Htr2b Promotes M1 Microglia Polarization and Neuroinflammation after Spinal Cord Injury via Inhibition of Neuregulin-1/ErbB Signaling.

The secondary injury of spinal cord injury (SCI) is dominated by neuroinflammation, which was caused by microglia M1 polarization. This study aimed to investigate the role and mechanism of Htr2b on neuroinflammation of SCI. The BV2 and HMC3 microglia were treated with lipopolysaccharide (LPS) or interferon (IFN)-γ to simulate in vitro models of SCI. Sprague-Dawley rats were subjected to the T10 laminectomy to induce animal model of SCI. Htr2b mRNA expression was measured by qRT-PCR. The expression of Htr2b and Iba-1 was detected by western blot and immunofluorescence. The expression of inflammatory cytokines in vitro and in vivo was also measured. Kyoto Encyclopedia of Genes and Genomes (KEGG) was employed to analyze Htr2b-regulated signaling pathways. Rat behavior was analyzed by the Basso, Beattie, and Bresnahan (BBB) and inclined plane test. Rat dorsal horn tissues were stained by hematoxylin-eosin (H&E) and Nissl to measure neuron loss. Htr2b was highly expressed in LPS- and IFN-γ-treated microglia and SCI rats. SCI modeling promoted M1 microglia polarization and increased levels of inflammatory cytokines. Inhibition of Htr2b by Htr2b shRNA or RS-127445 reduced the expression of Htr2b, Iba-1, and iNOS and suppressed cytokine levels. KEGG showed that Htr2b inhibited ErbB signaling pathway. Inhibition of Htr2b increased protein expression of neuregulin-1 (Nrg-1) and p-ErbB4. Inhibition of the ErbB signaling pathway markedly reversed the effect of Htr2b shRNA on M1 microglia polarization and inflammatory cytokines. Htr2b promotes M1 microglia polarization and neuroinflammation after SCI by inhibiting Nrg-1/ErbB signaling pathway.

The novel antibody fusion protein rhNRG1-HER3i promotes heart regeneration by enhancing NRG1-ERBB4 signaling pathway.

Stimulating cardiomyocyte proliferation in the adult heart has emerged as a promising strategy for cardiac regeneration following myocardial infarction (MI). The NRG1-ERBB4 signaling pathway has been implicated in the regulation of cardiomyocyte proliferation. However, the therapeutic potential of recombinant human NRG1 (rhNRG1) has been limited due to the low expression of ERBB4 in adult cardiomyocytes. Here, we investigated whether a fusion protein of rhNRG1 and an ERBB3 inhibitor (rhNRG1-HER3i) could enhance the affinity of NRG1 for ERBB4 and promote adult cardiomyocyte proliferation. In vitro and in vivo experiments were conducted using postnatal day 1 (P1), P7, and adult cardiomyocytes. Western blot analysis was performed to assess the expression and activity of ERBB4. Cardiomyocyte proliferation was evaluated using Ki67 and pH 3 immunostaining, while fibrosis was assessed using Masson staining. Our results indicate that rhNRG1-HER3i, but not rhNRG1, promoted P7 and adult cardiomyocyte proliferation. Furthermore, rhNRG1-HER3i improved cardiac function and reduced cardiac fibrosis in post-MI hearts. Administration of rhNRG1-HER3i inhibited ERBB3 phosphorylation while increasing ERBB4 phosphorylation in adult mouse hearts. Additionally, rhNRG1-HER3i enhanced angiogenesis following MI compared to rhNRG1. In conclusion, our findings suggest that rhNRG1-HER3i is a viable therapeutic approach for promoting adult cardiomyocyte proliferation and treating MI by enhancing NRG1-ERBB4 signaling pathway.

NGR4 and ERBB4 as Promising Diagnostic and Therapeutic Targets for Metabolic Disorders.

