KEGG Signaling Pathways Research Articles

ITRAQ-Based Proteomic Analysis of Spontaneous Achilles Tendon Rupture.

Spontaneous Achilles tendon rupture (SATR) predominantly affects middle-aged and elderly individuals with chronic injuries. However, the exact cause and mechanism of SATR remain elusive, and potential therapeutic intervention or prevention is still insufficient. The present study aimed to uncover the key pathological molecules by using iTRAQ proteomics. The results identified 2432 candidate proteins in SATR patients using iTRAQ proteomic analysis. A total of 307 differentially expressed proteins (DEPs) were identified and linked to 211 KEGG signaling pathways including Coronavirus disease (COVID-19), focal adhesion, and ribosomes. GO enrichment analysis highlighted significant enrichment in processes such as biological adhesion, ossification, lipid (APOA4) processes, and extracellular matrix (ECM) organization (collagen). PPI network analysis identified hub genes such as serum albumin (ALB), fibronectin (FN1), and actin cytoplasmic 1. The WB analysis confirmed that FN1 and the receptor for activated C kinase (RACK1) were downregulated in the SATR tendon. Immunohistochemical staining revealed that collagen I and III were suppressed, while collagen II and APOA4 expression were higher in the SATR pathological tissue (P < 0.05). However, the primary cultured tenocytes (PCTs) from SATR patients showed enhanced proliferation and, consistent with tissue staining, reduced collagen I and III and increased collagen II. Our findings reveal vital targets and pathways in SATR's etiological progression, offering a new perspective on the diagnosis, treatment, and prognosis of this complex disorder.

Acupuncture-induced gene co-expression networks in postmenopausal women with osteoarthritis and osteoporosis: In-silico analysis.

Objective: Bone is a tissue that is constantly remodeled to adjust the microarchitecture and maintain the mechanical needs of bone through the balance of bone resorption and formation processes. Alterations in these processes can lead to the development of different diseases, such as osteoarthritis and osteoporosis. In recent years, it has been shown that acupuncture is an effective treatment for pain, physical dysfunctions, and the immune system, so the stimulation of acupuncture points could affect genes associated with inflammatory processes and, therefore, osteoarthritis and osteoporosis. To analyze changes in gene expression post-acupuncture in data from a group of individuals with osteoarthritis that also manifests in osteoporosis. Method: Through using microarray technology and bioinformatics analysis, potential genes associated with osteoarthritis after acupuncture treatment are identified and compared with genes implicated in osteoporosis. The genes identified in each disease were evaluated through a KEGG signaling pathway analysis, where the results allowed the generation of an in-silico model that shows interaction networks between signaling pathways and genes involved in both diseases. Results: In this interaction, 37 differentially expressed genes were identified in patients with osteoarthritis before and after acupuncture treatment, and 665 differentially expressed genes was involved in osteoporosis. In the osteoarthritis group, 15 signaling pathways involved in this disease were obtained, and for osteoporosis, 13 signaling pathways associated with immunological processes that participate in bone metabolism were obtained osteoarthritis and osteoporosis are two age-associated diseases that are characterized by alterations in the bone remodeling mechanism induced by changes in gene expression profiles. Conclusions: Treatment with acupuncture can modify various cytokines involved in diseases related to the immune system so that it can have beneficial effects on osteoarthritis and osteoporosis. In addition, bioinformatics analysis allows us to know those signaling pathways through which they could have acupuncture effects. Graphical abstract: http://links.lww.com/AHM/A137.

Long Non-Coding RNA CRNDE, LINC00957, and AC072061.1 as a Promising Diagnostic and Prognostic Biomarker in Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is one of the most invasive types of brain cancer. LncRNAs can be considered a new prognostic and diagnostic biomarker in GBM. This study comprehensively explored the interaction of lncRNAs with mRNAs in the TCGA database and proposed a novel promising biomarker with favorable diagnostic and prognostic values. The public data of RNA-seq and related clinical data were downloaded from the TCGA database. Differential expression analysis was conducted in R. GO and KEGG signaling pathways were used for enrichment. The STRING database was used for PPI analysis. CE-network was constructed by STAR database. Kaplan-Meier survival analysis and ROC curve analysis to indicate the biomarkers' diagnostic and prognostic values. Differentially expressed data illustrated that 4428 mRNAs were differentially expressed in GBM. The GO and KEGG pathway analysis showed that the differentially expressed mRNAs were enriched in critical biological processes. The PPI showed that WEE1, BARD1, and CDK6 were the important PPI hubs. The ceRNA network data demonstrated critical lncRNAs. The data revealed that the lncRNA CRNDE, LINC00957, AC072061.1, AC068888.1, and DBH-AS1 are potential diagnostic prognostic biomarkers in the GBM patients. Altogether, we demonstrated lncRNA, and mRNA interaction and mentioned regulatory networks, considered a therapeutic option in GBM. In addition, we proposed potential diagnostic and prognostic biomarkers for the patients.

