Front Cover, Volume 40, Issue 12

Ulcerative colitis (UC) and rheumatoid arthritis (RA) are immune-mediated inflammatory diseases (IMIDs) with similar symptoms and common genomics. However, the relationship between UC and RA has not been investigated thoroughly. Therefore, this study aimed to establish the differentially expressed genes (DEGs) and potential therapeutic targets in UC and RA. Three microarray datasets (GSE38713, GSE1919, and GSE12251) were selected from the Gene Expression Omnibus (GEO) database for analysis. We used R software to identify the DEGs and performed enrichment analyses. Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and Cytoscape software were used to construct the protein-protein interaction (PPI) network and identify the hub genes. A regulatory network based on the constructed PPI was generated using StarBase and PROMO databases. We identified a total of 1542 and 261 DEGs in UC and RA. There were 169 common DEGs identified in both UC and RA, including 63 upregulated genes (DEGs1) and nine downregulated genes (DEGs2). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of DEGs1 and DEGs2 in the PPI network revealed that the genes enriched were involved in immunity. A total of 45 hub genes were selected based on high scores of correlation; three hub genes (SRGN, PLEK, and FCGR3B) were found to be upregulated in UC and RA, and downregulated in UC patients with response to infliximab treatment. The identification of novel DEGs and hub genes in the current study contributes to a novel perception for latent functional mechanisms and presents potential prognostic indicators and therapeutic targets in UC and RA.

To explore the mechanism of Hedyotis Diffusae Herba-Smilacis Glabrae Rhizoma(HDH-SGR) in treating lung adenocarcinoma based on big data bioinformatics combined with network pharmacology analysis and molecular docking technology. The chemical components and potential therapeutic targets of HDH-SGR were obtained from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP). Lung adenocarcinoma-related genes were obtained from The Cancer Genome Atlas(TCGA), Therapeutic Target Database(TTD), Pharmacogenetics and Pharmacogenomics Knowledge Base(PharmGKB), Online Mendelian Inheritance in Man(OMIM), DrugBank, and GeneCards. "Drug component-target" network was constructed using Cytoscape to screen out key compounds. STRING was used to build protein-protein interaction(PPI) network and core targets were screened out by Cytoscape-CytoNCA topology analysis. Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) analyses of target genes were performed by R-clusterProfiler. Finally, key compounds were docked to core target genes using AutoDock. The results showed that 22 active compounds and 499 potential therapeutic targets were obtained from HDH-SGR. A total of 14 332 lung adenocarcinoma-related targets were screened out through six data platforms, including 182 common targets. Fifteen core targets were screened out from the PPI network. GO and KEGG analyses revealed significant enrichment of relevant target genes in various biological processes, cellular functions(e.g., response to lipopolysaccharide, nuclear receptor activity, and ligand-activated transcription factor activity) and close relationship between target genes and non-small cell lung cancer signaling pathways. Based on the results of molecular docking validation, diosgenin, quercetin, naringenin, taxifolin, 2-methoxy-3-methyl-9,10-anthraquinone, stigmasterol, and β-sitosterol were able to bind tightly to the core targets. HDH-SGR can intervene in lung adenocarcinoma through multiple targets and signaling pathways, such as non-small cell lung cancer signaling pathways. The binding of active components in Chinese medicine to key targets is presumedly one of the mechanisms that produce therapeutic effects.

2018 Background: Glioblastoma (GBM), the most common primary brain tumor in adults, universally recurs and has a dismal prognosis. Therefore, there is an unmet need for new and more effective treatment strategies. Here, we aim to discover new therapeutic targets by identifying upregulated genes in GBM with known antineoplastic drug interactions. Methods: Publicly available, raw microarray expression data of patient-derived GBM samples and normal brain tissue were collected from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Subsequently, we applied functional genomic mRNA profiling (FGmRNA-profiling), a method that is able to correct the gene expression profile of an individual tumor for physiological and experimental factors, which are considered not to be relevant for the observed tumor phenotype. Next, the FGmRNA-profiles of healthy brain tissue and glioblastoma were used to perform a class comparison analysis. Significantly upregulated genes in GBM were prioritized based on: known interaction with antineoplastic agents and the current status of clinical evaluation in humans. Results: After FGmRNA-profiling 66 normal brain tissue samples and 1280 patient-derived GBM samples, class comparison identified 712 significantly upregulated genes. Of all significantly upregulated genes, 27 genes interacted with antineoplastic drugs. 17 out of these 27 druggable genes, including EGFR and VEGFA, have already been clinically evaluated in GBM, and had limited efficacy. Out of the 10 remaining druggable genes, we prioritized RRM2, MAPK9 and XIAP, as these genes are associated with biologic pathways involved in the carcinogenesis of GBM and are therefore considered as novel potential therapeutic targets. Conclusions: Based on data-driven prioritization, we identified three potential therapeutic druggable targets, which have not yet been explored in the context of glioblastoma. Further preclinical and clinical research on the inhibition of these druggable genes is necessary and may lead to an improvement of treatment outcomes for patients with GBM.

