Tumor Necrosis Factor Signaling Pathway Research Articles

Mechanism of Xuebijing Injection in treatment of sepsis-associated ARDS based on network pharmacology and in vitro experiment

The aim of this study was to investigate the effect and molecular mechanism of Xuebijing Injection in the treatment of sepsis-associated acute respiratory distress syndrome(ARDS) based on network pharmacology and in vitro experiment. The active components of Xuebijing Injection were screened and the targets were predicted by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP). The targets of sepsis-associated ARDS were searched against GeneCards, DisGeNet, OMIM, and TTD. Weishengxin platform was used to map the targets of the main active components in Xuebijing Injection and the targets of sepsis-associated ARDS, and Venn diagram was established to identify the common targets. Cytoscape 3.9.1 was used to build the "drug-active components-common targets-disease" network. The common targets were imported into STRING for the building of the protein-protein interaction(PPI) network, which was then imported into Cytoscape 3.9.1 for visualization. DAVID 6.8 was used for Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment of the common targets, and then Weishe-ngxin platform was used for visualization of the enrichment results. The top 20 KEGG signaling pathways were selected and imported into Cytoscape 3.9.1 to establish the KEGG network. Finally, molecular docking and in vitro cell experiment were performed to verify the prediction results. A total of 115 active components and 217 targets of Xuebijing Injection and 360 targets of sepsis-associated ARDS were obtained, among which 63 common targets were shared by Xuebijing Injection and the disease. The core targets included interleukin-1 beta(IL-1β), IL-6, albumin(ALB), serine/threonine-protein kinase(AKT1), and vascular endothelial growth factor A(VEGFA). A total of 453 GO terms were annotated, including 361 terms of biological processes(BP), 33 terms of cellular components(CC), and 59 terms of molecular functions(MF). The terms mainly involved cellular response to lipopolysaccharide, negative regulation of apoptotic process, lipopolysaccharide-mediated signaling pathway, positive regulation of transcription from RNA polyme-rase Ⅱ promoter, response to hypoxia, and inflammatory response. The KEGG enrichment revealed 85 pathways. After diseases and generalized pathways were eliminated, hypoxia-inducible factor-1(HIF-1), tumor necrosis factor(TNF), nuclear factor-kappa B(NF-κB), Toll-like receptor, and NOD-like receptor signaling pathways were screened out. Molecular docking showed that the main active components of Xuebijing Injection had good binding activity with the core targets. The in vitro experiment confirmed that Xuebijing Injection suppressed the HIF-1, TNF, NF-κB, Toll-like receptor, and NOD-like receptor signaling pathways, inhibited cell apoptosis and reactive oxygen species generation, and down-regulated the expression of TNF-α, IL-1β, and IL-6 in cells. In conclusion, Xuebijing Injection can regulate apoptosis and response to inflammation and oxidative stress by acting on HIF-1, TNF, NF-κB, Toll-like receptor, and NOD-like receptor signaling pathways to treat sepsis-associated ARDS.

Effects and Mechanisms of Ban-Xia Xie-Xin Decoction on Type 2 Diabetes Mellitus: Network Pharmacology Analysis and Experimental Evidence.

Studies have indicated that Ban-Xia Xie-Xin Decoction (BXXXD) has therapeutic effects on type 2 diabetes mellitus (T2DM). However, due to the complexity of components and diversity of targets, the mechanisms are still not fully elucidated. In this research, we systematically analysed the targets of BXXXD through the method of network pharmacology and further validated them through experiments. The active components and therapeutic targets were identified, and these targets were analysed by the methods of gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) analysis. Then, based on these network pharmacology analyses, we validated the main targets through animal experiments. A total of 169 active components and 159 targets were identified. KEGG analysis showed that the mitogen-activated protein kinase (MAPK) signalling pathway, tumour necrosis factor (TNF) signalling pathway, the phosphatidylinositol 3' -kinase (PI3K), Akt signalling pathway, and other pathways were related to the treatment of T2DM by BXXXD. PPI network analysis showed that the key genes included signal transducers and activators of transcription 3 (STAT3), JUN, TNF, Recombinant V-Rel Reticuloendotheliosis Viral Oncogene Homolog A (RELA), Akt/PKB- 1 (Protein kinase B), TP53, mitogen-activated protein kinase-1 (MAPK-1), mitogen-activated protein kinase-3 (MAPK-3), interleukin- 6 (IL6), and mitogen-activated protein kinase-14 (MAPK- 14), respectively. Animal experiments showed that BXXXD could reduce blood glucose and improve insulin resistance, which may be related to the mechanisms of inhibiting TNF, interleukin-1 (IL-1), IL-6, and interleukin-17 (IL-17) and promoting Akt phosphorylation. Our research revealed the mechanisms of BXXXD in the treatment of diabetes, which laid a solid foundation for further studies on the molecular mechanisms of BXXXD in the treatment of T2DM.

