Enrichment Analysis Of Targets Research Articles

Network pharmacology and molecular docking to explore the potential molecular mechanism of chlorogenic acid treatment of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a tumor type with a high mortality rate. Chlorogenic acid, abundant in resources and widely utilized in cancer treatments, has seen limited studies regarding its efficacy against OSCC. This paper investigates chlorogenic acid's mechanism in treating OSCC, aiming to guide the development of novel drugs. The study employed network pharmacology, molecular docking, and survival analysis methods. Network pharmacological analysis revealed chlorogenic acid targets 23 OSCC-related proteins, including ESR1, MMP2, MMP9, SRC, MAPK8, MAPK1, CDC42, ERBB2, ATM, and BRAF. Molecular docking simulations indicated that the primary target exhibits significant binding capacity with chlorogenic acid, with MMP9 associated with tumor migration and angiogenesis standing out. Survival analysis demonstrated that the downregulation of most primary targets correlates with improved survival rates in OSCC patients. Enrichment analysis of therapeutic targets highlighted the pivotal role of MAPK-ERK and MAPK-JNK signaling pathways in chlorogenic acid's efficacy against OSCC. This paper predicts chlorogenic acid's potential targets and proposes its molecular mechanism in treating OSCC, offering a theoretical foundation for its application in OSCC treatment. We used traditional Chinese medicine, a disease pharmacology-related information base, and an analysis platform to predict targets. The Cytoscape 3.9.1 and STING databases were used to address common targets for drugs and diseases, establish networks of protein interaction relationships, and screen core targets. Meastro11.5 was used for molecular docking simulation. R4.2.2 was used for survival analysis and joint target enrichment analysis. Network pharmacological analysis identified chlorogenic acid acting on 23 OSCC targets. Molecular docking simulations revealed a strong binding affinity of chlorogenic acid compounds with these targets, particularly MMP9, essential for tumor migration and angiogenesis. Survival analysis indicated that the downregulation of most core targets was correlated with improved OSCC patient survival. Enrichment analysis of therapeutic targets highlighted the critical roles of the MAPK-ERK and MAPK-JNK signaling pathways in the effectiveness of chlorogenic acid against OSCC. This study predicted the potential targets of chlorogenic acid in OSCC treatment and hypothesized its molecular mechanism, offering a theoretical foundation for its use in OSCC therapy.

Integrating Network Pharmacology and Experimental Verification to Explore the Pharmacological Mechanisms of Cordycepin against Pulmonary Arterial Hypertension in Rats.

Pulmonary Arterial Hypertension (PAH) is a fatal disease with high morbidity and mortality. Cordycepin has anti-inflammatory, antioxidant and immune enhancing effects. However, the role of Cordycepin in the treatment of PAH and its mechanism is not clear. The Cordycepin structure and PAH-related gene targets were obtained from public databases. The KEGG and GO enrichment analysis of common targets was performed in DAVID. PPI networks were also mapped using the STRING platform. AutoDock Vina, AutoDockTools, ChemBio3D and Pymol tools were selected for molecular docking of key targets. The therapeutic effects of Cordycepin on PAH were observed in Monocrotaline (MCT)-induced PAH rats and platelet-derived growth factor BB (PDGFBB)-induced rat pulmonary artery smooth muscle cells (PASMCs). The right ventricular systolic pressure (RVSP) was detected. HE staining, Western Blot, Scratch assay, EDU and TUNEL assays were used, respectively. Through Network Pharmacology and molecular docking, the Cordycepin-PAH core genes were found to be TP53, AKT1, CASP3, BAX and BCL2L1. In MCT-induced PAH rats, the administration of Cordycepin significantly reduced RVSP, and inhibited pulmonary vascular remodeling. In PDGFBB-induced PASMCs, Cordycepin reduced the migration and proliferation of PASMCs and promoted apoptosis. After the Cordycepin treatment, the protein expressions of TP53, Cleaved CASP3 and BAX were significantly increased, while the protein expressions of p-AKT1 and BCL2L1 were significantly decreased in MCT-PAH rats and PDGFBB-induced PASMCs. This study identified that TP53, AKT1, CASP3, BAX, and BCL2L1 were the potential targets of Cordycepin against PAH by ameliorating pulmonary vascular remodeling, inhibiting the abnormal proliferation and migration of PASMCs and increasing apoptosis of PASMCs. which provided a new understanding of the pharmacological mechanisms of Cordycepin in the treatment of PAH.

