Analysis Of Interactions Research Articles

Management of Islamic Philanthropy-Based Education Financing in Increasing Access to Free Education for Orphans Children

The article describes the management of Islamic philanthropy-based education financing in increasing access to free education for orphans and poor children at the Raudhatul Ulum Islamic boarding school, Sumberanyar Village, Lumajang Regency, East Java. This research uses qualitative research obtained by researchers based on data in the field. The research period starts from December 2023 to February 2024. The data source in this research is primary data obtained through interviews and direct observation with informants. The data analysis steps used in this research are the Interactive Analysis Model from Miles and Huberman: data reduction, data display, and conclusion drawing. Based on the research results after being dialogued with the results of the conceptual study, it can be described as Islamic philanthropy-based education financing management in Islamic boarding schools. Raudhatul Ulum Lumajang Regency includes three activities: planning sources of philanthropy-based education financing (waqf and infaq), allocating and distributing philanthropic fund financing, and monitoring and accountability (auditing) of philanthropic funds.

CircARCN1 aggravates atherosclerosis by regulating HuR-mediated USP31 mRNA in macrophages.

Circular RNAs (circRNAs) are considered important regulators of biological processes, but their impact on atherosclerosis development, a key factor in coronary artery disease (CAD), has not been fully elucidated. We aimed to investigate their potential use in patients with CAD and the pathogenesis of atherosclerosis. Patients with stable angina (SA) or acute coronary syndrome (ACS) and controls were selected for transcriptomic screening and quantification of circRNAs in blood cells. We stained carotid plaque samples for circRNAs and performed gain- and loss-of-function studies in vitro. Western blots, protein interaction analysis, and molecular approaches were used to perform the mechanistic study. ApoE-/- mouse models were employed in functional studies with adeno-associated virus-mediated genetic intervention. We demonstrated elevated circARCN1 expression in peripheral blood mononuclear cells from patients with SA or ACS, especially in those with ACS. Furthermore, higher circARCN1 levels were associated with a higher risk of developing SA and ACS. We also observed elevated expression of circARCN1 in carotid artery plaques. Further analysis indicated that circARCN1 was mainly expressed in monocytes and macrophages, which was also confirmed in atherosclerotic plaques. Our in vitro studies provided evidence that circARCN1 affected the interaction between HuR and ubiquitin-specific peptidase 31 (USP31) mRNA, resulting in attenuated USP31-mediated NF-κB activation. Interestingly, macrophage accumulation and inflammation in atherosclerotic plaques were markedly decreased when circARCN1 was knocked down with adeno-associated virus in macrophages of ApoE-/- mice, while circARCN1 overexpression in the model exacerbated atherosclerotic lesions. Our findings provide solid evidence macrophagic-expressed circARCN1 plays a role in atherosclerosis development by regulating HuR-mediated USP31 mRNA stability and NF-κB activation, suggesting that circARCN1 may serve as a factor for atherosclerotic lesion formation.

Constrained Catalytic Itinerary of a Retaining 3,6-Anhydro-D-Galactosidase, a Key Enzyme in Red Algal Cell Wall Degradation.

The marine Bacteroidota Zobellia galactanivorans has a polysaccharide utilization locus dedicated to the catabolism of the red algal cell wall galactan carrageenan and its unique and industrially important α-3,6-anhydro-D-galactose (ADG) monosaccharide. Here we present the first analysis of the specific molecular interactions the exo-(α-1,3)-3,6-anhydro-D-galactosidase ZgGH129 uses to cope with the strict steric restrictions imposed by its bicyclic ADG substrate - which is ring flipped relative to D-galactose. Crystallographic snapshots of key catalytic states obtained with the natural substrate and novel chemical tools designed to mimic species along the reaction coordinate, together with quantum mechanics/molecular mechanics (QM/MM) metadynamics methods and kinetic studies, demonstrate a retaining mechanism where the second step is rate limiting. The conformational landscape of the constrained 3,6-anhydro-D-galactopyranose ring proceeds through enzyme glycosylation B1,4 → [E4]‡ → E4/1C4 and deglycosylation E4/1C4 → [E4]‡ → B1,4 itineraries limited to the Southern Hemisphere of the Cremer-Pople sphere. These results demonstrate the conformational changes throughout catalysis in a non-standard, sterically restrained, bicyclic monosaccharide and provide a molecular framework for mechanism-based inhibitor design for anhydro-type carbohydrate-processing enzymes and for future applications involving carrageenan degradation. In addition, it provides a rare example of distinct niche-based conformational itineraries within the same carbohydrate-active enzyme family.

