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BMC Complementary and Alternative... Aug 2019Oxidative stress is an imbalance between the levels of reactive oxygen species (ROS), reactive nitrogen species (RNS) and endogenous antioxidants. The aetiology and...
BACKGROUND
Oxidative stress is an imbalance between the levels of reactive oxygen species (ROS), reactive nitrogen species (RNS) and endogenous antioxidants. The aetiology and pathogenesis of several oral diseases are attributed to this process. The antioxidant enzymes secreted in the saliva by submandibular glands maintain oral health through the scavenging of ROS. The objective of this work was to study the capacity of an aqueous extract of L. divaricata (AE), and its majority compound, nordihydroguariaretic acid (NDGA), to modulate the pro-oxidant/antioxidant status in submandibular glands in a model of oxidative stress induced by streptozotocin (STZ) in rats.
METHODS
To induce oxidative stress with STZ, a group of animals was treated i.p. with 1 X PBS (control group) and other group was injected i.p. once with STZ (60 mg/kg). Ten days after the treatment, blood samples were taken from the tail vain to determine the glucose levels. Animals with glucose values ≥300 mg/ml were selected. The submandibular glands of control and STZ treated animals were incubated with either the AE (500 μg/ml) or with NDGA (1.5 μg/ml), and the content of malondialdehyde (MDA), protein carbonyl groups, ROS and RNS, and the activity and expression of peroxidase (Px), superoxide dismutase (SOD) and inducible nitric oxide synthase (iNOS) were assayed.
RESULTS
AE decreased the levels of MDA (P < 0.01) and protein carbonyl groups (P < 0.05), and modulated the levels of ROS such as hydrogen peroxide (HO)(P < 0.01), superoxide anion (O) (P < 0.05) and nitric oxide (NO) (P < 0.05) in relation to the modulation of Px and iNOS expression. NDGA was found to be involved in these effects.
CONCLUSIONS
The antioxidant activity of the AE in the submandibular glands would allow the maintenance of the antioxidant pool to prevent oral oxidative diseases.
Topics: Animals; Antioxidants; Diabetes Mellitus, Experimental; Female; Larrea; Malondialdehyde; Masoprocol; Oxidative Stress; Oxidoreductases; Plant Extracts; Rats; Rats, Wistar; Submandibular Gland
PubMed: 31438933
DOI: 10.1186/s12906-019-2636-z -
Molecular and Cellular Endocrinology Dec 2019Creosote bush (Larrea tridentata)-derived nordihydroguaiaretic acid (NDGA) was shown to have profound effects on the core components of metabolic syndrome. This study...
Creosote bush (Larrea tridentata)-derived nordihydroguaiaretic acid (NDGA) was shown to have profound effects on the core components of metabolic syndrome. This study investigated the in vivo potential of NDGA for prevention or attenuation of the pathophysiologic abnormalities of NASH. A novel dietary NASH model with feeding C57BL/6J mice with a high trans-fat, high cholesterol and high fructose (HTF) diet, was used. The HTF diet fed mice exhibited obesity, insulin resistance, hepatic steatosis, fibrosis, inflammation, ER stress, oxidative stress, and liver injury. NDGA attenuated these metabolic abnormalities as well as hepatic steatosis and fibrosis together with attenuated expression of genes encoding fibrosis, progenitor and macrophage markers with no effect on the levels of mRNAs for lipogenic enzymes. NDGA increased expression of fatty acid oxidation genes. In conclusion, NDGA exerts anti-NASH/anti-fibrotic actions and raises the therapeutic potential of NDGA for treatment of NASH patients with fibrosis and other associated complications.
Topics: Animals; Antioxidants; Diet, High-Fat; Disease Models, Animal; Hyperlipidemias; Inflammation; Insulin Resistance; Larrea; Lipogenesis; Male; Masoprocol; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress
PubMed: 31415794
DOI: 10.1016/j.mce.2019.110538 -
International Journal of Molecular... Jun 2019Lipoprotein lipase (LPL) hydrolyzes triglycerides in lipoprotein to supply fatty acids, and its deficiency leads to hypertriglyceridemia, thereby inducing metabolic...
