IL-17 Signaling Pathway Research Articles

Exploring the action mechanism of Oxalis corniculata L. decoction in treating osteoarthritis utilizing liquid chromatography-mass spectrometry technology combined with network pharmacology.

This study aimed to identify the chemical constituents of Oxalis corniculata L. decoction. Furthermore, the mechanism of action of O corniculata L. decoction in treating osteoarthritis (OA) was investigated utilizing network pharmacology. The chemical composition of the O corniculata L. decoction was analyzed by employing UHPLC-Q-Exactive-MS/MS. Subsequently, a "compound-target-pathway" network was established through network pharmacology, offering a novel approach to identify the molecular mechanism underlying the treatment of OA with O corniculata L. decoction. Ultimately, the molecular docking technique was employed to validate the binding ability of the active ingredients with therapeutic targets. A total of 539 compounds were identified in O corniculata L. decoction. Topological analysis of the protein-protein interaction network indicated that compounds, including guanosine, naringenin-7-O-beta-D-glucuronide, noroxyhydrastinine, and chrysophanol 8-O-glucoside, have therapeutic potential for OA. In addition, GAPDH, TNF, TP53, epidermal growth factor receptor, and ESR1 may be key targets for the treatment of OA, primarily involving lipid and atherosclerosis, cellular senescence, IL-17 signaling pathway, and epidermal growth factor receptor tyrosine kinase inhibitor resistance signaling pathways. This method preliminarily identified the chemical composition of O corniculata L. decoction and predicted the active ingredients, potential targets, and signaling pathways of O corniculata L. decoction in treating OA. The findings of this research revealed the potential function of O corniculata L. decoction in anti-inflammation, alongside its ability to promote osteoblast proliferation and differentiation, providing new ideas for the processing of O corniculata L. herbs and related drug development.

Genetic causes of primary immunodeficiency in the Jordanian population.

Ιnborn errors of immunity (IEI) represents a heterogenous collection of >480 immune system anomalies, leading to severe infections, autoimmune disorders and malignancies. While these conditions are rare globally, their prevalence is notably higher in the Jordanian population, attributed to elevated rates of consanguinity. The intricate nature of IEI has driven the adoption of genomic technologies for the identification of associated genetic defects. In the present study, whole-exome sequencing was performed on nine Jordanian IEI patient samples, confirming germline single-nucleotide variations (SNVs) in 14 genes through Sanger sequencing. Of note, signal transducer and activator of transcription 1 (STAT1), elastase, neutrophil expressed (ELANE) and interferon induced with helicase c domain 1 (IFIH1) harbored mutations that were previously unreported in the Jordanian IEI population. In addition, mutations in capping protein regulator and myosin 1 linker 2 (c.3683C>T), TNFα-induced protein 3-interacting protein 1 (TNIP1) (c.460C>G) and STAT1 (c.1061T>C) were confirmed, marking their association with Jordanian IEI. For robustness, the genomic databases Ensemble, Genome AD and ClinVar were used to confirm the SNVs' associations with IEI. Kyoto Encyclopedia of Genes and Genomes pathway analysis also showed involvement of the IL-17 signaling pathway (including IL-17 receptor A), T-helper type 17 cell differentiation (including STAT1), the JAK-STAT signaling pathway (including STAT2 and tyrosine kinase 2), neutrophil extracellular trap formation (including ELANE), cocaine addiction [G protein signaling modulator 1 (GPSM1)] and cytokine-cytokine receptor interaction (IL-17 receptor C). In summary, exome sequencing identified a likely causative genetic defect in ELANE (PID-28), STAT1 (PID-30) and IFIH1 (PID-33). The present findings reveal the association of novel STAT1, ELANE mutations with the clinical phenotype of the patients, as well as known mutations in NLRP12, GPSM1 and TNIP1, in addition to novel ELANE, STAT1 and IFIH1 mutations associated in the context of Jordanian IEI.

EIF4A3-induced hsa_circ_0078136 inhibits the tumorigenesis of retinoblastoma via IL-17 signaling pathway.

