Protein Tyrosine Kinase Signaling Pathway Research Articles

Efficacy and Mechanism of Core Traditional Chinese Medicines for Treating Malignant Lymphoma based on Efficacy Studies: A Study Supported by Network Pharmacology and Molecular Docking.

The burden of malignant lymphoma in China is greater than the global equivalent. The randomized controlled trials provide medical evidence that TCM can improve the response and survival in patients with lymphoma. However, the mechanisms underlying remain undefined. Evidence-based data mining for traditional Chinese medicine (TCM) on improving response and survival in malignant lymphoma treatment was performed in this study. In addition, the mechanisms of TCM through network pharmacology and molecular docking were explored. The China national knowledge infrastructure, Wanfang Data, China Science and Technology Journal Database, PubMed, and Web of Science databases were searched to select TCM formulas with response and survival benefits in the treatment of malignant lymphomas. We then analyzed and visualized the tropism of taste, frequency of drug use, dosage, clustering, association rules mining (minimum support threshold as 0.20, the minimum confidence threshold as 0.80 and lift >1), and complex networks for potential core herb compositions using Excel, IBM SPSS Statistics 26, and IBM SPSS Modeler 18. TCM systems pharmacology, GeneCards, Online Mendelian Inheritance in Man, and other databases were used to screen potential core active ingredients and malignant lymphoma-related targets. The intersection targets were used to construct a protein interaction network using Cytoscape to obtain the key targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment were used to analyze the core target, and molecular docking of key components and targets was performed using CB-Dock2. Twenty-four Chinese herbal formulae were included, encompassing 107 herbs with mainly cold and warm properties and bitter and sweet flavors. They were associated with the yin meridians of the liver, spleen, and lungs. The TCMs underwent association rule analysis, identified 27 association rules, including 12 herb pairs and 13 angle medicine, and clustered into eight classes by clustering analysis. Combined with the results from mining analysis, Pinelliae (Ban-xia), Poria (Fu-ling), Atractylodis macrocephalae (Bai-zhu), Curcumae (E-zhu), and Sparganii (San-leng) were the potential core herbs According to network pharmacology and molecular docking, the main core components of the potential core drugs are hederagenin, cerevisterol, 14- acetyl-12-senecioyl-2E,8E,10E-atractylentriol, 12,13-epoxy-9-hydroxynonadeca-7,10-dienoic acid, cavidine, and baicalein. These core drugs are mainly involved in the pathways of EGFR tyrosine kinase inhibitor resistance, PD-1/L1, natural killer cell-mediated cytotoxicity, NF-κB, epithelial cell signaling in H. pylori infections, and Th17 cell differentiation. They aid in regulating the transmembrane receptor protein tyrosine kinase signaling pathway, ERBB signaling pathway, PI3K signaling pathway, and phosphorylation process. Ten key components and eight key targets, including baicalein and hederagenin, demonstrated strong binding activity. Collectively, some core herbs exerted anti-tumor effects through immune and inflammatory pathway modulation, inhibition of immune escape, and induction of cell apoptosis. These findings support future evidence-based research on malignant lymphoma treatment using TCM.

Integrated approach of network pharmacology, molecular docking, and clinical observations in evaluating the efficacy and safety of Bufei Huoxue capsules for pulmonary hypertension associated with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a persistent and progressive disorder characterized by airway or alveolar abnormalities, commonly leading to pulmonary hypertension (PH). This clinical observational study investigates the therapeutic mechanisms of Bufei Huoxue capsules (BHC) in treating PH in patients with COPD-linked PH (COPD-PH) using network pharmacology and molecular docking methods, and assesses the therapeutic efficacy and safety of BHCs. The active compounds and their target proteins in BHCs were sourced from the Traditional Chinese Medicine Systems Pharmacology database, with additional target proteins derived from the GeneCards and OMIM databases. An active network was constructed using Cytoscape 3.7.1, and interaction networks were established. Intersecting targets underwent Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using the Metascape database. Network pharmacology and molecular docking studies demonstrated favorable binding affinities of BHC active ingredients, such as quercetin, bavachalcone, and isobavachin, for key targets including PTGS1, ESR1, and PTGS2. Gene Ontology enrichment analysis highlighted the involvement of these targets in processes such as the positive regulation of locomotion, the transmembrane receptor protein tyrosine kinase signaling pathway, and peptidyl-tyrosine phosphorylation. KEGG pathway analysis indicated their roles in pathways related to cancer, AGE-RAGE signaling in diabetic complications, and prostate cancer. BHCs exhibit therapeutic effects on COPD-PH through multi-component, multi-target, and multi-pathway interactions. This clinical observational study confirms the efficacy and safety of BHCs in improving cardiac and pulmonary functions, enhancing exercise tolerance, and elevating the quality of life in patients with COPD-PH.

Mediating and moderating effects of plasma proteomic biomarkers on the association between poor oral health problems and incident dementia: The UK Biobank study.