Obese individuals are at high risk for developing type 2 diabetes mellitus, cardiovascular diseases, and nonalcoholic fatty liver disease. The aim of this review was to analyze the scientific literature and databases to reveal the fundamental role of neuregulin 4 (NRG4) and its receptors in the development of obesity-associated metabolic disorders. This review demonstrates that NRG4 and its receptors are promising therapeutic targets for the treatment of socially significant obesity-associated pathologies. The review contains nine chapters. Information on the structure of ERBB4 and NRG4 splice isoforms and subsequent activation of downstream targets is presented. The tissue-specific features of the NRG4 and ERBB4 genes and protein production are also highlighted. The role of NRG4 and ERBB3/4 in the pathophysiological mechanisms of the development of metabolic disorders in obesity is discussed in detail. The final chapter of the review is devoted to the miRNA-dependent regulation of NRG4 and ERBB4. Recent studies have shown that several miRNAs regulate ERBB4 expression, but no information was found on the interaction of NRG4 with miRNAs. We now demonstrate the putative relationships between NRG4 and let-7a-5p, let-7c-5p, miR-423-5p, miR-93-5p, miR-23a-3p, and miR-15b-5p for the first time. In addition, we found SNP mutations affecting the interaction of NRG4 and ERBB4 with miRNA in these genes as well as in miRNAs. In summary, this review provides a detailed and comprehensive overview of the role of NRG4 in obesity-associated metabolic disorders. The review summarizes all current studies on this topic and opens perspectives for future research.

Significance of microRNA-targeted ErbB signaling pathway genes in cardiomyocyte differentiation.

OBJECTIVE(S): Cardiomyocyte differentiation is a complex process that follows the progression of gene expression alterations. The ErbB signaling pathway is necessary for various stages of cardiac development. We aimed to identify potential microRNAs targeting the ErbB signaling pathway genes by in silico approaches. METHODS: Small RNA-sequencing data were obtained from GSE108021 for cardiomyocyte differentiation. Differentially expressed miRNAs were acquired via the DESeq2 package. Signaling pathways and gene ontology processes for the identified miRNAs were determined and the targeted genes of those miRNAs affecting the ErbB signaling pathway were determined. RESULTS: Results revealed highly differentially expressed miRNAs were common between the differentiation stages and they targeted the genes involved in the ErbB signaling pathway as follows: let-7g-5p targets both CDKN1A and NRAS, while let-7c-5p and let-7d-5p hit CDKN1A and NRAS exclusively. let-7 family members targeted MAPK8 and ABL2. GSK3B was targeted by miR-199a-5p and miR-214-3p, and ERBB4 was targeted by miR-199b-3p and miR-653-5p. miR-214-3p, miR-199b-3p, miR-1277-5p, miR-21-5p, and miR-21-3p targeted CBL, mTOR, Jun, JNKK, and GRB1, respectively. MAPK8 was targeted by miR-214-3p, and ABL2 was targeted by miR-125b-5p and miR-1277-5p, too. CONCLUSION: We determined miRNAs and their target genes in the ErbB signaling pathway in cardiomyocyte development and consequently heart pathophysiology progression.

miRNA-150_R-1 mediates the HIF-1/ErbB signaling pathway to regulate the adhesion of endometrial epithelial cells in cows experiencing retained placenta.

Retained placenta (RP) refers to reproductive disorders caused by the failure of fetal membranes to be expelled 12 h after delivery in dairy cows. Postpartum adhesion of the fetal membranes to the uterus causes diseases such as mastitis or endometritis, which threatening the profitability of the dairy industry. Emerging evidence suggests that micro RNAs (miRNAs) play crucial roles in various processes, such as the occurrence and progression of fetal membranes discharge. However, the molecular mechanisms of miRNAs in RP remain unknown. In this study, we performed RNA-sequencing to characterize the expression profiles of mRNAs and miRNAs in caudal vein blood samples of postpartum Holstein cows whose fetal membranes were discharged normally or retained to identify RP-related genes and evaluate their molecular mechanisms. We identified 44 differentially expressed miRNAs (19 upregulated and 25 downregulated) and 706 differentially expressed mRNAs (325 upregulated and 381 downregulated) in the RP group compared to the normal fetal membranes discharge group. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis revealed that differentially expressed mRNAs were mainly enriched in the extracellular matrix, cell adhesion, and autoimmunity-related biological processes or pathways. Further analyses using RNA-sequencing, a dual luciferase reporter system, quantitative reverse transcription-PCR, immunofluorescence, and western blotting verified that endothelial PAS domain protein 1 (EPAS1) is regulated by miR-150_R-1 in endometrial epithelial cells. We demonstrated the relationship between EPAS1 and RP and confirmed that EPAS1 is upregulated in the blood and placenta of cows that experience RP. Further, we proposed a model of the miRNA-mRNA negative regulatory network mediated by the HIF-1/ErbB signaling pathway to show its regulatory role in RP.

