Gene Enrichment Analysis Research Articles

CMTM6 promotes hepatocellular carcinoma invasion and metastasis and tumor-associated neutrophil immunoinfiltration through the Wnt/β-catenin pathway

BackgroundCMTM6 has been closely associated with the onset and progression of various tumor types. However, the precise mechanism by which CMTM6 operates in hepatocellular carcinoma remains elusive, necessitating further investigation.MethodsExpression levels of CMTM6 in hepatocellular carcinoma tissues and cells were analyzed using immunohistochemistry and quantitative real-time PCR. The correlation between CMTM6 expression in hepatocellular carcinoma tissues and clinical pathological characteristics, as well as patient prognosis, was investigated. Proliferation and apoptosis of hepatocellular carcinoma cells with silenced or overexpressed CMTM6 were assessed, alongside measurements of β-catenin and Wnt1 protein expression levels. In vivo research was conducted utilizing a murine subcutaneous transplantation model. Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed to elucidate the regulatory mechanism of CMTM6. Additionally, CD66b expression levels in tumor tissue were examined using immunohistochemistry, and the immune infiltration of CMTM6 and tumor-associated neutrophils (TANs) was analyzed.ResultsElevated expression levels of CMTM6 in hepatocellular carcinoma tissues and cells were found to be associated with poor patient prognosis. Overexpression of CMTM6 in hepatocellular carcinoma cells was demonstrated to promote cellular proliferation and inhibit apoptosis. Mechanistically, CMTM6 expression levels in hepatocellular carcinoma tissues were observed to positively correlate with β-catenin expression. GSEA and KEGG analysis revealed significant enrichment of CMTM6 in the Wnt/β-catenin pathway, indicating its involvement in pathway regulation. Furthermore, CMTM6 was found to be associated with immune infiltration of TANs in hepatocellular carcinoma tissues.ConclusionCMTM6 plays a pivotal role in the development and progression of hepatocellular carcinoma through regulation of the Wnt/β-catenin pathway via β-catenin. Moreover, CMTM6 demonstrates the capacity to promote immune infiltration of TANs in hepatocellular carcinoma tissues. Consequently, CMTM6 exhibits potential as both an early diagnostic marker and a novel therapeutic target for patients with hepatocellular carcinoma.

Integrated network pharmacology and transcriptomics to explore the mechanism of compound Dihuang granule (CDG) protects dopaminergic neurons by regulating the Nrf2/HMOX1 pathway in the 6-OHDA/MPP+-induced model of Parkinson’s disease

BackgroundParkinson's disease (PD) is a degenerative neurological disease that worsens over time. Ferroptosis has been proven to contribute to PD pathogenesis. CDG exhibits neuroprotective effects. However, CDG's potential mechanism in PD therapy remains uncertain.PurposeThe purpose of this investigation is to ascertain the specific molecular mechanisms of CDG against neuronal ferroptosis and present an alternative option for PD management.MethodsNetwork pharmacology along with LC–MS were used to identify possible targets and candidate pathways. Then RNA-sequencing combined in the in vitro and in vivo experiments were utilized to validate these findings.ResultsAccording to network pharmacology prediction, NFE2L2, HMOX1 and PTGS2 may be the key genes for ferroptosis in PD. In the in vivo experiments, CDG ultimately improved the neurobehavior of PD rats by alleviating the damage of dopamine neurons, decreasing the levels of MDA, ROS and Fe2+, increasing the GSH level, inhibiting ferroptosis by decreasing ACSL4, TF, and PTGS2 expression levels, and increasing the GPX4, FTH, Nrf2, and HMOX1 levels. RNA-seq analysis showed the differential genes in Model and CDG group were all enriched in Nrf2 and HMOX1, and the enrichment analysis of these differential genes showed they were closely related to the ferroptosis. Subsequently, in vitro experiments, the CDG, OE-Nrf2 and OE-HMOX1 group showed more active cell vitality, with decreasing levels of MDA, ROS, Fe2+, ACSL4, TF and PTGS2, and increasing level GSH, GPX4, FTH, Nrf2 and HMOX1.ConclusionCDG has a neuroprotective involvement in alleviating ferroptosis by regulating the Nrf2/HMOX1 pathway. Moreover, this research offers pharmacological evidence supporting the applications of CDG for treating PD.

