Monkeypox Virus Crosstalk with HIV: An Integrated Skin Transcriptome and Machine Learning Study.

The emergence of the monkeypox virus (MPXV) outbreak presents a formidable challenge to human health. Emerging evidence suggests that individuals with HIV have been disproportionately affected by MPXV, with adverse clinical outcomes and higher mortality rates. However, the shared molecular mechanisms underlying MPXV and HIV remain elusive. We identified differentially expressed genes (DEGs) from two public data sets, GSE219036 and GSE184320, and extracted common DEGs between MPXV and HIV. We further performed gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interactions (PPI), candidate drug assessment, and immune correlation of hub genes analysis. We validated the key biomarkers using multiple machine learning (ML) methods including random forest (RF), t-distributed stochastic neighbor embedding (tSNE), and uniform manifold approximation and projection (UMAP). A total of 59 common DEGs were identified between MPXV and HIV. Our functional analysis highlighted multiple pathways, including the ERK cascade, NF-κB signaling, and various immune responses, playing a collaborative role in the progression of both diseases. The PPI and gene co-expression networks were constructed, and five key genes with significant immune correlations were identified and validated by multiple ML models, including SPRED1, SPHK1, ATF3, AKT3, and AKT1S1. Our study emphasizes the common pathogenesis of HIV and MPXV and highlights the pivotal genes and shared pathways, providing new opportunities for evidence-based management strategies in HIV patients co-infected with MPXV.

Genetic evidence implicating circulating lipids and lipid drug targets in pterygium.

There is limited knowledge about the impact of circulating lipids and lipid-modifying drugs on pterygium development, with conflicting results reported. Our study aimed to address these questions by applying the Mendelian randomization (MR) approach. A two-step MR model was developed. In the first step, bidirectional two-sample MR was employed to establish the causal relationship between circulating lipids and pterygium risk. In the second step, drug-target MR analysis was conducted to assess the causal effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitors on pterygium outcomes. Genetically predicted low-density lipoprotein cholesterol (LDL-c) levels were found to be significantly associated with an increased risk of pterygium (Inverse variance weighted [IVW] odds ratio [OR] = 2.227; P = 1.53 × 10-4). Similarly, higher total cholesterol (TC) levels exhibited a suggestive association with greater susceptibility to pterygium (IVW OR = 1.806; P = 1.70 × 10-3). Through drug-target MR, a positive causal association was noted between HMGCR-mediated LDL-c levels and pterygium (IVW OR = 6.999; P = 0.016), suggesting that statins may be effective in reducing pterygium risk. The present findings suggest that circulating TC and LDL-c are risk factors for pterygium. Additionally, the results indicate that HMGCR inhibitors, which lower LDL-c levels, have a potential protective effect on pterygium outcomes. Further research is warranted to elucidate the underlying mechanisms involved in pterygium pathogenesis, with a particular focus on cholesterol metabolism.

Exploration of the common pathogenic link between COVID-19 and diabetic foot ulcers: An in silico approach.

Background and Aims: The Coronavirus Disease-19 (COVID-19) is posing an ongoing threat to human health. Patients of diabetic foot ulcer (DFU) are susceptible to COVID-19-induced adverse outcomes. Nevertheless, investigations into their mutual molecular mechanisms have been limited to date. In the present work, we tried to uncover the shared pathogenesis and regulatory gene targets of COVID-19 and DFU. Methods: In this study, we chose GSE161281 as the COVID-19 data set, which contained severe acute respiratory syndrome coronavirus 2 infected human induced embryonic stem cell-derived peripheral neurons (n = 2) with uninfected controls (n = 2). The GSE134431 designated as the DFU data set, comprising full-thickness DFU (n = 13) and diabetic foot skin (n = 8) samples from diabetic patients. The differential expressed genes (DEGs) were identified from GSE161281 and GSE134431, and the common DEGs between COVID-19 and DFU were extracted. Multifactor regulatory network and co-expression network of the common DEGs were analyzed, along with candidate drug prediction. Results: Altogether, six common DEGs (dickkopf-related protein 1 [DKK1], serine proteinase inhibitor A3 [SERPINA3], ras homolog family member D [RHOD], myelin protein zero like 3 [MPZL3], Claudin-11 [CLDN11], and epidermal growth factor receptor pathway substrate 8-like 1 [EPS8L1]) were found between COVID-19 and DFU. Functional analyses indicated that pathways of apoptotic and Wnt signaling may contribute to progression of COVID-19. Gene co-expression network implied the shared pathways of immune regulation and cytokine response participated collectively in the development of DFU and COVID-19. A multifactor regulatory network was constructed integrating the corresponding microRNAs (miRNAs) and transcription factors. Additionally, we proposed potential drug objects for the combined therapy. Conclusion: Our study revealed the shared molecular mechanisms underlying COVID-19 and DFU. The identified pivotal targets and common pathways can provide new perspectives for further research and assist the development of management strategies in patients of DFU complicated with COVID-19.