Theoretical insights into enantioselective [2 + 1] cyclopropanation reactions of diazo compounds with electron-deficient olefins.

The cyclopropane skeleton plays a significant role in bioactive molecules due to its distinctive structural properties. This has sparked keen interest and in-depth exploration in the field of stereoselective synthesis of cyclopropane derivatives. In the present study, the mechanism and the origin of stereoselectivity of diastereodivergent synthesis of cyclopropane derivatives via the catalyst-free [2 + 1]-cyclopropanation reactions of 3-diazo-N-methylindole (R1) with two types of electron-deficient olefins (R2 and R3) in both aqueous and toluene media have been studied using the DFT calculations. The findings indicate that these [2 + 1] cycloaddition reactions proceed in two stages, where the first step is not only the rate-determining step but also critically dictates the stereoselectivity of the product. The calculated diastereomeric ratios are in agreement with the experimental results. Furthermore, by utilizing non-covalent interaction (NCI) analysis and energy decomposition analysis based on molecular force fields (EDA-FF), we elucidated that the electrostatic interactions between reactant fragments in the transition state TS1s for the first step are the predominant factors determining the stereoselectivity, as opposed to the experimentally hypothesized steric hindrance and π-π stacking interactions. The geometrical structures of all minima and transition states on the potential energy surface (PES) in solvents water and toluene were fully optimized using the DFT method at the M06-2X(D3)/SMD/6-31 + G(d,p) level of theory. Single-point energy calculations were carried out based on the optimized geometries in the solution at the M06-2X(D3)/6-311 + G(d,p) level. All the DFT calculations were performed using the Gaussian 09 software. The optimized molecular structures were visualized using CYLview software. NCI analysis was performed using the Multiwfn and VMD softwares. The Multiwfn program was also used for CDFT and EDA-FF analyses.

Transcriptome profiling reveals dysregulation of inflammatory and protein synthesis genes in PCOS

To analyze the differential expression genes of polycystic ovary syndrome (PCOS), clarify their functions and pathways, as well as the protein–protein interaction network, identify HUB genes, and explore the pathological mechanism. PCOS microarray datasets were screened from the GEO database. Common differentially expressed genes (co-DEGs) were obtained using GEO2R and Venn analysis. Enrichment and pathway analyses were conducted using the DAVID online tool, with results presented in bubble charts. Protein–protein interaction analysis was performed using the STRING tool. HUB genes were identified using Cytoscape software and further interpreted with the assistance of the GeneCards database. A total of two sets of co-DEGs (108 and 102), key proteins (15 and 55), and hub genes (10 and 10) were obtained. The co-DEGs: (1) regulated inflammatory responses and extracellular matrix, TNF, and IL-17 signaling pathways; (2) regulated ribosomes and protein translation, ribosome and immune pathways. The key proteins: (1) regulated inflammation, immunity, transcription, matrix metabolism, proliferation/differentiation, energy, and repair; (2) regulated ubiquitination, enzymes, companion proteins, respiratory chain components, and fusion proteins. The Hub genes: (1) encoded transcription factors and cytokines, playing vital roles in development and proliferation; (2) encoded ribosomes and protein synthesis, influencing hormone and protein synthesis, associated with development and infertility. The dysregulated expression of inflammation and protein synthesis genes in PCOS may be the key mechanism underlying its onset and progression.

Placenta-derived mesenchymal stem cells promote diabetic wound healing via exosomal protein interaction networks.

There is a lack of effective treatment options for diabetic refractory wounds, which presents a critical clinical issue that needs to be addressed urgently. Our research has demonstrated that human placenta-derived mesenchymal stem cells (plaMSCs) facilitate the migration and proliferation of HaCat cells, thereby enhancing diabetic wound healing primarily via the exosomes derived from plaMSCs (plaMSCs-Ex). Using label-free proteomics, plaMSCs and their exosomes were analysed for proteome taxonomic content in order to explore the underlying effective components mechanism of plaMSCs-Ex in diabetic wound healing. Differentially expressed proteins enriched in plaMSCs-Ex were identified and underwent bioinformatics analysis including GO annotation, KEGG pathway enrichment, gene set enrichment analysis (GSEA) and protein-protein interaction analysis (PPI). Results showed that the proteins enriched in plaMSCs-Ex are significantly involved in extracellular matrix organisation, epithelium morphogenesis, cell growth, adhesion, proliferation and angiogenesis. PPI analysis filtered 2 wound healing-related clusters characterised by hub proteins such as POSTN, FN1, SPARC, TIMP1, SERPINE1, LRP1 and multiple collagens. In brief, the exosomal proteins derived from plaMSCs reveal diverse functions of regeneration and tissue remodelling based on proteomics analysis and potentially play a role in diabetic wound healing.