Abnormalities in the migration of neural precursor cells in familial bipolar disorder.

Cellular migration is a ubiquitous feature that brings brain cells into appropriate spatial relationships over time; and it helps in the formation of a functional brain. We studied the migration patterns of induced pluripotent stem cell-derived neural precursor cells (NPCs) from individuals with familial bipolar disorder (BD) in comparison with healthy controls. The BD patients also had morphological brain abnormalities evident on magnetic resonance imaging. Time-lapse analysis of migrating cells was performed, through which we were able to identify several parameters that were abnormal in cellular migration, including the speed and directionality of NPCs. We also performed transcriptomic analysis to probe the mechanisms behind the aberrant cellular phenotype identified. Our analysis showed the downregulation of a network of genes, centering on EGF/ERBB proteins. The present findings indicate that collective, systemic dysregulation may produce the aberrant cellular phenotype, which could contribute to the functional and structural changes in the brain reported for bipolar disorder. This article has an associated First Person interview with the first author of the paper.

Proteomics-based evaluation of the mechanism underlying vascular injury via DNA interstrand crosslinks, glutathione perturbation, mitogen-activated protein kinase, and Wnt and ErbB signaling pathways induced by crotonaldehyde.

Crotonaldehyde (CRA)-one of the major environmental pollutants from tobacco smoke and industrial pollution-is associated with vascular injury (VI). We used proteomics to systematically characterize the presently unclear molecular mechanism of VI and to identify new related targets or signaling pathways after exposure to CRA. Cell survival assays were used to assess DNA damage, whereas oxidative stress was determined using colorimetric assays and by quantitative fluorescence study; additionally, cyclooxygenase-2, mitogen-activated protein kinase pathways, Wnt3a, ß-catenin, phospho-ErbB2, and phospho-ErbB4 were assessed using ELISA. Proteins were quantitated via tandem mass tag-based liquid chromatography-mass spectrometry and bioinformatics analyses, and 34 differentially expressed proteins were confirmed using parallel reaction monitoring, which were defined as new indicators related to the mechanism underlying DNA damage; glutathione perturbation; mitogen-activated protein kinase; and the Wnt and ErbB signaling pathways in VI based on Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein-protein interaction network analyses. Parallel reaction monitoring confirmed significant (p < 0.05) upregulation (> 1.5-fold change) of 23 proteins and downregulation (< 0.667-fold change) of 11. The mechanisms of DNA interstrand crosslinks; glutathione perturbation; mitogen-activated protein kinase; cyclooxygenase-2; and the Wnt and ErbB signaling pathways may contribute to VI through their roles in DNA damage, oxidative stress, inflammation, vascular dysfunction, endothelial dysfunction, vascular remodeling, coagulation cascade, and the newly determined signaling pathways. Moreover, the Wnt and ErbB signaling pathways were identified as new disease pathways involved in VI. Taken together, the elucidated underlying mechanisms may help broaden existing understanding of the molecular mechanisms of VI induced by CRA.

The Role of ERBB Signaling Pathway-Related Genes in Kidney Renal Clear Cell Carcinoma and Establishing a Prognostic Risk Assessment Model for Patients.