Retinoblastoma (RB) is one of the most common intraocular cancers, with the highest prevalence among infants and young children under the age five. Numerous findings across the literature illustrate the involvement and significance of circular RNAs (circRNAs) in human malignancies, including RB. The current investigation attempted to decipher the exact roles and underlying mechanisms of a novel circRNA, hsa_circ_0078136, in RB progression. The hsa_circ_0078136 expression was evaluated in RB tumors and cell lines via qRT-PCR. The significance of hsa_circ_0078136 in RB was examined by performing CCK8 assay, transwell assays, western blotting of apoptotic and IL-17 signaling ligand molecules, and a subcutaneous xenograft tumor model. In addition, the interaction of circRNA and eukaryotic translation initiation factor 4A3 (EIF4A3) was determined with bioinformatics, western blot, and RIP assay. The hsa_circ_0078136 expression was reduced in RB tumor samples and cells. Additionally, its overexpression restricted the oncogenic properties of RB cells in vitro. Moreover, hsa_circ_0078136 overexpression lowered the protein levels of cytokine ligand molecules of IL-17 signaling pathway in RB cell lines. In vivo, hsa_circ_0078136 overexpression in subcutaneous tumor xenografts reduced tumor growth. We also observed that EIF4A3 binds to the downstream flanking sequence of hsa_circ_0078136 in the SHRPH pre-mRNA transcript, and EIF4A3 overexpression reduced hsa_circ_0078136 expression, suggesting that EIF4A3 inhibited hsa_circ_0078136 formation. Our results demonstrate that hsa_circ_0078136 is regulated by EIF4A3 and functions as a tumor suppressor via the IL-17 signaling pathway in RB.

Studies on the Anti-Inflammatory Effect of Xiaoyao Pills in The Treatment of Postmenopausal Osteoporosis in Mice.

Osteoporosis is a common metabolic disease of elderly and postmenopausal women, with no obvious symptoms during its early stages. In the latter stages of this condition, the patients are prone to fractures, and this can seriously affect their health and quality of life. The worldwide increase in life expectancy has made osteoporosis a global concern. The Xiaoyao pills were previously used in the treatment of depression. In addition, the drug appeared to have estrogen-like activity, which affected the expression of ALP, an early osteoblast-specific marker, and COL-1, a major component of bone extracellular matrix. Xiaoyao pills were assessed for their effects on postmenopausal osteoporosis (PMOM) in mice. The target information of each herbal component of Xiaoyao pills was accessed through the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Information from GeneCards, OMIM, PharmGkb, TTD, DrugBank, and other websites was used to construct the regulatory network of the herbal complex through Cytoscape and String network to assess the protein interactions. Mice were ovariectomized, and treated with high and low doses of Xiaoyao pills and these were compared to controls. Their symptoms were assessed by immunocytochemistry of bone tissues. The results suggested that Xiaoyao pills had the ability to alleviate the symptoms of PMOM in ovariectomized mice through the IL-17 signaling pathway. This drug has the potential to become a novel therapeutic agent for the treatment of osteoporosis.

Inhibitor of Myom3 inhibits proliferation and promotes differentiation of sheep myoblasts

Skeletal muscle quality and yield are important production traits in livestock, and improving skeletal muscle quality while increasing its yield is an important goal of economic breeding. The proliferation and differentiation process of sheep myoblasts directly affects the growth and development of their muscles, thereby affecting the yield of mutton. Myomesin 3 (Myom3), as a functional gene related to muscle growth, currently lacks research on its function in myoblasts. This study aims to investigate the effect of the Myom3 gene on the proliferation and differentiation of sheep myoblasts and its potential molecular mechanisms. The results showed that inhibitor of Myom3 in the proliferation phase of myoblasts resulted in significant downregulation of the proliferation marker gene paired box 7 (Pax7) and myogenic regulatory factors (MRFs; Myf5, Myod1, Myog, P < 0.01), a significant decrease in the EdU-positive cell rate (P < 0.05), and a significant increase in the cell apoptosis rate (P < 0.01), which inhibited the proliferation of myoblasts and promoted their apoptosis. During the differentiation phase of myoblasts, the inhibitor of Myom3 resulted in significant downregulation of the Pax7 gene, upregulation of MRFs (Myod1, Myog, P < 0.05), and a significant increase in fusion index (P < 0.05), promoting the differentiation of myoblasts. Further transcriptome sequencing revealed that differentially expressed genes in the Myom3 interference group were mainly enriched in the MAPK signaling pathway, TNF signaling pathway, and IL-17 signaling pathway. In summary, the inhibitor of Myom3 inhibits myoblast proliferation and promotes myoblast differentiation. Therefore, Myom3 has a potential regulatory effect on the growth and development of sheep muscles, and in-depth functional research can be used for molecular breeding practices in sheep.

