Molecular Docking Analysis Research Articles

Investigating the role of PmrB mutation on Colistin antibiotics drug resistance in Klebsiella Pneumoniae

Klebsiella pneumoniae, a member of the Enterobacteriaceae family, naturally resides in the digestive tracts of both healthy animals and humans. Carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a significant health risk for hospitalized patients worldwide, greatly reducing the effectiveness of commonly used antibiotics. This leaves healthcare providers with limited treatment options, often relying on colistin. PmrB is important for the survival of Klebsiella pneumonia and, a mutation in the PmrB protein is accountable for the development of colistin antibiotic resistance in Klebsiella pneumonia. This is especially important because colistin is a fundamental component in the treatment of pneumonia. Three mutated residues—T157P, G207D, and T246A—are responsible for colistin resistance. The structural alterations and underlying mechanisms in the PmrB protein that cause resistance owing to mutation remain unclear. As a result, this study is focused to the exploration of the putative mechanism of resistance resulting from these mutations, as well as the structure modification of normal and mutant PmrB proteins, using molecular docking and molecular dynamics simulations analysis. Our results demonstrated that the interaction paradigm for the mutants has been altered and thus showing a significant effect upon the hydrogen bonding network. Interestingly, the binding of Colistin with the three mutant demonstrate unstable behavior as compared with WT+Colistin. The proposed drug-resistance mechanism will help to guide the development of PmrB drugs. These finding may give a new framework for developing novel drugs against the mutant version of PmrB.

Ultrasonic-assisted DES extraction optimization, characterization, antioxidant and in silico study of polysaccharides from Angelica dahurica Radix

In this study, polysaccharides from Angelica dahurica Radix (ADR) were extracted by using ultrasonic-assisted deep eutectic solvent (DES) extraction method. The DES consist of choline chloride (HBA, hydrogen bonding acceptor) and 1, 4-butanediol (HBD, hydrogen bonding donor) with the molar ratio of 1:3 was proved as the best system for polysaccharides extraction. A Box-Behnken design with three factors and three levels was utilized to optimize ultrasonic power, extraction time and temperature for increased polysaccharides yield. The optimal extraction parameters were determined as follows: DES water content of 20 %, liquid–solid ratio of 10:1 mL/g, ultrasonic time of 21 min, temperature at 60 °C, and ultrasonic power of 435 W. These conditions yielded an extraction rate nearly matching the theoretical predicted value of the response surface model, surpassing the traditional hot water extraction method by 1.33 times and requiring less time. The antioxidant polysaccharides was assessed using DPPH,ABTS and Hydroxyl methods, which indicated that ADRP extracted by ultrasound assisted DES had excellent antioxidant capacity and showed a dose–response relationship with drug concentration. Structural analysis identified ADR polysaccharides as a heteropolysaccharide rich in sugar aldonic acids—namely, fucose, rhamnose, arabinose, galactose and glucose—with molar ratios of 0.47:1.99:17.61:64.76:15.17. The polysaccharides’ number-average molecular weight was determined to be 97.422 kDa, with a weight-average molecular weight of 245.678 kDa. Network pharmacology and molecular docking analysis suggest that the monosaccharides Rha and Ara could potentially interact with the proteins GSR and GSTA1, respectively, indicating that ADRP had good antioxidant potential and could be applied in multiple fields with promising development prospects in the future.

Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance.

Immune checkpoint blockade (ICB) triggers tumor ferroptosis. However, most patients are unresponsive to ICB. Tumors might evade ferroptosis in the tumor microenvironment (TME). Here, we discover SLC13A3 is an itaconate transporter in tumor cells and endows tumor ferroptosis resistance, diminishing tumor immunity and ICB efficacy. Mechanistically, tumor cells uptake itaconate via SLC13A3 from tumor-associated macrophages (TAMs), thereby activating the NRF2-SLC7A11 pathway and escaping from immune-mediated ferroptosis. Structural modeling and molecular docking analysis identify a functional inhibitor for SLC13A3 (SLC13A3i). Deletion of ACOD1 (an essential enzyme for itaconate synthesis) in macrophages, genetic ablation of SLC13A3 in tumors, or treatment with SLC13A3i sensitize tumors to ferroptosis, curb tumor progression, and bolster ICB effectiveness. Thus, we identify the interplay between tumors and TAMs via the SLC13A3-itaconate-NRF2-SLC7A11 axis as a previously unknown immune ferroptosis resistant mechanism in the TME and SLC13A3 as a promising immunometabolic target for treating SLC13A3+ cancer.

