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British Journal of Pharmacology Jan 2024The production of metallo-β-lactamases is a major mechanisms adopted by bacterial pathogens to resist carbapenems. Repurposing approved drugs to restore the efficacy of...
BACKGROUND AND PURPOSE
The production of metallo-β-lactamases is a major mechanisms adopted by bacterial pathogens to resist carbapenems. Repurposing approved drugs to restore the efficacy of carbapenems represents an efficient and cost-effective approach to fight infections caused by carbapenem resistant pathogens.
EXPERIMENTAL APPROACH
The nitrocefin hydrolysis assay was employed to screen potential New Delhi metallo-lactamase-1 (NDM-1) inhibitors from a commercially available U.S. Food and Drug Administration (FDA) approved drug library. The mechanism of inhibition was clarified by metal restoration, inductively coupled plasma mass spectrometry (ICP-MS) and molecular dynamics simulation. The in vitro synergistic antibacterial effect of the identified inhibitors with meropenem was determined by the checkerboard minimum inhibitory concentration (MIC) assay, time-dependent killing assay and combined disc test. Three mouse infection models were used to further evaluate the in vivo therapeutic efficacy of combined therapy.
KEY RESULTS
Twelve FDA-approved compounds were initially screened to inhibit the ability of NDM-1 to hydrolyse nitrocefin. Among these compounds, dexrazoxane, embelin, candesartan cilexetil and nordihydroguaiaretic acid were demonstrated to inhibit all tested metallo-β-lactamases and showed an in vitro synergistic bactericidal effect with meropenem against metallo-β-lactamases-producing bacteria. Dexrazoxane, embelin and candesartan cilexetil are metal ion chelating agents, while the inhibition of NDM-1 by nordihydroguaiaretic acid involves its direct binding to the active region of NDM-1. Furthermore, these four drugs dramatically rescued the treatment efficacy of meropenem in three infection models.
CONCLUSIONS AND IMPLICATIONS
Our observations indicated that dexrazoxane, embelin, candesartan cilexetil and nordihydroguaiaretic acid are promising carbapenem adjuvants against metallo-β-lactamases-positive carbapenem resistant bacterial pathogens.
Topics: Animals; Mice; Carbapenems; Meropenem; beta-Lactamase Inhibitors; Masoprocol; Dexrazoxane; Anti-Bacterial Agents; beta-Lactamases; Bacteria; Microbial Sensitivity Tests
PubMed: 37539785
DOI: 10.1111/bph.16210 -
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 -
PloS One 2023Tetra-O-methyl-nordihydroguaiaretic acid (terameprocol; M4N), a global transcription inhibitor, in combination with a second anticancer drug induces strong tumoricidal...
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.
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. In this study, we showed that after continuous oral consumption of high-fat (HF) diets containing M4N, the M4N concentration in most of the organs in mice reached ~1 μM (the M4N concentration in intestines and fat pads was as high as 20-40 μM) and treatment with the combination of M4N with temozolomide (TMZ) suppressed glycolysis and the tricarboxylic acid cycle in LN229 human glioblastoma implanted in xenograft mice. Combination treatment of M4N with TMZ also reduced the levels of lactate dehydrogenase A (LDHA), a key enzyme for glycolysis; lactate, a product of LDHA-mediated enzymatic activity; nicotinamide phosphoribosyltransferase, a rate-limiting enzyme for nicotinamide adenine dinucleotide plus hydrogen (NADH)/NAD+ salvage pathway; and NAD+, a redox electron carrier essential for energy metabolism. It was also shown that M4N suppressed oxygen consumption in cultured LN229 cells, indicating that M4N inhibited oxidative phosphorylation. Treatment with M4N and TMZ also decreased the level of hypoxia-inducible factor 1A, a major regulator of LDHA, under hypoxic conditions. The ability of M4N to suppress energy metabolism resulted in induction of the stress-related proteins activating transcription factor 4 and cation transport regulator-like protein 1, and an increase in reactive oxygen species production. In addition, the combination treatment of M4N with TMZ reduced the levels of oncometabolites such as 2-hydroxyglutarate as well as the aforementioned lactate. M4N also induced methylidenesuccinic acid (itaconate), a macrophage-specific metabolite with anti-inflammatory activity, in tumor microenvironments. Meanwhile, the ability of M4N to suppress energy metabolism prevented obesity in mice consuming HF diets, indicating that M4N has beneficial effects on normal tissues. 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.
