Target Screening Research Articles

Network pharmacology and molecular dynamics study of the effect of the Astragalus-Coptis drug pair on diabetic kidney disease.

Diabetic kidney disease (DKD) is the primary cause of end-stage renal disease. The Astragalus-Coptis drug pair is frequently employed in the management of DKD. However, the precise molecular mechanism underlying its therapeutic effect remains elusive. To investigate the synergistic effects of multiple active ingredients in the Astragalus-Coptis drug pair on DKD through multiple targets and pathways. The ingredients of the Astragalus-Coptis drug pair were collected and screened using the TCMSP database and the SwissADME platform. The targets were predicted using the SwissTargetPrediction database, while the DKD differential gene expression analysis was obtained from the Gene Expression Omnibus database. DKD targets were acquired from the GeneCards, Online Mendelian Inheritance in Man database, and DisGeNET databases, with common targets identified through the Venny platform. The protein-protein interaction network and the "disease-active ingredient-target" network of the common targets were constructed utilizing the STRING database and Cytoscape software, followed by the analysis of the interaction relationships and further screening of key targets and core active ingredients. Gene Ontology (GO) function and Kyoto Ency-clopedia of Genes and Genomes (KEGG) pathway enrichments were performed using the DAVID database. The tissue and organ distributions of key targets were evaluated. PyMOL and AutoDock software validate the molecular docking between the core ingredients and key targets. Finally, molecular dynamics (MD) simulations were conducted to simulate the optimal complex formed by interactions between core ingredients and key target proteins. A total of 27 active ingredients and 512 potential targets of the Astragalus-Coptis drug pair were identified. There were 273 common targets between DKD and the Astragalus-Coptis drug pair. Through protein-protein interaction network topology analysis, we identified 9 core active ingredients and 10 key targets. GO and KEGG pathway enrichment analyses revealed that Astragalus-Coptis drug pair treatment for DKD involves various biological processes, including protein phosphorylation, negative regulation of apoptosis, inflammatory response, and endoplasmic reticulum unfolded protein response. These pathways are mainly associated with the advanced glycation end products (AGE)-receptor for AGE products signaling pathway in diabetic complications, as well as the Lipid and atherosclerosis. Molecular docking and MD simulations demonstrated high affinity and stability between the core active ingredients and key targets. Notably, the quercetin-AKT serine/threonine kinase 1 (AKT1) and quercetin-tumor necrosis factor (TNF) protein complexes exhibited exceptional stability. This study demonstrated that DKD treatment with the Astragalus-Coptis drug pair involves multiple ingredients, targets, and signaling pathways. We propose a novel approach for investigating the molecular mechanism underlying the therapeutic effects of the Astragalus-Coptis drug pair on DKD. Furthermore, we suggest that quercetin is the most potent active ingredient and specifically targets AKT1 and TNF, providing a theoretical foundation for further exploration of pharmacologically active ingredients and elucidating their molecular mechanisms in DKD treatment.

Screening and validation of therapeutic targets for chronic sinusitis with nasal polyps based on proteomics

Objective: To identify potential therapeutic targets of chronic sinusitis with nasal polyps (CRSwNP) through proteomics screening of and verify its effectiveness experimentally. Methods: The nasal tissue samples were collected from patients undergoing surgical treatment in the Department of Otorhinolaryngology, Head and Neck Surgery in Yuhuangding Hospital of Yantai from June 2010 to December 2021, including 69 patients with CRSwNP and 39 patients in the control group. Tissue samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in data-independent acquisition (DIA) mode to find differentially expressed proteins. Bioinformatics tools were employed to analyze the functions of differentially expressed proteins. The expression of hematopoietic cell kinase (HCK) in nasal tissues of patients with CRSwNP was further confirmed by qPCR and western blot. The mouse model of CRSwNP was established and treated with HCK inhibitor. The levels of inflammatory factors IgE, IL-4 and IL-5 in serum of CRSwNP mice, both treated and untreated with HCK inhibitors, were detected by enzyme-linked immunosorbent assay (ELISA) across different experimental groups. The experimental data were analyzed by Graphpad Prism 9 software. Results: DIA analysis identified 1 850 differential proteins, including 760 up-regulated proteins and 1 090 down-regulated proteins. Weighted correlation network analysis (WGCNA) correlation analysis of phenotypic data such as cell count and CT score with the results of genomics indemnified 575 proteins of MEBrown module which intersected with 35 kinases further screened from 1 850 differential proteins, yielding eight protein kinases: HCK, SYK, PDK2, FGR, PRKCB, ROR1, CAMK1 and GRK6. qPCR showed that the expression of HCK in CRSwNP was significantly higher than that in the control group (P<0.05). Further experiments in mice confirmed that the secretion of IgE, IL-4 and IL-5 in the serum of CRSwNP group was significantly higher than the control group (all P<0.05), indicating successful model establishment. The intervention of HCK significantly decreased the secretion of IgE, IL-4 and IL-5 in serum of mice (all P<0.05). Conclusion: The HCK inhibitor can reduce the inflammatory index of mice with CRSwNP, and HCK is a potential therapeutic target of CRSwNP.

