Kyoto Encyclopedia Of Genes And Genomes Pathway Enrichment Analysis Research Articles

Dihydroartemisinin-ursodeoxycholic acid conjugate is a potential treatment agent for inflammatory bowel disease.

A novel artemisinin derivative, dihydroartemisinin-ursodeoxycholic acid conjugate (4), was found to exhibit strong immunosuppressive activity. Various methods were used to evaluate the immunosuppressive activity and mechanism of action of the compound to explore its potential applications. T cell proliferation, mixed lymphocyte reaction (MLR), and Th1/Th17 differentiation assays were used to evaluate the immunosuppressive activity of the compound. Differentially expressed genes from RNA sequencing were analysed with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, while enriched signalling pathways were further validated by western blotting (WB). In vivo efficacy was validated with delayed-type hypersensitivity (DTH) mouse models and dextran sodium sulphate (DSS)-induced inflammatory bowel disease (IBD) mouse model. Compound 4 inhibited concanavalin A -induced mouse splenic T cell proliferation (IC50=15nM) and anti-CD3/CD28-induced human primary T cell proliferation (IC50=30nM) while also reducing the secretion of hIFN-γ. Compound 4 exhibited similar inhibitory activity in MLR assay. Compound 4 dose-dependently inhibited human Th1/Th17 differentiation. The KEGG pathway enrichment analysis indicated that the genes related to T cell activation signalling pathways PI3K-AKT, MAPK, and NF-κB were significantly enriched. WB confirmed that compound 4 inhibited the AKT/MAPK and NF-κB signalling pathways. Compound 4 dose-dependently inhibited ear and foot pad swelling in DTH mouse models. In the DSS-induced IBD mouse model, compound 4 significantly decreased the disease activity index and colon density, and inhibited splenomegaly of the mice. The in vitro and in vivo results indicated that compound 4 has the potential to be developed into an anti-IBD drug.

Expression and clinical significance of ENC1 in gastrointestinal tumors: Bioinformatics analysis based on a public gene database.

To investigate the expression characteristics of ectodermal-neural cortex 1 (ENC1) in gastrointestinal tumors and its potential value in judging the prognosis of patient survival. RNA sequence (RNA-seq) data and patient survival data related to stomach adenocarcinoma (STAD) and colon adenocarcinoma (COAD) in gastric cancer and colon cancer from The Cancer Genome Atlas (TCGA) were downloaded for expression difference analysis and Cox survival regression analysis. A Kaplan-Meier (KM) survival curve was plotted to analyze the tumor invasion level of patients with different ENC1 expression levels, and the main influencing pathways of ENC1 were analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and protein network analysis. The data of 405 STAD samples and 494 COAD clinical samples of TCGA were analyzed, and it was found that the expression of ENC1 in tumor tissues of patients with both types of cancer was significantly higher than that in normal tissues, with Log2 fold change values of 1.97 and 2.06, respectively, P<0.001. Cox analysis revealed that the high expression of ENC1 was not significantly correlated with the prognosis and survival time of patients with gastric cancer and patients with colon cancer: overall survival (OS) hazard ratio (HR): 1.039, 95% confidence interval (CI): 0.890-1.213, P=0.627 for gastric cancer, OS HR: 0.886, 95% CI: 0.702-1.111, P=0.306 for colon cancer. KEGG pathway enrichment analysis of gene ENC1 revealed that ENC1 was mainly involved in neuroactive ligand-receptor interaction. The high expression of ENC1 was associated with various immune cells and different T cells such as basophils, CD4+ memory T cells, CD4+ TEM, and MV endothelial cells in gastric and colon cancers. The results of ENC1 protein interaction network analysis suggested that ENC1 may be involved in regulating neurite formation and neural crest cell differentiation. ENC1 expression is elevated in both gastric and colon cancers, and ENC1 is associated with various immune cells and different T cells such as basophils, CD4+ memory T cells, CD4+ TEM, and MV endothelial cells in both gastric and colon cancers, but ENC1 does not affect the survival and prognosis of patients.

Alterated gene expression in dilated cardiomyopathy after left ventricular assist device support by bioinformatics analysis.