Objective: We aimed to investigate the potential role of ERBB signaling pathway-related genes in kidney renal clear cell carcinoma (KIRC) and establish a new predictive risk model using various bioinformatics methods. Methods: We downloaded the KIRC dataset and clinicopathological information from The Cancer Genome Atlas database. Univariate Cox analysis was used to identify essential genes significantly associated with KIRC progression. Next, we used the STRING website to construct a protein-protein interaction network of ERBB signaling pathway-related molecules. We then used the least the absolute shrinkage and selection operator (LASSO) regression analysis to build a predictive risk model for KIRC patients. Next, we used multiple bioinformatics methods to analyze the copy number variation, single-nucleotide variation, and overall survival of these risk model genes in pan-cancer. At last, we used the Genomics of Drug Sensitivity in Cancer to investigate the correlation between the mRNA expression of genes associated with this risk model gene and drug sensitivity. Results: Through the LASSO regression analysis, we constructed a novel KIRC prognosis-related risk model using 12 genes: SHC1, GAB1, SOS2, SRC, AKT3, EREG, EIF4EBP1, ERBB3, MAPK3, transforming growth factor-alpha, CDKN1A, and PIK3CD. Based on this risk model, the overall survival rate of KIRC patients in the low-risk group was significantly higher than that in the high-risk group (p = 1.221 × 10-15). Furthermore, this risk model was associated with cancer metastasis, tumor size, node, stage, grade, sex, and fustat in KIRC patients. The receiver operating characteristic curve results showed that the model had better prediction accuracy. Multivariate Cox regression analysis showed that the model's risk score was an independent risk factor for KIRC. The Human Protein Atlas database was used to validate the protein expression of risk model-associated molecules in tumors and adjacent normal tissues. The validation results were consistent with our previous findings. Conclusions: We successfully established a prognostic-related risk model for KIRC, which will provide clinicians with a helpful reference for future disease diagnosis and treatment.

ErbB Signaling Pathway Genes Are Differentially Expressed in Monozygotic Twins Discordant for Sports-Related Concussion.

Transcriptional changes involved in neuronal recovery after sports-related concussion (SRC) may be obscured by inter-individual variation in mRNA expression and nonspecific changes related to physical exertion. Using a co-twin study, the objective of this study was to identify important differences in mRNA expression among a single pair of monozygotic (MZ) twins discordant for concussion. A pair of MZ twins were enrolled as part of a larger study of concussion biomarkers among collegiate athletes. During the study, Twin A sustained SRC, allowing comparison of mRNA expression to the nonconcussed Twin B. Twin A clinically recovered by Day 7. mRNA expression was measured pre-injury and at 6 h and 7 days postinjury using Affymetrix HG-U133 Plus 2.0 microarray. Changes in mRNA expression from pre-injury to each postinjury time point were compared between the twins; differences >1.5-fold were considered important. Kyoto Encyclopedia of Genes and Genomes identified biologic networks associated with important transcripts. Among 38,000 analyzed genes, important changes were identified in 153 genes. The ErbB (epidermal growth factor receptor) signaling pathway was identified as the top transcriptional network from pre-injury to 7 days postinjury. Genes in this pathway with important transcriptional changes included epidermal growth factor (2.41), epiregulin (1.73), neuregulin 1 (1.54) and mechanistic target of rapamycin (1.51). In conclusion, the ErbB signaling pathway was identified as a potential regulator of clinical recovery in a MZ twin pair discordant for SRC. A co-twin study design may be a useful method for identifying important gene pathways associated with concussion recovery.

Disentangling ERBB Signaling in Breast Cancer Subtypes-A Model-Based Analysis.

Targeted therapies have shown striking success in the treatment of cancer over the last years. However, their specific effects on an individual tumor appear to be varying and difficult to predict. Using an integrative modeling approach that combines mechanistic and regression modeling, we gained insights into the response mechanisms of breast cancer cells due to different ligand-drug combinations. The multi-pathway model, capturing ERBB receptor signaling as well as downstream MAPK and PI3K pathways was calibrated on time-resolved data of the luminal breast cancer cell lines MCF7 and T47D across an array of four ligands and five drugs. The same model was then successfully applied to triple negative and HER2-positive breast cancer cell lines, requiring adjustments mostly for the respective receptor compositions within these cell lines. The additional relevance of cell-line-specific mutations in the MAPK and PI3K pathway components was identified via L1 regularization, where the impact of these mutations on pathway activation was uncovered. Finally, we predicted and experimentally validated the proliferation response of cells to drug co-treatments. We developed a unified mathematical model that can describe the ERBB receptor and downstream signaling in response to therapeutic drugs targeting this clinically relevant signaling network in cell line that represent three major subtypes of breast cancer. Our data and model suggest that alterations in this network could render anti-HER therapies relevant beyond the HER2-positive subtype.

