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Bioorganic & Medicinal Chemistry Jan 2023The naturally-occurring di-catechol lignan nordihydroguaiaretic acid (NDGA) and an analog without methyl groups on the butyl linker both undergo intramolecular...
The naturally-occurring di-catechol lignan nordihydroguaiaretic acid (NDGA) and an analog without methyl groups on the butyl linker both undergo intramolecular cyclization at pH 7.4 to form dibenzocyclooctadienes. Both NDGA and these dibenzocyclooctadienes have been shown to prevent in vitro aggregation of α-synuclein, an intrinsically disordered protein associated with Parkinson's disease. NDGA possesses two vicinal methyl groups on the butyl linker and the presence of these methyl groups attenuates the rate of intramolecular cyclization versus the unsubstituted analog, in opposition to the anticipated Thorpe-Ingold effect, likely due to steric repulsions during cyclization. Numerous 1,2-bis-ethane di-catechols are known to inhibit α-synuclein aggregation in vitro and we hypothesize that these compounds undergo a similar intramolecular cyclization and the cyclized products may be responsible for the activity. To test this hypothesis we prepared a series of 1,2-bis-ethane di-catechols with 0, 2 and 4 methyl substituents on the linker. We have confirmed that these compounds undergo intramolecular cyclization to form dibenzocyclohexadienes and that steric interactions between the methyl substituents leads to an increase in the rate of intramolecular cyclization, which is in contrast to what was observed for lignan di-catechols. The rate of cyclization to form six-membered rings is 10-30 times more rapid than formation of eight membered rings and the dibenzocyclohexadienes also prevent in vitro aggregation of α-synuclein.
Topics: Humans; alpha-Synuclein; Masoprocol; Catechols; Parkinson Disease; Cyclization
PubMed: 36587551
DOI: 10.1016/j.bmc.2022.117147 -
Oral Diseases Nov 2023Collagen fibrils from carious dentin matrix are prone to enzymatic degradation. This study investigates the feasibility and mechanism of nordihydroguaiaretic acid...
OBJECTIVES
Collagen fibrils from carious dentin matrix are prone to enzymatic degradation. This study investigates the feasibility and mechanism of nordihydroguaiaretic acid (NDGA), as a collagen crosslinker, to bio-modify the demineralized dentin matrix.
METHODS
The physicochemical properties of the crosslinked dentin matrix were characterized by swelling ratio, ninhydrin assay, Fourier Transform Infrared spectroscopy, and atomic force microscopy. The collagenase degradation resistance was evaluated by measuring loss of dry mass, hydroproline release, loss of elasticity, and micro-nano structure integrity. The cytotoxicity of NDGA-crosslinked dentin collagen was evaluated by flow cytometry.
RESULTS
NDGA crosslinked dentin matrix without destroying the integrity of collagen. Mechanistically, NDGA formed bisquinone bond between two adjacent o-quinone groups, resulting in NDGA polymeric matrix in which collagen fibrils were embedded. NDGA modification could significantly enhance the stiffness of dentin matrix at macro-nano scale. The NDGA-crosslinked dentin matrix exhibited remarkably low collagen degradation and sustained bulk elasticity after collagenase challenge, which were attributed to decreased water content, physical masking of collagenase bind sites on collagen, and improved stiffness of collagen fibrils. Notably, NDGA-crosslinked dentin matrix exhibited excellent biocompatibility.
CONCLUSION
NDGA, as a biocompatible collagen crosslinker, improves the mechanical properties and biodegradation resistance of demineralized dentin matrix.
Topics: Masoprocol; Collagen; Collagenases; Dentin
PubMed: 36437605
DOI: 10.1111/odi.14453 -
Molecules (Basel, Switzerland) Oct 2022Fish by-product oil and lemon oil have potential applications as active ingredients in many industries, including cosmetics, pharmaceuticals and food. However, the...
Fish by-product oil and lemon oil have potential applications as active ingredients in many industries, including cosmetics, pharmaceuticals and food. However, the physicochemical properties, especially the poor stability, compromised the usage. Generally, nanoemulsions were used as an approach to stabilize the oils. This study employed an ultrasonication method to form oil-in-water nanoemulsion of lemon and fish by-product oils (NE-FLO). The formulation is produced at a fixed amount of 2 wt% fish by-product oil, 8 wt% lemon oil, 10 wt% surfactant, 27.7 wt% co-surfactants and 42 min of ultrasonication time. The size, polydispersity index (PDI) and zeta potential obtained were 44.40 nm, 0.077, and -5.02 mV, respectively. The biological properties, including antioxidant, antibacterial, cell cytotoxicity, and anti-inflammatory, showed outstanding performance. The antioxidant activity is comparable without any significant difference with ascorbic acid as standard and is superior to pure lemon oil. NE-FLO successfully inhibits seven Gram-positive and seven Gram-negative bacterial strains. NE-FLO's anti-inflammatory activity is 99.72%, comparable to nordihydroguaiaretic acid (NDGA) as the standard. At a high concentration of 10,000 µg·mL, NE-FLO is non-toxic to normal skin cells. These findings demonstrate that the NE-FLO produced in this study has significant potential for usage in various industries.
Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Emulsions; Fish Oils; Masoprocol; Plant Oils; Surface-Active Agents; Water
PubMed: 36235261
DOI: 10.3390/molecules27196725 -
Free Radical Biology & Medicine Nov 2022In response to wound signals, macrophages are immediately recruited to the injury where they acquire distinct phenotypes and functions, playing crucial roles both in...
In response to wound signals, macrophages are immediately recruited to the injury where they acquire distinct phenotypes and functions, playing crucial roles both in host defense and healing process. Although macrophage phenotypes have been intensively studied during wound healing, mostly using markers and expression profiles, the impact of the wound environment on macrophage shape and behaviour, and the underlying mechanisms deserve more in-depth investigation. Here, we sought to characterize the dynamics of macrophage recruitment and behaviour during aseptic wounding of the caudal fin fold of the zebrafish larva. Using a photo-conversion approach, we demonstrated that macrophages are recruited to the wounded fin fold as a single wave where they switch their phenotype. Intravital imaging of macrophage shape and trajectories revealed that wound-macrophages display a highly stereotypical set of behaviours and change their shape from amoeboid to elongated shape as wound healing proceeds. Using a pharmacological inhibitor of 15-lipoxygenase and protectin D1, a specialized pro-resolving lipid, we investigated the role of polyunsaturated fatty acid metabolism in macrophage behaviour. While inhibition of 15-lipoxygenase using PD146176 or Nordihydroguaiaretic acid (NDGA) decreases the switch from amoeboid to elongated shape, protectin D1 accelerates macrophage reverse migration and favours elongated morphologies. 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, and highlight the crucial role of lipid metabolism in the control of macrophage behaviour plasticity during inflammation in vivo.
Topics: Animals; Arachidonate 15-Lipoxygenase; Macrophages; Masoprocol; Wound Healing; Zebrafish
PubMed: 36162743
DOI: 10.1016/j.freeradbiomed.2022.09.021 -
Molecular Biology Reports Nov 2022Methylglyoxal (MGO) is a known toxic byproduct of glycolysis, with MGO-induced cytotoxicity believed to contribute to the pathogenesis of several diseases. Glyoxalase I...
BACKGROUND
Methylglyoxal (MGO) is a known toxic byproduct of glycolysis, with MGO-induced cytotoxicity believed to contribute to the pathogenesis of several diseases. Glyoxalase I (GLO1) is a key enzyme for eliminating MGO in mammalian cells, therefore, compounds affecting GLO1 activity are potential therapeutic agents for MGO-induced disorders. Previously, we found nordihydroguaiaretic acid (NDGA) as a potent GLO1 inhibitor.
METHODS
The inhibitory characteristics of NDGA were determined spectrophotometrically with recombinant GLO1. NDGA-induced growth-inhibition and accumulation of MGO-derived advanced glycation end products (AGEs) were examined in EA.hy926 cells.
RESULTS
NDGA showed significant inhibition of GLO1 enzymatic activity in a dose-dependent manner. Its K value was estimated to be 146-fold lower than that of myricetin, a known GLO1 inhibitor. The co-addition of MGO with NDGA to the cells resulted in significant growth inhibition, suggesting that MGO accumulation, sufficient to affect cell growth, was caused by NDGA inhibiting GLO1. These findings were supported by the observations that the addition of aminoguanidine, a typical MGO scavenger, significantly reversed cell-growth inhibition by co-addition of MGO with NDGA, and that an increase in intracellular MGO-derived AGEs was observed during incubation with the co-addition of MGO with NDGA.
CONCLUSION
NDGA was found to be a novel and potent inhibitor of GLO1. The co-addition of NDGA with MGO to the cells resulted in increased intracellular MGO accumulation followed by enhanced cell-growth inhibition.
Topics: Cell Proliferation; Lactoylglutathione Lyase; Magnesium Oxide; Masoprocol; Pyruvaldehyde; Humans; Cell Line
PubMed: 36127524
DOI: 10.1007/s11033-022-07929-6 -
Phytomedicine : International Journal... Nov 2022Dengue virus (DENV) is considered one of the most important pathogens in the world causing 390 million infections each year. Currently, the development of vaccines...
BACKGROUND
Dengue virus (DENV) is considered one of the most important pathogens in the world causing 390 million infections each year. Currently, the development of vaccines against DENV presents some shortcomings and there is no antiviral therapy available for its infection. An important challenge is that both treatments and vaccines must be effective against all four DENV serotypes. 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.
