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ACS Chemical Neuroscience May 2024Parkinson's disease arises from protein misfolding, aggregation, and fibrillation and is characterized by LB (Lewy body) deposits, which contain the protein α-synuclein...
Parkinson's disease arises from protein misfolding, aggregation, and fibrillation and is characterized by LB (Lewy body) deposits, which contain the protein α-synuclein (α-syn) as their major component. Another synuclein, γ-synuclein (γ-syn), coexists with α-syn in Lewy bodies and is also implicated in various types of cancers, especially breast cancer. It is known to seed α-syn fibrillation after its oxidation at methionine residue, thereby contributing in synucleinopathy. Despite its involvement in synucleinopathy, the search for small molecule inhibitors and modulators of γ-syn fibrillation remains largely unexplored. This work reveals the modulatory properties of cyclic-nordihydroguaiaretic acid (cNDGA), a natural polyphenol, on the structural and aggregational properties of human γ-syn employing various biophysical and structural tools, namely, thioflavin T (ThT) fluorescence, Rayleigh light scattering, 8-anilinonaphthalene-1-sulfonic acid binding, far-UV circular dichroism (CD), Fourier transform infrared spectroscopy (FTIR) spectroscopy, atomic force microscopy, ITC, molecular docking, and MTT-toxicity assay. cNDGA was observed to modulate the fibrillation of γ-syn to form off-pathway amorphous species that are nontoxic in nature at as low as 75 μM concentration. The modulation is dependent on oxidizing conditions, with cNDGA weakly interacting ( ∼10 M) with the residues at the N-terminal of γ-syn protein as investigated by isothermal titration calorimetry and molecular docking, respectively. Increasing cNDGA concentration results in an increased recovery of monomeric γ-syn as shown by sodium dodecyl sulfate and native-polyacrylamide gel electrophoresis. The retention of native structural properties of γ-syn in the presence of cNDGA was further confirmed by far-UV CD and FTIR. In addition, cNDGA is most effective in suppression of fibrillation when added at the beginning of the fibrillation kinetics and is also capable of disintegrating the preformed mature fibrils. These findings could, therefore, pave the ways for further exploring cNDGA as a potential therapeutic against γ-synucleinopathies.
Topics: Humans; gamma-Synuclein; Masoprocol; Protein Aggregates; Spectroscopy, Fourier Transform Infrared; Protein Aggregation, Pathological
PubMed: 38637513
DOI: 10.1021/acschemneuro.3c00793 -
Pediatric Rheumatology Online Journal Mar 2024Chronic non-bacterial osteomyelitis (CNO) is a rare, non-infection- related inflammatory disorder that affects children and teens. Clinical manifestations of CNO range...
INTRODUCTION
Chronic non-bacterial osteomyelitis (CNO) is a rare, non-infection- related inflammatory disorder that affects children and teens. Clinical manifestations of CNO range widely from moderate, time-limited, monofocal inflammation of the bone to extreme multifocal or chronically active inflammation of the bone.
OBJECTIVES
The main aim of this study was to explore the correlation between musculoskeletal (MSK) symptoms and health-related quality of life (HRQoL) in patients with CNO.
METHODS
Children and adults with CNO and their parents were asked to answer a web-based survey. The survey consisted of multiple questions centered around demographic, clinical and therapeutic data, MSK discomfort form based on the Nordic MSK Questionnaire and HRQoL based on Pediatric Quality of Life Inventory-4 (PedsQL-4) and PedsQL rheumatology module. The inclusion criteria included diagnosis of CNO before the age of 18. Patients who had malignancies or any chronic rheumatic, MSK, neurological disease prior to CNO onset were excluded.
RESULTS
There was a total of 68 participants, mostly females (66.2%), with median age 14 years and median disease duration 4.75 years. The median number of bones affected by CNO was 5 and ranged from 1 to 24 bones. Among the studied patients, 45 patients (66.2%) had MSK manifestations at the last month. The most commonly affected part was ankle and feet (26.5%). Regarding HRQoL, patients with MSK manifestations had lower scores than did patients without in PedsQL-4 (p < 0.001) including domains of physical functioning (p < 0.001), emotional functioning (p = 0.033), social functioning (p < 0.001) and school functioning (p = 0.007) in addition to lower scores in PedsQL rheumatology module (p < 0.001) including domains of pain and hurt (p < 0.001), daily activities (p < 0.001), treatment (p = 0.035), worry (p = 0.001) and communication (p < 0.001).
CONCLUSION
MSK manifestations have a negative impact on HRQoL in CNO patients. So, early identification and treatment are highly recommended.
Topics: Adult; Child; Female; Adolescent; Humans; Male; Quality of Life; Osteomyelitis; Foot; Musculoskeletal Diseases; Inflammation; Masoprocol
PubMed: 38448884
DOI: 10.1186/s12969-024-00971-7 -
GeroScience Apr 2024The Caenorhabditis Intervention Testing Program (CITP) is an NIH-funded research consortium of investigators who conduct analyses at three independent sites to identify...