Hsa_circ_0007401 regulates gemcitabine resistance of pancreatic cancer through the hsa-miR-6509-3p/fli1 axis

Pancreatic cancer is a highly malignant cancer with a poor prognosis. Owing to the strong drug resistance of pancreatic cancer, adjuvant chemotherapy has failed to achieve good results in clinical practice. The expression profile data of circular RNA (circRNA) (GSE110580), microRNA (miRNA) (GSE79234), and messenger RNA (mRNA) (GSE140077, GES35141) were obtained from the gene expression omnibus database. The Cancer-Specific circRNA Database identified the structural pattern of circRNA, and the starBase and circBank databases together predicted the miRNA of circRNA. The mirDIP database predicts the target mRNAs of miRNAs and identifies the ceRNA network of circRNA-miRNA-mRNA via negative regulatory mechanisms. The final validation was performed using clinical data from the cancer treatment response gene signature database of patients treated with gemcitabine for pancreatic cancer of the cancer genome atlas. By differential expression analysis, 22 differential circRNAs (8 upregulated and 14 downregulated), 70 differential microRNAs (37 upregulated and 33 downregulated), and 256 differential messenger RNA (DEmRNA) (161 upregulated and 95 downregulated) were obtained. Gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses showed that DEmRNAs were associated with drug response, exogenous cellular stimulation, and the tumor necrosis factor signaling pathway. The screened downregulated differential circular RNA (hsa_circ_0007401), upregulated differential microRNA (hsa-miR-6509-3p), and downregulated DEmRNA (FLI1) were consistent with the negative regulation mechanism of the ceRNA network, and FLI1 was significantly downregulated in the data of gemcitabine-resistant pancreatic cancer patients in the cancer genome atlas (n = 26).

Effect of bacillus subtilis strain Z15 secondary metabolites on immune function in mice

BackgroundPrevious studies have shown that secondary metabolites of Bacillus subtilis strain Z15 (BS-Z15) are effective in treating fungal infections in mice. To evaluate whether it also modulates immune function in mice to exert antifungal effects, we investigated the effect of BS-Z15 secondary metabolites on both the innate and adaptive immune functions of mice, and explored its molecular mechanism through blood transcriptome analysis.ResultsThe study showed that BS-Z15 secondary metabolites increased the number of monocytes and platelets in the blood, improved natural killer (NK) cell activity and phagocytosis of monocytes-macrophages, increased the conversion rate of lymphocytes in the spleen, the number of T lymphocytes and the antibody production capacity of mice, and increased the levels of Interferon gamma (IFN-γ), Interleukin-6 (IL-6), Immunoglobulin G (IgG) and Immunoglobulin M (IgM) in plasma. The blood transcriptome analysis revealed 608 differentially expressed genes following treatment with BS-Z15 secondary metabolites, all of which were significantly enriched in the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) terms for immune-related entries and pathways such as Tumor Necrosis Factor (TNF) and Toll-like receptor (TLR) signaling pathways, and upregulated expression levels of immune-related genes such as Complement 1q B chain (C1qb), Complement 4B (C4b), Tetracyclin Resistant (TCR) and Regulatory Factor X, 5 (RFX5).ConclusionsBS-Z15 secondary metabolites were shown to enhance innate and adaptive immune function in mice, laying a theoretical foundation for its development and application in the field of immunity.

High expression of RNF31 is associated with tumor immune cell infiltration and leads to poor prognosis in liver hepatocellular carcinoma

Ring finger protein 31 (RNF31) has been found to play an important role in tumor immunity. However, the role of RNF31 in liver hepatocellular carcinoma (LIHC) has not been reported. Therefore, we investigated the expression and prognostic value of RNF31 in patients with LIHC and explored its relationship with immune cell infiltration. The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA-LIHC) dataset was downloaded to analyse the impact of RNF31 on the prognosis and immune cell infiltration of LIHC. The Tumor Immune Estimation Resource (TIMER) database was used to analyse the correlation between RNF31 and tumor immune cell infiltration in LIHC. Additionally, we analysed the relationship between RNF31 and tumor necrosis factor (TNF) as well as the interferon-gamma (IFN-γ) signaling pathway. The expression of RNF31 in LIHC was significantly higher than that in normal tissues. Increased RNF31 expression was associated with decreased overall survival (OS) and relapse-free survival (RFS). An increase in RNF31 expression was closely related to the infiltration levels of immune cells (e.g., natural killer (NK) cells, CD8 + T cells, and B cells). RNF31 was also positively correlated with the expression of immune checkpoint genes in LIHC. Moreover, RNF31 may participate in TNF and IFN-γ signaling pathways. In conclusion, RNF31 is a potentially valuable prognostic biomarker in LIHC. RNF31 is also associated with immune cell infiltration in LIHC. RNF31 may be a potential target for immunotherapy of LIHC.

