Interleukin-6 Signaling Pathway Research Articles

Association of Microsatellite Instability and Gene Expression Profile in Colorectal Carcinoma and Potential Implications for Therapy.

Background and Objective: In sporadic colorectal carcinomas (CRC), microsatellite instability (MSI) pathways play important roles. Previously, we showed differences in DNA methylation patterns in microsatellite stable (MSS) colorectal carcinomas and MSI-CRC. In the current study, we explore the similarities and differences in gene expression profiles in MSS and MSI at the gene level and at the pathway level to better understand CRC pathogenesis and/or the potential for therapeutic opportunities. Material and Methods: Seventy-one CRC patients (MSI = 18, MSS = 53) were studied. Paired tumor and adjacent normal tissues were used for genome-wide gene expression assays. Result: At the gene level, we compared the list of differentially expressed genes (fold change (FC) ≥ 3 and FDR < 0.05) in tumor tissues compared to corresponding normal tissue in CRC patients with MSI tumors (190 genes) and MSS tumors (129 genes). Of these, 107 genes overlapped. The list of genes that were differentially expressed in MSI tumors only showed enrichment predominantly in two broad categories of pathways-(a) Inflammation-related pathways including the interleukin-17 (IL-17) signaling pathway, tumor necrosis factor (TNF) signaling pathway, chemokine signaling, nuclear factor kappa B (NFκB) signaling, and cytokine-cytokine interactions, and (b) metabolism-related pathways, including retinol metabolism, steroid hormone biosynthesis, drug metabolism, pentose and glucoronate interconversions, and ascorbate and aldarate metabolism. The genes in inflammation-related pathways were up-regulated whereas genes in metabolism-related pathways were down-regulated in MSI tumor tissue. Pathway-level analysis also revealed similar results confirming the gene enrichment findings. For example, the 150 genes involved in the IL-17 signaling pathway were on average up-regulated by 1.19 fold (CI 1.16-1.21) in MSI compared to 1.14 fold (CI 1.13-1.16) in MSS patients (interaction p = 0.0009). Conclusions: We document an association between MSI status and differential gene expression that broadens our understanding of CRC pathogenesis. Furthermore, targeting one or more of these dysregulated pathways could provide the basis for improved therapies for MSI and MSS CRC.

The potential mechanism of Guizhi Fuling Wan effect in the treatment of cervical squamous cell carcinoma: A bioinformatics analysis investigation.

As a global malignancy with high mortality rate, targeted drug development for Uterine Cervical Neoplasms is an important direction. The traditional formula Guizhi Fuling Wan (GFW) is widely used in gynecological diseases. However, its potential mechanism of action remains to be discovered. We retrieved GFW and cervical squamous cell carcinoma (CSCC) targets from public databases. The protein-protein interaction network was obtained by string computational analysis and imported Cytoscape_v3.9.0 to obtain the core network and the top 10 Hub genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used for enrichment analysis of the core network, and then molecular docking to verify whether the selected signaling pathway binds well to the core node. Finally, clinical prognostic analysis and expression differences of Hub genes were validated using the Cancer Genome Atlas database and R language. Our search yielded 152 common targets for GFW and CSCC. The interleukin-17 signaling pathway, tumor necrosis factor signaling pathway, and Toll-like signaling pathway were then selected for further molecular docking from the hub genes enrichment analysis results, which showed good binding. Among the Hub genes, JUN, VEGFA, IL1B, and EGF had a poor prognosis for CSCC. In conclusion, this study illustrates that GFW can have adjuvant therapeutic effects on CSCC through multiple targets and multiple pathways, providing a basis for further research.

Identification of potential diagnostic biomarkers associated with periodontitis by comprehensive bioinformatics analysis

