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Pathogen effector-induced assembly of resistosomes has been established as an important event for nucleotide binding and leucine-rich repeat-containing receptor (NLR) signaling in plants. The pentameric coiled-coil domain-containing NLR (CNL) resistosomes act as Ca2+-permeable channels, whereas the tetrameric Toll-interleukin 1-like receptor (TIR) NLR (TNL) resistosomes are NADase holoenzymes. TNL resistosomes catalyze the production of nucleotide-derived second messengers to activate the downstream helper NLRs activated disease resistance 1 (ADR1) and N requirement gene 1 (NRG1) of the CNL class. Thus, CNLs and TNLs converge on Ca2+ signals to trigger plant immunity. NLR signaling cross-talks with pattern-triggered immunity (PTI) signaling pathways. NLR signaling pathways in plants are negatively regulated by both hosts and pathogens. Nucleotide binding and leucine-rich repeat-containing receptors (NLRs) have a critical role in plant immunity through direct or indirect recognition of pathogen effectors. Recent studies have demonstrated that such recognition induces formation of large protein complexes called resistosomes to mediate NLR immune signaling. Some NLR resistosomes activate Ca2+ influx by acting as Ca2+-permeable channels, whereas others function as active NADases to catalyze the production of nucleotide-derived second messengers. In this review we summarize these studies on pathogen effector-induced assembly of NLR resistosomes and resistosome-mediated production of the second messengers of Ca2+ and nucleotide derivatives. We also discuss downstream events and regulation of resistosome signaling. [ABSTRACT FROM AUTHOR]

Oocyte in vitro maturation (IVM) is still a major challenge in human and animal assisted reproduction. Gradual instead of abrupt activation of the ovulatory cascade during IVM has been proposed to enhance nuclear-cytoplasmic synchrony and cumulus -oocyte communication, thus favoring oocyte developmental competence. Herein, we assessed the effects of neuregulin 1 (NRG1), an EGF- like factor that modulates EGFR signaling, on oocyte nuclear maturation dynamics, cumulus expansion and expression of mRNAs regulating these processes during IVM, as well as on post-IVF embryo development following AREG-stimulated IVM in cattle. In experiment 1, cumulus -oocyte complexes (COCs) were subjected to IVM with graded doses of NRG1 (1, 10 or 100 ng/mL) for 6, 9, 12, 20, and 24 h, after which oocyte nuclear status and cumulus mRNA expression were assessed. At 6 h of IVM, NRG1 at 1 ng/mL significantly decreased the percentage of GVBD (germinal vesicle breakdown) oocytes without altering later meiotic dynamics or the percentage of oocytes achieving meiosis II. In experiment 2, adding NRG1 (1 ng/mL) to the IVM medium did not affect cumulus expansion but increased the percentage of expanded and hatched blastocysts, and blastocyst total cell number following IVF/IVC. NRG1 decreased EGFR mRNA abundance while increasing NPR2 and PTX3 mRNA levels at 9 h, and TNFAIP6 mRNA abundance at 20 h of IVM. This is the first study that reports the modulatory effect of NGR1 during oocyte maturation in a mono-ovulatory species and demonstrates that this action may be applied during IVM to improve post-IVF embryo development. • NRG1 regulates the ovulatory cascade, particularly nuclear maturation dynamics, in cattle. • NRG1 supplementation during IVM improves post-IVF embryo development in cattle. [ABSTRACT FROM AUTHOR]

Neuregulin 1 (NRG1) is a risk gene for schizophrenia and involved in neurodevelopment and synaptic plasticity. Polymorphisms in NRG1 may affect psychotic symptoms in schizophrenia. This study investigated the effects of the single nucleotide polymorphism (SNP) rs6982890 on peripheral plasma NRG1 immunoreactivity, clinical symptoms and cognitive functions in schizophrenia patients. We recruited subjects from the Han population of northern China from 2010 to 2022. We first genotyped and analyzed 6 NRG1 SNPS in 1304 patients with schizophrenia and 871 healthy controls. Then, 91 patients with schizophrenia and 40 healthy controls were selected to detect the peripheral plasma NRG1 immunoreactivity by ELISA. Among them, 84 patients were divided into rs6982890 genotypes to analyze the correlation between NRG1 immunoreactivity and clinical symptoms. Rs6982890 allelic frequencies were statistically significant between patients and controls. Baseline peripheral plasma NRG1 immunoreactivity in patients were significantly lower than controls. NRG1 immunoreactivity in patients were significantly increased after 8 weeks of antipsychotic treatment and significantly correlated with clinical symptoms and cognitive function. Genotyping of patients with SNP rs6982890 indicated NRG1 immunoreactivity in CC genotype increased significantly after treatment, while CT genotype had no significant change. Baseline NRG1 immunoreactivity with the CT genotype were significantly higher than CC genotype. NRG1 SNP rs6982890 is significantly associated with schizophrenia in the Han population of northern China, and it may affect the effect of antipsychotic drug treatment by regulating the peripheral plasma NRG1 immunoreactivity. • To verify the genotype frequency of NRG1 SNP rs6982890 in the northern Han population. • Peripheral plasma NRG1 immunoreactivity was measured by Elisa in healthy controls and schizophrenia. • Different genotypes of NRG1 SNP rs6982890 have an effect on the expression of NRG1. • NRG1 expression was significantly correlated with psychiatric symptoms. [ABSTRACT FROM AUTHOR]

Given acquired resistance patterns to androgen deprivation therapy and second-generation androgen receptor (AR) inhibitors, it is crucial to identify and target the mechanisms by which prostate cancer cells persist despite AR inhibition. Previous work has shown that the upregulation and secretion of stromal-derived growth factor neuregulin 1 (NRG1) activates PI3K-AKT signaling through its binding to the HER2/HER3 receptor and promotes prostate cancer cell growth during antiandrogen treatment. Here, we determine the clinical context where this tumor microenvironment derived NRG1 impacts response to AR inhibition. Additionally, we show that selective inhibition of NRG1 mediated activation of HER2/HER3 signaling with a clinical grade bispecific humanized immunoglobulin G1, zenocutuzumab (Zeno, MCLA-128), in both in vitro and in vivo models can overcome resistance to AR-targeted therapies. We used purified epithelial (22Pc-EP) and fibroblast (22Pc-CAF) cell lines derived the patient-derived xenograft model (CWR22Pc), which is initially castration sensitive but can progress to castration resistant. The 22Pc-EP line is endogenous PTEN wild-type (22Pc-EPWT) and PTEN knock-out cells (22Pc-EPPTEN) were generated using CRISPR-Cas9. Cells were stimulated;with either recombinant NRG1 or conditioned media derived from the 22Pc-CAFs. Lysates were collected and prepared for western blot analysis to assess for activation of downstream signaling cascades, both with and without zenocutuzumab and enzalutamide treatment. Growth assays were also performed under similar conditions. 22Pc-EPWT and 22Pc-EPPTEN; cells were co-injected subcutaneously (10:1 ratio) in the;flanks of castrated male mice then treated with either;vehicle control, castration + enzalutamide (30mg/kg/day), or enzalutmide + zenocutuzumab (25mg/kg intraperitoneal injection weekly) once tumors were established. Tumor volume was measured bi-weekly and surviving mice were sacrificed after 7 weeks of therapy. Stimulation with recombinant NRG1 was able to activate downstream PI3K signaling in the 22Pc-EP cell lines, and this signal was more robust and sustained over time in the setting of PTEN loss. 22Pc-EPWT cells were responsive to enzalutamide and cell growth was decreased upon treatment, though this was overcome by stimulation with NRG. Treatment with zenocutuzumab restored the enzalutamide sensitive phenotype. 22Pc-EPPTEN cells were also sensitive to enzalutamide, but NRG1 stimulation paradoxically decreased cell growth and no response to zenocutuzumab was observed (Fig 1). Additionally, culturing cells with the 22Pc-CAF conditioned media conferred analogous results to recombinant NRG1 stimulation. In our in vivo experiment, enzalutamide significantly decreased tumor growth in both the PTEN wild-type and knock-out setting. However, only PTEN wild-type tumors were responsive to zenocutuzumab (Fig 2). Here, we show that NRG1 promotes prostate cancer cell survival and resistance to AR inhibition in PTEN wild-type prostate cancer cells. Activation of downstream PI3K-AKT signaling in a prostate cancer epithelial cell line was seen after both recombinant NRG1 stimulation and culturing with cancer associated fibroblast conditioned media. This supports a paracrine mediated action of NRG1 whereby it is secreted by stromal cells in the tumor microenvironment to promote resistance through PI3K signaling. Using zenocutuzumab, a novel clinical grade inhibitor of the NRG1-HER2/3 interaction, we were able to restore an androgen sensitive phenotype in both in vitro and in vivo models in the PTEN wild-type setting. High-risk PTEN wild-type prostate cancers may therefore be an appropriate population for future clinical studies. [ABSTRACT FROM AUTHOR]