Dextran-Sulfate-Sodium-Induced Colitis-Ameliorating Effect of Aqueous Phyllanthus emblica L. Extract through Regulating Colonic Cell Gene Expression and Gut Microbiomes.

The anti-inflammation effect of aqueous Phyllanthus emblica L. extract (APE) and its possible underlying mechanism in dextran sulfate sodium (DSS)-induced mice chronic colonic inflammation were studied. APE treatment significantly improved the colitic symptoms, including ameliorating the shortening of the colon, increasing the DSS-induced body weight loss, reducing the disease activity index, and reversing the condition of colon tissue damage of mucus lost and goblet cell reduction. Overproduction of serum pro-inflammatory cytokines were suppressed by the treatment of APE. Gut microbiome analysis showed that APE remodeled the structure of gut bacteria in phylum and genus levels, upregulating the abundance of phylum Bacteroidetes, family Muribaculaceae, and genus Bacteroides and downregulating the abundance of phylum Firmicutes. The reshaped gut microbiome caused metabolic functions and pathway change with enhanced queuosine biosynthesis and reduced polyamine synthesis pathway. Colon tissue transcriptome analysis further elucidated APE-inhibited mitogen-activated protein kinase (MAPK), cytokine-cytokine receptor interaction, and tumor necrosis factor (TNF) signaling pathways and the expressions of the genes that promote the progress of colorectal cancer. It turned out that APE reshaped the gut microbiome and inhibited MAPK, cytokine-cytokine receptor interaction, and TNF signaling pathways as well as the colorectal-cancer-related genes to exert its colitis protective effect.

The Mechanism of Ginkgo Biloba Extract in Treating Glioma

<i>Objective: </i>To explore the active components of ginkgo biloba and the possible targets and pathways for treating glioma. <i>Methods</i>: The chemical components and corresponding targets of Ginkgo biloba were searched by TCMSP, and the "component-target" network map was constructed by Cytoscape. The GenCards database, OMIM database and Disgenet database were used to search for glioma-related genes. Ginkgo biloba targets and glioma gene intersections were extracted using R software, and Veen maps were drawn to obtain key targets. PPI network construction and GO and KEGG enrichment analysis were performed by key targets. <i>Results: </i>A total of 27 active ingredients in Ginkgo biloba leaves and 5770 glioma target genes were collected, and 48 key targets were obtained. PPI analysis showed that the core targets were IL6, ESR1, EGFR, PPARG, VEGFA, CYP3A4, AHR, AR, PGR, etc. GO enrichment analysis is mainly concentrated in nuclear receptor activity, neurotransmitter receptor activity, fatty acid metabolic processes, response to foreign stimuli, etc. KEGG enrichment pathways are mainly manifested in: cholinergic synapses, resistance to EGFR tyrosine kinase inhibitors, tumor necrosis factor signaling pathway PI3K-Akt signaling pathway, etc. <i>Conclusion</i>: Ginkgo biloba can treat glioma through multi-target and multi-pathway, which is in line with the characteristics of holistic treatment of diseases in traditional Chinese medicine.

Effects of Atherogenic Factors on Endothelial Cells: Bioinformatics Analysis of Differentially Expressed Genes and Signaling Pathways.

(1) Background: Atherosclerosis is a serious medical condition associated with high morbidity and mortality rates. It develops over many years as a complex chain of events in the vascular wall involving various cells and is influenced by many factors of clinical interest. (2) Methods: In this study, we performed a bioinformatic analysis of Gene Expression Omnibus (GEO) datasets to investigate the gene ontology of differentially expressed genes (DEGs) in endothelial cells exposed to atherogenic factors such as tobacco smoking, oscillatory shear, and oxidized low-density lipoproteins (oxLDL). DEGs were identified using the limma R package, and gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein-protein interaction (PPI) network analysis were performed. (3) Results: We studied biological processes and signaling pathways involving DEGs in endothelial cells under the influence of atherogenic factors. GO enrichment analysis demonstrated that the DEGs were mainly involved in cytokine-mediated signaling pathway, innate immune response, lipid biosynthetic process, 5-lipoxygenase activity, and nitric-oxide synthase activity. KEGG pathway enrichment analysis showed that common pathways included tumor necrosis factor signaling pathway, NF-κB signaling pathway, NOD-like receptor signaling pathway, lipid and atherosclerosis, lipoprotein particle binding, and apoptosis. (4) Conclusions: Atherogenic factors such as smoking, impaired flow, and oxLDL contribute to impaired innate immune response, metabolism, and apoptosis in endothelial cells, potentially leading to the development of atherosclerosis.