Effects of brain microRNAs in cognitive trajectory and Alzheimer’s disease

microRNAs (miRNAs) have a broad influence on gene expression; however, we have limited insights into their contribution to rate of cognitive decline over time or Alzheimer’s disease (AD). Given this, we tested associations of 528 miRNAs with cognitive trajectory, AD hallmark pathologies, and AD clinical diagnosis using small RNA sequencing from the dorsolateral prefrontal cortex of 641 community-based donors. We found 311 miRNAs differentially expressed in AD or its endophenotypes after adjusting for technical and sociodemographic variables. Among these, 137 miRNAs remained differentially expressed after additionally adjusting for several co-occurring age-related cerebral pathologies, suggesting that some miRNAs are associated with the traits through co-occurring pathologies while others through mechanisms independent from pathologies. Pathway enrichment analysis of downstream targets of these differentially expressed miRNAs found enrichment in transcription, postsynaptic signalling, cellular senescence, and lipoproteins. In sex-stratified analyses, five miRNAs showed sex-biased differential expression for one or more AD endophenotypes, highlighting the role that sex has in AD. Lastly, we used Mendelian randomization to test whether the identified differentially expressed miRNAs contribute to the cause or are the consequence of the traits. Remarkably, 15 differentially expressed miRNAs had evidence consistent with a causal role, laying the groundwork for future mechanistic studies of miRNAs in AD and its endophenotypes.

Exploration of anti-atherosclerotic activity of 1,8-cineole through network pharmacology, molecular docking, and in vivo efficacy studies in high-fat-diet-induced atherosclerosis in hamsters.

The anti-atherogenic potential of liver X receptors (LXRs) has been attributed to their inhibitory role in macrophage-mediated inflammation and promotion of reverse cholesterol transport. This study aimed to evaluate the efficacy of an LXR agonist, 1,8-cineole (Eucalyptol), in atherosclerosis through network pharmacology, molecular docking, and in vivo efficacy studies in high-fat-diet-induced atherosclerosis in hamsters. Network pharmacology analysis was performed by identifying potential targets of 1,8-Cineole and atherosclerosis, followed by the construction of component-target-disease and protein-protein interaction networks. Gene Ontology and KEGG pathway enrichment analysis of targets were performed. The top 5 targets were selected for molecular docking studies. Atherosclerosis was induced in male Golden Syrian hamsters, and the results of network pharmacology were verified. Fifty-one overlapped targets were identified for 1,8-cineole and atherosclerosis. In the protein-protein interaction studies, the top 5 ranked proteins were PPARG, FXR, ABCA-1, ABCG1, and LXRΑ. KEGG pathway analysis and molecular docking showed that ABCA-1 and LXRΑ were correlated in atherosclerosis. Animal studies showed amelioration of atherosclerotic lesions in the aorta of animals treated with 1,8-cineole compared to disease control aortas. A dose-dependent attenuation in ABCA-1 levels and inflammatory markers was observed in animals treated with 1,8-cineole, comparable to its levels in normal animals. In conclusion, 1,8-cineole showed anti-atherosclerotic effects in Golden Syrian hamsters via LXRΑ-induced ABCA-1 overexpression.

Exploring the Mechanism of Comfrey in Lung Cancer Based on Network Pharmacology and Molecular Docking

Network pharmacology was used to investigate the active ingredients and mechanism of action of the Chinese medicine comfrey in lung cancer. Comfrey constituents and their targets were collected by searching the TCMSP and PubChem databases. The Gene Cards database was searched to extract target information for lung cancer. Based on the STRING database, Cytoscape 3.9.1 software was used to construct the PPI network of common targets of comfrey in lung cancer. We searched for common targets and performed GO and KEGG pathway enrichment analyses to build a 'network diagram' of TCM active ingredient-disease targets. The results of the pharmacological network analysis showed that after the screening, 12 compounds and 904 drug targets were obtained, and 147 drug-disease common targets were obtained, with AKT1, EGFR, TNF, and CASP3 as the core targets. After enrichment analysis of the above key targets, it was found that cancer pathways, prostate cancer, PI3K-Akt signaling pathway, endocrine resistance, and cancer proteoglycans were involved in the treatment of comfrey. The molecular docking results also showed that the comfrey compounds had good binding activities with the key targets, proving the accuracy of the network pharmacological prediction results. The results of this experiment provisionally verified the basic pharmacological effects of comfrey and its mechanism of action against lung cancer and provided directions for further research.