Combining Mendelian Randomization analysis and Network toxicology strategy to identify causality and underlying mechanisms of environmental pollutants with glioblastoma: A study of Methyl-4-hydroxybenzoate

BackgroundAn increasing number of environmental pollutants are associated with human diseases. We explored the mechanisms by which an aromatic small molecule -- Methyl-4-hydroxybenzoate (MEP) contribute to the development of glioblastoma (GBM). MethodsThe causality of MEP and GBM were identified via the Mendelian Randomization (MR) analysis. We identified the key targets by integrating the targets of GBM, differential expressed genes (DEGs) from GEO and target genes of MEP. The network of hub genes was obtained from STRING and Cytoscape tools and GO, KEGG enrichment analysis were conducted by clusterProfiler R package. These hub targets were executed molecular docking via Autodock software. ResultsMEP had a causal association with GBM as risk factors (P < 0.05, OR > 1). 46 key targets were derived, in which CASP3, MMP2 and CDK4 were screened as the hub targets. MEP might play a role in the GBM by affecting the pathways of neuroactive ligand-receptor interaction, Molecular docking analysis showed a good binding ability of between MEP and CASP3, MMP2, CDK4, CASP8 and MCL1. ConclusionsA causal relationship between MEP and GBM exists. CASP3, MMP2, CDK4, CASP8 and MCL1 have been identified as the crucial targets correlating with GBM. This discovery may provide an important insight into how environmental pollutants contribute to the development of GBM.

Pharmacokinetic profiling and network pharmacology of honey-fried Licorice: An Integrative workflow to study traditional Chinese medicines (TCMs)

Licorice, known as the “elder statesman,” is commonly used in traditional Chinese medicine (TCM) formulations. This study aims to establish a workflow combining animal and in silico experiments to elucidate the mechanisms of TCMs at both qualitative and quantitative levels. UPLC-Q-TOF-MS/MS was employed to qualitatively characterize the total components of honey-fried licorice and the plasma components after oral administration in Beagle dogs. A UPLC-Q-Trap-MS/MS method was developed for the pharmacokinetic study of honey-fried licorice components in Beagle dog plasma. Network pharmacology and molecular docking were utilized to explore the primary functional targets and pathways. In total, we identified 68 constituents in honey-fried licorice, with 28 detected in Beagle dog plasma, and 18 of them, mainly belong to flavonoids and terpenoids, showing significant exposure. The plasma pharmacokinetic study of these 18 constituents revealed that compounds like liquiritin, glycyrrhizic acid, licoricesaponin G2, and glycyrrhetic acid-3-o-glucuronide had significant exposure. Network pharmacology and molecular docking analyses identified MAPK3, PIK3CB, PIK3CA, RAF1, and EGFR as the main targets of the active constituents of honey-fried licorice, involved in pathways such as the Ras signaling pathway, human cytomegalovirus infection, and the MAPK signaling pathway. This study provides a comprehensive profile and pharmacokinetic characteristics of honey-fried licorice, offering insights into its pharmacological, toxicological, and clinical aspects. The established workflow can serve as a standard for investigating other TCMs.