A Fluid–Structure Interaction Analysis to Investigate the Influence of Magnetic Fields on Plaque Growth in Stenotic Bifurcated Arteries

A Fluid–Structure Interaction Analysis to Investigate the Influence of Magnetic Fields on Plaque Growth in Stenotic Bifurcated Arteries

Network Pharmacology Combined with Bioinformatics Analysis to Texplore the Potential Mechanism of Phellodendri Chinensis Cortex Against Bladder Cancer.

The pharmacological mechanism of Phellodendri Chinensis cortex (PCC) against diseases, especially bladder cancer (BC), has never been reported systematically. This study was designed to explore potential mechanism of PCC in treatment of BC. First, we used network pharmacology to discover the potential mechanism of Phellodendri Chinensis cortex and phellodendrine against bladder cancer. Then, we used bioinformatics analysis to verify the correlation between gene expression analysis, survival analysis and common targets. Finally, molecular docking was used to calculate the binding energies of phellodendrine and common targets.A total of 264 targets for PCC were predicted, and 391 BC-related targets were obtained from 4 databases. There were 54 potential targets, 315 biological processes, and 120 signaling pathways involved for PCC against BC. The CDKN2A expression increased and the ESR1, JUN, IL6, AR, and PTGS2 levels decreased in BC according to Gene Expression Profiling Interactive Analysis version 2. The high expression of JUN, MYC, EGFR, and EGF and low expression of VEGFA and PPARG were associated with short overall survival (OS). The high expression of AKT1, EGFR, and EGF and low expression of IL1β were associated with poor disease-free survival (DFS). The search of the intersection of phellodendrine and BC targets yielded 11 common targets, 50 biological processes, and 13 signaling pathways involved. High AURKA and FASN and low ESR1, JUN, ABCB1, and PTGS1 were expressed in BC. The high expression of FASN, ABCC1, PTGS1, JUN, and PIK3CA was associated with short OS, the high expression of PIK3CA and ABCC1 was associated with poor DFS prognosis. Phellodendrine showed a better binding affinity for PTGS2 protein with a docking score of -7.183 and a MM-GBSA result of -46.47 kcal/mol. This study revealed potential mechanism of PCC and phellodendrine against BC through network pharmacology and bioinformatics.

Genome-wide identification and molecular evolution of Dof gene family in Camellia oleifera

DNA binding with one finger(Dof) gene family is a class of transcription factors which play an important role on plant growth and development. Genome-wide identification results indicated that there were 45 Dof genes(ColDof) in C.oleifera genome. All 45 ColDof proteins were non-transmembrane and non-secretory proteins. Phosphorylation site analysis showed that biological function of ColDof proteins were mainly realized by phosphorylation at serine (Ser) site. The secondary structure of 44 ColDof proteins was dominated by random coil, and only one ColDof protein was dominated by α-helix. ColDof genes’ promoter region contained a variety of cis-acting elements, including light responsive regulators, gibberellin responsive regulators, abscisic acid responsive regulators, auxin responsive regulators and drought induction responsive regulators. The SSR sites analysis showed that the proportion of single nucleotide repeats and the frequency of A/T in ColDof genes were the largest. Non-coding RNA analysis showed that 45 ColDof genes contained 232 miRNAs. Transcription factor binding sites of ColDof genes showed that ColDof genes had 5793 ERF binding sites, 4381 Dof binding sites, 2206 MYB binding sites, 3702 BCR-BPC binding sites. ColDof9, ColDof39 and ColDof44 were expected to have the most TFBSs. The collinearity analysis showed that there were 40 colinear locis between ColDof proteins and AtDof proteins. Phylogenetic analysis showed that ColDof gene family was most closely related to that of Camellia sinensis var. sinensis cv.Biyun and Camellia lanceoleosa. Protein-protein interaction analysis showed that ColDof34, ColDof20, ColDof28, ColDof35, ColDof42 and ColDof26 had the most protein interactions. The transcriptome analysis of C. oleifera seeds showed that 21 ColDof genes were involved in the growth and development process of C. oleifera seeds, and were expressed in 221 C. oleifera varieties. The results of qRT-PCR experiments treated with different concentrations NaCl and PEG6000 solutions indicated that ColDof1, ColDof2, ColDof14 and ColDof36 not only had significant molecular mechanisms for salt stress tolerance, but also significant molecular functions for drought stress tolerance in C. oleifera. The results of this study provide a reference for further understanding of the function of ColDof genes in C.oleifera.

