Functional Pathway Enrichment Analysis Research Articles

Exploring a novel four-gene system as a diagnostic and prognostic biomarker for triple-negative breast cancer, using clinical variables

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis. This research aims to find real hub genes for prognostic biomarkers of TNBC therapy. The GEO datasets GSE27447 and GSE233242 were analyzed using R package limma to explore DEGs. The PPI was generated using the STRING database. Cytoscape software plug-ins were used to screen the hub genes. Using the DAVID database, GO functional enrichment and KEGG pathway enrichment analysis were performed. Different online expression databases were employed to investigate the functions of real hub genes in tumor driving, diagnosis, and prognosis in TNBC patients with various clinicopathologic characteristics. A total of one hundred DEGs were identified between both datasets. The seven hub genes were identified after the topological parameter analysis of the PPI network. The KEGG pathway and GO analysis suggest that four genes (PSMB1, PSMC1, PSMF1, and PSMD8) are highly enriched in proteasome and were finally considered as real hub genes. Additionally, the expression analysis demonstrated that hub genes were notably up-regulated in TNBC patients compared to controls. Furthermore, correlational analyses revealed the positive and negative correlations among the expression of the real hub genes and various ancillary data, including tumor purity, promoter methylation status, overall survival (OS), genetic alterations, infiltration of CD8+ T and CD4+ immune cells, and a few more, across TNBC samples. Finally, our analysis identified a couple of significant chemotherapeutic drugs, miRNAs and transcription factors (TFS) with intriguing curative potential. In conclusion, we identified four real hub genes as novel biomarkers to overcome heterogenetic-particular challenges in diagnosis, prognosis, and therapy for TNBC patients.

Comparative transcriptomic and proteomic analyses of two salt-tolerant alfalfa (Medicago sativa L.) genotypes: investigation of the mechanisms underlying tolerance to salt

Abiotic stressors such as salt stress restrict plant development and output, which lowers agricultural profitability. In this study, alfalfa (Medicago sativa L.) varieties with different levels of salt tolerance were examined using high-throughput RNA sequencing (RNA-Seq) and Tandem Mass Tags (TMT) technologies to study the reactions of the root systems to salt stress, from transcriptomics and proteomics perspectives. The varieties Atlantic (AT) and Zhongmu-1 (ZM-1) were selected and evaluated after 2 h and 6 h of treatment with 150 mM NaCl. The results showed that under salt stress for 2 h, 1810 differentially expressed genes (DEGs) and 160 differentially expressed proteins (DEPs) in AT were screened, while 9341 DEGs and 193 DEPs were screened in ZM-1. Under salt stress for 6 h, 7536 DEGs and 118 DEPs were screened in AT, while 11,754 DEGs and 190 DEPs were screened in ZM-1. Functional annotation and pathway enrichment analyses indicated that the DEGS and DEPs were mainly involved in the glutathione metabolism, biosynthesis of secondary metabolites, glycolysis/gluconeogenesis, carbon fixation in photosynthetic organisms, and photosynthesis pathways. A series of genes related to salt tolerance were also identified, including GSTL3 and GSTU3 of the GST gene family, PER5 and PER10, of the PER gene family, and proteins such as APR and COMT, which are involved in biosynthesis of secondary metabolites. This study provides insights into salt resistance mechanisms in plants, and the related genes and metabolic pathways identified may be helpful for alfalfa breeding in the future.

Exploration of Astragaloside IV in multiple organ dysfunction syndrome and hippocampus damage through network pharmacological analysis

Background: This study aims to investigate the potential therapeutic effect of Astragaloside IV on the hippocampus in multiple organ dysfunction syndrome (MODS) and its underlying mechanisms. Methods: Targets related to "Multiple Organ Dysfunction Syndrome," "Hippocampus," and "Astragaloside IV" were collected from the GeneCards database. Co-existing intersection targets were identified using a Venn diagram via the bioinformatics platform. A protein interaction network was constructed using the String database, and core targets were screened with the cytoHubba plug-in of Cytoscape software. GO functional enrichment and KEGG pathway enrichment analyses were performed using the DAVID database, and a "disease-site-drug-key target-KEGG pathway" network map was constructed to reveal the mechanisms of Astragaloside IV. Results: Two intersection targets were identified, and the protein interaction network showed their interactions. GO and KEGG analyses indicated that these targets are mainly involved in biological processes and pathways such as efferocytosis. The "disease-site-drug-key targets-KEGG pathway" network map further clarified that Astragaloside IV may treat MODS by affecting specific signaling pathways. Conclusion: Astragaloside IV may exert a therapeutic effect on the hippocampus in MODS by influencing pathways such as efferocytosis, offering new perspectives and potential targets for future research.