Schematic diagram showing NRG1 inhibit senescence by upregulating YAP. Dox induces cellular senescence through oxidative stress. NRG1 inhibited the phosphorylation of LATS1 and MST1, the core kinases of the Hippo pathway, thereby inhibiting YAP phosphorylation and degradation. This promoted the nuclear translocation of YAP, inhibiting senescence and attenuating Dox-induced cardiotoxicity. [Display omitted] • Dox-induced myocardial senescence is a pathological mechanism of its cardiotoxicity. • High expression of YAP inhibits Dox-induced cellular senescence. • NRG1 reduces Dox-induced cardiotoxicity by upregulating YAP to inhibit senescence. • The regulations of NRG1/Hippo/YAP reduce DOX-induced cardiotoxicity. The cardiotoxicity of Doxorubicin (Dox) limits its clinical application, creating an urgent need to investigate its underlying mechanism and develop effective therapies. Senescence plays an important role in Dox-induced cardiotoxicity (DIC). Recently, Neuregulin-1 (NRG1) was found to regulate Yes-associated protein (YAP), which was reported to inhibit senescence, suggesting that NRG1 might be used to treat DIC by inhibiting senescence through YAP regulation. We examined the changes and regulatory roles of YAP and senescence in Dox cardiotoxicity and whether NRG1 could reduce DIC in chronic DIC mice and Dox-treated H9c2 cells. Our study revealed that sustained small doses of Dox impaired cardiac function and H9c2 cell viability, induced myocardial senescence, and inhibited YAP expression. Conversely, high levels of YAP inhibited Dox-induced senescence in H9c2 cells, indicating that Dox promotes myocardial senescence by inhibiting YAP. In addition, we found that exogenous NRG1 inhibited the phosphorylation of LATS1 and MST1, thereby inhibiting YAP phosphorylation and promote the nuclear translocation of YAP, inhibiting senescence and attenuating Dox-induced cardiotoxicity. YAP knockdown or inhibition of YAP binding to TEA domain transcription factor protein （TEAD）blocks the protective effects of NRG1. In conclusion, our study suggests that Dox-induced myocardial senescence through YAP inhibition is one of the pathological mechanisms of its cardiotoxicity. Additionally, NRG1 reduces DIC by upregulating YAP to inhibit senescence. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 (HER2) is a key player in the pathogenesis and progression of breast cancer and is currently a primary target for breast cancer immunotherapy. Bioactivity determination is necessary to guarantee the safety and efficacy of therapeutic antibodies targeting HER2. Nevertheless, currently available bioassays for measuring the bioactivity of anti-HER2 mAbs are either not representative or have high variability. Here, we established a reliable reporter gene assay (RGA) based on T47D-SRE-Luc cell line that expresses endogenous HER2 and luciferase controlled by serum response element (SRE) to measure the bioactivity of anti-HER2 antibodies. Neuregulin-1 (NRG-1) can lead to the heterodimerization of HER2 on the cell membrane and induce the expression of downstream SRE-controlled luciferase, while pertuzumab can dose-dependently reverse the reaction, resulting in a good dose-response curve reflecting the activity of the antibody. After optimizing the relevant assay parameters, the established RGA was fully validated based on ICH-Q2 (R1), which demonstrated that the method had excellent specificity, accuracy, precision, linearity, and stability. In summary, this robust and innovative bioactivity determination assay can be applied in the development and screening, release control, biosimilar assessment and stability studies of anti-HER2 mAbs. • A robust RGA for anti-HER2 mAbs was firstly developed, optimized, and validated. • The RGA shows excellent precision, specificity, accuracy, linearity, and stability. • The RGA was suitable for the bioactivity determination of different anti-HER2 mAbs. • The RGA was MOA-reflective and may be suitable for the anti-HER2 ADCs. [ABSTRACT FROM AUTHOR]

The core clinical characteristics of autism, which is a neurodevelopmental disease, involve repetitive behavior and impaired social interactions. Studies have shown that the Notch and Neuregulin1 (NRG1) signaling pathways are abnormally activated in autism, but the mechanism by which these two signaling pathways interact to contribute to the progression of autism has not been determined. Our results suggest that the levels of Notch1, Hes1, NRG1, and phosphorylated ErbB4 in the cerebellum (CB), hippocampus (HC), and prefrontal cortex (PFC) were increased in rats with valproic acid (VPA)-induced autism compared to those in the Con group. However, 3, 5-difluorophenyl-L-alanyl-L-2-phenylglycine tert-butyl (DAPT), which is a Notch pathway inhibitor, ameliorated autism-like behavioral abnormalities and decreased the protein levels of NRG1 and phosphorylated ErbB4 in rats with VPA-induced autism; these results demonstrated that the Notch1/Hes1 pathway could participate in the pathogenesis of autism by regulating the NRG1/ErbB4 signaling pathway. Studies have shown that the Notch pathway regulates microglial differentiation and activation during the onset of neurological disorders and that microglia affect autism-like behavior via synaptic pruning. Therefore, we hypothesized that the Notch1/Hes1 pathway could regulate the NRG1/ErbB4 pathway and thus participate in the development of autism by regulating microglial functions. The present study showed that AG1478, which is an ErbB4 inhibitor, ameliorated the autism-like behaviors in a VPA-induced autism rat model, reduced abnormal microglial activation, and decreased NRG1 and Iba-1 colocalization; however, AG1478 did not alter Notch1/Hes1 activity. These results demonstrated that Notch1/Hes1 may participate in the microglial activation in autism by regulating NRG1/ErbB4, revealing a new mechanism underlying the pathogenesis of autism. • Notch1/Hes1 regulates NRG1/ErbB4 pathway in development of autism. • Notch1/Hes1 participates in microglial activation in VPA-induced autism rats. • NRG1/ErbB4 participates in microglial activation in a VPA-induced autism model. • Notch1/Hes1 participates in microglial activation in autism via NRG1/ErbB4. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is an emerging chronic liver disease. However, the underlying mechanisms remained poorly understood. Neuregulin (NRG) family participate in energy metabolism, and might be related to NAFLD. L02 cells were exposed to oleic acid to establish a cellular model of NAFLD. We analyzed the NAFLD cells with NRG1 and subsequent ErbB3 siRNA treatment. Cellular total lipid was stained by Oil Red O, while triglyceride content and inflammation markers were measured by enzymatic kits. The expressions of down-stream molecules were evaluated by western blot. In vitro, NRG1 could alleviate the steatosis of NAFLD, and inhibit the expression of IL-6 and TNF-α. The downregulation of ErbB3 aggravated steatosis, improved the levels of triglyceride, IL-6 and TNF-α in NRG1-treated NAFLD. Moreover, NRG1 treatment up-regulated ErbB3 phosphorylation, and increased the expression of PI3K and phosphorylation-AKT. When NRG1-treated NAFLD cells were transfected with ErbB3 siRNA, the expressions of ErbB3, p-ErbB3, p-AKT and PI3K were all reduced. NRG1 might play a protective role in the pathogenesis of NAFLD through ErbB3 phosphorylation to modulate the activation of PI3K-AKT pathway. The findings will expand the understanding of the mechanisms of NAFLD, and provide potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Meningiomas (MNs), arising from the arachnoid/meningeal layer, are nonresponsive to chemotherapies, with ~50% showing loss of the Neurofibromatosis 2 (NF2) tumor suppressor gene. Previously, we established NF2 loss activates mechanistic target of rapamycin complex 1 (mTORC1) and mechanistic target of rapamycin complex 2 (mTORC2) signaling, leading to clinical trials for NF2 and MN. Recently our omics studies identified activated ephrin (EPH) receptor and Src family kinases upon NF2 loss. Here, we report increased expression of several ligands in NF2-null human arachnoidal cells (ACs) and the MN cell line Ben-Men-1, particularly neuregulin-1/heregulin (NRG1), and confirm increased NRG1 secretion and activation of V-ERB-B avian erythroblastic leukemia viral oncogene homolog 3 (ERBB3) receptor kinase. Conditioned-medium from NF2-null ACs or exogenous NRG1 stimulated ERBB3, EPHA2, and mTORC1/2 signaling, suggesting pathway crosstalk. NF2-null cells treated with an ERBB3-neutralizing antibody partially downregulated mTOR pathway activation but showed no effect on viability. mTORC1/2 inhibitor treatment decreased NRG1 expression and downregulated ERBB3 while re-activating pAkt T308, suggesting a mechanism independent of NRG1-ERBB3 but likely involving activation of another upstream receptor kinase. Transcriptomics after mTORC1/2 inhibition confirmed decreased ERBB3/ERBB4 while revealing increased expression of insulin-like growth factor receptor 1 (IGF1R). Drug treatment co-targeting mTORC1/2 and IGF1R/insulin receptor attenuated pAkt T308 and showed synergistic effects on viability. Our findings indicate potential autocrine signaling where NF2 loss leads to secretion/activation of NRG1-ERBB3 signaling. mTORC1/2 inhibition downregulates NRG1-ERBB3, while upregulating pAkt T308 through an adaptive response involving IGF1R/insulin receptor and co-targeting these pathways may prove effective for treatment of NF2-deficient MN. [ABSTRACT FROM AUTHOR]