Periodontitis is a chronic inflammatory disease that affects the tissues surrounding the teeth, including the gums and the bones supporting the teeth. Early detection and intervention are crucial for effective management of periodontitis. Our study aims to identify a diagnostic biomarker for periodontitis and explore the pathways associated with the occurrence and development of periodontitis. The expression of gingival tissue from periodontitis and healthy control were downloaded from the Gene Expression Omnibus. The weighted gene co-expression network analysis (WGCNA) were used to analyze module genes associated with periodontitis and DESeq2 were performed to identify differently expressed genes (DEGs) between periodontitis and healthy control. Then the candidate genes were obtained by intersecting the genes from interest modules and DEGs. Functional enrichment analysis was performed using gene ontology and kyoto encyclopedia of gene and genomes, followed by the protein–protein interaction (PPI) network analysis. The hub genes were identified by the cytoCNA plugin in Cytoscape. Finally, immunohistochemical staining of the hub genes was performed to validate the findings. WGCNA analysis found that the expression of the MEblack module was significantly higher in individuals with periodontitis compared to those in the healthy control group. A total of 888 DEGs, including 750 upregulated and 138 downregulated genes, were identified. Finally, 427 candidate genes were identified potentially associated with periodontitis after intersecting the DEGs and the black module genes. Several critical signaling pathways were identified associated with periodontitis by functional enrichment analysis, including cytokine–cytokine receptor interaction, neutrophil extracellular trap formation, Staphylococcus aureus infection, and Interleukin-17 signaling pathway. The PPI network analysis revealed that C-X-C motif chemokine ligand 5 (CXCL5) and C-X-C motif chemokine ligand 6 (CXCL6) could play an important role in the process of periodontitis. The gene expression level of CXCL5 and CXCL6 detected using immunohistochemical verified the findings. In conclusion, we found that CXCL5 and CXCL6 are closely associated with the occurrence of periodontitis. Our present pilot study suggests that CXCL5 and CXCL6 have the potential to be used as a diagnostic biomarker of periodontitis.

Collagen Type II-Based Injectable Materials for Insitu Repair and Regeneration of Articular Cartilage Defect.

Repairing and regenerating articular cartilage defects (ACDs) have long been challenging for physicians and scientists. The rise of injectable materials provides a novel strategy for minimally invasive surgery to repair ACDs. In this study, we successfully developed injectable materials based on collagen type II, achieving hyaline cartilage repair and regeneration of ACDs. Analysis was conducted on the regenerated cartilage after materials injection. The histology staining demonstrated complete healing of the ACDs with the attainment of a hyaline cartilage phenotype. The biochemical and biomechanical properties are similar to the adjacent native cartilage without noticeable adverse effects on the subchondral bone. Further transcriptome analysis found that compared with the Native cartilage adjacent to the defect area, the Regenerated cartilage in the defect area repaired with type II collagen-based injection materials showed changes in cartilage-related pathways, as well as down-regulation of T cell receptor signaling pathways and interleukin-17 signaling pathways, which changed the immune microenvironment of the ACD area. Overall, these findings offer a promising injectable approach to treating ACDs, providing a potential solution to the challenges associated with achieving hyaline cartilage insitu repair and regeneration while minimizing damage to the surrounding cartilage.

Expression and clinical significance of interleukin-6 pathway in cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a typical inflammation-induced malignancy, and elevated serum interleukin-6 (IL-6) levels have been reported to be linked to the onset and progression of CCA. We aim to investigate the potential prognostic value of the IL-6 pathway for CCA. We detected the expressions of IL-6, IL-6R, glycoprotein (gp130), C-reactive protein (CRP), Janus kinase 2 (JAK2), and signal transducer and activator of transcription 3 (STAT3) in CCA tissue microarray using multiplex immunofluorescence. Furthermore, the clinical associations and prognostic values were assessed. Finally, single-cell transcriptome analysis was performed to evaluate the expression level of IL-6 pathway genes in CCA. The results revealed that the expression of IL-6 was lower, while the expression of STAT3 was higher in tumor tissues compared to normal tissues. Especially in tumor microenvironment, the expression of IL-6 pathway genes was generally downregulated. Importantly, gp130 was strongly correlated with JAK2 in tumor tissues, while it was moderately correlated with JAK2 in normal tissue. Although none of the gene expressions were directly associated with overall survival and disease-free survival, our study found that IL-6, IL-6R, CRP, gp130, and JAK2 were inversely correlated with vascular invasion, which is a risk factor for poor prognosis in patients with CCA. The findings from this study suggest that the IL-6 signaling pathway may have a potential prognostic value for CCA. Further investigation is needed to understand the underlying molecular mechanisms of the IL-6 pathway in CCA.

Circulating hsa-miR-320a and its regulatory network in type 1 diabetes mellitus.