Genome-Wide Identification and Characterization of CCT Gene Family from Microalgae to Legumes.

The CCT (CO, COL and TOC1) gene family has been elucidated to be involved in the functional differentiation of the products in various plant species, but their specific mechanisms are poorly understood. In the present investigation, we conducted a genome-wide identification and phylogenetic analysis of CCT genes from microalgae to legumes. A total of 700 non-redundant members of the CCT gene family from 30 species were identified through a homology search. Phylogenetic clustering with Arabidopsis and domain conservation analysis categorized the CCT genes into three families. Multiple sequence alignment showed that the CCT domain contains important amino acid residues, and each CCT protein contains 24 conserved motifs, as demonstrated by the motif analysis. Whole-genome/segment duplication, as well as tandem duplication, are considered to be the driving forces in the evolutionary trajectory of plant species. This comprehensive investigation into the proliferation of the CCT gene family unveils the evolutionary dynamics whereby WGD/segment duplication is the predominant mechanism contributing to the expansion of the CCT genes. Meanwhile, the examination of the gene expression patterns revealed that the expression patterns of CCT genes vary in different tissues and at different developmental stages of plants, with high expression in leaves, which is consistent with the molecular regulation of flowering in photosynthesis by CCT. Based on the protein-protein interaction analysis of CCT genes in model plants, we propose that the CCT gene family synergistically regulates plant development and flowering with light-signaling factors (PHYs and PIFs) and MYB family transcription factors. Understanding the CCT gene family's molecular evolution enables targeted gene manipulation for enhanced plant traits, including optimized flowering and stress resistance.

Moderate capsaicin-containing kochujang alleviates memory impairment through the gut-brain axis in rats with scopolamine-induced amnesia

This study investigated the efficacy and mechanism of traditionally made kochujang(TMK) with different capsaicin levels to alleviate memory impairment in rats with scopolamine-induced amnesia. Sprague-Dawley male rats were administered scopolamine (2 mg/kg bw/day) intraperitoneally to suppress the parasympathetic nervous system(PNS) and induce memory impairment. The rats were divided into four experimental groups, each consuming a diet containing 1 % kochujang in a 43-energy% high-fat diet(HFD) for 8 weeks. The TMK samples used for the study were categorized according to their capsaicin(CPS) content as follows: Low-CPS(0.5 mg%), medium-CPS(1.2 mg%), and high-CPS(1.7 mg%). In addition, factory-made kochujang (FMK; 1.1 mg% capsaicin) was also tested. The effects of kochujang were compared with the Control group(scopolamine), Positive-control(scopolamine+donepezil), and Normal-control(saline) fed HFD. Kochujang consumption reduced body weight and fat mass compared to the Control group. Compared to the Control, memory function measured using passive avoidance, water maze, and novel object recognition tests was enhanced in kochujang-fed rats, especially in the Medium-CPS group, similar to Positive-control. The Medium-CPS and Positive-control groups also exhibited inhibition of hippocampal cell death and increased cholesterol and triglyceride contents and mRNA expression of TNF-α and IL-1β in the brain tissue compared to the Control group. Additionally, TMK elevated short-chain fatty acid, particularly, butyrate concentration in the portal vein. Scopolamine disturbed large intestine cell morphology and gut microbiota composition, and kochujang improved them. Kochujang in the medium-CPS (1.2 mg%) had a more significant impact on the gut microbiota in the interaction analysis between gut microbiota and memory function. In conclusion, kochujang, especially with medium-CPS (1.2 mg%), is a potential dietary intervention to mitigate memory impairment and promote overall cognitive health through improving eubiosis, potentially linked to the gut-brain axis in PNS-suppressed rats.

AI-Powered Microfluidics: Shaping the Future of Phenotypic Drug Discovery.

