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BackgroundThe inflammatory response caused by microglia in the central nervous system plays an important role in Alzheimer's disease. Neuregulin-1 (NRG1) is a member of the neuregulin family and has been demonstrated to have anti-inflammatory properties. The relationship between NRG1, microglia phenotype and neuroinflammation remains unclear.Materials and MethodsBV2 cells were used to examine the mechanism of NRG1 in regulating microglia polarization. Neuronal apoptosis, inflammatory factors TNF-α and iNOS, microglia polarization, ErbB4 and NF-κB p65 expression were assessed.ResultsWe found that exogenous NRG1 treatment or overexpression improved microglial activity and reduced the secretion of the inflammatory factors TNF-α and iNOS in vitro. The expression of Bax in SH-SY5Y neuron cells incubated with medium collected from the NRG1 treatment group decreased. Additionally, our study showed that NRG1 treatment reduced the levels of the M1 microglia markers CD120 and iNOS and increased the levels of the M2 microglia markers CD206 and Arg-1. Furthermore, we observed that NRG1 treatment attenuated Aβ-induced NF-κB activation and promoted the expression of p-ErbB4 and that knockdown of ErbB4 abrogated the effects of NRG1 on NF-κB, Bax levels and M2 microglial polarization. Conclusion NRG1 inhibits the release of inflammatory factors in microglia and regulates the switching of the M1/M2 microglia phenotype, most likely via ErbB4-dependent inhibition of the NF-κB pathway.

Fusions in neuregulin 1 (NRG1) and neuregulin 2 (NRG2) genes are molecular features of non-small cell lung cancer (NSCLC). These rearrangements enhance ectopic expression of the NRG/ErbB receptor‐l...

SummaryInhibitory neurotransmission in amygdala is important for fear learning and memory. However, mechanisms that control the inhibitory activity in amygdala are not well understood. We provide evidence that neuregulin 1 (NRG1) and its receptor ErbB4 tyrosine kinase are critical for maintaining GABAergic activity in amygdala. Neutralizing endogenous NRG1, inhibition, or genetic ablation of ErbB4, which was expressed in a majority of palvalbumin (PV)+ neurons in amygdala, reduced GABAergic transmission and inhibited tone-cued fear conditioning. Specific ablation of ErbB4 in PV+ neurons reduced eIPSC/eEPSC ratios and impaired fear conditioning. Notably, expression of ErbB4 in amygdala was sufficient to diminish synaptic dysfunction and fear conditioning deficits in PV-ErbB4−/− mice. These observations indicated that NRG1 signaling maintains high GABAergic activity in amygdala and, thus, regulates fear memory. Considering that both NRG1 and ErbB4 are susceptibility genes of schizophrenia, our study sheds light on potential pathophysiological mechanisms of this disorder.

Forgetting of fear memory is a current medical therapy for posttraumatic stress disorder (PTSD), and hippocampal long-term depression (LTD) may be the underlying mechanism. Neuregulin 1 (NRG1), a trophic factor, reportedly modulates memory consolidation and synaptic plasticity. Fear memory was assessed using contextual fear conditioning. Electrophysiology was used to measure LTD and GABAergic transmission in the hippocampus. To determine the contribution of hippocampal NRG1 to fear memory forgetting and low-frequency stimulation (LFS)–induced LTD. Administration of NRG1 in the hippocampus accelerated forgetting of contextual fear memories. Furthermore, NRG1 had no effect on low-frequency stimulation–induced LTD in young mice but significantly facilitated the induction of LTD and GABAergic transmission in adult animals. More importantly, NRG1-facilitated LTD induction in adult mice could be blocked by inhibition of GABAA receptors and NMDAR activation. These findings suggest a role for NRG1 in fear memory forgetting and hippocampal LTD, providing a potential target for the development of drug-assisted PTSD therapy.