Utilization of soybean protein isolate hydrolysates as carriers: Improved encapsulation efficiency and stability of curcumin

This study aimed to explore the potential of soybean protein isolate hydrolysates (SPIH) prepared via Alcalase as delivery carriers and develop novel SPIH-Cur nanoparticles. Hydrolysis caused the varying degrees degradation in the 7S and 11S subunits, significantly enhancing SPI's antioxidant activity. The reduction in particle size and the exposure of hydrophobic groups in SPIH contributed to the formation of stable SPIH-Cur nanoparticles, due to their well binding capacity to curcumin (Cur). The 30 min SPIH-Cur sample exhibited the highest encapsulation efficiency (83.09 %), owing to its high binding affinity (Ka = 9.56 × 103 M−1). Encapsulation by SPIH also significantly improved Cur's thermal and light stability. Moreover, FTIR, fluorescence spectra, and molecular docking analyses revealed that the formation of SPIH-Cur were primarily driven by hydrophobic forces and hydrogen bonds. Above results provide a foundation for fabricating nanoparticles that deliver lipophilic bioactive compounds with high encapsulation efficiency and stability derived from SPIH.

Cedrol attenuates acute ischemic injury through inhibition of microglia-associated neuroinflammation via ERβ-NF-κB signaling pathways

Microglia-associated neuroinflammation plays essential roles in pathology of acute stroke. Cedrol, a natural compound extracted from ginger, has been shown to confer inhibitory effects on inflammation in various diseases. However, whether Cedrol suppresses neuroinflammation and protects brains from acute ischemic injury still remains unclear. In this study, we found that Cedrol inhibited microglia activation and the production of inflammatory factors in LPS-challenged microglia and the penumbra region of middle cerebral artery occlusion (MCAO) mice. We also found that Cedrol reduced the infarct size and mNSS scores and improved acute cerebral ischemia-induced behavioral outcomes, suggesting remarked neuroprotection of Cedrol. Molecular docking analysis showed that Cedrol bound to estrogen receptor β (ERβ) with moderate-strong affinity. Intriguingly, treatment with fulvestrant, an ER blocker, abolished the anti-inflammatory effects of Cedrol. Cedrol significantly reversed the LPS- and MCAO-induced increases in phosphorylation levels of IκB and NF-κB P65 in primary microglia and MCAO mice, respectively. Additionally, Cedrol was observed to rescue LPS-induced shuttling of NF-κB P65 from cytoplasm to nuclei in primary microglia, indicating inhibitory effects of Cedrol on NF-κB signaling. These results suggest microglia associated neuroinflammation may be mediated by ERβ-NF-κB signaling pathway. Together, our study reveals that Cedrol protected brain function from acute cerebral ischemia through inhibition of microglia-associated neuroinflammation via ERβ-NF-κB signaling pathways, and Cedrol may serve as an alternative option for treatment of acute stroke injury.

Glioblastoma Multiforme miRNA based Comprehensive Study to Validate Phytochemicals for Effective Treatment against Deadly Tumour through In Silico Evaluation.

Glioblastoma Multiforme (GBM) is a prevalent and deadly type of primary astrocytoma, constituting over 60% of adult brain tumors, and has a poor prognosis, with a high relapse rate within 7 months of diagnosis. Despite surgical, radiotherapy, and chemotherapy treatments, GBM remains challenging due to resistance. MicroRNA (miRNAs) control gene expression at transcriptional and post-transcriptional levels by targeting their messenger RNA (mRNA), and also contribute to the development of various neoplasms, including GBM. The present study focuses on exploring the miRNAs-based pathogenesis of GBM and evaluating most potential plant-based therapeutic agents with in silico analysis. Gene chips were retrieved from the Gene Expression Omnibus (GEO) database, followed by the Robust- RankAggereg algorithm to determine the Differentially Expressed miRNAs (DEMs). The predicted targets were intersected with the GBM-associated genes, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the overlapping genes was performed. At the same time, five phytochemicals were selected for the Connectivity map (CMap), and the most efficient ones were those that had undergone molecular docking analysis to obtain the potential therapeutic agents. The hsa-miR-10b, hsa-miR-21, and hsa-miR-15b were obtained, and eight genes were found to be associated with glioma pathways; VSIG4, PROCR, PLAT, and ITGB2 were upregulated while, CAMK2B, PDE1A, GABRA1, and KCNJ6 were downregulated. The drugs Resveratrol and Quercetin were identified as the most prominent drugs. These miRNAs-based drugs can be used as a curative agent for the treatment of GBM. However, in vivo, experimental data, and clinical trials are necessary to provide an alternative to conventional GBM cancer chemotherapy.