The plasma proteome can mediate poor oral health problems (POHP)'s link to incident dementia. We screened 37,269 UK Biobank participants 50-74years old(2006-2010) for prevalent POHP, further tested against 1463 plasma proteins and incident dementia over up to 15years of follow-up. Total effect (TE) of POHP-dementia through plasma proteomic markers was decomposed into pure indirect effect (PIE), interaction referent (INTREF), controlled direct effect (CDE), or mediated interaction (INTMED). POHP increased the risk of all-cause dementia by 17% (P < 0.05). Growth differentiation factor 15 (GDF15) exhibited the strongest mediating effects (PIE > 0, P < 0.001), explaining 28% the total effect of POHP on dementia, as a pure indirect effect. A first principal component encompassing top 4 mediators (GDF15, IL19, MMP12, and ACVRL1), explained 11% of the POHP-dementia effect as a pure indirect effect. Pathway analysis including all mediators (k = 173 plasma proteins) revealed the involvement of the immune system, signal transduction, metabolism, disease, and gene expression, while STRING analysis indicated that top mediators within the first principal component were also represented in the two largest proteomic clusters. The dominant biological GO pathway for the GDF15 cluster was GO:0007169 labeled as "transmembrane receptor protein tyrosine kinase signaling pathway." Dementia is linked to POHP mediated by GDF15 among several proteomic markers.

Analysis of MicroRNA Cargo in Circulating Extracellular Vesicles from HIV-Infected Individuals with Pulmonary Hypertension.

The risk of developing pulmonary hypertension (PH) in people living with HIV is at least 300-fold higher than in the general population, and illicit drug use further potentiates the development of HIV-associated PH. The relevance of extracellular vesicles (EVs) containing both coding as well as non-coding RNAs in PH secondary to HIV infection and drug abuse is yet to be explored. We here compared the miRNA cargo of plasma-derived EVs from HIV-infected stimulant users with (HIV + Stimulants + PH) and without PH (HIV + Stimulants) using small RNA sequencing. The data were compared with 12 PH datasets available in the GEO database to identify potential candidate gene targets for differentially altered miRNAs using the following functional analysis tools: ingenuity pathway analysis (IPA), over-representation analysis (ORA), and gene set enrichment analysis (GSEA). MiRNAs involved in promoting cell proliferation and inhibition of intrinsic apoptotic signaling pathways were among the top upregulated miRNAs identified in EVs from the HIV + Stimulants + PH group compared to the HIV + Stimulants group. Alternatively, the downregulated miRNAs in the HIV + Stimulants + PH group suggested an association with the negative regulation of smooth muscle cell proliferation, IL-2 mediated signaling, and transmembrane receptor protein tyrosine kinase signaling pathways. The validation of significantly differentially expressed miRNAs in an independent set of HIV-infected (cocaine users and nondrug users) with and without PH confirmed the upregulation of miR-32-5p, 92-b-3p, and 301a-3p positively regulating cellular proliferation and downregulation of miR-5571, -4670 negatively regulating smooth muscle proliferation in EVs from HIV-PH patients. This increase in miR-301a-3p and decrease in miR-4670 were negatively correlated with the CD4 count and FEV1/FVC ratio, and positively correlated with viral load. Collectively, this data suggest the association of alterations in the miRNA cargo of circulating EVs with HIV-PH.

FYN as an emerging biological biomarker for prognosis and potential therapeutic target in LGG

ABSTRACT Objectives This study aimed to explore the expression, clinical significance, and functional mechanism of FYN in lower-grade gliomas (LGG). Methods The mRNA and protein expression of FYN in LGG tissues were detected using databases including OncoLnc, GEPIA, and Human protein atlas (HPA). The UCSC Xena browser, TIMER, STRING and Metascape databases were used to investigate Kaplan–Meier survival curves, correlations between FYN expression and various types of immune cell infiltration, protein interaction network and possible functional mechanism. Results FYN expression in LGG, IDH mutation or 1p19q co-deletion subgroup was significantly higher than in corresponding control groups (p < 0.05). Patients with higher FYN expression had longer overall survival (p < 0.05). Male or no 1p19q co-deletion groups with higher FYN expression also had longer overall survival (p < 0.05). FYN expression had close correlation with infiltrating levels of cell purity, CD4+T cells, macrophages, and CD8+T cells (p < 0.05). Protein interaction network result showed correlation among FYN, SH2D1A, LCK, CAV1, SRC, CBL and PTK2. Functional enrichment analysis revealed that FYN and its related genes mainly participated in bacterial invasion of epithelial cells and natural killer cell mediated cytotoxicity. Peptidyl-tyrosine phosphorylation, negative regulation of anoikis, immune effector process, transmembrane receptor protein tyrosine kinase signaling pathway, epidermal growth factor receptor signaling pathway, and negative regulation of protein modification process may be the critical biological process. Conclusions FYN is up-expressed in LGG and related to its good prognosis. It participated in tumor pathophysiological processes and may be a therapeutic target for LGG.

