Search Tool For The Retrieval Of Interacting Genes/Proteins Research Articles

Systematic ocular phenotyping of 8,707 knockout mouse lines identifies genes associated with abnormal corneal phenotypes

PurposeCorneal dysmorphologies (CDs) are typically classified as either regressive degenerative corneal dystrophies (CDtrs) or defective growth and differentiation-driven corneal dysplasias (CDyps). Both eye disorders have multifactorial etiologies. While previous work has elucidated many aspects of CDs, such as presenting symptoms, epidemiology, and pathophysiology, the genetic mechanisms remain incompletely understood. The purpose of this study was to analyze phenotype data from 8,707 knockout mouse lines to identify new genes associated with the development of CDs in humans.Methods8,707 knockout mouse lines phenotyped by the International Mouse Phenotyping Consortium were queried for genes associated with statistically significant (P < 0.0001) abnormal cornea morphology to identify candidate CD genes. Corneal abnormalities were investigated by histopathology. A literature search was used to determine the proportion of candidate genes previously associated with CDs in mice and humans. Phenotypes of human orthologues of mouse candidate genes were compared with known human CD genes to identify protein-protein interactions and molecular pathways using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), Protein Analysis Through Evolutionary Relationships (PANTHER), and Kyoto Encyclopedia of Genes and Genomes.ResultsAnalysis of data from 8,707 knockout mouse lines identified 213 candidate CD genes. Of these, 37 (17%) genes were previously known to be associated with CD, including 14 in the mouse, 16 in humans, and 7 in both. The remaining 176 (83%) genes have not been previously implicated in CD. We also searched publicly available RNAseq data and found that 131 of the total 213 (61.5%) were expressed in adult human corneal tissue. STRING analysis showed several interactions within and between candidate and established CD proteins. All cellular pathways of the established genes were found in the PANTHER analysis of the candidate genes. Several of the candidate genes were implicated in corneal disease, such as TGF-ß signaling. We also identified other possible underappreciated mechanisms relevant to the human cornea.ConclusionsWe identified 213 mouse genes that resulted in statistically significant abnormal corneal phenotypes in knockout mice, many of which have not previously been implicated in corneal pathology. Bioinformatic analyses implicated candidate genes in several signaling pathways which are potential therapeutic targets.

Proteins and pathways involved in inflammation are longitudinally associated with total body bone mineral density among primarily hispanic overweight/obese adolescents and young adults.

Bone mineral density (BMD), an important marker of bone health, is regulated by a complex interaction of proteins. Plasma proteomic analyses can contribute to identification of proteins associated with changes in BMD. This may be especially informative in stages of bone accrual and peak BMD achievement (i.e., adolescence and young adulthood), but existing research has focused on older adults. This analysis in the Study of Latino Adolescents at Risk for Type 2 Diabetes (SOLAR; n = 304; baseline age 8-13, 100% Hispanic) explored associations between baseline proteins (n = 653 proteins) measured with Olink® plasma protein profiling and repeated annual DXA measures of BMD (average of 3.2 visits per participant). Covariate-adjusted linear mixed effect regression models were applied to estimate longitudinal protein-BMD associations using an adjusted p-value cutoff (P < 0.00068). Identified proteins were imported into the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database to determine significantly enriched protein pathways. Forty-four proteins, many of which are involved in inflammatory processes, were associated with longitudinal changes in total body BMD, including several proteins previously linked to bone health such as osteopontin (SPP1) and microfibrillar-associated protein 5 (MFAP5; both P < 0.00068). These 44 proteins were associated with enrichment of pathways including PI3K-Akt Signaling Pathway and Cytokine-Cytokine Receptor Interaction, supporting results from existing proteomics analyses in older adults. To evaluate whether protein associations were consistent into young adulthood, linear mixed effect models were repeated in a young adult cohort (n = 169; baseline age 17-22; 62.1% Hispanic) with 346 available overlapping Olink® protein measures. While there were no significant overlapping longitudinal protein associations between the cohorts, these findings suggest differences in protein regulation at different ages and provide novel insight on longitudinal protein associations with BMD in overweight/obese adolescents and young adults of primarily Hispanic origin, which may inform the development of biomarkers for bone health in youth.

The Anaphylactic and Anti-allergenic Properties of Shuanghuanglian: A Review.