Molecular mechanism of modified Huanglian Wendan decoction in the treatment of polycystic ovary syndrome.

To investigate the mechanism of modified Huanglian Wendan decoction in the intervention of polycystic ovary syndrome (PCOS) by network pharmacology and molecular docking. The ingredients and targets of modified Huanglian Wendan decoction were retrieved from the traditional Chinese medicine Systems Pharmacology database. Related targets of PCOS were screened by Comparative Toxicogenomics Database database. Cytoscape 3.7.2 (https://cytoscape.org/) was used to draw the target network diagram of "traditional Chinese medicine - ingredient - PCOS," STRING database was used to construct the target protein interaction network. NCA tool of Cystoscape 3.7.2 was used to carried out topology analysis on PPI network, core components and key targets were obtained. Gene ontology and Kyoto encyclopedia of genes and genomes enrichment analysis were carried out for the intersection targets by David database. AutoDockTools 1.5.6 software (https://autodock.scripps.edu/) was used to conduct molecular docking verification of key components and key targets. Ninety-one ingredients of the modified Huanglian Wendan decoction and 23,075 diseases targets were obtained, 155 Intersection targets of the drug and disease were obtained by R language, Veen plot was drawn. Gene ontology enrichment analysis obtained 432 biological processes, 67 cell components, 106 molecular functions. Fifty-four Kyoto encyclopedia of genes and genomes enrichment pathways (P < .05) including tumor necrosis factor, hypoxia-induced factors-1, calcium, and drug metabolism-cytochrome P450 signaling pathway. Molecular docking showed quercetin, luteolin, kaempferol, and baicalein were stable in docking with core targets. Network pharmacology and molecular docking were used to preliminarily study the mechanism of action of modified Huanglian Wendan decoction in the treatment of PCOS, which laid foundation for future experimental research and clinical application.

Identification of key genes and molecular pathways in type 2 diabetes mellitus and polycystic ovary syndrome via bioinformatics analyses.

Type 2 diabetes mellitus (T2DM) and polycystic ovary syndrome (PCOS) are highly prevalent endocrine system diseases. However, studies on the molecular mechanisms of T2DM and PCOS at the transcriptomic level are still few. Thus, we aimed to reveal the potential common genetic and molecular pathways between T2DM and PCOS via bioinformatics analyses. We downloaded the GSE10946 and GSE18732 datasets for T2DM and PCOS, respectively, from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database. These datasets were subjected to integrated differential and weighted gene co-expression network analyses (WGCNA) to screen common genes. Thereafter, functional enrichment and disease gene association analyses were performed, transcription factor (TF)-gene and TF-miRNA-gene regulatory networks were constructed, and finally, the relevant target drugs were identified. We identified common genes (BIRC3, DEPTOR, TNNL3, ADRA2A) in T2DM and PCOS. Pathway enrichment analysis depicted that the common genes were enriched in smooth muscle contraction, channel inhibitor activity, apoptosis, and tumor necrosis factor (TNF) signaling pathways. TFs such as SP7, KLF8, HCFC1, IRF1, and MLLT1 played key roles in TF regulatory networks. Orlistat was indicated to be an important gene-targeting drug. This study is the first study to explore four diagnostic biomarkers and gene regulatory networks for T2DM and PCOS. The findings of our study provide novel insights into the diagnosis and treatment of T2DM and PCOS.