FRI686 Phenotypic Profiling And Molecular Mechanisms In Hyperparathyroidism-jaw Tumor Syndrome

Abstract Disclosure: R. Tora: None. J. Welch: None. J. Sun: None. S.K. Agarwal: None. D.A. Bell: None. M. Merino: None. L.S. Weinstein: None. W.F. Simonds: None. S. Jha: None. Background: Hyperparathyroidism-Jaw Tumor (HPT-JT) syndrome is a heritable form of primary hyperparathyroidism (PHPT) that is associated with tumors in the parathyroid, jaw, kidney, and uterus. We previously presented on the clinical characteristics of primary hyperparathyroidism in our cohort. Methods: We now expand on the report through review of uterine tumors, immunohistochemical staining for parafibromin, sequencing of parathyroid and kidney tumor tissue, and RNA-seq of parathyroid tumors. Results: We identified 68 patients (36 males, 32 females) from 29 kindreds with HPT-JT with median age at last follow-up of 39 [29-53] years. Of these, 7 patients were unaffected (2 males, 5 females). Among females, 12/32 (38%) developed uterine tumors with multiple adenomyomatous polyps, an unusual form of endometrial polyps seen in 10/24 tumors (42%). Given that these types of lesions are very rare in the general population, it is likely that such epithelial-mesenchymal uterine proliferations are a characteristic feature of HPT-JT syndrome.Solid kidney tumors were seen in 4/61 patients (7%). Three had surgery for the tumors - 2/3 were female and had mixed epithelial stromal tumor, while the third patient, a 6-year old male, had metastatic Wilm’s tumor as his initial disease-related manifestation. Among these, two had a germline CDC73 variant at the p.M1 residue while the third patient had the germline variant p.L95P; however, sequencing of his tumor tissue showed a “second hit” at the p.M1 residue resulting in loss of heterozygosity in the tumor. The fourth patient, a female with p.Y55S variant, is being conservatively managed with no kidney surgery yet. All three women with kidney tumors also had a history of uterine tumors. Parafibromin staining of 19 available CDC73 related parathyroid tumors (13 adenomas and 6 carcinoma) did not correlate with histology or genotype. Pathway analysis of 21 parathyroid tumors (8 HPT-JT-related adenomas, 6 HPT-JT-related carcinomas and 7 sporadic parathyroid carcinoma with wild-type CDC73) showed a significant association of HPT-JT-related parathyroid carcinoma with growth, transmembrane receptor protein tyrosine kinase signaling and mesodermal commitment pathways. Conclusion: Multiple, recurrent atypical adenomyomatous uterine polyps appear to be characteristic of HPT-JT syndrome. Our findings support germline testing at a young age in first-degree relatives of patients with HPT-JT given onset of manifestations as early as 6 years. Variants at M1 residue appear to predispose to genitourinary tumors. At present, there are no therapeutic approaches to compensate for CDC73 inactivation. Future research to identify standards of care and therapeutics targets are warranted for this rare disease. Presentation: Friday, June 16, 2023

Phenotypic Profiling and Molecular Mechanisms in Hyperparathyroidism-jaw Tumor Syndrome.

Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is a heritable form of primary hyperparathyroidism caused by germline inactivating mutations in CDC73 encoding parafibromin and is associated with an increased risk of parathyroid cancer. There is little evidence to guide the management of patients with the disease. (1) Characterize the natural history of HPT-JT, (2) correlate genotype and histology of parathyroid tumors with parafibromin immunostaining, (3) understand molecular changes downstream to CDC73 loss. Retrospective study of patients with HPT-JT syndrome (genetically confirmed or affected first-degree relatives). Independent review of uterine tumor from 2 patients and staining for parafibromin on parathyroid tumors from 19 patients (13 adenomas, 6 carcinomas) was performed. RNA-sequencing was performed in 21 parathyroid samples (8 HPT-JT-related adenomas, 6 HPT-JT-related carcinomas, and 7 sporadic carcinomas with wild-type CDC73). We identified 68 patients from 29 kindreds with HPT-JT with median age at last follow-up of 39 [interquartile range, 29-53] years. A total of 55/68 (81%) developed primary hyperparathyroidism; 17/55 (31%) had parathyroid carcinoma. Twelve of 32 (38%) females developed uterine tumors. Of the 11 patients who had surgical resection for uterine tumors, 12/24 (50%) tumors were rare mixed epithelial mesenchymal polypoid lesions. Four of 68 patients (6%) developed solid kidney tumors; 3/4 had a CDC73 variant at p.M1 residue. Parafibromin staining of parathyroid tumors did not correlate with tumor histology or genotype. RNA-sequencing showed a significant association of HPT-JT-related parathyroid tumors with transmembrane receptor protein tyrosine kinase signaling pathway, mesodermal commitment pathway, and cell-cell adhesion. Multiple, recurrent atypical adenomyomatous uterine polyps appear to be enriched in women with HPT-JT and appear characteristic of the disease. Patients with CDC73 variants at p.M1 residue appear predisposed to kidney tumors. NCT04969926.