Differential expression of microRNAs in giant freshwater prawn (Macrobrachium rosenbergii) during the infection of Vibrio parahaemolyticus

MicroRNAs (miRNAs) are a category of small non-coding RNAs regarded as vital regulatory factors in various biological processes, especially immune regulation. The differently expressed miRNAs in Macrobrachium rosenbergii after the challenge of Vibrio parahaemolyticus were identified using high-throughput sequencing. A total of 18 known as well as 12 novel miRNAs were markedly differently expressed during the bacterial infection. The results of the target gene prediction and enrichment analysis indicated that a total of 230 target genes involved in a large variety of signaling pathways and biological processes were mediated by the miRNAs identified in the current research. Additionally, the effects of novel-miR-56, a representative differentially expressed miRNA identified in the previous infection experiment, on the immune-related gene expression in M. rosenbergii were explored. The expression of the immune-related genes including Spätzle1(Spz1), Spz4, Toll-like receptor 1 (TLR1), TLR2, TLR3, immune deficiency (IMD), myeloid differentiation factor 88 (MyD88), anti-lipopolysaccharide factor 1 (ALF1), crustin1, as well as prophenoloxidase (proPO) was significantly repressed in the novel-miR-56-overexpressed prawns. The expression of these genes tested in the novel-miR-56-overexpressed M. rosenbergii was still signally lower than the control in the subsequent V. parahaemolyticus challenge, despite the gene expression in each treatment increased significantly after the infection. Additionally, the cumulative mortality of the agomiR-56-treated prawns was significantly higher than the other treatments post the bacterial challenge. These results suggested that novel-miR-56 might function as a negative regulator of the immune-related gene expression of M. rosenbergii in the innate immune defense against V. parahaemolyticus.

Pharmacological mechanisms of Taohe Chengqi decoction in diabetic cardiovascular complications: A systematic review, network pharmacology and molecular docking

BackgroundDiabetic cardiovascular complications are the leading cause of diabetes-related deaths. These complications place an enormous and growing burden on global health systems and economies. The objective of this study was to conduct a systematic review on the therapeutic mechanisms of Taohe Chengqi Decoction (THCQD) in the treatment of diabetic cardiovascular complications. To predict the potential mechanisms of action of THCQD on diabetic cardiovascular complications using network pharmacology, and to validate these predictions through molecular docking analysis. MethodsTo collect relevant animal experiments, we searched a total of 6 databases. Eligibility for the study was determined based on inclusion and exclusion criteria. Data extraction was then performed on the literature. Methodological quality of animal studies was assessed using SYRCLE criteria. Based on network pharmacology, intersecting genes for THCQD and diabetic cardiovascular complications were obtained using Venny, PPI analysis and topology analysis of intersecting genes were performed; GO and KEGG were used for enrichment analysis and prediction of new targets of action. Molecular docking techniques were employed to model the interactions between drug components and target genes, thereby validating the results of network pharmacology predictions. ResultsA total of 16 studies were finally identified that fit the direction of this review. Included 6 studies of the myocardium, 1 study of the aortic arch, 5 studies of the femoral artery, 4 studies of the thoracic aorta. THCQD exhibited anti-inflammatory, anti-fibrotic and anti-atherosclerotic effects on cardiovascular complications in diabetic rats. Network pharmacology results showed that C0363 (Resveratrol), C0041 (Emodin), and C1114 (Baicalein) were the key components in the treatment of diabetic cardiovascular complications by THCQD. PPI results showed that INS, AKT1, TNF, ALB, IL6, IL1B as the genes that interact with the top 6. KEGG enrichment analysis identified the AGE-RAGE signaling pathway in diabetic complications as the most prominent pathway enriched by THCQD for diabetic cardiovascular complications genes. The results of molecular docking showed that the key active components demonstrated favorable interactions with their corresponding target genes. ConclusionIn conclusion, the results of both basic and web-based pharmacological studies support the beneficial effects of the natural herbal formulation THCQD on diabetic cardiovascular complications. This decoction has anti-inflammatory and antifibrotic properties and is effective in ameliorating diabetic cardiovascular disease. The network pharmacology results further support these ideas and identify the AGE-RAGE signaling pathway in diabetic complications as possibly the most relevant pathway for THCQD in the treatment of diabetic cardiovascular complications. The extent of the therapeutic potential of all-natural herbal components in the treatment of diabetic cardiovascular disease merits further investigation.

Maize miRNAs and their putative target genes involved in chilling stress response in 5-day old seedlings