Identification of pyroptosis-associated miRNAs in the immunoscape and prognosis of hepatocellular carcinoma

BackgroundHepatocellular carcinoma is one of the most prevalent types of liver malignancy and poses a severe threat to global health. Despite recent improvements in therapeutic approaches, treatment options for patients with advanced or recurrent HCC are still limited.Materials and methodsOur study analyzed miRNA differential expression using data from hepatocellular carcinoma patients in the Cancer Genome Atlas. Pyroptosis-related genes were identified from gene cards. Differential expression of miRNAs was analyzed using DESeq2 and visualized using ggplot2 and pheatmap. A prognostic risk model for pyroptosis-associated miRNAs was constructed using LASSO regression and validated by principal component analysis, Kaplan-Meier survival and ROC curve analysis. We also performed gene and pathway enrichment analysis. Immune cell infiltration and function in HCC were assessed using single-sample genomic enrichment analysis, and correlations with immune cells and function were explored. Also, CCK-8 assay as well as migration and invasion assays were performed after knockdown of miR-6844.ResultsWe have established and validated a prognostic risk model based on ten DEmiRNAs, which is important for the survival of HCC patients. Significant changes in immune cell infiltration and immune function were also found in high-risk patients. It also demonstrated that knockdown of miR-6844 inhibited HCC cell proliferation, migration and invasion, highlighting its role in HCC progression.ConclusionOur study reveals the implications of pyroptosis-associated differential miRNAs on the prognosis of patients with hepatocellular carcinoma and provides a foundation for novel HCC therapies, especially immunotherapy.

Genome-wide association studies and functional annotation of pre-weaning calf mortality and reproductive traits in Nellore cattle from experimental selection lines

BackgroundReproductive efficiency is crucial for the long-term economic sustainability of beef cattle production. Pregnancy loss and stillbirth are complex reproductive traits that do not yet have their genomic background fully understood, especially in zebu breeds (Bos taurus indicus). Hence, this study aimed to perform a genome-wide association study (GWAS) and functional annotation for conception success (CS), pregnancy loss (PL), stillbirth (SB), and pre-weaning calf mortality (PWM) in Nellore cattle. In this study, 3,728 cows with 17,094 reproductive records and 11,785 calves were evaluated. A total of 3,351 genotyped animals and 383,739 SNP markers were considered for GWAS analyses. SNP effects were estimated using the weighted single-step GWAS (WssGWAS), which considered two iterations. The top ten genomic windows with the highest contribution to the additive genetic variance of the traits were selected for gene annotation. Candidate genes were then analyzed for Gene Ontology terms (GO) and metabolic pathways.ResultsThe top ten genomic windows that explained the largest proportion of the direct additive genetic variance () for CS, PL, SB, and PWM accounted for 17.03% (overlapping with 79 genes), 16.76% (57 genes), 11.71% (73 genes), and 12.03% (65 genes) of the total , respectively. For CS, significant GO terms included Somitogenesis (GO:0001756), Somite Development (GO:0061053), and Chromosome Segregation (GO:0007059). Considering PL, the processes annotated were the Regulation of Hormone Secretion (GO:0046883), and Hormone Transport (GO:0009914), along with the Glucagon Signaling Pathway (bta04922). Embryonic Development (GO:0045995), and Cerebellum Development (GO:0021549) were the main biological processes found in the gene enrichment analysis for SB. For PWM, the Regulation of Glucose metabolic processes (GO:0010906), Zinc Ion Homeostasis (GO:0055069), Lactation (GO:0007595), and Regulation of Insulin Secretion (GO:0050796) were the most significant GO terms observed.ConclusionsThese findings provide valuable information on genomic regions, candidate genes, biological processes, and metabolic pathways that may significantly influence the expression of complex reproductive traits in Nellore cattle, offering potential contributions to breeding strategies and future genomic selection strategies.

Genomic Insights into Rheumatoid Arthritis through computational Profiling for Hub Genes