Comparative Genome and Evolution Analyses of an Endangered Stony Coral Species Dendrophyllia cribrosa Near Dokdo Islands in the East Sea.

Stony corals often harbor intracellular photosynthetic dinoflagellate algae that receive dissolved inorganic nutrients. However, Dendrophyllia cribrosa is a nonsymbiotic stony coral distributed in the western Pacific. We assembled a chromosome-level D. cribrosa genome using PacBio and Hi-C technologies. The final assembly was 625 Mb, distributed on 14 chromosomes, and contained 30,493 protein-coding genes. The Benchmarking Universal Single-Copy Orthologs analysis revealed a percentage of 96.8 of the metazoan genome. A comparative phylogenetic analysis revealed that D. cribrosa, which lacks symbionts, evolved to acquire cellular energy by expanding genes related to acyl-CoA metabolism and carbohydrate transporters. This species also has expanded immune-related genes involved in the receptor protein tyrosine kinase signaling pathway. In addition, we observed a specific expansion of calcification genes, such as coral acid-rich proteins and carbonic anhydrase, in D. cribrosa. This high-quality reference genome and comparative analysis provides insights into the ecology and evolution of nonsymbiotic stony corals.

Investigations of nitazoxanide molecular targets and pathways for the treatment of hepatocellular carcinoma using network pharmacology and molecular docking.

Nitazoxanide has been investigated for colorectal cancer and breast cancer. However, its molecular targets and pathways have not yet been explored for hepatocellular carcinoma (HCC) treatment. Utilizing a network pharmacology approach, nitazoxanide’s potential targets and molecular pathways for HCC treatment were investigated. HCC targets were extracted from the GeneCards database. Potential targets of nitazoxanide were predicted using Swiss Target Prediction and Super Pred. Intersecting targets were analyzed with VENNY online tool. Using Cytoscape, a protein-protein interaction (PPI), cluster, and core targets-pathways networks were constructed. Using the Database for Annotation, Visualization and Integrated Discovery (DAVID), gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted. The nitazoxanide was molecularly docked with anti-HCC core targets by employing Auto Dock Vina. A total of 168 potential targets of nitazoxanide, 13,415 HCC-related targets, and 153 intersecting targets were identified. The top eight anti-HCC core targets were identified: SRC, EGFR, CASP3, MMP9, mTOR, HIF1A, ERBB2, and PPARG. GO enrichment analysis showed that nitazoxanide might have anti-HCC effects by affecting gene targets involved in multiple biological processes (BP) (protein phosphorylation, transmembrane receptor protein tyrosine kinase (RTKs) signaling pathway, positive regulation of MAP kinase activity, etc.). KEGG pathways and core targets-pathways network analysis indicated that pathways in cancer and proteoglycans in cancer are two key pathways that significantly contribute to the anti-HCC effects of nitazoxanide. Results of molecular docking demonstrated the potential for active interaction between the top eight anti-HCC core targets and nitazoxanide. Our research offers a theoretical basis for the notion that nitazoxanide may have distinct therapeutic effects in HCC, and the identified pharmacological targets and pathways might function as biomarkers for HCC therapy.

Noggin proteins are multifunctional extracellular regulators of cell signaling.

Noggin is an extracellular cysteine knot protein that plays a crucial role in vertebrate dorsoventral patterning. Noggin binds and inhibits the activity of bone morphogenetic proteins via a conserved N-terminal clip domain. Noncanonical orthologs of Noggin that lack a clip domain (“Noggin-like” proteins) are encoded in many arthropod genomes and are thought to have evolved into receptor tyrosine kinase ligands that promote Torso/receptor tyrosine kinase signaling rather than inhibiting bone morphogenic protein signaling. Here, we examined the molecular function of noggin/noggin-like genes (ApNL1 and ApNL2) from the arthropod pea aphid using the dorso-ventral patterning of Xenopus and the terminal patterning system of Drosophila to identify whether these proteins function as bone morphogenic protein or receptor tyrosine kinase signaling regulators. Our findings reveal that ApNL1 from the pea aphid can regulate both bone morphogenic protein and receptor tyrosine kinase signaling pathways, and unexpectedly, that the clip domain is not essential for its antagonism of bone morphogenic protein signaling. Our findings indicate that ancestral noggin/noggin-like genes were multifunctional regulators of signaling that have specialized to regulate multiple cell signaling pathways during the evolution of animals.

Transcriptome analysis in patients with asthma after inhaled combination therapy with long-acting β2-agonists and corticosteroids.