An integrated bioinformatics approach to early diagnosis, prognosis and therapeutics of non-small-cell lung cancer

Non-small-cell lung cancer (NSCLC) is one of the most deadly tumors characterized by poor survival rates. Advances in therapeutics and precise identification of biomarkers can potentially reduce the mortality rate. Thus, this study aimed to identify a set of common and stable gene biomarkers through integrated bioinformatics approaches that might be effective for NSCLC early diagnosis, prognosis, and therapies. Four gene expression profiles (GSE19804, GSE19188, GSE10072, and GSE32863) downloaded from the Gene Expression Omnibus database to identify common differential expressed genes (DEGs). A total of 213 overlapping DEGs (oDEGs) between NSCLC and healthy samples were identified by using statistical LIMMA method. Then 6 common top-ranked key genes (KGs) (CENPF, CAV1, ASPM, CCNB2, PRC1, and KIAA0101) were selected by using four network-measurer methods in the protein– protein interaction network. The GO functional and KEGG pathway enrichment analysis were performed to reveal some significant functions and pathways associated with NSCLC progression. Transcriptional and post-transcriptional factors of KGs were identified through the regulatory interaction network. The prognostic power and expression level of KGs were validated by using the independent data through the Kaplan–Meier and Box plots, respectively. Finally, 4 KGs–guided repositioning candidate drugs (ZSTK474, GSK2126458, Masitinib, and Trametinib) were proposed. The stability of three top-ranked drug-target interactions (CAV1 vs. ZSTK474, CAV1 vs. GSK2126458, and ASPM vs. Trametinib) were investigated by computing their binding free energies for 140 ns MD-simulation based on MM-PBSA approach. Therefore, the findings of this computational study may be useful for early prognosis, diagnosis and therapies of NSCLC.

Proteomic Analysis of Follicular Fluid in Polycystic Ovary Syndrome: Insights into Protein Composition and Metabolic Pathway Alterations.

This study explores the proteomic composition of follicular fluid (FF) from women undergoing oocyte retrieval for in vitro fertilisation (IVF), with a focus on the effects of polycystic ovary syndrome (PCOS). FF samples were collected from 74 patients, including 34 with PCOS and 40 oocyte donors. Proteomic profiling using machine learning identified significant differences in protein abundance between the PCOS and control groups. Of the 484 quantified proteins, 20 showed significantly altered levels in the PCOS group. Functional annotation and pathway enrichment analysis pointed to the involvement of protease inhibitors and immune-related proteins in the pathophysiology of PCOS, suggesting that inflammation and immune dysregulation may play a key role. Additionally, HDL assembly was identified as a significant pathway, with apolipoprotein-AI (APOA1) and alpha-2-macroglobulin (A2M) as the major proteins involved. Notably, myosin light polypeptide 6 was the most downregulated protein, showing the highest absolute fold change, and may serve as a novel independent biomarker for PCOS.

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.

Comparative Impact of Organic Grass-Fed and Conventional Cattle-Feeding Systems on Beef and Human Postprandial Metabolomics-A Randomized Clinical Trial.