Shuanghuanglian (SHL) and its primary constituents have demonstrated protective effects against allergenic diseases. This review examines the anaphylactic and anti-allergenic activities of SHL and its constituents. We also discuss potential avenues for future research, particularly regarding the expansion of the clinical applications of SHL formulations (oral or nebulized) for the treatment of allergenic disorders. For this review, we searched the PubMed, Web of Science, and China National Knowledge Infrastructure databases for relevant publications. Additionally, details of the essential active components and target genes of SHL were obtained from the Traditional Chinese Medicine Systems Pharmacology database (TCMSP), and information on allergy-related genes was collected from the GeneCards and Online Mendelian Inheritance in Man(OMIM) databases. Lists of both the SHL target and disease-related genes were imported into the 'Draw Venn Diagram' tool on the website (http://bioinformatics.psb.ugen /web tools/Venn/). A protein-protein interaction network for SHL and disease targets was constructed with reference to the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and the potential pathways were identified based on Kyoto Encyclopaedia of Genes and Genome enrichment analyses. The allergenic reactions induced by SHL injection (intravenous) and its main constituents (intraperitoneal or intravenous injection) have been verified in animal experiments. Furthermore, the protective effects of SHL injection (intraperitoneal) and its individual Chinese herb components (intragastric administration), namely, Flos Lonicerae, Radix Scutellariae, and Fructus Forsythiae, as well as their main constituents (intraperitoneal or intragastric administration), have been verified in asthma, rhinitis, atopic dermatitis, and both IgE- and non-IgE-mediated systemic allergic responses. The network pharmacology analysis revealed that the therapeutic effects of SHL might be primarily mediated through the regulation of the IL-17 and TNF-α signalling pathways and Th17 cell differentiation. Accumulated research data provide a theoretical basis for the clinical application of SHL (via extravascular routes) in the treatment of allergenic diseases.

FOXF2 may inhibit esophageal squamous cell carcinoma growth and metastasis by regulating the EZR-ERBB2 axis.

FOXF2, a member of the transcription factor FOX family proteins, plays a key role in tumorigenesis and tumor aggressiveness. However, the potential molecular mechanism of FOXF2 in esophageal squamous cell carcinoma (ESCC) remains largely unknown. Exploring its role and mechanism in ESCC progression may help identify new diagnostic markers and therapeutic targets. The aim of this study is to investigate the potential functions of the FOXF2 gene within the context of ESCC and to elucidate the underlying molecular pathways involved. Using the GoMiner database, GeneCard database, Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and the COMPARTMENTS subcellular localization database, we identified the most likely downstream molecule of the FOXF2 gene, EZR; the subcellular locations of FOXF2 and EZR; the possible biological pathways [Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG)]; and the protein interactions networks of the EZR gene enriched from the OMICS datasets via Metascape. We also used The Cancer Genome Atlas database to analyze the correlation between EZR and ERBB signaling pathway. In addition, we verified the RNA and protein expression of the target genes using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). Furthermore, we employed Western blot analysis and plasmid transfection and lentiviral infection techniques to gene edit FOXF2 and EZR in different EC cells to obtain stable overexpression or knockdown of the cell lines. This was followed by ex vivo and in vivo experiments including migration assay, cell scratch assay, clone formation assay, and a xenotransplantation mouse model to validate the functional phenotype of the gene-edited cells. We found that knockdown of FOXF2 expression significantly enhanced the growth, invasion, and metastasis of ESCC cells both in vitro and in vivo. Moreover, we demonstrated that FOXF2 was predominantly expressed in the nucleus and directly interacted with EZR, thereby inhibiting EZR transcriptional expression, resulting in suppressed ERBB2 signal function, ultimately halting ESCC growth and metastasis. Taken together, these results reveal the tumor-suppressive functions of FOXF2 in inhibiting EZR-mediated ERBB2 activation, suggesting that FOXF2 could serve as a potential novel predicting prognostic biomarker for ESCC.

Bioinformatics analysis reveals VEGFC's prognostic significance in head and neck squamous cell carcinoma and its association with immune cell infiltration.