Exploring the mechanisms of Huangqin Qingfei Decoction on acute lung injury by LC-MS combined network pharmacology analysis

BackgroundAcute lung injury (ALI) is a respiratory disease characterized by pulmonary inflammation and increased microvascular permeability, resulting in significant mortality and a lack of effective pharmacological treatment. Huangqin Qingfei Decoction (HQQFD), a Traditional Chinese Medicine (TCM) prescription known for its heat-clearing and detoxifying properties, has shown efficacy in treating ALI. However, the underlying mechanisms of HQQFD to against ALI remain to be elucidated. PurposeThis study aims to discover the mechanisms and the principal bioactive compounds contributing to HQQFD's protective effects in the treatment of ALI. MethodsAn ultra-high performance liquid chromatography-Orbitrap high-resolution mass spectrometry (UHPLC-Orbitrap HRMS) method was employed to characterize the chemical profile in HQQFD and xenobiotics (prototypes and metabolites) in rat lung tissue. Based on prototypes identified, a symptom-guided pharmacological networks of ALI were performed. Molecular docking and extensive literature reviews were conducted to validate our findings. ResultsA total of 105 compounds were identified in HQQFD, and a total of 194 HQQFD-related xenobiotics (30 prototypes and 163 metabolites) were detected in rat lung tissue. Based on prototypes identified in rat lung, a symptom-guided pharmacological networks of ALI were constructed, AKT1, TNF, EGFR, MMP2, GSK3B, STAT3, MAPK8, IL-6, CDK2 and TP53 were finally identified as key targets. Subsequently, 11 compounds with protective and therapeutic activity were selected by molecular docking analysis, including genipin 1-gentiobioside, chrysin-6-C-α-L-arabinoside-8-C-β-d-glucoside, scutellarin, chrysin-6-C-β-d-glucoside-8-C-α-L-arabinoside, 6’’-O-[(E)-p-coumaroyl] genipin-gentiobioside, apigenin 7-O-glucoside, baicalin, dihydrobaicalin, wogonoside, crocin I, crocetin. Bioinformatics and literature analysis suggested that, baicalin, wogonoside, genipin 1-gentiobioside and crocetin may be the primary active compounds of HQQFD, potentially targeting GSK3B, MAPK8, IL-6, AKT1 and TNF for HQQFD in addressing ALI. The therapeutic effects of HQQFD may be mediated through the IL-17 and PI3K-AKT signaling pathways. ConclusionThe predominant components of HQQFD against ALI are baicalein, wogonoside, genipin 1-gentiobiosid and crocetin, with the IL-17 and PI3K-AKT pathways playing crucial roles. This study provides a foundational guide for future research and introduces innovative methods for exploring the mechanisms of other drug combinations or TCM formulas.

Protective effect of Lonicerae japonicae flos extract against doxorubicin-induced liver injury in mice

To explore the mechanism underlying the protective effect of Lonicerae japonicae flos (LJF) extract against doxorubicin (DOX) -induced liver injury in mice. Network pharmacology methods were used to obtain the intersection genes between LJF targets and disease targets, based on which the protein-protein interaction (PPI) network was constructed using STRING database for screening the core targets using Cytoscape software. DAVID database was used for bioinformatics analysis, and the core components and core targets were verified using molecular docking study. In a mouse model of DOX-induced liver injury, the effect of LJF extract on liver pathologies, serum levels of ALT and AST, and hepatic expressions of HYP, ROS, TNF-α, IL-6, COL-Ⅳ and P53 proteins were evaluated using HE and Masson staining, ELISA, and Western blotting. We identified 12 core targets from 43 intersection genes involving cancer pathway, IL-17 signaling pathway, and TNF signaling pathways. Molecular docking study suggested that 10 core components of LJF could bind to different core targets. The mice with DOX-induced liver injury showed elevated serum AST and ALT levels with obvious liver injury and fibrosis, increased ROS content, and enhanced expressions of TNF-α, IL-6, HYP, COL-Ⅳ and P53 proteins in the liver tissue. All these changes in the mouse models were significantly alleviated by treatment with LJF extract, suggesting obviously lowered levels of oxidative stress, inflammation and fibrosis in the liver tissues. LJF extract is capable of alleviating DOX-induced liver injury in mice by downregulating Trp53, TNF and IL-6 to reduce liver oxidative stress, inflammation and fibrosis.

Exosomes from Human iPSC-Derived Retinal Organoids Enhance Corneal Epithelial Wound Healing.