Lipoprotein lipase (LPL) hydrolyzes triglycerides in lipoprotein to supply fatty acids, and its deficiency leads to hypertriglyceridemia, thereby inducing metabolic syndrome (MetSyn). Nordihydroguaiaretic acid (NDGA) has been recently reported to inhibit LPL secretion by endoplasmic reticulum (ER)-Golgi redistribution. However, the role of NDGA on dyslipidemia and MetSyn remains unclear. To address this question, leptin receptor knock out (KO)-db/db mice were randomly assigned to three different groups: A normal AIN76-A diet (CON), a Western diet (WD) and a Western diet with 0.1% NDGA and an LPL inhibitor, (WD+NDGA). All mice were fed for 12 weeks. The LPL inhibition by NDGA was confirmed by measuring the systemic LPL mass and adipose LPL gene expression. We investigated whether the LPL inhibition by NDGA alters the metabolic phenotypes. NDGA led to hyperglycemia, hypertriglyceridemia, and hypercholesterolemia. More strikingly, the supplementation of NDGA increased the percentage of high density lipoprotein (HDL) (HDL) and decreased the percentage of HDL (HDL) compared to the WD group, which indicates that LPL inhibition modulates HDL subclasses. was NDGA increased adipose inflammation but had no impact on hepatic stress signals. Taken together, these findings demonstrated that LPL inhibition by NDGA aggravates metabolic parameters and alters HDL particle size.
Topics: Animals; Diet, Western; Lipoprotein Lipase; Lipoproteins, HDL; Male; Masoprocol; Mice; Mice, Knockout; Particle Size; Receptors, Leptin
PubMed: 31234537
DOI: 10.3390/ijms20123057 -
BMC Plant Biology May 2019Chinese jujube (Ziziphus jujuba Mill.) is a non-climacteric fruit; however, the underlying mechanism of ripening and the role of abscisic acid involved in this process...
BACKGROUND
Chinese jujube (Ziziphus jujuba Mill.) is a non-climacteric fruit; however, the underlying mechanism of ripening and the role of abscisic acid involved in this process are not yet understood for this species.
RESULTS
In the present study, a positive correlation between dynamic changes in endogenous ABA and the onset of jujube ripening was determined. Transcript analyses suggested that the expression balance among genes encoding nine-cis-epoxycarotenoid dioxygenase (ZjNCED3), ABA-8'-hydroxylase (ZjCYP707A2), and beta-glucosidase (ZjBG4, ZjBG5, ZjBG8, and ZjBG9) has an important role in maintaining ABA accumulation, while the expression of a receptor (ZjPYL8), protein phosphatase 2C (ZjPP2C4-8), and sucrose nonfermenting 1-related protein kinase 2 (ZjSnRK2-2 and ZjSnRK2-5) is important in regulating fruit sensitivity to ABA applications. In addition, white mature 'Dongzao' fruit were harvested and treated with 50 mg L ABA or 50 mg L nordihydroguaiaretic acid (NDGA) to explore the role of ABA in jujube fruit ripening. By comparative transcriptome analyses, 1103 and 505 genes were differentially expressed in response to ABA and NDGA applications on the 1st day after treatment, respectively. These DEGs were associated with photosynthesis, secondary, lipid, cell wall, and starch and sugar metabolic processes, suggesting the involvement of ABA in modulating jujube fruit ripening. Moreover, ABA also exhibited crosstalk with other phytohormones and transcription factors, indicating a regulatory network for jujube fruit ripening.
CONCLUSIONS
Our study further elucidated ABA-associated metabolic and regulatory processes. These findings are helpful for improving strategies for jujube fruit storage and for gaining insights into understand complex non-climacteric fruit ripening processes.
Topics: Abscisic Acid; Biomass; Biosynthetic Pathways; Ethylenes; Fruit; Gene Expression Profiling; Gene Expression Regulation, Plant; Gene Ontology; Genes, Plant; Masoprocol; Plant Growth Regulators; RNA, Messenger; Reproducibility of Results; Signal Transduction; Transcription Factors; Ziziphus
PubMed: 31068143
DOI: 10.1186/s12870-019-1802-2 -
Scientific Reports Feb 2019Growing evidence implicates α-synuclein aggregation as a key driver of neurodegeneration in Parkinson's disease (PD) and other neurodegenerative disorders. Herein, the...