Oncogenic gene fusions are hybrid genes that result from structural DNA rearrangements, leading to deregulated activity. Fusions involving the neuregulin-1 gene (NRG1) result in ErbB-mediated pathway activation and therefore present a rational candidate for targeted treatment. The most frequently reported NRG1 fusion is CD74-NRG1 , which most commonly occurs in patients with invasive mucinous adenocarcinomas (IMAs) of the lung, although several other NRG1 fusion partners have been identified in patients with lung cancer, including ATP1B1 , SDC4 , and RBPMS. NRG1 fusions are also present in patients with other solid tumors, such as pancreatic ductal adenocarcinoma. In general, NRG1 fusions are rare across different types of cancer, with a reported incidence of <1%, with the notable exception of IMA, which represents ≈2%–10% of lung adenocarcinomas and has a reported incidence of ≈10%–30% for NRG1 fusions. A substantial proportion (≈20%) of NRG1 fusion-positive non-small-cell lung cancer cases are nonmucinous adenocarcinomas. ErbB-targeted treatments, such as afatinib, a pan-ErbB tyrosine kinase inhibitor, are potential therapeutic strategies to address unmet treatment needs in patients harboring NRG1 fusions. • NRG1 fusions result in ErbB-mediated pathway activation and present a rational therapeutic target. • ErbB-targeted treatments, such as afatinib, can be effective therapeutic options in tumors harboring NRG1 fusions. • The incidence of NRG1 fusion-driven tumors is low, occurring in <1% of cancers, but is highest (≈10-30%) in invasive mucinous adenocarcinoma. [ABSTRACT FROM AUTHOR]

• Afatinib has demonstrated activity in patients with NRG1 fusion-positive tumors. • Real-world outcomes with/without afatinib were investigated in this patient population. • Most patients received afatinib in second-line, and when ECOG PS was 2–4. • Outcomes were favorable in both the afatinib and non-afatinib treatment groups. • Prospective clinical trials are needed in patients with NRG1 fusion-driven tumors. Neuregulin-1 (NRG1) fusions may drive oncogenesis via constitutive activation of ErbB signaling. Hence, NRG1 fusion-driven tumors may be susceptible to ErbB-targeted therapy. Afatinib (irreversible pan-ErbB inhibitor) has demonstrated activity in individual patients with NRG1 fusion-positive solid tumors. This study collected real-world data on demographics, clinical characteristics, and clinical outcomes in this patient population. In this retrospective, multicenter, non-comparative cohort study, physicians in the US-based Cardinal Health Oncology Provider Extended Network collected data from medical records of patients with NRG1 fusion-positive solid tumors who received afatinib (afatinib cohort) or other systemic therapies (non-afatinib cohort) in any therapy line. Objectives included demographics, clinical characteristics, and outcomes (overall response rate [ORR], progression-free survival [PFS], and overall survival [OS]). Patients (N = 110) with a variety of solid tumor types were included; 72 received afatinib, 38 other therapies. In the afatinib cohort, 70.8 % of patients received afatinib as second-line treatment and Eastern Cooperative Oncology Group performance status (ECOG PS) was 2–4 in 69.4 % at baseline. In the non-afatinib cohort, 94.7 % of patients received systemic therapy as first-line treatment and ECOG PS was 2–4 in 31.6 % at baseline. In the afatinib cohort, ORR was 37.5 % overall (43.8 % when received as first-line therapy); median PFS and OS were 5.5 and 7.2 months, respectively. In the non-afatinib cohort, ORR was 76.3 %; median PFS and OS were 12.9 and 22.6 months, respectively. This study provides real-world data on the characteristics of patients with NRG1 fusion-positive solid tumors treated with afatinib or other therapies; durable responses were observed in both groups. However, there were imbalances between the cohorts, and the study was not designed to compare outcomes. Further prospective/retrospective trials are required. [ABSTRACT FROM AUTHOR]

This study found NRG1 upregulation in esophageal cancer due to gene amplification, promoting tumor growth and metastasis. Afatinib inhibits NRG1-overexpressed ESCC effectively. [Display omitted] Esophageal squamous cell carcinoma (ESCC) is a highly aggressive tumor with significant heterogeneity in incidence and outcomes. The role of Neuregulin 1 (NRG1) in ESCC and its contribution to aggressiveness remain unknown. This study aims to investigate the functions and molecular mechanisms of NRG1 in ESCC as well as the treatment strategy for ESCC with overexpression of NRG1. We firstly demonstrated the upregulation of NRG1 and a negative correlation trend between patients' overall survival (OS) and the expression level of NRG1 in esophageal cancer. And then we found NRG1 promoted cell proliferation, migration, inhibited apoptosis, and accelerated tumorigenesis and metastasis in ESCC using cell lines and xenograft models. Furthermore, we discovered that NRG1 activated the NF-κB/MMP9 signaling pathway, contributing to the metastatic phenotype in ESCC. Finally, we show that afatinib (FDA approved cancer growth blocker) could inhibit ESCC with overexpressed NRG1 and down-regulation of NRG1 along with afatinib treatment provides higher efficient strategy. This study uncovers the critical role and molecular mechanism of NRG1 in ESCC tumorigenesis and metastasis, suggesting its potential as a novel biomarker for ESCC treatment. [ABSTRACT FROM AUTHOR]

Abstract Neuregulin 1 (NRG1) is a key candidate susceptibility gene for schizophrenia. It is reported that the function of NRG1 can be regulated by cleavage via the β-Secretase (BACE1), particularly during early development. While current knowledge suggested that schizophrenia might have different phenotypes, it is unknown whether BACE1-cleaved-NRG1 (BACE1-NRG1) activity is related to clinical phenotypes of schizophrenia. In the current study, we used a newly developed enzymatic assay to detect BACE1-NRG1 activity in the human plasma and investigated the levels of cleavage of NRG1 by BACE1 in the plasma from schizophrenia patients. Our results are the first to demonstrate that the level of plasma BACE1-NRG1 activity was significantly increased in subjects affected with schizophrenia compared with healthy controls. Interestingly, the elevated BACE1-NRG1 activity was correlated with the disease severity and duration of schizophrenia, such as patients suffering from shorter-term course and worse disease status expressed higher BACE1-NRG1 activity levels compared to whom with longer duration and less severity of the disease. Furthermore, this is also the first report that the alternation of BACE1-NRG1 activity was a substrate –specific event in schizophrenia. Together, our findings suggested that the plasma BACE1-NRG1 activity can be a potential biomarker for the early diagnosis of schizophrenia. Highlights • A novel enzyme-linked immunosorbent assay for plasma BACE1 cleavage NRG1 activity. • Elevated BACE1-NRG1 enzymatic activity in schizophrenia compared with health controls. • Plasma BACE1-NRG1 enzymatic activity associates with disease duration and severity of schizophrenia. • Plasma BACE1-NRG1 enzymatic activity was a substrate- specific event in schizophrenia. [ABSTRACT FROM AUTHOR]

Abstract Aims Enhanced hepatic gluconeogenesis is an important cause of hyperglycemia in type 2 diabetes. However, the regulatory mechanisms underlying disordered hepatic gluconeogenesis remains largely unclear. In the present study, we investigated the potential role of hepatic neuregulin 4 (Nrg4) in the regulation of gluconeogenesis in mice. Main methods Microarray analysis was performed in primary mouse hepatocytes treated with or without 8-Br-cAMP. Primary mouse hepatocytes transfected with Nrg4 overexpressing or shRNA adenovirus were used to detect the expressions of the key gluconeogenic genes and glucose output. Hepatic Nrg4 expression levels were measured in fasted C57/BL6 mice, obese ob / ob mice, diabetic db / db mice and Goto-Kakisaki (GK) rats. Pyruvate tolerance test was performed and gluconeogenic gene expressions were detected 7 days after Nrg4 shRNA adenovirus was injected into male C57BL/6 and db / db mice. Key findings Microarray analysis revealed that Nrg4 expression was significantly induced by 8-Br-cAMP in primary mouse hepatocytes, along with the upregulation of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Adenovirus-mediated overexpression or knockdown of Nrg4 in primary mouse hepatocytes increased or decreased PEPCK and G6Pase expressions as well as hepatic glucose production. Hepatic Nrg4 expression was induced by fasting in normal C57/BL6 mice, and markedly upregulated in obese ob / ob mice, diabetic db / db mice and GK rats. Hepatic Nrg4 knockdown in C57BL/6 and db / db mice improved pyruvate tolerance, with the downregulation of PEPCK, G6Pase, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Significance Hepatic Nrg4 plays a crucial role in the regulation of gluconeogenesis and may be a therapeutic target of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Abstract Little is known about the exact genes that confer vulnerability or resilience to environmental stressors during early neurodevelopment. Partial genetic deletion of neuregulin 1 (Nrg1) moderates the neurobehavioural effects of stressors applied in adolescence and adulthood, however, no study has yet examined its impact on prenatal stress. Here we examined whether Nrg1 deficiency in mice modulated the impact of prenatal stress on various behaviours in adulthood. Male heterozygous Nrg1 mice were mated with wild-type female mice who then underwent daily restraint stress from days 13 to 19 of gestation. Surprisingly, prenatal stress had overall beneficial effects by facilitating sensorimotor gating, increasing sociability, decreasing depressive-like behaviour, and improving spatial memory in adulthood. Such benefits were not due to any increase in maternal care, as prenatal stress decreased nurturing of the offspring. Nrg1 deficiency negated the beneficial behavioural effects of prenatal stress on all measures except sociability. However, Nrg1 deficiency interacted with prenatal stress to trigger locomotor hyperactivity. Nrg1 deficiency, prenatal stress or their combination failed to alter acute stress-induced plasma corticosterone concentrations. Collectively these results demonstrate that Nrg1 deficiency moderates the effects of prenatal stress on adult behaviour, but it does so in a complex, domain-specific fashion. Highlights • Prenatal stress (PS) had a beneficial effect on various behaviours in adult mice. • PS improved sensorimotor gating, sociability, spatial memory and stress coping. • Nrg1 deficiency reduced all the benefits of PS except for enhanced sociability. • Nrg1 deficiency and prenatal stress combined to trigger locomotor hyperactivity. [ABSTRACT FROM AUTHOR]

