Hereditas最新文献

Background: Coronavirus disease 2019 (COVID-19) caused a series of biological changes in cancer patients which have rendered the original treatment ineffective and increased the difficulty of clinical treatment. However, the clinical treatment for cancer patients infected with COVID-19 is currently unavailable. Since bioinformatics is an effective method to understand undiscovered biological functions, pharmacological targets, and therapeutic mechanisms. The aim of this study was to investigate the influence of COVID-19 infection in cancer patients and to search the potential treatments.

Methods: Firstly, we obtained the COVID-19-associated genes from seven databases and analyzed the cancer pathogenic genes from Gene Expression Omnibus (GEO) databases, respectively. The Cancer/COVID-19-associated genes were shown by Venn analyses. Moreover, we demonstrated the signaling pathways and biological functions of pathogenic genes in Cancer/COVID-19.

Results: We identified that Go-Ichi-Ni-San complex subunit 1 (GINS1) is the potential therapeutic target in Cancer/COVID-19 by GEPIA. The high expression of GINS1 was not only promoting the development of cancers but also affecting their prognosis. Furthermore, eight potential compounds of Cancer/COVID-19 were identified from CMap and molecular docking analysis.

Conclusion: We revealed the GINS1 is a potential therapeutic target in cancer patients infected with COVID-19 for the first time, as COVID-19 will be a severe and prolonged pandemic. However, the findings have not been verified actually cancer patients infected with COVID-19, and further studies are needed to demonstrate the functions of GINS1 and the clinical treatment of the compounds.

Background: Nonalcoholic Fatty Liver Disease (NAFLD) is a chronic Liver Disease prevalent all over the world. It has become more and more common in Japan, China and most western developed countries. The global prevalence rate is 25.24%, and the trend is increasing year by year. Related studies have shown that Cynarine has certain liver protection, lipid lowering and immune intervention effects. So, this study to systematically predict and analyze the mechanism of Cynarine in the treatment of non-alcoholic fatty liver disease (NAFLD) based on the integration of network pharmacology, molecular docking, and cell experiment.

Methods: We performed Heatmap and Venn diagram analyses to identify genes and targets in Cynarine treat NAFLD. The network of Cynarine-therapeutic targets and the protein-protein interaction network (PPI) was constructed. We used gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to visualize associated functional pathways. The Sybyl tool was used to dock the Cynarine with key therapeutic targets molecularly. Finally, cell experiments were applied to validate the role of Cynarine in the treatment of NAFLD.

Results: The Cynarine could act on 48 targets of NAFLD, and the role of CASP3, TP53, MMP9, ELANE, NOTCH1 were more important. The PPI network showed that immune and inflammation-related targets played a pivotal role. The KEGG analysis found that the PI3K-Akt signaling pathway, cell cycle and MAPK signaling pathway may be the main pathways for Cynarine to prevent and treat NAFLD. Molecular docking studies confirmed that Cynarine has good binding activity with therapeutic targets. Cynarine reduced the fat deposition ability of NAFLD model cells, and effectively reduced the levels of ALT and AST released by liver cells due to excessive lipid accumulation. We also found that Cynarine inhibited the expression of AKT1 and MAPK1.

Conclusions: This study revealed that Cynarine could significantly reduce the fat deposition ability of NAFLD model cells, which may be closely related to the effective regulation of AKT1 and MAPK1 expression by Cynarine.

Objective: Gastric cancer is one of the most common and deadly types of cancer. The molecular mechanism of gastric cancer progression remains unclear.

Materials and methods: Four hub genes were identified through GEO and TCGA database screening and analysis. Prognostic analysis revealed that COL5A2 was the most likely to affect the prognosis of gastric cancer among the four hub genes. The relationships between COL5A2 and clinical variables and immune cell infiltration were analyzed. Then, COL5A2 was analyzed for single-gene differences and related functional enrichment. Using the starBase database for prediction and analysis, miRNAs and pseudogenes/lncRNAs that might combine with COL5A2 were identified; thus, the ceRNA network was constructed. Finally, the network was verified by Cox analysis and qPCR, and a nomogram was constructed.