Berberine alleviates ETEC-induced intestinal inflammation and oxidative stress damage by optimizing intestinal microbial composition in a weaned piglet model.

Enterotoxigenic Escherichia coli (ETEC) is the main diarrhea-causing pathogen in children and young animals and has become a global health concern. Berberine is a type of "medicine and food homology" and has a long history of use in China, particularly in treating gastrointestinal disorders and bacterial diarrhea. In this study, we explored the effects of berberine on growth performance, intestinal inflammation, oxidative damage, and intestinal microbiota in a weaned piglet model of ETEC infection. Twenty-four piglets were randomly divided into four groups-a control group (fed a basal diet [BD] and infused with saline), a BD+ETEC group (fed a basal diet and infused with ETEC), a LB+ETEC group (fed a basal diet with 0.05% berberine and infused with ETEC infection), and a HB+ETEC group (fed a basal diet with 0.1% berberine and infused with ETEC). Berberine significantly improved the final body weight (BW), average daily gain (ADG), and average daily feed intake (ADFI) (P<0.05) of piglets, and effectively decreased the incidence of diarrhea among the animals (P<0.05). Additionally, berberine significantly downregulated the expression levels of the genes encoding TNF-α, IL-1β, IL-6, IL-8, TLR4, MyD88, NF-κB, IKKα, and IKKβ in the small intestine of piglets (P<0.05). ETEC infection significantly upregulated the expression of genes coding for Nrf2, CAT, SOD1, GPX1, GST, NQO1, HO-1, GCLC, and GCLM in the small intestine of the animals (P<0.05). Berberine significantly upregulated 12 functional COG categories and 7 KEGG signaling pathways. A correlation analysis showed that berberine significantly increased the relative abundance of beneficial bacteria (Gemmiger, Pediococcus, Levilactobacillus, Clostridium, Lactiplantibacillus, Weissella, Enterococcus, Blautia, and Butyricicoccus) and decreased that of pathogenic bacteria (Prevotella, Streptococcus, Parabacteroides, Flavonifractor, Alloprevotella) known to be closely related to intestinal inflammation and oxidative stress in piglets. In conclusion, ETEC infection disrupted the intestinal microbiota in weaned piglets, upregulating the TLR4/MyD88/NF-κB and Nrf2 signaling pathways, and consequently leading to intestinal inflammation and oxidative stress-induced damage. Our data indicated that berberine can optimize intestinal microbiota balance and modulate the TLR4/MyD88/NF-κB and Nrf2 signaling pathways, thus helping to alleviate intestinal inflammation and oxidative damage caused by ETEC infection in weaned piglets.

Angiopoietin-like 4 facilitates human aortic smooth muscle cell phenotype switch and dysfunctions through the PI3K/Akt signaling in aortic dissection

PurposeVascular smooth muscle cell (VSMC) phenotype switch and dysfunctions have been reported to participate in aortic dissection (AD) progression. This study was aimed to investigate the role of angiopoietin-like 4 (ANGPTL4) in regulating VSMCs phenotype switch. Materials and methodsKey genes were analyzed in AD using public datasets, and it was found that the central differential gene ANGPTL4 was up-regulated in AD. The KEGG signaling pathway annotation was performed to validate the associated pathways, and the expression of ANGPTL4 was verified using multiple datasets and clinical samples. Furthermore, the specific functions of ANGPTL4 on platelet-derived growth factor-BB (PDGF-BB)-treated human aortic smooth muscle cell (HASMC) phenotypes were investigated. The dynamic effects of ANGPTL4 and core signaling antagonists on HASMC phenotypes were examined. ResultsHub gene ANGPTL4 was significantly up-regulated in AD. ANGPTL4 was linked to the PI3K/Akt signaling, angiogenesis, and neovascularization and remodeling. ANGPTL4 overexpression further enhanced PDGF-BB effects on HASMC phenotypes, including promoted cell viability and migration, decreased contractile VSMC markers α-SMA and SM22α, elevated ECM degradation markers MMP-2 and MMP-9, and promoted phosphorylation of PI3K and Akt. ANGPTL4 knockdown partially abolished PDGF-BB-induced contractile/synthetic VSMCs imbalance and HASMC dysfunctions. Furthermore, in ANGPTL4-overexpressing HASMCs pre-treated with PDGF-BB, the PI3K/Akt signaling inhibitor LY294002 also partially eliminated the effects caused by the PDGF-BB treatment and ANGPTL4 overexpression. ConclusionsANGPTL4 is significantly up-regulated in AD. ANGPTL4 overexpression further enhanced PDGF-BB effects on HASMC phenotype switch and dysfunctions, which might be involved in the PI3K/Akt signaling.