A systematic pharmacology-based in vivo study to reveal the effective mechanism of Yupingfeng in asthma treatment

BackgroundThe clinical effect of Yupingfeng (YPF) has been confirmed in asthma patients, however, it lacks a study to verify its pharmacological mechanism. Hypothesis/purposeTo reveal the molecular basis and potential pharmacological mechanism of YPF in the treatment of asthma. Study design and methodsFirst, a systems pharmacology-based method integrating pharmacokinetic screening, target prediction, network analyses, GO and KEGG analyses were used for the systematic deciphering of the mechanism of YPF in asthma. Second, differentially expressed genes (DEGs) between asthma patients and healthy controls were identified by GEO2R online tool. Third, based on systems pharmacology and DEGs results, molecular docking was performed utilizing the Discovery Studio 2020 Client version to detect the binding capacity between compounds and targets. Finally, ovalbumin (OVA)-challenged C57BL/6 mice were treated with YPF or its effective compound to assess the predictions. ResultsA total of 35 active compounds were filtered out, with 87 potential targets being identified for further analysis after target fishing and matching. Quercetin, kaempferol, and wogonin were identified as the main ingredients in YPF. The signaling pathways of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), tumor necrosis factor (TNF) and IL-17 were identified as the top signaling pathways in KEGG enrichment analysis. GEO2R tools of NCBI discovered five DEGs that overlapped with the therapeutic targets of YPF. Wogonin was proven to be the top active compound in YPF through the results of molecular docking. In vivo experiments indicated that YPF and wogonin significantly attenuated airway resistance and lung inflammation by decreasing the levels of inflammatory cytokines and key factors in PI3K/AKT, IL-17, and TNF signaling pathways. ConclusionsYPF and its main active compound wogonin may exert some therapeutic effects on asthma inflammation through multiple molecular targets and signaling pathways including PI3K/AKT, IL-17 and TNF-α.

Residual periodontal ligament in the extraction socket promotes the dentin regeneration potential of DPSCs in the rabbit jaw

BackgroundBecause of the low regeneration efficiency and unclear underlying molecular mechanism, tooth regeneration applications are limited. In this study, we explored the influence of residual periodontal ligament on the dentin regeneration potential of dental pulp stem cells (DPSCs) in the jaw.MethodsTo establish a tooth regeneration model, the incisors of New Zealand white rabbits were extracted while preserving residual periodontal ligament, followed by the implantation of DPSCs. After 3 months, micro-computed tomography (micro-CT), stereomicroscopy and scanning electron microscopy (SEM) were used to observe the volume, morphology and microstructure of regenerated tissue. Histological staining and immunostaining analyses were used to observe the morphological characteristics and expression of the dentin-specific proteins DMP1 and DSPP. To explore the mechanism, DPSCs and periodontal ligament stem cells (PDLSCs) were cocultured in vitro, and RNA was collected from the DPSCs for RNA-seq and bioinformatic analysis.ResultsThe results of micro-CT and stereomicroscopy showed that the number of sites with regeneration and the volume of regenerated tissue in the DPSCs/PDL group (6/8, 1.07 ± 0.93 cm3) were larger than those in the DPSCs group (3/8, 0.23 ± 0.41 cm3). The results of SEM showed that the regenerated dentin-like tissue in the DPSCs and DPSCs/PDL groups contained dentin tubules. Haematoxylin and eosin staining and immunohistochemical staining indicated that compared with the DPSCs group, the DPSCs/PDL group showed more regular regenerated tissue and higher expression levels of the dentin-specific proteins DMP1 and DSPP (DMP1: P = 0.02, DSPP: P = 0.01). RNA-seq showed that the coculture of DPSCs with PDLSCs resulted in the DPSCs differentially expressing 427 mRNAs (285 upregulated and 142 downregulated), 41 lncRNAs (26 upregulated and 15 downregulated), 411 circRNAs (224 upregulated and 187 downregulated), and 19 miRNAs (13 upregulated and 5 downregulated). Bioinformatic analysis revealed related Gene Ontology function and signalling pathways, including extracellular matrix (ECM), tumour necrosis factor (TNF) signalling and chemokine signalling pathways.ConclusionsResidual periodontal ligament in the extraction socket promotes the dentin regeneration potential of DPSCs in the jaw. RNA-seq and bioinformatic analysis revealed that ECM, TNF signalling and chemokine signalling pathways may represent the key factors and signalling pathways.