Highlights • Glucagon-like peptide-1, Relaxin-2, Neuregulin-1, and Ghrelin each modify sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a) leading to increased calcium uptake into the SR which increases the speed and amount of cardia relaxation. • These peptides inhibit cardiac fibroblasts/myofibroblasts that produce the collagen leading to myocardial fibrosis. • These peptides induce phosphorylation of Phospholamban (PLN), the primary regulator of SERCA2a, removing its reversible inhibition of SERCA2a. • These peptides act by attenuation of deleterious signaling cascades, and induction of adaptive pathways, representing potential targets for treatment of heart failure with preserved ejection fraction. Abstract Heart failure with preserved ejection fraction (HFpEF) represents an important cardiac condition because of its increasing prevalence, resistance to treatment and high associated morbidity and mortality. Two of the major mechanisms responsible for HFpEF are impaired cardiomyocyte sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a), which is responsible for calcium reuptake into the SR, and cardiac fibroblasts/myofibroblasts that produce collagen or myocardial fibrosis. Phospholamban (PLB), in the SR and endoplasmic reticulum, is the primary regulator of SERCA2a in the heart and acts as a reversible inhibitor of SERCA2a. Glucagon-like peptide-1, a 30 amino acid peptide, improves diastolic function through increasing SERCA2a expression and activity as well as by decreasing phosphorylation of Ryanodine receptors. It also enhances collagen production through enhanced procollagen IalphaI/IIIalphaI, connective tissue growth factor, fibronectin, TGF-β3 as well as Interleukin −10, −1beta, and −6 gene expression. Relaxin-2, a two chain, 53 amino acid peptide, increases Ser16- and Thr17-phosphorylation levels of PLB, thereby relieving SERCA2a of its inhibition. H3 Relaxin inhibits TGF-β1-stimulated collagen deposition through H3 relaxin-induced increases in pSmad2. Neuregulin-1, an epidermal growth factor, induces nitric oxide and PI-3 kinase activation that enhance SERCA2 activity. Neuregulin-1 was associated with less myocardial macrophage infiltration and cytokine expression reducing collagen deposition. Ghrelin, a 28 amino acid peptide, improves SERCA2a function by inducing PLB phosphorylation. Ghrelin also reduces cardiac fibrosis. In summary, Glucagon-like peptide-1, Relaxin-2, Neuregulin-1, and Ghrelin each modify calcium dynamics, collagen expression, and myocardial fibrosis through attenuation of deleterious signaling cascades, and induction of adaptive pathways, representing potential therapeutic targets for HFpEF. [ABSTRACT FROM AUTHOR]

Highlights • SCI can induce activation of astrocytes and microglia in both mouse PFC and HIP. • SCI can alter Nrg1 signaling in both mouse PFC and HIP. • Nrg1 may have a therapeutic role in counteracting SCI-induced brain damage. Abstract Accumulated evidence has recently demonstrated that spinal cord injury (SCI) can lead to chronic damage in a wide range of brain regions. Neuregulin 1 (Nrg1) signaling has been broadly recognized as an important mechanism contributing to neural differentiation and regeneration. We here studied the effect of SCI on Nrg1 signaling in prefrontal cortex (PFC) and hippocampus (HIP) in a mouse model. As was indicated by the increased levels of GFAP and Iba-1, our results demonstrated that SCI significantly induced activation of astrocytes and microglial cells in both PFC and HIP. In addition, both western blot and morphological assay demonstrated that Nrg1 was altered in both regions at 8 weeks post SCI, which was accompanied with decreased phosphorylation levels of its cognitive receptors Neu and ErbB4. Our combined results indicated that SCI can influence Nrg1 signaling, which may contribute to the worsening of pathophysiological changes in major brain regions during SCI. These results also suggested that exogenous Nrg1 treatment may have a therapeutic role in counteracting SCI-induced brain damage. [ABSTRACT FROM AUTHOR]

• It is unclear whether solitary and pneumonic type IMA are biologically identical. • Solitary and pneumonic type IMA have no differences in genetic alternations. • MUC1 and MUC6 are associated with stepwise progression of IMA. • Solitary and pneumonic type IMA may be genetically of the same origin. Invasive mucinous lung adenocarcinoma (IMA) has unique radiological findings and pathological characteristics. IMA is classified into solitary and pneumonic types; however, it is unclear whether these are biologically identical. A single-center retrospective analysis was performed for 70 IMA patients (solitary type [n = 38] and pneumonic type [n = 32]) who underwent pulmonary resection between January 2010 and December 2018. We compared clinical and biological characteristics between the two types. The frequencies of genetic alternations such as EGFR, KRAS, BRAF, GNAS, ERBB2, TP53, NRG1, and MET were not different. Immunohistochemically, expression of MUC1 was significantly more common in the pneumonic type (5.0% versus 20.0%, p = 0.01) and diffuse MUC6 positive in the solitary type (39.0% versus 13.0%, p = 0.02). We further classified solitary types into those with or without ground-glass opacity (GGO) and pneumonic types into those with or without crazy-paving appearance (CPA), and evaluated their surgical outcomes. Five-year overall survival and relapse free survival rates were 95.8%/86.6%, 64.3%/70.7%, 74.6%/68.9%, and 50.0%/28.6% in patients with solitary type with GGO, solitary type without GGO, pneumonic type without CPA, and pneumonic type with CPA, respectively. There were no differences in genetic alternations; however, mucin expression pattern was different. Surgical outcomes were different according to the presence of GGO in the solitary type and the presence of CPA in the pneumonic type. These findings suggested a stepwise progression from solitary to pneumonic IMA. [ABSTRACT FROM AUTHOR]

Elevated levels of the type III ( III ) isoforms of neuregulin 1 ( NRG1 ) have been observed in the brains of schizophrenia patients that carry NRG1 Hap ICE risk alleles, which is thought to contribute to the aetiology of the disease. We generated transgenic mice with forebrain driven Nrg1 III overexpression ( Nrg1 III tg ) and previously found that male heterozygous Nrg1 type III tg mice exhibit several schizophrenia-relevant behaviours including social and cognitive deficits as well as impaired sensorimotor gating. A number of mouse models for other Nrg1 isoform types exhibit sex-specific phenotypes yet sex-specific effects of Nrg1 III overexpression had not been evaluated. Thus, in this study we tested female Nrg1 III transgenic mice using a comprehensive behavioural phenotyping battery relevant to positive, negative and cognitive symptoms of schizophrenia. Firstly, forebrain Nrg1 III mRNA overexpression was confirmed in female transgenic mice using by qPCR. In the open field test, female Nrg1 III mice exhibited a blunted response to an acute challenge with the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801. Female Nrg1 III tg mice also exhibited moderately impaired short-term memory. Other behavioural domains including sensory abilities, motor functions, baseline locomotion, anxiety, sociability, social recognition memory, fear conditioning and prepulse inhibition were unperturbed in Nrg1 III tg females. Together these results illustrate that overexpressing forebrain Nrg1 III in female mice modifies the locomotive response to NMDA receptor antagonism without causing severe alterations to a number of other schizophrenia-related behavioural domains. The data suggest that behavioural effects of Nrg1 III overexpression may be sex-dependent. [ABSTRACT FROM AUTHOR]

Abstract Schizophrenia (SCZ) has long been recognized as a highly heterogeneous disorder. Patients differed in their clinical manifestations, prognosis, and underlying pathophysiologies. Here we presented and applied a framework for finding subtypes of SCZ utilizing genome-wide association study (GWAS) and clinical data. We postulated that genetic information may help stratify patient into useful subgroups, and incorporation of other clinical information and cognitive profiles will further improve patient subtyping. We conducted cluster analysis in 387 Hong Kong Chinese with SCZ. First we performed 'single-view' clustering using genetic or clinical data alone, then proceeded to 'multi-view' clustering (MVC) accounting for both types of information. We validated clustering results by assessing subgroup differences in various outcomes. We found significant differences in outcomes including treatment response, disease course and symptom severity (Simes overall p-value using MVC = 1.64E-9). Overall speaking, we identified three subgroups with good, intermediate and poor prognosis respectively. MVC generally out-performed single-view methods. The analysis was repeated for different sets of input SNPs, and stratified analysis of male and female patients, and the results remained largely robust. We also found significant enrichment for SCZ loci among the SNPs selected by the cluster algorithm. Numerous selected genes (e.g. NRG1, ERBB4, NRXN1, ANK3) and pathways (e.g. neuregulin-ErbB4 and calcium signaling) were implicated in SCZ or related pathophysiological processes. This is first study to combine both genetic and clinical data for subtyping SCZ, and to employ genome-wide SNP data in cluster analysis of a complex disease. This work points to a new way of GWAS analysis of translational potential. [ABSTRACT FROM AUTHOR]

