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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 -
Molecules (Basel, Switzerland) Jan 2020Lignans are widely produced by various plant species; they are a class of natural products that share structural similarity. They usually contain a core scaffold that is... (Review)
Review
Lignans are widely produced by various plant species; they are a class of natural products that share structural similarity. They usually contain a core scaffold that is formed by two or more phenylpropanoid units. 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. Among them, two types of antiviral lignans-podophyllotoxin and bicyclol, which are used to treat venereal warts and chronic hepatitis B (CHB) in clinical, serve as examples of using lignans for antivirals-are discussed in some detail. Prospects of lignans in antiviral drug discovery are also discussed.
Topics: Antiviral Agents; Benzodioxoles; Biological Products; Biphenyl Compounds; Drug Development; Furans; Lignans; Masoprocol; Plants; Podophyllotoxin
PubMed: 31906391
DOI: 10.3390/molecules25010183 -
Computers in Biology and Medicine Apr 2021Papain-Like Protease (PLpro) is a key protein for SARS-CoV-2 viral replication which is the cause of the emerging COVID-19 pandemic. Targeting PLpro can suppress viral...
Papain-Like Protease (PLpro) is a key protein for SARS-CoV-2 viral replication which is the cause of the emerging COVID-19 pandemic. Targeting PLpro can suppress viral replication and provide treatment options for COVID-19. Due to the dynamic nature of its binding site loop, PLpro multiple conformations were generated through a long-range 1 micro-second molecular dynamics (MD) simulation. Clustering the MD trajectory enabled us to extract representative structures for the conformational space generated. Adding to the MD representative structures, X-ray structures were involved in an ensemble docking approach to screen the FDA approved drugs for a drug repositioning endeavor. Guided by our recent benchmarking study of SARS-CoV-2 PLpro, FRED docking software was selected for such a virtual screening task. The results highlighted potential consensus binders to many of the MD clusters as well as the newly introduced X-ray structure of PLpro complexed with a small molecule. For instance, three drugs Benserazide, Dobutamine and Masoprocol showed a superior consensus enrichment against the PLpro conformations. Further MD simulations for these drugs complexed with PLpro suggested the superior stability and binding of dobutamine and masoprocol inside the binding site compared to Benserazide. Generally, this approach can facilitate identifying drugs for repositioning via targeting multiple conformations of a crucial target for the rapidly emerging COVID-19 pandemic.
Topics: Binding Sites; Coronavirus 3C Proteases; Crystallography, X-Ray; Cysteine Proteinase Inhibitors; Drug Repositioning; Enzyme Stability; Humans; Molecular Dynamics Simulation; SARS-CoV-2
PubMed: 33662683
DOI: 10.1016/j.compbiomed.2021.104295 -
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 -
Molecules (Basel, Switzerland) Nov 2021In this study, the antioxidant and antiradical properties of some phyto lignans (nordihydroguaiaretic acid, secoisolariciresinol, secoisolariciresinol diglycoside, and...
In this study, the antioxidant and antiradical properties of some phyto lignans (nordihydroguaiaretic acid, secoisolariciresinol, secoisolariciresinol diglycoside, and α-(-)-conidendrin) and mammalian lignans (enterodiol and enterolactone) were examined by different antioxidant assays. For this purpose, radical scavenging activities of phyto and mammalian lignans were realized by 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) radical (ABTS) scavenging assay and 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) scavenging assay. Additionally, the reducing ability of phyto and mammalian lignans were evaluated by cupric ions (Cu) reducing (CUPRAC) ability, and ferric ions (Fe) and [Fe-(TPTZ)2] complex reducing (FRAP) abilities. Also, half maximal inhibitory concentration (IC) values were determined and reported for DPPH and ABTS scavenging influences of all of the lignan molecules. The absorbances of the lignans were found in the range of 0.150-2.320 for Fe reducing, in the range of 0.040-2.090 for Cu reducing, and in the range of 0.360-1.810 for the FRAP assay. On the other hand, the IC values of phyto and mammalian lignans were determined in the ranges of 6.601-932.167 µg/mL for DPPH scavenging and 13.007-27.829 µg/mL for ABTS scavenging. In all of the used bioanalytical methods, phyto lignans, as secondary metabolites in plants, demonstrated considerably higher antioxidant activity compared to that of mammalian lignans. In addition, it was observed that enterodiol and enterolactone exhibited relatively weaker antioxidant activities when compared to phyto lignans or standard antioxidants, including butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), Trolox, and α-tocopherol.