Study on the mechanism of ischemic stroke treatment based on network pharmacology and Raman spectroscopy in the larval zebrafish model, Calculus Bovis as a case

Calculus Bovis (C. bovis) is a precious traditional Chinese medicine of animal origin, and it is one of the traditional medicines for treating cerebral inflammatory diseases such as stroke. However, the pharmacological action of C. bovis on ischemic stroke (IS) and its mechanism are still unclear. The purpose of this study was to investigate the potential mechanism to treat IS. Chemical constituents of different varieties of C. bovis were analyzed and confirmed by HPLC-MS/MS technique. We constructed a component and corresponding target network and drug-disease target protein–protein interaction (PPI) network. GO and KEGG enrichment analysis were performed. The molecular docking of the main compound with the target protein. Subsequently, the potential mechanism of therapy for IS was verified in vivo by zebrafish model. We introduced Raman spectroscopy to detect changes in the biochemical composition of zebrafish. 13 active chemical constituents and 129 potential targets were selected. 122 KEGG signaling pathways were obtained. The binding energy of the main compounds is less than −4.5. The results of animal experiments showed that C. bovis could significantly improve Ponatinib-induced IS, decrease the aggregation degree of brain macrophages, reduce the number of macrophage migrations, and significantly increase the expression level of NR3C1. Raman information indicated that the biochemical composition in the brain of the Ponatinib-induced group shifted to the control group. The mechanism may be related to anti-inflammatory process and regulation of lipid metabolism. This study demonstrates that Raman spectroscopy has great potential as a drug evaluation tool in living larval zebrafish.

ITRAQ proteomics analysis of placental tissue with gestational diabetes mellitus.

Gestational diabetes mellitus is an endocrine and metabolic disorder that appears for the first time during pregnancy and causes varying degrees of short- and/or long-term effects on the mother and child. The etiology of the disease is currently unknown and isobaric tags for relative and absolute quantitation proteomics approach, the present study attempted to identify potential proteins in placental tissues that may be involved in the pathogenesis of GDM and adverse foetal pregnancy outcomes. Pregnant women with GDM hospitalised were selected as the experimental group, and pregnant women with normal glucose metabolism as the control group. The iTRAQ protein quantification technology was used to screen the differentially expressed proteins between the GDM group and the normal control group, and the differentially expressed proteins were analysed by GO, KEGG, PPI, etc., and the key proteins were subsequently verified by western blot. Based on the proteomics of iTRAQ, we experimented with three different samples of placental tissues from GDM and normal pregnant women, and the total number of identified proteins were 5906, 5959, and 6017, respectively, which were similar in the three different samples, indicating that the results were reliable. Through the Wayne diagram, we found that the total number of proteins coexisting in the three groups was 4475, and 91 differential proteins that could meet the quantification criteria were strictly screened, of which 32 proteins were up-regulated and 59 proteins were down-regulated. By GO enrichment analysis, these differential proteins are widely distributed in extracellular membrane-bounded organelle, mainly in extracellular exosome, followed by intracellular vesicle, extracellular organelle. It not only undertakes protein binding, protein complex binding, macromolecular complex binding, but also involves molecular biological functions such as neutrophil degranulation, multicellular organismal process, developmental process, cellular component organization, secretion, regulated exocytosis. Through the analysis of the KEGG signaling pathway, it is found that these differential proteins are mainly involved in HIF-1 signaling pathway, Glycolysis/Gluconeogenesis, Central carbon metabolism in cancer, AMPK signaling pathway, Proteoglycans in cancer, Protein processing in endoplasmic reticulum, Thyroid cancer, Alcoholism, Glucagon signaling pathway. This preliminary study helps us to understand the changes in the placental proteome of GDM patients, and provides new insights into the pathophysiology of GDM.