This study investigated the therapeutic effects of exosomes derived from human-induced pluripotent stem cell (hiPSC)-derived retinal organoids (ROs) on corneal epithelial wound healing. Exosomes were isolated from the culture medium of the hiPSC-derived ROs (Exo-ROs) using ultracentrifugation, and then they were characterized by a nanoparticle tracking analysis and transmission electron microscopy. In a murine model of corneal epithelial wounds, these exosomes were topically applied to evaluate their healing efficacy. The results demonstrated that the exosome-treated eyes showed significantly enhanced wound closures compared with the controls at 24 h post-injury. The 5-ethyl-2'-deoxyuridine assay and quantitative reverse transcription polymerase chain reaction revealed a substantial increase in cell proliferation and a decrease in inflammatory marker contents in the exosome-treated group. The RNA sequencing and exosomal microRNA analysis revealed that the Exo-RO treatment targeted various pathways related to inflammation and cell proliferation, including the PI3K-Akt, TNF, MAPK, and IL-17 signaling pathways. Moreover, the upregulation of genes related to retinoic acid and eicosanoid metabolism may have enhanced corneal epithelial healing in the eyes treated with the Exo-ROs. These findings suggest that hiPSC-derived RO exosomes could be novel therapeutic agents for promoting corneal epithelial wound healing.

Haemonchus contortus alters distribution and utilization of protein and amino acids in different tissues of host sheep

The objective was to determine host animal protein/amino acid redistribution and use among the abomasum, duodenum and muscle of sheep infected with Haemonchus contortus. Sixteen male Ujumqin sheep (32.4 ± 3.9 kg) were dewormed and randomly assigned to two groups, infected or not infected with H. contortus (GIN and CON). The GIN group had lower (P < 0.05) dry matter intake, average daily gain, and live body weight than CON, with extensive focal infiltration of lymphocytes in the lamina propria and bottom of the abomasal epithelium. In the abomasum and duodenum, there were 100 and 220 genes, respectively, that were up-regulated, whereas 56 and 149 were down-regulated. In the abomasum, the most enriched KEGG pathways were related to immunity and inflammation reaction, including: viral protein interaction with cytokine and cytokine receptor (P = 0.017), influenza A (P = 0.030), IL-17 signaling pathway (P = 0.030). In the duodenum, KEGG pathways were more enriched in nutrient metabolism, including pancreatic secretion (P < 0.001), protein digestion and absorption (P < 0.001), graft-versus-host disease (P = 0.004). Furthermore, most genes related with the above KEGG pathways were increased in the abomasum but decreased in the duodenum. Amino acid profiles in abomasum and duodenum of CON and GIN groups were clustered in a partial least-squares discriminant analysis model, with significant changes in 36 and 19 metabolites in abomasal and duodenal chyme, respectively. Further confirmed by transcriptome-targeted metabolome association analysis, GIN mainly enhanced metabolism of arginine and sulphur amino acids in abomasum and those metabolic pathways were associated. Meanwhile, GIN mainly decreased pyruvate related amino acid metabolism in duodenum. Moreover, concentrations of Arg (P = 0.036), His (P = 0.027), and Cys (P = 0.046) in longissimus thoracis et lumborum were decreased in GIN, whereas concentrations of Gly (P = 0.012) and Ala (P = 0.046) were increased. In conclusion, H. contortus enhanced metabolism of arginine and sulphur amino acids in the abomasum; decreased pyruvate metabolism in the duodenum; and drove more protein/amino acids for abomasal tissues to resist physical and immune damage, reducing protein and amino acids in duodenum and muscle for support host growth. Specific nutrients (such like arginine, histidine, and cysteine) may play important role in control gastrointestinal nematode infection for ruminant.

Myrislignan ameliorates the progression of osteoarthritis: An in vitro and in vivo study

Osteoarthritis (OA) is a prevalent disease of the musculoskeletal system that causes functional deterioration and diminished quality of life. Myrislignan (MRL) has a wide range of pharmacological characteristics, including an anti-inflammatory ability. Although inflammation is a major cause of OA, the role of MRL in OA treatment is still not well-understood. In this study, we analyze the anti-inflammatory and anti-ECM degradation effects of MRL both in vivo and in vitro. Rat primary chondrocytes were treated with interleukin-1β (IL-1β) to simulate inflammatory environmental conditions and OA in vitro. The in vivo OA rat model was established by anterior cruciate ligament transection (ACLT) on rat. Our investigation discovered that MRL lowers the IL-1β-activated tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX2) and inducible nitric-oxide synthase (iNOS) expression in chondrocytes. Moreover, MRL effectively alleviates IL-1β-induced extracellular matrix (ECM) degradation and promotes ECM synthesis in chondrocytes by upregulating the mRNA level expression of collagen-II and aggrecan (ACAN), downregulating the expression of matrix metalloproteinases-3,-13 (MMP-3, MMP-13), and a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5). Gene expression profiles of different groups identified DEGs that were mainly enriched in functions associated with NF-κB signaling pathway, and other highly enriched in functions related to TNF, IL-17, Rheumatoid arthritis and cytokine-cytokine receptor signaling pathways. Venn interaction of DEGs from the abovementioned five pathways showed that Nfkbia, Il1b, Il6, Nfkb1, Ccl2, Mmp3 were highly enriched DEGs. In addition, our research revealed that MRL suppresses NF-κB and modulates the Nrf2/HO-1/JNK signaling pathway activated by IL-1β in chondrocytes. In vivo research shows that MRL slows the progression of OA in rats. Our findings imply that MRL might be a viable OA therapeutic choice.

