Fucoxanthin attenuates LPS-induced acute lung injury via inhibition of the TLR4/MYD88 signaling axis

Acute lung injury (ALI) is a critical clinical condition with a high mortality rate. It is believed that the inflammatory storm is a critical contributor to the occurrence of ALI. Fucoxanthin is a natural extract from marine seaweed with remarkable biological properties, including antioxidant, anti-tumor, and anti-obesity. However, the anti-inflammatory activity of Fucoxanthin has not been extensively studied. The current study aimed to elucidate the effects and the molecular mechanism of Fucoxanthin on lipopolysaccharide-induced acute lung injury. In this study, Fucoxanthin efficiently reduced the mRNA expression of pro-inflammatory factors, including IL-10, IL-6, iNOS, and Cox-2, and down-regulated the NF-kappaB signaling pathway in Raw264.7 macrophages. Furthermore, based on the network pharmacological analysis, our results showed that anti-inflammation signaling pathways were screened as fundamental action mechanisms of Fucoxanthin on ALI. Fucoxanthin also significantly ameliorated the inflammatory responses in LPS-induced ALI mice. Interestingly, our results revealed that Fucoxanthin prevented the expression of TLR4/MyD88 in Raw264.7 macrophages. We further validated Fucoxanthin binds to the TLR4 pocket using molecular docking simulations. Altogether, these results suggest that Fucoxanthin suppresses the TLR4/MyD88 signaling axis by targeting TLR4, which inhibits LPS-induced ALI, and fucoxanthin inhibition may provide a novel strategy for controlling the initiation and progression of ALI

Physicochemical Properties, Structural Characterization, Immunoenhancing and Hypoglycemic Activities of Fucoidan Extracts from Two Sargassums Species

In this study, the chemical compositions, structures, immunomodulatory and hypoglycemic activities of fucoidans from Sargassum zhangii (SZ-Fuc) and Sargassum hemiphylla (SH-Fuc) were analyzed and compared. The results showed that the sulfate group content and molecular mass of SZ-Fuc were (29.74 ± 0.01)% and 111.28 kDa, respectively, and SZ-Fuc had a relatively loose surface structure. The main chain of SZ-Fuc was composed of (→1) linked fucose, xylose, glucose, mannose and galactose, (1→3)- and (1→4)- linked xylose, (1→2)-linked mannose, (1→3)-, (1→4)- and (1→6)-linked galactose, and (1→4)- and (1→6)-linked glucose. Meanwhile, the sulfate group content and molecular mass of SH-Fuc were (44.11 ± 0.01)% and 1 166.48 kDa, respectively, SH-Fuc had a compact surface structure, and its main chain contained (→1), (1→3)- and (1→4)-linked fucose, (→1), (1→4)- and (1→6)-linked glucose, (→1) and (1→2)-linked mannose, and (1→4)-linked galactose. Besides, both SZ-Fuc and SH-Fuc had branched structures. They significantly increased NO release from RAW264.7 cells and improved the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), indicating good immunomodulatory activity. The immunomodulatory activity of SZ-Fuc was better than that of SH-Fuc, while the inhibitory effect of SH-Fuc on α-glucosidase was better than that of SZ-Fuc, suggesting that SH-Fuc had better hypoglycemic potential. This study can provide a theoretical basis for polysaccharides from S. zhangii and S. hemiphylla in the development of functional and nutritional foods with immunomodulatory and blood glucose-reducing activity

Gossypol Inhibits Non-small Cell Lung Cancer Cells Proliferation by Targeting EGFRL858R/T790M