Rheumatoid arthritis (RA) is a complex autoimmune disorder predominantly affecting joints, with its etiology and response to treatment still not fully understood despite extensive historical documentation. This study aims to shed light on the differentially expressed genes (DEGs) associated with RA progression, potentially identifying new drug targets and management strategies. This study analyzed gene expression data (GSE193193) from the Gene Expression Omnibus (GEO) database, identifying 3672 significant DEGs out of 36107 initially retrieved genes. Among these, 283 genes were up-regulated and 360 were down-regulated. Gene enrichment analysis was performed to uncover relevant gene ontology terms and pathways. Subsequently, network construction and analysis, along with hub gene prediction using Cytoscape's MCODE and CytoHubba plugins, were conducted. Key genes identified in this study include HBB, ALAS2, GATA1, AHSP, HBG1, HBG2, HBD, KLF1, SLC4A1, EPB42, ZMYND10, DNAJC7, HYDIN, LRRC6, FN1, NCAM1, FASLG, CTCF, SMAD4, and STAT1. These genes are implicated not only in RA but also in other diseases, presenting them as potential therapeutic targets. Additionally, three transcription factors (GATA1, NFKB1, and RELA) and one miRNA (has-mir-27a-3p) were identified as key regulators of these hub genes. In conclusion, this study not only enhances our understanding of the molecular mechanisms underlying RA but also identifies several critical DEGs and regulatory factors that could serve as promising targets for therapeutic intervention. The identification of these genes and regulatory elements paves the way for the development of targeted treatments, which could significantly improve disease management and patient outcomes. Future research focusing on these identified targets may lead to innovative strategies for combating RA and potentially other autoimmune disorders, thereby offering new hope to patients affected by these conditions.

Single-cell transcriptome analysis reveals status changes of immune cells in chronic kidney disease.

The immune system plays a crucial role in the development of kidney diseases. Chronic kidney disease (CKD) can lead to various complications, potentially affecting multiple systems throughout the body. Currently, the description of the immune system in human CKD is not comprehensive enough. Constructing a CKD kidney atlas using single-cell RNA sequencing (scRNA-seq) can provide deeper insights into the composition and functional changes of immune cells in CKD, facilitating the discovery of new therapeutic targets. We processed and integrated scRNA-seq datasets from healthy and CKD kidneys from three independent cohorts using the same approach (including 42 normal samples and 23 chronic kidney disease samples). Subsequently, we conducted gene enrichment and intercellular communication analysis to construct an immune cell atlas of the kidneys in CKD patients. We identified nine major kidney cell clusters. Further clustering analysis of different immune cell clusters revealed that, compared to normal kidneys, CKD patients' kidneys had decreased CD16+ NK cells while CD4+ naive helper T cells and CCR7+ DC increased. Partial activation of the WNT signaling pathway was observed in T cells and NK cells of CKD patients, while some metabolism-related genes were inhibited. Myeloid cell subgroups also exhibited abnormal signaling pathway alterations. Additionally, we discovered a unique population of SPP1 macrophages in CKD, which are recruited by chemokines released from aPT and aTAL cell subpopulations. These SPP1 macrophages may promote cellular fibrosis through the signaling of SPP1, FN1, and various receptors. We established a human CKD kidney immune cell atlas and identified SPP1 macrophages as a unique cell type in CKD. The interaction between SPP1 macrophages and damaged cells may serve as a potential therapeutic target for treating CKD in the future.

Daidzein Inhibits Non-small Cell Lung Cancer Growth by Pyroptosis.

Non-Small-Cell Lung Cancer (NSCLC) represents the leading cause of cancer deaths in the world. We previously found that daidzein, one of the key bioactivators in soy isoflavone, can inhibit NSCLC cell proliferation and migration, while the molecular mechanisms of daidzein in NSCLC remain unclear. We developed an NSCLC nude mouse model using H1299 cells and treated the mice with daidzein (30 mg/kg/day). Mass spectrometry analysis of tumor tissues from daidzein-treated mice identified 601 differentially expressed proteins (DEPs) compared to the vehicle-treated group. Gene enrichment analysis revealed that these DEPs were primarily associated with immune regulatory functions, including B cell receptor and chemokine pathways, as well as natural killer cell-mediated cytotoxicity. Notably, the NOD-like receptor signaling pathway, which is closely linked to pyroptosis, was significantly enriched. Further analysis of key pyroptosis-related molecules, such as ASC, CASP1, GSDMD, and IL-1β, revealed differential expression in NSCLC versus normal tissues. High levels of ASC and CASP1 were associated with a favorable prognosis in NSCLC, suggesting that they may be critical effectors of daidzein's action. In NSCLC-bearing mice treated with daidzein, RT-qPCR and Western blot analyses showed elevated mRNA and protein levels of ASC, CASP1, and IL-1β but not GSDMD, which was consistent with the proteomic data. In summary, this study demonstrated that daidzein inhibits NSCLC growth by inducing pyroptosis. Key pathway modulators ASC, CASP1, and IL-1β were identified as primary targets of daidzein. These findings offer insights into the molecular mechanisms underlying the anti-NSCLC effects of daidzein and could offer dietary recommendations for managing NSCLC.