BackgroundIn the context of early sowing of maize as a promising adaptation strategy that could significantly reduce the negative effects of climate change, an in-depth understanding of mechanisms underlying plant response to low-temperature stress is demanded. Although microRNAs (miRNAs) have been recognized as key regulators of plant stress response, research on their role in chilling tolerance of maize during early seedling stages is scarce. Therefore, it is of great significance to explore chilling-responsive miRNAs, reveal their expression patterns and associated target genes, as well as to examine the possible functions of the conserved and novel miRNAs. In this study, the role of miRNAs was examined in 5d-old maize seedlings of one tolerant and one sensitive inbred line exposed to chilling (10/8 °C) stress for 6 h and 24 h, by applying high throughput sequencing.ResultsA total of 145 annotated known miRNAs belonging to 30 families and 876 potentially novel miRNAs were identified. Differential expression (DE) analysis between control and stress conditions identified 98 common miRNAs for both genotypes at one time point and eight miRNAs at both time points. Target prediction and enrichment analysis showed that the DE zma-miR396, zma-miR156, zma-miR319, and zma-miR159 miRNAs modulate growth and development. Furthermore, it was found that several other DE miRNAs were involved in abiotic stress response: antioxidative mechanisms (zma-miR398), signal transduction (zma-miR156, zma-miR167, zma-miR169) and regulation of water content (zma-miR164, zma-miR394, zma-miR396). The results underline the zma-miRNAs involvement in the modulation of their target genes expression as an important aspect of the plant’s survival strategy and acclimation to chilling stress conditions.ConclusionsTo our understanding, this is the first study on miRNAs in 5-d old seedlings’ response to chilling stress, providing data on the role of known and novel miRNAs post-transcriptional regulation of expressed genes and contributing a possible platform for further network and functional analysis.

On the mechanism of wogonin against acute monocytic leukemia using network pharmacology and experimental validation

Wogonin is a natural flavone compound from the plant Scutellaria baicalensis, which has a variety of pharmacological activities such as anti-cancer, anti-virus, anti-inflammatory, and immune regulation. However, the potential mechanism of wogonin remains unknown. This study was to confirm the molecular mechanism of wogonin for acute monocytic leukemia treatment, known as AML-M5. The potential action targets between wogonin and acute monocytic leukemia were predicted from databases. The compound-target-pathway network and protein-protein interaction network (PPI) were constructed. The enrichment analysis of related targets and molecular docking were performed. The network pharmacological results of wogonin for AML-M5 treatment were verified using the THP-1 cell line. 71 target genes of wogonin associated with AML-M5 were found. The key genes TP53, SRC, AKT1, RELA, HSP90AA1, JUN, PIK3R1, and CCND1 were preliminarily found to be the potential central targets of wogonin for AML-M5 treatment. The PPI network analysis, GO analysis and KEGG pathway enrichment analysis demonstrated that the PI3K/AKT signaling pathway was the significant pathway in the wogonin for AML-M5 treatment. The antiproliferative effects of wogonin on THP-1 cells of AML-M5 presented a dose-dependent and time-dependent manner, inducing apoptosis, blocking the cell cycle at the G2/M phase, decreasing the expressions of CCND1, CDK2, and CyclinA2 mRNA, as well as AKT and p-AKT proteins. The mechanisms of wogonin on AML-M5 treatment may be associated with inhibiting cell proliferation and regulating the cell cycle via the PI3K/AKT signaling pathway.

Research hotspots and evolving trends of barrier dysfunction in acute lung injury and acute respiratory distress syndrome

Endothelial and epithelial barrier dysfunction due to increased permeability and heightened inflammatory reactions influences the emergence of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Nevertheless, bibliometric research comparing endothelial and epithelial barriers is limited. Therefore, this bibliometric study analyzed the Web of Science Core Collection (WoSCC) of the Science Citation Index Expanded literature to explore present research priorities and development tendencies within this field. We conducted a comprehensive search (October 18, 2023) on WoSCC from January 1, 2010, to October 18, 2023, focusing on articles related to endothelial and epithelial barriers in ALI and ARDS. Retrieved data were visualized and analyzed using R-bibliometrix, VOS viewer 1.6.19, and CiteSpace 6.2. R4. Functional enrichment analysis of gene targets identified in the keyword list using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene ontology databases, and based on the STRING database to construct a PPI network to predict core genes. A total of 941 original articles and reviews were identified. The United States had the highest number of publications and citations and the highest H-index and G-index. According to the Collaboration Network Analysis graph, the United States and China had the strongest collaboration. Birukova AA had the most publications and citations among all authors, while eight of the top ten institutions with mediator centrality were located in the United States. The American Journal of Physiology-Lung Cellular and Molecular Physiology was the leading journal and had the most well-established publication on endothelial and epithelial barriers in ALI and ARDS. Bibliometric analysis revealed that the most frequently used keywords were acute lung injury, ARDS, activation, expression, and inflammation. RHOA appeared most frequently among gene-related keywords, and the PI3K-AKT signaling pathway had the highest count in KEGG pathway enrichment. Research on endothelial versus epithelial barriers in ALI and ARDS remains preliminary. This bibliometric study examined cooperative network connections among countries, authors, journals, and network associations in the cited references. Investigation of the functions of the endothelial and epithelial barriers in ALI/ARDS associated with COVID-19 has recently gained significant attention.