Unveiling underlying mechanism of combined He–Ne laser and UV mutagenesis in Bacillus subtilis CICC 21927: A transcriptomic analysis

Conventional random mutation breeding remains the simplest and most cost-effective approach in enhancing strains in fermentation industry. Nonetheless, extensive research on compound mutagenesis are limited to screening target strains, and few studies on the interaction mechanism of compound mutagenesis factors. Herein, transcriptomic was employed to elucidate the molecular mechanism behind helium-neon (He–Ne) laser and ultraviolet (UV) compound mutagenesis in Bacillus subtilis. Transcriptomic sequencing analysis was conducted on five sample groups (control/CK, UV, laser/LA, UV-laser/UL, and laser-UV/LU), facilitating the statistical comparison of differentially expressed genes (DEGs) across 4 sample relationships (CK-vs-UV, CK-vs-LA, CK-vs-LU, and CK-vs-UL). The DEGs revealed that UV irradiation improved the biosynthesis of pyrimidine nucleotides by upregulating the activity of key enzymes (pyrimidine nucleotides synthetase, pyruvate dehydrogenase, phosphotransferase system (PTS) fructose-specific enzyme), while laser irradiation stimulated metabolism through the regulation of transmembrane transporter activity. Further KEGG enrichment analysis of 1891 DEGs in UV-vs-LU sample relationship unveiled 89 genes significantly enriched in the two-component system, which potentially linked to phytochrome. Moreover, analysis of 784 DEGs in UV-vs-UL sample relationship indicated up-regulation of genes associated with translation, replication, and genetic repair pathways, affirming the laser's induction of UV damage repair mechanisms. Subsequently, 9 pivotal genes (liaS, yvfT, yxdK, cheA, ykoW, uvrC, pcrA, recA, and ruvB) were selected for quantitative reverse transcriptional PCR (qRT-PCR) validation, demonstrating consistent trends with transcriptomic data. Conclusively, our findings unveiled interplay mechanism between UV and laser compound mutagenesis at molecular level, offered valuable insights for mutagenesis mode selection and further elucidation of mutagenesis mechanisms.

Synthesis and Structure of Novel Phenothiazine Derivatives, and Compound Prioritization via In Silico Target Search and Screening for Cytotoxic and Cholinesterase Modulatory Activities in Liver Cancer Cells and In Vivo in Zebrafish.