Exploring the potential molecular targets of hydroxymethylbutyrate and glucosamine fortified whey protein drink to modulate sarcopenia and Alzheimer's disease by in silico and in vitro studies

Fortified foods have garnered significant attention as potential therapeutic strategies with less adverse effects and ready accessibility. However, precise formulation is required to optimize their beneficial effects. Our study aimed to unravel the mechanisms of a functional protein beverage, hydroxymethylbutyrate and glucosamine fortified whey protein drink (HG-WPD), as a possible intervention combatting sarcopenia and Alzheimer's disease (AD) by network pharmacology, molecular docking, and experimental assays. This study investigates the molecular pathways through which HG-WPD acts, by combining in silico and in vitro analyses. Our in silico study predicted the important target proteins, including acetylcholinesterase (AChE), matrix metalloproteinase 9 (MMP9), and angiotensin-converting enzyme (ACE), linked to both diseases. The molecular docking analysis showed that hydroxymethylbutyrate and glucosamine exhibited a notable binding affinity to these proteins, therefore suggesting their possible use as multi-target medicinal agents. In vitro studies on C2C12 myotubes showed that HG-WPD reduced dexamethasone-induced cell death highlighting its potential anti-sarcopenic actions. Furthermore, confirming their possible function in reducing cognitive impairment in AD, the antioxidant tests showed great activity of both substances. The results imply that HG-WPD is potentially effective for future therapeutic approaches as a functional food product with dual benefits in combatting sarcopenia and AD.

Computational screening of phytochemicals present in some Nigerian medicinal plants against sickle cell disease

Four hundred Phytochemical (bio-active) compounds having predictive activity for treating Sickle Cell Anemia were screened, using PASS online computational resource. Twenty-six compounds out of the four hundred compounds which showed high probability for treating sickle were further screened for pharmacokinetics profiles (ADMET properties) using SwissAdmet, AdmetSAR 2 and Pro-tox II online resources. Only thirteen compounds that displayed good ADMET properties from the twenty-six were further used for DFT calculations and molecular docking against carbonmonoxy sickle hemoglobin (PDB ID: 5E6E). Molecular docking analysis reinforced by DFT calculations showed that two compounds, phenanthrene-5,6-dione (A9) and 2-(3,4-dihydroxyphenyl)-5,7-dihydroxychromen-4-one (A13, Luteolin) had the best binding affinity of − 8.3 and − 8.9 kcal/mol, respectively, compared to voxelotor (GBT-440), a drug use in treating sickle cell disease. Molecular dynamic simulations showed that 2-(3,4-dihydroxyphenyl)-5,7-dihydroxychromen-4-one (A13, Luteolin) is highly stable with the protein than voxelotor.

Design, synthesis, and evaluation of some benzimidazole analogs as AMPK agonists

AMP-activated protein kinase is a crucial regulator of cellular metabolism with potential therapeutic implications in various diseases. In this study, the benzimidazole scaffold was chosen for investigation with EX-229 as the lead compound. Modifications were made to the terminal carboxyl group, and the methylindole moiety was replaced with phenylpyrrolidinone to synthesize and assess the AMP-activated protein kinase-activating properties of 13 benzimidazole derivatives. In vitro studies have shown that most of the synthesized compounds have significant excitatory effects on AMP-activated protein kinase. Particularly, A11 demonstrated the most potent activity with an EC50 value of 39 nM. Combining activity data and molecular docking analysis revealed the necessity of end-molecule hydrogen bond donors for LYS29, and the importance of an appropriate torsion angle at the pyrrolidinone position to facilitate the formation of a crucial hydrogen bond with LYS31. These discoveries offer preliminary insights into the interaction of small-molecule drugs with the AMP-activated protein kinase protein and establish a foundation for the future development of AMP-activated protein kinase activators guided by structure–activity relationships.