Cattle-feeding systems may have health implications for consumers of beef products. Organic grass-fed (GRA) and conventional (CON) cattle-feeding systems may result in beef products with differing metabolite profiles and therefore could impact the postprandial metabolomic response of consumers. This study aims to measure whole beef metabolomics and postprandial metabolomic response of consumers between GRA and CON beef to elucidate potential health implications. This study followed a randomized double-blind crossover design with healthy male and female subjects (n = 10). Plasma samples were taken at fasting (0) and postprandially for four hours after consumption of a steak from each condition. Untargeted metabolomic analysis of whole beef and human plasma samples used LC/MS. Multivariate and pathway enrichment analysis in MetaboAnalyst was used to investigate metabolite and biochemical pathways that distinguished CON and GRA. Cattle-feeding systems impacted both postprandial and whole beef steak metabolomic profiles. Metabolites that contributed to this variation included carnitine species (Proionylcarnitine), fatty acids, amino acids (L-valine), and Calamendiol. These metabolites have been associated with oxidative stress, inflammation, and cardiovascular health. Functional pathway enrichment analysis revealed numerous amino acid degradation pathways, especially branched-chain amino acids, and fatty acid degradation that changed throughout the postprandial time course. These findings suggest that CON and GRA cattle-feeding systems differentially impact whole beef metabolomics, as well as consumer postprandial metabolic responses and the associated health implications.

Signaling Pathways in Clear Cell Renal Cell Carcinoma and Candidate Drugs Unveiled through Transcriptomic Network Analysis of Hub Genes

Clear cell renal cell carcinoma (ccRCC) is a type of kidney cancer. It advances quickly and often metastasizes, making the prognosis for patients challenging. This study used weighted gene co-expression network analysis (WGCNA) to study gene expression data of different stages of ccRCC obtained in the GEO database. The analysis identified three significant highly preserved gene modules across the datasets: GSE53757, GSE22541, GSE66272, and GSE73731. Functional annotation and pathway enrichment analysis using DAVID revealed inflammatory pathways (e.g., NF-kB, Hippo, and HIF-1 pathways) that may drive ccRCC development and progression. The study also introduced the involvement of viral infections associated with the disease in the metabolic reprogramming of ccRCC. A drug repurposing analysis was also conducted to identify potential drug candidates for ccRCC using the upregulated and downregulated hub genes. The top candidates are ziprasidone (dopamine and serotonin receptor antagonist) and fentiazac (cyclooxygenase inhibitor). Other drug candidates were also obtained, such as phosphodiesterase/DNA methyltransferase/ATM kinase inhibitors, acetylcholine antagonists, and NAD precursors. Overall, the study’s findings suggest that identifying several genes and signaling pathways related to ccRCC may uncover new targets, biomarkers, and even drugs that can be repurposed, which can help develop new and effective treatments for the disease.

Low-dose 60Co-γ-ray irradiation promotes the growth of cucumber seedlings by inducing CsSAUR37 expression.

Cucumber (Cucumis sativus L.) is a major vegetable crop grown globally, with a cultivation history of more than 3000years. The limited genetic diversity, low rate of intraspecific variation, and extended periods of traditional breeding have resulted in slow progress in their genetic research and the development of new varieties. Gamma (γ)-ray irradiation potentially accelerates the breeding progress; however, the biological and molecular effects of γ-ray irradiation on cucumbers are unknown. Exposing cucumber seeds to 0, 50, 100, 150, 200, and 250Gy doses of 60Co-γ-ray irradiation, this study aimed to investigate the resulting phenotype and physiological characteristics of seedling treatment to determine the optimal irradiation dose. The results showed that low irradiation doses (50-100Gy) enhanced root growth, hypocotyl elongation, and lateral root numbers, promoting seedling growth. However, high irradiation doses (150-250Gy) significantly inhibited seed germination and growth, decreasing the survival rate of seedlings. More than 100Gy irradiation significantly decreased the total chlorophyll content while increasing the malondialdehyde (MDA) and H2O2 content in cucumber. Transcriptome sequencing analysis at 0, 50, 100, 150, 200, and 250Gy doses showed that gene expression significantly differed between low and high irradiation doses. Gene Ontology enrichment and functional pathway enrichment analyses revealed that the auxin response pathway played a crucial role in seedling growth under low irradiation doses. Further, gene function analysis revealed that small auxin up-regulated gene CsSAUR37 was a key gene that was overexpressed in response to low irradiation doses, promoting primary root elongation and enhancing lateral root numbers by regulating the expression of protein phosphatase 2Cs (PP2Cs) and auxin synthesis genes.

