepatic steatosis. Obesity Kimura K, et al (2023) - Tetra-O-methyl-nordihydroguaiaretic acid inhibits energy metabolism and synergistically induces anticancer effects with temozolomide on LN229 glioblastoma tumors implanted in mice while preventing obesity in normal mice that consume high-fat diets. PLoS One. 2023 May 25;18(5):e0285536. [FULL TEXT] Chan JKW, et al (2018) - Nordihydroguaiaretic Acid, a Lignan from Larrea tridentata (Creosote Bush), Protects Against American Lifestyle- Induced Obesity Syndrome Diet-Induced Metabolic Dysfunction in Mice. J Pharmacol Exp Ther. 2018 May;365(2):281-290. [FULL TEXT] … we provide evidence that NDGA improves metabolic dysregulation by simultaneously modulating the PPARα transcription factor and key genes involved in fatty acid oxidation, key antioxidant and lipogenic enzymes, and apoptosis and ER stress signaling pathways. Parkinson’s Disease see also Amyloid above Smirnova NA, et al (2016) - Bioactive Flavonoids and Catechols as Hif1 and Nrf2 Protein Stabilizers - Implications for Parkinson's Disease. Aging Dis. 2016 Dec 1;7(6):745-762. [FULL TEXT] NDGA from the Creosote bush resembles the best flavonoids in their ability to directly stabilize HIF1 and Nrf2 and is superior with respect to LOX inhibition thus favoring this compound over others. Given much higher bioavailability and stability of NDGA than any flavonoid, NDGA has been tested in a 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-animal model of Parkinson's Disease and demonstrated neuroprotective effects. Caruana M, et al (2012) - Polyphenolic compounds are novel protective agents against lipid membrane damage by α-synuclein aggregates in vitro. Biochim Biophys Acta. 2012 Nov;1818(11):2502-10. [ABS] Cumulative evidence now suggests that the abnormal aggregation of the protein α- synuclein (αS) is a critical factor in triggering neurodegeneration in Parkinson's disease (PD). In particular, a fundamental pathogenetic mechanism appears to involve targeting of neuronal membranes by soluble oligomeric intermediates of αS, leading to their disruption or permeabilisation. … A select group of potent inhibitory compounds included apigenin, baicalein, morin, nordihydroguaiaretic acid, and black tea extract. … that can effectively hinder membrane damage by αS aggregates. These may serve as a viable source of lead compounds for the development and design of novel therapeutic agents in PD. Siddique YH, et al (2012) - The dietary supplementation of nordihydroguaiaretic acid (NDGA) delayed the loss of climbing ability in Drosophila model of Parkinson's disease. J Diet Suppl. 2012 Mar;9(1):1-8. [ABS] Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons and the aggression of alpha Synuclein (αS) in the brain. Drosophila mutants and transgenes have provided a platform to understand the mechanistic insight associated with the degenerative diseases. A number of polyphenols have been reported to inhibit the αS aggregation resulting in the possible prevention of PD… NDGA at 0.01 l/ml did not showed any significant delay in the loss of climbing ability of PD model flies. However, NDGA doses at 0.1, 0.5, and 1.0 l/ml showed a dose dependent significant (p < .05) delay in the loss of climbing ability of PD model flies as compared to the untreated PD flies. The results suggest that the NDGA is potent in delaying the climbing disability of PD model flies and also supports the utility of this model in studying PD symptoms. Wound Healing Sipka T, et al (2022) - Macrophages undergo a behavioral switch during wound healing in zebrafish. Free Radic Biol Med. 2022 Nov 1;192:200- 212. [ABS] Altogether, our findings suggest that individual macrophages at the wound switch their phenotype leading to important changes in behaviour and shape to adapt to changing environment… Nordihydroguaiaretic acid (NDGA) decreases the switch from amoeboid to elongated shape. Zhang X, et al (2015) - Combination of amniotic epithelial cells with NDGA promotes the survival of transplanted AECs in spinal cord- injured rats. Neurol Res. 2015 Nov;37(11):1015-24. [ABS] Our previous research has shown that seeding amniotic epithelial cells (AECs) in chemically extracted acellular muscle scaffold (CEAMC) better promotes the functional