Topics: Animals; Antioxidants; Benzothiazoles; Biphenyl Compounds; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Butylene Glycols; Chromans; Copper; Free Radical Scavengers; Ions; Iron; Lignans; Lipid Peroxidation; Mammals; Masoprocol; Phytochemicals; Picrates; Sulfonic Acids; Tetrahydronaphthalenes
PubMed: 34885681
DOI: 10.3390/molecules26237099 -
Physiological Research Feb 2020Autologous and allogenic human pericardia used as biomaterials for cardiovascular surgery are traditionally crosslinked with glutaraldehyde. In this work, we have... (Comparative Study)
Comparative Study
Autologous and allogenic human pericardia used as biomaterials for cardiovascular surgery are traditionally crosslinked with glutaraldehyde. In this work, we have evaluated the resistivity to collagenase digestion and the cytotoxicity of human pericardium crosslinked with various concentrations of glutaraldehyde in comparison with pericardium crosslinked by genipin, nordihydroguaiaretic acid, tannic acid, and in comparison with unmodified pericardium. Crosslinking retained the wavy-like morphology of native pericardium visualized by second harmonic generation microscopy. The collagenase digestion products were analyzed using SDS-PAGE, capillary electrophoresis, and a hydroxyproline assay. Glutaraldehyde and genipin crosslinking protected the native pericardium efficiently against digestion with collagenase III. Only low protection was provided by the other crosslinking agents. The cytotoxicity of crosslinked pericardium was evaluated using xCELLigence by monitoring the viability of porcine valve interstitial cells cultured in eluates from crosslinked pericardium. The highest cell index, reflecting both the number and the shape of the monitored cells was observed in eluates from genipin. Crosslinking pericardium grafts with genipin therefore seems to be a promising alternative procedure to the traditional crosslinking with glutaraldehyde, because it provides similarly high protection against degradation with collagenase, without cytotoxic effects.
Topics: Biocompatible Materials; Cross-Linking Reagents; Glutaral; Humans; Iridoids; Masoprocol; Pericardium; Tannins; Transplants
PubMed: 31852209
DOI: 10.33549/physiolres.934335 -
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 -
Nature Chemical Biology Jul 2020Leukotrienes (LT) are lipid mediators of the inflammatory response that are linked to asthma and atherosclerosis. LT biosynthesis is initiated by 5-lipoxygenase (5-LOX)...
Leukotrienes (LT) are lipid mediators of the inflammatory response that are linked to asthma and atherosclerosis. LT biosynthesis is initiated by 5-lipoxygenase (5-LOX) with the assistance of the substrate-binding 5-LOX-activating protein at the nuclear membrane. Here, we contrast the structural and functional consequences of the binding of two natural product inhibitors of 5-LOX. The redox-type inhibitor nordihydroguaiaretic acid (NDGA) is lodged in the 5-LOX active site, now fully exposed by disordering of the helix that caps it in the apo-enzyme. In contrast, the allosteric inhibitor 3-acetyl-11-keto-beta-boswellic acid (AKBA) from frankincense wedges between the membrane-binding and catalytic domains of 5-LOX, some 30 Å from the catalytic iron. While enzyme inhibition by NDGA is robust, AKBA promotes a shift in the regiospecificity, evident in human embryonic kidney 293 cells and in primary immune cells expressing 5-LOX. Our results suggest a new approach to isoform-specific 5-LOX inhibitor development through exploitation of an allosteric site in 5-LOX.
Topics: Allosteric Site; Arachidonate 5-Lipoxygenase; Biological Products; Catalytic Domain; Cloning, Molecular; Crystallography, X-Ray; Escherichia coli; Gene Expression; Genetic Vectors; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase Inhibitors; Masoprocol; Models, Molecular; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Protein Multimerization; Recombinant Proteins; Substrate Specificity; Triterpenes
PubMed: 32393899
DOI: 10.1038/s41589-020-0544-7 -
Journal of Experimental Botany Jan 2019The common fig bears a unique closed inflorescence structure, the syconium, composed of small individual drupelets that develop from the ovaries, which are enclosed in a...
The common fig bears a unique closed inflorescence structure, the syconium, composed of small individual drupelets that develop from the ovaries, which are enclosed in a succulent receptacle of vegetative origin. The fig ripening process is traditionally classified as climacteric; however, recent studies have suggested that distinct mechanisms exist in its reproductive and non-reproductive parts. We analysed ABA and ethylene production, and expression of ABA-metabolism, ethylene-biosynthesis, MADS-box, NAC, and ethylene response-factor genes in inflorescences and receptacles of on-tree fruit treated with ABA, ethephon, fluridone, and nordihydroguaiaretic acid (NDGA). Exogenous ABA and ethephon accelerated fruit ripening and softening, whereas fluridone and NDGA had the opposite effect, delaying endogenous ABA and ethylene production compared to controls. Expression of the ABA-biosynthesis genes FcNCED2 and FcABA2, ethylene-biosynthesis genes FcACS4, FcACOL, and FcACO2, FcMADS8, 14, 15, FcNAC1, 2, 5, and FcERF9006 was up-regulated by exogenous ABA and ethephon. NDGA down-regulated FcNCED2 and FcABA2, whereas fluridone down-regulated FcABA2; both down-regulated the ethylene-related genes. These results demonstrate the key role of ABA in regulation of ripening by promoting ethylene production, as in the climacteric model plant tomato, especially in the inflorescence. However, increasing accumulation of endogenous ABA until full ripeness and significantly low expression of ethylene-biosynthesis genes in the receptacle suggests non-climacteric, ABA-dependent ripening in the vegetative-originated succulent receptacle part of the fruit.
Topics: Abscisic Acid; Ethylenes; Ficus; Fruit; Gene Expression Regulation, Plant; Inflorescence; Masoprocol; Organophosphorus Compounds; Plant Growth Regulators; Plant Proteins; Pyridones
PubMed: 30239815
DOI: 10.1093/jxb/ery333 -
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