BACKGROUND: Astrocytoma is the most common primary brain tumor. The combination of adhesion molecules, proteases, and cytokines that regulate their expression likely underlies tumor progression. The cytokine of neuregulin 1 (NRG1) has a role in progression and invasion of tumor cells by activating signal after binding its receptor. AIM: To identification NRG1 expression with characteristic of intracranial astrocytoma patient is the purpose of this study. METHODS: This study uses analytic method with retrospective study. It analyzed the association between NRG1 expressions in astrocytoma patients. The study included 32 samples which were admitted to Haji Adam Malik Hospital Medan from September 2016 to August 2018. RESULTS: There was no significant association between NRG1 expression with age (p = 0.853) and gender (p = 0.565) of astrocytoma patients, while there was a significant association between NRG1 expression with cell proliferation (p = 0.00), WHO grading of astrocytoma (p = 0.00), and outcomes (p = 0.023). According to this study, the most common results are strong NRG1 expression has many cells proliferation in 10 (31.1%) patients, strong NRG1 expression with Grade IV astrocytoma found in 7 (21.9%) patients, and moderate NRG1 expression in live patient found in 7 (21.9%) patient. CONCLUSION: There is significant association between NRG1 expression and cell proliferation, WHO grading of astrocytoma, and outcomes.

Endothelial cells (ECs) secrete different paracrine signals that modulate the function of adjacent cells; two examples of these paracrine signals are nitric oxide (NO) and neuregulin-1 (NRG1), a cardioprotective growth factor. Currently, it is undetermined whether one paracrine factor can compensate for the loss of another. Herein, we hypothesized that NRG1 can compensate for endothelial NO synthase (eNOS) deficiency. We characterized eNOS null and wild-type (WT) mice by cardiac ultrasound and histology and we determined circulating NRG1 levels. In a separate experiment, eight groups of mice were divided into four groups of eNOS null mice and WT mice; half of the mice received angiotensin II (ANG II) to induce a more severe phenotype. Mice were randomized to daily injections with NRG1 or vehicle for 28 days. eNOS deficiency increased NRG1 plasma levels, indicating that ECs increase their NRG1 expression when NO production is deleted. eNOS deficiency also increased blood pressure, lowered heart rate, induced cardiac fibrosis, and affected diastolic function. In eNOS null mice, ANG II administration not only increased cardiac fibrosis but also induced cardiac hypertrophy and renal fibrosis. NRG1 administration prevented cardiac and renal hypertrophy and fibrosis caused by ANG II infusion and eNOS deficiency. Moreover, Nrg1 expression in the myocardium is shown to be regulated by miR-134. This study indicates that administration of endothelium-derived NRG1 can compensate for eNOS deficiency in the heart and kidneys. NEW & NOTEWORTHY ECs compensate for eNOS deficiency by increasing the secretion of NRG1. NRG1 administration prevents cardiac and renal hypertrophy and fibrosis caused by ANG II infusion and eNOS deficiency. NRG1 expression is regulated by miR-134.

Previously, we investigated gene expression in a high aldehyde dehydrogenase 1 expression (ALDH1high) population of urothelial carcinoma (UC) cells as UC cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) and found that NRG1 expression was upregulated in ALDH1high cells. NRG1 is a trophic factor that contains an epidermal growth factor (EGF)-like domain that signals by stimulating ERBB receptor tyrosine kinases and the cytoplasmic domain. NRG1 has been determined to be involved in frequent gene fusions with other partners in several malignancies and has a role in carcinogenesis through the NRG1 EGF-like domain and its cognitive receptor ERBBs. We thus aimed to elucidate the function of NRG1 in UC CSCs/CICs in this study. Both NRG1α and NRG1-β1 were preferentially expressed in ALDH1high cells compared with ALDH1low cells; however, siRNA experiments revealed that NRG1-β1 but not NRG1-α has a role in sphere formation. The EGF-like domain of NRG1 had a role in sphere formation of UC cells to some extent but was not essential. The intracellular domain of NRG1 did not have a role in sphere-formation. Inhibition of γ-secretase suppressed sphere formation. These findings indicate that cleavage of NRG1-β1 by γ-secretase plays an important role in UC CSC/CIC proliferation; however, the downstream targets of NRG1-β1 remain elusive.

