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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 -
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 -
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 -
Current Cancer Drug Targets 2020Nordihydroguaiaretic acid (NDGA) is a plant lignan obtained from creosote bush, Larrea tridentata and is known to possess antioxidant, anticancer activities and is used... (Review)
Review
Nordihydroguaiaretic acid (NDGA) is a plant lignan obtained from creosote bush, Larrea tridentata and is known to possess antioxidant, anticancer activities and is used in traditional medicine in North America and Mexico. However, its prolonged consumption leads to liver damage and kidney dysfunction. Despite its toxicity and side effects, there is little awareness to forbid its consumption and its use in the treatment of medical ailments has continued over the years. Several reports discuss its therapeutic efficiency and its medical applications have tremendously been on the rise to date. There has been a recent surge of interest in the chemical synthesis of NDGA derivatives for therapeutic applications. NDGA derivatives have been developed as better alternatives to NDGA. Although several NDGA derivatives have been chemically synthesized as evidenced by recent literature, there is a paucity of information on their therapeutic efficacies. This review is to highlight the medicinal applications of NDGA, its toxicity evaluations and discuss the chemical derivatives of NDGA synthesized and studied so far and suggest to continue research interests in the development of NDGA analogs for therapeutic applications. We suggest that NDGA derivatives should be investigated more in terms of chemical synthesis with preferred conformational structures and exploit their biological potentials with future insights to explore in this direction to design and develop structurally modified NDGA derivatives for potential pharmacological properties.
Topics: Animals; Humans; Hydrophobic and Hydrophilic Interactions; Masoprocol; Molecular Conformation
PubMed: 31642411
DOI: 10.2174/1568009619666191022141547 -
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 -
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 -
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 -
Archiv Der Pharmazie Oct 2014Nordihydroguaiaretic acid (NDGA) is a phenolic compound obtained from the leaves of the evergreen desert shrub Larrea tridentata (Creosote bush), which has been used... (Review)
Review
Nordihydroguaiaretic acid (NDGA) is a phenolic compound obtained from the leaves of the evergreen desert shrub Larrea tridentata (Creosote bush), which has been used anciently in folk medicine for the treatment of multiple diseases. At the molecular level, NDGA is a potent scavenger of reactive oxygen species. Lipoxygenase inhibition by NDGA has been broadly studied over several cell models; however, NDGA exerts other antioxidant properties and cytoprotective effects in non-tumor cells, which are related with its role as modulator of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) antioxidant pathway. In contrast, in tumor cells NDGA exerts pro-apoptotic activity and anti-tumor effects. Different effects of NDGA have been observed in mitochondria, where NDGA prevents mitochondrial damage in non-tumor cells and induces loss of mitochondrial function in tumor cells. Moreover, NDGA exerts beneficial effects in diverse diseases like cancer, renal damage, Huntington's disease, Alzheimer's disease, and other neurodegenerative pathologies. This work represents a critical review about relevant NDGA mechanisms, cellular effects, and signal pathways involved with possible useful effects.
Topics: Animals; Antineoplastic Agents; Antioxidant Response Elements; Drug Design; Free Radical Scavengers; Gene Expression Regulation; Humans; Lipoxygenase Inhibitors; Masoprocol; Mitochondria; Molecular Structure; NF-E2-Related Factor 2; Neuroprotective Agents; Reactive Oxygen Species; Signal Transduction; Structure-Activity Relationship
PubMed: 25100573
DOI: 10.1002/ardp.201400159