Head and neck squamous cell carcinoma (HNSCC) has a poor prognosis due to late diagnosis and complex molecular mechanisms. Vascular endothelial growth factor C (VEGFC) is associated with angiogenesis and lymphangiogenesis. This study aimed to investigate VEGFC's prognostic value in HNSCC and its correlation with immune cell infiltration. VEGFC gene expression was analyzed in HNSCC patients using Tumor Immune Estimation Resource 2.0 (TIMER2.0), Gene Expression Profiling Interactive Analysis (GEPIA), and University of ALabama at Birmingham CANcer data analysis Portal (UALCAN) databases, focusing on differential expression and clinical-pathological correlations. The impact of VEGFC on overall survival (OS) and disease-free survival (DFS) was assessed using GEPIA. RNA-seq profiles and clinical information from 503 HNSCC tumor tissues and 44 normal control tissues obtained from The Cancer Genome Atlas (TCGA) database were subjected to univariate and multivariate Cox regression analyses to develop a prognostic nomogram. The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database was used for a protein-protein interaction (PPI) network, while the Tumor-Immune System Interaction Database (TISIDB) for immune-related associations. Expression was further validated with the Gene Expression Omnibus dataset (GSE6631) and reverse transcription quantitative polymerase chain reaction (RT-qPCR). VEGFC was significantly upregulated in HNSCC and closely correlated with age, gender, race, and tumor stage (P<0.05). PPI and co-expression gene analysis identified ITGA3, NT5E, and PXN as highly associated with VEGFC (R>0.6, P<0.05), which are mainly enriched in PI3K/Akt, MAPK signaling pathway, and cancer-associated glycoproteins. High VEGFC expression predicted poor OS (P=0.003) and DFS (P=0.03). Univariate and multivariate Cox regression analyses confirmed VEGFC as an independent prognostic factor for HNSCC. The prognostic nomogram accurately predicted 1-, 3-, and 5-year survival and calibration curve was very close to ideal 45-degree diagonal line. VEGFC also correlated with immune cells infiltration, including B cells, CD4+ T cells, CD8+ T cells, as well as immune-related markers such as tumor-infiltrating lymphocytes (TILs) markers, immune modulators, and inflammatory chemokines (P<0.05). VEGFC may serve as an independent prognostic factor and potential immunotherapeutic target in HNSCC, offering insights into patient risk stratification and personalized treatment strategies.

Lycopene's therapeutic mechanisms in epididymitis: a network pharmacology and experimental study.

Epididymitis, a common disease of the male reproductive system, is often caused by nonspecific infections. Antibiotics alone cannot reverse histopathological changes or prevent long-term reproductive issues. Lycopene (LYC), a potent antioxidant, has shown potential in alleviating epididymitis, yet its specific mechanisms remain unclear. This study used network pharmacology and in vivo experiments to explore LYC's mechanisms in treating epididymitis. Epididymitis- and LYC-related target proteins were identified from multiple databases and analyzed using the Venny platform. Protein interactions were examined with the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and key targets were identified via topological analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using the Database for Annotation, Visualization and Integrated Discovery (DAVID) database. Target-pathway networks were visualized in Cytoscape, molecular docking was performed with AutoDock Vina, and LYC's effects were validated in a lipopolysaccharide (LPS)-induced epididymitis mouse model. Network pharmacology results indicated that LYC's effects involve the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, which plays a crucial role in regulating inflammation and apoptosis. In vivo, LYC improved epididymal pathology, reduced inflammatory cell infiltration, and decreased key inflammatory cytokines, including interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). By inhibiting PI3K/AKT activation, LYC modulated inflammation and reduced apoptosis. Additionally, LYC enhanced antioxidant enzyme activity and elevated the B-cell lymphoma-extra large (Bcl-xL) ratio, reducing oxidative stress and apoptosis. Molecular docking supported these findings, showing strong binding affinities with PI3K/AKT pathway targets. This study highlights LYC's potential as an adjunctive treatment for epididymitis, targeting inflammation and oxidative stress via the PI3K/AKT pathway. These findings suggest that LYC could enhance current therapies and provide new options for the clinical management of epididymitis.

MDM2 interacts with PTEN to inhibit endothelial cell development and promote deep vein thrombosis via the JAK/STAT signaling pathway.

Deep vein thrombosis (DVT) is a prevalent clinical condition, which markedly affects patients' quality of life, commonly leading to post‑thrombotic syndrome. The present study aimed to elucidate the intricate interplay between murine double minute‑2 (MDM2) and phosphatase and tensin homolog (PTEN), thus shedding new light on their role in the pathogenesis of DVT. The results showed that both MDM2 and PTEN were upregulated in venous blood samples obtained from patients with DVT. However, MDM2 or PTEN knockdown markedly increased the proliferation, migration, invasion, apoptosis and angiogenesis of oxidized low‑density lipoprotein‑treated human umbilical vein endothelial cells (HUVECs). Furthermore, MDM2 silencing downregulated PTEN. The association between MDM2 and PTEN was verified through comprehensive analyses, including Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) analysis and co‑immunoprecipitation assays. The effect of PTEN on DVT was evaluated by Kyoto Encyclopedia of Genes and Genomes and STRING analysis, which demonstrated that PTEN displayed an inhibitory role in the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway. Notably, treatment with AG‑490, an inhibitor of JAK/STAT signaling, reversed the protective effect of PTEN knockdown on the behavior of HUVECs. In summary, the results of the current study indicated that both MDM2 and PTEN were upregulated in patients with DVT. The interaction between MDM2 and PTEN was also verified, thus providing novel insights into their potential collaborative role in the development of DVT. Overall, MDM2 and PTEN may interact to inhibit endothelial cell development and promote the occurrence of DVT via inhibiting the JAK/STAT signaling pathway.