Assessment of genetic structure and trait associations of Watkins wheat landraces under Egyptian field conditions

BackgroundWheat landraces represent a reservoir of genetic diversity that can support wheat improvement through breeding. A core panel of 300 Watkins wheat landraces, as well as 16 non-Watkins landraces and elite wheat cultivars, was grown during the 2020–2021 and 2021–2022 seasons at four Agricultural Research Stations in Egypt, Gemmiza, Nubaria, Sakha, and Sids, to evaluate the core panel for agromorphological and yield-related traits. The genetic population structure within these genotypes were assessed using 35,143 single nucleotide polymorphisms (SNPs).ResultsCluster analyses using Discriminant Analysis of Principal Components (DAPC) and k-means revealed three clusters with moderate genetic differentiation and population structure, possibly due to wheat breeding systems and geographical isolation. The best ancestry was k = 4, but k = 2 and k = 3 were also significant. A genome-wide association study (GWAS) identified clustered marker trait associations (MTAs) linked to thousand kernel weight on chromosome 5A, plant height on chromosomes 3B and 1D, days to heading on chromosomes 2A, 4B, 5B and 1D, and plant maturity on chromosomes 3A, 2B, and 6B. In the future, these MTAs can be used to accelerate the incorporation of beneficial alleles into locally adapted germplasm through marker-assisted selection. Gene enrichment analysis identified key genes within these loci, including Reduced height-1 (Rht-A1) and stress-related genes.ConclusionThese findings underscore significant genetic connections and the involvement of crucial biological pathways.

Single-cell RNA Sequencing Analysis Reveals the Role of Cancerassociated Fibroblasts in Skin Melanoma.

Mechanism of fibroblasts in skin melanoma (SKME) revealed by single-cell RNA sequencing data. SKME is responsible for more than 80% of skin-related cancer deaths. Cancer-associated fibroblasts (CAFs) generate inflammatory factors, growth factors and extracellular matrix proteins to facilitate cancer cell growth, metastasis, drug resistance and immune exclusion. However, molecular mechanisms of CAFs in SKME are still lacking. Our goal was to reveal the role of CAFs in SKME. We downloaded the single-cell RNA sequencing (scRNA-seq) dataset from the Gene Expression Omnibus (GSE215120) database. Then, the Seurat package was applied to analyze the single-cell atlas of SKME data, and cell subsets were annotated with the CellMarker database. The molecular mechanisms of CAFs in SKME were disclosed via differential gene expression and enrichment analysis, Cellchat and SCENIC methods. Using scRNA-seq data, three SKME cases were used and downscaled and clustered to identify 11 cell subgroups and 5 CAF subsets. The enrichment of highly expressed genes among the 5 CAF subsets suggests that cell migration-inducing hyaluronan-binding protein (CEMIP) + fibroblasts and naked cuticle homolog 1 (NKD1)+ fibroblasts were closely associated with epithelial to mesenchymal transition. Cellchat analysis revealed that CAF subpopulations promoted melanocyte proliferation through Jagged1 (JAG1)-Notch homolog 1 (NOTCH1), JAG1-NOTCH3 and migration through pleiotrophin (PTN)-syndecan-3 (SDC3) receptor-ligand pairs. The SCENIC analysis identified that most of the transcription factors in each CAF subpopulation played a certain role in the metastasis of melanoma and were highly expressed in metastatic SKME samples. Specifically, we observed that CEMIP+ fibroblasts and NKD1+ fibroblasts had potential roles in participating in immune therapy resistance. Collectively, we uncovered a single-cell atlas of SKME and revealed the molecular mechanisms of CAFs in SKME development, providing a base for immune therapy and prognosis assessment. Our study reveals that 5 CAFs in SKME have a promoting effect on melanocyte proliferation and metastasis. More importantly, CEMIP+ fibroblasts and NKD1+ fibroblasts displayed close connections with immune therapy resistance. These findings help provide a good basis for future immune therapy and prognosis assessment targeting CAFs in SKME.