EGFR Signaling in Lung Fibrosis.

In this review article, we will first provide a brief overview of the ErbB receptor-ligand system and its importance in developmental and physiological processes. We will then review the literature regarding the role of ErbB receptors and their ligands in the maladaptive remodeling of lung tissue, with special emphasis on idiopathic pulmonary fibrosis (IPF). Here we will focus on the pathways and cellular processes contributing to epithelial-mesenchymal miscommunication seen in this pathology. We will also provide an overview of the in vivo studies addressing the efficacy of different ErbB signaling inhibitors in experimental models of lung injury and highlight how such studies may contribute to our understanding of ErbB biology in the lung. Finally, we will discuss what we learned from clinical applications of the ErbB1 signaling inhibitors in cancer in order to advance clinical trials in IPF.

The significance of the neuregulin-1/ErbB signaling pathway and its effect on Sox10 expression in the development of terminally differentiated Schwann cells in vitro.

PURPOSE: The purpose of this study was to explore the significance of the neuregulin-1/ErbB signaling pathway and its effect on Sox10 expression in the course of the differentiation of mouse bone marrow mesenchymal stem cells into Schwann-like cells in vitro. MATERIALS AND METHODS: The experiment was conducted with three groups-control, TAK 165, and HRG-off. In the control group, we used the classical induction method of adding ß-ME, RA, FSK, b-FGF, PDGF, and neuregulin (HRG); the cells were collected on the 7th day. Using the same basic protocol as the control group, the specific ErbB2 inhibitor mubritinib (TAK 165) was added to block the neuregulin-1/ErbB pathway in the TAK 165 group, while HRG was not added in the HRG-off group. We detected the degree of differentiation of stem cells into Schwann-like cells by using RT-PCR to examine the expression of Sox10, NRG-1, ErbB2, ErbB3, and ErbB4 and by using immunofluorescence staining to examine the Schwann cell marker S100B, Glial Fibrillary Acidic Protein (GFAP) and P75. RESULTS: Our results showed that the proliferation of Schwann cells was reduced and apoptosis was increased in the TAK 165 group and the HRG-off group. Sox10 was stably expressed and NRG-1, ErbB2, and ErbB3 increased in the control group. However, the expression of Sox10 in the TAK 165 group was obviously decreased at the end of induced differentiation; meanwhile, the degree of stem cell differentiation also decreased. CONCLUSIONS: the neuregulin-1/ErbB signaling pathway plays an important role in the differentiation of bone marrow mesenchymal stem cells into Schwann-like cells and can promote the maintenance of Sox10 。.

Sustained ErbB Activation Causes Demyelination and Hypomyelination by Driving Necroptosis of Mature Oligodendrocytes and Apoptosis of Oligodendrocyte Precursor Cells.