Crosstalk between TRPV1 and immune regulation in Fuchs endothelial corneal dystrophy.

Fuchs endothelial corneal dystrophy (FECD) is the leading indication for corneal transplantation worldwide. Our aim was to investigate the role of transient receptor potential vanilloid subtype 1 (TRPV1) and the associated immune regulation contributing to this pathological condition. Significant upregulation of TRPV1 was detected in the H2O2-induced in vitro FECD model. Based on gene expression microarray dataset GSE142538 and in vitro results, a comprehensive immune landscape was studied and a negative correlation was found between TRPV1 with different immune cells, especially regulatory T cells (Tregs). Functional analyses of the 313 TRPV1-related differentially expressed genes (DEGs) revealed the involvement of TRP-regulated calcium transport, as well as inflammatory and immune pathways. Four TRPV1-related core genes (MAPK14, GNB1, GNAQ, and ARRB2) were screened, validated by microarray dataset GSE112039 and the combined validation dataset E-GEAD-399 & 564, and verified by in vitro experiments. Our study suggested a potential crosstalk between TRPV1 and immune regulation contributing to FECD pathogenesis. The identified pivotal biomarkers and immune-related pathways provide a novel framework for future mechanistic and therapeutic studies of FECD.

Mining the potential therapeutic targets for COVID-19 infection in patients with severe burn injuries via bioinformatics analysis.

The Coronavirus Disease-19 (COVID-19) pandemic is posing a serious challenge to human health. Burn victims are susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leading to delayed recovery and even profound debilitation. Nevertheless, the molecular mechanisms underlying COVID-19 and severe burn are yet to be elucidated. In our work, the differentially expressed genes (DEGs) were identified from GSE157852 and GSE19743, and the common DEGs between COVID-19 and severe burn were extracted. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interactions (PPI), gene coexpression network, and multifactor regulatory network analysis of hub genes were carried out. A total of 44 common DEGs were found between COVID-19 and severe burn. Functional analyses indicated that the pathways of immune regulation and cytokine response participated collectively in the development of severe burn and progression of COVID-19. Ten significant hub genes were identified, including MERTK, SIRPA, TLR3, ITGB1, DPP4, PTPRC, LY75, IFIT1, IL4R, and CD2. In addition, the gene coexpression network and regulatory network were constructed containing 42 microRNAs (miRNAs) and 2 transcription factors (TFs). Our study showed the shared pathogenic link between COVID-19 and severe burn. The identified common genes and pivotal pathways pave a new road for future mechanistic researches in severe burn injuries complicated with COVID-19.

Uncovering the role of transient receptor potential channels in pterygium: a machine learning approach.