Medical Treatment of Hypercortisolism with Relacorilant: Final Results of the Phase 3 GRACE Study

Diabetic cardiomyopathy (DCM) is a cardiometabolic syndrome, manifested by ventricular diastolic or systolic dysfunction which occurs in approximately 12% of diabetic patients. Diabetes perpetuates the development of microvascular complications that can exacerbate cardiovascular pathologies. Understanding the common molecular targets underlying these two conditions is important for designing effective interventions that can address diabetes and related complications simultaneously. Herein, we aim to investigate the underlying network of key modules associated with diabetic cardiomyopathy. In current study, microarray gene expression profiles of diabetic and cardiomyopathy patients possessing accession number (GSE30122 and GSE20966) and (GSE89714, GSE3586, and GSE1145) were retrieved from Gene Expression Omnibus (GEO) database to explore key modulators. The differentially expressed genes (DEGs) were analyzed via GEO2R tool, based on the cut off criteria (p ≤ 0.05) and log2(FC)>|±1|. 37 overlapped DEGs were identified which then subjected to miRNA target prediction, protein-protein interaction (PPI) network construction and module screening via TargetScan, ShinyGO, STRING, and Cytoscape respectively, to screen hub genes as potential targets. Functional gene enrichment analysis identified enrichment of DEGs in heart contraction, apoptosis, cytokines signaling, beta adrenergic signaling and GPCR neurotransmitter receptor activity. The miRNA-mRNA regulatory network identified 9 hub genes, including ADRB1, TGFB2, RAP2A, CALD1, WIPF1, ATP10a, AKAP1, NR4A3, EXT1 and 4 hub miRNAs including miR-199-5, miR-200a, mir141-3, and miR-19-3p based on their degree of connectivity and centrality within the network. Conclusively, our analysis unveiled hub genes and miRNAs associated with diabetes-linked cardiomyopathy that might considered as biomarkers and offer a reliable tool for developing effective therapeutic strategies in future.

Integrating transcriptome and metabolome to explore the formation of fruit aroma in different types of pepper

The fruity aroma of capsicum is a crucial aspect of its flavor profile, and it is imperative to thoroughly investigate the metabolic and genetic foundations underlying its formation. In this study, 7 samples from 5 pepper varieties were used as test materials, and the detection of volatile organic compounds was carried out by SPME-GC-MS/MS. The transcriptome sequencing work was completed using the Illumina platform, and further completed the difference analysis and correlation analysis. 766 volatile organic compounds were detected, 136.6 Gb of clean data were obtained, and a significant difference was found in metabolites and gene expression among different samples. Through further difference analysis, it was found that the contents of 50 metabolites in DC351 (55 DAP) and DC612 with aromatic fruits were significantly higher than those of other varieties; additionally, the rOAV value of 8 metabolites exceeded 1. And ester and terpene metabolites were the key metabolites of pepper fruit aroma. 20 modules have achieved gene enrichment analysis. Further analysis revealed key genes involved in the lipoxygenase and MEP pathways. For example, genes such as alcohol dehydrogenase (Capana06g000848) were closely related to the content of lipid metabolites such as acetic acid nonyl ester, while genes such as 1-deoxy-D-xylulose-5-phosphate reductase (Capana03g000964) were closely related to the content of terpenoid metabolites such as 1- (2,6,6-trimethyl-1,3-cyclohexan-1-yl) - and (E) -. In conclusion, our research is expected to uncover key metabolites and genes related to the aroma of pepper fruits, which is of great significance for trait improvement and genetic research.

The efficacy of plasma exosomal miRNAs as predictive biomarkers for PD-1 blockade plus chemotherapy in gastric cancer.

The response of gastric cancer (GC) patients to first-line programmed cell death 1 (PD-1) blockade and S-1 plus oxaliplatin (SOX) chemotherapy varies considerably, and the underlying mechanisms driving this variability remain elusive. Exosomal microRNAs (miRNAs or miRs) have emerged as potential biomarkers for efficacy prediction due to their roles in GC biology and stable expression in serum. In this study, we aimed to identify biomarkers to predict patients' response to anti-PD-1 therapy and further elucidate the potential mechanisms by which these exosomal miRNAs modulate the immune response in GC. Serum exosomes were extracted from 11 GC patients (five in the primary cohort and six in the validation cohort) treated with SOX and camrelizumab (a PD-1 inhibitor). High-throughput sequencing was performed to identify miRNA expression profiles, after which hierarchical clustering and a differential expression analysis were conducted. Functional enrichment analyses of the target genes for the significantly upregulated miRNAs were performed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The validation of the candidate miRNAs was carried out by quantitative polymerase chain reaction (qPCR) in an independent cohort. MiRNA sequencing identified 3,083 miRNAs, of which 74 (42 upregulated and 32 downregulated) were differentially expressed between the responders and non-responders. The GO and KEGG pathway analyses of the top 20 upregulated miRNAs indicated that the target genes were significantly involved in transcription regulation, cytoplasmic processes, and protein binding, and that key pathways included the PI3K-AKT, MAPK, RAP1, and RAS signaling pathways. Consistent with the sequencing findings, the qPCR validation results showed significant differences in the expression levels of miRNA451a and miRNA142-5p between the responders and non-responders. This study identified specific plasma exosomal miRNAs in GC patients that differ between responders and non-responders to PD-1 monoclonal antibody therapy combined with chemotherapy. These miRNAs could serve as predictive biomarkers, paving the way for precision medicine and personalized therapy in the treatment of GC.