Heart transplantation is the best treatment for end-stage dilated cardiomyopathy (DCM). Left ventricular assist device (LVAD) support is becoming more prevalent and may delay heart transplantation. Gene expression of the left ventricular myocardium usually changes following LVAD implantation. In this study, we aimed to identify potential biomarkers to determine the prognosis of patients with DCM after receiving LVAD support. We extracted microarray datasets from Gene Expression Omnibus (GEO), including GSE430 and GSE21610. There were 28 paired DCM samples in the GSE430 and GSE21610 profiles. Differentially expressed genes (DEGs) were identified at LVAD implantation and heart transplantation. DEGs were annotated according to Gene Ontology (GO) and analyzed according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. A protein-protein interaction (PPI) network was constructed. The top 10 crucial genes were predicted using Cytoscape plugin CytoHubba in conformity with the network degree algorithm. The levels of gene expression and the diagnostic values of crucial genes were confirmed in the clinical datasets. The 28 DEGs were clustered into the GSE datasets. GO annotations and KEGG pathway enrichment analyses revealed that inflammation might be involved. They were associated with correlative inflammation. Combined with PPI networks, these results revealed CytoHubba's top 10 hub genes, including CCL2, CXCL12, CXCL1, CTGF/CCN2, CX3CR1, POSTN, FKBP5, SELE, AIF1, and BMP2. Among them, CCL2, CXCL12, FKBP5, and BMP2 might be considered prognostic and diagnostic biomarkers after LVAD support and have confirmed their validity in clinical datasets. The area under the curve of the four main hub genes was more than 0.85, indicating high diagnostic ability and good prognosis for patients with DCM with LVAD implantation. However, a significant effect of CCL2, CXCL12, FKBP5, and BMP2 expression was not observed on the left ventricular end-diastolic diameter (LVEDD), left ventricular ejection fraction (LVEF), cardiac index (CI), or support time of LVAD. CCL2, CXCL12, FKBP5, and BMP2 could be potential gene biomarkers for patients with DCM after LVAD support. These findings provide critical clues for the therapeutic management of patients with DCM and LVADs. LVEDD, LVEF, CI, and support time of LVAD were not correlated with the expression of these hub genes.

Analysis of differentially expressed genes related to cerebral ischaemia in young rats based on the Gene Expression Omnibus database.

The incidence rate of cerebral infarction in young people is increasing day by day, the age of onset tends to be younger, and its internal pathogenesis and mechanism are very complicated, which leads to greater difficulties in treatment. Therefore, it is essential to analyze the key pathway that affects the onset of cerebral infarction in young people from the perspective of genetics. To compare the differentially expressed genes in the brain tissue of young and aged rats with middle cerebral artery occlusion and to analyse their effect on the key signalling pathway involved in the development of cerebral ischaemia in young rats. The Gene Expression Omnibus 2R online analysis tool was used to analyse the differentially expressed genes in the GSE166162 dataset regarding the development of cerebral ischaemia in young and aged groups of rats. DAVID 6.8 software was further used to filter the differentially expressed genes. These genes were subjected to Gene Ontology (GO) function analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to determine the key gene pathway that affects the occurrence of cerebral ischaemia in young rats. Thirty-five differentially expressed genes (such as Igf2, Col1a2, and Sfrp1) were obtained; 73 GO enrichment analysis pathways are mainly involved in biological processes such as drug response, amino acid stimulation response, blood vessel development, various signalling pathways, and enzyme regulation. They are involved in molecular functions such as drug binding, protein binding, dopamine binding, metal ion binding, and dopamine neurotransmitter receptor activity. KEGG pathway enrichment analysis showed a significantly enriched pathway: The cyclic adenosine monophosphate (c-AMP) signalling pathway. The c-AMP signalling pathway might be the key pathway in the intervention of cerebral infarction in young people.

Network Pharmacology Prediction and Experimental Validation of &lt;em&gt;Trichosanthes&lt;/em&gt;-&lt;em&gt;Fritillaria thunbergii&lt;/em&gt; Action Mechanism Against Lung Adenocarcinoma

We aimed to study the mechanism of Trichosanthes-Fritillaria thunbergii in treating lung adenocarcinoma (LUAD) based on network pharmacology and experimental verification. The effective components and potential targets of Trichosanthis and Fritillaria thunbergii were collected by high-throughput experiment and reference-guided (HERB) database of traditional Chinese medicine and a similarity ensemble approach (SEA) database, and the LUAD-related targets were queried by the GeneCards and Online Mendelian Inheritance in Man (OMIM) databases. A drug-component-disease-target network was constructed by Cytoscape software. Protein-protein interaction (PPI) network, gene ontology (GO) function, and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses were conducted to obtain core targets and key pathways. An aqueous extract of Trichosanthes-Fritillaria thunbergii and A549 cells were used for the subsequent experimental validation. Through the HERB database and literature search, 31 effective compounds and 157 potential target genes of Trichosanthes-Fritillaria thunbergii were screened, of which 144 were regulatory targets of Trichosanthes-Fritillaria thunbergii in the treatment of lung adenocarcinoma. The GO functional enrichment analysis showed that the mechanism of action of Trichosanthes-Fritillaria thunbergii against lung adenocarcinoma is mainly protein phosphorylation. The KEGG pathway enrichment analysis suggested that the treatment of lung adenocarcinoma by Trichosanthes-Fritillaria thunbergii mainly involves the PI3K/AKT signaling pathway. The experimental validation showed that an aqueous extract of Trichosanthes-Fritillaria thunbergii could inhibit the proliferation of A549 cells and the phosphorylation of AKT. Through network pharmacology and experimental validation, it was verified that the PI3K/AKT signaling pathway plays a vital role in the action of Trichosanthes-Fritillaria thunbergii in treating lung adenocarcinoma.