Introduction: Asthma is one of the major public health problems that imposes a great burden on societal, financial, and healthcare around the world. Asthma poorly affects the health-related quality of life and daily activities of patients. Treatment of asthma, including inhaled corticosteroids (ICS) and long-acting beta-agonists (LABAs), mainly aims to improve the lung function and reduce symptoms and exacerbations. Current treatment regimens are symptom-based strategies, and the status of airway inflammation after treatment is yet unknown. We conducted this study to understand the comprehensive inflammation or airway remodeling status of patients after ICS-LABA treatment through RNA transcriptome analysis.Materials and methods: Eight newly diagnosed asthmatic patients and two healthy subjects were recruited in this study. Asthmatic patients underwent blood tests, lung function test, and RNA transcriptome analysis before and after ICS-LABA treatment.Results: In comparison with healthy subjects, pretreatment asthmatic patients had higher expression of protein tyrosine kinase and related signaling pathways. After ICS-LABA treatment, the expression of nuclear receptor transcription coactivator, N-acetyltransferase, protein tyrosine kinase, nuclear receptor, and RNA polymerase II-activating transcription factor were downregulated. However, the post-treatment asthmatic patients still had higher expression of cysteine-type endopeptidase, endodeoxyribonuclease, apolipoprotein, and unfolded protein was still upregulated than healthy subjects.Conclusions: The combination of ICS/LABAs decreased airway inflammatory and remodeling pathways. However, allergen stimulation-related pathways were still upregulated in patients after ICS/LABA treatment. The combination of medication and allergen removal is a complete strategy for asthma.

Estrogen Induces Transcriptomic Changes Associated with Oncogenic Phenotypes in Inflammatory Breast Cancer

Inflammatory Breast Cancer (IBC) is rare and the most aggressive subtype of all breast cancers, reporting rapid progression, poor prognosis, and a unique clinical diagnosis. Approximately ~30% of IBC cases are classified as triple negative breast cancer (TNBC), meaning they do not test positive for hormone receptors (estrogen and progesterone) and amplification of the human epidermal growth factor receptor 2 (HER2); therefore limiting the effectiveness of hormonal therapeutics. However, recent studies have reported that estrogen (E2) can induce a rapid E2-response in IBC cells to enhance migration and invasion phenotypes by activation of novel cytoplasmic and membrane localized estrogen receptors (ERα36 isoform and G protein-coupled receptor 30 (GPR30)); both suggested as possible therapeutic targets. However, the role of these receptors in the estrogen genomic signaling pathway remains elusive and there is still no data published related to an E2-induced transcriptional stimulation of genes associated with IBC's aggressive phenotype. Here, we evaluated gene expression changes related to E2 in IBC cell lines SUM149PT to identify target genes and biological pathways associated with IBC's aggressive phenotype. We hypothesized that E2 exposure can induce transcriptional stimulation of genes related to migration and invasion phenotypes in IBC cells SUM149PT. Methods We performed RNA-seq (Illumina NextSeq PE 2x75bp) in 2 study groups (ETOH-treated and E2-treated) to identify specific changes in the expression of genes associated with migration and invasion in IBC SUM149PT. Functional and enrichment analysis of differentially expressed genes were performed using Metascape. qPCR was performed to validate a subset of genes related to the enriched terms associated with the migration and invasion phenotypes. Results After E2 exposue (3hrs), we have identified 370 significantly dysregulated genes (p<0.05), including the ZNF268 gene (adj. p-val significant), which can be potential therapeutic targets. Functional annotation of these genes showed association with mammary gland epithelial cell proliferation, actin cytoskeleton organization, and transmembrane receptor protein tyrosine kinase signaling pathway. Data acquired from these experiments will contribute to the better understanding of IBC's transcriptomic signature and create new opportunities to develop novel targeted therapies.

Network pharmacology-based study of the therapeutic mechanism of resveratrol for Alzheimer's disease

To investigate the therapeutic mechanism of resveratrol (RES) for Alzheimer's disease (AD) in light of network pharmacology. We searched PubChem, BATMAN-TCM, Genecards, AD, TTD, String 11.0, AlzData, SwissTargetPrediction, Metascape and other databases for the therapeutic targets of RES and human AD-related targets. The intersection was determined using Venny 2.1 to obtain the therapeutic targets of RES for AD. The protein-protein interaction (PPI) network was constructed, the gene ontology (GO) was enriched and the Kyoto Encyclopedia of Genes and Genomes pathway (KEGG pathway) were analyzed. Cytoscape 3.7.1 software was used to construct a target-signaling pathway network of RES in the treatment of AD. Molecular docking verification was carried out on SwissDock (http://www.swissdock.ch/docking). We examined a 293Tau cell model of AD for changes in protein levels of pS396, pS199, Tau5, CDK5, glycogen synthase kinase 3β (GSK3β) and p-GSK3β in response to RES treatment using Western blotting. We obtained 182 targets of RES, 525 targets related to AD, and 36 targets of RES for AD treatment, among which 34.6% of the targets were protein-modifying enzymes, 27.7% were metabolite invertase, 13.8% were gene-specific transcriptional regulators, and 10.3% were transporters. The core key targets of RES in the treatment of AD included INS, APP, ESR1, MMP9, IGF1R, CACNA1C, MAPT (microtubule- associated protein Tau), MMP2, TGFB1 and GSK3B. Enrichment analysis of GO biological process suggested that the biological function of RES in AD treatment mainly involved the response to β-amyloid protein, positive regulation of transferase activity, the transmembrane receptor protein tyrosine kinase signaling pathway, regulation of behavior, learning or memory, aging, and transmembrane transport. KEGG pathway enrichment analysis showed that the most significantly enriched signaling pathways were AD pathway, PI3K-AKT signaling pathway, cGMP-PKG signaling pathway, and MAPK signaling pathway. Molecular docking results showed that RES had strong binding with ESR1, GSK3B, MMP9, IGF1R, APP and INS. In the cell model of AD, treatment with 50 μmol/L RES for 12 h significantly reduced the levels of pS396 and pS199 by regulating CDK5 and GSK3β activity (P < 0.001). RES produces therapeutic effects on AD by acting on multiple targets and affecting multiple signaling pathways and improves AD-associated pathologies via a direct action on Aβ and Tau pathological processes.