Increasing evidence from human and animal model studies indicates the significant role of microRNAs (miRNAs) in pancreatic beta cell function, insulin signaling, immune responses, and pathogenesis of type 1 diabetes (T1D). We aimed, using next-generation sequencing, to screen miRNAs from peripheral blood mononuclear cells of eight independent Kuwaiti-Arab families with T1D affected siblings, consisting of 18 T1D patients and 18 unaffected members, characterized by no parent-to-child inheritance pattern. Our analysis revealed 20 miRNAs that are differentially expressed in T1D patients compared with healthy controls. Module-based weighted gene co-expression network analysis prioritized key consensus miRNAs in T1D pathogenesis. These included hsa-miR-320a-3p, hsa-miR-139-3p, hsa-miR-200-3p, hsa-miR-99b-5p and hsa-miR-6808-3p. Functional enrichment analysis of differentially expressed miRNAs indicated that PI3K-AKT is one of the key pathways perturbed in T1D. Gene ontology analysis of hub miRNAs also implicated PI3K-AKT, along with mTOR, MAPK, and interleukin signaling pathways, in T1D. Using quantitative RT-PCR, we validated one of the key predicted miRNA-target gene-transcription factor networks in an extended cohort of children with new-onset T1D positive for islet autoantibodies. Our analysis revealed that hsa-miR-320a-3p and its key targets, including PTEN, AKT1, BCL2, FOXO1 and MYC, are dysregulated in T1D, along with their interacting partners namely BLIMP3, GSK3B, CAV1, CXCL3, TGFB, and IL10. Receiver Operating Characteristic analysis highlighted the diagnostic potential of hsa-miR-320a-3p, CAV1, GSK3B and MYC for T1D. Our study presents a novel link between hsa-miR-320a-3p and T1D, and highlights its key regulatory role in the network of mRNA markers and transcription factors involved in T1D pathogenesis.

Blockade of the interleukin-6 signaling pathway in rheumatoid arthritis: Effects on obesity, adipocytokines and glucose metabolism

Interleukin (IL) 6 is one of the key cytokines whose role in the inflammation development in rheumatoid arthritis (RA), is well proven. The pleiotropic effects of the cytokine and biologic agents that inhibit its action have been studied much worse. The review provides information on the effects of IL-6 and blocking its signaling pathway on adipose tissue, glucose metabolism and adipocytokine levels in RA. It has been shown that prolonged blockade of IL-6 receptors does not lead to the adipose tissue accumulation and improves glycemic control, although it is not clear whether such effect is associated only with the anti-inflammatory properties of tocilizumab and sarilumab. Moreover, the mechanism of this beneficial effect is not fully understood, since the data on increased sensitivity of peripheral tissues to insulin during tocilizumab treatment are ambiguous. Perhaps changes in the relationship of adipocytokines or hormones play a certain role.

Exploring the potential mechanism of Simiao Yongan decoction in the treatment of diabetic peripheral vascular disease based on network pharmacology and molecular docking technology

The study aims to investigate the potential action targets and molecular mechanisms of Simiao Yongan decoction (SMYAD) in treating diabetic peripheral vascular disease (DPVD) by utilizing network pharmacology analysis and molecular docking technology. The components and targets of SMYAD were screened using the TCMSP database, while DPVD-related genes were obtained from the GeneCards, OMIM, and Disgenet databases. After intersecting the gene sets, a Protein-Protein Interaction (PPI) network was established, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were carried out. The practical chemical components and core targets identified were molecularly docked using AutoDock software. A total of 126 active compounds were screened from which 25 main components included quercetin, rutoside, hesperidin, naringin, and β-sitosterol were determined to be the active components most associated with the core targets. A total of 224 common target genes were obtained. Among them, JUN, AKT1, MAPK3, TP53, STAT3, RELA, MAPK1, FOS, and others are the expected core targets of traditional Chinese medicine. The top-ranked GO enrichment analysis results included 727 biological processes (BP), 153 molecular functions (MF), and 102 cellular components (CC). KEGG pathway enrichment analysis involved mainly 178 signaling pathways, such as cancer signaling pathway, AGE-RAGE signaling pathway, interleukin-17 signaling pathway, tumor necrosis factor signaling pathway, endocrine resistance signaling pathway, cell aging signaling pathway, and so on. The molecular docking results demonstrate that the principal chemical components of SMYAD exhibit considerable potential for binding to the core targets. SMYAD has the potential to treat DPVD through various components, targets, and pathways. Its mechanism of action requires further experimental investigation.