Exploring the mechanism of Tingli Pill in the treatment of HFpEF based on network pharmacology and molecular docking.

To explore the mechanism of action of Tingli Pill (TLP) in the treatment of heart failure with preserved ejection fraction (HFpEF) by using network pharmacology and molecular docking technology. The active components and targets of TLP were screened using the TCMSP and UniProt databases. HFpEF-related targets were identified using the OMIM and GeneCards databases. Drug-disease intersection targets were obtained via Venny 2.1.0, as well as establishing the "component-target" network and screening out the core active components. Construct a protein-protein interaction network of intersecting targets using the STRING database as well as Cytoscape software and filter the core targets. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis of core targets were performed using the Metascape database. The core active components of TLP for HFpEF were quercetin, kaempferol, β-sitosterol, isorhamnetin and hederagenin. The core targets of TLP for HFpEF were JUN, MAPK1, TP53, AKT1, RELA, TNF, MAPK14, and IL16. Gene ontology enrichment analysis obtained 1528 biological processes, 85 cell components, and 140 molecular functions. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis yielded 1940 signaling pathways, mainly involved in lipid and atherosclerosis, regulation of apoptotic signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, oxidative stress, TNF signaling pathway, and IL-17 signaling pathway. TLP has the characteristics of multi-component, multi-target, and multi-pathway in the treatment of HFpEF. This study lays the foundation for revealing the pharmacodynamic substances and mechanism of TLP in the treatment of HFpEF.

Network pharmacology integrated molecular docking of fucoidan against oral cancer and in vitro evaluation- A study using GEO datasets

Oral cancer is a widespread health concern in rural India due to a lack of awareness, delayed diagnosis and limited access to affordable treatment options. The current chemotherapy has notable side effects, underscoring the need for new drug candidates with improved bioavailability and specificity. In this current research, fucoidan, a sulphated polysaccharide, was extracted from the brown algae Spatoglossum asperum, and shown to be cytotoxic in vitro against oral cancer cells (KB cell line) at an IC50 of 107.76 µg/ml, suggesting its potential as a drug candidate. This study further aimed to explore the potential therapeutic implications of fucoidan in managing oral cancer using network pharmacology. PharmMapper, Comparative Toxicogenomics Database and SuperPred were initially used to identify fucoidan protein targets. The identified targets were further screened against Gene Expression Omnibus (GSE23558, GSE25099 and GSE146483), OMIM, TCGA and GeneCards datasets to identify oral cancer-specific protein targets. The interactions between the selected proteins were visualised using STRING and Cytoscape. Subsequently, Database for Annotation, Visualization and Integrated Discovery was used for gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of candidate targets. The cancer-related network was assessed using CancerGeneNet, while life expectancy based on the expression of the top 10 CytoHubba ranked hub genes was evaluated using Kaplan-Meier plots. Finally, EGFR, AKT1, HSP90AA1 and SRC were selected for docking and molecular dynamics simulation with fucoidan, using Maestro and GROMACS, respectively. Communicated by Ramaswamy H. Sarma

Uncovering the Mechanism of Chinese Hawthorn Leaf on Myocardial Ischemia Based on Network Pharmacology, Molecular Docking Verification, and In Vitro Studies.

Hawthorn leaf has shown therapeutic effects in the patients with myocardial ischemia. Our study combines network pharmacology, molecular docking techniques, and in vitro experimentwith the aim of revealing the mechanism of hawthorn leaves in the treatment of myocardial ischemia. The active ingredients and corresponding targets of hawthorn leaf through Traditional Chinese Medicine System Pharmacology and Swiss Target Prediction databases. Targets related to myocardial ischemia were retrieved by Gene Card, Online Mendelian Inheritance in Man, Disgenet, and Therapeutic Targets Database databases. Cytoscape software was used to construct an ingredient-target-organ network and enrichment analysis of common targets was analyzed. Molecular docking verification of the core compound and target interactions was performed using MOE software. In vitro cell experiment was performed to verify the findings from bioinformatics analysis. Six active components and 107 potential therapeutic targets were screened. The protein-protein interaction network analysis indicated that 10 targets, including AKT1 and EGFR, were hub genes. Quercetin, kaempferol and isorhamnetin were taken as core active components. Through pathway enrichment analysis, nearly 455 Gene Ontology entries and 77 Kyoto Encyclopedia of Genes and Genomes pathways were obtained, mainly including PI3K/Akt, estrogen and other signaling pathways. Molecular docking prediction showed that three main active ingredients were firmly combined with the core targets. Cellular experiments showed that quercetin alleviated oxidative damage in cells and regulated the expression of PI3K, P-AKT/AKT and Bax/Bcl-2 proteins. This study identified the potential targets of Hawthorn leaf against myocardial ischemia using network pharmacology and in vitro verification, which provided a new understanding of the pharmacological mechanisms of Hawthorn leaf in treatment of myocardial ischemia.