Exploring the potential mechanisms of Acer tegmentosum Maxim in preventing alcoholic liver disease based on network pharmacology and molecular docking

To investigate the potential mechanisms of Acer tegmentosum Maxim (AT) in preventing Alcoholic liver disease (ALD), this study used network pharmacology and molecular docking methods to screen the main active ingredients of AT for preventing core target proteins related to ALD, conducted GO and KEGG pathway enrichment analysis and performed molecular docking and visualisation. The results showed that AT’s top five active components were kaempferol-3-rhamnoside, salidroside, linoleic acid, ethyl linoleate, and tyrosol. The top five core target proteins for preventing ALD with AT were SRC, AKT1, STAT3, MAPK1, and ESR1. Gene enrichment analysis indicated that AT may inhibit the occurrence of ALD by improving inflammation and cancer pathways, and the core components of AT were well combined with critical targets, further elucidated the preventive mechanism of ALD through multiple components, targets, and pathways. It can provide a new idea for studying the mechanism of AT active ingredients to prevent ALD.

CRHBP, a novel multiple cancer biomarker connected with better prognosis and anti-tumorigenicity

BackgroundThe corticotropin-releasing hormone-binding protein (CRHBP) plays a crucial role in regulating corticotropin release. Little is known about the role of CRHBP, a major regulator of neuroendocrine, autonomic, and stress adaptation, in tumors. In this study, we aimed to investigate the clinical and molecular landscapes of CRHBP in various types of tumors.MethodsWe investigated the role of CRHBP in different types of tumors using publicly available databases and performed a comparative expression analysis of CRHBP-related genes in pan-cancer prognosis using methylation profiling, tumor-infiltrating immune cell expression analysis, gene enrichment analysis, and protein-protein interaction analysis, identified common pathways, and in vitro evaluation.ResultsWe evaluated CRHBP expression across tumor and corresponding normal tissues using the data from The Cancer Genome Atlas and the Genotype-Tissue Expression database. CRHBP was downregulated in most tumors and was identified as an important factor for predicting the prognosis of patients with cancer. Intracellular metabolic pathways and hormone-related processes were involved in the functional mechanisms of CRHBP. Mechanistically, the downregulation of CRHBP was attributed to the upregulation of four miRNAs in most tumors, and CRHBP expression was related to tumor-infiltrating immune cells in tumors. Overexpression of CRHBP significantly inhibited cell proliferation of LUAD, LIHC, and KIRC cell lines, while inhibition of cell mobility was found only in KIRC and HCC cells.ConclusionsThis study provides a comprehensive summary of the systemic role of CRHBP expression in various types of tumors, highlighting the prognostic importance and clinical significance of tumors. Furthermore, CRHBP decreases cell proliferation and mobility in cancer cell lines associated with OS and DFS, further research is needed to understand the underlying mechanisms and explore clinical applications.

SKA1/2/3 is a prognostic and predictive biomarker in esophageal adenocarcinoma and squamous cell carcinoma