PURPOSE
We evaluated the in vitro virucidal and antiviral activity of NDGA on DENV serotype 1 (DENV1), including the study of its mechanism of action, to provide more evidence on its antiviral activity.
METHODS
The viability of viral particles was quantified by the plaque-forming unit reduction method. NDGA effects on DENV1 genome and viral proteins were evaluated by qPCR and immunofluorescence, respectively. Lysosomotropic activity was assayed using acridine orange and neutral red dyes.
RESULTS
NDGA showed in vitro virucidal and antiviral activity against DENV1. The antiviral effect would be effective within the first 2 h after viral internalization, when the uncoating process takes place. In addition, we determined by qPCR that 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. Considering the inhibitory activity of NDGA on the cellular lipid metabolism, we compared the antiviral effect of two inhibitors acting on two different pathways of this type of metabolism: 1) resveratrol that inhibits the sterol regulatory element of binding proteins, and 2) caffeic acid that inhibits the 5-lipoxygenase (5-LOX) enzyme. Only caffeic acid produced an inhibitory effect on DENV1 infection. We studied the lysosomotropic activity of NDGA on host cells and found, for the first time, that this compound inhibited the acidification of cell vesicles which would prevent DENV1 uncoating process.
CONCLUSION
The present work contributes to the knowledge of NDGA activity on DENV. We describe its activity on DENV1, a serotype different to those that have been already reported. Moreover, we provide evidence on which stage/s of the viral replication cycle NDGA exerts its effects. We suggest that the mechanism of action of NDGA on DENV1 is related to its lysosomotropic effect, which inhibits the viral uncoating process.
Topics: Acridine Orange; Antiviral Agents; Arachidonate 5-Lipoxygenase; Caffeic Acids; Coloring Agents; Dengue Virus; Masoprocol; Neutral Red; RNA; Resveratrol; Serogroup; Sterols; Viral Proteins; Virus Replication
PubMed: 36126544
DOI: 10.1016/j.phymed.2022.154424 -
Journal of Microbiology and... Sep 2022This study investigated the contribution of lipoxygenase (LOX) inhibitors, nordihydroguaiaretic acid (NDGA), tetra--methyl nordihydroguaiaretic acid (MN) and zileuton...
This study investigated the contribution of lipoxygenase (LOX) inhibitors, nordihydroguaiaretic acid (NDGA), tetra--methyl nordihydroguaiaretic acid (MN) and zileuton (ZIL), and thromboxane A2 (TXA) inhibitor 4,5-diphenylimidazole (DPI) in the proliferation of infection. None of the compounds affected the uptake of into the macrophages. We determined the effect of neutralizing leukotriene B4 (LTB4) receptor and showed that the uptake of the bacteria was inhibited at 30 min post-infection. MN treatment attenuated intracellular survival of at 2 h post-incubation but it was not observed in the succeeding time points. DPI treatment showed reduced survival of at 24 h post-incubation while blocking LTB4 receptor was observed to have a lower intracellular growth at 48 h post-incubation suggesting different action of the inhibitors in the course of the survival of within the cells. Reduced proliferation of the bacteria in the spleens of mice was observed in animals treated with ZIL or DPI. Increased serum cytokine level of TNF-α and MCP-1 was observed in mice treated with MN or ZIL while a lower IFN-γ level in ZIL-treated mice and a higher IL-12 serum level in DPI-treated mice were observed at 7 d post-infection. At 14 d post-infection, ZIL-treated mice displayed reduced serum level of IL-12 and IL-10. Overall, inhibition of 5-LOX or TXA or a combination therapy promises a potential alternative therapy against infection. Furthermore, strong ligands for LTB4 receptor could also be a good candidate for the control of infection.
Topics: Animals; Brucella abortus; Brucellosis; Cytokines; Interleukin-10; Interleukin-12; Leukotriene B4; Lipoxygenase Inhibitors; Lipoxygenases; Masoprocol; Mice; Receptors, Leukotriene B4; Thromboxane A2; Tumor Necrosis Factor-alpha
PubMed: 36039381
DOI: 10.4014/jmb.2207.07026 -
Journal of Ethnopharmacology Oct 2022Larrea divaricata Cav. (Zygophyllaceae) (jarilla) is a native plant of South America widely distributed across Argentina and used in popular medicine to treat diabetes...
ETHNOPHARMACOLOGICAL RELEVANCE
Larrea divaricata Cav. (Zygophyllaceae) (jarilla) is a native plant of South America widely distributed across Argentina and used in popular medicine to treat diabetes and hypercholesterolemia by the Diaguita-Calchaquí, Amaichas, and Quilmes indigenous communities and by non-indigenous population (criollos) of Calamuchita, in the province of Córdoba, Argentina. L. divaricata has also proved to have anti-inflammatory properties. However, the antidiabetic effects and the nutritional properties of the aqueous extract (AE) of this plant remain to be scientifically determined.