Inhibitory mechanism of apigenin, quercetin, and phloretin on α-glucosidase

Flavonoids present promising potential as α-glucosidase inhibitors, with potential benefits in lowering blood glucose levels. In our previous study, apigenin, quercetin, and phloretin obtained from whole-grain highland barley demonstrated notable efficacy as α-glucosidase inhibitors. Therefore, in this study, we used enzyme kinetics, fluorescence spectroscopy, circular dichroism, and molecular docking to explore the interactions between apigenin, quercetin, and phloretin, and α-glucosidase. With the addition of three flavonoids, the inhibitory effect of all the flavonoids on α-glucosidase activity was reversible and exhibited a mixed-type pattern. Molecular docking analysis revealed that the three flavonoids predominantly bind to yeast-derived α-glucosidase mainly through hydrophobic interactions and van der Waals forces, whereas the interaction with human-derived α-glucosidase involved hydrophobic interactions. Further experiments revealed that the flavonoids quenched the fluorescence of α-glucosidase due to the complex formation between the flavonoids and α-glucosidase, leading to changes in the protein secondary structure and conformational changes, which was further supported by molecular dynamics simulations. These results provided insights into the mechanism of the flavonoid inhibition of α-glucosidase. These findings could promote the consumption of whole-grain highland barley and the development of hypoglycemic foods rich in flavonoids.

Network-Pharmacology-Based Study on Active Phytochemicals and Molecular Mechanism of Cnidii Fructus in Treating Colorectal Cancer.

Cnidii Fructus (CF) is known for its antibacterial, anti-inflammatory, and antitumor properties, as well as its activities against kidney deficiency and impotence. In this study, we aimed to explore the anti-CRC cancer effect and molecular mechanism of CF via network pharmacology and in vitro antitumor experiments. Network pharmacology was used to investigate the anti-CRC mechanism of CF. First, a series of databases was used to screen the active phytochemical targets and anti-CRC core targets. Then, the GO and KEGG pathways were analyzed to predict possible mechanisms. Molecular docking analysis explore core targets-phytochemicals interactions. In vitro antitumor experiments were carried on verifying anti-CRC mechanism of CF. In this study, 20 active ingredient targets and 50 intersecting targets were analyzed by Cytoscape software 3.9.1 to obtain the core genes and phytochemicals. Then, the GO and KEGG pathways of 50 intersecting targets were analyzed to predict possible mechanisms. The results from GO and KEGG indicated that CF has significant antitumor efficacy, which involves many signaling pathways, such as PI3K/AKT and p53. The five core targets and five core phytochemicals were screened for molecular docking to show protein-ligand interactions. According to the results of molecular docking, the compound O-acetylcolumbianetin was selected for the anti- CRC functional verification in vitro. MTT assay showed that O-acetylcolumbianetin significantly inhibited the proliferation of colorectal HCT116 cells in a time- and quantity-dependent manner. O-acetylcolumbianetin can promote the expression of CASP3 protein, induce HCT116 cells apoptosis, thus exert anti-CRC effect. This study preliminarily verified the anti-CRC effect and molecular mechanism of CF and provided a reference for Traditional Chinese Medicine anti-tumor subsequent research.