Exploring the Mechanism of Action of Lycium barbarum in Treating Allergic Rhinitis Using Network Pharmacology and Molecular Docking

Objective: Approximately 10%-40% of the global population is affected by allergic rhinitis, and Lycium barbarum has a long history of dual use as a herbal medicine and also as a food. This study utilized network pharmacology and molecular docking to explore the mechanism of action of Lycium barbarum in treating allergic rhinitis. Methods: We screened active ingredients and potential action targets of Lycium barbarum using the TCMSP database. Relevant targets for allergic rhinitis diseases were accessed through the GeneCards and OMIM databases. GO function enrichment and KEGG pathway enrichment analyses of key targets were conducted using the DAVID database. Molecular docking validation was performed using Autodock Vina software to confirm the affinity between the core protein targets and the key active ingredients. Results: Network pharmacological analysis identified 35 major active ingredients of Lycium barbarum, 87 drug targets, and 2200 disease targets. GO functional analysis and KEGG pathway enrichment analysis revealed that the mechanism of action of Lycium barbarum in treating allergic rhinitis involves multiple pathways, including the HIF-1 signaling pathway, IL-17 signaling pathway, and TNF signaling pathway. Molecular docking results demonstrated good binding activity between the main active ingredients and the core protein target. Conclusion: Lycium barbarum exhibits multi-component, multi-target, and multi-pathway actions in treating allergic rhinitis by regulating relevant pathways and targets.

The use of metagenomic and untargeted metabolomics in the analysis of the effects of the Lycium barbarum glycopeptide on allergic airway inflammation induced by Artemesia annua pollen

Ethnopharmacological relevanceThe prevalence of allergic airway inflammation (AAI) worldwide is high. Artemisia annua L. pollen is spread worldwide, and allergic diseases caused by its plant polysaccharides, which are closely related to the intestinal microbiota, have anti-inflammatory effects. Further isolation and purification of Lycium barbarum L. yielded its most effective component Lycium barbarum L. glycopeptide (LbGP), which can inhibit inflammation in animal models. However, its therapeutic effect on AAI and its mechanism of regulating the intestinal flora have not been fully investigated. Aim of the studyTo explore LbGP in APE-induced immunological mechanisms of AAI and the interaction mechanism of the intestinal flora and metabolites. MethodsA mouse model of AAI generated from Artemisia annua pollen was constructed, and immunological indices related to the disease were examined. A combination of macrogenomic and metabolomic analyses was used to investigate the effects of LbGP on the gut microbial and metabolite profiles of mice with airway inflammation. ResultsLbGP effectively alleviated Artemisia. annua pollen extract (APE)-induced AAI, corrected Th1/Th2 immune dysregulation, decreased Th17 cells, increased Treg cells, and altered the composition and function of the intestinal microbiota. LbGP treatment increased the number of OdoribacterandDuncaniella in the intestines of the mice, but the numble of Alistipes and Ruminococcus decreased. Metabolite pathway enrichment analysis were used to determine the effects of taurine and hypotaurine metabolism, bile acid secretion, and pyrimidine metabolism pathways on disease. ConclusionOur results revealed significant changes in the macrogenome and metabolome following APE and LbGP intervention, revealed potential correlations between gut microbial species and metabolites, and highlighted the beneficial effects of LbGP on AAI through the modulation of the gut microbiome and host metabolism.

Uncovering the mechanisms of diosmin in treating obesity-related kidney injury based on network pharmacology, molecular docking, and in vitro validation.

