Target Characterization of Kaempferol against Myocardial Infarction Using Novel In Silico Docking and DARTS Prediction Strategy.
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ABSTRACT:
SUBMITTER: Wu X
PROVIDER: S-EPMC8657499 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The in silico single gene deletion step was adapted to simulate the knock-out of all targets of a drug on an objective function such as growth or energy balance. Based on publicly available and in-house large scale transcriptomic data, metabolic models for melanoma were reconstructed, enabling the prediction of 28 candidate drugs and estimating their respective efficacy.
| EGAS00001006463 | EGA
Project description:Background and Objectives: This study aims to illustrate the mechanisms underlying the therapeutic effect of Icariin after myocardial infarction (MI). Materials and Methods: Based on the network pharmacology strategy, we predict the therapeutic targets of Icariin against MI and investigate the pharmacological molecular mechanisms. A topological network was created. Biological process and Kyoto Encyclopedia of Genes and Genomes pathway enrichment were also performed. We also conducted the molecular docking analysis to stimulate the component-target interaction further and validate the direct bind effect. Results: Network pharmacology analysis identified 61 candidate genes related to the therapeutic effect of Icariin against MI. EGFR, AKT1, TP53, JUN, ESR1, PTGS2, TNF, RELA, HSP90AA1, and BCL2L1 were identified as hub genes. The biological processes of the candidate targets were significantly involved in the reactive oxygen species metabolic process, response to hypoxia, response to decreased oxygen levels, response to oxidative stress, regulation of reactive oxygen species metabolic process, and so forth. Overall, biological process enrichment analysis indicated that the protective effect of Icariin against MI might be associated with oxidative stress. Moreover, the pathway analysis showed that the candidate targets were closely associated with lipid and atherosclerosis, AGE-RAGE signaling pathway in diabetic complications, HIF-1 signaling pathway, etc. We identified the conformation with the lowest affinity score as the docking conformation. The simulated molecular docking was displayed to illustrate the topical details of the binding sites between Icariin and TNF protein. Conclusions: This study provides an overview of the mechanisms underlying the protective effect of Icariin against MI.
| S-EPMC10056910 | biostudies-literature
Project description:Identifying the molecular targets for the beneficial or detrimental effects of small-molecule drugs is an important and currently unmet challenge. We have developed a method, drug affinity responsive target stability (DARTS), which takes advantage of a reduction in the protease susceptibility of the target protein upon drug binding. DARTS is universally applicable because it requires no modification of the drug and is independent of the mechanism of drug action. We demonstrate use of DARTS to identify known small-molecule-protein interactions and to reveal the eukaryotic translation initiation machinery as a molecular target for the longevity-enhancing plant natural product resveratrol. We envisage that DARTS will also be useful in global mapping of protein-metabolite interaction networks and in label-free screening of unlimited varieties of compounds for development as molecular imaging agents.
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Project description:Physapubenolide (PB), a withanolide-type compound extracted from the traditional herb Physalis minima L., has been demonstrated to exert remarkable cytotoxicity against cancer cells; however, its molecular mechanisms are still unclear. In this study, we demonstrated that PB inhibited cell proliferation and migration in melanoma cells by inducing cell apoptosis. The anticancer activity of PB was further verified in a melanoma xenograft model. To explore the mechanism underlying the anticancer effects of PB, we carried out an in silico target prediction study, which combined three approaches (chemical similarity searching, quantitative structure-activity relationship (QSAR), and molecular docking) to identify the targets of PB, and found that PB likely targets 3-hydroxy-methylglutaryl CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway, which promotes cancer cell proliferation, migration, and metastasis. We further demonstrated that PB interacted with HMGCR, decreased its protein expression and inhibited the HMGCR/YAP pathway in melanoma cells. In addition, we found that PB could restore vemurafenib sensitivity in vemurafenib-resistant A-375 cells, which was correlated with the downregulation of HMGCR. In conclusion, we demonstrate that PB elicits anticancer action and enhances sensitivity to vemurafenib by targeting HMGCR.