Characterization of ulvan polysaccharide extracted from Ulva pertusa and its effect on thermal, rheological, and gelling properties of rice flour

Three ulvan fractions (UPs 1–3) were extracted from Ulva pertusa via hot-water extraction. UP1 exhibited a molecular weight of 729,151 Da, while UPs 2 and 3 ranged from 19,952 to 750,384 Da. These fractions differed in monosaccharide, uronic acid, and sulfate levels. Zeta potentials for polysaccharide solutions (0.2–0.6 % w/v) ranged from −34.4 to −25.1, all demonstrating shear-thinning behavior. Incorporating UPs 1–3 solutions (0.2–0.6 % w/v) with rice flour increased gelatinization temperatures and modified pasting properties, increasing peak time, peak viscosity, and trough viscosity while reducing breakdown, final, and setback viscosities. Ulvan polysaccharide improved the viscous behavior of rice flour paste, indicated by increased loss modulus and tan δ (p > 0.05). Furthermore, ulvan polysaccharide improved the microstructure and texture of rice flour gel, with UP1 (0.6 % w/v) forming denser matrices and better texture. Molecular docking analysis suggested that hydrogen bonding is the primary interaction between rice glutelin and ulvan components.

Synthesis, Spectral Characterisation, DFT Calculations, Biological Evaluation and Molecular Docking Analysis of New Mannich Compounds Derived from Cyclopentanone

This research outlines the efficient one-pot calcium chloride-catalysed synthesis of three novel Mannich bases: M1, M2 and M3. M1 and M2 resulted from the condensing of benzaldehyde with m-nitroaniline and m-bromoaniline, respectively, in conjunction with cyclopentanone. However, M3 was obtained through the reaction of p-methoxybenzaldehyde, m-bromoaniline and cyclopentanone. The isolated compounds were thoroughly characterised using elemental analysis and various analytical and spectroscopic techniques, including the determination of their melting points, electrospray mass spectrometry (ESMS), Fourier transform infrared (FTIR), electronic spectroscopy (UV-Vis), and nuclear magnetic resonance (NMR) spectroscopy (1H- and 13C-NMR). Thermal stability (TGA and DTA analysis) of the three Mannich compounds was also examined. The newly synthesised Mannich bases exhibit remarkable potential as metal ion complexing agents and as fundamental building blocks for forming small organic molecules, particularly bioactive molecules and novel ligands for coordination chemistry. In addition to their structural significance, the biological efficacy of these compounds was assessed, revealing their excellent antimicrobial properties toward bacterial and fungal species. These activities suggest their potential use in combating microbial infections. Theoretical DFT simulations employing the B3LYP functional at the 6-311++G(d,p) level provided a thorough analysis of the stability of compounds, electrical properties, and geometry. Additionally, molecular docking studies of the Mannich compounds with two protein targets, 5IQ9 and 5VBU (both relevant for drug discovery) were performed. These studies revealed that the three Mannich compounds exhibit similar binding energies and effective interaction with both the 5IQ9 and 5VBU proteins, suggesting the potential of these Mannich compounds as dual inhibitors targeting both proteins.

IN SILICO ANALYSIS OF MOMORDICA CHARANTIA L. AS ANTIDIABETIC AGENTS THROUGH ACTIVATION OF HUMAN UDP-GALACTOSE 4-EPIMERASE RECEPTORS

This study investigates the antidiabetic potential of compounds found in Momordica charantia L., commonly known as bitter melon, through molecular docking and ADME (Absorption, Distribution, Metabolism, and Excretion) analysis. Utilizing in silico methods, several bioactive compounds from bitter melon, such as charantin, vicine, momordenol, momordicilin, and momordicoside, were evaluated for their ability to interact with the human UDP-Galactose 4-Epimerase receptor, a key enzyme involved in glucose metabolism. The docking results indicate that these compounds exhibit strong binding affinities, suggesting their role in glucose regulation. Further ADME analysis revealed that the compounds generally comply with the Lipinski Rule of Five, indicating favorable drug-like properties, though some compounds exhibited potential toxicities requiring further investigation. These findings highlight the potential of Momordica charantia as a source of antidiabetic agents, warranting additional in vivo and clinical studies to confirm their efficacy and safety in managing diabetes mellitus.