Determining the mechanism of Shuxuening injection against liver cirrhosis through network pharmacology and animal experiments

ObjectiveTo screen and identify the key active molecules, signaling pathways, and therapeutic targets of Shuxuening (SXN) injection for treating liver cirrhosis (LC) and to evaluate its therapeutic potential using a mouse model. MethodsTarget genes of SXN and LC were retrieved from public databases, and enrichment analysis was performed. A protein–protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), and hub genes were identified using Molecular Complex Detection (MCODE). LC was induced in rats and mice via intraperitoneal injections of diethylnitrosamine and carbon tetrachloride (CCl4) for 12 weeks. Starting at week 7, SXN was administered intraperitoneally to the mice in the treatment group. Serum and liver tissues of the mice were collected for the detection of indicators, pathological staining, and expression analysis of hub targets using quantitative real-time polymerase chain reaction (qRT-PCR). ResultsWe identified 368 overlapping genes (OLGs) between SXN and LC targets. These OLGs were subsequently used to build a PPI network and to screen for hub genes. Enrichment analysis showed that these genes were associated with cancer-related pathways, including phosphoinositide-3-kinase/Akt and mitogen-activated protein kinase signaling and various cellular processes, such as responses to chemicals and metabolic regulation. In vivo experiments demonstrated that SXN treatment significantly improved liver function and pathology in CCl4-induced LC mice by reducing inflammation and collagen deposition. Furthermore, qRT-PCR demonstrated that SXN regulated the expression of MAPK8, AR and CASP3 in the livers of LC mice. ConclusionThis study highlighted the therapeutic effects of SXN in alleviating LC using both bioinformatics and experimental methods. The observed effect was associated with modulation of hub gene expression, particularly MAPK8, and CASP3.

Alterations in the placental proteome in association with the presence of black carbon particles: A discovery study

BackgroundExposure to ambient air pollution is known to cause direct and indirect molecular expression changes in the placenta, on the DNA, mRNA, and protein levels. Ambient black carbon (BC) particles can be found in the human placenta already very early in gestation. However, the effect of in utero BC exposure on the entire placental proteome has never been studied to date. ObjectivesWe explored whether placental proteome differs between mothers exposed to either high or low BC levels throughout the entire pregnancy. MethodsWe used placental tissue samples from the ENVIRONAGE birth cohort, of 20 non-smoking, maternal- and neonate characteristic-matched women exposed to high (n = 10) or low (n = 10) levels of ambient BC throughout pregnancy. We modeled prenatal BC exposure levels based on the mother's home address and measured BC levels in the fetal side of the placenta. The placental proteome was analyzed by nano-liquid chromatography Q-TOF mass spectrometry. PEAKS software was used for protein identification and label-free quantification. Protein-protein interaction and functional pathway enrichment analyses were performed with the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) software. ResultsThe accumulation of BC particles in placenta was 2.19 times higher in the high versus low exposure group (20943.4 vs 9542.7 particles/mm³; p = 0.007). Thirteen proteins showed a ≥2-fold expression difference between the two exposure groups, all overexpressed in the placentas of women prenatally exposed to high BC levels. Three protein-protein interactions were enriched within this group, namely between TIMP3 and COL4A2, SERPINE2 and COL4A2, and SERPINE2 and GP1BB. Functional pathway enrichment analysis put forward pathways involved in extracellular matrix-receptor interaction, fibrin clot formation, and sodium ion transport regulation. DiscussionPrenatal BC exposure affects the placental proteome. Future research should focus on the potential consequences of these alterations on placental functioning, and health and disease during early childhood development.

Construction of competitive endogenous RNA network and identification of potential regulatory axis in vascular calcification.

Competitive endogenous RNAs (ceRNA) theory has been proved in numerous biological processes. Nevertheless, there is a lack of research applying the ceRNA theory to the study of vascular calcification (VC) in chronic kidney diseases (CKD). In the present study, a ceRNA network was constructed after conducting transcriptome sequencing of differentially expressed genes, followed by experimental validation to identify a new target for the diagnosis and treatment of vascular calcification. Total RNA was extracted from β-glycerophosphate (β-GP) cultured vascular smooth muscle cells (VSMCs) on Day 7. Illumina HiSeq platform was utilized to build sequencing libraries. GO and KEGG analysis was conducted to identify the function of the differentially expressed genes. Protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. A ceRNA network was established based on TargetScan, miRDB, miRWALK, and miRanda database. Western blot and qRT-PCR were used to explore the expression level of protein and RNA, respectively. The direct binding sites were confirmed by dual-luciferase reporter assay. In total, 647 differentially expressed lncRNAs and 289 differentially expressed mRNAs were identified (|log2FC| ≥ 1, p < .05). The function of differentially expressed mRNAs was mainly enriched in negative regulation of osteoblast differentiation, regulation of RNA metabolic process, and other typical pathways. The ceRNA network was generated with a total of 107 interaction pairs. The lncRNA Prrc2c/miR-145-5p/Smad3 axis was considered a potential regulatory pathway within the ceRNA network. The regulatory relationship and targets of this ceRNA axis were validated via invitro experiments. For the first time, we found that lncRNA Prrc2c was highly expressed and promoted calcification of VSMCs. Luciferase reporter assay showed that lncRNA Prrc2c could bind miR-145-5p at site 1755-1761. Similarly, luciferase reporter assay showed that miR-145-5p inhibited Smad3 expression by binding to its 3'UTR. Our findings provide a comprehensive examination of the ceRNA networks in vascular smooth muscle cells (VSMCs) treated with high phosphorate. Specifically, we have identified the role of lncRNA Prrc2c in promoting VSMC calcification through the miR-145-5p/Smad3 axis.