Tregs dysfunction aggravates postoperative cognitive impairment in aged mice

ObjectivesEnhanced neuroinflammation is an important mechanism underlying perioperative neurocognitive disorders. Regulatory T cells (Tregs) play a crucial role in regulating systemic immune responses. The present study was aimed to investigate the participation of Tregs in the development of postoperative cognitive dysfunction (POCD).MethodsSurgery-associated neurocognitive disorder was induced in 18-month-old mice subjected to internal fixation of tibial fracture. Morris water maze was used to examine mice cognitive function. Splenic Tregs were collected for RNA sequencing and flow cytometry. Levels of inflammatory factors in the circulation and hippocampus were measured by enzyme-linked immunosorbent assay. Protein presences of tight junction proteins were detected by immunofluorescence.ResultsSurgery of internal fixation of tibial fracture induced cognitive impairment in aged mice, accompanied by elevated plasma levels of inflammatory factors and increased circulating Tregs. Transfusion of Tregs from young mice partially restored the structure of the blood–brain barrier and alleviated POCD in aged mice. Compared with young Tregs, differentially expressed genes in aged Tregs were enriched in tumor necrosis factor (TNF) signaling pathway and cytokine–cytokine receptor interaction. Flow cytometry revealed that aged Tregs had blunted functions under basal and stimulated conditions. Blockade of the CD25 epitope protected the blood–brain barrier structure, reduced TNF-α levels in the hippocampus, and improved surgery-associated cognition in aged mice.ConclusionsBlocking peripheral regulatory T cells improves surgery-induced cognitive function in aged mice. Therefore, aged Tregs play an essential role in the occurrence of POCD.

Network-Based Method to Investigate the Promoted Cell Apoptosis Mechanisms of Oridonin in OSCC through the RNA-Transcriptome.

The morbidity of oral cancer is high in the world. Oridonin is a traditional Chinese medicine that can effectively inhibit oral squamous cell carcinoma (OSCC) growth, but its mechanism remains unclear. Our previous data showed that oridonin inhibited CAL-27 cell proliferation and promoted apoptosis. Herein, we explored the mechanism and target of oridonin in human OSCC through RNA sequencing and integration of multiple bioinformatics analysis strategies. Differences in gene expression can be analyzed with RNA sequencing. Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), gene set enrichment analysis (GSEA), Disease Ontology (DO), and other enrichment analyses were used to evaluate differentially expressed genes (DEGs). Protein-protein interaction (PPI) networks were built via the STRING database. It was found that tumor necrosis factor (TNF) signaling pathway, cytokine-cytokine receptor interaction, and nuclear factor-kappa B (NF-kappaB) signaling pathway were associated with the therapeutic effects of oridonin in OSCC. Three key genes (BIRC3, TNFSF10, and BCL6) were found to associate with cell apoptosis in OSCC cells treated with oridonin. Quantitative PCR assays verified the expression of apoptosis-related DEGs: TNFSF10, BIRC3, AIFM2, BCL6, BCL2L2, and Bax. Western blots were employed for verifying proteins expression associated with DEGs: cleaved caspase 3, Bax, Bcl-w, anti-cIAP2, and anti-TRAIL. In conclusion, our findings reveal the molecular pathways and targets by which oridonin can treat and induce cytotoxic effects in OSCC: by affecting the signaling including TNF, NF-κB, and cytokine-cytokine receptor interaction and by regulating the key gene BIRC3, TNFSF10, and BCL6. It should be noted that further clinical trial validation is very necessary. Combined with current research trends, our existing research may provide innovative research drugs for the treatment of OSCC.

11.4 T ultra-high static magnetic field has no effect on morphology but induces upregulation of TNF signaling pathway based on transcriptome analysis in zebrafish embryos

As magnetic resonance imaging (MRI) scanners with ultra-high field (UHF) have optimal performance, scientists have been working to develop high-performance devices with strong magnetic fields to improve their diagnostic potential. However, whether an MRI scanner with UHF poses a risk to the safety of the organism require further evaluation. This study evaluated the effects of 11.4 Tesla (T) UHF on embryonic development using a zebrafish model. Multiple approaches, including morphological parameters, physiological behaviors, and analyses of the transcriptome at the molecular level, were determined during 5 days after laboratory-controlled exposure from 6 hour post fertilization (hpf) to 24 hpf. No significant effects were observed in embryo mortality, hatching rate, body length, Left-Right patterning, locomotor behavior, etc. RNA-sequencing analysis revealed up-regulated tumor necrosis factor (TNF) inflammatory factors and activated TNF signaling pathways in the 11.4 T exposure group. The results were further validated using qPCR. Our findings indicate that although UHF exposure under 11.4 T has no effect on the development of zebrafish embryos, it has specific effects on the immune response that require further investigation.

Dynamic changes in marker components during the stir-frying of Pharbitidis Semen, and network analysis of its potential effects on nephritis.