Molecular docking and ADME evaluation of plant-based bioactive molecules targeting nonsense-mediated mRNA decay pathway factors to modulate tumorigenesis

Cancer is a global health challenge that requires continuous efforts to discover effective anticancer drugs. Phytochemicals are compounds found in plants that often have medicinal properties. They possess a wide range of bioactive properties, including anticancer activity. Their multiple mechanisms of action in different physiological processes in humans make them promising candidates in the anticancer therapeutics development. The presence of these compounds makes plants valuable resources for traditional medicine and modern pharmaceutical research as well. Natural products from plants and marine sources are being used to find new anticancer agents. In humans, different cellular pathways are involved in the tumorigenesis process. Many studies have shown the role of the nonsense-mediated mRNA decay (NMD) pathway in the process of tumorigenesis. This NMD pathway is controlled by multiple proteins. In this study, we conducted a molecular docking analysis of 50 phytochemicals against the human NMD factor up-frameshit2 (UPF2) protein. The results of the molecular docking experiment and ADME properties indicate that 4 of these molecules (Genistein, Trihydroxyflavone, Baicalein and Epigallocatechin) have the potential to modulate the NMD pathway. Furthermore, these molecules comply with Lipinski's rule of five. The effects of these 4 phytochemicals may be further evaluated using in vitro and in vivo methods for novel anticancer therapeutic development.

Machine learning models reveal ARHGAP11A's impact on lymph node metastasis and stemness in NSCLC.

Most patients with non-small cell lung cancer (NSCLC) are diagnosed at an advanced stage of the disease, which complicates treatment due to a heightened risk of metastasis. Consequently, the timely identification of biomarkers associated with lymph node metastasis is essential for improving the clinical management of NSCLC patients. In this research, the WGCNA algorithm was utilized to pinpoint genes linked to lymph node metastasis in NSCLC. A cluster analysis was carried out to investigate how these genes correlate with the prognosis and the outcomes of immunotherapy for NSCLC patients. Following this, diagnostic and prognostic models were created and validated through various machine learning methodologies. The random forest technique highlighted the importance of ARHGAP11A, leading to an in-depth examination of its role in NSCLC. By analyzing 78 tissue chip samples from NSCLC patients, the study confirmed the association between ARHGAP11A expression, patient prognosis, and lymph node metastasis. Finally, the influence of ARHGAP11A on NSCLC cells was assessed through cell function experiments. This research utilized the WGCNA technique to identify 25 genes that are related to lymph node metastasis, clarifying their connections with tumor invasion, growth, and the activation of stemness pathways. Cluster analysis revealed significant associations between these genes and lymph node metastasis in NSCLC, especially concerning immunotherapy and targeted treatments. A diagnostic system that combines various machine learning approaches demonstrated strong efficacy in forecasting both the diagnosis and prognosis of NSCLC. Importantly, ARHGAP11A was identified as a key prognostic gene associated with lymph node metastasis in NSCLC. Molecular docking analyses suggested that ARHGAP11A has a strong affinity for targeted therapies within NSCLC. Additionally, immunohistochemical assessments confirmed that higher levels of ARHGAP11A expression correlate with unfavorable outcomes for NSCLC patients. Experiments on cells showed that reducing ARHGAP11A expression can hinder the proliferation, metastasis, and stemness traits of NSCLC cells. This investigation reveals the novel insight that ARHGAP11A may function as a potential biomarker connected to lymph node metastasis in NSCLC. Moreover, reducing the expression of ARHGAP11A has demonstrated the ability to diminish tumor stemness characteristics, presenting a promising opportunity for improving treatment strategies for this condition.

Traditional Chinese herbal formula, Fuzi-Lizhong pill, produces antidepressant-like effects in chronic restraint stress mice through systemic pharmacology