Purpose: Oncogenic fusions involving the neuregulin 1 (NRG1) gene are found in approximately 0.2% of cancers of diverse histologies. The resulting chimeric NRG1 proteins bind predominantly to HER3, leading to HER3-HER2 dimerization and activation of downstream growth and survival pathways. HER3 is, therefore, a rational target for therapy in NRG1 fusion–driven cancers. Experimental Design: We developed novel patient-derived and isogenic models of NRG1-rearranged cancers and examined the effect of the anti-HER3 antibody, seribantumab, on growth and activation of signaling networks in vitro and in vivo. Results: Seribantumab inhibited NRG1-stimulated growth of MCF-7 cells and growth of patient-derived breast (MDA-MB-175-VII, DOC4-NRG1 fusion) and lung (LUAD-0061AS3, SLC3A2-NRG1 fusion) cancer cells harboring NRG1 fusions or NRG1 amplification (HCC-95). In addition, seribantumab inhibited growth of isogenic HBEC cells expressing a CD74-NRG1 fusion (HBECp53-CD74-NRG1) and induced apoptosis in MDA-MB-175-VII and LUAD-0061AS3 cells. Induction of proapoptotic proteins and reduced expression of the cell-cycle regulator, cyclin D1, were observed in seribantumab-treated cells. Treatment of MDA-MB-175-VII, LUAD-0061AS3, and HBECp53-CD74-NRG1 cells with seribantumab reduced phosphorylation of EGFR, HER2, HER3, HER4, and known downstream signaling molecules, such as AKT and ERK1/2. Significantly, administration of seribantumab to mice bearing LUAD-0061AS3 patient-derived xenograft (PDX) and OV-10-0050 (ovarian cancer with CLU-NRG1 fusion) PDX tumors induced regression of tumors by 50%–100%. Afatinib was much less effective at blocking tumor growth. Conclusions: Seribantumab treatment blocked activation of the four ERBB family members and of downstream signaling, leading to inhibition of NRG1 fusion–dependent tumorigenesis in vitro and in vivo in breast, lung, and ovarian patient-derived cancer models.

Bromodomain and extra-terminal (BET) proteins are epigenetic readers that bind to acetylated lysines of histones and regulate gene transcription. BET protein family members mediate the expression of various oncogenic drivers in ovarian cancer, such as the MYC and Neuregulin 1 (NRG1) genes. BRD4, the most thoroughly studied member of the BET family, is amplified in a significant subset of high-grade serous carcinomas (HGSC) of the ovary. It has been reported that BET inhibitors can attenuate the proliferation and dissemination of ovarian cancer cells by inhibiting oncogenic pathways, such as the FOXM1 and JAK/STAT pathways. BET inhibition can re-sensitize resistant ovarian cancer cells to already approved anticancer agents, including cisplatin and PARP inhibitors. This synergism was also confirmed in vivo in animal models. These and other preclinical results provide a promising basis for the application of BET inhibitors in ovarian cancer treatment. Currently, Phase I/II clinical trials explore the safety and efficacy profiles of BET inhibitors in various solid tumors, including ovarian tumors. Here, we review current knowledge on the molecular effects and preclinical activities of BET inhibitors in ovarian tumors. BET proteins have emerged as new druggable targets for ovarian cancer. BET inhibitors may enhance antitumor activity when co-administered with conventional treatment regimens. Results from ongoing Phase I/II studies are anticipated to confirm this notion.

The search for a source of endothelial cells (ECs) with translational therapeutic potential remains crucial in regenerative medicine. Human blood-derived endothelial colony-forming cells (ECFCs) represent a promising source of autologous ECs due to their robust capacity to form vascular networks in vivo and their easy accessibility from peripheral blood. However, whether ECFCs have distinct characteristics with translational value compared to other ECs remains unclear. Here, we show that vascular networks generated with human ECFCs exhibited robust paracrine support for human pluripotent stem cell-derived cardiomyocytes (iCMs), significantly improving protection against drug-induced cardiac injury and enhancing engraftment at ectopic (subcutaneous) and orthotopic (cardiac) sites. In contrast, iCM support was notably absent in grafts with vessels lined by mature-ECs. This differential trophic ability was due to a unique high constitutive expression of the cardioprotective growth factor neuregulin-1 (NRG1). ECFCs, but not mature-ECs, were capable of actively releasing NRG1, which, in turn, reduced apoptosis and increased the proliferation of iCMs via the PI3K/Akt signaling pathway. Transcriptional silencing of NRG1 abrogated these cardioprotective effects. Our study suggests that ECFCs are uniquely suited to support human iCMs, making these progenitor cells ideal for cardiovascular regenerative medicine.

