Histone deacetylases (HDACs) are implicated in the pathology of various cancers, and their pharmacological blockade has proven to be promising in reversing the malignant phenotypes. However, lack of ...crystal structures of some of the human HDAC isoforms (e.g., HDAC10) hinders the design of the isoform-selective inhibitor. Here, the recently solved X-ray crystal structure of Danio rerio (zebrafish) HDAC10 (Protein Data Bank (PDB) ID; 5TD7, released on 24 May 2017) was retrieved from the PDB and used as a template structure to model the three-dimensional structure of human HDAC10. The overall quality of the best model (M0017) was assessed by computing its z-score-a measure of the deviation of the total energy of the structure with respect to an energy distribution derived from random conformations and by docking of known HDAC10 inhibitors to its catalytic cavity. Furthermore, to identify potential HDAC10-selective inhibitor ligand-based virtual screening was carried out against the ZINC database. The free modeled structure of HDAC10 and its complexes with quisinostat and the highest-ranked compound ZINC19749069 were submitted to molecular dynamics simulation. The comparative analysis of root-mean-squared deviation, root-mean-squared fluctuation, radius of gyration (Rg), and potential energy of these systems showed that HDAC10-ZINC19749069 complex remained the most stable over time. Thus, M0017 could be potentially used for structure-based inhibitor against HDAC10, and ZINC19749069 may provide a scaffold for further optimization.
Communicated by Ramaswamy H. Sarma
Liquidambar orientalis Mill., commonly called the Anatolian sweetgum or Sigla tree, is endemic to southwestern Turkey. It has been historically significant in traditional medicine. In our research, ...we delved into the therapeutic attributes of its oil, emphasizing its antioxidant, antimicrobial, and antitumor properties. The primary chemical constituent of the gum is styrene, accounting for 78.5 %. The gum demonstrated antioxidant capabilities in several assays, including in 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH), 2,2′‐azinobis(3‐ethylbenzothiazoline‐6‐sulfonic acid) (ABTS), cupric reducing antioxidant capacity (CUPRAC) and ferric reducing antioxidant power (FRAP). It displayed bactericidal actions against various gram‐positive bacteria, such as Staphylococcus aureus, and gram‐negative strains, including Escherichia coli. Additionally, the oil showcased potent antitumor effects against breast (MDA‐MB‐231), lung (A549), and prostate (PC3) cancer cell lines. These effects were found to be both time‐ and dose‐dependent. L. orientalis Mill. oil showed the best antitumor activity against breast, lung, and prostate cancer cell lines after the 24 h and 48 h treatment. Its oil might induce autophagy in the PC3 prostate cancer cell line, whereas its cytotoxicity against MDA‐MB‐231 and A549 cancer cell lines might not be correlated with autophagy or apoptosis pathways. In conclusion, the oil from the Sigla tree offers promising therapeutic potential and warrants further exploration.
Non-peptide ligands of oxytocin receptor (OTR) have promising potentialities as therapeutic agents with improved pharmacological properties. WAY-267,464 is a non-peptide agonist which loses its ...agonist activity when its resorcinol moiety is methylated, yielding a partial antagonist (denoted here, WAY-Methylated). This study attempts to rationalize these opposing activities by comparative analyses of structural dynamicsof OTR in complex with these ligands.
Glide extra precision (XP) docking with and without positional constraints was employed to probe alternative binding poses of both WAY-267,464 and WAY-Methylated. The more preferred configuration of each system was subjected to an extended 2 μs MD simulation and the physics-based Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) binding energy was used to rank the complexes with improved accuracy, in addition to empirical-based Glide docking score. Network analysis was performed, and the identified critical residues were cross-referenced with the experimental mutagenesis data.
The added methyl groups in the antagonist WAY-Methylated enhanced hydrophobicity, resulting in a flipped binding pose deeper in the binding pocket. Interestingly, OTR responded to the methylation by stabilizing the initial inactive conformation, decreasing fluctuations and increasing the overall secondary structural composition. Conversely, the agonist WAY-267,464 produced larger fluctuations to allow the receptor to change from the default inactive state to a state of partial activation. These transitions were further supported by the identified critical residues overlapping with experimental mutagenesis data.
These findings provide insights into the activation mechanism of OTR by WAY-267.464 and its antagonism by WAY-Methylated.
Iron-deficiency anemia (IDA) or iron deficiency (ID) is by far the most common form of disorder affecting the cognitive development, physical growth and school performance of children in developing ...countries including Nigeria.
In the present study, we aimed to examine whether IDA or ID, or both are associated with oxidative stress or otherwise by assessing the perturbations in oxidative stress markers including malondialdehyde (MDA), catalase (CAT) and superoxide dismutase (SOD).