Introduction: Pharbitidis Semen (PS) has been widely used in traditional Chinese medicine to treat several diseases such as nephritis. PS is usually stir-fried to enhance its therapeutic efficacy before use in clinical practice. However, the changes in phenolic acids during stir-frying and the mechanisms of their therapeutic effects on nephritis are still unclear. Methods: Here, we studied the processing-induced chemical changes and elucidated the mechanism of PS in the treatment of nephritis. We determined the levels of the 7 phenolic acids in raw PS (RPS) and stir-fried PS (SPS) using high-performance liquid chromatography, analyzed the dynamic compositional changes during stir-frying, and used network analysis and molecular docking to predict and verify compound targets and pathways corresponding to nephritis. Results: The dynamic changes in the 7 phenolic acids in PS during stir-frying are suggestive of a transesterification reaction. Pathway analysis revealed that the targets of nephritis were mainly enriched in the AGE-RAGE, hypoxia-inducible factor-1, interleukin-17, and tumor necrosis factor signaling pathways among others. Molecular docking results showed that the 7 phenolic acids had good binding ability with the key nephritic targets. Discussion: The potential pharmaceutical basis, targets, and mechanisms of PS in treating nephritis were explored. Our findings provide a scientific basis for the clinical use of PS in treating nephritis.

Unravelling the anti-inflammatory mechanism of Allium cepa: an integration of network pharmacology and molecular docking approaches.

Allium cepa, commonly known as onion, is a widely consumed spice that possesses numerous pharmacological properties. A. cepa bioactive components are often explored in the treatment of inflammation-related complications. However, the molecular mechanism via which they exert their anti-inflammatory effects remains unknown. Therefore, this study aimed to elucidate the anti-inflammatory mechanism of A. cepa bioactive components. Consequently, the bioactive compounds of A. cepa were obtained from a database, while the potential targets of the sixty-nine compounds with desirable pharmacokinetic properties were predicted. Subsequently, the targets of inflammation were acquired from the GeneCards database. The protein-protein interaction (PPI) between the sixty-six shared targets of the bioactive compounds and inflammation was retrieved from the String database and visualized using Cytoscape v3.9.1 software. Gene Ontology (GO) analysis of the ten core targets from the PPI network revealed that A. cepa bioactive compounds could be involved in regulating biological processes such as response to oxygen-containing compounds and response to inflammation while Kyoto Encyclopaedia of Genes and Genomes (KEGG) analysis revealed that A. cepa compounds might modulate pathways including AGE-RAGE signaling pathway, interleukin (IL)-17 signalling pathway, and tumor necrosis factor signaling pathway. Molecular docking analysis showed that 1-O-(4-Coumaroyl)-beta-D-glucose, stigmasterol, campesterol, and diosgenin have high binding affinities for core targets including EGFR, ALB, MMP9, CASP3, and CCL5. This study successfully elucidated the potential anti-inflammatory mechanism of A. cepa bioactive compounds, hence, providing new insights into the development of alternative anti-inflammatory drugs.

Identification of a Necroptosis-Related Prognostic Signature and Associated Regulatory Axis in Lung Adenocarcinoma.

Lung cancer is considered to be the second most aggressive and rapidly fatal cancer after breast cancer. Necroptosis, a novel discovered pattern of cell death, is mediated by Receptor-interacting serine/threonine-protein kinase 1 (RIPK1), Receptor-interacting serine/threonine-protein kinase 3 (RIPK3), and Mixed Lineage Kinase Domain Like Pseudokinase (MLKL). For the purpose of developing a prognostic model, Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was conducted. Using Pearson's correlation analysis, we evaluated the correlation between necroptosis-related markers and tumor immune infiltration. A bioinformatics analysis was conducted to construct a necroptosis-related regulatory axis. There was a downregulation of most of necroptosis-related genes in lung adenocarcinoma (LUAD) versus lung tissues but an increase in PGAM5, HMGB1, TRAF2, EZH2 levels. We also summarized the Single Nucleotide Variant (SNV) and copy number variation (CNV) of necroptosis-related genes in LUAD. Consensus clustering identified two clusters in LUAD with distinct immune cell infiltration and ESTIMATEScore. Genes related to necroptosis were associated with necroptosis, Tumor necrosis factor (TNF) signaling pathway, and apoptosis according to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Four prognostic genes (ALDH2, HMGB1, NDRG2, TLR2) were combined to develop a prognostic gene signature for LUAD patients, which was highly accurate in predicting prognosis. Univariate and multivariate analysis identified HMGB1, pT stage, and pN stage as independent factors impacting on LUAD patients' prognosis. A significant correlation was found between the level of TLR2 and NDRG2 and clinical stage, immunity infiltration, and drug resistance. Additionally, the progression of LUAD might be regulated by lncRNA C5orf64/miR-582-5p/NDRG2/TLR2. The current bioinformatics analysis identified a necroptosis-related prognostic signature for LUAD and their relation to immunity infiltration. This result requires further investigation.