Red algae natural products for prevention of lipopolysaccharides (LPS)-induced liver and kidney inflammation and injuries.

Background: The liver and kidney inflammation due to bacterial infection is one of the most common pathological problems leading to tissue damage or disease. In many liver and kidney disorders, which represent serious global health burden with a high economic cost, oxidative stress-related inflammation and apoptosis are important pathogenic components, finally resulting in acute liver and/or kidney failure. Erythropoietin and its analogues are well known to influence the interaction between apoptosis and inflammation in liver and kidney. Objective: The aim of the present study is to investigate and clarify the effect of Galaxaura oblongata (G. oblongata) red algae on lipopolysaccharides (LPS)-induced acute liver and kidney injury of mice with endotoxemia and associated molecular mechanism from inflammation, apoptosis and oxidative stress levels. Results: The current study cleared out that treatment of rats with the G. oblongata extract prior to LPS injection significantly lowered serum cytokines, including NF-κB, MPO and LPO, and improved liver apoptosis through suppressing protein tyrosine kinase signaling pathway, and that may be due to antibacterial activity as well antioxidant capacity of G. oblongata extract. Conclusion: The present study was cleared out the possibility of administration of G. oblongata red algae as a multi products source for biotechnological, medical, nutraceutical and pharmaceutical applications due to highly antioxidant and anti-inflammatory capacities even although more investigations are required for separating, purifying and characterizing these bioactive compounds.

Intervention mechanism of Qingwen Baidu Yin on cytokine storm based on network pharmacology

The aim of this paper was to explore the intervention mechanism of Qingwen Baidu Yin in cytokine storm based on network pharmacology. TCMSP and TCMIP V2.0 server were used to predict all chemical components and action targets of Qingwen Baidu Yin. Diseases that could be treated by Qingwen Baidu Yin were predicted through Enrichr database. A compound target interaction(PPI) network diagram was constructed using STRING 11.0. OmicShare was used to analyzed the gene ontology(GO) enrichment and enrichment of the Kyoto encyclopedia of genes and genomes(KEGG) pathway of core targets. Component-target-path network diagram was constructed with Cytoscape 3.6.0 software. After analysis of the database, 267 compounds were screened for Qingwen Baidu Yin, involving 1 450 targets, and a protein interaction network was constructed. Total 219 core target proteins were predicted, such as NFKB1, STAT1, RAF1, IL2, JAK1, IL6, TNF, BCL2 and other important targets, and 221 core target pathways were enriched, including cancer pathway, Kaposi's sarcoma-associated herpes virus infection, chemokine signal pathway, PI3 K-AKT signal pathway, EB virus infection, virus carcinogenesis and T cell receptor signaling pathways, a collection of which were highly related to cytokine storms. GO annotation analysis suggested that Qingwen Baidu Yin Decoction may exert therapeutic effects by regulating protein phosphorylation, cell response to cytokine stimulation, cell proliferation, inflammatory response, transmembrane receptor protein tyrosine kinase signaling pathway, and cytokine-mediated signaling pathways. This study revealed potential active components of Qingwen Baidu Yin in defending against cytokine storm and its possible mechanism of action, and provided theoretical basis and technical support for further clinical application of this prescription.

Identification of the differential expression of genes and upstream microRNAs in small cell lung cancer compared with normal lung based on bioinformatics analysis.