Sepsis is a diagnostic and therapeutic challenge and is associated with morbidity and a high risk of death. Metabolomic and lipidomic profiling in sepsis can identify alterations in metabolism and might provide useful insights into the dysregulated host response to infection, but investigations in dogs are limited. We aimed to use untargeted metabolomics and lipidomics to characterize metabolic pathways in dogs with sepsis to identify therapeutic targets and potential diagnostic and prognostic biomarkers. In this prospective observational cohort study, we examined the plasma metabolomes and lipidomes of 20 healthy control dogs and compared them with those of 21 client-owned dogs with sepsis. Patient data including signalment, physical exam findings, clinicopathologic data and clinical outcome were recorded. Metabolites were identified using an untargeted mass spectrometry approach and pathway analysis identified multiple enriched metabolic pathways including pyruvaldehyde degradation; ketone body metabolism; the glucose-alanine cycle; vitamin-K metabolism; arginine and betaine metabolism; the biosynthesis of various amino acid classes including the aromatic amino acids; branched chain amino acids; and metabolism of glutamine/glutamate and the glycerophospholipid phosphatidylethanolamine. Metabolites were identified with high discriminant abilities between groups which could serve as potential biomarkers of sepsis including 13,14-Dihydro-15-keto Prostaglandin A2; 12(13)-DiHOME (12,13-dihydroxy-9Z-octadecenoic acid); and 9-HpODE (9-Hydroxyoctadecadienoic acid). Metabolites with higher abundance in samples from nonsurvivors than survivors included 3-(2-hydroxyethyl) indole, indoxyl sulfate and xanthurenic acid. Untargeted lipidomic profiling revealed multiple sphingomyelin species (SM(d34:0)+H; SM(d36:0)+H; SM(d34:0)+HCOO; and SM(d34:1D3)+HCOO); lysophosphatidylcholine molecules (LPC(18:2)+H) and lipophosphoserine molecules (LPS(20:4)+H) that were discriminating for dogs with sepsis. These biomarkers could aid in the diagnosis of dogs with sepsis, provide prognostic information, or act as potential therapeutic targets.

Identification and qualitative characterization of new therapeutic targets in Stenotrophomonas maltophilia through in silico proteome exploration

Somatostatin receptor 2 (SSTR2) is overexpressed in a majority of neuroendocrine neoplasms, including small-cell lung carcinomas (SCLCs). SSTR2 was previously considered an inhibitory receptor on cell growth, but its agonists had poor clinical responses in multiple clinical trials. The role of this receptor as a potential therapeutic target in lung cancer merits further investigation. We evaluated the expression of SSTR2 in a cohort of 96 primary tumors from patients with SCLC and found 48% expressed SSTR2. Correlation analysis in both CCLE and an SCLC RNAseq cohort confirmed high-level expression and identified an association between NEUROD1 and SSTR2. There was a significant association with SSTR2 expression profile and poor clinical outcome. We tested whether SSTR2 expression might contribute to tumor progression through activation of downstream signaling pathways, using in vitro and in vivo systems and downregulated SSTR2 expression in lung cancer cells by shRNA. SSTR2 downregulation led to increased apoptosis and dramatically decreased tumor growth in vitro and in vivo in multiple cell lines with decreased AMPKα phosphorylation and increased oxidative metabolism. These results demonstrate a role for SSTR2 signaling in SCLC and suggest that SSTR2 is a poor prognostic biomarker in SCLC and potential future therapeutic signaling target.

Pan-Cancer Analysis Reveals Netrin-1 Receptors as Potential Tumor Biomarkers and Therapeutic Targets