Efficacy of Huangkui Capsules in the Treatment of Diabetic Kidney Disease: A Systematic Review and Using Network Pharmacology

ABSTRACT Diabetic kidney disease (DKD), a severe and common microvascular complication of diabetes mellitus, has become a major cause of end-stage renal disease. Huangkui capsule (HKC) has been widely used to treat DKD. This meta-analysis aimed to provide high-quality evidence for the clinical application of HKC in DKD. The following databases: China National Knowledge Infrastructure, Wanfang Database, Chongqing VIP, SinoMed, Web of Science, EMBASE, PubMed, and The Cochrane Library, were searched for randomized controlled trials using the search theme: “angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) combined with HKC for treatment of DKD” from their inception dates till August 2022. Studies were selected following our inclusion and exclusion criteria, and we extracted the required data. RevMan 5.3 was used for data statistics and analysis. Based on the main components identified by high performance liquid chromatography, the SwissADME, SwissTargetPrediction, and UniProt databases were used to predict the target genes of HKC. OMIM, DrugBank, GeneCards, and DisGeNet databases were used to predict DKD-related target genes. Venny 2.0 was then used to find the common targets in HKC and DKD. We conducted an HKC-ingredients-targets-DKD network using Cytoscape and a protein-protein interaction (PPI) network using the STRING database. Finally, we performed a Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis using the DAVID database. Exactly 15 studies were included in this meta-analysis. Compared with the control group using ACEI/ARB only, ACEI/ARB combined with HKC was found to significantly lower the urine albumin excretion rate (UAER; standard mean difference [SMD] = −1.92, 95% confidence interval [CI] [−2.93, −0.92]), 24h urinary total protein (24h-UTP; mean difference [MD] = −0.41, 95% CI [−0.64, −0.18], P = 0.0004), serum creatinine (SCr; SMD = −0.68, 95% CI [−1.02, −0.34]), blood urea nitrogen (BUN; SMD = −0.59, 95% CI [−1.04, 0.14], P = 0.01), total cholesterol (TC; MD = −1.22, 95% CI [−2.04, 0.39], P = 0.004, and triglyceride (TG) levels (MD = −0.54, 95% CI [−0.94, −0.15], P = 0.007). There was no significant difference in low-density lipoprotein cholesterol levels (MD = −0.45, 95% CI [−1.21, 0.31], P = 0.24) and adverse effects (RR = 0.98, 95% CI [0.43, 2.22], P = 0.96) between the two groups. Exactly 127 genes were obtained using network pharmacology and were the common target genes of HKC and DKD. PPI network showed that the key targets are SRC, AKT1, HSP90AA1, PIK3R1, SYK, FYN, ESR1, and F2. GO analysis and KEGG pathway enrichment analysis showed that HKC could alleviate the pathological glomerular changes by inhibiting the activity of the PI3K/Akt signaling pathway. The combination of ACEI/ARB and HKC has a good safety profile and may be effective for the prevention of DKD by reducing UAER, 24h-UTP, TC, and TG levels. Furthermore, HKC may treat DKD primarily by inhibiting the PI3K-Akt signaling pathway, and further experimental studies are required to verify this hypothesis.

Exploring the active ingredients and potential mechanisms of action of sinomenium acutum in the treatment of rheumatoid arthritis based on systems biology and network pharmacology.

Objective: To investigate and predict the targets and signaling pathways of sinomenium acutum (SA) in the treatment of rheumatoid arthritis (RA) through systems biology and network pharmacology, and to elucidate its possible mechanisms of action. Methods: We screened the active ingredients and corresponding target proteins of SA in Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), Traditional Chinese Medicines Integrated Database (TCMID) and Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine (BATMAN); and obtained the targets of rheumatoid arthritis diseases in a database of gene-disease associations (DisGeNET), Online Mendelian Inheritance in Man (OMIM) database. The two targets were mapped by Venn diagram and the intersection was taken. The intersecting targets were used to construct protein-protein interaction (PPI) network maps in the String database, and Metascape was used for Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Finally, the molecular docking technique was applied to validate and further clarify the core target of SA for the treatment of rheumatoid arthritis. Results: A total of six active ingredients and 217 potential targets were obtained after screening; 2,752 rheumatoid arthritis-related targets and 66 targets common to RA and SA. GO function and KEGG pathway enrichment analysis yielded 751 GO function entries (652 GO biological processes, 59 GO molecular functions and 40 GO cellular components) and 77 KEGG signaling pathways. It mainly involves pathways related to neural activity ligand-receptor interaction pathways, cancer pathways, calcium signaling channels, Th17 cell differentiation and others, which are mainly classified into four categories, including regulation of immunity, anti-inflammation, regulation of cell growth and apoptosis, and signaling. The molecular docking results showed that the binding energy of PTGS2, CASP3, JUN and PPARG to the key components beta-sitosterol, 16-epi-Isositsirikine, Sinomenine and Stepholidine were ≤ -6.5kcal/mol, suggesting the existence of molecular binding sites. Conclusion: SA acts on key targets such as PTGS2, CASP3, JUN, and PPARG to modulate signaling pathways such as neural activity ligand-receptor interaction, cancer, calcium ion, NF-κB, and Th17 cell differentiation to regulate immunity, anti-inflammation, modulation of cell cycle, bone metabolism, and signaling for the treatment of RA. It was also confirmed that the treatment of RA with SA has multi-component, multi-target, multi-pathway and multi-mechanism characteristics.