Targeting Interleukin-17 as a Novel Treatment Option for Fibrotic Diseases.

Fibrosis is the end result of persistent inflammatory responses induced by a variety of stimuli, including chronic infections, autoimmune reactions, and tissue injury. Fibrotic diseases affect all vital organs and are characterized by a high rate of morbidity and mortality in the developed world. Until recently, there were no approved antifibrotic therapies. In recent years, high levels of interleukin-17 (IL-17) have been associated with chronic inflammatory diseases with fibrotic complications that culminate in organ failure. In this review, we provide an update on the role of IL-17 in fibrotic diseases, with particular attention to the most recent lines of research in the therapeutic field represented by the epigenetic mechanisms that control IL-17 levels in fibrosis. A better knowledge of the IL-17 signaling pathway implications in fibrosis could design new strategies for therapeutic benefits.

Interleukin-6: Unravelling its role in sarcopenia pathogenesis and exploring therapeutic avenues

This review explores the intricate relationship between interleukin-6 (IL-6) and sarcopenia, a prevalent condition characterized by progressive skeletal muscle loss, particularly in aging populations. Emphasizing the rising prevalence and health challenges posed by sarcopenia, the paper delves into the multifunctional roles of IL-6 in immune response, inflammation and inflammaging associated with sarcopenia. Significantly elevated in sarcopenic individuals, IL-6 prompts an exploration of its molecular impact on muscle wasting. The review critically assesses IL-6 as a potential biomarker for sarcopenia diagnosis and prognosis while also examining therapeutic interventions targeting IL-6 signaling pathways, offering a foundation for future research and the development of targeted therapeutic strategies to alleviate the impact of this debilitating condition.

Identification of overlay differentially expressed genes in both rats and goats with blast lung injury through comparative transcriptomics

PurposeTo identify the potential target genes of blast lung injury (BLI) for the diagnosis and treatment. MethodsThis is an experimental study. The BLI models in rats and goats were established by conducting a fuel-air explosive power test in an unobstructed environment, which was subsequently validated through hematoxylin-eosin staining. Transcriptome sequencing was performed on lung tissues from both goats and rats. Differentially expressed genes were identified using the criteria of q ≤ 0.05 and |log2 fold change| ≥ 1. Following that, enrichment analyses were conducted for gene ontology and the Kyoto Encyclopedia of Genes and Genomes pathways. The potential target genes were further confirmed through quantitative real-time polymerase chain reaction and enzyme linked immunosorbent assay. ResultsObservations through microscopy unveiled the presence of reddish edema fluid, erythrocytes, and instances of focal or patchy bleeding within the alveolar cavity. Transcriptome sequencing analysis identified a total of 83 differentially expressed genes in both rats and goats. Notably, 49 genes exhibited a consistent expression pattern, with 38 genes displaying up-regulation and 11 genes demonstrating down-regulation. Enrichment analysis highlighted the potential involvement of the interleukin-17 signaling pathway and vascular smooth muscle contraction pathway in the underlying mechanism of BLI. Furthermore, the experimental findings in both goats and rats demonstrated a strong association between BLI and several key genes, including anterior gradient 2, ankyrin repeat domain 65, bactericidal/permeability-increasing fold containing family A member 1, bactericidal/permeability-increasing fold containing family B member 1, and keratin 4, which exhibited up-regulation. ConclusionsAnterior gradient 2, ankyrin repeat domain 65, bactericidal/permeability-increasing fold containing family A member 1, bactericidal/permeability-increasing fold containing family B member 1, and keratin 4 hold potential as target genes for the prognosis, diagnosis, and treatment of BLI.

Model-Based Exploration of the Impact of Prophylactic Tocilizumab on IL-6 Dynamics in Multiple Myeloma Patients Receiving Teclistamab Treatment