Obesity increases the risk of kidney injury, involving various pathological events such as inflammation, insulin resistance, lipid metabolism disorders, and hemodynamic changes, making it a significant risk factor for the development and progression of chronic kidney disease. Diosmin, a natural flavonoid glycoside, exhibits anti-inflammatory, antioxidant, anti-lipid, and vasodilatory effects. However, whether diosmin has a protective effect on obesity-related kidney injury remains unclear. The molecular formula of diosmin was obtained, and diosmin and target genes related to obesity-related kidney injury were screened. The interaction between overlapping target genes was analyzed. GO functional enrichment and KEGG pathway enrichment analyses were performed on overlapping target genes. Molecular docking was employed to assess the binding strength between overlapping target genes. Palmitic acid-induced damage to HK-2 cells, which were then treated with diosmin. Subsequently, the expression levels of relevant mRNAs and proteins were measured. Network analysis identified 219 potential diosmin target genes, 6800 potential target genes related to obesity-related kidney injury, and 93 potential overlapping target genes. Protein-protein interaction networks and molecular docking results revealed that AKT1, TNF-α, SRC, EGFR, ESR1, CASP3, MMP9, PPAR-γ, GSK-3β, and MMP2 were identified as key therapeutic targets, and they exhibited stable binding with diosmin. GO analysis indicated that these key targets may participate in inflammation, chemical stress, and protein phosphorylation. KEGG revealed that pathways in cancer, AGE-RAGE signaling pathway, PI3K-AKT signaling pathway, PPAR signaling pathway, and insulin resistance as crucial in treating obesity-related kidney injury. CCK-8 assay showed that diosmin significantly restored the viability of HK-2 cells affected by palmitic acid. Oil Red O staining demonstrated that diosmin significantly improved lipid deposition in HK-2 cells induced by palmitic acid. PCR results showed that diosmin inhibited the mRNA levels of AKT1, TNF-α, EGFR, ESR1, CASP3, MMP9, GSK-3β, and MMP2 while promoting the mRNA level of PPAR-γ. Western blot analysis revealed that diosmin restored PPAR-γ protein expression, inhibited NF-kB p-p65 protein expression, and reduced TNF-α protein expression. Diosmin demonstrated multi-target and multi-pathway effects in the treatment of obesity-associated renal injury, with key targets including AKT1, TNF-α, EGFR, ESR1, CASP3, MMP9, PPAR-γ, GSK-3β, and MMP2. The mechanism may be through the modulation of the PPAR-γ/NF-κB signaling pathway, which can attenuate inflammatory responses and protect the kidney.

A novel m6A reader RBFOX2 expression is increased in oral squamous cell carcinoma and promotes tumorigenesis

Background and ObjectiveOral squamous cell carcinoma (OSCC) is a significant global health concern due to its aggressive nature and poor prognosis. Recent research has highlighted the important role of RNA modifications in cancer biology, especially N6-methyladenosine (m6A) modifications, which are controlled by a complex interplay of m6A regulators. This study specifically investigates RBFOX2, a new m6A reader, and its involvement in OSCC. MethodsOur study primarily utilized OSCC tissue, adjacent normal tissue samples, OSCC cell lines, and normal healthy oral keratinocytes to validate RBFOX2 mRNA expression. Additionally, we used the TCGA-HNSCC dataset for large cohort analysis and clinicopathological characterization. Furthermore, we visualized the RBFOX2 network to identify the primary functions of the protein. ResultsOur research shows a noticeable increase in RBFOX2 expression in OSCC tissues compared to adjacent non-tumorous tissues, as determined by quantitative PCR and immunohistochemistry analyses. Functional pathway enrichment analysis revealed that RBFOX2 is involved in the receptor tyrosine kinase signaling pathway and the Hippo signaling pathway, which plays a critical role in oral cancer development and progression. Clinically, elevated RBFOX2 expression correlated with advanced tumor stages and poorer patient outcomes, demonstrating its prognostic value. These findings indicate that RBFOX2 acts as an oncogenic driver in OSCC as an m6A reader, facilitating the expression of m6A-modified oncogenes. ConclusionOur study identifies RBFOX2 as a critical player in OSCC pathogenesis and opens avenues for novel therapeutic strategies targeting the m6A regulatory machinery in this malignancy.

METTL5 enhances the mRNA stability of TPRKB through m6A modification to facilitate the aggressive phenotypes of hepatocellular carcinoma cell