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), a phenolic dibenzenediol lignan, were explored using an array of biochemical and biophysical methodologies. NDGA analogs induced modest, progressive compaction of monomeric α-synuclein, preventing aggregation into amyloid-like fibrils. This conformational remodeling preserved the dynamic adoption of α-helical conformations, which are essential for physiological membrane interactions. Oxidation-dependent NDGA cyclization was required for the interaction with monomeric α-synuclein. NDGA analog-pretreated α-synuclein did not aggregate even without NDGA-analogs in the aggregation mixture. Strikingly, NDGA-pretreated α-synuclein suppressed aggregation of naïve untreated aggregation-competent monomeric α-synuclein. Further, cyclized NDGA reduced α-synuclein-driven neurodegeneration in Caenorhabditis elegans. The cyclized NDGA analogs may serve as a platform for the development of small molecules that stabilize aggregation-resistant α-synuclein monomers without interfering with functional conformations yielding potential therapies for PD and related disorders.
Topics: Amyloid; Animals; Caenorhabditis elegans; Cell Membrane; Humans; Masoprocol; Parkinson Disease; Phospholipids; Protein Aggregation, Pathological; alpha-Synuclein
PubMed: 30814575
DOI: 10.1038/s41598-019-39480-z -
Lipids in Health and Disease Feb 2019Diabetic encephalopathy is a chronic complications of diabetes mellitus that affects the central nervous system. We evaluated the effect of ω3 and ω6 polyunsaturated...
BACKGROUND
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.
METHODS
One hundred twenty spontaneous diabetic eSS male rats and 38 non-diabetic Wistar, used as healthy control, received monthly by intraperitoneal route, ω3 or ω6 PUFA (6.25 mg/kg) alone or plus NDGA (1.19 mg/kg) for 12 months. Diabetic rats had a worse performance in behavioural Hole-Board test. Histopathological analysis confirmed lesions in diabetic rats brain tissues. We also detected low expression of synaptophysin, a protein linked to release of neurotransmitters, by immunohistochemically techniques in eSS rats brain. Biochemical and histopathological studies of brain were performed at 12th month. Biochemical analysis showed altered parameters related to metabolism. High levels of markers of oxidative stress and inflammation were detected in plasma and brain tissues. Data were analysed by ANOVA test and paired t test was used by comparison of measurements of the same parameter at different times.
RESULTS
The data obtained in this work showed that behavioural, biochemical and morphological alterations observed in eSS rats are compatible with previously reported indices in diabetic encephalopathy and are associated with increased glucolipotoxicity, chronic low-grade inflammation and oxidative stress burden. Experimental treatments assayed modulated the values of studied parameters.
CONCLUSIONS
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.
Topics: Animals; Blood Glucose; Brain; Brain Diseases; Diabetic Neuropathies; Dietary Supplements; Disease Models, Animal; Fatty Acids, Omega-3; Glucose Tolerance Test; Hippocampus; Male; Masoprocol; Oxidative Stress; Rats; Rats, Wistar
PubMed: 30736810
DOI: 10.1186/s12944-018-0938-7 -
Immunopharmacology and Immunotoxicology Feb 2019Nephrotoxicity is a highly manifested complication in cancer patients undergoing cisplatin therapy. Oxidative stress, nitrosative stress, and inflammation are the major...
Nephrotoxicity is a highly manifested complication in cancer patients undergoing cisplatin therapy. Oxidative stress, nitrosative stress, and inflammation are the major patho-mechanisms of cisplatin-induced nephrotoxicity. The purpose of this study was to determine the protective effect of pretreatment and post-treatment of nordihydroguaiarectic acid (NDGA) on cisplatin-induced nephrotoxicity. Cisplatin-induced renal damage was accessed by biochemical estimation of nephrotoxicity markers, oxidative and nitrosative stress whereas inflammatory markers were accessed by ELISA technique. Cisplatin administration had resulted in renal injury associated with oxidative stress, nitrosative stress as evident by increased MDA, ROS, and nitrite level with decreased antioxidants such as SOD, catalase and, glutathione. Furthermore, cisplatin treated animals exhibited a noticeable pro-inflammatory response with the substantial increase in renal levels of TNF-α, IL-1β, and IL-6 and decrease in the renal level of IL-10. NDGA 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.
Topics: Animals; Antioxidants; Body Weight; Cisplatin; Female; Kidney; Kidney Function Tests; Lipid Peroxidation; Masoprocol; Nitrosative Stress; Organ Size; Oxidative Stress; Rats; Rats, Sprague-Dawley
PubMed: 30604648
DOI: 10.1080/08923973.2018.1547741 -
International Journal of Biological... Feb 2019This study demonstrates the antiglycation activity of Nordihydroguaiaretic acid, a lignin from the creosote bush (Larrea tridentate), which has also been proven to...