Introduction: Teclistamab is the only approved B-cell maturation antigen (BCMA) × CD3 bispecific antibody (BsAb) with personalized, weight-based dosing for the treatment of patients with triple-class exposed relapsed/refractory multiple myeloma (RRMM).In the MajesTEC-1 study (NCT03145181 and NCT04557098), the incidence of all grade (mostly grade 1 or 2) cytokine release syndrome (CRS) was 72.1% (Moreau et al. 2022). The cytokine interleukin-6 (IL-6) is found to be increased in the serum of patients with CRS (Shimabukuro-Vornhagen et al. 2018). Tocilizumab is a humanized IL-6 receptor-inhibiting monoclonal antibody. As a competitive antagonist, tocilizumab inhibits the IL-6 pathway by competing with IL-6 for binding to IL-6 receptor (IL-6R), resulting in lower IL-6R receptor occupancy (RO) by IL-6, thereby blocking IL-6 signaling. By blocking IL-6R, tocilizumab also reduces IL-6R-mediated IL-6 clearance, which leads to an increase in serum IL-6 levels (Uchiyama et al. 2008). It has been published previously that a single dose of prophylactic tocilizumab reduced the overall incidence of CRS to 26% after teclistamab administration, which represents a 64% reduction compared to the CRS incidence observed in MajesTEC-1 (van de Donk et al. 2023). A mechanism-based PK/PD model was used to evaluate the impact of tocilizumab prophylactic treatment on the soluble IL-6R (sIL-6R), IL-6 and the duration of the blockade of IL-6 signaling pathway in the patients following teclistamab treatment. Methods: A mechanism-based PK/PD model was built by using reported tocilizumab PK parameters and sIL-6R target engagement. The time course of IL-6R RO for patients receiving prophylactic tocilizumab following teclistamab treatment was estimated from the PK profiles of tocilizumab and competitive binding kinetics. Among the patients with evaluable serum IL-6 levels, the highest peak serum IL-6 concentration in the patients who didn't have CRS (N=9) from prophylactic tocilizumab cohort of MajesTEC-1 was selected as the worst-case scenario. The IL-6R RO in patients receiving prophylactic tocilizumab in the worst-case scenario was characterized by model simulations and the results were compared to the calculated IL-6R RO in the cohorts following teclistamab treatment without prophylactic tocilizumab (N=40). Results: Time course of serum IL-6 levels following teclistamab treatment showed higher and earlier induction in the cohort with tocilizumab prophylaxis compared to the cohort without tocilizumab prophylaxis. Among the patients who received tocilizumab prophylactic treatment, the median peak serum IL-6 level was 208.6 pg/mL and the highest peak serum IL-6 level was 1701.8 pg/mL in patients who didn't have CRS. The model simulation results showed that a single dose of tocilizumab at 8 mg/kg IV given prophylactically could lower the IL-6R RO by IL-6. In a patient with 1700 pg/mL of serum IL-6 treated with tocilizumab, IL-6R RO was maintained below the level of RO achieved with 10 pg/mL of serum IL-6 in the absence of tocilizumab for approximately 10 days. An IL-6 level of 10 pg/mL was considered as a representative value in the patients who did not have CRS following teclistamab at the approved dosing regimen without prophylactic tocilizumab, as more than half (58%) of these patients showed peak serum IL-6 level below 10 pg/mL. The duration of IL-6R RO reduction covers the two step-up doses (SUD) and the first full treatment dose according to the teclistamab approved dosing schedule. Conclusions: The modeling and simulation results showed that a single dose of tocilizumab given prophylactically at 8 mg/kg could block IL-6R RO for approximately 10 days following the 1 st step up dose of teclistamab. The results further support this approach for lowering overall risk of CRS during the SUD schedule in multiple myeloma patients treated with teclistamab.

Xiegan-Liangxue-Jiedu Decoction Alleviated Psoriasis and Depressionlike Behavior in a Mouse Model: Role of the AC–cAMP–PKA–CREB Signaling Pathway