Plasma Proteomics of Type 2 Diabetes, Hypertension, and Co-Existing Diabetes/Hypertension in Thai Adults.

The study explored proteomics to better understand the relationship between type 2 diabetes (T2DM) and hypertension (HT) in Thai adults, using shotgun proteomics and bioinformatics analysis. Plasma samples were taken from 61 subjects: 14 healthy subjects (mean age = 40.85 ± 7.12), 13 with T2DM (mean age = 57.38 ± 6.03), 16 with HT (mean age = 66.87 ± 10.09), and 18 with coexisting T2DM/HT (mean age = 58.22 ± 10.65). Proteins were identified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Protein-protein interactions were analyzed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) version 11.5. We identified six unique proteins in T2DM patients, including translationally controlled 1 (TPT1) and nibrin (NBN), which are associated with the DNA damage response. In HT patients, seven unique proteins were identified, among them long-chain fatty acid-CoA ligase (ASCL), which functions in the stimulation of triacylglycerol and cholesterol synthesis, and NADPH oxidase activator 1 (NOXA1), which is involved in high blood pressure via angiotensin II-induced reactive oxygen species (ROS)-generating systems. In coexisting T2DM/HT patients, six unique proteins were identified, of which two-microtubule-associated protein 1A (MAP1A)-might be involved in dementia via RhoB-p53 and diacylglycerol kinase beta (DGKB), associated with lipid metabolism. This study identified new candidate proteins that are possibly involved in the pathology of these diseases.

The Identification of New Pharmacological Targets for the Treatment of Glaucoma: A Network Pharmacology Approach

Background: Glaucoma is a progressive optic neuropathy characterized by the neurodegeneration and death of retinal ganglion cells (RGCs), leading to blindness. Current glaucoma interventions reduce intraocular pressure but do not address retinal neurodegeneration. In this effort, to identify new pharmacological targets for glaucoma management, we employed a network pharmacology approach. Methods: We first retrieved transcriptomic data from GEO, an NCBI database, and carried out GEO2R (an interactive web tool aimed at comparing two or more groups of samples in a GEO dataset). The GEO2R statistical analysis aimed at identifying the top differentially expressed genes (DEGs) and used these as input of STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) app within Cytoscape software, which builds networks of proteins starting from input DEGs. Analyses of centrality metrics using Cytoscape were carried out to identify nodes (genes or proteins) involved in network stability. We also employed the web-server software MIRNET 2.0 to build miRNA–target interaction networks for a re-analysis of the GSE105269 dataset, which reports analyses of microRNA expressions. Results: The pharmacological targets, identified in silico through analyses of the centrality metrics carried out with Cytoscape, were rescored based on correlations with entries in the PubMed and clinicaltrials.gov databases. When there was no match (82 out of 135 identified central nodes, in 8 analyzed networks), targets were considered “potential innovative” targets for the treatment of glaucoma, after further validation studies. Conclusions: Several druggable targets, such as GPCRs (e.g., 5-hydroxytryptamine 5A (5-HT5A) and adenosine A2B receptors) and enzymes (e.g., lactate dehydrogenase A or monoamine oxidase B), were found to be rescored as “potential innovative” pharmacological targets for glaucoma treatment.

Evaluating the mitochondrial structure and gene expression profile of regenerated liver tissues in mice after 85% partial hepatectomy.