Exploring the potential of predicted miRNAs on the genes involved in the expansion of hematopoietic stem cells

A major challenge in therapeutic approaches applying hematopoietic stem cells (HSCs) is the cell quantity. The primary objective of this study was to predict the miRNAs and anti-miRNAs using bioinformatics tools and investigate their effects on the expression levels of key genes predicted in the improvement of proliferation, and the inhibition of differentiation in HSCs isolated from Human umbilical cord blood (HUCB). A network including genes related to the differentiation and proliferation stages of HSCs was constructed by enriching data of text (PubMed) and StemChecker server with KEGG signaling pathways, and was improved using GEO datasets. Bioinformatics tools predicted a profile from miRNAs containing miR-20a-5p, miR-423-5p, and chimeric anti-miRNA constructed from 5′-miR-340/3′-miR-524 for the high-score genes (RB1, SMAD4, STAT1, CALML4, GNG13, and CDKN1A/CDKN1B genes) in the network. The miRNAs and anti-miRNA were transferred into HSCs using polyethylenimine (PEI). The gene expression levels were estimated using the RT-qPCR technique in the PEI + (miRNA/anti-miRNA)-contained cell groups (n = 6). Furthermore, CD markers (90, 16, and 45) were evaluated using flow cytometry. Strong relationships were found between the high-score genes, miRNAs, and chimeric anti-miRNA. The RB1, SMAD4, and STAT1 gene expression levels were decreased by miR-20a-5p (P < 0.05). Additionally, the anti-miRNA increased the gene expression level of GNG13 (P < 0.05), whereas the miR-423-5p decreased the CDKN1A gene expression level (P < 0.01). The cellular count also increased significantly (P < 0.05) but the CD45 differentiation marker did not change in the cell groups. The study revealed the predicted miRNA/anti-miRNA profile expands HSCs isolated from HUCB. While miR-20a-5p suppressed the RB1, SMAD4, and STAT1 genes involved in cellular differentiation, the anti-miRNA promoted the GNG13 gene related to the proliferation process. Notably, the mixed miRNA/anti-miRNA group exhibited the highest cellular expansion. This approach could hold promise for enhancing the cell quantity in HSC therapy.

M6A- and m5C- modified lncRNAs orchestrate the prognosis in cutaneous melanoma and m6A- modified LINC00893 regulates cutaneous melanoma cell metastasis.

As the most important modifications on the RNA level, N6-methyladenosine (m6A-) and 5-methylcytosine (m5C-) modification could have a direct influence on the RNAs. Long non-coding RNAs (lncRNAs) could also be modified by methylcytosine modification. Compared with mRNAs, the function of lncRNAs could be more potent to some extent in biological processes like tumorigenesis. Until now, rare reports have been done associated with cutaneous melanoma. Herein, we wonder if the m6A- and m5C- modified lncRNAs could influence the immune landscape and prognosis in melanoma, and we also want to find some lncRNAs which could directly affect the malignant behaviors of melanoma. Systematically, we explored the expression pattern of m6A- and m5C- modified lncRNAs in melanoma from datasets including UCSC Xena and NCBI GEO, and the prognostic lncRNAs were selected. Then, according to the expression pattern of lncRNAs, melanoma samples from these datasets were divided into several subtypes. Prognostic model, nomogram survival model, drug sensitivity, GO, and KEGG pathway analysis were performed. Furthermore, among several selected lncRNAs, we identified one lncRNA named LINC00893 and investigated its expression pattern and its biological function in melanoma cell lines. We identified 27 m6A- and m5C- related lncRNAs which were significantly associated with survival, and we made a subtype analysis of melanoma samples based on these 27 lncRNAs. Among the two subtypes, we found differences of immune cells infiltration between these two subtypes. Then, LASSO algorithm was used to screen the optimized lncRNAs combination including ZNF252P-AS1, MIAT, FAM13A-AS1, LINC-PINT, LINC00893, AGAP2-AS1, OIP5-AS1, and SEMA6A-AS1. We also found that there was a significant correlation between the different risk groups predicted based on RS model and the actual prognosis. The nomogram survival model based on independent survival prognostic factors was also constructed. Besides, sensitivity to chemotherapeutic agents, GO and KEGG analysis were performed. In different risk groups, a total of 14 drug molecules with different distributions were obtained, which included AZD6482, AZD7762, AZD8055, camptothecin, dasatinib, erlotinib, gefitinib, gemcitabine, GSK269962A, nilotinib, rapamycin, and sorafenib. A total of 55 significantly related biological processes and 17 KEGG signaling pathways were screened. At last, we noticed that LINC00893 had a relatively lower expression in melanoma tissue and cell lines compared with adjacent tissues and epidermal melanocyte, and down-regulation of LINC00893 could promote the malignant behavior of melanoma cells in A875 and MV3. In these two melanoma cell lines, down-regulation of m6A-related molecules like YTHDF3 and METTL3 could promote the expression of LINC00893. We made an analysis of m6A- and m5C- related lncRNAs in melanoma samples and a prediction of these lncRNAs' role in prognosis, tumor microenvironment, immune infiltration, and clinicopathological features. We also found that LINC00893, which is potentially regulated by m6A modification, could serve as a tumor-suppressor in melanoma and play an inhibitory role in melanoma metastasis.