recovery of spinal cord injury (SCI) than scaffold alone. However, the massive death of transplanted cells, which is related to early inflammatory response, is still a problem in cell therapy. Our previous study proved that nordihydroguaiaretic acid (NDGA) inhibits inflammation after SCI. In this study, we tested a strategy of combining the early administration of NDGA and the transplantation of AEC-seeded CEAMC to treat SCI. The results showed that simply increasing the number of surviving amniotic epithelial cells [AECs] had no significant benefits in spinal cord injury therapy, but NDGA administration ameliorated transplanted AEC survival demonstrating the potential value of NDGA in the cellular transplantation treatment of SCI. Zñiga-Toalá A, et al (2013) - Nordihydroguaiaretic acid induces Nrf2 nuclear translocation in vivo and attenuates renal damage and apoptosis in the ischemia and reperfusion model. Phytomedicine. 2013 Jul 15;20(10):775-9. [ABS] NDGA was able to induce Nrf2 translocation in vivo in kidneys of rats submitted to both U-NX and I/R injury and to protect against renal histological damage and apoptosis. It is concluded that the pretreatment of NDGA is able to induce in vivo nuclear Nrf2 translocation in kidney of rats suggesting that this may be involved in the renoprotection against I/R. Xue H, et al (2013) - NDGA reduces secondary damage after spinal cord injury in rats via anti-inflammatory effects. Brain Res. 2013 Jun 21;1516:83-92. [ABS] In this study, we investigated the anti-inflammatory effects of NDGA in spinal cord injury (SCI). First, … an increased number of neurons after NDGA administration. The data showed that the numbers of apoptotic cells and the proliferative extent of astrocytes were significantly decreased by the use of NDGA. The anti-inflammatory effect of NDGA was evaluated by measuring myeloperoxidase (MPO) levels as an indicator of neutrophil activity, macrophage/microglia numbers, and expression of inflammatory cytokines including IL-1β and TNF-α. NDGA treatment significantly decreased the MPO level and the number of macrophages/microglia. In addition, NDGA also suppressed the expression of IL-1β and TNF-α after spinal cord injury. These data suggest that anti-inflammatory action by NDGA can reduce secondary damage after SCI. MISC orales-Ubaldo AL, et al (2022) - Phytochemical Compounds and Pharmacological Properties of Larrea tridentata. Molecules. 2022 Sep; 27(17): 5393. [FULL TEXT] ,… Larrea tridentata is a perennial shrub used in traditional medicine in northern Mexico and the southern United States to treat infertility, rheumatism, arthritis, colds, diarrhea, skin problems, pain, inflammation and excess body weight. Scientific research has revealed its beneficial effects—antioxidant, antitumor, neuroprotective, regenerative, antibacterial, antiviral, antifungal, anthelmintic, antiprotozoal and insecticidal—although reports indicate that some compounds in Larrea tridentata may be hepatotoxic and nephrotoxic. Therefore, the aim of this review was to highlight the updates regarding phytochemical compounds and the pharmacological properties of Larrea tridentata. Reyes-Melo KY, et al (2021) - Larrea tridentata and its Biological Activities. In Current Topics in Medicinal Chemistry Vol 21, Issue 26, 2021. [ABS] Larrea tridentata is a dominant shrub in the deserts of North America and is recognized for its various traditional uses. More than 50 traditional uses have been recorded. Regarding its chemical composition, the products of the mevalonate, shikimate, and malonate pathways are predominant. L. tridentata has nordihydroguaiaretic acid (NDGA) … reported to exhibit antibacterial, antiprotozoal, anthelmintic, antifungal, antiviral, anticancer, and antioxidant activities Ou M, et al (2021) - Polyunsaturated Fatty Acid Diet and Upregulation of Lipoxin A4 Reduce the Inflammatory Response of Preeclampsia. J Proteome Res. 2021 Jan 1;20(1):357-368. [ABS] Nordihydroguaiaretic acid (NDGA) regulated LXA4 expression and inflammation levels by affecting LOX. Inhibition of lipoxygenase 5 activity by NDGA upregulated the expressions of LOX12 and LOX15, while LXA4 reversed LXA4, nitric oxide downregulation, and TNF-α upregulation by NDGA. Mala John GS, et al (2020) - Nordihydroguaiaretic Acid in Therapeutics: Beneficial to Toxicity Profiles and the Search for its Analogs. Curr Cancer Drug Targets. 