N6-methyladenosine (m6A) modification plays an important role in RNA molecular functions, therefore affecting the initiation and development of hepatocellular carcinoma (HCC). Herein, multiple datasets were applied to conduct a comprehensive analysis of DEGs within HCC and the analysis revealed significant dysregulation of numerous genes. Functional and signaling pathway enrichment analyses were performed. Further, TP53RK binding protein (TPRKB) emerged as a significant factor, exhibiting high expression level within HCC tissue samples and cells which could predict HCC patients’ poor OS. Knockdown investigations of TPRKB in vitro demonstrated the effect of TPRKB knockdown on attenuating the aggressiveness of HCC cells by suppressing the viability, colony formation, invasive ability, and migratory ability, inducing cell cycle arrest, and facilitating the apoptosis of HCC cells. Investigations in vivo revealed that TPRKB knockdown significantly suppressed tumor growth in mice model. Additionally, the study identified methyltransferase 5, N6-adenosine (METTL5) as a potential regulator of TPRKB expression via m6A modification, positively regulating TPRKB expression by enhancing TPRKB mRNA stability. The dynamic effects of METTL5 and TPRKB upon the phenotypes of HCC cells further confirmed that TPRKB overexpression partially abolished the anti-cancer effects of METTL5 knockdown upon the aggressiveness of HCC cells. Conclusively, our findings uncover that TPRKB, significantly overexpressed in HCC, exerts a critical effect on promoting tumor aggressiveness, and its expression shows to be positively regulated by METTL5 via m6A methylation. These insights deepen the understanding of HCC pathogenesis and open new avenues for targeted therapies, highlighting that METTL5-TPRKB axis is an underlying new therapeutic target in HCC management.

The potential of Gynostemma pentaphyllum in the treatment of hyperlipidemia and its interaction with the LOX1-PI3K-AKT-eNOS pathway.

Gynostemma pentaphyllum, a traditional Chinese medicine, is widely used to treat various diseases, but its therapeutic effects and mechanisms of action on hyperlipidemia remain unclear. This study aims to investigate the effects of Danshen leaf on hyperlipidemia through network pharmacology, molecular docking, and cellular experiments, elucidating its multifaceted mechanism of action within the LOX1-PI3K-AKT-eNOS pathway. First, the active ingredients and targets of G. pentaphyllum were screened using the Traditional Chinese Medicine Systems Pharmacology database. Then, targets for hyperlipidemia were identified using the OMIM and GeneCards databases, and potential therapeutic targets for G. pentaphyllum in treating hyperlipidemia were determined. An active ingredient-target network was constructed using Cytoscape software, and a protein-protein interaction (PPI) network was built and visualized using the STRING database and Cytoscape software. Finally, GO functional and KEGG pathway enrichment analyses were performed, and the predicted mechanisms were validated through molecular docking and cell experiments. 85 targets for G. pentaphyllum and 1556 for Hyperlipidemia were screened, with 53 common targets. Twenty-four active ingredients of G. pentaphyllum were found to be involved in the treatment of hyperlipidemia. Key nodes such as Rhamnazin, Isofucosterol, and quercetin, and targets NCOA2, NR3C2, PGR, and PPARG showed high relevance. In the PPI network, 8 nodes, including IL6, PPARG, and VEGFA, exhibited high centrality. GO functional and KEGG pathway enrichment analyses indicated that G. pentaphyllum may treat hyperlipidemia by influencing various biological functions and pathways, such as DNA-binding transcription factor binding, RNA polymerase II-specific DNA-binding transcription factor binding, and lipid and atherosclerosis. Cell experiments demonstrated that G. pentaphyllum significantly regulated the expression of key proteins in the LOX1-PI3K-AKT-eNOS pathway, thereby improving hyperlipidemia. G. pentaphyllum improves hyperlipidemia by mediating the LOX1-PI3K-AKT-eNOS pathway. This study provides a new theoretical basis and experimental evidence for applying G. pentaphyllum to treating hyperlipidemia.

Exploring Novel Genome Instability-associated lncRNAs and their Potential Function in Pan-Renal Cell Carcinoma.