Phenothiazines (PTZ) are antipsychotics known to modulate a variety of neurotransmitter activities that include dopaminergic and cholinergic signaling and have been identified as potential anticancer agents in vitro. However, it is important to also test whether a highly cytotoxic, repurposed, or novel PTZ has low toxicity and neuromodulatory activity in vivo using vertebrate model organisms, such as zebrafish. In this study, we synthesized novel phenothiazines and screened them in vitro in liver cancer and in vivo in zebrafish embryos/larvae. The syntheses of several intermediate PTZ 10-yl acyl chlorides were followed by elemental analysis and determination of 1H NMR and 13C NMR mass (ESI+) spectra of a large number of novel PTZ 10-carboxamides. Cytotoxicities of 28 PTZ derivatives (1-28) screened against Hep3B and SkHep1 liver cancer cell lines revealed five intermediate and five novel leads along with trifluoperazine (TFP), prochlorperazine (PCP), and perphenazine, which are relatively more cytotoxic than the basic PTZ core. Overall, the derivatives were more cytotoxic to Hep3B than SkHep1 cells. Moreover, in silico target screening identified cholinesterases as some of the commonest targets of the screened phenothiazines. Interestingly, molecular docking studies with acetylcholinesterase (AChE) and butyrylcholinesterase proteins showed that the most cytotoxic compounds 1, 3, PCP, and TFP behaved similar to Huprin W in their amino acid interactions with the AChE protein. The highly cytotoxic intermediate PTZ derivative 1 exhibited a relatively lower toxicity profile than those of 2 and 3 during the zebrafish development. It also modulated in vivo the cholinesterase activity in a dose-dependent manner while significantly increasing the total cholinesterase activity and/or ACHE mRNA levels, independent of the liver cancer cell type. Our screen also identified novel phenothiazines, i.e., 8 and 10, with significant cytotoxic and cholinesterase modulatory effects in liver cancer cells; yet both compounds had low levels of toxicity in zebrafish. Moreover, they modulated the cholinesterase activity or expression of ACHE in a cancer cell line-specific manner, and compound 10 significantly inhibited the cholinesterase activity in zebrafish. Accordingly, using a successful combination of in silico, in vitro, and in vivo approaches, we identified several lead anticancer and cholinesterase modulatory PTZ derivatives for future research.

The Chameleon Strategy-A Recipe for Effective Ligand Screening for Viral Targets Based on Four Novel Structure-Binding Strength Indices.

The RNA viruses SARS-CoV, SARS-CoV-2 and MERS-CoV encode the non-structural Nsp16 (2'-O-methyltransferase) that catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to the first ribonucleotide in mRNA. Recently, it has been found that breaking the bond between Nsp16 and SAM substrate results in the cessation of mRNA virus replication. To date, only a limited number of such inhibitors have been identified, which can be attributed to a lack of an effective "recipe". The aim of our study was to propose and verify a rapid and effective screening protocol dedicated to such purposes. We proposed four new indices describing structure-binding strength (structure-binding affinity, structure-hydrogen bonding, structure-steric and structure-protein-ligand indices) were then applied and shown to be extremely helpful in determining the degree of increase or decrease in binding affinity in response to a relatively small change in the ligand structure. After initial pre-selection, based on similarity to SAM, we limited the study to 967 compounds, so-called molecular chameleons. They were then docked in the Nsp16 protein pocket, and 10 candidate ligands were selected using the novel structure-binding affinity index. Subsequently the selected 10 candidate ligands and 8 known inhibitors and were docked to Nsp16 pockets from SARS-CoV-2, MERS-CoV and SARS-CoV. Based on the four new indices, the best ligands were selected and a new one was designed by tuning them. Finally, ADMET profiling and molecular dynamics simulations were performed for the best ligands. The new structure-binding strength indices can be successfully applied not only to screen and tune ligands, but also to determine the effectiveness of the ligand in response to changes in the target viral entity, which is particularly useful for assessing drug effectiveness in the case of alterations in viral proteins. The developed approach, the so-called chameleon strategy, has the capacity to introduce a novel universal paradigm to the field of drugs design, including RNA antivirals.

Global insights into keloid formation: An international systematic review of regional genetic risk factors and commonalities.

Keloid disorder is a morbid and disfiguring benign fibroproliferative disease with a higher incidence in groups with darker skin pigmentation. Predicting keloidogenesis in patients is difficult with treatment primarily aimed at preventing further scar expansion and improving aesthetics without addressing their unknown underlying pathophysiology. We aimed to identify potential genetic predispositions to keloid scarring in the literature. A search was conducted on 21 August 2023, by the first and second authors independently from 1985 to August 2023 using PubMed, MEDLINE, Embase, Web of Science, Scopus and CINAHL. The following MeSH terms were used: 'Keloid', 'Risk' and 'Genetic'. Two researchers independently searched for studies based on titles and abstracts and screened filtered articles by reviewing full text. If no agreement could be reached, a third senior author designated whether the article should be included. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement as the basis of our organisation. Human studies with genetic analysis to determine an association of a protein or gene to keloidogenesis were selected for inclusion. Studies in languages other than English, reviews, conference articles, and book chapters were excluded. Fifty studies met inclusion criteria. The human leukocyte antigen (HLA) system was broadly implicated, and the DRB1*15 allele was associated with an increased risk of keloid in three separate ethnic groups. Some HLA Class I alleles were associated with keloid in one population but not in others. Additionally, polymorphisms in the E3 ubiquitin-protein ligase (NEDD4) signal cascade and vitamin D receptor (VDR) have been implicated in diverse groups. No current genetic test can predict keloid risk. Our review identified candidate predisposing genes, including NEDD4, VDR and components of the HLA system. Further studies in heterogeneous populations are needed to identify reliable screening targets.