Phenotypic drug discovery (PDD), which involves harnessing biological systems directly to uncover effective drugs, has undergone a resurgence in recent years. The rapid advancement of artificial intelligence (AI) over the past few years presents numerous opportunities for augmenting phenotypic drug screening on microfluidic platforms, leveraging its predictive capabilities, data analysis, efficient data processing, etc. Microfluidics coupled with AI is poised to revolutionize the landscape of phenotypic drug discovery. By integrating advanced microfluidic platforms with AI algorithms, researchers can rapidly screen large libraries of compounds, identify novel drug candidates, and elucidate complex biological pathways with unprecedented speed and efficiency. This review provides an overview of recent advances and challenges in AI-based microfluidics and their applications in drug discovery. We discuss the synergistic combination of microfluidic systems for high-throughput screening and AI-driven analysis for phenotype characterization, drug-target interactions, and predictive modeling. In addition, we highlight the potential of AI-powered microfluidics to achieve an automated drug screening system. Overall, AI-powered microfluidics represents a promising approach to shaping the future of phenotypic drug discovery by enabling rapid, cost-effective, and accurate identification of therapeutically relevant compounds.

A preliminary investigation of sex differences in cognitive and fMRI changes following 28 days of cannabis abstinence

BackgroundPrevious studies have investigated the influence of cannabis on cognition among people with MS (pwMS), yet the influence of sex in the context of cannabis use remains unexplored. We aim to fill this gap by investigating cannabis-sex related differences in verbal learning, memory and processing speed in association with fMRI (resting state, and task-based) metrics. MethodOur sample consisted of 19 long-term, frequent cannabis users (8 males, 11 females). Assessments were conducted at baseline and after 28 days of cannabis abstinence. The tests included measures of verbal memory (Selective Reminding Test (SRT)), working memory (n-back), information processing speed (Symbol Digit Modalities Test (SDMT)) and the resting state DMN. To evaluate the effects of cannabis abstinence, we performed a group x time interaction analysis using repeated measures ANCOVA. This analysis controlled for several covariates, including the level of disability (EDSS), baseline cannabis THC metabolite levels, and cannabis withdrawal symptoms. By controlling for these variables, we aimed to isolate the impact of cannabis abstinence on cognitive performance over time. Statistical significance was set at p < 0.05. ResultsThere were no baseline cognitive differences between the sexes. After 28 days of cannabis abstinence, females performed better on the Selective Reminding Test (SRT) (p = 0.04), with a large effect size (η² = 0.286). The mean correct response improved over time for females, but there was no statistically significant group x time interaction on the Symbol Digit Modalities Test (SDMT) and the n-back task. Resting state default mode network data showed overall increased activation in females relative to males at day 28, which meshed with lower brain activation during task-based fMRI paradigms. ConclusionCannabis negated sex-based cognitive differences. Functional MRI task-based paradigms revealed less cerebral activation in females compared to males, which was associated with comparable or better cognitive performance in females, particularly after cannabis abstinence.

FlowAtlas: an interactive tool for high-dimensional immunophenotyping analysis bridging FlowJo with computational tools in Julia.

As the dimensionality, throughput and complexity of cytometry data increases, so does the demand for user-friendly, interactive analysis tools that leverage high-performance machine learning frameworks. Here we introduce FlowAtlas: an interactive web application that enables dimensionality reduction of cytometry data without down-sampling and that is compatible with datasets stained with non-identical panels. FlowAtlas bridges the user-friendly environment of FlowJo and computational tools in Julia developed by the scientific machine learning community, eliminating the need for coding and bioinformatics expertise. New population discovery and detection of rare populations in FlowAtlas is intuitive and rapid. We demonstrate the capabilities of FlowAtlas using a human multi-tissue, multi-donor immune cell dataset, highlighting key immunological findings. FlowAtlas is available at https://github.com/gszep/FlowAtlas.jl.git.

A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes. Investigating these genes' functional implications shed light on neurological, thyroidal, bone metabolism, and hematopoietic pathways that necessitate future investigation for blood pressure management that caters to sleep health lifestyle. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausible nature of distinct influences of both sleep duration extremes in cardiovascular health. Several of our loci are specific towards a particular population background or sex, emphasizing the importance of addressing heterogeneity entangled in gene-environment interactions, when considering precision medicine design approaches for blood pressure management.