Dietary aromatase inhibitor treatment converts XY gsdf homozygous mutants to sub-fertile male in Nile tilapia (Oreochromis niloticus)

Gonadal soma-derived factor (gsdf) belongs to the TGF-β superfamily and is critical for sex determination and differentiation in fish. XY gsdf−/− Nile tilapia (Oreochromis niloticus) show male-to-female sex reversal 1 month after hatching (mah) and are infertile at the adult age; however, the functions of gsdf in spermatogenesis in fish are unclear. Herein, XY gsdf−/− Nile tilapia were converted to males with testis by feeding 200 μg/g letrozole (LE), an aromatase inhibitor, from 1 to 4 mah. The testis somatic index of XY gsdf−/− LE fish was significantly lower than that of XY gsdf+/+ LE fish at 6 mah. The artificial fertilization ratio of XY gsdf−/− LE fish sperm (53.22 ± 4.35%) was significantly lower than that of XY gsdf+/+ LE fish (86.33 ± 1.53%), indicating that XY gsdf−/− LE male fish were sub-fertile. Testes of LE XY gsdf−/− and gsdf+/+ fish at 6 mah were used for a transcriptome analysis. Compared with the testis of XY gsdf+/+ LE fish, 1426 and 1654 genes were up-regulated and down-regulated in the testis of XY gsdf−/− LE individuals, respectively. A KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis revealed that the differentially expressed genes (DEGs) were engaged in 21 pathways, including cancer, cell growth and death, and endocrine system pathways. Genes related to steroidogenesis and meiosis, such as cyp19a1a, foxl2, and cyp17a1, were significantly up-regulated, whereas sycp3, dmc1, and aldh1a1 were significantly down-regulated in the testis. In addition, a serum steroid hormone analysis showed that 17β-estradiol and 11-ketotestosterone levels of XY gsdf−/− LE fish were significantly higher and lower than those of XY gsdf+/+ LE fish. These findings demonstrated that endocrine system disruption in XY gsdf−/− LE might explain the decrease in fertility. This research establishes the groundwork for future research on the function of gsdf in spermatogenesis in fish.

Five-hub genes identify potential mechanisms for the progression of asthma to lung cancer.

Previous studies have shown that asthma is a risk factor for lung cancer, while the mechanisms involved remain unclear. We attempted to further explore the association between asthma and non-small cell lung cancer (NSCLC) via bioinformatics analysis. We obtained GSE143303 and GSE18842 from the GEO database. Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) groups were downloaded from the TCGA database. Based on the results of differentially expressed genes (DEGs) between asthma and NSCLC, we determined common DEGs by constructing a Venn diagram. Enrichment analysis was used to explore the common pathways of asthma and NSCLC. A protein-protein interaction (PPI) network was constructed to screen hub genes. KM survival analysis was performed to screen prognostic genes in the LUAD and LUSC groups. A Cox model was constructed based on hub genes and validated internally and externally. Tumor Immune Estimation Resource (TIMER) was used to evaluate the association of prognostic gene models with the tumor microenvironment (TME) and immune cell infiltration. Nomogram model was constructed by combining prognostic genes and clinical features. 114 common DEGs were obtained based on asthma and NSCLC data, and enrichment analysis showed that significant enrichment pathways mainly focused on inflammatory pathways. Screening of 5 hub genes as a key prognostic gene model for asthma progression to LUAD, and internal and external validation led to consistent conclusions. In addition, the risk score of the 5 hub genes could be used as a tool to assess the TME and immune cell infiltration. The nomogram model constructed by combining the 5 hub genes with clinical features was accurate for LUAD. Five-hub genes enrich our understanding of the potential mechanisms by which asthma contributes to the increased risk of lung cancer.

Identification of potential biomarkers for colorectal cancer by clinical database analysis and Kaplan-Meier curves analysis.

This study aimed to explore critical genes as potential biomarkers for the diagnosis and prognosis of colorectal cancer (CRC) for clinical utility. To identify and screen candidate genes involved in CRC carcinogenesis and disease progression, we downloaded microarray datasets GSE89076, GSE73360, and GSE32323 from the GEO database identified differentially expressed genes (DEGs), and performed a functional enrichment analysis. A protein-protein interaction network was constructed, and correlated module analysis was performed using STRING and Cytoscape. The Kaplan-Meier survival curve shows the survival of the hub genes. The expression of cyclin-dependent kinase (CDK1), cyclin B1 (CCNB1), and PCNA in tissues and changes in tumor grade were analyzed. A total of 329 DEGs were identified, including 264 upregulated and 65 downregulated genes. The functions and pathways of DEGs include the mitotic cell cycle, poly(A) RNA binding replication, ATP binding, DNA replication, ribosome biogenesis in eukaryotes, and RNA transport. Forty-seven Hub genes were identified, and biological process analysis showed that these genes were mainly enriched in cell cycle and DNA replication. Patients with mutations in CDK1, PCNA, and CCNB1 had poorer survival rates. CDK1, PCNA, and CCNB1 were significantly overexpressed in the tumor tissues. The expression of CDK1 and CCNB1 gradually decreased with increasing tumor grade. CDK1, CCNB1, and PCNA can be used as potential markers for the diagnosis and prognosis of CRC. These genes are overexpressed in colon cancer tissues and are associated with low survival rates in CRC patients.