The hepatitis C virus (HCV) non-structural protein 3 (NS3) is essential for HCV maturation. The NS3/4A protease is a target for several HCV treatments and is a well-known target for HCV drug discovery. The protein is membrane associated and thus probably interacts with other membrane proteins. However, the vast majority of known NS3 host partners are soluble proteins rather than membrane proteins, most likely due to lack of appropriate platforms for their discovery. Utilization of an integrated microfluidics platform enables analysis of membrane proteins in their native form. We screened over 2800 membrane proteins for interaction with NS3 and 90 previously unknown interactions were identified. Of these, several proteins were selected for validation by co-immunoprecipitation and for NS3 proteolytic activity. Bearing in mind the considerable number of interactions formed, together with the popularity of NS3/4A protease as a drug target, it was striking to note its lack of proteolytic activity. Only a single protein, Neuregulin1, was observed to be cleaved, adding to the 3 known NS3/4A cleavage targets. Neuregulin1 participates in neural proliferation. Recent studies have shown its involvement in HCV infection and hepatocellular carcinoma. We showed that NS3/4A triggers an increase in neuregulin1 mRNA levels in HCV infected cells. Despite this increase, its protein concentration is decreased due to proteolytic cleavage. Additionally, its EGF-like domain levels were increased, possibly explaining the ErbB2 and EGFR upregulation in HCV infected cells. The newly discovered protein interactions may provide insights into HCV infection mechanisms and potentially provide new therapeutic targets against HCV. [ABSTRACT FROM AUTHOR]

Gamma oscillations within the cerebral cortex and hippocampus are associated with cognitive processes, including attention, sensory perception, and memory formation; a deficit in gamma regulation is a common symptom of neurologic and psychiatric disorders. Accumulating evidence has suggested that gamma oscillations result from the synchronized activity of cell assemblies coordinated mainly by parvalbumin-positive inhibitory interneurons. The modulator molecules for parvalbumin-positive interneurons are major research targets and have the potential to control the specific oscillatory rhythm and behavior originating from neural coordination. Neuregulin-1 and brain-derived neurotrophic factor have been focused on as synaptic trophic factors that are associated with gamma oscillations. Synaptic activity converts precursor trophic factors into their biologically active forms by proteolytic cleavage, which could, in turn, modulate cell excitability and synaptic plasticity through each receptor's signaling. From these findings, the processing of trophic factors by proteases in a synaptic microenvironment might involve gamma oscillations during cognition. Here, we review the trophic modulation of gamma oscillations through extracellular proteolysis and its implications in neuronal diseases. [ABSTRACT FROM AUTHOR]

Little is known about valid predictive markers for functional outcomes in an at-risk for psychosis population. In a cohort of 185 individuals (age: 13–35 years) at high risk (HR) and ultra-high risk (UHR), we assessed pan- NRG1 mRNA levels across good functional status (GFS) and poor functional status (PFS) at baseline, and good functional outcome (GFO) and poor functional outcome (PFO) at 12-month follow-up. NRG1 mRNA levels were significantly higher in individuals with PFO than individuals with GFO at 12-month follow-up. Our findings suggest that NRG1 might emerge as a predictive marker for functional outcomes in at-risk for psychosis population. [ABSTRACT FROM AUTHOR]

Mice with a mutation in the transmembrane domain of the schizophrenia risk gene, neuregulin 1 ( Nrg1 TM HET), are more susceptible to the neuro-behavioural effects of Δ 9 -tetrahydrocannabinol (D 9 -THC), the principal psychoactive component in cannabis. However, NRG1 is transcriptionally complex with over 30 different isoforms, most of which carry a transmembrane domain, raising the question which NRG1 isoform(s) may contribute to this phenotype. Type III NRG1 / Nrg1 is the most brain abundant isoform and brain studies have identified increased levels of type III NRG1 mRNA in humans carrying a NRG1 risk haplotype for schizophrenia. To investigate whether mice heterozygous for type III Nrg1 (i.e. knockout: type III Nrg1 +/− ) are more susceptible to the behavioural effects of acute doses of D 9 -THC, we injected male mice with either vehicle or D 9 -THC (3 or 10 mg/kg) before testing them for locomotion, anxiety, social interaction, and sensorimotor gating. Acute D 9 -THC led to reduced locomotion and reduced social interaction, but increased anxiety in mice. Furthermore, type III Nrg1 males displayed a robust deficit in sensorimotor gating and demonstrated reduced following during social interaction across drug conditions. However, they did not show a change in behavioural susceptibility to acute D 9 -THC compared to controls. These results reinforce the validity of type III Nrg1 +/− mice for schizophrenia research and suggest that loss of function of type III Nrg1 may not be responsible for the exaggerated response to acute D 9 -THC observed in heterozygous Nrg1 TM mice. This highlights the importance of careful consideration of Nrg1 isoform type differences. [ABSTRACT FROM AUTHOR]

Neuregulin1 (NRG1) is a differentiation factor that regulates glial development, survival, synaptogenesis, axoglial interactions, and microglial activation. We previously reported that a targeted NRG1 antagonist (HBD-S-H4) given intrathecally, reduces inflammatory microglial activation in a spinal cord pain model and a neurodegenerative disease mouse model in vivo, suggesting that it may have effects in neuroninflammatory and neuronal disorders. We hypothesized that expression of HBD-S-H4 in the central nervous system (CNS) could reduce disease severity in experimental autoimmune encephalomyelitis (EAE), a widely used animal model for multiple sclerosis (MS). In the present study, we generated tetO-HBD-S-H4, a single transgenic (Tg) mouse line in, which the fusion protein in expressed in the brain, resulting in reduction of disease severity in both male and female mice when compared to sex- and age-matched wild type littermates. We also generated GFAP-tTA:tetO-HBD-S-H4 double Tg mice, which express this fusion protein in the brain and the spinal cord, they displayed sex differences in the reduction of disease severity. In healthy mice, expression of HBD-S-H4 in the CNS does not result in any significant neurological or other overt phenotypes. In myelin oligodendrocyte glycoprotein (MOG)-induced EAE, female double Tg mice show delayed disease onset and reduced disease severity compared to male double Tg as well as wild type littermates. In male double Tg mice, the levels of HBD-S-H4 gene expression negatively correlates with disease severity and increased microglia associated genes' expression. In conclusion, expression of neuregulin antagonist in the brain and spinal cord protects females but not males, suggesting a complex interplay between NRG1 and sex difference in EAE that may be associated with microglia-mediated inflammation. This study provides important information for understanding the heterogeneity of disease pathology and the therapeutic potential of targeting microglial activation in male and female MS patients. [ABSTRACT FROM AUTHOR]

Background: NRG1 fusion-positive lung cancers have emerged as potentially actionable events in lung cancer, but clinical support is currently limited and no evidence of efficacy of this approach in cancers beyond lung has been shown. Patients and methods: Here, we describe two patients with advanced cancers refractory to standard therapies. Patient 1 had lung adenocarcinoma and patient 2 cholangiocarcinoma. Whole-genome and transcriptome sequencing were carried out for these cases with select findings validated by fluorescence in situ hybridization. Results: Both tumors were found to be positive for NRG1 gene fusions. In patient 1, an SDC4-NRG1 gene fusion was detected, similar gene fusions having been described in lung cancers previously. In patient 2, a novel ATP1B1-NRG1 gene fusion was detected. Cholangiocarcinoma is not a disease type in which NRG1 fusions had been described previously. Integrative genome analysis was used to assess the potential functional significance of the detected genomic events including the gene fusions, prioritizing therapeutic strategies targeting the HER-family of growth factor receptors. Both patients were treated with the pan HER-family kinase inhibitor afatinib and both displayed significant and durable response to treatment. Upon progression sites of disease were sequenced. The lack of obvious genomic events to describe the disease progression indicated that broad transcriptomic or epigenetic mechanisms could be attributed to the lack of prolonged response to afatinib. Conclusion: These observations lend further support to the use of pan HER-tyrosine kinase inhibitors for the treatment of NRG1 fusion-positive in both cancers of lung and hepatocellular origin and indicate more broadly that cancers found to be NRG1 fusion-positive may benefit from such a clinical approach regardless of their site of origin. Clinical trial information: Personalized Oncogenomics (POG) Program of British Columbia: Utilization of Genomic Analysis to Better Understand Tumour Heterogeneity and Evolution (NCT02155621). [ABSTRACT FROM AUTHOR]