Genomic instability can drive clonal evolution, continuous modification of tumor genomes, and tumor genomic heterogeneity. The molecular mechanism of genomic instability still needs further investigation. This study aims to identify novel genome instabilityassociated lncRNAs (GI-lncRNAs) and investigate the role of genome instability in pan-Renal cell carcinoma (RCC). A mutator hypothesis was employed, combining the TCGA database of somatic mutation (SM) information, to identify GI-lncRNAs. Subsequently, a training cohort (n = 442) and a testing cohort (n = 439) were formed by randomly dividing all RCC patients. Based on the training cohort dataset, a multivariate Cox regression analysis lncRNAs risk model was created. Further validations were performed in the testing cohort, TCGA cohort, and different RCC subtypes. To confirm the relative expression levels of lncRNAs in HK-2, 786-O, and 769-P cells, qPCR was carried out. Functional pathway enrichment analyses were performed for further investigation. A total of 170 novel GI-lncRNAs were identified. The lncRNA prognostic risk model was constructed based on LINC00460, AC073218.1, AC010789.1, and COLCA1. This risk model successfully differentiated patients into distinct risk groups with significantly different clinical outcomes. The model was further validated in multiple independent patient cohorts. Additionally, functional and pathway enrichment analyses revealed that GI-lncRNAs play a crucial role in GI. Furthermore, the assessments of immune response, drug sensitivity, and cancer stemness revealed a significant relationship between GI-lncRNAs and tumor microenvironment infiltration, mutational burden, microsatellite instability, and drug resistance. In this study, we discovered four novel GI-lncRNAs and developed a novel signature that effectively predicted clinical outcomes in pan-RCC. The findings provide valuable insights for pan-RCC immunotherapy and shed light on potential underlying mechanisms.

Integrative bioinformatics analysis for the identification of hub genes and Virtual screening of phytochemicals to inhibit AURKA in HepatoCellular carcinoma

HepatoCellular Carcinoma (HCC) is one of the most deadly and prevalent neoplasia, accounting for nearly 830,180 mortalities and 905,677 fresh occurrences worldwide annually. Aggressive malignancy with multifaceted etiologies increases in occurrence due to inadequate early diagnosis and ineffective treatment outcomes. Hence the present study aims to identify novel HCC associated biomarkers and inhibit the plausible genes through phytocompounds. Herein, we have implemented the meta-analysis of GSE36376, GSE57957 and GSE84598 micro-array profiles by utilizing GEO2R which resulted in identification of 1683 aberrantly expressed genes. The predicted DEGs were further subjected to Functional annotation and pathway enrichment analysis by using Blast2GO and ExpressAnalyst respectively. Successively, Protein-Protein Interaction analysis was performed by Cytoscape software, and the top 11 most significant hub nodes were identified. The most frequently occurring hub gene Aurora Kinase A (AURKA) was considered as plausible target for subsequent identification of inhibitors. The plant-derived small molecules retrieved from NPACT database were subjected to molecular docking, Molecular dynamic simulations and MMGBSA analysis against AURKA. Conclusively, findings from our study postulates Garcinone C and Silymarin targeting elevated AURKA levels which may contribute as potential inhibitors for HCC patients. However, these outcomes provide only computational insights for targeted HCC-therapeutics but for clinical application of Garcinone C and Silymarin in vitro and in vivo molecular validations are still warranted.

Role of blood metabolites in mediating the effect of gut microbiome on the mutated-RAS/BRAF metastatic colorectal cancer-specific survival

BackgroundRecent studies have linked alterations in the gut microbiome and metabolic disruptions to the invasive behavior and metastasis of colorectal cancer (CRC), thus affecting patient prognosis. However, the specific relationship among gut microbiome, metabolite profiles, and mutated-RAS/BRAF metastatic colorectal cancer (M-mCRC) remains unclear. Furthermore, the potential mechanisms and prognostic implications of metabolic changes induced by gut microbiome alterations in patients with M-mCRC still need to be better understood.MethodsWe conducted Mendelian randomization (MR) to evaluate the causal relationship of genetically predicted 196 gut microbiome features and 1400 plasma metabolites/metabolite ratios on M-mCRC-specific survival. Additionally, we identified significant gut microbiome-metabolites/metabolite ratio associations based on M-mCRC. Metabolite information was annotated, and functional annotation and pathway enrichment analyses were performed on shared proteins corresponding to significant metabolite ratios, aiming to reveal potential mechanisms by which gut microbiome influences M-mCRC prognosis via modulation of human metabolism.ResultsWe identified 11 gut microbiome features and 49 known metabolites/metabolite ratios correlated with M-mCRC-specific survival. Furthermore, we identified 17 gut microbiome-metabolite/metabolite ratio associations specific to M-mCRC, involving eight lipid metabolites and three bilirubin degradation products. The shared proteins corresponding to significant metabolite ratios were predominantly localized within the integral component of the membrane and exhibited enzymatic activities such as glucuronosyltransferase and UDP-glucuronosyltransferase, crucial in processes such as glucuronidation, bile secretion, and lipid metabolism. Moreover, these proteins were significantly enriched in pathways related to ascorbate and aldarate metabolism, pentose and glucuronate interconversions, steroid hormone biosynthesis, and bile secretion.ConclusionOur study offers novel insights into the potential mechanisms underlying the impact of the gut microbiome on the prognosis of M-mCRC. These findings serve as a meaningful reference for exploring potential therapeutic targets and strategies in the future.