2020;20(2):86-103. [ABS] Nordihydroguaiaretic acid (NDGA) is a plant lignan obtained from creosote bush, Larrea tridentata and is known to possess antioxidant, anticancer activities and is used in traditional medicine in North America and Mexico. … This review is to highlight the medicinal applications of NDGA, its toxicity evaluations and discuss the chemical derivatives of NDGA synthesized and studied so far and suggest to continue research interests in the development of NDGA analogs for therapeutic applications. Kang I, et al (2019) - Lipoprotein Lipase Inhibitor, Nordihydroguaiaretic Acid, Aggravates Metabolic Phenotypes and Alters HDL Particle Size in the Western Diet-Fed db/db Mice. Int J Mol Sci. 2019 Jun 22;20(12):3057. [FULL TEXT] Aguirre-Joya JA, et al (2018) - The physicochemical, antifungal and antioxidant properties of a mixed polyphenol based bioactive film. Heliyon. 2018 Dec 17;4(12):e00942. [FULL TEXT] Physicochemical, antifungal and antioxidant properties of a pectin - aloe mucilage - candelilla wax - Larrea tridentata polyphenols based bioactive film were evaluated. … suitable to be applied on model fruits. Huang L, et al (2018) - Design, synthesis, and evaluation of NDGA analogues as potential anti-ischemic stroke agents. Eur J Med Chem. 2018 Jan 1;143:1165-1173. [ABS] 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. Alonso MR, et al (2017) - Stability of an Aqueous Extract of Larrea divaricata Cav. during a Simulated Digestion Process. Phytother Res. 2017 Nov;31(11):1708-1714. [ABS] Larrea divaricata Cav. (Zygophyllaceae) is a South American plant widely distributed in Argentina that is used in folk medicine to treat inflammatory diseases. The aqueous extract is known to have well-documented biological activities such as antitumour, immunomodulatory, antimicrobial, antiinflammatory and antioxidant. … Although the levels of polyphenols and flavonoids decreased upon incubation in gastric and intestinal fluids, the extract maintained its antioxidant activity related to the presence of nordihydroguaiaretic acid. These results are promising and encourage the potential use of the extract by the oral route as a supplement or phytomedicine with antioxidant activity. Martins S, et al (2013) - Solid-state fermentation as a strategy to improve the bioactive compounds recovery from Larrea tridentata leaves. Appl Biochem Biotechnol. 2013 Nov;171(5):1227-39. [ABS] The basidiomycete Phanerochaete chrysosporium was used in the experiments due to its ability to degrade lignin. …. Scanning electron microscopy micrographs revealed a major disorganization and porosity of the plant structure after fermentation, and Fourier transform infrared spectroscopy spectra indicated a possible solubilization of some constituents of lignocellulose fraction after this process, which may have favored the solvent action in the later stage. Palacio L, et al (2012) - Phenolic compound production in relation to differentiation in cell and tissue cultures of Larrea divaricata (Cav.). Plant Sci. 2012 Sep;193-194. [ABS] The lignan nordihydroguaiaretic acid (NDGA) and its derivatives existing in Larrea divaricata species show a wide range of pharmacological activities which makes this genus an interesting target to consider the plant in vitro cultivation systems as a feasible alternative source for their production. These compounds are potentially useful in treating diseases related to heart condition, asthma, arteriosclerosis, viral and bacterial infections, inflammation and cancer… Plantlets regenerated from adventitious shoots of L. divaricata calli did not show the same phenolic pattern as wild plants, with levels of NDGA and quercetin being 3.6- and 5.9-fold lower, respectively. Apraiz A, et al (2012) - Dihydroceramide accumulation and reactive oxygen species are distinct and nonessential events in 4-HPR- mediated leukemia cell death. Biochem Cell Biol. 2012 Apr;90(2):209-23. [FULL TEXT] 4-(Hydroxyphenyl)retinamide (4-HPR) is a synthetic retinoid with a strong apoptotic effect towards different cancer cell lines in vitro, and it is currently tested in clinical trials. … NDGA, described as a lipoxygenase inhibitor, exerted a significantly higher antioxidant activity than vitamin E and abrogated 4-HPR-mediated ROS. L JM, et al (2011) - Nordihydroguaiaretic acid (NDGA) inhibits ritonavir- induced endothelial dysfunction in porcine pulmonary arteries. Med Sci Monit. 