BackgroundEsophageal carcinoma (ESCA) ranks among the most prevalent malignant tumors globally. Despite significant advancements in treatment options and improved patient outcomes, the 5-year survival rate remains unsatisfactory. The spindle and kinetochore associated complex subunit 1/2/3 (SKA1/2/3) attached to the kinetochore (KT) in the metaphase of mitosis are implicated in the occurrence and development of various tumors. However, the expression patterns, diagnostic significance and prognostic implications of SKA1/2/3 in ESCA have not been comprehensively determined.MethodsTCGA, UALCAN, Kaplan-Meier Plotter, and TIMER databases were leveraged to dissect the expression patterns, prognostic implications and diagnostic value of SKA1/2/3 in ESCA patients, as well as to investigate the potential regulatory mechanism of SKA1/2/3 in the onset and progression of ESCA.ResultsIn ESCA, SKA1/2/3 exhibited substantial expression, with higher levels relating significantly with clinicopathological features and patient prognosis. Enrichment analysis of genes co-expressed with SKA1/2/3 highlighted their involvement in the cell cycle, DNA replication and p53 signaling pathway. Protein-protein interaction (PPI) analysis identified ten hub genes that were not only markedly upregulated but also portended a poor prognosis in ESCA. Additionally, immune infiltration assays uncovered a significant link between SKA1/2/3 expression and the immune cell infiltration within ESCA. Silencing of SKA1/2/3 significantly suppresses cell proliferation and migration, while concurrently promoting apoptosis in ESCA cells.ConclusionsSKA1/2/3 may serve as promising biomarkers for the prognosis and diagnosis of ESCA, which holds promise as a novel therapeutic target for the disease.

Whole-genome sequencing analysis of Japanese autism spectrum disorder trios.

Autism spectrum disorder (ASD) is a genetically and phenotypically heterogeneous neurodevelopmental disorder with a strong genetic basis. Conducting the first comprehensive whole-genome sequencing (WGS) analysis of Japanese ASD trios, this study aimed to elucidate the clinical significance of pathogenic variants and enhance the understanding of ASD pathogenesis. WGS was performed on 57 Japanese patients with ASD and their parents, investigating variants ranging from single-nucleotide variants to structural variants (SVs), short tandem repeats (STRs), mitochondrial variants, and polygenic risk score (PRS). Potentially pathogenic variants that could explain observed phenotypes were identified in 18 patients (31.6%) overall and in 10 of 23 patients (43.5%) with comorbid intellectual developmental disorder (IDD). De novo variants in PTEN, CHD7, and HNRNPH2 were identified in patients referred for genetic counseling who exhibited previously reported phenotypes, including one patient with ASD who had profound IDD and macrocephaly with PTEN L320S. Analysis of the AlphaFold3 protein structure indicated potential inhibition of intramolecular interactions within PTEN. SV analysis identified deletions in ARHGAP11B and TMLHE. A pathogenic de novo mitochondrial variant was identified in a patient with ASD who had a history of encephalitis and cognitive decline. GO enrichment analysis of genes with nonsense variants and missense variants (Missense badness, PolyPhen-2, and Constraint >1) showed associations with regulation of growth and ATP-dependent chromatin remodeler activity. No reportable results were obtained in the analysis of STR and PRS. Characterizing the comprehensive genetic architecture and phenotypes of ASD is a fundamental step towards unraveling its complex biology.

Network pharmacology‑based analysis and in vitro experimental verification of the inhibitory role of luteoloside on gastric cancer cells via the p53/p21 pathway.

The present study aimed to investigate the inhibitory effect of luteoloside on the proliferation, migration and invasion of gastric cancer (GC) cells based on network pharmacology and in vitro experiments. GC-associated targets were obtained from the GeneCards and Online Mendelian Inheritance in Man databases. Gene Ontology functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed using the Database for Annotation, Visualization and Integrated Discovery. Protein-protein interaction (PPI) networks and herb-active ingredient-target gene-signaling pathway networks were constructed using the Search Tool for the Retrieval of Interacting Genes and proteins and Cytoscape software to analyze core target genes and pathways. In addition, the alkaline comet assay was performed to assess DNA damage, demonstrating that luteoloside induces DNA double-strand breaks in a concentration-dependent manner, as indicated by increased comet tail lengths. γ-H2AX detection through western blot analysis further corroborated these findings, showing significant upregulation of this DNA damage marker in luteoloside-treated GC cells. The human GC cell line NCI-N87 was utilized for in vitro experiments to investigate the impact of different doses of luteoloside on cell proliferation, invasion and migration using Cell Counting Kit-8, scratch-wound and Transwell assays, respectively. The underlying molecular mechanism of luteoloside was explored using western blot analysis. The successfully constructed PPI network revealed the p53, Akt1, Bcl-2 and Caspase-3 proteins as the core targets, all of which showed good binding activity with luteoloside. The in vitro experiments demonstrated that luteoloside treatment significantly inhibited GC-cell proliferation, migration and invasion. The western blot results showed notable concentration-dependent upregulation of p53 and p21 protein expression and downregulation of Bcl-2 protein expression following luteoloside treatment. Overall, luteoloside inhibited the proliferation, migration and invasion of GC cells by activating the p53/p21 signaling pathway.