Dendrobium nobile active ingredient Dendrobin A against hepatocellular carcinoma via inhibiting nuclear factor kappa-B signaling

ObjectiveDendrobin A, a typical active ingredient of the traditional Chinese medicine Dendrobium nobile, has potential clinical application in cancer treatment; however, its effect and mechanism in anti-hepatocellular carcinoma (HCC) remain unsolved. MethodThe effects of Dendrobin A on the viability, migration, invasion, cycle, apoptosis, and epithelial-mesenchymal transition of HepG2 and SK-HEP-1 cells were verified by in vitro experiments. mRNA sequencing was performed to screen the differentially expressed genes (DEGs) of HCC cells before and after Dendrobin A treatment, following GO enrichment and KEGG signaling pathway analyses. Mechanistically, molecular docking was used to evaluate the binding of Dendrobin A with proteins p65 and p50, before further verifying the activation of nuclear factor kappa-B (NF-κB) signaling. Finally, the antiproliferative effect of Dendrobin A on HCC cells was explored through animal experiments. ResultsDendrobin A arrested cell cycle, induced apoptosis, and inhibited proliferation, migration, invasion, and blocked epithelial-mesenchymal transition in HepG2 and SK-HEP-1 cells. mRNA sequencing identified 830 DEGs, involving various biological processes. KEGG analysis highlighted NF-κB signaling. Molecular docking revealed strong binding of Dendrobin A with p65 and p50 proteins, and western blotting confirmed reduced levels of p-p65 and p-p50 in HCC cells post Dendrobin A treatment. NF-κB agonist PMA reversed Dendrobin A-inhibited cell proliferation migration and invasion. In vivo experiments showed that Dendrobin A inhibited HCC cell growth. ConclusionOur findings suggest that Dendrobin A exhibits anti-HCC properties by inhibiting the activation of the NF-κB pathway. These results provide a scientific basis for utilizing Dendrobium nobile in anti-HCC therapies.

Anti-Melanogenic Activity of Ethanolic Extract from Garcinia atroviridis Fruits Using In Vitro Experiments, Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation.

Melanin, the pigment responsible for human skin color, increases susceptibility to UV radiation, leading to excessive melanin production and hyperpigmentation disorders. This study investigated the ethanolic extract of Garcinia atroviridis fruits for its phenolic and flavonoid contents, antioxidant activity, and impact on melanogenesis pathways using qRT-PCR and Western blot analysis. Utilizing network pharmacology, molecular docking, and dynamics simulations, researchers explored G. atroviridis fruit extract's active compounds, targets, and pharmacological effects on hyperpigmentation. G. atroviridis fruit extract exhibited antioxidant properties, scavenging DPPH• and ABTS•+ radicals radicals and chelating copper. It inhibited cellular tyrosinase activity and melanin content in stimulated B16F10 cells, downregulating TYR, TRP-1, phosphorylated CREB, CREB, and MITF proteins along with transcription levels of MITF, TYR, and TRP-2. LC-MS analysis identified thirty-three metabolites, with seventeen compounds selected for further investigation. Network pharmacology revealed 41 hyperpigmentation-associated genes and identified significant GO terms and KEGG pathways, including cancer-related pathways. Kaempferol-3-O-α-L-rhamnoside exhibited high binding affinity against MAPK3/ERK1, potentially regulating melanogenesis by inhibiting tyrosinase activity. Stable ligand-protein interactions in molecular dynamics simulations supported these findings. Overall, this study suggests that the ethanolic extract of G. atroviridis fruits possesses significant antioxidant, tyrosinase inhibitory, and anti-melanogenic properties mediated through key molecular targets and pathways.