Small cell lung cancer (SCLC) is one of the most lethal cancer, mainly attributing to its high tendency to metastasis. Mounting evidence has demonstrated that genes and microRNAs (miRNAs) are related to human cancer onset and progression including invasion and metastasis.An eligible gene dataset and an eligible miRNA dataset were downloaded from the Gene Expression Omnibus (GEO) database based our screening criteria. Differentially expressed genes (DE-genes) or DE-miRNAs for each dataset obtained by the R software package. The potential target genes of the top 10 DE-miRNAs were predicted by multiple databases. For annotation, visualization and integrated discovery, Metascape 3.0 was introduced to perform enrichment analysis for the DE-genes and the predicted target genes of the selected top 10 DE-miRNAs, including Pathway and Process Enrichment Analysis or protein–protein interaction enrichment analysis. The intersection of predicted target genes and DE-genes was taken as the final DE-genes. Then apply the predicted miRNAs-targets relationship of top 10 DE-miRNAs to the final DE-genes to gain more convinced DE-miRNAs, DE-genes and their one to one relationship.GSE19945 (miRNA microarray) and GSE40275 (gene microarray) datasets were selected and downloaded. 56 DE-miRNAs and 861 DE-genes were discovered. 297 miRNAs-targets relationships (284 unique genes) were predicted as the target of top 10 upregulating DE-miRNAs. 245 miRNAs-targets relationships (238 unique genes) were identified as the target of top 10 downregulating DE-miRNAs. The key results of enrichment analysis include protein kinase B signaling, transmembrane receptor protein tyrosine kinase signaling pathway, negative regulation of cell differentiation, response to growth factor, cellular response to lipid, muscle structure development, response to growth factor, signaling by Receptor Tyrosine Kinases, epithelial cell migration, cellular response to organic cyclic compound, Cell Cycle (Mitotic), DNA conformation change, cell division, DNA replication, cell cycle phase transition, blood vessel development, inflammatory response, Staphylococcus aureus infection, leukocyte migration, and myeloid leukocyte activation. Differential expression of genes-upstream miRNAs (RBMS3-hsa-miR-7–5p, NEDD9-hsa-miR-18a-5p, CRIM1-hsa-miR-18a-5p, TGFBR2-hsa-miR-9–5p, MYO1C-hsa-miR-9–5p, KLF4-hsa-miR-7–5p, EMP2-hsa-miR-1290, TMEM2-hsa-miR-18a-5p, CTGF-hsa-miR-18a-5p, TNFAIP3-hsa-miR-18a-5p, THBS1-hsa-miR-182–5p, KPNA2-hsa-miR-144–3p, GPR137C-hsa-miR-1–3p, GRIK3-hsa-miR-144–3p, and MTHFD2-hsa-miR-30a-3p) were identified in SCLC.RBMS3, NEDD9, CRIM1, KPNA2, GPR137C, GRIK3, hsa-miR-7–5p, hsa-miR-18a-5p, hsa-miR-144–3p, hsa-miR-1–3p along with the pathways included protein kinase B signaling, muscle structure development, Cell Cycle (Mitotic) and blood vessel development may gain a high chance to play a key role in the prognosis of SCLC, but more studies should be conducted to reveal it more clearly.

A network analysis revealed the essential and common downstream proteins related to inguinal hernia.

Although more than 1 in 4 men develop symptomatic inguinal hernia during their lifetime, the molecular mechanism behind inguinal hernia remains unknown. Here, we explored the protein-protein interaction network built on known inguinal hernia-causative genes to identify essential and common downstream proteins for inguinal hernia formation. We discovered that PIK3R1, PTPN11, TGFBR1, CDC42, SOS1, and KRAS were the most essential inguinal hernia-causative proteins and UBC, GRB2, CTNNB1, HSP90AA1, CBL, PLCG1, and CRK were listed as the most commonly-involved downstream proteins. In addition, the transmembrane receptor protein tyrosine kinase signaling pathway was the most frequently found inguinal hernia-related pathway. Our in silico approach was able to uncover a novel molecular mechanism underlying inguinal hernia formation by identifying inguinal hernia-related essential proteins and potential common downstream proteins of inguinal hernia-causative proteins.

Comparison of the mutation profile between pancreatic head/neck and body/tail cancers.

e15752 Background: Carcinomas in the pancreatic head/neck and body/tail represent different clinicopathological characteristics, but little is known about the underlying genetic mechanisms. The present study aims to explore the differences in mutation profile between pancreatic head and body/tail cancers. Methods: Fifty-four patients were retrospectively enrolled in the present study. DNA was purified from qualified formalin-fixed, paraffin-embedded tissue blocks of the tumor and corresponding adjacent normal tissue and subjected to target-capture next generation sequencing (TGS). Somatic mutations were identified, which further underwent gene ontology (GO) and KEGG pathway analysis. Results: The most frequently mutated genes in carcinomas of the pancreatic head were KRAS (61.3%), TP53(38.7%), and CDKN2A (16.1%), while that of the pancreatic body/tail were KRAS (95.7%), TP53(87%), CDKN2A (26.1%), and ARID1A (26.1%). The prevalence of TP53 and KRAS mutations in pancreatic head and body/tail cancers were significantly different from each other (p = 0.0006 and p = 0.0037, respectively). Pancreatic head/neck cancers also preserved a broader KRAS mutation spectrum than their counterparts of the body/tail. Pathway analyses revealed that mutations in cancer of pancreatic head/neck were enriched for genes involved in the protein amino acid phosphorylation, regulation of cell proliferation, transmembrane receptor protein tyrosine kinase signaling pathway, and phosphorylation pathways, while cancers of the pancreatic body/tail were enriched for genes involved in colorectal cancers. Conclusions: Cancer of the pancreatic head/neck and body/tail have distinct mutation profiles.