Oligodendrocytes are vulnerable to genetic and environmental insults and its injury leads to demyelinating diseases. The roles of ErbB receptors in maintaining the CNS myelin integrity are largely unknown. Here, we overactivate ErbB receptors that mediate signaling of either neuregulin (NRG) or epidermal growth factor (EGF) family growth factors and found their synergistic activation caused deleterious outcomes in white matter. Sustained ErbB activation induced by the tetracycline-dependent mouse tool Plp-tTA resulted in demyelination, axonal degeneration, oligodendrocyte precursor cell (OPC) proliferation, astrogliosis, and microgliosis in white matter. Moreover, there was hypermyelination before these inflammatory pathologic events. In contrast, sustained ErbB activation induced by another tetracycline-dependent mouse tool Sox10+/rtTA caused hypomyelination in the corpus callosum and optic nerve, which appeared to be a developmental deficit and did not associate with OPC regeneration, astrogliosis, or microgliosis. By tracing the differentiation states of cells expressing tetracycline-controlled transcriptional activator (tTA)/reverse tTA (rtTA)-dependent transgene or pulse-labeled reporter proteins in vitro and in vivo, we found that Plp-tTA targeted mainly mature oligodendrocytes (MOs), whereas Sox10+/rtTA targeted OPCs and newly-formed oligodendrocytes (NFOs). The distinct phenotypes of mice with ErbB overactivation induced by Plp-tTA and Sox10+/rtTA consolidated their nonoverlapping targeting preferences in the oligodendrocyte lineage, and enabled us to demonstrate that ErbB overactivation in MOs induced necroptosis that caused inflammatory demyelination, whereas in OPCs induced apoptosis that caused noninflammatory hypomyelination. Early interference with aberrant ErbB activation ceased oligodendrocyte deaths and restored myelin development in both mice. This study suggests that aberrant ErbB activation is an upstream pathogenetic mechanism of demyelinating diseases, providing a potential therapeutic target.SIGNIFICANCE STATEMENT Primary oligodendropathy is one of the etiologic mechanisms for multiple sclerosis, and oligodendrocyte necroptosis is a pathologic hallmark in the disease. Moreover, the demyelinating disease is now a broad concept that embraces schizophrenia, in which white matter lesions are an emerging feature. ErbB overactivation has been implicated in schizophrenia by genetic analysis and postmortem studies. This study suggests the etiologic implications of ErbB overactivation in myelin pathogenesis and elucidates the pathogenetic mechanisms.

Integrated Network Pharmacology Analysis and In Vitro Validation Revealed the Potential Active Components and Underlying Mechanistic Pathways of Herba Patriniae in Colorectal Cancer.

Herba Patriniae (HP) are medicinal plants commonly used in colorectal cancer (CRC) patients. In this study, network pharmacology was used to predict the active components and key signaling pathways of HP in CRC. Patrinia heterophylla, one type of HP, was chosen for validation of the network pharmacology analysis. The phytochemical profile of Patrinia heterophylla water extract (PHW) was determined by UHPLC-MS. MTT, RT-PCR, and Western blot assays were performed to evaluate the bioactivities of PHW in colon cancer cells. Results showed that 15 potentially active components of HP interacted with 28 putative targets of CRC in the compound-target network, of which asperglaucide had the highest degree. Furthermore, the ErbB signaling pathway was identified as the pathway mediated by HP with the most potential against CRC. Both RT-PCR and Western blot results showed that PHW significantly downregulated the mRNA and protein levels of EGFR, PI3K, and AKT in HCT116 cells. Asperglaucide, present in PHW, exhibited an anti-migratory effect in HCT116 cells, suggesting that it could be an active component of PHW in CRC treatment. In conclusion, this study has provided the first scientific evidence to support the use of PHW in CRC and paved the way for further research into the underlying mechanisms of PHW against CRC.

Long noncoding RNA HOXC-AS3 enhances the progression of cervical cancer via activating ErbB signaling pathway.