Background: Overexpression of epidermal growth factor receptor (EGFR) has been reported to be implicated in the pathogenesis of non-small cell lung cancer (NSCLC). Several EGFR inhibitors have been used in clinical treatment of NSCLC, but the emergence of EGFRL858R/T790M resistant mutation has reduced the efficacy of the clinical used EGFR inhibitors. There is an urgent need to develop novel EGFRL858R/T790M inhibitors for better NSCLC treatment.Methods: By screening a natural product library, we have identified gossypol as a novel potent inhibitor targeting EGFRL858R/T790M. The activity of gossypol on NSCLC cells was evaluated by cell proliferation, cell apoptosis and cell migration assays. Kinase activity inhibition assay and molecular docking were used to study the inhibition mechanism of gossypol to EGFRL858R/T790M. Western blotting was performed to study the molecular mechanism of gossypol inhibiting the downstream pathways of EGFR.Results: Gossypol inhibited the cell proliferation and cell migration of NSCLC cells, and induced caspase-dependent cell apoptosis of NSCLC cells by upregulating the expression of pro-apoptotic protein BAD. Molecular docking revealed that gossypol could bind to the kinase domain of EGFRL858R/T790M with good binding affinity through hydrogen bonds and hydrophobic interactions. Gossypol inhibited the kinase activity of EGFRL858R/T790M with EC50 of 150.1 nM. Western blotting analysis demonstrated that gossypol inhibited the phosphorylation of EGFR and its downstream signal pathways in a dose-dependent manner.Conclusion: Gossypol inhibited cell proliferation and induced apoptosis of NSCLC cells by targeting EGFRL858R/T790M. Our findings provided a basis for developing novel EGFRL858R/T790M inhibitors for treatment of NSCLC

Identification of Novel Arachidonic Acid 15-Lipoxygenase Inhibitors Based on the Bayesian Classifier Model and Computer-Aided High-Throughput Virtual Screening

Ferroptosis is an iron-dependent lipid peroxidative form of cell death that is distinct from apoptosis and necrosis. ALOX15, also known as arachidonic acid 15-lipoxygenase, promotes ferroptosis by converting intracellular unsaturated lipids into oxidized lipid intermediates and is an important ferroptosis target. In this study, a naive Bayesian machine learning classifier with a structure-based, high-throughput screening approach and a molecular docking program were combined to screen for three compounds with excellent target-binding potential. In the absorption, distribution, metabolism, excretion, and toxicity characterization, three candidate molecules were predicted to exhibit drug-like properties. The subsequent molecular dynamics simulations confirmed their stable binding to the targets. The findings indicated that the compounds exhibited excellent potential ALOX15 inhibitor capacity, thereby providing novel candidates for the treatment of inflammatory ischemia-related diseases caused by ferroptosis

The Inhibitors of CDK4/6 from a Library of Marine Compound Database: A Pharmacophore, ADMET, Molecular Docking and Molecular Dynamics Study

Background: CDK4/6 (Cyclin-dependent kinases 4/6) are the key promoters of cell cycle transition from G1 phase to S phase. Thus, selective inhibition of CDK4/6 is a promising cancer treatment. Methods: A total of 52,765 marine natural products were screened for CDK4/6. To screen out better natural compounds, pharmacophore models were first generated, then the absorption, distribution, metabolism, elimination, and toxicity (ADMET) were tested, followed by molecular docking. Finally, molecular dynamics simulation was carried out to verify the binding characteristics of the selected compounds. Results: Eighty-seven marine small molecules were screened based on the pharmacophore model. Then, compounds 41369 and 50843 were selected according to the ADMET and molecular docking score for further kinetic simulation evaluation. Finally, through molecular dynamics analysis, it was confirmed that compound 50843 maintained a stable conformation with the target protein, so it has the opportunity to become an inhibitor of CDK4/6. Conclusion: Through structure-based pharmacophore modeling, ADMET, the molecular docking method and molecular dynamics (MD) simulation, marine natural compound 50843 was proposed as a promising marine inhibitor of CDK4/6

Design and Synthesis of Novel Podophyllotoxins Hybrids and the Effects of Different Functional Groups on Cytotoxicity

Development of novel anticancer therapeutic candidates is one of the key challenges in medicinal chemistry. Podophyllotoxin and its derivatives, as a potent cytotoxic agent, have been at the center of extensive chemical amendment and pharmacological investigation. Herein, a new series of podophyllotoxin-N-sulfonyl amidine hybrids (4a–4v, 5a–5f) were synthesized by a CuAAC/ring-opening procedure. All the synthesized podophyllotoxins derivatives were evaluated for in vitro cytotoxic activity against a panel of human lung (A-549) cancer cell lines. Different substituents’, or functional groups’ antiproliferative activities were discussed. The –CF3 group performed best (IC50: 1.65 μM) and exhibited more potent activity than etoposide. Furthermore, molecular docking and dynamics studies were also conducted for active compounds and the results were in good agreement with the observed IC50 values