Objectives Psoriasis vulgaris is an immune-mediated inflammatory skin disease that is associated with depression. In this study, we investigated the effect of Xiegan–Liangxue–Jiedu (XGLXJD) decoction, a traditional Chinese medicine formula, on psoriasis based on network pharmacology, molecular docking, and animal experiments. Materials and Methods A protein–protein interaction (PPI) network was constructed using the overlapping targets of XGLXJD decoction and psoriasis. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using Metascape database. High-performance liquid chromatography (HPLC) was used to investigate the main compounds of XGLXJD decoction. Molecular docking was performed to predict the potential interaction between the main compounds and proteins of interest. A C57 mouse model of psoriasis was established via continuous exposure to imiquimod. Seven days later, the XGLXJD decoction was orally administered at increasing doses for 6 days. The psoriasis area and severity index were calculated. Hematoxylin and eosin staining was used to examine skin morphology. Enzyme-linked immunosorbent assay (ELISA) was used to determine the serum levels of adenylyl cyclase (AC), cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), interleukin-17 (IL-17), and tumor necrosis factor-α (TNF-α). Sucrose preference test and forced swimming test were used to assess depression-like behavior. Immunohistochemical (IHC) staining and immunofluorescence were used to investigate the cAMP-response element binding protein (CREB) signaling pathway. Results Overall, 162 overlapping targets were generated. A total of 398 biological processes, 84 molecular functions, and 47 cellular components were identified via GO analysis, whereas 140 pathways were identified via KEGG pathway analysis. The most notable signaling pathways were cAMP as well as downstream IL-17 and TNF-α signaling pathways. HPLC analysis revealed that the main compounds of XGLXJD decoction were paeoniflorin, isorhamnetin, quercetin, luteolin, kaempferol, and baicalein. The molecular docking assay indicated that the docking energies of the main compounds of XGLXJD decoction to the top hub genes were less than −5 kcal/mol. ELISA revealed that the administration of XGLXJD decoction decreased the levels of pro-inflammatory cytokines (TNF-α and IL-17). Furthermore, the AC, cAMP, and PKA levels were enhanced after its administration. IHC staining demonstrated that the administration of XGLXJD decoction activated the AC–cAMP–PKA–CREB signaling pathway in skin. In addition, it enhanced sucrose preference and forced swimming time percentage. It also enhanced the expression of cAMP and PKA in the hippocampus. Conclusion XGLXJD decoction alleviated psoriasis and depression-like behavior. The AC–cAMP–PKA–CREB signaling pathway may play a crucial role in mediating this effect.

Effect of TRAF6-knockout on gene expression and lncRNA expression in Epithelioma papulosum cyprini (EPC) cells

ABSTRACT TRAF6 is a key immune gene that plays a significant role in toll-like receptor signal transduction and activates downstream immune genes involved in antiviral immunity in fish. To explore the role of TRAF6 in Epithelioma papulosum cyprini (EPC) cells, we knocked out the TRAF6 gene using the Clustered Regularly Interspaced Short Palindromic Repeats-Cas9 (CRISPR-Cas9) technique and then analyzed the transcriptomes of the knockout cells. In this study, we identified that 232 transcripts were differentially expressed in naive cells. Using the pipeline, we identified 381 novel lncRNAs in EPC cells, 23 of which were differentially expressed. Gene Ontology enrichment analysis demonstrated that differentially expressed genes (DEG) are implicated in various immune processes, such as neutrophil chemotaxis and mitogen-activated protein kinase binding. In addition, the KEGG pathway analysis revealed enrichment in immune-related pathways (Interleukin-17 signaling pathway, cytokine-cytokine receptor interaction, and TNF signaling pathway). Furthermore, the target genes of the differentially expressed lncRNAs were implicated in the negative regulation of interleukin-6 and tumor necrosis factor production. These results indicate that lncRNAs and protein-coding genes participate in the regulation of immune and metabolic processes in fish.

Integrative Transcriptomics and Proteomics Analysis Reveals Immune Response Process in Bovine Viral Diarrhea Virus-1-Infected Peripheral Blood Mononuclear Cells.

Bovine viral diarrhea virus (BVDV) causes bovine viral diarrhea-mucosal disease, inflicting substantial economic losses upon the global cattle industry. Peripheral blood mononuclear cells (PBMCs) are the central hub for immune responses during host-virus infection and have been recognized as crucial targets for BVDV infection. In order to elucidate the dynamics of host-BVDV-1 interaction, this study harnessed RNA-seq and iTRAQ methods to acquire an extensive dataset of transcriptomics and proteomics data from samples of BVDV-1-infected PBMCs at the 12-h post-infection mark. When compared to mock-infected PBMCs, we identified 344 differentially expressed genes (DEGs: a total of 234 genes with downregulated expression and 110 genes with upregulated expression) and 446 differentially expressed proteins (DEPs: a total of 224 proteins with downregulated expression and 222 proteins with upregulated expression). Selected DEGs and DEPs were validated through quantitative reverse transcriptase-polymerase chain reaction and parallel reaction monitoring. Gene ontology annotation and KEGG enrichment analysis underscored the significant enrichment of DEGs and DEPs in various immunity-related signaling pathways, including antigen processing and presentation, complement and coagulation cascades, cytokine-cytokine receptor interaction, and the NOD-like receptor signaling pathway, among others. Further analysis unveiled that those DEGs and DEPs with downregulated expression were predominantly associated with pathways such as complement and coagulation cascades, the interleukin-17 signaling pathway, cytokine-cytokine receptor interaction, the PI3K-Akt signaling pathway, the tumor necrosis factor signaling pathway, and the NOD-like receptor signaling pathway. Conversely, upregulated DEGs and DEPs were chiefly linked to metabolic pathways, oxidative phosphorylation, complement and coagulation cascades, and the RIG-I-like receptor signaling pathway. These altered genes and proteins shed light on the intense host-virus conflict within the immune realm. Our transcriptomics and proteomics data constitute a significant foundation for delving further into the interaction mechanism between BVDV and its host.