Topics: Humans; Animals; Mice; Masoprocol; Temozolomide; Glioblastoma; Diet, High-Fat; NAD; Cell Line, Tumor; Energy Metabolism; Tumor Microenvironment
PubMed: 37228120
DOI: 10.1371/journal.pone.0285536 -
Chembiochem : a European Journal of... Sep 2023Escherichia coli and other Enterobacteriaceae thrive in robust biofilm communities through the coproduction of curli amyloid fibers and phosphoethanolamine cellulose....
Escherichia coli and other Enterobacteriaceae thrive in robust biofilm communities through the coproduction of curli amyloid fibers and phosphoethanolamine cellulose. Curli promote adhesion to abiotic surfaces and plant and human host tissues and are associated with pathogenesis in urinary tract infection and food-borne illness. The production of curli in the host has also been implicated in the pathogenesis of neurodegenerative diseases. We report that the natural product nordihydroguaiaretic acid (NDGA) is effective as a curlicide in E. coli. NDGA prevents CsgA polymerization in vitro in a dose-dependent manner. NDGA selectively inhibits cell-associated curli assembly and inhibits uropathogenic E. coli biofilm formation. More broadly, this work emphasizes the ability to evaluate and identify bioactive amyloid assembly inhibitors by using the powerful gene-directed amyloid biogenesis machinery in E. coli.
Topics: Humans; Escherichia coli; Escherichia coli Proteins; Masoprocol; Polymerization; Amyloid; Amyloidogenic Proteins; Biofilms; Bacterial Proteins
PubMed: 37195016
DOI: 10.1002/cbic.202300266 -
Computational Biology and Chemistry Dec 2018Developments of novel inhibitors to prevent the function of 5-lipoxygenase (5-LOX) proteins that are responsible for a variety of inflammatory and allergic disease are a...
Developments of novel inhibitors to prevent the function of 5-lipoxygenase (5-LOX) proteins that are responsible for a variety of inflammatory and allergic disease are a major challenge in the scientific community. In this study, robust QSAR classification models for predicting 5-LOX activity were developed using machine learning algorithms. The Support Vector Machines (SVM), Logistic Regression, k-Nearest Neighbour (NN) and Decision Trees were adopted to improve the prediction ability of the classification models. The most informative molecular descriptors that contribute to the prediction of 5-LOX activity are screened from e-Dragon, Ochem, PowerMV and Combined databases using Filter-based feature selection methods such as Correlation Feature Selection (CFS) and Information Gain (IG). Performances of the models were measured by 5-fold cross-validation and external test sets prediction. Evaluation of performance of feature selection revealed that the CFS method outperforms the IG method for all descriptor databases except for PowerMV database. The best ensemble classification model was obtained with the IG filtered 'PowerMV' descriptor database using kNN (k = 5) algorithm which displayed an overall accuracy of 76.6% for the training set and 77.9% for the test set. Finally, we employed this model as a virtual screening tool for identifying potential 5-LOX inhibitors from the e-Drug3D drug database and found 43 potential hit candidates. This top screened hits containing one known 5-LOX inhibitors zileuton as well as novel scaffolds. These compounds further screened by applying molecular docking simulation and identified four potential hits such as Belinostat, Masoprocol, Mefloquine and Sitagliptin having a comparable binding affinity to zileuton.
Topics: Arachidonate 5-Lipoxygenase; Drug Evaluation, Preclinical; Humans; Lipoxygenase Inhibitors; Logistic Models; Molecular Docking Simulation; Quantitative Structure-Activity Relationship
PubMed: 30321850
DOI: 10.1016/j.compbiolchem.2018.10.002 -
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 -
Modulation of arachidonic acid-evoked cardiorespiratory effects by the central lipoxygenase pathway.Respiratory Physiology & Neurobiology Jul 2020We previously reported that intracerebroventricularly (ICV) injected arachidonic acid (AA) could produce pressor and bradycardic responses on the cardiovascular system...
We previously reported that intracerebroventricularly (ICV) injected arachidonic acid (AA) could produce pressor and bradycardic responses on the cardiovascular system and hyperventilation effect on the respiratory system by activating cyclooxygenase (COX). We also demonstrated that centrally injected AA-induced cardiovascular and respiratory responses were mediated by COX-metabolites, such as thromboxane A (TXA), prostaglandin (PG) D, PGE, and PGF. Brain tissue is also able to express the lipoxygenase (LOX) enzyme and LOX-induced AA-metabolites. The current study was designed to investigate the possible mediation of the central LOX pathway in AA-induced cardiorespiratory effects in anesthetized rats. Central pretreatment with different doses of a non-selective LOX inhibitor, nordihydroguaiaretic acid (NDGA) (500 and 1000 μg; ICV) partially blocked the AA (0.5 μmol; ICV)-evoked pressor and bradycardic cardiovascular responses in male anesthetized Sprague Dawley rats. Pretreatment with different doses of NDGA (500 and 1000 μg; ICV) also reduced AA-induced hyperventilation responses, with an increase in tidal volume, respiratory rate and minute ventilation, in the rats. Moreover, AA-induced increasing pO and decreasing pCO responses were diminished by central NDGA pretreatment. In summary, our findings show that the central LOX pathway might mediate, at least in part, centrally administered AA-evoked cardiorespiratory and blood gases responses.