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Project description:BackgroundDuring the second wave of the COVID-19 pandemic, an unusual increase in cases of mucormycosis was observed in India, owing to immunological dysregulation caused by the SARS-CoV-2 and the use of broad-spectrum antibiotics, particularly in patients with poorly controlled diabetes with ketoacidosis to have contributed to the rise, and it has been declared an epidemic in several states of India. Because of the black colouring of dead and dying tissue caused by the fungus, it was dubbed "black fungus" by several Indian media outlets. In this study, attempts were taken to unmask novel therapeutic options to treat mucormycosis disease. Rhizopus species is the primary fungi responsible for 70% of mucormycosis cases.ResultsWe chose three important proteins from the Rhizopus delemar such as CotH3, Lanosterol 14 alpha-demethylase and Mucoricin which plays a crucial role in the virulence of Mucorales. Initially, we explored the physiochemical, structural and functional insights of proteins and later using AutoDock Vina, we applied computational protein-ligand binding modelling to perform a virtual screening around 300 selected compounds against these three proteins, including FDA-approved drugs, FDA-unapproved drugs, investigational-only drugs and natural bioactive compounds. ADME parameters, toxicity risk and biological activity of those compounds were approximated via in silico methods. Our computational studies identified six ligands as potential inhibitors against Rhizopus delemar, including 12,28-Oxamanzamine A, vialinin B and deoxytopsentin for CotH3; pramiconazole and saperconazole for Lanosterol 14 alpha-demethylase; and Hesperidin for Mucoricin. Interestingly, 12,28-Oxamanzamine A showed a maximum binding affinity with all three proteins (CotH3: - 10.2 kcal/mol Lanosterol 14 alpha-demethylase: - 10.9 kcal/mol Mucoricin: - 8.6 kcal/mol).ConclusionsIn summary, our investigation identified 12,28-Oxamanzamine A, vialinin B, deoxytopsentin, pramiconazole, saperconazole and hesperidin as potent bioactive compounds for treating mucormycosis that may be considered for further optimisation techniques and in vitro and in vivo studies.Supplementary informationThe online version contains supplementary material available at 10.1186/s42269-022-00704-4.
| S-EPMC8802264 | biostudies-literature
Project description:Although numerous therapies are widely applied clinically and stem cells and/or biomaterial based in situ implantations have achieved some effects, few of these have observed robust myocardial regeneration. The beneficial effects on cardiac function and structure are largely acting through paracrine signaling, which preserve the border-zone around the infarction, reduce apoptosis, blunt adverse remodeling, and promote angiogenesis. Ionic extracts from biomaterials have been proven to stimulate paracrine effects and promote cell-cell communications. Here, the paracrine stimulatory function of bioactive ions derived from biomaterials is integrated into the clinical concept of administration and proposed "ion therapy" as a novel strategy for myocardial infarction. In vitro, silicon- enriched ion extracts significantly increase cardiomyocyte viability and promote cell-cell communications, thus stimulating vascular formation via a paracrine effect under glucose/oxygen deprived conditions. In vivo, by intravenous injection, the bioactive silicon ions act as "diplomats" and promote crosstalk in myocardial cells, stimulate angiogenesis, and improve cardiac function post-myocardial infarction.
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Project description:Myocardial infarction is a prevalent and life-threatening cardiovascular disease. The main goal of existing interventional therapies is to restore coronary reperfusion while few are designed to ameliorate the pathology of heart diseases via targeting the post-translational modifications of those critical proteins. Small ubiquitin-like modifier (SUMO) proteins are recently discovered to form a new type of protein post-translational modifications (PTM), known as SUMOylation. SUMOylation and deSUMOylation are dynamically balanced in the maintenance of various biological processes including cell division, DNA repair, epigenetic transcriptional regulation, and cellular metabolism. Importantly, SUMOylation plays a critical role in the regulation of cardiac functions and the pathology of cardiovascular diseases, especially in heart failure and myocardial infarction. This review summarizes the current understanding on the effects of SUMOylation and SUMOylated proteins in the pathophysiology of myocardial infarction and identifies the potential treatments against myocardial injury via targeting SUMO. Ultimately, this review recommends SUMOylation as a key therapeutic target for treating cardiovascular diseases.