Evaluating the significance of ECSCR in the diagnosis of ulcerative colitis and drug efficacy assessment.

The main challenge in diagnosing and treating ulcerative colitis (UC) has prompted this study to discover useful biomarkers and understand the underlying molecular mechanisms. In this study, transcriptomic data from intestinal mucosal biopsies underwent Robust Rank Aggregation (RRA) analysis to identify differential genes. These genes intersected with UC key genes from Weighted Gene Co-expression Network Analysis (WGCNA). Machine learning identified UC signature genes, aiding predictive model development. Validation involved external data for diagnostic, progression, and drug efficacy assessment, along with ELISA testing of clinical serum samples. RRA integrative analysis identified 251 up-regulated and 211 down-regulated DEGs intersecting with key UC genes in WGCNA, yielding 212 key DEGs. Subsequently, five UC signature biomarkers were identified by machine learning based on the key DEGs-THY1, SLC6A14, ECSCR, FAP, and GPR109B. A logistic regression model incorporating these five genes was constructed. The AUC values for the model set and internal validation data were 0.995 and 0.959, respectively. Mechanistically, activation of the IL-17 signaling pathway, TNF signaling pathway, PI3K-Akt signaling pathway in UC was indicated by KEGG and GSVA analyses, which were positively correlated with the signature biomarkers. Additionally, the expression of the signature biomarkers was strongly correlated with various UC types and drug efficacy in different datasets. Notably, ECSCR was found to be upregulated in UC serum and exhibited a positive correlation with neutrophil levels in UC patients. THY1, SLC6A14, ECSCR, FAP, and GPR109B can serve as potential biomarkers of UC and are closely related to signaling pathways associated with UC progression. The discovery of these markers provides valuable information for understanding the molecular mechanisms of UC.

Exposure to volatile organic compounds and growth indicators in adolescents: Unveiling the association and potential intervention strategies

Environmental pollutant is considered to be one of the important factors affecting adolescent growth. However, the effects of volatile organic compounds (VOCs) exposure on adolescent growth have not been assessed. Data from the National Health and Nutrition Examination Survey (NHANES) 2011–2018 was used to examine the associations between VOCs exposure and adolescent growth indicators through three statistical models. The mediating effect of bone mineral density (BMD) on these associations was examined. The potential pathways and key targets were identified by the network pharmacology analysis methods. This study included 746 adolescents. Three statistical methods consistently showed a negative correlation between VOCs exposure and adolescent growth indicators. Furthermore, BMD mediated the relationship between VOCs exposure and adolescent growth indicators, with mediated proportion ranging from 4.3 % to 53.4 %. Network pharmacology analysis found a significant enrichment in IL-17 signaling pathway. Moreover, the adverse effects of VOCs exposure on adolescent growth were observed to significantly attenuate in adolescents with high serum vitamin D levels. Our results suggested that VOCs exposure was an adverse factor affecting adolescent growth, with BMD playing a significant regulatory role, and IL-17 signaling pathway was the underlying mechanism. Vitamin D supplementation may be a viable strategy to prevent VOCs exposure from affecting adolescent growth.

The immunotherapy mechanism of Hedyotis Diffusae Herba in treating liver cancer: a study based on network pharmacology, bioinformatics, and experimental validation.