Non-target discovery and risk prediction of per- and polyfluoroalkyl substances (PFAS) and transformation products in wastewater treatment systems

Wastewater treatment plants (WWTPs) serve as the main destination of many wastes containing per- and polyfluoroalkyl substances (PFAS). Here, we investigated the occurrence and transformation of PFAS and their transformation products (TPs) in wastewater treatment systems using high-resolution mass spectrometry-based target, suspect, and non-target screening approaches. The results revealed the presence of 896 PFAS and TPs in aqueous and sludge phases, of which 687 were assigned confidence levels 1–3 (46 PFAS and 641 TPs). Cyp450 metabolism and environmental microbial degradation were found to be the primary metabolic transformation pathways for PFAS within WWTPs. An estimated 52.3 %, 89.5 %, and 13.6 % of TPs were believed to exhibit persistence, bioaccumulation, and toxicity effects, respectively, with a substantial number of TPs posing potential health risks. Notably, the length of the fluorinated carbon chain in PFAS and TPs was likely associated with increased hazard, primarily due to the influence of biodegradability. Ultimately, two high riskcompounds were identified in the effluent, including one PFAS (Perfluorobutane sulfonic acid) and one enzymatically metabolized TP (23-(Perfluorobutyl)tricosanoic acid@BTM0024_cyp450). It is noteworthy that the toxicity of some TPs exceeded that of their parent compounds. The results from this study underscores the importance of PFAS TPs and associated environmental risks.

Advances in Computational Methods for Drug Design: A Revolution in Pharmaceutical Development

Computational methods of drug design involve the use of various software and algorithms to predict the properties of drug molecules, screen for potential targets, and optimize drug candidates for therapeutic efficacy, it lowering the cost of drug research and development time. The discovery and development of a novel medicine is a lengthy, complex, expensive, and high-risk process that has no commercial counterpart. CADD has previously been used to uncover drugs that have gone through clinical trials and become innovative medicines for many ailments. CADD approaches are widely divided into two categories: structure-based drug design (SBDD) and ligand-based drug design (LBDD). SBDD is used when the three-dimensional structures of target proteins are available, while LBDD design is used in the absence of receptor 3D information and relies on knowledge of molecules that bind to the biological target of interest. Some applications in CADD are Lead Optimization, Virtual screening (VS), ADMET prediction, and toxicity prediction. Medicinal chemists use a variety of computational approaches to modify the chemical structure of a compound to maximize its in vitro activity, drug discovery is driven by the idea that a ligand with higher binding affinity to a target should be more efficacious than that with lower binding affinity to the same target. Target flexibility is one of the key issues that still need to be resolved in drug discovery. The majority of molecular docking tools give the ligand high flexibility, but they fix or give the protein's residues close to or inside the active site only limited flexibility. It is very difficult to provide complete molecular flexibility to the protein as this increases the space and time complexity of the computation. In conclusion, computational methods have revolutionized the field of drug design by enabling faster, more cost-effective, and more efficient drug discovery