Causal associations between sexually transmitted infections, depression, and self-harm: a mendelian randomization and cross-sectional study

BackgroundThe causal relationships between sexually transmitted infections, depression, and self-harm remain unclear.MethodsWe executed various Mendelian Randomization (MR) analyses. At the same time, a cross-sectional analysis from NHANES was used for verification and an enrichment analysis was also utilized to explore the potential common gene functions.ResultsWe found that STIs may have a potential causal effect on depression (P = 0.002) and self-harm (P = 0.003). Conversely, self-harm has been identified as a risk factor for the acquisition of STIs (P = 0.006), while there is no evidence to support an effect of depression on STIs. Furthermore, mediation MR indicated that monocyte absolute count played a mediating role in the association between STIs and depression, accounting for 7.7%. And then, the weighted regression analysis of the cross-sectional analysis demonstrated a significant association between one of the common STIs, HPV, and depression. Gene enrichment analysis suggested that the PI3K-Akt signalling pathway and the infectious virus signalling pathway may represent a common underlying pathogenesis.ConclusionSTIs may increase the risk of depression and self-harm, while self-harm might also represent a risk factor for STIs, which could provide insights and a foundation for the control of STIs and mental health monitoring in clinical practice.

CCT39-COMT1/BGLU18-2 module promotes lignin biosynthesis in poplar

Lignin is a crucial constituent of cell walls and plays a pivotal role in plant growth and development. However, the transcriptional regulatory network governing lignin biosynthesis is not fully understood. In this study, we observed that PpnCCT39 overexpression resulted in greener stems, larger basal diameters, and increased stem dry weight. Additionally, the secondary xylem of lines overexpressing PpnCCT39 was wider, had larger xylem fiber cell areas, and thicker cell walls, compared to those of wild-type plants. Furthermore, PpnCCT39 overexpression led to elevated lignin content and enhanced the rigidity of secondary cell walls. RNA-seq and ChIP-seq association analyses identified 826 potential regulatory target genes of PpnCCT39 that were upregulated and expressed in 1-month-old PpnCCT39 overexpression lines. Gene enrichment analyses revealed enrichment in pathways related to cell wall formation, xylem and phloem development, and the phenylpropanoid pathway. Two genes involved in lignin biosynthesis, PagCOMT1 and PagBGLU18–2, exhibited significantly increased expression in stems of lines overexpressing PpnCCT39, as demonstrated by high FPKM values and RT-qPCR results. Further investigations using yeast one-hybrid, dual-luciferase assays, and electrophoretic mobility shift assays demonstrated that PpnCCT39 directly activates the transcription of PagCOMT1 and PagBGLU18–2, thereby promoting lignin biosynthesis. This study elucidated the transcriptional regulatory mechanism of PpnCCT39 in poplars and revealed its role in activating the expression of key lignin biosynthesis genes. PpnCCT39 facilitates lignin biosynthesis and secondary growth processes, offering a novel theoretical framework for modulating lignin biosynthesis and enhancing timber yield through molecular design.

KLF4 promotes cisplatin resistance by activating mTORC1 signaling in ovarian cancer

Ovarian cancer (OC) is a highly fatal gynecological malignancy worldwide, and cisplatin (CDDP) is commonly used as an initial chemotherapy treatment for OC. Nonetheless, most patients ultimately face recurrence because of resistance to cisplatin. Therefore, it is imperative to investigate the underlying mechanisms of drug resistance in OC. By analyzing differential gene expression using TCGA, GDSC, and GEO public databases, we discovered that increased KLF4 expression is strongly linked to chemotherapy resistance and unfavorable outcomes in OC. Subsequent validation through immunohistochemistry and western blotting confirmed the upregulated KLF4 expression in cisplatin-resistance OC cells lines and tissues. To investigate the function of KLF4, functional experiments were performed both in vitro and in vivo. We observed that knocking down KLF4 impaired cisplatin-resistance of OC. Further mechanism research based on RNA-seq and gene enrichment analysis revealed that interfering KLF4 suppressed the activation of mTORC1 pathway. Finally, rescue experiment demonstrated that using mTORC1 pathway inhibitor could attenuate the cisplatin resistance induced by the overexpression of KLF4. In conclusion, our research indicates that KLF4 promotes cisplatin resistance through the activation of mTORC1 signaling, and proposes that inhibiting KLF4 might serve as a viable therapeutic approach to overcoming drug resistance in ovarian cancer.