Alzheimer's disease is a neurodegenerative disease mainly characterized by cortico-neuronal atrophy, impaired memory and other cognitive declines. On the other hand, schizophrenia is a neuro-developmental disorder with an overtly active central nervous system pruning system resulting into abrupt connections with common symptoms including disorganised thoughts, hallucination and delusion. Nevertheless, the fronto-temporal anomaly presents itself as a common denominator for the two pathologies. There is even a strong presumption of increased risk of developing co-morbid dementia for schizophrenic individuals and psychosis for Alzheimer's disease patients, overall leading to a further deteriorated quality of life. However, convincing proofs of how these two disorders, although very distant from each other when considering their aetiology, develop coexisting symptoms is yet to be resolved. At the molecular level, the two primarily neuronal proteins β-amyloid precursor protein and neuregulin 1 have been considered in this relevant context, although the conclusions are for the moment only hypotheses. In order to propose a model for explaining the psychotic schizophrenia-like symptoms that sometimes accompany AD-associated dementia, this review projects out on the similar sensitivity shared by these two proteins regarding their metabolism by the β-site APP cleaving enzyme 1. • Half of Alzheimer's disease (AD) patients develop psychotic symptoms. • Neuregulin 1 is genetically and functionally tightly linked to schizophrenia. • BACE1 is involved in the cleavage of both βAPP and neuregulin 1. • BACE1 levels and activity are increased in AD. • The BACE1/Nrg1/ErbB4/NMDARs axis could underlie the appearance of psychosis in AD. [ABSTRACT FROM AUTHOR]

Background Neuregulin-1β (NRG-1β) has great potential to be developed into therapeutics for neuroprotection. The aim of the current study was to analyze the effects and possible signaling pathway of NRG-1β on brain tissues in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). Methods In order to observe the protective effect of NRG-1β on MCAO/R, the neurological deficit and infarct volume were measured using a modified neurological severity score (mNSS) test and by triphenyl tetrazolium chloride (TTC) staining. In order to detect the antagonistic effect of NRG-1β on nerve cells and the blood–brain barrier (BBB), the morphology and structure of cortical brain tissues were observed by Evans Blue (EB) staining, hematoxylin–eosin (H&E) and Nissl staining, in situ cell death detection kit, and transmission electron microscopy (TEM). In order to investigate whether NRG-1β exhibited a significant neuroprotective effect via the JNK signaling pathway, the activity of JNK and the levels of phospho-MKK4, phospho-JNK, pan-JNK and phospho-c-Jun were tested using a JNK activity screening kit, immunofluorescent labeling, and western blot analysis, respectively. Results In the NRG-1β treatment group, accompanied with a decrease in JNK activity, the protein levels of phospho-JNK, phospho-MKK4 and phospho-c-Jun decreased, the ischemia-induced apoptosis decreased, the abnormal morphological structures of nerve cells were ameliorated, the integrity of the BBB was restored, and infarct volume was reduced. At the same time, neurological function was significantly recovered. Conclusion NRG-1β exerts a neuroprotective effect through the JNK signaling pathway in MCAO/R rats. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) results in significant tissue damage that underlies functional impairments. Pharmacological interventions to confer neuroprotection and promote cell replacement are essential for SCI repair. We previously reported that Neuregulin-1 (Nrg-1) is acutely and permanently downregulated after SCI. Nrg-1 is a critical growth factor for differentiation of neural precursor cells (NPCs) into myelinating oligodendrocytes. We showed that intrathecal delivery of Nrg-1 enhances oligodendrocyte replacement following SCI. While an effective delivery system, intrathecal and systemic administration of growth factors with diverse biological targets may pose adverse off-target effects. Here, we have developed and optimized an injectable biodegradable poly(lactic- co -glycolic acid) (PLGA) microparticles system for sustained and prolonged intraspinal delivery of Nrg-1 in SCI. Recombinant human Nrg-1β1 peptide was encapsulated into PLGA microparticles. Optimal Nrg-1 release rate and duration were achieved by manipulating the porosity and size of PLGA particles. Our in vitro analysis showed a direct correlation between particle size and porosity with Nrg-1 release rate, while Nrg-1 loading efficiency in PLGA microparticles was inversely correlated with particle porosity. In SCI, local intraspinal injection of PLGA-Nrg-1 microparticles maintained significantly higher tissue levels of Nrg-1 for a long-term duration compared to Nrg-1 delivered intrathecally by osmotic pumps. Bioactivity of Nrg-1 in PLGA microparticles was verified by promoting oligodendrocyte differentiation of NPCs in vitro , and preservation of oligodendrocytes and axons in SCI. PLGA-Nrg-1 also attenuated neuroinflammation and glial scarring following SCI. We show, for the first time, the feasibility, efficacy and safety of PLGA microparticle system for local and controlled administration of Nrg-1 in SCI. [ABSTRACT FROM AUTHOR]

Cerebellum undergoes degenerative changes in neurodegenerative diseases. Two main factors including oxidative stress and neuroinflammation mediate neurodegeneration. Neuregulin-1 (Nrg1) has been implicated in many neurodegenerative diseases, while the underlying mechanisms are unknown. We hypothesized that Nrg1 prevents oxidative stress and neuroinflammation in neurodegeneration. We found a positive correlation between Nrg1 protein levels and ErbB4 and ErbB2 receptor phosphorylation in microarrays of normal human cerebellar tissue. In addition, Nrg1 was also co-localized with pErbB4 and pErbB2. Primary mouse cerebellar granule neurons (CGNs) were treated with H 2 O 2 or LPS combined with recombinant Nrg1β (rNrg1β). Western blot analysis and immunofluorescence revealed that H 2 O 2 and LPS-induced neuronal toxicity down-regulated the activation of ErbB receptors and Akt1, and the ratio of Bcl2/Bax, which was reversed by rNrg1β. In vivo studies showed that LPS-induced neuroinflammation in mouse cerebellum down-regulated pErbB4, pErbB2, pAkt1/Akt1 and Bcl2/Bax levels, whereas rNrg1β treatment reversed the changes. Immunohistochemistry and Western blot analysis showed that rNrg1β alleviates neuroinflammation by reducing the number of microglial cells and astrocytes and the expression of IL1β. Our results indicate that Nrg1 protects against oxidative stress and neuroinflammation in mouse cerebellum, suggesting potential therapeutic application in neuroinflammation associated with neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

A robust, disease-relevant phenotype is paramount to the validity of genetic mouse models, which are an important tool in understanding complex diseases. Recent evidence from genome-wide association studies suggests the genetic contribution of parents to offspring is not equivalent. Despite this, few studies to date have examined the potential impact of parent genotype (i.e. origin of mutation) on the offspring of disease-relevant genetic mouse models. To elucidate the potential impact of the sex of the mutant parent on offspring phenotype, we characterized male and female offspring of an established schizophrenia mouse model, which had been generated using two different breeding schemes, in a range of disease-relevant behaviours. We compared heterozygous type III neuregulin 1 mutant ( type III Nrg1 +/− ) and wild type-like control (WT) offspring from mutant father x WT mother pairings with offspring from mutant mother x WT father pairings. Offspring were tested in schizophrenia-relevant paradigms including the elevated plus maze (EPM), fear conditioning (FC), prepulse inhibition (PPI), social interaction (SI), and open field (OF). We found type III Nrg1 +/− males from mutant fathers, but not mutant mothers, showed deficits in contextual fear-associated memory and exhibited increased social interaction, compared to their WT littermates. Type III Nrg1 +/− females across breeding colonies only exhibited a subtle change to their acoustic startle response and sensorimotor gating. These results suggest a paternal-dependent transmission of genetically induced behavioural characteristics. Though the mechanisms governing this phenomenon are unclear, our results show that parental origin of mutation can alter the behavioural phenotype of genetic mouse models. Thus, researchers should carefully consider their breeding scheme when dealing with genetic mouse models of diseases such as schizophrenia. [ABSTRACT FROM AUTHOR]

Neuregulins ( Nrg ) are a gene family that binds to tyrosine kinase receptors of the ErbB family. The protein of Nrg1 is to be involved in heart formation, migration of neurons, axonal pathfinding and synaptic function. A relation between Nrg1 and schizophrenia is assumed. Chronic impairment in schizophrenia is characterized by different positive and negative symptoms. Detectable markers of this disease in human and in animal models are activity, social behavior and sensory processing. In this study we compared heterozygous Nrg1 mutant mice in behavior and quantification of dopaminergic and serotoninergic neurons with wild type-like littermates. In the Nrg1 mutant mice the epidermal growth factor-like domain is replaced by the neomycin resistance gene. We found significant differences in locomotor and pain perception behavior. No differences were found in specific schizophrenia social interaction and prepulse inhibition behavior. The number of dopaminergic and serotoninergic neurons did not differ in the investigated regions ventral tegmental area, substantia nigra, periaqueductal grey and raphe nuclei. In conclusion, this analyzed Nrg1 mutant mice model did not serve as a complete schizophrenia model. Particular aspects of schizophrenia disease in locomotor and sensory behavior deficits could represent in this Nrg1 mutant mice. Beside several different models could Nrg1 deficiency represent an endophenotype of schizophrenia disease. [ABSTRACT FROM AUTHOR]