Topics: Animals; Arachidonic Acid; Arterial Pressure; Blood Gas Analysis; Carbon Dioxide; Heart Rate; Injections, Intraventricular; Lipoxygenase; Lipoxygenase Inhibitors; Masoprocol; Oxygen; Partial Pressure; Rats; Respiratory Rate; Tidal Volume
PubMed: 32339697
DOI: 10.1016/j.resp.2020.103441 -
Journal of Plant Physiology Aug 2020Fig fruit is well-known for its attractive flavor, color, and nutritional and medicinal value. Anthocyanin contributes to the fruit's color and constitutes a high...
Fig fruit is well-known for its attractive flavor, color, and nutritional and medicinal value. Anthocyanin contributes to the fruit's color and constitutes a high percentage of the total antioxidant content of the fig fruit. We quantified the major anthocyanins and characterized the expression levels of anthocyanin-biosynthesis and transcription factor genes in fruit treated on-tree with exogenous abscisic acid (ABA) or ethephon, or the ABA inhibitors nordihydroguaiaretic acid (NDGA) or fluridone. The major anthocyanins cyanidin 3-O-glucoside and cyanidin 3-O-rutinoside were found in significantly higher quantities in exogenous ABA- and ethephon-treated fruit, with early dark purple color compared to the controls. On the other hand, NDGA- and fluridone-treated fruit had significantly lower amounts of anthocyanins, with less purple color coverage than controls. Expression levels of the anthocyanin-biosynthesis genes FcPAL, FcCHS2, FcCHI, FcF3H, FcDFR, FcANS, FcUFGT and Fc3RT were upregulated by exogenous ABA and ethephon treatment, and downregulated by NDGA and fluridone treatment. The MYB-bHLH-WD40 complex-related genes of ripe fig fruit were identified. In particular, FcMYB113 was strongly upregulated by exogenous ABA and ethephon, and strongly downregulated by NDGA and fluridone. In addition, moderate upregulation of FcGL3 and FcWD40 was observed with exogenous ABA and ethephon treatment, and moderate downregulation in NDGA- and fluridone-treated fruit. These results indicate that ABA can initiate anthocyanin biosynthesis, which ultimately improves the color and nutritional value of fig fruit, enhancing their attractiveness to consumers.
Topics: Abscisic Acid; Anthocyanins; Color; Ficus; Fruit; Masoprocol; Organophosphorus Compounds; Pigmentation; Plant Growth Regulators; Pyridones
PubMed: 32554070
DOI: 10.1016/j.jplph.2020.153192 -
Cell Biochemistry and Biophysics Jun 2023Nordihydroguaiaretic acid (NDGA), a dicatechol and phytochemical polyphenolic antioxidant and an established inhibitor of human arachidonic acid (AA) 5-lipoxygenase...
Classic Phytochemical Antioxidant and Lipoxygenase Inhibitor, Nordihydroguaiaretic Acid, Activates Phospholipase D through Oxidant Signaling and Tyrosine Phosphorylation Leading to Cytotoxicity in Lung Vascular Endothelial Cells.