Two hub genes of bipolar disorder, a bioinformatics study based on the GEO database

Bipolar disorder is a mood illness that affects many people. It has a high recurrence frequency and will cause significant damage to the patient's social function. At present, the pathogenesis of BD is not clear. The National Center for Biotechnology Information (NCBI) established and maintained the Gene Expression Omnibus (GEO) database, a gene expression database. For bioinformatics analysis, researchers can obtain expression data from the internet. At present, the samples of the dataset used in the research of BD are mostly from brain tissue, and the data containing blood samples are rarely used. GEO databases (GSE46416, GSE5388, and GSE5389) were used to retrieve public data, and utilizing the online tool GEO2R, differentially expressed genes (DEGs) were retrieved. The common DEGs between the samples of patients with BD and the samples of the normal population were screened by Venn diagrams. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to perform functional annotation and pathway enrichment analysis of DEGs. A protein-protein interaction network (PPI) was built to investigate hub genes on this basis. There were 117 up-regulated DEGs and 38 down-regulated DEGs discovered, with two hub genes [SRC, CDKN1A] among the up-regulated DEGs. These two hub genes were also highly enriched in the oxytocin signaling pathway, proteoglycans in cancer and bladder cancer, according to KEGG analysis. The results of the receiver operating characteristic curve (ROC) of SRC and CDKN1A in the three datasets strongly suggested that SRC and CDKN1A were potential diagnostic markers of BD. The results strongly suggest that SRC and CDKN1A are related to the pathogenesis of BD.

Early changes of microRNAs in blood one month after bariatric surgery

BackgroundChanges in microRNAs (miRNAs) are relevant to bariatric surgery and its comorbidities. The characteristics of changes in miRNAs of the early postoperative period following both bariatric procedures, sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), as well as the factors that related to the effectiveness of early weight loss remain unclear.MethodsWe recruited 18 patients who performed SG and 15 patients who performed RYGB. Their preoperative and 1-month postoperative clinical data and fasting serum samples were collected, and the latter were analyzed by RNA-sequencing. Differential expression analysis of miRNAs was performed by the R-tool. Functional classification annotation and pathway enrichment analysis of targeted genes were analyzed by KOBAS software. The change profiles of miRNAs for both surgeries and their correlation with clinical characteristics and weight loss effectiveness were further analyzed.ResultsA total of 85 differentially expressed miRNAs were identified before and after SG, while a total of 76 were found before and after RYGB. The target genes of these miRNAs were similar in the Gene Ontology enrichment analysis in SG and RYGB, and the enrichment analysis in the Kyoto Encyclopedia of Genes and Genomes was mainly related to metabolic pathways. Hsa-miR-493-5p, hsa-miR-184, and hsa-miR-3199 exhibited similar changes in SG and RYGB, and the former two were correlated with clinical characteristics. Hsa-miR-6729-5p, hsa-miR-4659b-5p, and hsa-miR-2277-5p were correlated with the weight loss effectiveness of SG, while hsa-miR-4662a-5p was correlated with the weight loss effectiveness of RYGB.ConclusionsShort-term metabolic improvement and weight loss occurring after SG and RYGB surgery might be related to changes in miRNAs, which act on multiple biological pathways by regulating genes. In addition, some clinical characteristics and miRNAs were related to the effectiveness of early weight loss after SG and RYGB surgery.Clinical Trial RegistrationChiCTR2200058333.