Results: First, we found that COL5A2, COL12A1, BGN and THBS2 were highly expressed in gastric cancer. COL5A2 had statistical significance in overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) analysis. Immune infiltration analysis suggested that COL5A2 might influence the changes in the tumor immune microenvironment. The StarBase database was used to predict that 3 pseudogenes and 7 lncRNAs might inhibit the hsa-miR-200b-3p-COL5A2 axis in gastric cancer. The pseudogenes/lncRNA-hsa-miR-200b-3p-COL5A2 ceRNA network was identified and verified using Cox regression analysis and PCR. Finally, we constructed a nomogram.

Conclusions: We elucidated the regulatory role of the pseudogenes/lncRNA-hsa-miR-200b-3p-COL5A2 network in gastric cancer progression and constructed a nomogram. These studies may provide effective treatments and potential prognostic biomarkers for gastric cancer.

Background: Ulcerative colitis (UC) refers to an intractable intestinal inflammatory disease. Its increasing incidence rate imposes a huge burden on patients and society. The UC etiology has not been determined, so screening potential biomarkers is critical to preventing disease progression and selecting optimal therapeutic strategies more effectively.

Methods: The microarray datasets of intestinal mucosal biopsy of UC patients were selected from the GEO database, and integrated with R language to screen differentially expressed genes and draw proteins interaction network diagrams. GO, KEGG, DO and GSEA enrichment analyses were performed to explore their biological functions. Through machine learning and WGCNA analysis, targets that can be used as UC potential biomarkers are screened out. ROC curves were drawn to verify the reliability of the results and predicted the mechanism of marker genes from the aspects of immune cell infiltration, co-expression analysis, and competitive endogenous network (ceRNA).

Results: Two datasets GSE75214 and GSE87466 were integrated for screening, and a total of 107 differentially expressed genes were obtained. They were mainly related to biological functions such as humoral immune response and inflammatory response. Further screened out five marker genes, and found that they were associated with M0 macrophages, quiescent mast cells, M2 macrophages, and activated NK cells in terms of immune cell infiltration. The co-expression network found significant co-expression relationships between 54 miRNAs and 5 marker genes. According to the ceRNA hypothesis, NEAT1-miR-342-3p/miR-650-SLC6A14, NEAT1-miR-650-IRAK3, and XIST-miR-342-3p-IRAK3 axes were found as potential regulatory pathways in UC.

Conclusion: This study screened out five biomarkers that can be used for the diagnosis and treatment of UC, namely SLC6A14, TIMP1, IRAK3, HMGCS2, and APOBEC3B. Confirmed that they play a role in the occurrence and development of UC at the level of immune infiltration, and proposed a potential RNA regulatory pathway that controls the progression of UC.

Background: ATM (ataxia-telangiectasia mutated) protein kinase is highly conserved in metazoan, and plays a critical role at DNA damage response, oxidative stress, metabolic stress, immunity, RNA biogenesis etc. Systemic profiling of ATM regulated genes, including protein-coding genes, miRNAs, and long non-coding RNAs, will greatly improve our understanding of ATM functions and its regulation.  RESULTS: 1) differentially expressed protein-coding genes, miRNAs, and long non-coding RNAs in atm mutated flies were identified at physiological condition and after X-ray irradiation. 2) functions of differentially expressed genes in atm mutated flies, regardless of protein-coding genes or non-coding RNAs, are closely related with metabolic process, immune response, DNA damage response or oxidative stress. 3) these phenomena are persistent after irradiation. 4) there is a cross-talk regulation towards miRNAs by ATM, E2f1, and p53 during development and after irradiation. 5) knock-out flies or knock-down flies of most irradiation-induced miRNAs were sensitive to ionizing radiation.

Conclusions: We provide a valuable resource of protein-coding genes, miRNAs, and long non-coding RNAs, for understanding ATM functions and regulations. Our work provides the new evidence of inter-dependence among ATM-E2F1-p53 for the regulation of miRNAs.

Background: Liver ischemia reperfusion injury (LIRI) is not only a common injury during liver transplantation and major hepatic surgery, but also one of the primary factors that affect the outcome of postoperative diseases. However, there are still no reliable ways to tackle the problem. Our study aimed to find some characteristic genes associated with immune infiltration that affect LIRI, which can provide some insights for future research in the future. Therefore, it is essential for the treatment of LIRI, the elucidation of the mechanisms of LIRI, and exploring the potential biomarkers. Efficient microarray and bioinformatics analyses can promote the understanding of the molecular mechanisms of disease occurrence and development.