Transcriptome-based network analysis reveals hub immune genes and pathways of hepatopancreas against LPS in Amphioctopus fangsiao

The hepatopancreas is the biggest digestive organ in Amphioctopus fangsiao (A. fangsiao), but also undertakes critical functions like detoxification and immune defense. Generally, pathogenic bacteria or endotoxin from the gut microbiota would be arrested and detoxified in the hepatopancreas, which could be accompanied by the inevitable immune responses. In recent years, studies related to cephalopods immune have been increasing, but the molecular mechanisms associated with the hepatopancreatic immunity are still unclear. In this study, lipopolysaccharide (LPS), a major component of the cell wall of Gram-negative bacteria, was used for imitating bacteria infection to stimulate the hepatopancreas of A. fangsiao. To investigate the immune process happened in A. fangsiao hepatopancreas, we performed transcriptome analysis of hepatopancreas tissue after LPS injection, and identified 2615 and 1943 differentially expressed genes (DEGs) at 6 and 24 h post-injection, respectively. GO and KEGG enrichment analysis showed that these DEGs were mainly involved in immune-related biological processes and signaling pathways, including ECM-receptor interaction signaling pathway, Phagosome signaling pathway, Lysosome signaling pathway, and JAK-STAT signaling pathways. The function relationships between these DEGs were further analyzed through protein-protein interaction (PPI) networks. It was found that Mtor, Mapk14 and Atm were the three top interacting DEGs under LPS stimulation. Finally, 15 hub genes involving multiple KEGG signaling pathways and PPI relationships were selected for qRT-PCR validation. In this study, for the first time we explored the molecular mechanisms associated with hepatopancreatic immunity in A. fangsiao using a PPI networks approach, and provided new insights for understanding hepatopancreatic immunity in A. fangsiao.

Deciphering anoikis resistance and identifying prognostic biomarkers in clear cell renal cell carcinoma epithelial cells.

This study tackles the persistent prognostic and management challenges of clear cell renal cell carcinoma (ccRCC), despite advancements in multimodal therapies. Focusing on anoikis, a critical form of programmed cell death in tumor progression and metastasis, we investigated its resistance in cancer evolution. Using single-cell RNA sequencing from seven ccRCC patients, we assessed the impact of anoikis-related genes (ARGs) and identified differentially expressed genes (DEGs) in Anoikis-related epithelial subclusters (ARESs). Additionally, six ccRCC RNA microarray datasets from the GEO database were analyzed for robust DEGs. A novel risk prognostic model was developed through LASSO and multivariate Cox regression, validated using BEST, ULCAN, and RT-PCR. The study included functional enrichment, immune infiltration analysis in the tumor microenvironment (TME), and drug sensitivity assessments, leading to a predictive nomogram integrating clinical parameters. Results highlighted dynamic ARG expression patterns and enhanced intercellular interactions in ARESs, with significant KEGG pathway enrichment in MYC + Epithelial subclusters indicating enhanced anoikis resistance. Additionally, all ARESs were identified in the spatial context, and their locational relationships were explored. Three key prognostic genes-TIMP1, PECAM1, and CDKN1A-were identified, with the high-risk group showing greater immune infiltration and anoikis resistance, linked to poorer prognosis. This study offers a novel ccRCC risk signature, providing innovative approaches for patient management, prognosis, and personalized treatment.

Screening of drug targets for tuberculosis on the basis of transcription factor regulatory network and mRNA sequencing technology.

Tuberculosis is a worldwide epidemic disease, posing a serious threat to human health. To find effective drug action targets for Mycobacterium tuberculosis, differentially expressed genes in tuberculosis patients and healthy people were screened by mRNA sequencing in this study. A total of 556 differentially expressed genes in tuberculosis patients and healthy people were screened out by mRNA sequencing technology. 26 transcription factors and 66 corresponding target genes were screened out in the AnimalTFDB 3.0 database, and a transcription factor regulatory network was constructed. Three key transcription factors (TP53, KLF5 and GATA2) and one key gene (AKT1) were screened as new potential drug targets and diagnostic targets for tuberculosis by MCODE cluster analysis, and the key genes and key transcription factors were verified by RT-PCR. Finally, we constructed the and a key factor and KEGG signaling pathway regulatory network to clarify the possible molecular pathogenesis of tuberculosis. This study suggested M. tuberculosis may activate the AKT1 gene expression by regulating transcription factors TP53, KLF5, and GATA2, thus activating the B cell receptor signaling pathway to induce the infection and invasion of M. tuberculosis. AKT1, TP53, KLF5, and GATA2 can be used as new potential drug targets for tuberculosis.