Effect of Shan Zha (Hawthorn or Crataegus) on gastrointestinal cancer: A network pharmacology and molecular docking study

BackgroundShan Zha (Hawthorn or Crataegus) is a traditional Chinese medicine (TCM) most commonly used for the treatment of hyperlipidemia. Gastrointestinal cancer is closely correlated with blood lipid levels. This study illustrates the potential anticancer effects of Shan Zha on gastrointestinal tumors based on network pharmacology and molecular docking. MethodsHawthorn's bioactive ingredients and drug targets were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine version 2.0 (TCMIP v2.0), and Herbal Ingredients' Targets Platform (HIT 2.0) databases. Validated disease targets of gastrointestinal cancer were obtained from the Therapeutic Targets Database (TTD) and HIT 2.0 databases. Protein–protein interaction analysis of intersecting genes was performed using the Search Tool for the Retrieval of Interacting Genes (STRING) database. The functions of these genes were further analyzed by performing gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking verification was performed using Molecular Operating Environment (MOE) software. ResultsFour main bioactive components were identified in Shan Zha. A total of 271 potential drug targets were identified, and 393 gastrointestinal-tumor targets were obtained. Through protein interaction analysis of intersecting targets, the main components of Shan Zha were found to interact more closely with proteins such as tumor protein p53 (TP53), AKT serine/threonine kinase 1 (AKT1), JUN proto-oncogene (JUN), interleukin 6 (IL6), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor A (VEGFA). KEGG pathway enrichment analysis showed a total of 127 pathways, mainly involving pathways in multiple types of cancer, the Phosphatidylinositol 3-kinase-Akt (PI3K-Akt) signaling pathway, and EGFR tyrosine kinase inhibitor resistance. Combined with The Cancer Genome Atlas (TCGA) differential analysis, key targets, including TP53, cyclin D1 (CCND1), EGFR, and VEGFA, were screened. Molecular docking results showed that quercetin and kaempferol had the good binding potential for TP53, CCND1, EGFR, and VEGFA. ConclusionThese findings suggest that Shan Zha exerts its effects on gastrointestinal cancers through a multitarget, multi-component, and a multi-pathway mechanism.

Mechanism of Berberis atrocarpa anthocyanin against Alzheimer's disease based on network pharmacology and experimental verification

This study aimed to explore the potential mechanism of Berberis atrocarpa Schneid. anthocyanin against Alzheimer's disease(AD) based on network pharmacology, molecular docking technology, and in vitro experiments. Databases were used to screen out the potential targets of the active components of B. atrocarpa and the targets related to AD. STRING database and Cytoscape 3.9.0 were adopted to construct a protein-protein interaction(PPI) network and carry out topological analysis of the common targets. Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses were performed on the target using the DAVID 6.8 database. Molecular docking was conducted to the active components and targets related to the nuclear factor kappa B(NF-κB)/Toll-like receptor 4(TLR4) pathway. Finally, lipopolysaccharide(LPS) was used to induce BV2 cells to establish the model of AD neuroinflammation for in vitro experimental validation. In this study, 426 potential targets of active components of B. atrocarpa and 329 drug-disease common targets were obtained, and 14 key targets were screened out by PPI network. A total of 623 items and 112 items were obtained by GO functional enrichment analysis and KEGG pathway enrichment analysis, respectively. Molecular docking results showed that NF-κB, NF-κB inhibitor(IκB), TLR4, and myeloid differentiation primary response 88(MyD88) had good binding abilities to the active components, and malvidin-3-O-glucoside had the strongest binding ability. Compared with the model group, the concentration of nitric oxide(NO) decreased at different doses of malvidin-3-O-glucoside without affecting the cell survival rate. Meanwhile, malvidin-3-O-glucoside down-regulated the protein expressions of NF-κB, IκB, TLR4, and MyD88. This study uses network pharmacology and experimental verification to preliminarily reveal that B. atrocarpa anthocyanin can inhibit LPS-induced neuroinflammation by regulating the NF-κB/TLR4 signaling pathway, thereby achieving the effect against AD, which provides a theoretical basis for the study of its pharmacodynamic material basis and mechanism.

Biomarker analysis from a phase I/I1b study of regorafenib and nivolumab (rego/nivo) in microsatellite stable (MSS) colorectal cancer (CRC).