Medulloblastoma (MB) is an aggressive brain tumor that predominantly affects children. Recent high-throughput sequencing studies suggest that the noncoding RNA genome, in particular long noncoding RNAs (lncRNAs), contributes to MB subgrouping. Here we report the identification of a novel lncRNA, lnc-HLX-2-7, as a potential molecular marker and therapeutic target in Group 3 MBs. Publicly available RNA sequencing (RNA-seq) data from 175 MB patients were interrogated to identify lncRNAs that differentiate between MB subgroups. After characterizing a subset of differentially expressed lncRNAs in vitro and in vivo, lnc-HLX-2-7 was deleted by CRISPR/Cas9 in the MB cell line. Intracranial injected tumors were further characterized by bulk and single-cell RNA-seq. Lnc-HLX-2-7 is highly upregulated in Group 3 MB cell lines, patient-derived xenografts, and primary MBs compared with other MB subgroups as assessed by quantitative real-time, RNA-seq, and RNA fluorescence in situ hybridization. Depletion of lnc-HLX-2-7 significantly reduced cell proliferation and 3D colony formation and induced apoptosis. Lnc-HLX-2-7-deleted cells injected into mouse cerebellums produced smaller tumors than those derived from parental cells. Pathway analysis revealed that lnc-HLX-2-7 modulated oxidative phosphorylation, mitochondrial dysfunction, and sirtuin signaling pathways. The MYC oncogene regulated lnc-HLX-2-7, and the small-molecule bromodomain and extraterminal domain family‒bromodomain 4 inhibitor Jun Qi 1 (JQ1) reduced lnc-HLX-2-7 expression. Lnc-HLX-2-7 is oncogenic in MB and represents a promising novel molecular marker and a potential therapeutic target in Group 3 MBs.

Role of Jak3 in Chronic Myeloid Leukemia: Evidence To Identify Jak3 as a Potential Therapeutic Target.

Amaç: DNA tamir mekanizmalarında (DTM) görev alan genlerin ifade değişimleri glioblastomda (GBM) radyoterapi direnci ile ilişkilendirilmiştir. DTM’de rol oynayan genlerin biyoinformatik yöntemlerle tanımlanması GBM tedavisinde kullanılabilecek potansiyel yeni hedeflerin belirlenmesine yardımcı olabilir. Bu çalışmanın amacı, DNA tamir mekanizmalarında rol oynayan genlerin biyoinformatik yöntemler kullanılarak GBM tümörlerinde tanımlanmasıdır. Yöntem: DNA tamiri mekanizmaları ile ilişkili genler “Reactome” ve “KEGG” veri tabanları üzerinde tanımlandı. GBM tümörlerinde genlere ait mRNA ifade profilleri GEO GDS1813 ve GDS2853 veri setlerinde “Orange Canvas” yazılımı kullanılarak incelendi. Genlerdeki genetik değişimler cBioPortal veri tabanı kullanılarak GBM TCGA olgularında tanımlandı. GEPIA2, değişen gen ifadelerinin TCGA GBM hasta sağ kalım süreleri üzerindeki etkisini göstermek için kullanıldı. Bulgular: ERCC6, FAN1, MBD4, PARP1 ve UNG genlerinin mRNA ifade profillerinin GBM tümörlerinde değişime uğradığı bulundu. Tanımlanan genler için farklı tipte mutasyonlar ve kopya sayı değişimleri TCGA GBM olgularında gözlendi. Yüksek ve düşük gen ifade profillerinin GBM hastalarının genel ve hastalıksız sağ kalım süreleri üzerinde etkisi olmadığı saptandı. Sonuç: Bu çalışmada tanımlanan ERCC6, PARP1 ve UNG genleri baskılanması durumunda GBM’de radyoterapi etkinliğini arttırabilecek potansiyel birer terapötik hedef olabilir.

Inflammation is the fundamental protective response; however disordered immuno-response can cause chronic human disease, including cancer. Inflammatory cells and mediators are essential to the tumor microenvironment and dissection of this complex molecular and cellular milieu may elucidate a connection between cancer and inflammation and help to identify potential novel therapeutic targets. Thus, focusing on transcription factor NF-κB and E2F1 in inflammation-associated cancer is urgent. NF-κB activation is prevalent in carcinomas, mainly driven by inflammatory cytokines in the tumor microenvironment. E2F1 is also involved in regulating immune responses. Understanding the crosstalk between the two pathways may contribute to the development of novel anti-cancer drugs.

Circular RNAs (circRNAs) may be potential biomarkers or therapeutic targets of hemophagocytic syndrome (HPS) due to their high stability, covalently closed structure and implicated roles in gene regulation. The aim of the present study was to determine and characterize the circRNAs from natural killer (NK)/T-cell lymphoma-associated hemophagocytic syndrome (NK/T-LAHS). CircRNA in NK/T-LAHS and healthy control patient serum were assessed using next-generation sequencing (NGS). One hundred and forty-three differentially expressed circRNAs of which 114 were up-regulated and 29 were down-regulated in NK/T-LAHS patients were identified. Next, Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses to explore the roles of these circRNAs were utilized, and a microRNA (miRNA) target gene prediction software to predict the interaction of circRNAs and miRNAs was used. Moreover, five circRNAs were then selected as NK/T-LAHS candidate circRNAs which were related to tumors and contained NK/T-LAHS-related miRNA-binding sites. Using real-time PCR, the significant up-regulation of these five circRNAs in NK/T-LAHS patient serum were verified. Together these results show that circRNAs may serve as valuable diagnostic biomarkers of early NK/T-LAHS, with potential therapeutic targets in disease progression.