Danggui-Shaoyao-San (DSS) ameliorates the progression of osteoarthritis via suppressing the NF-κB signaling pathway: an in vitro and in vivo study combined with bioinformatics analysis.

Osteoarthritis (OA) is a common chronic age-related joint disease characterized primarily by inflammation of synovial membrane and degeneration of articular cartilage. Accumulating evidence has demonstrated that Danggui-Shaoyao-San (DSS) exerts significant anti-inflammatory effects, suggesting that it may play an important role in the treatment of knee osteoarthritis (KOA). In the present study, DSS was prepared and analyzed by high-performance liquid chromatography (HPLC). Bioinformatics analyses were carried out to uncover the functions and possible molecular mechanisms by which DSS against KOA. Furthermore, the protective effects of DSS on lipopolysaccharide (LPS)-induced rat chondrocytes and cartilage degeneration in a rat OA model were investigated in vivo and in vitro. In total, 114 targets of DSS were identified, of which 60 candidate targets were related to KOA. The target enrichment analysis suggested that the NF-κB signaling pathway may be an effective mechanism of DSS. In vitro, we found that DSS significantly inhibited LPS-induced upregulation of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP3), and matrix metalloproteinase-13 (MMP13). Meanwhile, the degradation of collagen II was also reversed by DSS. Mechanistically, DSS dramatically suppressed LPS-induced activation of the nuclear factor kappa B (NF-κB) signaling pathway. In vivo, DSS treatment prevented cartilage degeneration in a rat OA model. DSS could ameliorate the progression of OA through suppressing the NF-κB signaling pathway. Our findings indicate that DSS may be a promising therapeutic approach for the treatment of KOA.

Comprehensive Investigation of m6A Regulators for Prognosis in Head and Neck Squamous Cell Carcinoma.

The early detection of head and neck squamous cell carcinoma (HNSCC) has an important impact on the clinical prognosis. N6-methyladenosine (m6A) is involved in the post-transcriptional regulation of tumorigenesis and development. In this study, the prognosis and biological functions of m6A regulator targets in HNSCC were explored. RNA-Seq expression data and clinical information from TCGA-HNSCC and GSE23036 datasets were collected. The mRNA levels of IGF2BP2 and IGF2BP3 in tumor tissues were significantly up-regulated. Differential expression and functional enrichment analysis of potential targets for IGF2BP2 and IGF2BP3 obtained from the m6A2Target database showed that they were significantly enriched in cell cycle-related pathways. The Cox regression analysis was performed to establish a three-mRNA signature including PLAU, LPIN1 and AURKA. The prognostic effect was verified in the external dataset GSE41613. Further studies revealed that the three-mRNA signature was significantly associated with survival in the clinical subgroup. The ROC curve, Harrell consistency index and decision curve comparison used to compare the predictive effect of the three-mRNA signature and the other signatures in previous studies showed that the three-mRNA signature had better predictive effect on the prognosis of HNSCC patients. The three-mRNA signature expression were verified in HNSCC cell lines with qRT-PCR and Western blot. Sequence analysis showed that m6A-modification sites existed on PLAU, LPIN1 and AURKA genes. In conclusion, the three-mRNA signature has been proved to be useful on evaluating the prognosis and contributing to the personalized treatment of HNSCC, and IGB2BP2/3 were related to the cell cycle in HNSCC.

Silver Nanoparticles (AgNPs) Uptake by Caveolae-Dependent Endocytosis is Responsible for Their Selective Effect Towards Castration Resistant Prostate Cancer.