Liver cancer is a malignant tumor that develops on or inside the liver. Hedyotis diffusa Willd (HDW) plays a significant role in anti-tumor activities; however, its mechanism against liver cancer remains unclear. This study aims to evaluate the immunotherapeutic mechanism of HDW in treating liver cancer through network pharmacology, bioinformatics analysis, and experimental validation. Network pharmacology was utilized to identify the active components and potential targets of HDW from the TCMSP database. A potential target protein-protein interaction (PPI) network was constructed using the STRING database, followed by function and pathway enrichment analysis of the targets using GO and KEGG methods. In addition, the key targets for HDW against liver cancer were identified using five different algorithms in Cytoscape. The TCGA and HPA databases were used to assess the mRNA and protein expression of core target genes in normal liver and liver cancer tissues and their relationship with overall survival in liver cancer, as well as their role in immune infiltration. Molecular docking between the core components of HDW and the core targets was performed using PyMOL software. The effects of HDW on the proliferation and apoptosis of liver cancer cells were examined using MTT and flow cytometry. The regulatory effects of the core component quercetin on core targets were validated using RT-qPCR and Western blot. A total of 163 potential targets were identified by searching for intersections among 7 types of active components and all potential and liver cancer targets. PPI network analysis revealed the core targets IL6 and TNF. GO enrichment analysis involved 2089 biological processes, 76 cellular components, and 196 molecular functions. KEGG enrichment analysis suggested that the anti-cancer effects of HDW might be mediated by the AGE-RAGE signaling pathway, IL-17 signaling pathway, TNF signaling pathway, PI3K-Akt signaling pathway, and NF-κB signaling pathway. Database validation of key targets showed that mRNA and protein expression results for the IL6 gene were contradictory, while those for the TNF gene were consistent, both being underexpressed in liver cancer. Importantly, the expression of IL6 and TNF was related to the infiltration of 24 types of immune cells, with the highest correlation with macrophages. Molecular docking showed that IL6 and TNF had high binding stability with quercetin, with binding energies of - 7.4 and - 6.0kJ∙mol-1, respectively. Experimental validation showed that quercetin inhibited liver cancer cell proliferation and promoted apoptosis in a dose-dependent manner, with protein results indicating that quercetin downregulated the mRNA and protein expression of IL6 and TNF, and upregulated key proteins in the AGE-RAGE signaling pathway, AGEs, and RAGE. This study comprehensively elucidates the activity, potential targets, and molecular mechanisms of HDW against liver cancer, providing a promising strategy for the scientific basis and treatment mechanism of traditional Chinese medicine in treating liver cancer.

Manipulating host secreted protein gene expression: an indirect approach by HPV11/16 E6/E7 to suppress PBMC cytokine secretion

Human papillomavirus (HPV) 11/16 E6/E7 proteins have been recognized to be pivotal in viral pathogenesis. This study sought to uncover the potential mechanisms of how HPV11/16 E6/E7-transfected keratinocytes inhibit cytokine secretion in peripheral blood mononuclear cells (PBMC). Upon co-culturing HPV11/16 E6/E7-transfected keratinocytes with PBMC in a non-contact manner, we observed a marked decrease in various cytokines secreted by PBMC. To determine if this suppression was mediated by specific common secreted factors, we conducted transcriptomic sequencing on these transfected cells. This analysis identified 53 common differentially secreted genes in all four HPV-transfected cells. Bioinformatics analysis demonstrated these genes were predominantly involved in immune regulation. Results from quantitative PCR (qPCR) and an extensive literature review suggested the downregulation of 12 genes (ACE2, BMP3, BPIFB1, CLU, CST6, CTF1, HMGB2, MMP12, PDGFA, RNASE7, SULF2, TGM2), and upregulation of 7 genes (CCL17, CCL22, FBLN1, PLAU, S100A7, S100A8, S100A9), may be crucial in modulating tumor immunity and combating pathogenic infections, with genes S100A8 and S100A9, and IL-17 signaling pathway being particularly noteworthy. Thus, HPV11/16 E6/E7 proteins may inhibit cytokine secretion of immune cells by altering the expression of host-secreted genes. Further exploration of these genes may yield new insights into the complex dynamics of HPV infection.

Network Pharmacology and Experimental Validation Explore the Pharmacological Mechanisms of Herb Pair for Treating Rheumatoid Arthritis.

This study aimed to elucidate the multitarget mechanism of the Mori Ramulus - Taxilli Herba (MT) herb pair in treating rheumatoid arthritis (RA). The targets of the herb pair and RA were predicted from databases and screened through cross-analysis. The core targets were obtained using protein-protein interaction (PPI) network analysis. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed. Finally, animal experiments were conducted to validate the anti-RA effect and mechanism of this herb pair. This approach successfully identified 9 active compounds of MT that interacted with 6 core targets (AKT1, TNF, IL6, TP53, VEGFA, and IL1β). Pathway and functional enrichment analyses revealed that MT had significant effects on the TNF and IL-17 signaling pathways. The consistency of interactions between active components and targets in these pathways was confirmed through molecular docking. Moreover, the potential therapeutic effect of MT was verified in vivo, demonstrating its ability to effectively relieve inflammation by regulating these targeted genes and pathways. The present work suggests that the therapeutic effect of MT herb pair on RA may be attributed to its ability to regulate the TNF signaling pathway and IL-17 signaling pathway.