2011 Nov;17(11):BR312-318. [FULL TEXT] HIV infection and treatment with highly active antiretroviral therapy (HAART) including HIV protease inhibitor ritonavir (RTV) have been associated with endothelial dysfunction and cardiovascular disease including pulmonary arterial hypertension. The objective of this study was to determine if nordihydroguaiaretic acid (NDGA), a natural herbal antioxidant found in the creosote bush Larrea tridentate, can protect vascular tissues against RTV-induced vascular injury. …while NDGA improved these vasomotor responses... In addition, treatment of RTV significantly decreased eNOS mRNA levels in both porcine PAs and HPAECs, and reduced eNOS immunoreactivity in porcine PAs, while NDGA significantly inhibited this effect of RTV. Furthermore, NDGA significantly blocked RTV-induced increase of superoxide anion in the PA rings and inhibited RTV-induced decrease of glutathione in HPAECs. CONCLUSIONS: NDGA effectively inhibits the detrimental effects of HIV protease inhibitor RTV on vasomotor functions in porcine PAs. NDGA also blocks RTV-induced decrease of eNOS expression and increase of oxidative stress in both porcine PAs and HPAECs. This study may provide valuable information for the development of effective strategies for the prevention and treatment of HAART-associated cardiovascular complications. Dynein Dynactin Famulski JK, et al (2011) - Dynein/Dynactin-mediated transport of kinetochore components off kinetochores and onto spindle poles induced by nordihydroguaiaretic acid. PLoS One. 2011 Jan 28;6(1):e16494. [FULL TEXT] 3 The mitotic checkpoint functions to ensure accurate chromosome segregation by regulating the progression from metaphase to anaphase. Once the checkpoint has been satisfied, it is inactivated in order to allow the cell to proceed into anaphase and complete the cell cycle. The minus end-directed microtubule motor dynein/dynactin has been implicated in the silencing of the mitotic checkpoint by "stripping" checkpoint proteins off kinetochores. A recent study suggested that Nordihydroguaiaretic acid (NDGA) stimulates dynein/dynactin-mediated transport of its cargo including ZW10 (Zeste White 10) …we found that treatment with NDGA induced a robust accumulation and complete stabilization of hZW10 at spindle poles. This finding suggests that NDGA may not induce dynein/dynactin transport but rather interfere with cargo release. Lastly, we determined that NDGA induced accumulation of checkpoint proteins at the poles requires dynein/dynactin-mediated transport, hZW10 kinetochore localization and kinetochore-microtubule attachments but not tension or Aurora B kinase activity. Estrogen e.g., receptor α Kim SA, et al (2016) - Estrogenic compound attenuates angiotensin II- induced vascular smooth muscle cell proliferation through interaction between LKB1 and estrogen receptor α. J Pharmacol Sci. 2016 Sep;132(1):78-85. [ABS] The prevalence rate of cardiovascular disease is higher for males than females, and estradiol (E2) induces AMP-activated protein kinase (AMPK) activation, which is known to regulate proliferation of VSMC. We identified the estrogenic properties of nordihydroguaiaretic acid (NDGA, a lignan phytoestrogen) that inhibit VSMC proliferation and explored the underlying mechanisms. Both the phosphorylation and expression of LKB1 were increased by NDGA. In addition, NDGA significantly attenuated angiotensin II (Ang II)-induced VSMC proliferation. … Taken together, the beneficial effects of estrogenic compound (E2 and NDGA) on inhibition of VSMC proliferation are mediated by interaction between LKB1 and ERα, suggesting a potential mechanism for females having less cardiovascular disease. Note: LKB1 regulates cell polarity and scaffolding interactions. It is a tumor suppressor gene also known as serine/threonine protein kinase. It also regulates cell cycle and apoptosis. A germ line mutation leads to Peutz-Jeghers syndrome.