Spatiotemporal Variation in Ecological Environmental Quality and Its Response to Different Factors in the Xia-Zhang-Quan Urban Agglomeration over the Past 30 Years

The interactions between economic development, environmental sustainability, population growth, and urbanization are vital in assessing the ecological dynamics of urban agglomerations. This study explores the relationship between economic development, environmental sustainability, population growth, and urbanization within the Xia-Zhang-Quan urban agglomeration in Fujian Province from 1989 to 2022. Utilizing Landsat remote sensing images, we calculated the Remote Sensing Ecological Index (RSEI) to evaluate changes in ecological quality. The results show that the average RSEI values for 1989, 2000, 2010, and 2022 were 0.5829, 0.5607, 0.5827, and 0.6195, respectively, indicating an initial decline followed by a significant increase, culminating in an overall upward trend. The spatial distribution of RSEI classification shows that the study area has the largest proportion of mainly “good” ecological quality. The proportion of areas with “excellent” ecological environmental quality has increased (13.41% in 1989 and 25.12% in 2022), while those with “general” quality has decreased (28.03% in 1989 and 21.21% in 2022). Over the past three decades, Xiamen experienced substantial ecological degradation (RSEI change of −0.0897), Zhangzhou showed marked improvement (RSEI change of 0.0519), and Quanzhou exhibited slight deterioration (RSEI change of −0.0396). Central urban areas typically had poorer ecological conditions but showed signs of improvement, whereas non-central urban regions demonstrated significant environmental enhancement. The factor detector analysis identified land use as the dominant factor influencing ecological environmental quality, with precipitation having a relatively minor impact. Interaction analysis revealed that all other factors demonstrated bi-variable enhancement or nonlinear enhancement, suggesting that the interactive effects of these factors are greater than the effects of individual factors alone. Land use consistently showed solid explanatory power. Temperature also exhibited significant influence in 2022 when interacting with other factors. Due to urban planning that can plan for land use, these findings suggest that effective urban planning can harmonize economic development with ecological protection within the Xia-Zhang-Quan urban agglomeration.

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.

Identification and prognostic analysis of metabolic genes associated with TP53 mutation in multiple myeloma

ABSTRACT Background TP53 gene mutation is crucial in determining the prognosis of Multiple Myeloma (MM) patients. Understanding metabolic genes linked to TP53 mutation is vital for developing targeted therapies for these patients. Method We analyzed The Cancer Genome Atlas (TCGA) dataset to identify genes related to TP53 mutation and metabolism. Using univariate Cox regression and protein–protein interaction (PPI) analysis, we identified key genes. We categorized patients into high and low metabolism groups via non-negative matrix factorization (NMF) clustering, which led to the discovery of relevant differential genes. Integrating these with genes from the Gene Expression Omnibus (GEO) datasets and PPI interactions, we pinpointed crucial metabolic genes associated with TP53 mutation in MM. Additionally, we conducted prognostic analyses involving survival curves and receiver operating characteristic (ROC) charts. Results Our study reveals that the metabolic gene ribonucleotide reductase M2 (RRM2), linked to TP53 mutation, correlates positively with the International Staging System (ISS) stage in MM patients and is an independent prognostic risk factor. In the TCGA dataset, among the 767 patients, the 35 MM patients with TP53 mutation generally had poor survival outcomes. Specifically, the patients with both TP53 mutation and high RRM2 expression had a 2-year survival rate of only 38.87%, whereas those with normal TP53 function and low RRM2 expression had a 2-year survival rate of 86.31% (p < 0.001). Conclusion RRM2 significantly impacts MM prognosis and is associated with TP53 mutation, presenting itself as a potential therapeutic target and prognostic marker for MM.

Theoretical exploring of potential mechanisms of antithrombotic ingredients in danshen-chishao herb-pair by network pharmacological study, molecular docking and zebrafish models