Emerging evidence reveals that long noncoding RNAs (lncRNAs) contribute to human tumorigenesis. Nevertheless, the function of HOXC cluster antisense RNA 3 (HOXC-AS3) in human cervical cancer (CC) remains largely unknown. The levels of HOXC-AS3, miR-105-5p and SOS1 in CC tissues and cells were monitored by reverse transcription-polymerase chain reaction (RT-PCR) and western blot (WB). Gain- and loss-of-function experiments were conducted to verify the function of HOXC-AS3 and miR-105-5p in CC cells. Meanwhile, cell proliferation, apoptosis, migration and invasion were examined by the cell counting kit-8 (CCK8) experiment, colony formation assay, flow cytometry and Transwell assay. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were carried out to test the regulatory interaction of HOXC-AS3, miR-105-5p and SOS1. In addition, in vivo experiment was performed to certain the role of HOXC-AS3 in tumorigenesis of CC. HOXC-AS3 was overexpressed in CC tissues (vs. adjacent normal tissues) and CC cells. Besides, the higher HOXC-AS3 profile was associated with the poorer clinical prognosis of CC patients. Overexpression of HOXC-AS3 promoted cell growth, migration and invasion, hampered apoptosis, whereas knocking down HOXC-AS3 exhibited the reverse effects. MiR-105-5p was a downstream target of HOXC-AS3, and it mediated the HOXC-AS3-induced oncogenic effects. Mechanistically, the bioinformatic analysis illustrated that SOS1 was targeted by miR-105-5p. Up-regulating SOS1 heightened the growth, migration and invasion of CC cells by enhancing the ErbB signaling pathway, which was reversed by miR-105-5p. Up-regulated HOXC-AS3 aggravates CC by promoting SOS1 expression via targeting miR-105-5p.

Effect of regulation of the NRG1/ErbB4 signaling pathway on the visual cortex synaptic plasticity of amblyopic adult rats.

This study aimed to investigate the effect of the neuregulin-1/epidermal growth factor 4 (NRG1/ErbB4) signaling pathway on visual cortex synaptic plasticity in adult amblyopic rats with monocular deprivation (MD). Compared with the control group, the P wave latency and amplitude of the MD group were prolonged and low, respectively, with reduced synaptic plasticity-related protein expression, lower number of visual cortex neurons, and increased apoptosis of visual cortex neurons. Recombinant neuregulin-1 (rNRG1) administration activated the NRG1/ErbB4 signaling pathway and improved the visual cortex synaptic plasticity in MD amblyopic rats. However, the effects of rNRG1 were reversed by AG1478 (ErbB4 receptor blockers). The NRG1/ErbB4 signaling pathway in the parvalbumin neurons from MD rats was also inactivated. Amblyopic rats had significantly low cell activity and downregulated expression of synaptic plasticity-related proteins. Thus, exogenous administration of NRG1 can activate ErbB4 signal transduction and improve the damaged synaptic plasticity of the visual cortex among amblyopic rats. Further studies are warranted to explore the potential for clinical management of amblyopia.

Extreme Glycemic Fluctuations Debilitate NRG1, ErbB Receptors and Olig1 Function: Association with Regeneration, Cognition and Mood Alterations During Diabetes.

Neuronal regeneration is crucial for maintaining intact neural interactions for perpetuation of cognitive and emotional functioning. The NRG1-ErbB receptor signaling is a key pathway for regeneration in adult brain and also associated with learning and mood stabilization by modulating synaptic transmission. Extreme glycemic stress is known to affect NRG1-ErbB-mediated regeneration in brain; yet, it remains unclear how the ErbB receptor subtypes are differentially affected due to such metabolic variations. Here, we assessed the alterations in NRG1, ErbB receptor subtypes to study the regenerative potential, both in rodents as well as in neuronal and glial cell models of hyperglycemia and hypoglycemic insults during hyperglycemia. The pro-oxidant and anti-oxidant status leading to degenerative changes in brain regions were determined. The spatial memory and anxiogenic behaviour of experimental rodents were tested using 'T' maze and Elevated Plus Maze. Our data revealed that the extreme glycemic discrepancies during diabetes and recurrent hypoglycemia lead to altered expression of NRG1, ErbB receptor subtypes, Syntaxin1 and Olig1 that shows association with impaired regeneration, synaptic dysfunction, demyelination, cognitive deficits and anxiety.

RNA binding protein CUGBP1 mediates the liver metastasis of colorectal cancer by regulating the ErbB signal pathway.