Here, a total of eighty-one IDA, ID, and healthy control subjects of twenty-seven replicates each, were recruited and investigated. Human serum MDA, CAT and SOD levels were quantitatively analyzed using Enzyme-Linked Immunosorbant Assay.
Mean serum MDA levels of IDA (5.10 ± 2.35 mmol/L) and ID (4.05 ± 1.35 mmol/L) groups were found to perturb significantly (p < 0.05), being higher than those of control (3.30 ± 0.95 mmol/L) subjects. Similarly, mean serum MDA levels of IDA (5.10 ± 2.35 mmol/L) group was found to be significantly (p < 0.05) higher when compared with ID (4.05 ± 1.35 mmol/L) subjects. Conversely, mean serum CAT and SOD activities of IDA (8.35 ± 2.21 ng/mL and 340.70 ± 153.65 ng/mL) group were found to differ significantly (p < 0.05), and those of ID (9.40 ± 1.47 ng/mL and 435.00 ± 144.75 ng/mL) subjects were found to perturb slightly (p > 0.05), being lower than those of control (10.40 ± 4.31 ng/mL and 482.12 ± 258.37 ng/mL) subjects.
Taken together, the results of the present study showed that lipid peroxidation was dramatically increased in both IDA and ID subjects in hydroperoxide-superoxide-dependent manner; in contrast, enzymatic antioxidant capacity was drastically decreased in both IDA and ID groups as evidenced by biochemical markers.
Several species within the genera Cassia or Senna have a treasure of traditional medicines worldwide and can be a promising source of bioactive molecules. The objective of the present study was to ...evaluate the phenolic content and antioxidant and enzyme inhibition activities of leaf methanolic extracts of C. fistula L., C. grandis L., S. alexandrina Mill., and S. italica Mill. The two Cassia spp. contained higher total polyphenolic content (42.23–49.75 mg GAE/g) than the two Senna spp., and C. fistula had significantly (p ˂ 0.05) the highest concentration. On the other hand, the Senna spp. showed higher total flavonoid content (41.47–59.24 mg rutin equivalent per g of extract) than that found in the two Cassia spp., and S. alexandrina significantly (p ˂ 0.05) accumulated the highest amount. HPLC–MS/MS analysis of 38 selected bioactive compounds showed that the majority of compounds were identified in the four species, but with sharp variations in their concentrations. C. fistula was dominated by epicatechin (8928.75 µg/g), C. grandis by kaempferol-3-glucoside (47,360.04 µg/g), while rutin was the major compound in S. italica (17,285.02 µg/g) and S. alexandrina (6381.85). The methanolic extracts of the two Cassia species exerted significantly (p ˂ 0.05) higher antiradical activity, metal reducing capacity, and total antioxidant activity than that recorded from the two Senna species’ methanolic extracts, and C. fistula displayed significantly (p ˂ 0.05) the highest values. C. grandis significantly (p ˂ 0.05) exhibited the highest metal chelating power. The results of the enzyme inhibition activity showed that the four species possessed anti-AChE activity, and the highest value, but not significantly (p ≥ 0.05) different from those obtained by the two Cassia spp., was exerted by S. alexandrina. The Cassia spp. exhibited significantly (p ˂ 0.05) higher anti-BChE and anti-Tyr properties than the Senna spp., and C. grandise revealed significantly (p ˂ 0.05) the highest values. C. grandise revealed significantly (p ˂ 0.05) the highest α- amylase inhibition, while the four species had more or less the same effect against the α-glucosidase enzyme. Multivariate analysis and in silico studies showed that many of the identified phenols may play key roles as antioxidant and enzyme inhibitory properties. Thus, these Cassia and Senna species could be a promising source of natural bioactive agents with beneficial effects for human health.
Hippomarathrum scabrum L. is an endemic medicinal plant in Turkey; however, there have been few studies investigating the phytochemistry and biological properties of these plants has not been ...investigated. The aim of this work is to determine the chemical composition of different extracts (extracts obtained by using supercritical carbon dioxide extraction, accelerated solvent extraction, homogenizer‐assisted extraction, microwave‐assisted extraction, and ultrasound‐assisted extraction from Hippomarathrum scabrum L., and evaluate their biological properties. The analysis revealed that 5‐O‐caffeoylquinic acid, rutin, and isorhamnetin 3‐O‐rutinoside were the main bioactive compounds. The extract obtained by accelerated extraction contains the highest concentration of 5‐O‐Caffeoylquinic acid (7616.74 ± 63.09 mg/kg dry extract) followed by the extract obtained by homogenizer‐assisted extraction (6682.53 ± 13.04 mg/kg dry extract). In antioxidant tests, all extracts expressed significant antioxidant activity. Also, cytotoxic and anticancer effects of these plant extracts were detected in the human prostate cancer cell line. Intrinsic apoptotic genes were up‐regulated and anti‐apoptotic genes were down‐regulated in human prostate cancer cells after inhibition concentration dose treatment. The findings are promising, and suggest the use of these plant extracts could be used as natural sources with different biological activities, as well as anticancer agents.