Nordihydroguaiaretic acid (NDGA), a dicatechol and phytochemical polyphenolic antioxidant and an established inhibitor of human arachidonic acid (AA) 5-lipoxygenase (LOX) and 15-LOX, is widely used to ascertain the role of LOXs in vascular endothelial cell (EC) function. As the modulatory effect of NDGA on phospholipase D (PLD), an important lipid signaling enzyme in ECs, thus far has not been reported, here we have investigated the modulation of PLD activity and its regulation by NDGA in the bovine pulmonary artery ECs (BPAECs). NDGA induced the activation of PLD (phosphatidic acid formation) in cells in a dose- and time-dependent fashion that was significantly attenuated by iron chelator and antioxidants. NDGA induced the formation of reactive oxygen species (ROS) in cells in a dose- and time-dependent manner as evidenced from fluorescence microscopy and fluorimetry of ROS and electron paramagnetic resonance spectroscopy of oxygen radicals. Also, NDGA caused a dose-dependent loss of intracellular glutathione (GSH) in BPAECs. Protein tyrosine kinase (PTyK)-specific inhibitors significantly attenuated NDGA-induced PLD activation in BPAECs. NDGA also induced a dose- and time-dependent phosphorylation of tyrosine in proteins in cells. NDGA caused in situ translocation and relocalization of both PLD and PLD isoforms, in a time-dependent fashion. Cyclooxygenase (COX) inhibitors were ineffective in attenuating NDGA-induced PLD activation in BPAECs, thus ruling out the activation of COXs by NDGA. NDGA inhibited the AA-LOX activity and leukotriene C (LTC) formation in cells. On the other hand, the 5-LOX-specific inhibitors, 5, 8, 11, 14-eicosatetraynoic acid and kaempferol, were ineffective in activating PLD in BPAECs. Antioxidants and PTyK-specific inhibitors effectively attenuated NDGA cytotoxicity in BPAECs. The PLD-specific inhibitor, 5-fluoro-2-indolyl deschlorohalopemide (FIPI), significantly attenuated and protected against the NDGA-induced PLD activation and cytotoxicity in BPAECs. For the first time, these results demonstrated that NDGA, the classic phytochemical polyphenolic antioxidant and LOX inhibitor, activated PLD causing cytotoxicity in ECs through upstream oxidant signaling and protein tyrosine phosphorylation.
Topics: Animals; Cattle; Humans; Antioxidants; Phosphorylation; Masoprocol; Lipoxygenase Inhibitors; Reactive Oxygen Species; Oxidants; Endothelial Cells; Phospholipase D; Enzyme Inhibitors; Lung; Tyrosine
PubMed: 36820994
DOI: 10.1007/s12013-023-01128-1 -
The Journal of Pharmacology and... May 2018To determine the effects of nordihydroguaiaretic acid (NDGA) on metabolic and molecular changes in response to feeding a typical American fast food or Western diet, mice...
To determine the effects of nordihydroguaiaretic acid (NDGA) on metabolic and molecular changes in response to feeding a typical American fast food or Western diet, mice were fed an American lifestyle-induced obesity syndrome (ALIOS) diet and subjected to metabolic analysis. Male C57BL/6J mice were randomly assigned to the ALIOS diet, the ALIOS diet supplemented with NDGA (NDGA+ALIOS), or a control diet and were maintained on the specific diet for 8 weeks. Mice fed the ALIOS diet showed increased body, liver, and epididymal fat pad weight as well as increased plasma alanine transaminase (ALT) and aspartate aminotransferase (AST) levels (a measure of liver injury) and liver triglyceride content. Coadministration of NDGA normalized body and epididymal fat pad weight, ALT and AST levels, and liver triglycerides. NDGA treatment also improved insulin sensitivity but not glucose intolerance in mice fed the ALIOS diet. In mice fed the NDGA+ALIOS diet, NDGA supplementation induced peroxisome proliferator-activated receptor (PPAR; the master regulator of fatty acid oxidation) and mRNA levels of carnitine palmitoyltransferases and , key genes involved in fatty acid oxidation, compared with the ALIOS diet. NDGA significantly reduced liver endoplasmic reticulum (ER) stress response C/EBP homologous protein, compared with chow or the ALIOS diet, and also ameliorated ALIOS diet-induced elevation of apoptosis signaling protein, caspase 3. Likewise, NDGA downregulated the ALIOS diet-induced mRNA levels of , fatty acid synthase , and diacylglycerol acyltransferase NDGA treatment of ALIOS-fed mice upregulated the hepatic expression of antioxidant enzymes, glutathione peroxidase 4, and peroxiredoxin 3 proteins. In conclusion, we provide evidence that NDGA improves metabolic dysregulation by simultaneously modulating the PPAR transcription factor and key genes involved in fatty acid oxidation, key antioxidant and lipogenic enzymes, and apoptosis and ER stress signaling pathways.
Topics: Adipogenesis; Animals; Apoptosis; Diet, Western; Endoplasmic Reticulum Stress; Fatty Acids; Larrea; Life Style; Lipogenesis; Liver; Male; Masoprocol; Mice; Mice, Inbred C57BL; Obesity; Oxidation-Reduction; PPAR alpha; RNA, Messenger; Signal Transduction; Up-Regulation
PubMed: 29472517
DOI: 10.1124/jpet.117.243733