AD16 attenuates neuroinflammation induced by cerebral ischemia through down-regulating astrocytes A1 polarization

A1 polarization of astrocytes mediated prolonged inflammation contributing to brain injury in ischemic stroke. We have previously shown that AD16 protects against neonatal hypoxic-ischemic brain damage in vivo and oxygen-glucose deprivation in vitro. More recently, AD16 has demonstrated safety, tolerability, and favorable pharmacokinetics in a randomized controlled phase I trial. In this study, we utilized a rat model of transient middle cerebral artery occlusion (tMCAO) to explore whether the anti-inflammatory compound AD16 protects against ischemic brain injury by regulating A1 polarization and its underlying mechanisms. Our results showed that AD16 treatment significantly reduced the brain infarcted volume and improved neurological function in tMCAO rats. GO analysis results show that differential genes among the Sham, tMCAO and AD16 treatment groups are involved in the regulation of cytokine and inflammatory response. KEGG enrichment pathways analysis mainly enriched in cytokine-cytokine receptor interaction, viral protein interaction with cytokine-cytokine receptor, TNF, chemokine, NF-κB and IL-17 signaling pathway. Furthermore, AD16 treatment decreased the permeability of the blood-brain barrier and suppressed neuroinflammation. AD16 treatment also significantly reduced the polarization of A1 and inhibited NF-κB and JAK2/STAT3 signaling pathways. This study demonstrates that AD16 protects against brain injury in ischemic stroke by reducing A1 polarization to suppress neuroinflammation through downregulating NF-κB and JAK2/STAT3 signaling. Our findings uncover a potential molecular mechanism for AD16 and suggest that AD16 holds promising therapeutic potential against cerebral ischemia.

Key genes and immune infiltration patterns and the clinical implications in psoriasis patients.

Psoriasis is an immune-mediated skin disease, closely related to immune regulation. The aim was to understand the pathogenesis of psoriasis further, reveal potential therapeutic targets, and provide new clues for its diagnosis, treatment, and prevention. Expression profiling data were obtained from the Gene Expression Omnibus (GEO) database for skin tissues from healthy population and psoriasis patients. Differentially expressed genes (DEGs) were selected for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) analysis separately. Machine learning algorithms were used to obtain characteristic genes closely associated with psoriasis. Receiver operating characteristic (ROC) curve was used to assess the diagnostic value of the characteristic genes for psoriasis. The Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was used to calculate the proportion of immune cell infiltration. Correlation analysis was used to characterize the connection between gene expression and immune cell, Psoriasis Area and Severity Index (PASI). A total of 254 DEGs were identified in the psoriasis group, including 185 upregulated and 69 downregulated genes. GO was mainly enriched in cytokine-mediated signaling pathway, response to virus, and cytokine activity. KEGG was mainly focused on cytokine-cytokine receptor interaction and IL-17 signaling pathway. GSEA was mainly in chemokine signaling pathway and cytokine-cytokine receptor interaction. The machine learning algorithm screened nine characteristic genes C10orf99, GDA, FCHSD1, C12orf56, S100A7, INA, CHRNA9, IFI44, and CXCL9. In the validation set, the expressions of these nine genes increased in the psoriasis group, and the AUC values were all>0.9, consistent with those of the training set. The immune infiltration results showed increased proportions of macrophages, T cells, and neutrophils in the psoriasis group. The characteristic genes were positively or negatively correlated to varying degrees with T cells and macrophages. Nine characteristic genes were highly expressed in the moderate to severe psoriasis group and positively correlated with PASI scores. High levels of nine characteristic genes C10orf99, GDA, FCHSD1, C12orf56, S100A7, INA, CHRNA9, IFI44, and CXCL9 were risk factors for psoriasis, the differential expression of which was related to the regulation of immune system activity and PASI scores, affecting the proportions of different immune cells and promoting the occurrence and development of psoriasis.

The oncogenic kinase TOPK upregulates in psoriatic keratinocytes and contributes to psoriasis progression by regulating neutrophils infiltration