Partial hepatectomy (PH) is the primary method used for treating liver injury and transplantation. The regeneration process after hepatectomy requires an adequate energy supply, and mitochondria serve as the primary source of energy. Alterations in genes related to the respiratory chain complex may impact the liver regeneration process. The aim of this study was the changes in mitochondrial structure and mitochondrial function in 85% PH. A PH (up to 85%) model was developed using male C57BL/6 mice, and the regenerated liver tissue was harvested after 24 hours. Hematoxylin and eosin staining and transmission electron microscopy were used for morphological studies. In terms of proliferation, a positive proliferating cell nuclear antigen (PCNA) rate was detected via immunohistochemistry. Real-time polymerase chain reaction was performed to identify differentially expressed genes (DEGs), which were screened using a P value of <0.05 and a |fold change| of ≥1.5. The Hiplot online tool was used for generating a volcano plot and conducting correlation analyses. R software was employed for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses for the DEGs. A combined Search Tool for the Retrieval of Interacting Genes/Proteins (STRING)-Cytoscape method was used for protein-protein interaction (PPI) network analyses, whereas cytoHubba was used to the screen core DEGs. After 85% PH, we observed steatosis, an increased PCNA positivity rate, mitochondrial swelling, and a reduced number of cristae due to cristae disintegration. We screened 30 DEGs that were associated with different processes, including oxidation-reduction, oxidoreductase activity, electron transfer activity, organelle envelope, inner mitochondrial membrane processes, and oxidative phosphorylation as well as those involved in nonalcoholic fatty liver disease (NAFLD). We identified a total of six hub genes: COX4I1, ATP5B, UQCRC2, CYC1, ATP5O, and ATP5A1. The 85% PH model promotes mitochondrial complex protein expression, thereby providing energy for liver regeneration. The enriched genes were associated with oxidation-reduction, electron transfer activity, and inner mitochondrial membrane processes.

Identification and Validation of Telomere-Related Gene Signature in Intervertebral Disc Degeneration.

This study investigates the role of telomere-related differentially expressed genes (TRDEGs) in intervertebral disc degeneration (IVDD) through comprehensive bioinformatics analyses. Data were sourced from the Gene Expression Omnibus (GEO) with datasets GSE245147 and GSE124272 used for initial identification and validation, respectively. The GSE245147 dataset comprised transcriptional profiles from nucleus pulposus cells of both degenerated and non-degenerated human nucleus pulposus (NP) tissues. Using the limma package, 198TRDEGs were identified by intersecting differentially expressed genes (DEGs) with telomere-related genes (TRGs) from the TelNet database. Functional enrichment analyses using the Database for Annotation, Visualization and Integrated Discovery (DAVID) revealed that TRDEGs are significantly involved in cell division, chromosome segregation, and other mitotic processes. Protein-protein interaction (PPI) networks constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database and visualized with Cytoscape (Cytoscape Consortium, San Diego, CA, USA) identified key hub genes such as CDK1, CCNA2, and AURKB. Pearson correlation and receiver operating characteristic (ROC) analyses highlighted five hub genes (ASPM, BUB1B, CDC20, KIF2C, TTK) with significant predictive value for IVDD. Additionally, mRNA-microRNA (miRNA) interaction analysis using NetworkAnalyst identified key miRNAs interacting with these hub genes. This study provides insights into the molecular mechanisms of IVDD and identifies potential targets for therapeutic intervention.

Bioinformatics analysis reveals SOD1 is a prognostic factor in lung adenocarcinoma.

Lung cancer is a major cause of cancer-related deaths worldwide. Unfortunately, non-small cell lung cancer (NSCLC) often lacks clear clinical symptoms and molecular markers for early diagnosis, which can hinder the initiation of timely treatments. In this study, we conducted an extensive bioinformatics analysis of copper-zinc superoxide dismutase (SOD1), a molecule linked to lung adenocarcinoma (LUAD) to enhance early detection and treatment approaches for this condition. A bioinformatics analysis was conducted using a dataset from The Cancer Genome Atlas (TCGA) database. Several analytical methods, such as a differential expression analysis, a Kaplan-Meier survival analysis, a clinicopathological analysis, an enrichment analysis, protein-protein interaction (PPI) network construction using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and an immunoreactivity analysis of SOD1 expression in LUAD using TIMER were employed. We further validated the expression of SOD1 in LUAD through in vitro experiments using quantitative polymerase chain reaction (qPCR) and Western blot. Our findings indicate that LUAD tissues exhibited significantly higher expression levels of SOD1 than healthy tissues. The univariate Cox analysis showed that the elevated level was linked to unfavorable overall survival (OS) rates. Further, the Cox regression analysis of multiple variables suggested that elevated SOD1 expression levels acted as an autonomous prognosticator for unfavorable OS. We also conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, and a gene set enrichment analysis (GSEA) and observed differential pathway enrichment among patients with high SOD1 expression. In addition, a correlation between SOD1 and immune cell infiltration was found. The in vitro experiments confirmed that SOD1 expression was upregulated in LUAD. SOD1 could serve as a reliable prognostic indicator in individuals diagnosed with LUAD. Our findings may prove valuable in the development of therapeutic and prognostic markers for LUAD. The potential clinical utility of SOD1 in LUAD requires further investigation.