Decoding Hippophae rhamnoides’ action of mechanism in Sjögren’s syndrome: A network pharmacology and molecular docking study

This study aimed to decode the potential bioactive compounds and action mechanism of Hippophae rhamnoides in treating Sjögren’s syndrome using network pharmacology and molecular docking approach. The Traditional Chinese Medicine Systematic Pharmacology Database and Analysis Platform (TCMSP) and HERB (a High--throughput Experiment- and Reference-guided database of TCM) database were used to identify the active components of -Hippophae rhamnoides and their targets. Databases, including GeneCards, Online Mendelian Inheritance (OMIM), and DisGeNET, were used to acquire the major targets of action in Sjögren’s syndrome. Venn diagrams were constructed to identify the compound gene targets. Then the Search Tool for the Retrieval of Interacting genes/proteins database (STRING) platform was used to build a protein–protein interaction (PPI) network to analyze the potential protein functional modules. Analysis of Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was performed through the Metascape platform to predict their biological processes and decipher the mechanism of action. The drug component–target–action pathway network was constructed through the Cytoscape 3.8.2 software. Furthermore, the AutoDock Vina software was used to perform molecular docking of core components and key targets, validating binding affinity between potential core components and key targets. Twenty-two Hippophae rhamnoide candidate compounds and 208 potential targets for Sjögren’s syndrome were acquired. The network analysis showed that the core active ingredients of Hippophae rhamnoides in regulating Sjögren’s syndrome were quercetin, kaempferol, and beta-sitosterol (β-sitosterol). Core targets included albumin (ALB), epidermal growth factor receptor (EGFR), Caspase-3 (CASP3), peroxisome proliferator-activated receptor gamma (PPAR-gamma or PPARG), estrogen receptor (ER) ESR1, heat shock protein HSP 90-alpha, EC 3.6.4.10 (HSP90AA1), plasminogen, EC 3.4.21.7 (PLG), MAPK14, MAPK8, and MAPK1. The KEGG analyses demonstrated that Hippophae rhamnoides could exert their functioning against Sjögren’s syndrome by reacting with the lipid and atherosclerosis signaling pathway and tumor necrosis factor (TNF) signaling pathway. Further, molecular docking analysis suggested that 10 compounds of Hippophae rhamnoides could be effective to treat Sjögren’s syndrome by matching five core genes to docking pockets. This study indicated that Hippophae rhamnoides’ functioning effects on Sjögren’s syndrome could be attributed to the regulation of a network comprising multi-targets, multi-compounds, and multi-pathways.

Isorhamnetin inhibits inflammatory response to alleviate DHEA-induced polycystic ovary syndrome in rats

Objective To explore the role of isorhamnetin on polycystic ovary syndrome (PCOS) in rats. Methods Sprague Dawley (SD) rats were subcutaneously injected with dehydroepiandrosteron (DHEA) to establish PCOS model. Hematoxylin and eosin (H&E) staining and TdT-mediated dUTP Nick-End Labeling (TUNEL) were used to measure histological changes and apoptosis of ovary tissues. The levels of serum hormones and inflammatory factors in ovary tissues were measured by enzyme-linked immuno sorbent assay (ELISA). Results In DHEA-induced PCOS rats, the levels of serum glucose, insulin, testosterone and luteinizing hormone (LH) were enhanced, estradiol (E2), sex hormone-binding globulin (SHBG), follicle stimulating hormone (FSH) levels were decreased, inflammatory levels and apoptosis of ovary tissues were increased. Additionally, DHEA increased the body weight, ovary weight, and ovary volume, cystic follicles, and decreased corpus luteum. Moreover, the tumor necrosis factor (TNF) signaling pathway was activated in PCOS rats. The levels of TNF receptor superfamily member 1 A (TNFR1), TNF-α, and fas cell surface death feceptor (FAS) were enhanced in ovary tissues of DHEA induced PCOS rats. Isorhamnetin (ISO) treatment after DHEA modeling markedly reduced serum levels of glucose, insulin, testosterone and LH, increased E2, SHBG, FSH level, decreased inflammatory levels, and inhibited apoptosis and decreased body weight, ovary weight, and ovary volume. The levels of TNFR1, TNF-α, and FAS were markedly decreased after ISO treatment in PCOS rats. Additionally, ISO alone had no significant effect on rats. Conclusion Isorhamnetin inhibits inflammatory response to alleviate DHEA-induced PCOS in rats by inactivating the TNF signaling pathway.