Castration Resistant Prostate Cancer (CRPC) is characterized by poor prognosis and limited therapeutic options. AgNPs functionalized with glucose (G-AgNPs) were observed cytotoxic to CRPC cell lines (PC-3 and Du-145) and not LNCaP. This study aims to evaluate AgNPs and G-AgNPs' uptake mechanisms in these cells and understand their role in the selective effect against CRPC cells. Uptake of AgNPs and G-AgNPs was assessed through transmission electron microscopy (TEM). A microRNA (miRNAs) analysis approach was used to uncover the main molecular differences responsible for the endocytic mechanisms' regulation. Caveolin (Cav) 1 and 2 mRNA and protein levels were assessed in the three cell lines. Caveolae-dependent endocytosis was inhibited with genistein or siCav1- and siCav2- in PC-3 and Du-145 and resazurin assay was used to evaluate viability after AgNPs and G-AgNPs administration. Caveolae-dependent endocytosis was induced with Cav1+ and Cav2+ plasmids in LNCaP, resazurin assay was used to evaluate viability after AgNPs and G-AgNPs administration and TEM to assess their location. AgNPs and G-AgNPs were not uptaked by LNCaP. miRNA analysis revealed 37 upregulated and 90 downregulated miRNAs. Functional enrichment analysis of miRNAs' targets resulted in enrichment of terms related to endocytosis and caveolae. We observed that Cav1 and Cav2 are not expressed in LNCaP. Inhibiting caveolae-dependent endocytosis in Du-145 and PC-3 led to a significative reduction of cytotoxic capacity of AgNPs and G-AgNPs and induction of caveolae-dependent endocytosis in LNCaP lead to a significative increase as well as their uptake by cells. This study shows the potential of these AgNPs as a new therapeutic approach directed to CRPC patients, uncovers caveolae-dependent endocytosis as the uptake mechanism of these AgNPs and highlights deregulation of Cav1 and Cav2 expression as a key difference in hormone sensitive and resistant PCa cells which may be responsible for drug resistance.

In silico prioritiziation of drug repositioning candidates for Alzheimer’s disease using signature search meta‐analysis

AbstractBackgroundAlzheimer’s disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder with no effective treatment. Due to the genetic, pathological, and clinical heterogeneity among patients with AD, traditional drug development has struggled to target AD‐related pathways. Drug repositioning is a promising alternative to de novo drug development that investigates the potential of existing drugs to be effective in AD. Transcriptome signature matching is one repositioning approach that relies on the signature reversion principle to identify candidate drugs. In this study, we report on several potential candidate drugs for AD obtained by meta‐analyzing transcriptome‐based signature search methods on AMP‐AD nominated target genes for AD that are differentially expressed across seven brain regions.MethodAs search input, we used genes that are nominated as AD targets by the AMP‐AD initiative and significantly differentially expressed in at least one brain region. We compared their expression signatures against the CMAP and LINCS reference databases via four signature search methods (CMAP, LINCS, gCMAP, and correlation‐based methods). Significant candidate drugs were ranked based on their score for each search method and then meta‐analyzed using an ensemble rank aggregation approach employing a modified version of the Dowdall rule. Top‐scoring candidate drugs for AD were annotated using literature search and functional enrichment analysis results.ResultHighest‐scoring drugs in the meta‐analysis included psycholeptics and psychoanaleptics (including acetylcholinesterase inhibitors), antibiotics, antivirals, histone deacetylase (HDAC) inhibitors, and anti‐inflammatory agents. Among those were drugs that are already used for symptomatic treatment of AD or are currently investigated in clinical trials. Novel candidate drugs reported here include antipsychotics, corticosteroids, and calcium channel blockers. Functional enrichment analysis of known targets of these candidate drugs showed shared targeting of biological processes related to dopaminergic synaptic transmission, calcium ion transport regulation, and alkaloid metabolic processConclusionGene expression signature matching is a promising approach for in silico drug repositioning. Our results describe several novel potential candidate drugs for AD obtained through the signature reversion principle, demonstrating the utility of meta‐analyzing data across brain regions and signature search strategies in prioritizing drug repositioning candidates for AD.

Network pharmacology-based research on the effect of Scutellaria baicalensis on osteosarcoma and the underlying mechanism.

To explore the anti-tumor effects of Scutellaria baicalensis on osteosarcoma and its mechanism. Network pharmacology and molecular docking techniques were applied to investigate the effect and mechanism of Scutellaria baicalensis on osteosarcoma (OS). We analyzed the protein-protein interaction (PPI) network for potential targets of Scutellaria baicalensis for treating osteosarcoma and identified hub targets. We used KM curves to screen for hub targets that could effectively prolong the survival time of OS patients. We systematically performed gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis of the Scutellaria baicalensis potential targets and predicted the Scutellaria baicalensis molecular mechanism and function in treating osteosarcoma. Through molecular docking, the binding process between the hub targets, which could prolong the survival time of sarcoma patients, and Scutellaria baicalensis was simulated. PPI network analysis of potential therapeutic targets discriminated 12 hub targets. The KM curves of the hub targets showed that upregulation of RXRA, RELA, ESR1, TNF, IL6, IL1B, and RB1 expression, and downregulation of MAPK1, VEGFA, MAPK14, CDK1, and PPARG expression were effective in improving the 5-year survival rate of OS patients. GO and KEGG enrichment demonstrated that Scutellaria baicalensis regulated multiple signaling pathways of OS. Molecular docking results indicated that Scutellaria baicalensis could bind freely to the above hub target, which could prolong the survival time of sarcoma patients. Scutellaria baicalensis acted on osteosarcoma by regulating a signaling network formed by hub targets connecting multiple signaling pathways. Scutellaria baicalensis appears to have the potential to serve as a therapeutic drug for osteosarcoma and to prolong the survival of OS patients.