Histone deacetylase (HDAC) inhibitors have gained attention over the past three decades because of their potential in the treatment of different diseases including various forms of cancers, ...neurodegenerative disorders, autoimmune, inflammatory diseases, and other metabolic disorders. To date, 5 HDAC inhibitor drugs are marketed for the treatment of hematological malignancies and several drug-candidate HDAC inhibitors are at different stages of clinical trials. However, due to the toxic side effects of these drugs resulting from the lack of target selectivity, active studies are ongoing to design and develop either class-selective or isoform-selective inhibitors. Computational methods have aided the discovery of HDAC inhibitors with the desired potency and/or selectivity. These methods include ligand-based approaches such as scaffold hopping, pharmacophore modeling, three-dimensional quantitative structure–activity relationships (3D-QSAR); and structure-based virtual screening (molecular docking). The current trends involve the application of the combination of these methods and incorporating molecular dynamics simulations coupled with Poisson–Boltzmann/molecular mechanics generalized Born surface area (MM-PBSA/MM-GBSA) to improve the prediction of ligand binding affinity. This review aimed at understanding the current trends in applying these multilayered strategies and their contribution to the design/identification of HDAC inhibitors.
In this study, the methanolic and infusion extracts of two species,
and
subsp.
, were tested for their chemical composition and biological abilities (antioxidant, enzyme inhibitory and ...anti-inflammatory effects). The extracts yielded total phenolic and flavonoid contents in the range of 83.43-127.52 mg GAE/g and 9.41-46.34 mg RE/g, respectively. HPLC analysis revealed rosmarinic acid to be a major component of the studied extracts (15.85-26.43%). The best ABTS radical scavenging ability was observed in the methanol extract of
with 379.11 mg TE/g, followed by in the methanol extract of
(360.93 mg TE/g). In the CUPRAC assay, the highest reducing ability was also found in the methanol extract of
with 802.22 mg TE/g. The phosphomolybdenum ability ranged from 2.39 to 3.61 mmol TE/g. In terms of tyrosinase inhibitory effects, the tested methanol extracts (83.18-89.66 mg KAE/g) were higher than the tested water extracts (18.74-19.11 mg KAE/g). Regarding the BChE inhibitory effects, the methanol extracts were active on the enzyme while the water extracts showed no inhibitory effect on it. Overall, the methanolic extracts showed better enzyme inhibition compared to the infusion extracts. Molecular docking also showed the selected exhibited potential binding affinities with all enzymes, with a preference for cholinesterases. Additionally, the extracts were effective in attenuating the LPS-induced increase in COX-2 and IL-6 gene expression in isolated colon, thus indicating promising anti-inflammatory effects. The preliminary results of this study suggest that these species are good natural sources of antioxidants and also provide some scope as enzyme inhibitors, most likely due to their bioactive contents such as phenolic acids, and thus can be exploited for different applications related to health promotion and disease prevention.
Artemisia annua L. (Asteraceae Family) is an important plant in Asia that has been used for treating different diseases, including fever due to malaria, wounds, tubercolisis, scabues, pain, ...convulsions, diabetes, and inflammation. In this study we aimed to evaluate the effects of different polarity extracts (hexane, dichloromethane, ethyl acetate, ethanol, ethanol/water (70 %) and water) from A. annua against the burden of inflammation and oxidative stress occurring in colon tissue exposed to LPS. In parallel, chemical composition, antiradical, and enzyme inhibition effects against α‐amylase, α‐glucosidase, tyrosinase, and cholinesterases were evaluated. The water extract contained the highest content of the total phenolic with 34.59 mg gallic acid equivalent (GAE)/g extract, while the hexane had the highest content of the total flavonoid (20.06 mg rutin equivalent (RE)/g extract). In antioxidant assays, the polar extracts (ethanol, ethanol/water and water) exhibited stronger radical scavenging and reducing power abilities when compared to non‐polar extracts. The hexane extract showed the best AChE, tyrosinase and glucosidase inhibitory effects. All extracts revealed effective anti‐inflammatory agents, as demonstrated by the blunting effects on COX‐2 and TNFα gene expression. These effects seemed to be not related to the only phenolic content. However, it is worthy of interest to highlight how the higher potency against LPS‐induced gene expression was shown by the water extract ; thus suggesting a potential phytotherapy application in the management of clinical symptoms related to inflammatory colon diseases, although future in vivo studies are needed to confirm such in vitro and ex vivo observations.
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