Network mechanism of scutellarin in improving Parkinson's disease through network pharmacology analysis

Objective: To investigate the network mechanism of scutellarin in improving Parkinson's disease. Methods: The keywords "scutellarin (SCU)" and "Parkinson's Disease (PD)" were entered into the GeneCards (https://www.genecards.org/) database to find and download the genes related to SCU and PD, and analyze the common targets of SCU and PD by Venny 2.1.0 software package, then perform biological processes (BP), cellular components (CC), molecular function (MF), KEGG signaling pathway analysis. Then, the intersecting genes were uploaded to the String platform for protein interaction network (PPI) construction, and the top 10 core target genes of SCU for PD were screened and compared in the literature to assess the possible roles. Results: 22 genes related to SCU and 8163 genes associated with PD were downloaded from GeneCards by using the keywords "scutellarin" and "Parkinson's Disease". 8163 genes were downloaded, and 21 common genes were obtained by cross-gene analysis of drugs and diseases. GO and KEGG analysis of the intersecting genes showed that the most likely BP, CC, and MF associated with drug diseases were involved in positive regulation of gene expression, cytoplasm, and protein kinase binding, and the top one KEGG signaling pathways were HIF-1 signaling pathway. The PPI network was constructed and 10 core molecules including BCL2L1, HIF1A, STAT3, CASP3, AKT1, MTOR, CCL2, MAPK14, NFE2L2, and ABCB1 were identified. The main biological processes for these core molecules are involved in TOR signaling, PD-L1 expression, and PD-1 checkpoint pathway in cancer. Conclusion: This paper expounds on the related targets of SCU and PD. Moreover, the core network was deciphered, and the key targets for clinical treatment of PD were found.

Tamarix aphylla derived metabolites ameliorate indomethacin-induced gastric ulcers in rats by modulating the MAPK signaling pathway, alleviating oxidative stress and inflammation: In vivo study supported by pharmacological network analysis.

Nature has proven to be a treasure resource of bioactive metabolites. In this regard, Tamarix aphylla (F. Tamaricaceae) leaves crude extract was investigated for its gastroprotective effect against indomethacin-induced damage to the gastric mucosa. Additionally, phytochemical investigation of the methanolic extract afforded eight flavonoids' derivatives (1-8). On pharmacology networking study, the isolated compounds identified 123 unique targets where only 45 targets were related to peptic ulcer conditions, these 45 targets include 11 targets specifically correlate to gastric ulcer. The protein-protein interaction defined the PTGS2 gene as one of the highly interacted genes and the complete pharmacology network defined the PTGS2 gene as the most represented gene. The top KEGG signaling pathways according to fold enrichment analysis was the EGFR tyrosine kinase inhibitor resistance pathway. As a result, these findings highlighted the significance of using T. aphylla leaves crude extract as an anti-gastric ulcer candidate, which provides a safer option to chemical antisecretory medicines, which are infamous for their negative side effects. Our findings have illuminated the potent anti-inflammatory and antioxidant effects of T. aphylla, which are likely mediated by suppressing IL-1β, IL-6, TNF-α, and MAPK signaling pathways, without compromising gastric acidity.

The investigation on stress mechanisms of Sepia esculenta larvae in the context of global warming and ocean acidification

Sepia esculenta is a tasty and nutritious cephalopod. But the trend toward global warming is accelerating with massive emissions of greenhouse gases. An increase in seawater temperature and a decrease in pH are a great challenge for artificial breeding and culture of S. esculenta. In this study, we investigated the contingency mechanism of S. esculenta larvae under both high temperature and low pH conditions by transcriptome analysis. A total of 1235 DEGs were identified. functional enrichment analysis results suggest that high temperature and low pH conditions led to malignant proliferation in exceptional cells of S. esculenta larvae. A comprehensive analysis of the KEGG signaling pathway and protein-protein interaction network (PPI) identified sixteen key genes under both high temperature and low pH conditions. The three genes with the highest quantities of interactions or involved in more KEGG signaling pathways were identified as hub genes affecting normal physiological processes in S. esculenta. In this study, the effects of global warming and ocean acidification on the metabolism and immunity of S. esculenta larvae were preliminarily investigated to provide necessary help for S. esculenta captive breeding in the face of global climate change.

Transcriptomic analysis revealed potential regulatory biomarkers and repurposable drugs for breast cancer treatment.