Macrophage CAPN4 regulates CVB3-induced cardiac inflammation and injury by promoting NLRP3 inflammasome activation and phenotypic transformation to the inflammatory subtype

Exploring the immune mechanism of coxsackievirus B3 (CVB3)-induced myocarditis may provide a promising therapeutic strategy. Here, we investigated the regulatory role of macrophage CAPN4 in the phenotypic transformation of macrophages and NOD-like receptor protein 3 (NLRP3) inflammasome activation. We found that CAPN4 was the most upregulated subtype of the calpain family in CVB3-infected bone marrow-derived macrophages (BMDMs) and Raw 264.7 cells after CVB3 infection and was upregulated in cardiac macrophages from CVB3-infected mice. Conditional knockout of CAPN4 (CAPN4flox/flox; LYZ2-Cre, CAPN4-cKO mice) ameliorated inflammation and myocardial injury and improved cardiac function and survival after CVB3 infection. Enrichment analysis revealed that macrophage differentiation and the interleukin signaling pathway were the most predominant biological processes in macrophages after CVB3 infection. We further found that CVB3 infection and the overexpression of CAPN4 promoted macrophage M1 polarization and NLRP3 inflammasome activation, while CAPN4 knockdown reversed these changes. Correspondingly, CAPN4-cKO alleviated CVB3-induced M1 macrophage transformation and NLRP3 expression and moderately increased M2 transformation in vivo. The culture supernatant of CAPN4-overexpressing or CVB3-infected macrophages impaired cardiac fibroblast function and viability. Moreover, macrophage CAPN4 could upregulate C/EBP-homologous protein (chop) expression, which increased proinflammatory cytokine release by activating the phosphorylation of transducer of activator of transcription 1 (STAT1) and 3 (STAT3). Overall, these results suggest that CAPN4 increases M1-type and inhibits M2-type macrophage polarization through the chop-STAT1/STAT3 signaling pathway to mediate CVB3-induced myocardial inflammation and injury. CAPN4 may be a novel target for viral myocarditis treatment.

Mechanistic Insights into the Roles of the IL-17/IL-17R Families in Pancreatic Cancer.

The members of the cytokine interleukin 17 (IL-17) family, along with their receptors (IL-17R), are vital players in a range of inflammatory diseases and cancer. Although generally regarded as proinflammatory, the effects they exhibit on cancer progression are a double-edged sword, with both antitumor and protumor activities being discovered. There is growing evidence that the IL-17 signaling pathways have significant impacts on the tumor microenvironment (TME), immune response, and inflammation in various types of cancer, including pancreatic cancer. However, the detailed mechanistic functions of the IL-17/IL-17R families in pancreatic cancer were rarely systematically elucidated. This review considers the role of the IL-17/IL-17R families in inflammation and tumor immunity and elaborates on the mechanistic functions and correlations of these members with pathogenesis, progression, and chemoresistance in pancreatic cancer. By summarizing the advanced findings on the role of IL-17/IL17R family members and IL-17 signaling pathways at the molecular level, cellular level, and disease level in pancreatic cancer, this review provides an in-depth discussion on the potential of IL-17/IL-17R as prognostic markers and therapeutic targets in pancreatic cancer.