BACKGROUND: The CUGBP1 (CELF1) is differentially expressed in liver metastasis and no liver metastasis colorectal cancers (CRC) tissues and the function of CUGBP1 in CRC is still unclear. METHODS: Five cases of colorectal adenocarcinoma and 6 cases of liver metastatic CRC lesions were collected and subjected to cDNA microarray and bioinformatical analyses. The quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to confirm the result. Cell function assays were used to study the function of CUGBP1, and the western blot was used to discover the change of the downstream molecules. RESULTS: CUGBP1 was significantly elevated in liver metastatic CRC lesions. Besides, the CUGBP1 can promote proliferation, colony formation, invasion, metastasis abilities as well as increase the apoptosis rates of CRC cells. ERBB2 was positively related to the CUGBP1. Western blot results found that silence of CUGBP1 decreased the protein level of p-AKT and p-ERK without influence the expression level of total protein of AKT and ERK. CONCLUSIONS: CUGBP1 can promote liver metastasis of CRC by promoting the phosphorylation of AKT and ERK through the ErbB signaling pathway. CUGBP1 is a potential biomarker for early detection of CRC and maybe a novel therapeutic target of CRC treatment, especially in liver metastasis.

Antioxidant Effects and Potential Molecular Mechanism of Action of Limonium aureum Extract Based on Systematic Network Pharmacology.

Oxidative stress is the redox imbalance state of organisms that involves in a variety of biological processes of diseases. Limonium aureum (L.) Hill. is an excellent wild plant resource in northern China, which has potential application value for treating oxidative stress. However, there are few studies that focused on the antioxidant effect and related mechanism of L. aureum. Thus, the present study combining systematic network pharmacology and molecular biology aimed to investigate the antioxidant effects of L. aureum and explore its underlying anti-oxidation mechanisms. First, the antioxidant activity of L. aureum extracts was confirmed by in vitro and intracellular antioxidant assays. Then, a total of 11 bioactive compounds, 102 predicted targets, and 70 antioxidant-related targets were obtained from open source databases. For elucidating the molecular mechanisms of L. aureum, the PPI network and integrated visualization network based on bioinformatics assays were constructed to preliminarily understand the active compounds and related targets. The subsequent enrichment analysis results showed that L. aureum mainly affect the biological processes involving oxidation-reduction process, response to drug, etc., and the interference with these biological processes might be due to the simultaneous influence on multiple signaling pathways, including the HIF-1 and ERBB signaling pathways. Moreover, the mRNA levels of predicted hub genes were measured by qRT-PCR to verify the regulatory effect of L. aureum on them. Collectively, this finding lays a foundation for further elucidating the anti-oxidative damage mechanism of L. aureum and promotes the development of therapeutic drugs for oxidative stress.

Characteristics of genomic mutations and signaling pathway alterations in thymic epithelial tumors.

BACKGROUND: To elucidate the mechanisms of thymic epithelial tumor (TET) canceration by characterizing genomic mutations and signaling pathway alterations. METHODS: Primary tumor and blood samples were collected from 21 patients diagnosed with TETs (thymoma and thymic cancer), 15 of whom were screened by nucleic acid extraction and whole exon sequencing. Bioinformatics was used to comprehensively analyze the sequencing data for these samples, including gene mutation information and the difference of tumor mutation burden (TMB) between thymoma and thymic carcinoma groups. We performed signaling pathway and functional enrichment analysis using the WebGestalt 2017 toolkit. RESULTS: ZNF429 (36%) was the gene with the highest mutation frequency in thymic carcinoma. Mutations in BAP1 (14%), ABI1 (7%), BCL9L (7%), and CHEK2 (7%) were exclusively detected in thymic carcinoma, whereas ZNF721 mutations (14%) and PABPC1 (14%) were found exclusively in thymoma. The mean TMB values for thymic carcinoma and thymoma were 0.722 and 0.663 mutations per megabase (Mb), respectively, and these differences were not statistically significant. The ErbB signaling pathway was enriched in the thymoma and intersection groups, and pathways of central carbon metabolism in cancer, longevity regulating and MAPK signaling were only found in the thymoma group, while pathways in cancer (hsa05200) was found in the thymoma and thymic carcinoma groups. CONCLUSIONS: Multiple differences in somatic genes and pathways have been identified. Our findings provide insights into differences between thymoma and thymic carcinoma that could aid in designing personalized clinical therapeutic strategies.