Tissue engineering is a promising strategy to promote heart regeneration after a myocardial infarction (MI). In this study, we investigated the reparative potential of a system that combines adipose-derived stem cells (ADSCs) with microparticles (MPs) loaded with neuregulin (NRG), named ADSC-NRG-MPs, on a rat MI model. First, cells were attached to the surface of MPs encapsulating NRG and coated with a 1:1 mixture of collagen and poly- d -lysine. One week after in vivo administration, the system favored the shift of macrophage expression from a pro-inflammatory to a regenerative phenotype. At long-term, the adhesion of ADSCs to MPs resulted in an increased cell engraftment, with cells being detectable in the tissue up to three months. In consonance, better tissue repair was observed in the animals treated with cells attached to MPs, which presented thicker left ventricles than the animals treated with ADSCs alone. Moreover, the presence of NRG in the system promoted a more complete regeneration, reducing the infarct size and stimulating cardiomyocyte proliferation. Regarding vasculogenesis, the presence of ADSCs and NRG-MPs alone stimulated vessel formation when compared to the control group, but the combination of both induced the largest vasculogenic effect, promoting the formation of both arterioles and capillaries. Importantly, only when ADSCs were administered adhered to MPs, they were incorporated into newly formed vessels. Collectively, these findings demonstrate that the combination of ADSCs, MPs and NRG favored a synergy for inducing a greater and more complete improvement in heart regeneration and provided strong evidence to move forward with preclinical studies with this strategy. [ABSTRACT FROM AUTHOR]

The complex genetic origins of many human disorders suggest that epistatic (gene × gene) interactions may contribute to a significant proportion of their heritability estimates and phenotypic heterogeneity. Simultaneous disruption of the developmental genes and schizophrenia risk factors Neuregulin-1 (NRG1) and Disrupted-in-schizophrenia 1 (DISC1) in mice has been shown to produce disease-relevant and domain-specific phenotypic profiles different from that observed following disruption of either gene alone. In the current study, anxiety and stress responsivity phenotypes in male and female mutant mice with simultaneous disruption of DISC1 and NRG1 were examined. NRG1 × DISC1 mutant mice were generated and adult mice from each genotype were assessed for pain sensitivity (hot plate and tail flick tests), anxiety (light-dark box), and stress-induced hypothermia. Serum samples were assayed to measure circulating levels of pro-inflammatory cytokines. Mice with the NRG1 mutation, irrespective of DISC1 mutation, spent significantly more time in the light chamber, displayed increased core body temperature following acute stress, and decreased pain sensitivity. Basal serum levels of cytokines IL8, IL1β and IL10 were decreased in NRG1 mutants. Mutation of DISC1, in the absence of epistatic interaction with NRG1, was associated with increased serum levels of IL1β. Epistatic effects were evident for IL6, IL12 and TNFα. NRG1 mutation alters stress and pain responsivity, anxiety, and is associated with changes in basal cytokine levels. Epistasis resulting from synergistic NRG1 and DISC1 gene mutations altered pro-inflammatory cytokine levels relative to the effects of each of these genes individually, highlighting the importance of epistatic mechanisms in immune-related pathology. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is a neuromuscular disease originated by mutations in the dystrophin gene. A promising therapeutic approach deals with functional substitution of dystrophin by utrophin, a structural homolog that might be able to compensate dystrophin absence in DMD muscle fibers. It has been described that both interleukin-6 (IL-6) and neuregulin-1 (NRG-1; Heregulin-HRG) induce utrophin expression in skeletal muscle. We investigated a possible functional link among IL-6, NRG-1 and utrophin, in normal (C57) and dystrophic ( mdx ) skeletal muscle cells. Western Blot analysis allowed us to demonstrate that IL-6 (100 ng/mL) induces NRG-1 receptor phosphorylation (ErbB2/ErbB3) in both cell types, in a process that depends on intracellular Ca 2 + and metalloproteinase activity; it also induces a transient increase of ERK1 and GABPα phosphorylation only in dystrophic myotubes. Semiquantitative PCR showed that IL-6 treatment increases utrophin mRNA levels just in mdx myotubes. We observed that utrophin mRNA induction was abolished by BAPTA-AM (an intracellular Ca 2 + chelator), GM6001 (a general metalloproteinase inhibitor), genistein (a general protein tyrosine kinase inhibitor), PD-158780 (an ErbB receptor tyrosine kinase inhibitor) and PD-98059 (a MEK inhibitor), whereas Ly-294002 and wortmannin (PI3K inhibitors) did not affect utrophin induction evoked by IL-6 in dystrophic myotubes. Our results suggest that IL-6 induces utrophin expression in mdx myotubes through activation of a NRG-1/ErbBs signaling cascade. Soluble NRG-1 elicited by proteolytic processing of transmembrane NRG-1 might induce ErbBs phosphorylation and ERK1/2 pathway activation, leading to utrophin up-regulation. [ABSTRACT FROM AUTHOR]

Neuregulins are important growth factors involved in cardiac development and response to stress. Certain isoforms and fragments of neuregulin have been found to be cardioprotective. The effects of a full-length neuregulin-1β isoform, glial growth factor 2 (GGF2; USAN/INN; also called cimaglermin) were investigated in vitro. Various dosing regimens were then evaluated for their effects on left ventricular (LV) function in rats with surgically-induced myocardial infarction. In vitro , GGF2 bound with high affinity to erythroblastic leukemia viral oncogene (ErbB) 4 receptors, potently promoted Akt phosphorylation, as well as reduced cell death following doxorubicin exposure in HL1 cells. Daily GGF2 treatment beginning 7–14 days after left anterior descending coronary artery ligation produced improvements in LV ejection fraction and other measures of LV function and morphology. The improvements in LV function (e.g. 10% point increase in absolute LV ejection fraction) with GGF2 were dose-dependent. LV performance was substantially improved when GGF2 treatment was delivered infrequently, despite a serum half-life of less than 2 h and could be maintained for more than 10 months with treatment once weekly or once every 2 weeks. These studies confirm previous findings that GGF2 may improve contractile performance in the failing rat heart and that infrequent exposure to GGF2 may improve LV function and impact remodeling in the failing myocardium. GGF2 is now being developed for the treatment of heart failure in humans. [ABSTRACT FROM AUTHOR]

Neuregulin-1 (NRG-1), an endogenously produced polypeptide, is the ligand of cardiomyocyte ErbB receptors, with cardiovascular protective effects. In the present study, we explored whether the cardioprotective effect of NRG-1 against I/R injury is mediated by inhibiting myocardial endoplasmic reticulum (ER) stress. In vitro , NRG-1 directly inhibited the upregulation of ER stress markers such as glucose-regulated protein 78, CCAAT/enhancer binding protein homologous protein and cleaved caspase-12 induced by the ER stress inducers tunicamycin or dithiothreitol in both neonatal and adult ventricular myocytes. Attenuating ErbB signals by an ErbB inhibitor AG1478 or ErbB4 knockdown and preincubation with phosphoinositide 3-kinase inhibitors all reversed the effect of NRG-1 inhibiting ER stress in cultured neonatal rat cardiomyocytes. Concurrently, cardiomyocyte ER stress and apoptosis induced by hypoxia-reoxygenation were decreased by NRG-1 treatment in vitro . Furthermore, in an in vivo rat model of myocardium ischemia/reperfusion (I/R), intravenous NRG-1 administration significantly decreased ER stress and myocardial infarct size induced by I/R. NRG-1 could protect the heart against I/R injury by inhibiting myocardial ER stress, which might be mediated by the phosphoinositide 3-kinase/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

A high rate of heavy tobacco smoking among people with schizophrenia has been suggested to reflect self-medication and amelioration of cognitive dysfunction, a core feature of schizophrenia. NMDAR hypofunction is hypothesized to be a mechanism of cognitive dysfunction, and excessive schizophrenia-linked neuregulin 1 (NRG1) signaling through its receptor ErbB4 can suppress NMDAR function by preventing Src-mediated enhancement of NMDAR responses. Here we investigated whether chronic nicotine exposure in rats by subcutaneous injection of nicotine (0.5–1 mg/kg, twice daily for 10–15 days) counteracts the suppressive effect of NRG1β on NMDAR-mediated responses recorded from CA1 pyramidal cells in acute hippocampal slices. We found that NRG1β, which prevents the enhancement of NMDAR responses by the Src-family-kinase-activating peptide pYEEI in naive rats, failed to block the effect of pYEEI in nicotine-exposed rats. In naive rats, NRG1β acts only on GluN2B-NMDARs by blocking their Src-mediated upregulation. Chronic nicotine exposure causes enhanced GluN2B-NMDAR responses via Src upregulation and recruits Fyn for the enhancement of GluN2A-NMDAR responses. NRG1β has no effect on both enhanced basal GluN2B-NMDAR responses and Fyn-mediated enhancement of GluN2A-NMDAR responses. Src-mediated enhancement of GluN2B-NMDAR responses and Fyn-mediated enhancement of GluN2A-NMDAR responses initiate long-term potentiation (LTP) of AMPAR synaptic responses in naive and nicotine-exposed CA1 pyramidal cells, respectively. These results suggest that NRG1β suppresses LTP by blocking Src-mediated enhancement of GluN2B-NMDAR responses, but has no effect on LTP in nicotine-exposed rats. These effects of chronic nicotine exposure may counteract the negative effect of increased NRG1-ErbB4 signaling on the cellular mechanisms of learning and memory in individuals with schizophrenia, and therefore may motivate heavy smoking. [ABSTRACT FROM AUTHOR]