188 Background: Our previous phase I/Ib study revealed modest clinical efficacy of rego/nivo in refractory MSS-CRC, implying benefits in selected populations. This has prompted us to investigate predictive biomarkers. Methods: Pre-treatment tumor samples from the previous phase Ib rego/nivo study were obtained and assessed for mRNA sequencing (RNAseq). Response-associated transcripts were identified using DESeq2 method and annotated using gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis. Results: A total of 19 pretreatment tumor samples were analyzed including 14 patients (pts) with disease control (DC) (2 partial response and 12 stable disease) and 5 pts with progression disease (PD). We observed significant upregulation of 89 genes including SFTPB ( P&lt;0.001), SFTPA1 ( P&lt;0.001), ERICH6B ( P&lt;0.001) , XIST ( P&lt;0.001), IGHV2-26 ( P&lt;0.001), RETNLB ( P=0.005), VWA5B1 ( P=0.033), IGHV3-53 ( P&lt;0.001), POTEH ( P=0.015), IGHV1-3 ( P=0.001) and downregulation of 70 genes including AFAP1-AS1 ( P=0.022), PRSS21( P&lt;0.001), NTSR1 ( P&lt;0.001), CALB1 ( P=0.033), FAM83A ( P=0.013), TBL1Y ( P=0.045), WNT7A ( P=0.022), PADI1 ( P&lt;0.001), KRT6A ( P=0.030), KRT17 ( P=0.002) on RNA sequencing in the DC compared to PD. GO pathway enrichment analyses revealed 44 significantly upregulated pathways including positive regulation of B cell activation ( P&lt;0.001), B cell receptor signaling pathway ( P&lt;0.001), Phagocytosis engulfment ( P&lt;0.001), Fc-gamma receptor signaling pathway involved in phagocytosis ( P&lt;0.001), endocytosis ( P&lt;0.001), immunoglobulin receptor binding ( P&lt;0.001), serine-type endopeptidase activity ( P&lt;0.001) in the DC compared with PD group. Nine downregulated pathways including cell-substrate junction assembly ( P&lt;0.001), extracellular matrix (ECM) organization ( P=0.030), and ephrin receptor activity ( P=0.046) were observed in the DC compared with PD. KEGG pathway enrichment analysis revealed 8 significantly downregulated pathways including PI3K-Akt signaling ( P=0.009), ECM-receptor interaction ( P=0.006), Focal adhesion ( P=0.028), and Glycine, serine and threonine metabolism ( P=0.007) pathways in the DC compared with PD. Conclusions: RNAseq and following gene set enrichment analysis between pts with DC and PD revealed several dysregulated pathways involving immune regulation including macrophage and B cell activation, and also PI3-Akt signaling, ECM organization/receptor interaction, and adhesion, which are consistent with previous translational studies in other solid tumors. These dysregulated genes and pathways related to differentially expressed genes may need to be further evaluated as potential predictive biomarkers for rego/nivo or other tyrosine kinase inhibitor plus PD-1 blockade in MSS-CRC.

Mechanism of Huangjing Qianshi Decoction in treatment of prediabetic mice based on transcriptome sequencing

Based on transcriptome sequencing technology, the mouse model of prediabetes treated with Huangjing Qianshi Decoction was sequenced to explore the possible mechanism of treating prediabetes. First of all, transcriptome sequencing was performed on the normal BKS-DB mouse group, the prediabetic model group, and the Huangjing Qianshi Decoction treatment group(treatment group) to obtain differentially expressed genes in the skeletal muscle samples of mice. The serum biochemical indexes were detected in each group to screen out the core genes of Huangjing Qianshi Decoction in prediabetes. Gene Ontology(GO) database and Kyoto Encyclopedia of Genes and Genomes(KEGG) database were used to conduct signaling pathway enrichment analysis of differentially expressed genes, and real-time quantitative polymerase chain reaction(RT-qPCR) was used to verify them. The results showed that the levels of fasting blood glucose(FBG), fasting insulin(FINS), insulin resistance index(HOMA-IR), total cholesterol(TC), triglycerides(TG), and low-density lipoprotein cholesterol(LDL-C) in the mouse model were significantly decreased after treatment with Huangjing Qianshi Decoction. In the results of differential gene screening, there were 1 666 differentially expressed genes in the model group as compared with the normal group, and there were 971 differentially expressed genes in the treatment group as compared with the model group. Among them, interleukin-6(IL-6) and NR3C2 genes, which were closely related to the regulation of insulin resis-tance function, were significantly up-regulated between the model group and the normal group, and vascular endothelial growth factor A(VEGFA) genes were significantly down-regulated between the model group and the normal group. However, the expression results of IL-6, NR3C2, and VEGFA genes were adverse between the treatment group and the model group. GO functional enrichment analysis found that the biological process annotation mainly focused on cell synthesis, cycle, and metabolism; cell component annotation mainly focused on organelles and internal components; and molecular function annotation mainly focused on binding molecular functions. KEGG pathway enrichment analysis found that it involved the protein tyrosine kinase 6(PTK6) pathway, CD28-dependent phosphoinositide 3-kinase/protein kinase B(PI3K/AKT) pathway, p53 pathway, etc. Therefore, Huangjing Qianshi Decoction can improve the state of prediabetes, and the mechanism may be related to cell cycle and apoptosis, PI3K/AKT pathway, p53 pathway, and other biological pathways regulated by IL-6, NR3C2, and VEGFA.