Combining network pharmacology and bioinformatics to identify bioactive compounds and potential mechanisms of action of Sedum aizoon L in the treatment of atherosclerosis

Sedum aizoon L (SL) is a medicinal plant containing several active components with anti-inflammatory, hemostatic, and blood pressure lowering effects. The aim of this research was to investigate the main pathways, mechanisms, and active components of SL to treat atherosclerosis (AS) through network pharmacology. The active ingredients and their targets of action were obtained by setting the active ingredient-screening conditions using SL as a keyword in the Traditional Chinese Medicine (TCM) System Pharmacology Database and Analysis Platform. The differentially expressed genes related to AS were obtained from the Gene Expression Omnibus database, and the targets related to the treatment of AS were retrieved from databases, such as DisGeNet and GENECARDs, and the targets of AS and SL were intersected using the Cytoscape software platform and applied to construct a drug–compound–target–pathway network map. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, and protein–protein interaction were performed to explore the mechanisms of action of SL against AS. In all, 12 active ingredients were screened from the chemical composition of SL, among which myricetin, oleanolic acid, ursolic acid, sitosterol, and beta-sitosterol were the major active ingredients for the anti-atherosclerotic effect of SL. Combining the active ingredient–target network and disease–target protein–protein interaction (PPI) network, GO and KEGG analysis, tumor necrosis factor signaling pathway, and interleukin-17 signaling pathway were the key pathways of action. SL acts as an anti-atherosclerotic agent through multiple chemical components, targets, and pathways. The active ingredients of SL mainly play the role of prevention and treatment of AS by inhibiting inflammatory response, as an antioxidant, and by lowering blood lipids, thereby providing the theoretical basis for its clinical use.

Discovery of Natural Multitarget Xanthine Oxidase Inhibitors for Therapeutic Hyperuricemia Using Virtual Screening, Network Pharmacology and in vitro Experimental Verification

AbstractIn this research, based on an important target xanthine dehydrogenase/oxidase (XDH/XO) of therapeutical hyperuricemia, natural multitarget XO inhibitors are discovered from Chinese herbal medicine. As a result, 31 natural active compounds are found using network pharmacology, molecular docking and dynamic simulation computational approaches. Further experimental verification shows that hesperetin, notopterol and cnidimol B are the promising lead compounds as multitarget XO inhibitors. Moreover, hesperetin, as an obvious competitive inhibitor, has the best bioactivities (IC50=13.63±0.12 μM). Additionally, inhibitory mechanism illustrates that these compounds treat hyperuricemia through targets HPRT1, NT5E, XDH, HSP90AA1, STAT3, ESRI, PPARG, MAPK1, MAPK3 SIRT1, mTOR and TLR4. Relevant signaling pathways involve in SCF‐Kit signaling pathway, interleukin signaling pathway, immune system, PDGFR signaling pathway in disease, and cellular response to heat stress. Therefore, the current research provides a new idea for discovery and development of novel XOIs, and has innovative significance for the expansion of related drug research.

Melittin inhibits tumor cell migration and enhances cisplatin sensitivity by suppressing IL-17 signaling pathway gene LCN2 in castration-resistant prostate cancer.

Melittin is a small molecule polypeptide extracted from the abdominal cavity of bees, which is used to treat inflammatory diseases and relieve pain. However, the antitumor effect of melittin and its mechanisms remain unclear, especially in castration-resistant prostate cancer (CRPC). Through CCK-8 assay, colony formation assay, wound healing assay and Transwell migration assay, we explored the effect of melittin on CRPC cell lines. In addition, with microarray analysis, gene ontology analysis and kyoto encyclopedia of genes and genomes analysis, this study identified key genes and signaling pathways that influence the growth of PC-3 cells. Meanwhile, the effect of melittin on CRPC was also verified through subcutaneous tumor formation experiments. Finally, we also tested the relevant indicators of human prostate cancer (PCa) specimens through immunohistochemistry and H＆E stating. Here, melittin was verified to inhibit the cell proliferation and migration of CPRC. Moreover, RNA-sequence analysis demonstrated that Interleukin-17 (IL-17) signaling pathway gene Lipocalin-2 (LCN2) was downregulated by melittin treatment in CRPC. Further investigation revealed that overexpression of LCN2 was able to rescue tumor suppression and cisplatin sensitivity which melittin mediated. Interestingly, the expression of LCN2 is highly related to metastasis in PCa. In brief, our study indicates that LCN2 plays an oncogenic role in CRPC and melittin may be selected as an attractive candidate for CRPC therapy.