| S-EPMC8355363 | biostudies-literature
Project description:BackgroundA strategy of administering a transfusion only when the hemoglobin level falls below 7 or 8 g per deciliter has been widely adopted. However, patients with acute myocardial infarction may benefit from a higher hemoglobin level.MethodsIn this phase 3, interventional trial, we randomly assigned patients with myocardial infarction and a hemoglobin level of less than 10 g per deciliter to a restrictive transfusion strategy (hemoglobin cutoff for transfusion, 7 or 8 g per deciliter) or a liberal transfusion strategy (hemoglobin cutoff, <10 g per deciliter). The primary outcome was a composite of myocardial infarction or death at 30 days.ResultsA total of 3504 patients were included in the primary analysis. The mean (±SD) number of red-cell units that were transfused was 0.7±1.6 in the restrictive-strategy group and 2.5±2.3 in the liberal-strategy group. The mean hemoglobin level was 1.3 to 1.6 g per deciliter lower in the restrictive-strategy group than in the liberal-strategy group on days 1 to 3 after randomization. A primary-outcome event occurred in 295 of 1749 patients (16.9%) in the restrictive-strategy group and in 255 of 1755 patients (14.5%) in the liberal-strategy group (risk ratio modeled with multiple imputation for incomplete follow-up, 1.15; 95% confidence interval [CI], 0.99 to 1.34; P = 0.07). Death occurred in 9.9% of the patients with the restrictive strategy and in 8.3% of the patients with the liberal strategy (risk ratio, 1.19; 95% CI, 0.96 to 1.47); myocardial infarction occurred in 8.5% and 7.2% of the patients, respectively (risk ratio, 1.19; 95% CI, 0.94 to 1.49).ConclusionsIn patients with acute myocardial infarction and anemia, a liberal transfusion strategy did not significantly reduce the risk of recurrent myocardial infarction or death at 30 days. However, potential harms of a restrictive transfusion strategy cannot be excluded. (Funded by the National Heart, Lung, and Blood Institute and others; MINT ClinicalTrials.gov number, NCT02981407.).
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Project description:BackgroundStrain analyses derived from cardiovascular magnetic resonance-feature tracking (CMR-FT) provide incremental prognostic benefit in patients sufferring from acute myocardial infarction (AMI). This study aims to evaluate and revalidate previously reported prognostic implications of comprehensive strain analyses in a large independent cohort of patients with ST-elevation myocardial infarction (STEMI).MethodsOverall, 566 STEMI patients enrolled in the CONDITIONING-LIPSIA trial including pre- and/or postconditioning treatment in addition to conventional percutaneous coronary intervention underwent CMR imaging in median 3 days after primary percutaneous coronary intervention. CMR-based left atrial (LA) reservoir (Es), conduit (Ee), and boosterpump (Ea) strain analyses, as well as left ventricular (LV) global longitudinal strain (GLS), circumferential strain (GCS), and radial strain (GRS) analyses were carried out. Previously identified cutoff values were revalidated for risk stratification. Major adverse cardiac events (MACE) comprising death, reinfarction, and new congestive heart failure were assessed within 12 months after the occurrence of the index event.ResultsBoth atrial and ventricular strain values were significantly reduced in patients with MACE (p < 0.01 for all). Predetermined LA and LV strain cutoffs enabled accurate risk assessment. All LA and LV strain values were associated with MACE on univariable regression modeling (p < 0.001 for all), with LA Es emerging as an independent predictor of MACE on multivariable regression modeling (HR 0.92, p = 0.033). Furthermore, LA Es provided an incremental prognostic value above LVEF (a c-index increase from 0.7 to 0.74, p = 0.03).ConclusionExternal validation of CMR-FT-derived LA and LV strain evaluations confirmed the prognostic value of cardiac deformation assessment in STEMI patients. In the present study, LA strain parameters especially enabled further risk stratification and prognostic assessment over and above clinically established risk parameters.Clinical trial registrationClinicalTrials.gov, identifier NCT02158468.
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Project description:Melianone, the protolimonoid (24, 25-epoxyflindissone), was isolated from the medicinal tree species, Swietenia mahagoni (L.) JACQ (Meliaceae). The compound isolated from petroleum ether leaf extracts (5.39%) was quantified using high-performance thin-layer chromatography (HPTLC) method. In antimicrobial assays melianone inhibited Salmonella ser. Typhi with an MIC of 0.053 µM. Induced Fit Docking (IFD) of the ligand, melianone, with proteins involved in anaerobic virulence of the pathogen, revealed that it binds with FocA (a transport protein of formate ions) at its "periplasmic opening" with a glide energy of - 51.8576 kcal mol-1. Melianone altered the overall conformation of the protein (protomer A) by 0.347 Å RMSD. It induced a notable protein topology (Ω loop region) shift in the channel from an intermediate-open to a closed-state conformation and was supported by molecular dynamic simulations performed. FocA, a protein that contributes to its survival under anaerobic conditions, was further evaluated experimentally, after exposure of Salmonella ser. Typhi to melianone, resulting in the altered homeostasis of formate.
| S-EPMC7527380 | biostudies-literature