Method: Data from GSE151648 were downloaded from GEO data sets, and we performed a comprehensive analysis of the differential expression, biological functions and interactions of LIRI-associated genes. Then we performed Gene ontology (GO) analysis and Kyotoencydlopedia of genes and genomes (KEGG) enrichment analysis of DEGs. At last, we performed a protein-protein interaction network to screen out hub genes.

Results: A total of 161 differentially expressed genes (DEGs) were identified. GO analysis results revealed that the changes in the modules were mostly enriched in the neutrophil degranulation, neutrophil activation involved in immune response, and neutrophil mediated immunity. KEGG enrichment analysis of DEGs demonstrated that LIRI mainly involved the cytokine-cytokine receptor interaction. Our data indicated that macrophages and neutrophils are closely related to LIRI. 9 hub genes were screened out in the protein-protein interaction network.

Conclusions: In summary, our data indicated that neutrophil degranulation, neutrophil activation involved in immune response, neutrophil mediated immunity and cytokine-cytokine receptor interaction may play a key role in LIRI, HRH1, LRP2, P2RY6, PKD1L1, SLC8A3 and TNFRSF8, which were identified as potential biomarkers in the occurrence and development of LIRI. However, further studies are needed to validate these findings and explore the molecular mechanism of these biomarkers in LIRI.

Background: Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries and its prevalence is increasing. As an emerging therapy with a promising efficacy, immunotherapy has been extensively applied in the treatment of solid tumors. In addition, chromatin regulators (CRs), as essential upstream regulators of epigenetics, play a significant role in tumorigenesis and cancer development.

Methods: CRs and immune checkpoint-related genes (ICRGs) were obtained from the previous top research. The Genome Cancer Atlas (TCGA) was utilized to acquire the mRNA expression and clinical information of patients with EC. Correlation analysis was utilized for screen CRs-related ICRGs (CRRICRGs). By Cox regression and least absolute shrinkage and selection operator (LASSO) analysis, prognosis related CRRICRGs were screened out and risk model was constructed. The Kaplan-Meier curve was used to estimate the prognosis between high- and low-risk group. By comparing the IC50 value, the drugs sensitivity difference was explored. We obtained small molecule drugs for the treatment of UCEC patients based on CAMP dataset.

Results: We successfully constructed a 9 CRRICRs-based prognostic signature for patients with UCEC and found the riskscore was an independent prognostic factor. The results of functional analysis suggested that CRRICRGs may be involved in immune processes associated with cancer. Immune characteristics analysis provided further evidence that the CRRICRGs-based model was correlated with immune cells infiltration and immune checkpoint. Eight small molecule drugs that may be effective for the treatment of UCEC patients were screened. Effective drugs identified by drug sensitivity profiling in high- and low-risk groups.

Conclusion: In summary, our study provided novel insights into the function of CRRICRGs in UCEC. We also developed a reliable prognostic panel for the survival of patients with UCEC.

Background: The prevalence of Alzheimer's disease (AD) varies based on gender. Due to the lack of early stage biomarkers, most of them are diagnosed at the terminal stage. This study aimed to explore sex-specific signaling pathways and identify diagnostic biomarkers of AD.

Methods: Microarray dataset for blood was obtained from the Gene Expression Omnibus (GEO) database of GSE63060 to conduct differentially expressed genes (DEGs) analysis by R software limma. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene set enrichment analysis (GSEA) were conducted. Immune checkpoint gene expression was compared between females and males. Using CytoHubba, we identified hub genes in a protein-protein interaction network (PPI). Then, we evaluated their distinct effectiveness using unsupervised hierarchical clustering. Support vector machine (SVM) and ten-fold cross-validation were used to further verify these biomarkers. Lastly, we confirmed our findings by using another independent dataset.