Anti-infectious pneumonia target discovery and molecular mechanism study of Jingfang Granules

This study aimed to identify the direct pharmacological targets of Jingfang Granules in treating infectious pneumonia via &quot;target fishing&quot; strategy. Moreover, the molecular mechanism of Jingfang Granules in treating infectious pneumonia was also investigated based on target-related pharmacological signaling pathways. First, the Jingfang Granules extract-bound magnetic nanoparticles were prepared, which were incubated with lipopolysaccharide(LPS)-induced mouse pneumonia tissue lysates. The captured proteins were analyzed by high-resolution mass spectrometry(HRMS), and the target groups with specific binding to the Jingfang Granules extract were screened out. Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis was used to identify the target protein-associated signaling pathways. On this basis, the LPS-induced mouse model of infectious pneumonia was established. The possible biological functions of target proteins were verified by hematoxylin-eosin(HE) staining and immunohistochemical assay. A total of 186 Jingfang Granules-specific binding proteins were identified from lung tissues. KEGG pathway enrichment analysis showed that the target protein-associated signaling pathways mainly included Salmonella infection, vascular and pulmonary epithelial adherens junction, ribosomal viral replication, viral endocytosis, and fatty acid degradation. The target functions of Jingfang Granules were related to pulmonary inflammation and immunity, pulmonary energy metabolism, pulmonary microcirculation, and viral infection. Based on the in vivo inflammation model, Jingfang Granules significantly improved the alveolar structure of the LPS-induced mouse model of infectious pneumonia and down-regulated the expressions of tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6). Meanwhile, Jingfang Gra-nules significantly up-regulated the expressions of key proteins of mitochondrial function COX Ⅳ and ATP, microcirculation-related proteins CD31 and Occludin, and proteins associated with viral infection DDX21 and DDX3. These results suggest that Jingfang Gra-nules can inhibit lung inflammation, improve lung energy metabolism and pulmonary microcirculation, resist virus infection, thus playing a protective role in the lung. This study systematically explains the molecular mechanism of Jingfang Granules in the treatment of respiratory inflammation from the perspective of target-signaling pathway-pharmacological efficacy, thereby providing key information for clinical rational use of Jingfang Granules and expanding potential pharmacological application.

The efficacy and mechanism of berberine in improving aging-related cognitive dysfunction: A study based on network pharmacology.

To analyze the effects and mechanisms of berberine in the treatment of aging-related cognitive dysfunction based on network pharmacology methods, molecular docking techniques, and animal experiments. A mouse model of cognitive dysfunction was constructed by subcutaneous injection of D-galactose (D-gal) for 10 weeks, and the neuroprotective effects of berberine on aging-related cognitive dysfunction mice were evaluated by the Morris water maze (MWM) and immunofluorescence staining. The targets of berberine were obtained by SwissTargetPrediction, GeneCards, and PharmMapper. Putative targets of cognitive dysfunction were obtained by GeneCards, TTD, and DrugBank database. The STRING database and Cytoscape software were applied for protein-protein interaction (PPI) analysis and further screening of core targets. The DAVID database was used for Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) enrichment analysis to clarify the biological processes and pathways involved in the intersection targets, and AutoDockTools was adopted for molecular docking verification of core targets. Finally, the core genes were validated using real-time quantitative PCR. The MWM results showed that treatment with berberine significantly improved spatial learning and memory in mice with cognitive decline induced by D-gal. Immunofluorescence staining indicated that berberine modified the levels of aging-related markers in the brain. A total of 386 berberine putative targets associated with cognitive dysfunction were identified based on the public database. The core targets of berberine for improving cognitive function, include Mapk1, Src, Ctnnb1, Akt1, Pik3ca, Tp53, Jun, and Hsp90aa1. GO enrichment and KEGG pathway enrichment analyses indicated that the mechanism of berberine in the treatment of aging-related cognitive dysfunction is attributed to pathways such as PI3K-AKT and MAPK pathways. In vivo experiments further confirmed that Akt1, Ctnnb1, Tp53, and Jun were involved in the neuroprotective actions of berberine. This study reveals the multi-target and multi-pathway effects of berberine on regulating aging-related cognitive dysfunction, which provides preclinical evidence and may promote new drug development in mitigating cognitive dysfunction.

Identification and analysis of key microRNAs derived from osteoarthritis synovial fluid exosomes.

Identification and analysis of key microRNAs derived from osteoarthritis synovial fluid exosomes.

Identification of potential biomarkers for papillary thyroid carcinoma by comprehensive bioinformatics analysis.

To perform bioinformatics analysis on the papillary thyroid carcinoma (PTC) gene chip dataset to explore new biological markers for PTC. The gene expression profiles of GSE3467 and GSE6004 chip data were collected by GEO2R, and the differentially expressed genes (DEGs) were selected for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Protein-protein interaction (PPI) relationship analysis was achieved using STRING, and the hub genes were obtained using the Cytoscape software. GEPIA was used to validate the expressions of the hub genes in the normal and tumor tissues and to conduct survival analyses. Pertinent genetic pathology results were fetched using the HPA database. Finally, the key genes were clinically verified by reverse transcription-polymerase chain reaction. 97 genes were jointly up-regulated and 107 genes were jointly down-regulated in GSE3467 and GSE6004. GO function enrichment analysis revealed that the DEGs were involved in the regulation of calcium ion transport into cytosol, integrin binding, and cell adhesion molecule binding. KEGG pathway enrichment analysis indicated that the DEGs were chiefly associated with thyroid cancer and non-small cell lung cancer. According to the PPI network, 30 key target genes were identified. Only the expressions of ANK2, TLE1, and TCF4 matched between the normal and tumor tissues, and were associated with disease prognosis. When compared with the normal thyroid tissues, the protein and mRNA expressions of ANK2, TLE1, and TCF4 were down-regulated in PTC. Significant differences exist in overall gene expression between the thyroid tissues of patients with PTC and those of healthy people. Furthermore, the differential genes ANK2, TLE1, and TCF4 are expected to be reliable molecular markers for the mechanism study and diagnosis of PTC.