Breast cancer (BC) is the most widespread cancer worldwide. Over 2 million new cases of BC were identified in 2020 alone. Despite previous studies, the lack of specific biomarkers and signaling pathways implicated in BC impedes the development of potential therapeutic strategies. We employed several RNAseq datasets to extract differentially expressed genes (DEGs) based on the intersection of all datasets, followed by protein-protein interaction network construction. Using the shared DEGs, we also identified significant gene ontology (GO) and KEGG pathways to understand the signaling pathways involved in BC development. A molecular docking simulation was performed to explore potential interactions between proteins and drugs. The intersection of the four datasets resulted in 146 DEGs common, including AURKB, PLK1, TTK, UBE2C, CDCA8, KIF15, and CDC45 that are significant hub-proteins associated with breastcancer development. These genes are crucial in complement activation, mitotic cytokinesis, aging, and cancer development. We identified key microRNAs (i.e., hsa-miR-16-5p, hsa-miR-1-3p, hsa-miR-147a, hsa-miR-195-5p, and hsa-miR-155-5p) that are associated with aggressive tumor behavior and poor clinical outcomes in BC. Notable transcription factors (TFs) were FOXC1, GATA2, FOXL1, ZNF24 and NR2F6. These biomarkers are involved in regulating cancer cell proliferation, invasion, and migration. Finally, molecular docking suggested Hesperidin, 2-amino-isoxazolopyridines, and NMS-P715 as potential lead compounds against BC progression. We believe that these findings will provide important insight into the BC progression as well as potential biomarkers and drug candidates for therapeutic development.

Sex dimorphic response to osteocyte miR21 deletion in murine calvaria bone as determined by RNAseq analysis.

Low levels of microRNA (miR) 21 may explain the higher osteocyte apoptosis with Cx43-deficient and aged female mice. However, miR21 exerts a sex-divergent role in osteocytes, regulating bone mass and architecture through non-cell autonomous effects on osteoblasts and osteoclasts, via sex-specific regulation of osteocyte cytokine production. miR21 deficiency improves bone strength in females, and, to a higher extent, in male miR21-deficient mice. To understand the molecular basis for the effects of miR21 deletion, mRNA was isolated from miR21fl/fl (controls) or miR21-deficient (by deletion in cells expressing Cre recombinase under the control of the 8kb fragment of the DMP1 promoter: miR21ΔOt mice). miR21 was 50% lower in miR21ΔOt whole calvaria bone compared to control mice of the corresponding sex. RNAseq was performed in 4 samples/sex and genotype. There were 152 genes with <.05 P-value and >1 absolute log2 fold change in the male data analysis, and expression of most genes was higher in the miR21fl/fl group. Two of the genes, Actn3 and Myh4, had a false discovery rate < 0.1. Gene enrichment analysis of significant genes on both KEGG pathways and gene ontology (GO) gene sets shows that the significant genes were enriched in muscle contraction. Some muscle-related genes like Actn3 were included in multiple significant pathways. For females, only 65 genes had P-value <.05 and >1 absolute log2 fold change. Yet, no significant KEGG or GO pathways, including ≥5 significant genes, were seen, and no overlap of significant genes was found between male and female samples. Therefore, deletion of miR21 has a stronger effect on male transcriptome in calvaria, compared to females. Further, no enrichment of any pathway was detected in female samples. Thus, either there are no differences between 2 groups in female or the effect size is small, and a larger sample size is needed to uncover miR21-dependent differences.

Analysis of immune cell infiltration characteristics in severe acute pancreatitis through integrated bioinformatics

The etiopathogenesis of severe acute pancreatitis (SAP) remains poorly understood. We aim to investigate the role of immune cells Infiltration Characteristics during SAP progression. Gene expression profiles of the GSE194331 dataset were retrieved from the GEO. Lasso regression and random forest algorithms were employed to select feature genes from genes related to SAP progression and immune responses. CIBERSORT was utilized to estimate differences in immune cell types and proportions and the relationship between immune cells and gene expression. We performed pathway enrichment analysis using GSEA to examine disparities in KEGG signaling pathways when comparing the two groups. Additionally, CMap analysis was executed to identify prospective small molecular compounds. The three hub genes (CBLB, JADE2, RNF144A) were identified that can predict SAP progression. Analysis of CIBERSORT and TISIDB databases has shown that there are significant differences in immune cell expression levels between the normal and SAP groups, and three hub genes (CBLB, JADE2, RNF144A) were highly correlated with multiple immune cells, regulating the characteristics of immune cell infiltration in the microenvironment. Finally, drug prediction through the Connectivity Map database suggested that compounds such as Entecavir, KU-0063794, Y-27632, and Antipyrine have certain effects as potential targeted drugs for the treatment of SAP. CBLB, JADE2, and RNF144A are hub genes in SAP, potentially playing important roles in SAP progression. This finding further broadens the understanding of the etiopathogenesis of SAP and provides a feasible basis for future research on diagnostic and immunotherapeutic targets for SAP.