This study demonstrates the antiglycation activity of Nordihydroguaiaretic acid, a lignin from the creosote bush (Larrea tridentate), which has also been proven to assist in the treatment of cancer, neurological disorders, and cardiovascular complications. We determined the antiglycation activity of NDG based on spectroscopic analysis, molecular interactions and circular dichroism studies with albumin. It was also seen that NDG inhibits the aggregation of albumin, after glycation, using Thioflavin T binding and confocal imaging. Results suggest that NDG is a potent inhibitor of advanced glycation end products formation. NDG was found to impart protective effects on albumin by preventing glycation modification of lysine residues (Lys20, Phe36, Lys41, Lys131, and Lys132) due to glycation.
Topics: Animals; Cattle; Glycosylation; Masoprocol; Molecular Docking Simulation; Protein Aggregates; Protein Conformation; Serum Albumin, Bovine
PubMed: 30416092
DOI: 10.1016/j.ijbiomac.2018.10.173 -
Enzyme and Microbial Technology Jan 2019Nordihydroguaiaretic acid (NDGA) is the major lignan of the creosote bush Larrea tridentata known for its antioxidative and pharmacological properties. Here we present...
Nordihydroguaiaretic acid (NDGA) is the major lignan of the creosote bush Larrea tridentata known for its antioxidative and pharmacological properties. Here we present the identification of glucansucrases for NDGA glucosylation and the physicochemical and biological characterization of the glucosides. Extracellular glucansucrase of L. pseudomesenteroides DSM 20193 was selected from 19 glucansucrase positive Leuconostoc and Weissella strains. Kinetic analysis of the PEG-fractionated enzyme revealed a K of 6.6 mM and a k of 2.6 s for NDGA. Full-factorial design methodology was used to optimize conversion resulting in 95.5% total NDGA glucosides. In total 7 glucosides were detected by LC-MS ranging from mono- to triglucoside. The 4-O-α-D-monoglucoside and the symmetrical 4,4'-O-α-D-diglucoside were the major products in all biotransformations. Water solubility and half-life stability at 45 °C increased significantly in the order diglucoside > monoglucoside > aglycon. Analysis of cellular antioxidative capacity exhibited a time-dependent activity increase pointing towards glucoside hydrolysis. Accordingly, NDGA-glucosides impaired metastasis of triple negative breast cancer cells to the same degree as the aglycon with 35% reduction of cell migration by the mono- and 34% reduction by the diglucoside after 20 h.
Topics: Antioxidants; Cell Movement; Female; Glucosides; Glycosyltransferases; Humans; Iridoid Glucosides; Larrea; Masoprocol; Triple Negative Breast Neoplasms; Tumor Cells, Cultured
PubMed: 30396401
DOI: 10.1016/j.enzmictec.2018.10.002 -
British Journal of Pharmacology Feb 2019Previous studies have shown that Creosote bush-derived nordihydroguaiaretic acid (NDGA) exerts beneficial actions on the key components of metabolic syndrome including...
BACKGROUND AND PURPOSE
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.
EXPERIMENTAL APPROACH
HFrD fed Sprague-Dawley rats treated with NDGA or one of the six analogues were used. Serum samples were analysed for blood metabolites, whereas liver samples were quantified for changes in various mRNA levels by real-time RT-PCR.
KEY RESULTS
Oral gavage of HFrD-fed rats for 4 days with NDGA analogues 1 and 2 (100 mg·kg ·day ) suppressed the hepatic triglyceride content, whereas the NDGA analogues 2, 3 and 4, like NDGA, decreased the plasma triglyceride levels by 70-75%. qRT-PCR measurements demonstrated that among NDGA analogues 1, 2, 4 and 5, analogue 4 was the most effective at inhibiting the mRNA levels of some key enzymes and transcription factors involved in lipogenesis. All four analogues almost equally inhibited the key genes involved in triglyceride synthesis and fatty acid elongation. Unlike NDGA, none of the analogues affected the genes of hepatic fatty acid oxidation or transport.
CONCLUSIONS AND IMPLICATIONS
Our data suggest that NDGA analogues 1, 2, 4 and 5, particularly analogue 4, exert their anti-hyperlipidaemic actions by negatively targeting genes of key enzymes and transcription factors involved in lipogenesis, triglyceride synthesis and fatty acid elongation. These analogues have therapeutic potential.
Topics: Animals; Hyperlipidemias; Hypolipidemic Agents; Male; Masoprocol; Molecular Docking Simulation; Molecular Structure; Rats; Rats, Sprague-Dawley
PubMed: 30374952
DOI: 10.1111/bph.14528