BackgroundSalvia miltiorrhiza (Danshen, DS) and Radix Paeoniae Rubra (Chishao, CS) herbal pair (DS-CS) is a famous traditional Chinese combination which has been used as antithrombotic formular for centuries. However, there is still lack of sufficient scientific evidence to illustrate its underlying mechanisms. The purpose of this study is to investigate the antithrombotic effects of DS-CS extract in zebrafish and explore its possible mechanism of action.MethodsThe quality of traditional Chinese medicines DS and CS granules was evaluated using High Performance Liquid Chromatography (HPLC). Subsequently, the therapeutic effect of the DS-CS combination and its components, Salvianolic Acid A (SAA) and Paeoniflorin (PF), in various concentrations on thrombosis was experimentally validated. Moreover, the interaction between DS-CS and the thrombosis disease targets was analyzed through network pharmacology, predicting the potential antithrombotic mechanism of DS-CS. Molecular docking and in vivo zebrafish experiments were conducted to validate the predicted targets, with qRT-PCR utilized for target validation.ResultsDS-CS exhibited anti-thrombotic effect in zebrafish with concentrations ranging from 25 to 300 μg/mL. The co-administration of PF and SAA at 25 μg/mL each revealed a synergistic antithrombotic effect exceeding that of individual components when contrasted with PHZ treatment. Protein–protein interaction (PPI) analysis identified key genes, including Albumin (ALB), Proto-oncogene tyro-sine-protein kinase Src (SRC), Matrix metalloproteinase-9 (MMP9), Caspase-3 (CASP3), Epidermal growth factor receptor (EGFR), Fibroblast growth factor 2 (FGF2), Vascular endothelial growth factor receptor 2 (KDR), Matrix metalloprotein-ase-2(MMP2), Thrombin (F2), and Coagulation factor Xa (F10), associated with the antithrombotic action of PF and SAA. Furthermore, KEGG pathway analysis indicated involvement of lipid metabolism and atherosclerosis pathways. Molecular docking revealed strong binding of PF and SAA to pivotal hub genes, such as SRC, EGFR, and F10. The experimental findings demonstrated that DS-CS could upregulate the mRNA expression levels of EGFR while inhibiting F10 and SRC mRNA levels, thereby ameliorating thrombotic conditions.ConclusionThis research provided valuable insights into the potential mechanisms underlying the antithrombotic activity of DS-CS. Our findings suggested that PF and SAA could be the key active ingredients responsible for this activity. The antithrombotic effects of DS-CS appeared to be mediated through the regulation of mRNA expression of SRC, EGFR, and F10. These results enhanced our understanding of DS-CS's therapeutic potential and lay the groundwork for future studies to further elucidate its mechanisms of action.

An integrated bioinformatics analysis to identify the shared biomarkers in patients with obstructive sleep apnea syndrome and nonalcoholic fatty liver disease.

Obstructive sleep apnea (OSA) syndrome and nonalcoholic fatty liver disease (NAFLD) have been shown to have a close association in previous studies, but their pathogeneses are unclear. This study explores the molecular mechanisms associated with the pathogenesis of OSA and NAFLD and identifies key predictive genes. Using the Gene Expression Omnibus (GEO) database, we obtained gene expression profiles GSE38792 for OSA and GSE89632 for NAFLD and related clinical characteristics. Mitochondrial unfolded protein response-related genes (UPRmtRGs) were acquired by collating and collecting UPRmtRGs from the GeneCards database and relevant literature from PubMed. The differentially expressed genes (DEGs) associated with OSA and NAFLD were identified using differential expression analysis. Gene Set Enrichment Analysis (GSEA) was conducted for signaling pathway enrichment analysis of related disease genes. Based on the STRING database, protein-protein interaction (PPI) analysis was performed on differentially co-expressed genes (Co-DEGs), and the Cytoscape software (version 3.9.1) was used to visualize the PPI network model. In addition, the GeneMANIA website was used to predict and construct the functional similar genes of the selected Co-DEGs. Key predictor genes were analyzed using the receiver operating characteristic (ROC) curve. The intersection of differentially expressed genes shared between OSA and NAFLD-related gene expression profiles with UPRmtRGs yielded four Co-DEGs: ASS1, HDAC2, SIRT3, and VEGFA. GSEA obtained the relevant enrichment signaling pathways for OSA and NAFLD. PPI network results showed that all four Co-DEGs interacted (except for ASS1 and HDAC2). Ultimately, key predictor genes were selected in the ROC curve, including HDAC2 (OSA: AUC = 0.812; NAFLD: AUC = 0.729), SIRT3 (OSA: AUC = 0.775; NAFLD: AUC = 0.750), and VEGFA (OSA: AUC = 0.812; NAFLD: AUC = 0.861) (they have a high degree of accuracy in predicting whether a subject will develop two diseases). In this study, four co-expression differential genes for OSA and NAFLD were obtained, and they can predict the occurrence of both diseases. Transcriptional mechanisms involved in OSA and NAFLD interactions may be better understood by exploring these key genes. Simultaneously, this study provides potential diagnostic and therapeutic markers for patients with OSA and NAFLD.