Lewis(y) antigen-mediated positive feedback loop induces and promotes chemotherapeutic resistance in ovarian cancer.

The present study aimed to investigate the association between Lewis(y) antigen and chemoresistance in ovarian cancer and to elucidate the underlying molecular mechanisms. Lewis(y) expression in chemoresistant ovarian cancer tissues and cells was detected by immunohistochemistry. α1,2‑fucosyltransferase (FUT1) expression in different ovarian cancer chemotherapy-resistant cells was analyzed by reverse transcription-quantitative PCR (RT-qPCR). Genes differentially expressed in the chemoresistant and sensitive groups were screened using a gene chip followed by validation using RT-qPCR and western blot analysis. We found that Lewis(y) and FUT1 expression in ovarian cancer cells was significantly increased following the induction of drug resistance. The positive expression rate and intensity of Lewis(y) in ovarian cancer chemoresistant tissues were also significantly higher than those in the sensitive group. Compared with the non-resistant cell lines, the differentially expressed genes were mainly enriched in the terms related to the transmembrane receptor protein tyrosine kinase signaling pathway and positive regulation of cell proliferation. Interaction network analysis predicted genes participating in the regulation of apoptotic processes. The highly differential expression of AnnexinA4 (ANXA4), BCL2 interacting killer(BIK), transmembrane4L six family member4(TM4SF4) and pleckstrin homology-like domain familyA member1 (PHLDA1) was validated using RT-qPCR in ovarian cancer cell lines. Finally, ANXA4 expression was increased at both the mRNA and protein level in the drug‑resistant cells, and in addition, ANXA4 contained a Lewis(y) structure. The expression of Bcl-2 and other anti-apoptotic proteins increased with the increase of Lewis(y) expression. After blocking Lewis(y) using an antibody, the expression of the involved signaling pathway and apoptosis-related proteins decreased significantly. These findings provide strong evidence that Lewis(y) is a component of the structure of the ANXA4 membrane protein. Its overexpression can abnormally activate signaling pathways and regulate the expression of a number of factors, forming a positive feedback loop to induce the chemoresistance of ovarian cancer cells, and ultimately promoting the progression of ovarian cancer.

Dietary genistein supplementation in laying broiler breeder hens alters the development and metabolism of offspring embryos as revealed by hepatic transcriptome analysis.

Genistein (GEN) is a type of isoflavone mainly derived from soy products. In this experiment, we added 40 and 400 mg/kg GEN to the diet of laying broiler breeder hens to clarify the maternal effects of GEN on the development and metabolism of chick embryos. GEN treatment at 40 mg/kg increased embryonic length, weight, and liver index, as well as the width of the proliferative zone in the tibial growth plate of chick embryos. Gene ontology (GO) cluster analysis of the hepatic transcriptome showed that GEN treatment promoted embryonic development and cell proliferation. Low-dose GEN treatment increased insulin growth factor-binding protein (IGFBP)3 mRNA expression in the embryonic liver, whereas high-dose GEN treatment increased IGFBP5 expression and activated the apoptosis and protein tyrosine kinase signaling pathways. Furthermore, adding supplemental GEN to the diet of hens promoted the glycolysis process in the embryonic liver through the insulin-signaling pathway, upregulated target genes (phosphoglucomutase-2, hexokinase 1, dihydroxyacetone phosphate by aldolase, phosphofructokinase, platelet, and enolase 2), and enhanced the transport of carboxylic acids and cholesterol and the synthesis of unsaturated fatty acid (arachidonic acid) in the embryonic liver through upregulation of liver X receptor, sterol regulatory element-binding protein 1, and patatin-like phospholipase A. Additionally, GEN treatment increased fatty acid β-oxidation and Na+/K+-ATPase activity in the embryonic liver through activation of peroxisome proliferator-activated receptors (PPARs; PPARα and PPARδ) and the AMPK signaling pathway, which could provide energy for embryonic development. In addition, GEN treatment in hens increased superoxide dismutase activity and metallothionein expression in the chick embryonic liver and promoted lymphocyte proliferation through upregulation of mRNA expression of CDKN1A, IL12RB1, Sox11, PRKAR1A, PRKCQ, and TCF3. The improved immunity and antioxidant capacity, as a result of maternal GEN effects, was conducive to embryonic development. In summary, the addition of GEN to the diet of laying broiler breeder hens significantly promoted the development and metabolism of chick embryos.-Lv, Z., Fan, H., Zhang, B., Ning, C., Xing, K., Guo, Y. Dietary genistein supplementation in laying broiler breeder hens alters the development and metabolism of offspring embryos as revealed by hepatic transcriptome analysis.