BackgroundT-LAK cell-oriented protein kinase (TOPK) strongly promotes the malignant proliferation of cancer cells and is recognized as a promising biomarker of tumor progression. Psoriasis is a common inflammatory skin disease featured by excessive proliferation of keratinocytes. Although we have previously reported that topically inhibiting TOPK suppressed psoriatic manifestations in psoriasis-like model mice, the exact role of TOPK in psoriatic inflammation and the underlying mechanism remains elusive.MethodsGEO datasets were analyzed to investigate the association of TOPK with psoriasis. Skin immunohistochemical (IHC) staining was performed to clarify the major cells expressing TOPK. TOPK conditional knockout (cko) mice were used to investigate the role of TOPK-specific deletion in IMQ-induced psoriasis-like dermatitis in mice. Flow cytometry was used to analyze the alteration of psoriasis-related immune cells in the lesional skin. Next, the M5-induced psoriasis cell model was used to identify the potential mechanism by RNA-seq, RT-RCR, and western blotting. Finally, the neutrophil-neutralizing antibody was used to confirm the relationship between TOPK and neutrophils in psoriasis-like dermatitis in mice.ResultsWe found that TOPK levels were strongly associated with the progression of psoriasis. TOPK was predominantly increased in the epidermal keratinocytes of psoriatic lesions, and conditional knockout of TOPK in keratinocytes suppressed neutrophils infiltration and attenuated psoriatic inflammation. Neutrophils deletion by neutralizing antibody greatly diminished the suppressive effect of TOPK cko in psoriasis-like dermatitis in mice. In addition, topical application of TOPK inhibitor OTS514 effectively attenuated already-established psoriasis-like dermatitis in mice. Mechanismly, RNA-seq revealed that TOPK regulated the expression of some genes in the IL-17 signaling pathway, such as neutrophils chemokines CXCL1, CXCL2, and CXCL8. TOPK modulated the expression of neutrophils chemokines via activating transcription factors STAT3 and NF-κB p65 in keratinocytes, thereby promoting neutrophils infiltration and psoriasis progression.ConclusionsThis study identified a crucial role of TOPK in psoriasis by regulating neutrophils infiltration, providing new insights into the pathogenesis of psoriasis.

Forsythiaside A ameliorates bleomycin-induced pulmonary fibrosis by inhibiting oxidative stress and apoptosis.

Pulmonary fibrosis (PF) is a common clinically critical disease characterized by high morbidity and high mortality. Forsythiaside A (FA) is a phenylethanol glycoside component in Forsythia suspensa, which has anti-inflammatory, antioxidant, and antiviral activities. However, the effects of FA on bleomycin (BLM)-induced PF are unclear. The present study explored the role of FA in the amelioration of oxidative stress and apoptosis in BLM-induced PF as well as the possible underlying mechanisms, in vivo and in vitro. Network pharmacology was used to collect the effects of FA on BLM-induced PF. Subsequently, further observation of the effects of FA on mice with PF by pulmonary pathological changes, transmission electron microscopy, real-time polymerase chain reaction, Western blot analysis, immunofluorescence, and immunohistochemistry. An in vitro model was constructed by inducing A549 with transforming growth factor beta-1 (TGF-β1) to observe the effect of FA on epithelial cell apoptosis. Network pharmacology predicted signaling pathways such as IL-17 signaling pathway and Relaxin signaling pathway. The results of in vivo studies showed that FA ameliorated BLM-induced PF through inhibition of fibrosis, modulation of apoptosis, and oxidative stress. In addition, FA promoted TGF-β1-induced apoptosis in A549 cells. The results of our study suggested that FA could protect mice against BLM-induced PF by regulating oxidative stress and apoptosis as well as the Epithelial mesenchymal transition pathway.

Identification of PLAC8 as a Potential Biomarker for the Diagnosis of Interstitial Cystitis.

Interstitial cystitis is a diagnosis of exclusion due to the complexity of its etiology and pathology, which is a chronic disease with an unknown etiology. To our knowledge, few studies were performed to identify predictive biomarkers for interstitial cystitis. This study aimed to identify and validate potential biomarkers for Interstitial Cystitis (IC). The interstitial cystitis datasets were retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified by using the R package and were subjected to functional and pathway enrichment analysis. Key biomarkers of interstitial cystitis were identified by using Lasso regression analysis and the SVM-RFE algorithm. The diagnostic value of key biomarkers was validated in internal and external datasets, and pathways that relate to biomarkers of interstitial cystitis were screened. The ssGSEA was employed to identify the immune cells closely related to biomarkers. The expression of PLAC8 in patients with interstitial cystitis was detected by Immune-Histochemistry (IHC). Sixteen differentially expressed genes associated with interstitial cystitis were identified, which were primarily linked to the biological process of the chemokine signaling pathway. PLAC8, identified as a biomarker for interstitial cystitis, was validated to express a significantly different between IC and normal bladder tissues. PLAC8-related pathways were analyzed, with a focus on NF-κB, TNF, Toll-like receptor, chemokine, IL-17, and JAK-STAT signaling pathways. PLAC8 was proved to be closely related to immune activations, which is similar to the pathogenesis of IC, which is a chronic dysregulated immune disease. Meanwhile, we also observed a higher level of PLAC8 in IC tissues. PLAC8 has promising application prospects as a biomarker for interstitial cystitis diagnosis. These findings could aid in the diagnosis and treatment of interstitial cystitis.