Recent advances in protein precipitation-based methods for drug-target screening

Drug targets are biological macromolecules that bind drug molecules in vivo. Therefore, the system-wide identification of drug targets plays a vital role in fully understanding the mechanism of drug action, efficacy, and side effects. The unbiased screening of drug targets may accelerate the process of drug discovery and candidate screening. Mass spectrometry is a key tool for large-scale protein identification and accurate quantification owing to its high acquisition speed, resolution, and sensitivity. Mass spectrometry-based proteomics has been widely used for drug-target screening. It can systematically identify the protein-target landscape of a drug and elucidate drug-protein interactions. Commonly used drug-target characterization methods, such as labeling-based affinity enrichment, require the chemical derivatization of drug molecules, which is not only time-consuming but may also affect the affinity of the drug towards its targets. Furthermore, the spatial effects of the derivatization groups may block interactions between the drug and its targets. Considering the disadvantages of affinity-enrichment methods, strategies that do not require chemical derivatization have received widespread attention. Proteins may undergo denaturation, unfolding, and precipitation under different conditions such as high temperatures, extreme pH, denaturants, and mechanical stress. Binding to small-molecule drugs may alter the folding balance of target proteins. The conformational stability of target proteins can be stabilized by binding with drugs, and protein-drug complexes are more resistant than free proteins to the precipitation induced by different conditions. Based on this mechanism, various large-scale drug-target identification methods using protein precipitation have been developed by combining proteomics and mass spectrometry analysis, including thermal proteome profiling and solvent-, mechanical stress-, and pH-induced protein precipitation. These methods have been successfully applied to the characterization of small-molecule drug targets. In this review, we describe the protein precipitation-based methods used for the high-throughput discovery of drug targets and elucidation of the interactions between drugs and proteins in the past decade. We also summarize the characteristics of each method and discuss their application potential in drug-efficacy evaluation and drug discovery.

Analysis of factors influencing the recurrence of diabetic foot ulcers.

The aim of this study is to investigate the factors influencing the recurrence of diabetic foot ulcers (DFU) and provide guidance for reducing the recurrence rate. A total of 211 patients diagnosed with DFU who were hospitalized and discharged from the hospital from October 2015 to January 2020 were included as the study cohort. Participants were divided into two groups according to whether the foot ulcer recurred during the 2-year follow-up period: a recurrence group (n=84) and a non-recurrence group (n=127). The following data were collected and analyzed for the two groups of patients: general information, foot information, laboratory indicators, diabetes comorbidities, and complications. (1) The overall recurrence rate of diabetic foot ulcers (DFU) within 2 years was 39.8%, indicating a high recurrence rate. (2) Significant differences were observed between the two patient groups in terms of BMI, HbA1c, TBIL, CRP, financial situation, foot deformity, first ulcer on the sole of the foot, previous amputation history, Wagner grade of the first ulcer, osteomyelitis, DFU duration(>60 days), lower limb vascular reconstruction, peripheral arterial disease (PAD), and diabetic peripheral neuropathy (DPN) (t=2.455; Z=-1.988, -3.731, -3.618; χ2=7.88, 5.004, 3.906, 17.178, 16.237, 5.007, 24.642, 4.782, 29.334, 10.253). No significant differences were found for the other indicators. (3) Logistic regression analysis revealed that TBIL (OR=0.886, p=0.036) was a protective factor against ulcer recurrence. In contrast, PAD, previous amputation history, DPN, and the first ulcer on the sole of the foot (OR=3.987, 6.758, 4.681, 2.405; p<0.05 or p<0.01) were identified as risk factors for ulcer recurrence. Early screening and preventive education targeting high-risk factors such as DPN, PAD and the initial ulcer location on the sole of the foot are essential to mitigate the high long-term recurrence rate of DFU. Furthermore, the protective role of TBIL in preventing ulcer recurrence underscores the importance of monitoring bilirubin levels as part of a comprehensive management strategy for DFU patients.

Correlation Studies Are Essential for Achieving World Health Organization Cervical Screening Targets

Correlation Studies Are Essential for Achieving World Health Organization Cervical Screening Targets

FBLN2 is associated with Goldenhar syndrome and is essential for cranial neural crest cell development.