Summary Neural circuits in the cerebral cortex consist of excitatory pyramidal cells and inhibitory interneurons. These two main classes of cortical neurons follow largely different genetic programs, yet they assemble into highly specialized circuits during development following a very precise choreography. Previous studies have shown that signals produced by pyramidal cells influence the migration of cortical interneurons, but the molecular nature of these factors has remained elusive. Here, we identified Neuregulin 3 (Nrg3) as a chemoattractive factor expressed by developing pyramidal cells that guides the allocation of cortical interneurons in the developing cortical plate. Gain- and loss-of-function approaches reveal that Nrg3 modulates the migration of interneurons into the cortical plate in a process that is dependent on the tyrosine kinase receptor ErbB4. Perturbation of Nrg3 signaling in conditional mutants leads to abnormal lamination of cortical interneurons. Nrg3 is therefore a critical mediator in the assembly of cortical inhibitory circuits. [ABSTRACT FROM AUTHOR]

While estrogens have been shown to modulate EGFR/HER-1 and HER-2/neu expression in experimental systems, the effects of estrogen deprivation on expression levels of the HER-receptors and the neuregulin (NRG)1 ligand in breast cancers remain unknown. Here, we measured EGFR/HER-1-4 and NRG1 mRNA in ER positive tumors from 85 postmenopausal breast cancer patients before and after two weeks ( n = 64) and three months ( n = 85) of primary treatment with an aromatase inhibitor (AI). In tumors lacking HER-2/neu amplification, quantitative real-time PCR analyses revealed EGFR/HER-1 and NRG1 to vary significantly between the three time points (before therapy, after 2 weeks and after 3 months on treatment; P ≤ 0.001 for both). Pair-wise comparison revealed a significant increase in EGFR/HER-1 already during the first two weeks of treatment ( P = 0.049) with a further increase for both EGFR/HER-1 and NRG1 after 3 months on treatment ( P ≤ 0.001 and P = 0.001 for both comparing values at 3 months to values at baseline and 2 weeks respectively). No difference between tumors responding versus non-responders was recorded. Further, no significant change in any parameter was observed among HER-2/neu amplified tumors. Analyzing components of the HER-2/neu PI3K/Akt downstream pathway, the PIK3CA H1047R mutation was associated with treatment response ( P = 0.035); however no association between either AKT phosphorylation status or PIK3CA gene mutations and EGFR/HER-1 or NRG1 expression levels were observed. Our results indicate primary AI treatment to modulate expression of HER-family members and the growth factor NRG1 in HER-2/neu non-amplified breast cancers in vivo . Potential implications to long term sensitivity warrants further investigations. [ABSTRACT FROM AUTHOR]

The endocannabinoid system is dysregulated in schizophrenia. Mice with heterozygous deletion of neuregulin 1 ( Nrg1 HET mice) provide a well-characterised animal model of schizophrenia, and display enhanced sensitivity to stress and cannabinoids during adolescence. However, no study has yet determined whether these mice have altered brain endocannabinoid concentrations. Nrg1 application to hippocampal slices decreased 2-arachidonoylglycerol (2-AG) signalling and disrupted long-term depression, a form of synaptic plasticity critical to spatial learning. Therefore we specifically aimed to examine whether Nrg1 HET mice exhibit increased 2-AG concentrations and disruption of spatial learning. As chronic stress influences brain endocannabinoids, we also sought to examine whether Nrg1 deficiency moderates adolescent stress-induced alterations in brain endocannabinoids. Adolescent Nrg1 HET and wild-type (WT) mice were submitted to chronic restraint stress and brain endocannabinoid concentrations were analysed. A separate cohort of WT and Nrg1 HET mice was also assessed for spatial learning performance in the Morris Water Maze. Partial genetic deletion of Nrg1 increased anandamide concentrations in the amygdala and decreased 2-AG concentrations in the hypothalamus. Further, Nrg1 HET mice exhibited increased 2-AG concentrations in the hippocampus and impaired spatial learning performance. Chronic adolescent stress increased anandamide concentrations in the amygdala, however, Nrg1 disruption did not influence this stress-induced change. These results demonstrate for the first time in vivo interplay between Nrg1 and endocannabinoids in the brain. Our results demonstrate that aberrant Nrg1 and endocannabinoid signalling may cooperate in the hippocampus to impair cognition, and that Nrg1 deficiency alters endocannabinoid signalling in brain stress circuitry. [ABSTRACT FROM AUTHOR]

• In this study, correlations between rs35753505 SNP of NRG1 gene with schizophrenia, psychopathology and verbal intelligence were analyzed. • Our results show that rs35753505 polymorphism of NRG1 is associated with schizophrenia. • Our results recommend that the correlation between two variables, the rs35753505 polymorphism significantly increases the PANSS test results. • Investigating the coexistence of alleles and genotypic correlation of Neuregulin 1 (NRG1) mononucleotide polymorphism rs35753505, with psychopathology and intelligence in different ethnicities with more population is encouraged. Schizophrenia is one of the most severe psychiatric disorders. About 0.5 to 1% of the world's population suffers from this non-Mendelian disorder. Environmental and genetic factors seem to be involved in this disorder. In this article, we investigate the alleles and genotypic correlation of mononucleotide rs35753505 polymorphism of Neuregulin 1 (NRG1), one of the selected genes of schizophrenia, with psychopathology and intelligence. 102 independent and 98 healthy patients participated in this study. DNA was extracted by the salting out method and the polymorphism (rs35753505) were amplified by polymerase chain reaction (PCR). Sanger sequencing was performed on PCR products. Allele frequency analysis was performed using COCAPHASE software, and genotype analysis was performed using Clump22 software. According to our study's statistical findings, all case samples from the three categories of men, women, and overall participants significantly differed from the control group in terms of the prevalence of allele C and the CC risk genotype. The rs35753505 polymorphism significantly raised Positive and Negative Syndrome Scale (PANSS) test results, according to a correlation analysis between the two variables. However, this polymorphism led to a significant decrease in overall intelligence in case samples compared to control samples. In this study, it seems that the rs35753505 polymorphism of NRG1 gene has a significant role in the sample of patients with schizophrenia in Iran and also in psychopathology and intelligence disorders. [ABSTRACT FROM AUTHOR]

• Exosomal miR-125a-3p in serum predicted response to anti-PD-1/PD-L1 therapy in NSCLC. • MiR-125a-3p was a more useful predictor than tumoral PD-L1 in low PD-L1 expression. • High expression of miR-125a-3p was associated with worse prognosis. • MiR-125a-3p regulates PD-L1 expression via neuregulin 1 suppression in NSCLC cells. Versatile biomarkers for immune checkpoint inhibitors (ICI) efficacy in patients with cancer remain to be identified. Liquid biopsy using serum-derived exosomal microRNAs (miRNAs) are widely investigated as diagnostic and therapeutic outcome predictors in patients with cancer. However, exosomal miRNAs linked to the response to ICI in patients with non-small cell lung cancer (NSCLC) remain elusive thus far. Methods: The value of serum-derived exosomal miRNAs in predicting the effect of anti-programmed cell death-1 (PD-1)/anti-programmed cell death-ligand 1 (PD-L1) monotherapy in 41 patients with advanced NSCLC was assessed. We performed functional analysis of candidate miRNAs using NSCLC cell lines. Results: Exosomal miR-125a-3p was associated with response to treatment with ICI. Exosomal miR-125a-3p was more useful in predicting response to ICI versus tumoral PD-L1 in patients with low PD-L1 expression <50 %). Moreover, high expression of miR-125a-3p was associated with worse progression-free and overall survival. In H1975 and H441 cells, induction of miR-125a-3p regulated PD-L1 expression via suppression of neuregulin 1 (NRG1). Conclusions: Exosomal miR-125a-3p is a potential predictor of response to anti-PD-1/PD-L1 therapy in advanced NSCLC patients with low PD-L1 expression. [ABSTRACT FROM AUTHOR]

To investigate the potential role of EGFR, ErbBs receptors and neuregulins in human adipose tissue physiology in obesity. Gene expression analysis in human subcutaneous (SAT) and visceral (VAT) adipose tissue in three independent cohorts [two cross-sectional (N = 150, N = 87) and one longitudinal (n = 25)], and in vitro gene knockdown and overexpression experiments were performed. While both SAT and VAT ERBB2 and ERBB4 mRNA increased in obesity, SAT EGFR mRNA was negatively correlated with insulin resistance, but did not change in obesity. Of note, both SAT and VAT EGFR mRNA were significantly associated with adipogenesis and increased during human adipocyte differentiation. In vitro experiments revealed that EGFR, but not ERBB2 and ERBB4, gene knockdown in preadipocytes and in fully differentiated human adipocytes resulted in decreased expression of adipogenic-related genes. ERBB2 gene knockdown also reduced gene expression of fatty acid synthase in fully differentiated adipocytes. In addition, neuregulin 2 (NRG2) mRNA was associated with expression of adipogenic genes in human adipose tissue and adipocytes, and its overexpression increased expression of EGFR and relevant adipogenic genes. This study demonstrates the association between adipose tissue ERBB2 and obesity, confirms the relevance of EGFR on human adipogenesis, and suggests a possible adipogenic role of NRG2. [Display omitted] • EGFR expression seems to be required for human adipogenesis. • ErbB2 and ErbB4 expression were significantly increased in obesity. • Neuregulin 2 might exert a possible role in human adipogenesis. • The induction of human adipose EGFR might improve adipose tissue dysfunction, [ABSTRACT FROM AUTHOR]