Construction and analysis of a survival-associated competing endogenous RNA network in breast cancer.

Recently, increasing studies have shown that non-coding RNAs are closely associated with the progression and metastasis of cancer by participating in competing endogenous RNA (ceRNA) networks. However, the role of survival-associated ceRNAs in breast cancer (BC) remains unknown. The Gene Expression Omnibus database and The Cancer Genome Atlas BRCA_dataset were used to identify differentially expressed RNAs. Furthermore, circRNA-miRNA interactions were predicted based on CircInteractome, while miRNA-mRNA interactions were predicted based on TargetScan, miRDB, and miRTarBase. The survival-associated ceRNA networks were constructed based on the predicted circRNA-miRNA and miRNA-mRNA pairs. Finally, the mechanism of miRNA-mRNA pairs was determined. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of survival-related mRNAs were performed using the hypergeometric distribution formula in R software.The prognosis of hub genes was confirmed using gene set enrichment analysis. Based on the DE-circRNAs of the top 10 initial candidates, 162 DE-miRNAsand 34 DE-miRNAs associated with significant overall survival were obtained. The miRNA target genes were then identified using online tools and verified using the Cancer Genome Atlas (TCGA) database. Overall, 46 survival-associated DE-mRNAs were obtained. The results of GO and KEGG pathway enrichment analyses implied that up-regulated survival-related DE-mRNAs were mostly enriched in the "regulation of cell cycle" and "chromatin" pathways, while down-regulated survival-related DE-mRNAs were mostly enriched in "negative regulation of neurotrophin TRK receptor signaling" and "interleukin-6 receptor complex" pathways. Finally, the survival-associated circRNA-miRNA-mRNA ceRNA network was constructed using 34 miRNAs, 46 mRNAs, and 10 circRNAs. Based on the PPI network, two ceRNA axes were identified. These ceRNA axescould be considered biomarkers for BC.GSEA results revealed that the hub genes were correlated with "VANTVEER_BREAST_CANCER_POOR_PROGNOSIS", and the hub genes were verified using BC patients' tissues. In this study, we constructed a circRNA-mediated ceRNA network related to BC. This network provides new insight into discovering potential biomarkers for diagnosing and treating BC.

An integrative analysis of an lncRNA-mRNA competing endogenous RNA network to identify functional lncRNAs in uterine leiomyomas with RNA sequencing.

Objective: To explore the functions of mRNAs and lncRNAs in the occurrence of uterine leiomyomas (ULs) and further clarify the pathogenesis of UL by detecting the differential expression of mRNAs and lncRNAs in 10 cases of UL tissues and surrounding normal myometrial tissues by high-throughput RNA sequencing. Methods: The tissue samples of 10 patients who underwent hysterectomy for UL in Lianyungang Maternal and Child Health Hospital from January 2016 to December 2021 were collected. The differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs) were identified and further analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The protein-protein interaction network (PPI) was constructed in Cytoscape software. Functional annotation of the nearby target cis-DEmRNAs of DElncRNAs was performed with the Database for Annotation, Visualization, and Integrated Discovery (DAVID) (https://david.ncifcrf.gov/). Meanwhile, the co-expression network of DElncRNA-DEmRNA was constructed in Cytoscape software. Results: A total of 553 DElncRNAs (283 upregulated DElncRNAs and 270 downregulated DElncRNAs) and 3,293 DEmRNAs (1,632 upregulated DEmRNAs and 1,661 downregulated DEmRNAs) were obtained. GO pathway enrichment analysis revealed that several important pathways were significantly enriched in UL such as blood vessel development, regulation of ion transport, and external encapsulating structure organization. In addition, cytokine-cytokine receptor interaction, neuroactive ligand-receptor interaction, and complement and coagulation cascades were significantly enriched in KEGG pathway enrichment analysis. A total of 409 DElncRNAs-nearby-targeted DEmRNA pairs were detected, which included 118 DElncRNAs and 136 DEmRNAs. Finally, we found that the top two DElncRNAs with the most nearby DEmRNAs were BISPR and AC012531.1. Conclusion: These results suggested that 3,293 DEmRNAs and 553 DElncRNAs were differentially expressed in UL tissue and normal myometrium tissue, which might be candidate-identified therapeutic and prognostic targets for UL and be considered as offering several possible mechanisms and pathogenesis of UL in the future.