Goldenhar syndrome, a rare craniofacial malformation, is characterized by developmental anomalies in the first and second pharyngeal arches. Its etiology is considered to be heterogenous, including both genetic and environmental factors that remain largely unknown. To further elucidate the genetic cause in a five-generation Goldenhar syndrome pedigree and exploit the whole-exome sequencing (WES) data of this pedigree, we generated collapsed haplotype pattern markers based on WES and employed rare variant nonparametric linkage analysis. FBLN2 was identified as a candidate gene via analysis of WES data across the significant linkage region. A fbln2 knockout zebrafish line was established by CRISPR/Cas9 to examine the gene's role in craniofacial cartilage development. fbln2 was expressed specifically in the mandible during the zebrafish early development, while fbln2 knockout zebrafish exhibited craniofacial malformations with abnormal chondrocyte morphologies. Functional studies revealed that fbln2 knockout caused abnormal chondrogenic differentiation, apoptosis, and proliferation of cranial neural crest cells (CNCCs), and downregulated the bone morphogenic protein (BMP) signaling pathway in the zebrafish model. This study demonstrates the role of FBLN2 in CNCC development and BMP pathway regulation, and highlights FBLN2 as a candidate gene for Goldenhar syndrome, which may have implications for the selection of potential screening targets and the development of treatments for conditions like microtia-atresia.

Systematically investigate the mechanism underlying the therapeutic effect of Astragalus membranaceus in ulcerative colitis

BackgroundWhether Astragalus membranaceus is an effective drug in treatment of ulcerative colitis (UC) and how it exhibit activity effect on UC is unclear. MethodsTCMSP, GeneCards, String, and DAVID database were used to screening target genes construct PPI network and performed for GO and KEGG pathway enrichment analysis respectively. Molecular docking and animal experiment were performed. The body weight and disease activity index (DAI) of mice were recorded. ELISA kits were used to detect the levels of CAT, SOD, MDA and IL-6, IL-10, TNF-α in the blood of mice. Western blot kits were utilized to measured the expressions of MAPK14, RB1, MAPK1, JUN, ATK1, and IL2 proteins. ResultsThe active components of Astragalus membranaceus mainly including 7-O-methylisomucronulatol, quercetin, kaempferol, formononetin and isrhamnetin. Astragalus membranaceus may inhibited the expression of TNF-α, IL-6, MDA, and promoted the expression of CAT, SOD, IL-10. The expression levels of MAPK14, RB1, MAPK1, JUN and ATK1 proteins were significantly decreased while IL2 protein increased administrated with Astragalus membranaceus. ConclusionsAstragalus membranaceus is an effective drug in treatment of UC according to related to above targets that may exhibits the anti-UC effect via its antioxidant pathway and regulating the balance of pro-inflammatory and anti-inflammatory factors.

One-Step Synthesis and Oriented Immobilization of Strep-Tag II Fused PDGFRβ for Screening Intracellular Domain-Targeted Ligands.

Accurate orientations and stable conformations of membrane receptor immobilization are particularly imperative for accurate drug screening and ligand-protein affinity analysis. However, there remain challenges associated with (1) traditional recombination, purification, and immobilization of membrane receptors, which are time-consuming and labor-intensive; (2) the orientations on the stationary phase are not easily controlled. Herein, a novel one-step synthesis and oriented-immobilization membrane-receptor affinity chromatography (oSOMAC) method was developed to realize high-throughput and accurate drug screening targeting specific domains of membrane receptors. We employed Strep-tag II as a noncovalent immobilization tag fused into platelet-derived growth factor receptor β (PDGFRβ) through CFPS, and meanwhile, the Strep-Tactin-modified monolithic columns are prepared in batches. The advantages of oSOMAC are as follows: (1) targeted membrane receptors can be expressed independent of living cell within 1-2 h; (2) orientation of membrane receptors can be flexibly controlled and active sites can expose accurately; and (3) targeted membrane receptors can be synthesized, purified, and orientation-immobilized on monolithic columns in one step. Accordingly, three potential PDGFRβ intracellular domain targeted ligands: tanshinone IIA (Tan IIA), hydroxytanshinone IIA, and dehydrotanshinone IIA were successfully screened out from Salvia miltiorrhiza extract through oSOMAC. Pharmacological experiments and molecular docking further demonstrated that Tan IIA could attenuate hepatic stellate cells activation by targeting the protein kinase domain of PDGFRβ with a KD value of 9.7 μM. Ultimately, the novel oSOMAC method provides an original insight for accurate drug screening and interaction analysis which can be applied in other membrane receptors.