Globally, colorectal cancer (CRC) is the third most prevalent cancer and the second leading cause of cancer-related deaths. Circular RNAs (circRNAs) are single-stranded RNA with covalently closed-loop structures and are highly stable, conserved, and abundantly expressed in various organs and tissues. Recent research found abnormal circRNA expression in CRC patients’ blood/serum, cells, CRC tissues, and exosomes. Furthermore, mounting data demonstrated that circRNAs are crucial to the development of CRC. CircRNAs have been shown to exert biological functions by acting as microRNA sponges, RNA-binding protein sponges, regulators of gene splicing and transcription, and protein/peptide translators. These characteristics make circRNAs potential markers for CRC diagnosis and prognosis, potential therapeutic targets, and circRNA-based therapies. However, further studies are still necessary to improve the understanding of the roles and biological mechanisms of circRNAs in the development of CRC. In this review, up-to-date research on the role of circRNAs in CRC was examined, focusing on their potential application in CRC diagnosis and targeted therapy, which would advance the knowledge of the functions of circRNAs in the development and progression of CRC.

IntroductionChronic obstructive pulmonary disease (COPD) is a progressive lung disorder characterized by persistent respiratory symptoms and progressive airflow obstruction. The global rise in COPD incidence and mortality imposes a significant societal burden. Despite its prevalence, the intricate pathogenesis of COPD remains incompletely understood. This study aimed to identify molecular markers and potential therapeutic targets by integrating known COPD-related genes and analyzing RNA-Seq and expression microarray data.Material and methodsWe conducted a comprehensive analysis by combining RNA-Seq and expression microarray data for COPD, focusing on known COPD-associated genes. Differential expression analysis revealed insights into the cellular biological processes and signaling pathways underlying COPD pathogenesis. Functional modules closely linked to COPD were identified through protein interaction network analysis.ResultsThe analysis of differentially expressed genes (DEGs) highlighted the significance of cellular processes such as chemotaxis, cell migration, cellular stress, and apoptosis in COPD pathogenesis. Key signaling pathways, including NF-κB, JAK-STAT, T cell receptor, and NOD-like receptor pathways, were identified as crucial contributors to COPD development. Protein interaction network analysis revealed functional modules associated with COPD. Validation through qRT-PCR and immunoblotting confirmed PTX3 and CYP1B1 as core genes, suggesting their potential as biomarkers and therapeutic targets for COPD.ConclusionsOur findings provide valuable insights into the molecular landscape of COPD, identifying PTX3 and CYP1B1 as promising candidates for further investigation as potential biomarkers and therapeutic targets. This research contributes to a better understanding of COPD pathogenesis, offering avenues for the development of targeted interventions to address this escalating global health concern.

Bushao Tiaozhi Capsule (BSTZC) is a novel drug in China that is used in clinical practice and has significant therapeutic effects on hyperlipidemia (HLP). In our previous study, BSTZC has a good regulatory effect on lipid metabolism of HLP rats. However, its bioactive compounds, potential targets, and underlying mechanism remain largely unclear. We extracted the active ingredients and targets in BSTZC from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and literature mining. Subsequently, core ingredients, potential targets, and signaling pathways were determined through bioinformatics analysis, including constructed Drug-Ingredient-Gene symbols-Disease (D-I-G-D), protein–protein interaction (PPI), the Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Finally, the reliability of the core targets was evaluated using in vivo studies. A total of 36 bioactive ingredients and 209 gene targets were identified in BSTZC. The network analysis revealed that quercetin, kaempferol, wogonin, isorhamnetin, baicalein and luteolin may be the core ingredients. The 26 core targets of BSTZC, including IL-6, TNF, VEGFA, and CASP3, were considered potential therapeutic targets. Furthermore, GO and KEGG analyses indicated that the treatment of HLP by BSTZC might be related to lipopolysaccharide, oxidative stress, inflammatory response and cell proliferation, differentiation and apoptosis. The pathway analysis showed enrichment for different pathways like MAPK signaling pathway, AGE-RAGE signaling pathway in diabetic, IL-17 signaling pathway and TNF signaling pathway. In this study, network pharmacology analysis, and experiment verification were combined, and revealed that BSTZC may regulate key inflammatory markers and apoptosis for ameliorating HLP.