OBJECTIVES: We aimed at identifying the role of transient receptor potential (TRP) channels in pterygium. METHODS: Based on microarray data GSE83627 and GSE2513, differentially expressed genes (DEGs) were screened and 20 hub genes were selected. After gene correlation analysis, 5 TRP-related genes were obtained and functional analyses of gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed. Multifactor regulatory network including mRNA, microRNAs (miRNAs) and transcription factors (TFs) was constructed. The 5 gene TRP signature for pterygium was validated by multiple machine learning (ML) programs including support vector classifiers (SVC), random forest (RF), and k-nearest neighbors (KNN). Additionally, we outlined the immune microenvironment and analyzed the candidate drugs. Finally, in vitro experiments were performed using human conjunctival epithelial cells (CjECs) to confirm the bioinformatics results. RESULTS: Five TRP-related genes (MCOLN1, MCOLN3, TRPM3, TRPM6, and TRPM8) were validated by ML algorithms. Functional analyses revealed the participation of lysosome and TRP-regulated inflammatory pathways. A comprehensive immune infiltration landscape and TFs-miRNAs-mRNAs network was studied, which indicated several therapeutic targets (LEF1 and hsa-miR-455-3p). Through correlation analysis, MCOLN3 was proposed as the most promising immune-related biomarker. In vitro experiments further verified the reliability of our in silico results and demonstrated that the 5 TRP-related genes could influence the proliferation and proinflammatory signaling in conjunctival tissue contributing to the pathogenesis of pterygium. CONCLUSIONS: Our study suggested that TRP channels played an essential role in the pathogenesis of pterygium. The identified pivotal biomarkers (especially MCOLN3) and pathways provide novel directions for future mechanistic and therapeutic studies for pterygium.

Characterization of immune landscape and development of a novel N7-methylguanine-related gene signature to aid therapy in recurrent aphthous stomatitis.

OBJECTIVES: Recurrent aphthous stomatitis (RAS) is the most common inflammatory disease of the oral mucosa resulting in an impaired life quality and even leading to tumors in susceptible populations. N7-Methylguanine (m7G) plays a vital role in various cellular activities but has not yet been investigated in RAS. We aimed at picturing the immune landscape and constructing an m7G-related gene signature, and investigating candidate drugs and gene-disease association to aid therapy for RAS. METHODS: For our study, m7G-related differentially expressed genes (DEGs) were screened. We outlined the immune microenvironment and studied the correlations between the m7G-related DEGs and immune cells/pathways. We performed functional enrichment analyses and constructed the protein-protein interaction (PPI) and multifactor regulatory network in RAS. The m7G-related hub genes were extracted to formulate the corresponding m7G predictive signature. RESULTS: We obtained 11 m7G-related DEGs and studied a comprehensive immune infiltration landscape, which indicated several immune markers as possible immunotherapeutic targets. The PPI and multifactor regulatory network was constructed and 4 hub genes (DDX58, IFI27, IFIT5, and PML) were identified, followed by validation of the corresponding m7G predictive signature for RAS. GO and KEGG analyses revealed the participation of JAK-STAT and several immune-related pathways. Finally, we suggested candidate drugs and gene-disease associations for potential RAS medical interventions. CONCLUSIONS: The present study pictured a comprehensive immune infiltration landscape and suggested that m7G played a vital role in RAS through immune-related pathways. This study provided new insight for the future investigation of the mechanisms and therapeutic strategies for RAS.

Nanofibrous Membrane Dressings Loaded With Sodium Hydrogen Sulfide/Endothelial Progenitor Cells Promote Wound Healing.

Hydrogen sulfide (H2S) has been identified as an important gasotransmitter. H2S donor can release H2S sustained and is used as wound dressing. Endothelial progenitor cells (EPCs), given their regenerative ability, have also been reported to enhance wound healing. However, effective drug carriers are missing for the clinical application of H2S and EPCs. In this study, we investigated a novel drug carrier nanofibrous membrane, which was prepared by blending the recombinant spider silk protein (rMaSp) and sodium hydrogen sulfide (NaHS) by electrospun. Our results show that the rMaSp/NaHS nanofibrous membrane is associated with high hemocompatibility and cytocompatibility and is capable of stably releasing H2S for a long period of time. We also tested the rMaSp/NaHS membrane loaded with EPCs in an in vivo cutaneous wound model. We showed that the rMaSp/NaHS/EPC system significantly enhances wound regeneration efficiency as compared to rMaSp membrane and rMaSp/NaHS membrane. This study provides key evidence supporting the clinical application of nanofibrous membrane in the field of skin tissue regeneration.