The role of IQCB1 in liver cancer: a bioinformatics analysis.

Liver hepatocellular carcinoma (LIHC) is a prevalent malignancy globally, exhibiting substantial incidence and mortality rates. Early diagnosis and prevention of metastasis are crucial for the benefit of patients with liver cancer. The present study aimed to elucidate the involvement of IQCB1 in liver cancer through the utilization of bioinformatics. The samples utilized in this study were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Initially, the TCGA-LIHC dataset was employed to examine the expression of IQCB1, and its validation was performed on the GSE25097 dataset. Subsequently, Kaplan-Meier (KM) analysis was conducted to evaluate the prognostic significance of IQCB1 in LIHC, and its correlation with clinical pathological features was also investigated. Furthermore, a protein-protein interaction (PPI) network consisting of 20 proteins associated with IQCB1 was constructed using data from the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were carried out. A risk model was formulated to assess the prognostic significance and its prognostic value was compared to that of IQCB1 in isolation. Furthermore, an examination was conducted to explore the correlation between IQCB1 and immune infiltration, along with the involvement of immunological checkpoints. A drug sensitivity assessment of IQCB1 was performed using the Genomics of Drug Sensitivity in Cancer (GDSC) database. Additionally, the Tumor Immune Single-cell Hub (TISCH) database was utilized to investigate the association between IQCB1 and the tumor microenvironment (TME). The expression of IQCB1 was observed to be significantly elevated in tumor samples. Furthermore, patients with high expression levels of IQCB1 demonstrated a poorer prognosis. Additionally, IQCB1 exhibited significant correlations with MKI67, hepatitis B virus (HBV), hepatitis C virus (HCV), and alpha-fetoprotein (AFP). GO and KEGG analyses revealed enrichment of multiple signaling pathways. Subsequently, an investigation was conducted to examine the association between IQCB1 and the activity of ten signaling pathways related to tumor development. A positive correlation was observed between IQCB1 expression and T-helper 2 (Th2) cells, whereas a negative correlation was observed between IQCB1 expression and Th17 cells. Furthermore, a positive association was found between IQCB1 and immune checkpoints, particularly with CD276. Analysis of single-cell data from the TISCH database revealed widespread expression of IQCB1 in the TME. Additionally, screening revealed that among 12 drugs related to IQCB1, a subset of 10 drugs demonstrated negative correlations, whereas two drugs exhibited positive correlations. IQCB1 has the potential to function as a diagnostic and prognostic molecular marker, and its association with immune infiltration and checkpoint mechanisms has been observed.

Construction and verification of an innovative immune-related and hallmark gene sets prognostic model for bladder cancer.

Bladder cancer (BC) is a life-threatening malignancy with high mortality rates. Current prognostic models are insufficient in accurately predicting clinical outcomes, impeding personalized treatment strategies. This study aimed to identify BC subtypes and prognostic gene sets by analyzing changes in immune and hallmark gene sets activity in tumor and adjacent non-tumor tissues to enhance patient outcomes. Utilizing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), gene set variation analysis (GSVA) was applied to C7 immune-related and hallmark gene sets from the Molecular Signatures Database (MSigDB). The CancerSubtype R package was utilized for clustering these gene sets into three categories, from which 109 candidate sets were identified using Venn diagrams. A refined subset of seven gene sets was selected through least absolute shrinkage and selection operator (LASSO) regression for the construction of a risk model. Model validity was confirmed with receiver operating characteristic (ROC) and calibration curves, and a nomogram was constructed to integrate risk scores with clinical parameters. Finally, genes from the gene sets of the model were acquired and analyzed for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and protein-protein interactions (PPI) via plugin Molecular Complex Detection (MCODE) and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) in Cytoscape in both tumor and non-tumor tissues. Three BC subtypes were characterized by immunologic and hallmark gene sets, with subtype 1 patients showing worse survival. The prognostic model, based on seven gene sets, effectively stratified risk, with high-risk patients having significantly shorter survival. GO, KEGG, and PPI analyses indicated distinct influences of non-tumor and tumor tissues on the prognosis of BC patients. We constructed and validated a novel prognostic model for risk stratification in BC based on immunologic and hallmark genes sets, which presents a novel perspective on rational treatment approaches and accurate prognostic evaluations for BC by considering both tumor and adjacent non-tumor tissues. This highlights the importance of focusing on alterations in both tumor and adjacent non-tumor tissues, rather than solely on the tumor itself.