Exploring the pharmacological mechanism of Xianlian Jiedu decoction in the treatment of colorectal Cancer based on network pharmacology, molecular docking and experimental validation

BackgroundXianlian Jiedu Decoction (XLJDD) is a clinical effective prescription for the treatment of colorectal cancer (CRC) for several decades. However, the effective mechanism and targets of action of XLJDD are still unclear. This study aims to discover the pharmacological mechanism of XLJDD by employing a combination of network pharmacology, molecular docking and in vitro and in vivo experimental validation. MethodsMultiple databases, including TCMSP, Swiss Target Prediction, Drugbank, Geencards, Malacards, Therapeutic Target Database (TTD) and Disgenet, were searched and identified the targets of ingredients from XLJDD and the targets associated with CRC. The common targets of ingredients and disease were analyzed, and the visualization network of protein-protein interaction (PPI) were constructed using STRING database and to identified the core targets based on Cytoscape software. Metascape database was employed for GO and KEGG enrichment analysis of common targets. The active ingredients of XLJDD and core targets were verified through molecular docking test. Subsequently, in vitro and in vivo experiments were performed to validate the analysis results using CT-26 and HCT116 cell lines and AOM/DSS mice model. ResultsA total of 36 active components and 122 targets were identified for XLJDD, while 1728 targets associated with CRC were obtained. Among them, there were 71 common targets between ingredients and disease. And 19 core targets (AKT1, TNF, PTGS2, CASP3, EGFR, ESR1, MMP9, IL1B, CCND1, PPARG, ERBB2, SIRT1, MMP2, BCL2L1, MAPK1, PPARA, PGR, AR and SERPINE1.) were finally screened from PPI network. GO analysis enriched a total of 99 entries, with 74 related to biological processes, 20 to molecular functions, and 5 to cellular components. The KEGG enrichment pathway analysis demonstrated that the biological discrepancy was mainly focused on the tumorigenesis-, inflammation-, and mechanism-related pathways. Molecular docking presented the great bonding ability of 19 key targets with 17 active constituents. Experiments based on CT-26 and HCT116 cells verified that XLJDD could inhibit the proliferation of colorectal cancer cells. In addition, XLJDD inhibited tumor progression in mice. Finally, the results of molecular biology experiments showed that XLJDD could activate the colorectal cancer-related PTEN/AKT/FoXO1 pathway, and up-regulate the expression levels of key genes such as AKT1, TNF, PTGS2 and down-regulate the expression levels of CASP3. ConclusionsThis study revealed comprehensively the targets and mechanism for the efficacy of XLJDD in treatment of CRC. Furthermore, the results were achieved through in vitro experiment of CT-26 and HCT116 cell lines, and in vivo experiment of AOM/DSS mice.

Chemical Space of Small Molecule Exploration for the Elucidation of Cough Suppressant Pharmacology of Ying Su Ke/Zi

IntroductionChronic cough, a prevalent condition, lacks effective medical solutions. Traditionally, Ying Su Ke/Zi (derived from Papaver somniferum L.) has been used in certain ethnic herbal formulas to address cough. However, there is a notable absence of molecular-level exploration regarding their mechanism for treating cough. MethodsStarting with the chemical ingredients of Ying Su Ke/Zi, this study used principal component analysis to explore the chemical space of these compounds and set four rounds of screening criteria based on the chemical space distribution to quickly identify active compounds. Following that, their targets were predicted using the weighted ensemble system model, and target enrichment analysis was executed. ResultsIn total, 247 compounds in Ying Su Ke/Zi were data-mined from literature reports, based on which four rounds of screening yielded 88 potential active chemicals, mostly alkaloids. Besides, 168 target proteins, mostly G-protein-coupled receptors, were identified, and meanwhile the results of the enrichment analysis revealed that these target proteins are, mostly, localised at cell membranes, cell junctions, and cell projections, and they were primarily involved in biological processes ranging from stimulus response, signalling, and bioregulation, possessing molecular functions concerning altering molecular transduction activity and binding. Moreover, the key biological pathways covered by these target proteins are neuroactive receptor-ligand interaction pathway, serotonergic synapse pathway, etc. ConclusionsIntegrating the foregoing findings with the pathophysiological characteristics of cough, the current study reveals that Ying Su Ke/Zi exert their antitussive pharmacological effects primarily via opioidergic and serotonergic mechanisms.