The Caenorhabditis Intervention Testing Program (CITP) is an NIH-funded research consortium of investigators who conduct analyses at three independent sites to identify chemical interventions that reproducibly promote health and lifespan in a robust manner. The founding principle of the CITP is that compounds with positive effects across a genetically diverse panel of Caenorhabditis species and strains are likely engaging conserved biochemical pathways to exert their effects. As such, interventions that are broadly efficacious might be considered prominent compounds for translation for pre-clinical research and human clinical applications. Here, we report results generated using a recently streamlined pipeline approach for the evaluation of the effects of chemical compounds on lifespan and health. 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. Additionally, these two antioxidants conferred assay-specific effects in some studies-for example, decreasing survival for certain genetic backgrounds in manual survival assays in contrast with extended lifespan as assayed using automated C. elegans Lifespan Machines. We also observed that GTE and NDGA impact on older adult mobility capacity is dependent on genetic background, and that GTE reduces oxidative stress resistance in some Caenorhabditis strains. Overall, our analysis of the five compounds supports the general idea that genetic background and assay type can influence lifespan and health effects of compounds, and underscores that lifespan and health can be uncoupled by chemical interventions.
Topics: Animals; Humans; Aged; Antioxidants; Masoprocol; Caenorhabditis elegans; Caenorhabditis; Longevity; Health Promotion; Plant Extracts; Tea; Mammals
PubMed: 37923874
DOI: 10.1007/s11357-023-00978-0 -
Journal of Biomolecular Structure &... Sep 2023Resistin is a cysteine-rich secretory hormone that induces resistance to insulin, and its elevated expression is correlated with the onset of diabetes and several...
Resistin is a cysteine-rich secretory hormone that induces resistance to insulin, and its elevated expression is correlated with the onset of diabetes and several related metabolic disorders. Resistin performs its inhibitory role by connecting three identical subunits through Cys22-based disulfide linkages. The necessity to inhibit the formation of resistin trimer is one of the essential means to prevent the aggravation of diabetes mellitus type 2, obesity, and atherosclerosis. This study was conducted to screen the clinically approved drugs to find the most potent one to inhibit resistin with the best pharmacokinetics and drug-likeness properties. A total of 4654 clinically approved drugs were docked against the Cys22 residue of resistin. The top ten drugs with the highest high-precision (XP) docking scores were selected. Ioversol and masoprocol showed the highest XP docking and Molecular Mechanics-Generalized Born Surface Area (MMGBSA) scores, respectively, with double hydrogen bonding with the targeted Cys22. Molecular dynamics (MD) simulations showed that the masoprocol-resistin complex exhibited lower root mean square deviation (RMSD), radius of gyration, and root mean square fluctuation (RMSF) values than those observed in the ioversol-resistin complex. Both drugs induced drastic conformational changes in resistin monomer interactions. However, ioversol did not prove satisfying drug-likeness properties, while masoprocol showed the most favourable pharmacokinetic and drug-likeness properties. This study has demonstrated that masoprocol offers a novel inhibitory effect on resistin with the highest ligand affinity, making it a promising drug for combating insulin resistance.Communicated by Ramaswamy H. Sarma.
PubMed: 37671847
DOI: 10.1080/07391102.2023.2254842 -
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 the Science of Food and... Dec 2023To determine how abscisic acid (ABA) affects tomato fruit ripening at the protein level, mature green cherry tomato fruit were treated with ABA, nordihydroguaiaretic...
BACKGROUND
To determine how abscisic acid (ABA) affects tomato fruit ripening at the protein level, mature green cherry tomato fruit were treated with ABA, nordihydroguaiaretic acid (NDGA) or sterile water (control, CK). The proteomes of treated fruit were analyzed and quantified using tandem mass tags (TMTs) at 7 days after treatment, and the gene transcription abundances of differently expressed proteins (DEPs) were validated with quantitative real-time polymerase chain reaction.
RESULTS
Postharvest tomato fruit underwent faster color transformation and ripening than the CK when treated with ABA. In total, 6310 proteins were identified among the CK and treatment groups, of which 5359 were quantified. Using a change threshold of 1.2 or 0.83 times, 1081 DEPs were identified. Among them, 127 were upregulated and 127 were downregulated in the ABA versus CK comparison group. According to KEGG and protein-protein interaction network analyses, the ABA-regulated DEPs were primarily concentrated in the photosynthesis system and sugar metabolism pathways, and 102 DEPs associated with phytohormones biosynthesis and signal transduction, pigment synthesis and metabolism, cell wall metabolism, photosynthesis, redox reactions, allergens and defense responses were identified in the ABA versus CK and NDGA versus CK comparison groups.
CONCLUSION
ABA affects tomato fruit ripening at the protein level to some extent. The results of this study provided comprehensive insights and data for further research on the regulatory mechanism of ABA in tomato fruit ripening. © 2023 Society of Chemical Industry.
Topics: Abscisic Acid; Solanum lycopersicum; Fruit; Proteomics; Plant Growth Regulators; Masoprocol; Plant Proteins; Gene Expression Regulation, Plant
PubMed: 37421609
DOI: 10.1002/jsfa.12838 -
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 -
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