Unveiling FRG1’s DNA repair role in breast cancer

The FRG1(FSHD region gene 1) gene has emerged as a pivotal tumor suppressor in both breast and prostate cancer. HPF1 (Histone PARylation Factor 1), a gene crucial in the base excision repair (BER) mechanism for single-stranded DNA (ssDNA) lesions, showcases a robust correlation with FRG1. This implies that FRG1 might have the capacity to influence BER via HPF1, potentially playing a role in tumorigenesis. Using a comprehensive approach that integrates in-silico analyses involving differential gene expression, KEGG (Kyoto Encyclopedia of Genes and Genomes), GO (Gene Ontology), and STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) databases, we unravelled the intricate network of genes and pathways influenced by FRG1, which includes BER. Our linear regression analysis unveiled a positive relationship between FRG1 and key genes crucial for BER. Notably, breast cancer patients with low FRG1 expression exhibited a significantly higher frequency of mutation in TP53. To enhance the accuracy of our analysis, we conducted qRT-PCR assays, which demonstrated that FRG1 affects the transcription of DNA base excision repair genes, showing differential expression in breast cancer cells. Moreover, through the Alkaline Comet Assay, a technique that quantifies DNA damage at the single-cell level, we observed diminished DNA repair capabilities when FRG1 levels are low. Risk scores were calculated using the Cox regression coefficients, and we found notable differences in Overall Survival (OS) and mRNA expression of DEGs in the low and high-risk groups. In summary, our findings shed light on the pivotal role of FRG1 in maintaining DNA repair efficiency within breast cancer cells.

Tropomodulin 3 Overexpression as a Marker for Platinum Resistance and Immune Infiltration in Ovarian Cancer.

The cytoskeleton plays an important role in platinum resistance in ovarian cancer. Tropomodulin 3 (TMOD3) is critical in the development of many tumors, but its role in the drug resistance of ovarian cancer remains unexplored. By analyzing data from the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases, this study compared TMOD3 expression in ovarian cancer and normal tissues, and examined the expression of TMOD3 after platinum treatment in platinum-sensitive and platinum-resistant ovarian cancers. The Kaplan-Meier method was used to assess the effect of TMOD3 on overall survival (OS) and progression-free survival (PFS) in ovarian cancer patients. microRNAs (miRNAs) targeting TMOD3 were predicted using TargetScan and analyzed using the TCGA database. Tumor Immune Estimation Resource (TIMER) and an integrated repository portal for tumor-immune system interactions (TISIDB) were used to determine the relationship between TMOD3 expression and immune infiltration. TMOD3 coexpression networks in ovarian cancer were explored using LinkedOmics, the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), and The Database for Annotation, Visualization, and Integrated Discovery (DAVID) Bioinformatics. The results showed that TMOD3 was highly expressed in ovarian cancer and was associated with the grading, staging, and metastasis of ovarian cancer. TMOD3 expression was significantly reduced in platinum-treated ovarian cancer cells and patients. However, TMOD3 expression was higher in platinum-resistant ovarian cancer cells and tissues compared to platinum-sensitive ones. Higher TMOD3 expression was significantly associated with lower OS and PFS in ovarian cancer patients treated with platinum-based chemotherapy. miRNA-mediated post-transcriptional regulation is likely responsible for high TMOD3 expression in ovarian cancer and platinum-resistant ovarian tissues. The expression of TMOD3 mRNA was associated with immune infiltration in ovarian cancer. These findings indicate that TMOD3 is highly expressed in ovarian cancer and is closely associated with platinum resistance and immune infiltration.

Potential Mechanisms Underlying the Therapeutic Roles of Gancao fuzi Decoction in Cold-dampness Obstruction Syndrome-type Knee Osteoarthritis.

The key active components and potential molecular mechanism of Gancao Fuzi</i> decoction (GFD) in the treatment of cold-dampness obstruction-type knee osteoarthritis (KOA) remain unclear. To explore the mechanism of GFD in the treatment of cold-dampness obstruction syndrome-type KOA by network pharmacology. The potential active components and targets of the four herbs in GFD (Fuzi, Guizhi, Baizhu, and Gancao) were screened using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. The targets of KOA were obtained with the Comparative Toxicogenomics Database (CTD), the GeneCards database, and the DisGeNET database, and the common targets of the drugs and disease were ultimately obtained. Cytoscape (v.3.7.1) was used to draw the active component-target network, and the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) (v.11.0) database was used to construct the protein interaction network. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used for the Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the intersecting targets. A total of 102 potential active components and 208 targets of GFD in the treatment of cold-dampness obstruction syndrome-type KOA were screened. GFD treatment was found to be closely related to many inflammatory signalling pathways in the treatment of KOA. The effect of GFD on cold-dampness obstruction syndrome-type KOA is mediated by multicomponent, multitarget, and multichannel mechanisms, which provides the basis for further experimental study of its pharmacodynamic material basis and mechanism.