Identification of PLK1-PBD Inhibitors from the Library of Marine Natural Products: 3D QSAR Pharmacophore, ADMET, Scaffold Hopping, Molecular Docking, and Molecular Dynamics Study

PLK1 is found to be highly expressed in various types of cancers, but the development of inhibitors for it has been slow. Most inhibitors are still in clinical stages, and many lack the necessary selectivity and anti-tumor effects. This study aimed to create new inhibitors for the PLK1-PBD by focusing on the PBD binding domain, which has the potential for greater selectivity. A 3D QSAR model was developed using a dataset of 112 compounds to evaluate 500 molecules. ADMET prediction was then used to select three molecules with strong drug-like characteristics. Scaffold hopping was employed to reconstruct 98 new compounds with improved drug-like properties and increased activity. Molecular docking was used to compare the efficient compound abbapolin, confirming the high-activity status of [(14S)-14-hydroxy-14-(pyridin-2-yl)tetradecyl]ammonium,[(14S)-15-(2-furyl)-14-hydroxypentadecyl]ammonium and [(14S)-14-hydroxy-14-phenyltetradecyl]ammonium. Molecular dynamics simulations and MMPBSA were conducted to evaluate the stability of the compounds in the presence of proteins. An in-depth analysis of [(14S)-15-(2-furyl)-14-hydroxypentadecyl]ammonium and [(14S)-14-hydroxy-14-phenyltetradecyl]ammonium identified them as potential candidates for PLK1 inhibitors

Ferroptosis-Related Gene GCLC Is a Novel Prognostic Molecular and Correlates with Immune Infiltrates in Lung Adenocarcinoma

Ferroptosis, a newly discovered iron-dependent type of cell death, has been found to play a crucial role in the depression of tumorigenesis. However, the prognostic value of ferroptosis-related genes (FRGs) in lung adenocarcinoma (LUAD) remains to be further elucidated. Differential expression analysis and univariate Cox regression analysis were utilized in this study to search for FRGs that were associated with the prognosis of LUAD patients. The influences of candidate markers on LUAD cell proliferation, migration, and ferroptosis were evaluated by CCK8, colony formation, and functional experimental assays in association with ferroptosis. To predict the prognosis of LUAD patients, we constructed a predictive signature comprised of six FRGs. We discovered a critical gene (GCLC) after intersecting the prognostic analysis results of all aspects, and its high expression was associated with a bad prognosis in LUAD. Correlation research revealed that GCLC was related to a variety of clinical information from LUAD patients. At the same time, in the experimental verification, we found that GCLC expression was upregulated in LUAD cell lines, and silencing GCLC accelerated ferroptosis and decreased LUAD cell proliferation and invasion. Taken together, this study established a novel ferroptosis-related gene signature and discovered a crucial gene, GCLC, that might be a new prognostic biomarker of LUAD patients, as well as provide a potential therapeutic target for LUAD patients

Identification of Potential Inhibitors of MurD Enzyme of Staphylococcus aureus from a Marine Natural Product Library

Staphylococcus aureus is an opportunistic pathogen that can cause fatal bacterial infections. MurD catalyzes the formation of peptide bond between UDP-N-acetylehyl-l-alanine and d-glutamic acid, which plays an important role in the synthesis of peptidoglycan and the formation of cell wall by S. aureus. Because S. aureus is resistant to most existing antibiotics, it is necessary to develop new inhibitors. In this study, Schrodinger 11.5 Prime homology modeling was selected to prepare the protein model of MurD enzyme, and its structure was optimized. We used a virtual screening program and similarity screening to screen 47163 compounds from three marine natural product libraries to explore new inhibitors of S. aureus. ADME provides analysis of the physicochemical properties of the best performing compounds during the screening process. To determine the stability of the docking effect, a 100 ns molecular dynamics was performed to verify how tightly the compound was bound to the protein. By docking analysis and molecular dynamics analysis, both 46604 and 46608 have strong interaction with the docking pocket, have good pharmacological properties, and maintain stable conformation with the target protein, so they have a chance to become drugs for S. aureus. Through virtual screening, similarity screening, ADME study and molecular dynamics simulation, 46604 and 46608 were selected as potential drug candidates for S. aureus