Results: A total of 37 female-specific DEGs and 27 male-specific DEGs were identified from GSE63060 datasets. Analyses of enrichment showed that female-specific DEGs primarily focused on energy metabolism, while male-specific DEGs mostly involved in immune regulation. Three immune-checkpoint-relevant genes dysregulated in males. In females, however, these eight genes were not differentially expressed. SNRPG, RPS27A, COX7A2, ATP5PO, LSM3, COX7C, PFDN5, HINT1, PSMA6, RPS3A and RPL31 were regarded as hub genes for females, while SNRPG, RPL31, COX7C, RPS27A, RPL35A, RPS3A, RPS20 and PFDN5 were regarded as hub genes for males. Thirteen hub genes mentioned above was significantly lower in both AD and mild cognitive impairment (MCI). The diagnostic model of 15-marker panel (13 hub genes with sex and age) was developed. Both the training dataset and the independent validation dataset have area under the curve (AUC) with a high value (0.919, 95%CI 0.901-0.929 and 0.803, 95%CI 0.789-0.826). Based on GSEA for hub genes, they were associated with some aspects of AD pathogenesis.

Conclusion: DEGs in males and females contribute differently to AD pathogenesis. Algorithms combining blood-based biomarkers may improve AD diagnostic accuracy, but large validation studies are needed.

Background: C-C chemokine receptor 5 (CCR5) has recently been recognized as an underlying therapeutic target for various malignancies. However, the association of CCR5 with prognosis in the head and neck squamous cell carcinoma (HNSC) patients and tumor-infiltrating lymphocytes (TILs) is unclear.

Methods: In the current experiment, methods such as the Tumor Immune Estimation Resource Analysis (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, and Kaplan-Meier plotter Analysis were used to comprehensively evaluate the expression of CCR5 in human various malignancies and the clinical prognosis in HNSC patients. Subsequently, we used the TIMER database and the TISIDB platform to investigate the correlation between CCR5 expression levels and immune cell infiltration in the HNSC tumor microenvironment. Furthermore, immunomodulatory and chemokine profiling were performed using the TISIDB platform to analyse the correlation between CCR5 expression levels and immunomodulation in HNSC patients.

Results: We found that CCR5 expression in HNSC tumor tissues was significantly upregulated than in normal tissues. In HNSC, patients with high CCR5 expression levels had worse overall survival (OS, HR = 0.59, p = 0.00015) and worse recurrence-free survival (RFS, HR = 3.27, p = 0.00098). Upregulation of CCR5 expression is closely associated with immunomodulators, chemokines, and infiltrating levels of CD4+ T cells, neutrophils, macrophages, and myeloid dendritic cells. Furthermore, upregulated CCR5 was significantly associated with different immune markers in the immune cell subsets of HNSC.

Conclusions: High expression of CCR5 plays an important prognostic role in HNSC patients and may serve as a prognostic biomarker correlated with immune infiltration, and further studies are still needed to investigate therapeutic targeting HNSC patients in the future.

Background: Diabetic nephropathy (DN) is the major cause of end-stage renal disease worldwide. The mechanism of tubulointerstitial lesions in DN is not fully elucidated. This article aims to identify novel genes and clarify the molecular mechanisms for the progression of DN through integrated bioinformatics approaches.

Method: We downloaded microarray datasets from Gene Expression Omnibus (GEO) database and identified the differentially expressed genes (DEGs). Enrichment analyses, construction of Protein-protein interaction (PPI) network, and visualization of the co-expressed network between mRNAs and microRNAs (miRNAs) were performed. Additionally, we validated the expression of hub genes and analyzed the Receiver Operating Characteristic (ROC) curve in another GEO dataset. Clinical analysis and ceRNA networks were further analyzed.

Results: Totally 463 DEGs were identified, and enrichment analyses demonstrated that extracellular matrix structural constituents, regulation of immune effector process, positive regulation of cytokine production, phagosome, and complement and coagulation cascades were the major enriched pathways in DN. Three hub genes (CD53, CSF2RB, and LAPTM5) were obtained, and their expression levels were validated by GEO datasets. Pearson analysis showed that these genes were negatively correlated with the glomerular filtration rate (GFR). After literature searching, the ceRNA networks among circRNAs/IncRNAs, miRNAs, and mRNAs were constructed. The predicted RNA pathway of NEAT1/XIST-hsa-miR-155-5p/hsa-miR-486-5p-CSF2RB provides an important perspective and insights into the molecular mechanism of DN.

Conclusion: In conclusion, we identified three genes, namely CD53, CSF2RB, and LAPTM5, as hub genes of tubulointerstitial lesions in DN. They may be closely related to the pathogenesis of DN and the predicted RNA regulatory pathway of NEAT1/XIST-hsa-miR-155-5p/hsa-miR-486-5p-CSF2RB presents a biomarker axis to the occurrence and development of DN.