AIM OF THE STUDY
The aim of the present work was to evaluate the capacity of an aqueous extract of L. divaricata (AE) and its main compound nordihydroguaiaretic acid (NDGA) to modulate the glucose, cholesterol, triglycerides and oxidative stress levels in STZ-induced diabetes in mice. The general objective of the present work was to search for extracts that can be used as adjuvant therapy in for diabetes. The suitability of the extract to be used as a dietary supplement was also assessed by determining the proximate amount of fibre, lipids, proteins, and minerals.
MATERIALS AND METHODS
Diabetes was induced in mice by administration of streptozotocin (STZ). AE and NDGA were administered by the oral route. The animals' glycaemia was periodically monitored in blood samples obtained from the tail vein. The glucose dehydrogenase method was used. The effect of the AE on cholesterol, triglycerides, oxidative stress, lipid peroxidation and reduced glutathione (GSH) levels were determined in plasma samples by spectrophotometric assays.
RESULTS
In STZ-treated mice, AE significantly decreased glucose (33%, ****p < 0.0001) and cholesterol levels (32%, **p < 0.01). AE and NDGA decreased lipid peroxidation (30% and 38%, respectively, ****p < 0.0001), and increased GSH levels (20%, **p < 0.01). The effects of AE on glucose and lipid levels could not be ascribed to NDGA; however, this compound was involved in the extract antioxidant effects. The overall effects of AE were probably related to its antioxidant activity and to the anti-hyperglycaemic effect mainly mediated by flavonoids, fibre (carbohydrates) and mineral elements such as potassium, calcium, magnesium, and zinc. The AE protein content also confers the extract nutritional properties.
CONCLUSIONS
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.
Topics: Animals; Antioxidants; Diabetes Mellitus, Experimental; Glucose; Hypoglycemic Agents; Larrea; Masoprocol; Mice; Plant Extracts; Streptozocin; Triglycerides; Water
PubMed: 35659916
DOI: 10.1016/j.jep.2022.115429 -
Sensors (Basel, Switzerland) Mar 2022In this study, we demonstrate that Raman microscopy combined with computational analysis is a useful approach to discriminating accurately between brain tumor...
In this study, we demonstrate that Raman microscopy combined with computational analysis is a useful approach to discriminating accurately between brain tumor bio-specimens and to identifying structural changes in glioblastoma (GBM) bio-signatures after nordihydroguaiaretic acid (NDGA) administration. 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 novel outcome presented here is the use of phenylalanine as a biomarker for differentiating between samples and assessing drug efficacy. Treatment with a low NDGA dose shows a decline in abnormal lipid-protein metabolism, which is inferred by the formation of lipid droplets and a decrease in altered protein content. 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.
Topics: Antioxidants; Glioblastoma; Humans; Masoprocol; Phenylalanine; Reactive Oxygen Species
PubMed: 35408257
DOI: 10.3390/s22072643 -
Computational and Mathematical Methods... 2022Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease for which there is a lack of therapeutic options. Genome-wide association studies (GWASs) have...
Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease for which there is a lack of therapeutic options. Genome-wide association studies (GWASs) have identified over 100 genetic loci associated with RA susceptibility; however, the most causal risk genes (RGs) associated with, and molecular mechanism underlying, RA remain unknown. In this study, we collected 95 RA-associated loci from multiple GWASs and detected 87 candidate high-confidence risk genes (HRGs) from these loci via integrated multiomics data (the genome-scale chromosome conformation capture data, enhancer-promoter linkage data, and gene expression data) using the Bayesian integrative risk gene selector (iRIGS). Analysis of these HRGs indicates that these genes were indeed, markedly associated with different aspects of RA. Among these, 36 and 46 HRGs have been reported to be related to RA and autoimmunity, respectively. Meanwhile, most novel HRGs were also involved in the significantly enriched RA-related biological functions and pathways. Furthermore, drug repositioning prediction of the HRGs revealed three potential targets (ERBB2, IL6ST, and MAPK1) and nine possible drugs for RA treatment, of which two IL-6 receptor antagonists (tocilizumab and sarilumab) have been approved for RA treatment and four drugs (trastuzumab, lapatinib, masoprocol, and arsenic trioxide) have been reported to have a high potential to ameliorate RA. In summary, we believe that this study provides new clues for understanding the pathogenesis of RA and is important for research regarding the mechanisms underlying RA and the development of therapeutics for this condition.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Autoimmunity; Bayes Theorem; Computational Biology; Drug Development; Drug Repositioning; Gene Regulatory Networks; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Risk Factors
PubMed: 35140805
DOI: 10.1155/2022/6783659