Ethnopharmacological relevanceFuzi-Lizhong pill (FLP) is a well-validated traditional Chinese medicine (TCM) formula that has long been used in China for gastrointestinal disease and adjunctive therapy for depression. In our previous study, we reported that the principal herb of FLP, Aconitum carmichaelii Debx. (Fuzi), exhibits antidepressant-like effects. However, there have been no reports on whether FLP produces antidepressant-like effects and its potential molecular mechanisms. Aim of the studyWe aim to demonstrate the antidepressant-like effects of FLP in chronic restraint stress (CRS) mice and to explore the associated molecular mechanisms. Materials and methodsThe active components and probable molecular targets of FLP, as well as the targets related to depression, were identified through network pharmacology. A protein-protein interaction (PPI) network was generated using the overlapping targets, followed by the visualization as well as identification of the core targets associated with the antidepressant-like action of FLP. Subsequently, KEGG and GO enrichment analyses were conducted. UHPLC-MS/MS was employed to further detect the active compounds in FLP. Molecular docking was applied to assess the connections between the active components as well as the core targets. The efficacy of FLP in treating depression and its molecular mechanisms were examined using western blotting, ELISA, 16S rRNA sequencing, HE staining, Nissl staining, and Golgi-Cox staining in a CRS-induced mouse model. ResultsNetwork pharmacology and UHPLC-MS/MS analyses indicated that the active compounds of FLP comprised taraxerol, songorine, neokadsuranic acid B, ginkgetin, hispaglabridin B, quercetin, benzoylmesaconine and liquiritin. KEGG pathway analysis implicated that the PI3K/Akt/mTOR as well as MAPK signaling pathways are closely related to the therapeutic effects of FLP on depression. Molecular docking analysis demonstrated that the main components of FLP bind to PI3K, AKT, mTOR, BDNF and MAPK. FLP significantly decreased immobility in mice that were elevated by CRS in the FST and the TST. FLP also significantly increased sucrose preference in mice after CRS in the SPT. FLP upregulated proteins associated with BDNF-TrkB and PI3K/Akt/mTOR signaling and downregulated proteins associated with MAPK signaling. Serum levels of CORT, IL-6, IL-1β, and TNF-α in CRS mice were significantly decreased following treatment with FLP. In addition, FLP ameliorated CRS-induced gut microbiota dysbiosis as demonstrated by 16S rRNA sequencing analysis. FLP ameliorated CRS-induced intestinal inflammation and neuronal damage. Finally, antidepressant-like effects and concomitant increases in dendritic spine density induced by FLP administration were also reduced after rapamycin treatment. ConclusionThese results demonstrate that FLP has antidepressant-like effects in mice exposed to CRS that involve activation of the PI3K/Akt/mTOR signaling pathway, increase in spinogenesis, inhibition of the MAPK signaling pathway, decrease in inflammation, and amelioration of gut microbiota dysbiosis. These findings provide novel evidence for the clinical application of FLP on depression.

Evaluation of natural compounds as VEGFR-2 inhibitors for breast cancer therapy: insights from molecular docking and drug-likeness analysis

Breast cancer remains one of the most common cancers worldwide, with VEGFR-2 (KDR) playing a key role in tumor angiogenesis. Inhibiting VEGFR-2 is a promising therapeutic strategy. Natural compounds are increasingly studied for their potential to inhibit VEGFR-2. This study aims to assess the binding affinity of 11 natural compounds (andrographolide, alpha-mangostin, pinostrobin, pinocembrin, ethyl-p-methoxycinnamate (EPMS), xanthorrhizol, galangin, gamma-mangostin, curcumin, cinnamaldehyde, and alashanoid B) to the VEGFR-2 protein through molecular docking and Lipinski's rule analysis, identifying promising candidates for breast cancer treatment. Molecular docking simulations were performed for 11 compounds and sunitinib as a control, with binding energies and interactions analyzed. The compounds were also evaluated for drug-likeness using Lipinski’s rule of five. Curcumin showed the highest binding affinity to VEGFR-2 with a binding energy of -9.9 kcal/mol, surpassing sunitinib (-9.4 kcal/mol). Key interactions were observed with active site residues Cys919 and Asp1046. All tested compounds met the criteria for oral bioavailability per Lipinski’s rules. Curcumin demonstrates potential as a VEGFR-2 inhibitor due to its favorable binding affinity and drug-like properties. Enhancing curcumin’s bioavailability is recommended for effective therapeutic application.