Effects and Mechanism of Morinda Officinalis How on Metabolism-Associated Fatty Liver Disease.

This study aims to investigate the effects and mechanism of Morinda Officinalis How (MOH), a lianoid shrub with potential therapeutic properties, on Metabolism- Associated Fatty Liver Disease (MAFLD). bjective: The objective of this study was to construct a MOH-MAFLD network prediction model and explore the effect of MOH on MAFLD and its underlying mechanism in vivo. Screening of MAFLD targets was performed using the DisGeNET database. Venny database was used to establish the MOH-MAFLD interaction network map, while the STRING database was applied to assess the Protein-Protein Interaction (PPI) network. The central target gene was screened using Gene Ontology (GO) function analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. GO function enrichment analysis revealed that MOH affected MAFLD through apoptosis and estrogen-related pathways. KEGG pathway enrichment and PPI network analysis indicated that MOH might mitigate MAFLD by reducing apoptosis and improving lipid metabolism. Additionally, 6 weeks of MOH treatment in rats decreased caspase-3 levels and increased Bcl-2, Estrogen receptor α(Esr1), and JUN proteins, thus ameliorating MAFLD progression. MOH could delay the progression of MAFLD by affecting estrogen-related pathways, reducing cell stress, and inhibiting apoptosis.

Screening of Phosphoinositide-3 Kinase Inhibitors from Argemone mexicana Leaves

Background: Phosphoinositide 3 kinase belongs to the enzyme family which is responsible for the development of cellular trafficking and uncontrolled cellular division which in turn to cancer metastasis. Activation of the PI3k-Akt-mTOR pathway tends to promote oncogenesis in Lung Cancer and its mutation leads to resistance in EGFR tyrosine kinase inhibitors. Objective: Inhibition of the initial PI3k receptor through natural bioactive phytocompounds from Argemone mexicana that may prevent the side effects caused by the synthetic medication and improve the patient's life quality as natural medicine. Method: According to the previous research we did the Bioactive phytochemical screening from the methanol extract (AME) and powder (AMP) of A. mexicana leaf by analysing the GC-MS (Agilent), UPLC-QTOF-ESI-MS (Waters India Pvt Limited). Analyzed phytochemicals from the studies were subjected to molecular docking analysis using SeeSAR 9.2 software against PI3K (PDP ID: 4FA6) receptor. Result: GC-MS revealed 40 compounds including Cryptopine (17.5), beta-sitosterol (9.57), and Protopine (8.6) were found as major compounds. LC-MS analysis showed the presence of major compounds with 13 elements compared to the literature survey in both positive and negative ESI ranges. 29 compounds from the GC-MS and LC-MS were selected for analyzing the interaction between the cancer receptor-ligand complex according to the binding strategy. Conclusion: Phytoconstituents such as Galactitol, Succinic acid and N-feruloyltryamine from A. mexicana showed good binding affinity range and maximised hydrogen bonding that may assure possessing anticancer effect by controlling the PI3K pathway. This study would lead a major role in the preliminary screening of Drug Targets against the PI3K receptor.

Unlocking Novel Therapeutic Avenues: Drug Repurposing and Virtual Screening for Breast Cancer Targeting the Estrogen Receptor

This study explores the potential of drug repurposing for breast cancer therapy through virtual screening of Food and Drug Administration (FDA)-approved drugs against breast cancer-related targets. The estrogen receptor alpha ligand-binding domain, a key player in breast cancer progression, served as the primary target for virtual screening. Utilizing the DrugRep Virtual Screening Server and AutoDockVina, several compounds were identified with high binding affinities to the target protein. Notably, estradiol, benzhydrocodone, and ezetimibe emerged as top hits, showcasing diverse physicochemical properties and suggesting novel therapeutic possibilities. The structural fidelity of the estrogen receptor complex was validated through PDB-REDO refinement, enhancing the reliability of the binding interactions predicted. These findings underscore the potential of drug repurposing as a strategy for uncovering new therapeutic options in breast cancer treatment, warranting further biological validation and clinical exploration

Trauma Exposure Moderates the Link Between Cognitive Flexibility and Suicide Risk in Pre-Adolescent Children

Objectives Trauma exposure (TE) and cognitive flexibility (CF) are risk factors for self-injurious thoughts and behaviors (SITBs). However, it is unknown whether these risk factors contribute to mechanisms associated with distinct categories of SITBs. The current study examined the potential moderating role of TE in the relationships between CF and multiple SITBs, including active suicidal ideation (SI), passive SI, non-suicidal self-injury (NSSI), and history of suicide attempt (SA), among pre-adolescent children. Methods A total of 11,326 children from the Adolescent Brain Cognitive Development study were included in the present study. SITBs and TE were measured by the Kiddy Schedule for Affective Disorder and Schizophrenia (KSADS). CF was measured using the NIH Cognitive Toolbox. Results Cumulative TE moderated the relationship of CF to active SI. Higher CF was associated with lower odds of current SI in children with a single lifetime TE, but not in children without trauma or with two or more TE. As a main effect, two or more TE predicted higher odds of active SI, passive SI, and lifetime SA, but not NSSI. Higher CF was associated with lower odds of passive SI, with effects not moderated by trauma exposure. Conclusion The current results clarify previously inconsistent findings about the relationship of CF to SI by identifying cumulative TE as a moderator. CF served as a protective factor against SI, but only in children with a single lifetime trauma. Implications for screening and treatment targets of children at risk for distinct categories of SITBs are discussed.

Investigating the mechanism of Fuling-Banxia-Dafupi in the treatment of diabetic kidney disease using network pharmacology and molecular docking

Go deeply into the molecular mechanism of Fuling-Banxia-Dafupi in the treatment of diabetic kidney disease (DKD) by network pharmacology and molecular docking. Fuling-Banxia-Dafupi is a pair of traditional Chinese medicine for diabetic kidney disease, which can slow down the development of diabetic kidney disease. Screening active components and targets of Fuling-Banxia-Dafupi using the TCMSP database. The Uniprot database was also used to identify effective drug targets. DKD-related Targets were retrieved from the Gene Cards database, and the overlap between these targets and Fuling-Banxia-Dafupi was obtained. GO and KEGG pathway concentration analyses were showed using Metascape, and the results were presented by the microcredit platform. A total of 616 active ingredients and targets were confrimed and intersected with 3,951 diabetic neuropathy-related targets, resulting in 306 common targets. Baicalein and cerevisterol are the core components of Fuling-Banxia-Dafupi, and the key targets are TP53, SRC, and STAT 3. PI3K-Akt signalling pathway is an important pathway. The molecular docking indicated that its main active components and target proteins have good binding activity.

Construction of a ceRNA network and screening of potential biomarkers and molecular targets in male smokers with chronic obstructive pulmonary disease.

Circular RNAs (circRNAs) play an important role in the occurrence and development of diseases. However, the role of circRNAs in male smokers with chronic obstructive pulmonary disease (COPD) remains unclear. Stable COPD patients and healthy controls were recruited. Peripheral blood mononuclear cells (PBMCs) were extracted. After high-throughput RNA sequencing (RNA-Seq) of PBMCs, a bioinformatics method was used to analyse differentially expressed (DE) circRNAs (DEcircRNAs) and mRNAs (DEmRNAs). Total of 114 DEcircRNAs and 58 DEmRNAs were identified. Functional enrichment analysis showed that processes related to COPD include the regulation of interleukin (IL)-18, IL-5 and the NLRP3 inflammasome; differentiation of T helper type 1 (Th1), Th2, and Th17 cells, and the AMPK, Wnt, JAK-STAT, and PI3K-Akt signalling pathways. In the protein-protein interaction (PPI) network, the core genes were MYO16, MYL4, SCN4A, NRCAM, HMCN1, MYOM2, and IQSEC3. Small-molecule prediction results revealed potential drugs for the COPD treatment. Additionally, the circRNA-miRNA-mRNA competitive endogenous RNA (ceRNA) regulatory network was constructed. This study identified a set of dysregulated circRNAs and mRNAs and revealed potentially important genes, pathways, new small-molecule drugs and ceRNA regulatory networks in male smokers with COPD. These circRNAs might be prospective biomarkers or potential molecular targets of the ceRNA mechanism for COPD.