The aim of this study was to identify the roles of neuregulin 1 (NRG1) during the tumor progression in non-small-cell lung cancer (NSCLC). NSCLC patients with lung squamous cell carcinoma and lung adenocarci-noma were enrolled in this study. The expression of NRG1, vascular endothelial growth factor (VEGF) and surviving in clinical specimens was examined using immunohistochemistry analysis. The cytokine production in plasma was evaluated by ELISA. The levels of NRG1-associated molecules were determined using western blotting. The proliferation and apoptosis of cells with NRG1 knockdown were accessed by CCK-8 assay and flow cytometry. Upregulation of NRG1 as well as tumor-associated angiogenesis markers VEGF and survivin was detected in tissue and serum samples of NSCLC patients compared with the control. Furthermore, positive correlation with NSCLC levels and VEGF/survivin was also found in NSCLC specimens. In addition, upregulation of NRG1, VEGF and survivin was associated with poor overall survival in NSCLC patients. Moreover, enhanced production of NRG1 was detected in serum samples from NSCLC patients compared with healthy donors, and ROC analysis revealed the importance of NRG1 levels on distinguishing NSCLC samples and the controls. These findings suggested the novel diagnostic value of NRG1 in NSCLC. Additionally, upregulated protein levels of NRG1 and its target genes were also found in tissues samples of NSCLC patients compared with normal controls. These data indicated that NRG1 was a promising marker NSCLC, and it could be involved in tumor progression by targeting its downstream target including ErbB-Akt axis. Furthermore, the growth of lung cancer cells was suppressed by the knockdown of NRG1. Our findings could provide guidance for more accurate diagnosis for NSCLC, and future therapeutic approaches might be developed by better understanding of NRG-1-modulated molecular mechanisms during the tumor development in NSCLC.

Background: Gene–environment interactions contribute to schizophrenia aetiology. Neuregulin 1 is a well-established genetic risk factor for schizophrenia, and elevated expression of type III neuregulin 1 mRNA in the dorsolateral prefrontal cortex is observed in patients with a core risk haplotype. A mouse model of type III Nrg1 overexpression ( Nrg1 III tg) possesses face and construct validity for schizophrenia; however, the sensitivity of these transgenic mice to environmental risk factors relevant to schizophrenia is unknown. Aims: To determine sensitivity of Nrg1 III tg mice to the psychostimulant methamphetamine (METH) in schizophrenia and addiction-relevant behavioural tests. Methods: We examined behavioural responses of adult male and female Nrg1 III tg mice METH (1–3 mg/kg) in schizophrenia-relevant paradigms (drug-induced locomotion, sensorimotor gating) and drug reward (conditioned place preference). Results: Male Nrg1 III tg mice were less sensitive to METH-induced stereotypies, yet showed a greater negative impact of METH on prepulse inhibition compared with wild type-like males. In contrast, female Nrg1 III tg mice were less sensitive to METH-induced locomotion than wild type-like females, while sensorimotor gating was similarly impaired by METH between the genotypes. There were no genotype differences for METH reward, or anxiety-like and exploratory behaviours. Conclusions: These results indicate that overexpression of Nrg1 type III modulates schizophrenia-relevant behaviours, and may help to explain increased sensitivity to the psychoactive effects of METH in patients with schizophrenia.

Psoriasis vulgaris is a chronic inflammatory skin condition, associated with both a physical and a psychological burden . psoriasis is portrayed by erythematous plaques covered with slivery scales over the extensor surfaces, scalp, and lumbosacral locale . Neuregulin-1β (NRG-1) is a layer bound or discharged development and separation factor that intercedes its activity by official to ErbB receptors . The point of our work is to evaluate serum level of neuregulin1-β in psoriatic patients, trying to clarify its part in the sickness pathogenesis and its connection with the illness seriousness and its connection to cardiovascular capacity, foundational and pneumonic hypertension in psoriatic patients. Case control study included 40 patients with psoriasis (Group A). What's more 40 clearly sound controls of coordinated age and sex (Group B). Finding of psoriasis was made based on the patient's set of experiences and the ordinary clinical highlights. Serum NRG-1 levels estimated by chemical connected immunosorbent test (ELISA) . We found that complete psoriasis bunch demonstrated essentially higher serum NRG-1 when contrasted with control gathering , and NRG-1 expanded bit by bit with expanded seriousness of psoriasis . No critical contrasts were found in serum NRG-1 fixation as per sex, smoking and hypertension . NRG-1 indicated huge positive relationship with PASI and seriousness; huge positive connection with pneumonic course systolic weight (PASP) ; critical negative relationship with launch division (EF).

Hypertrophic scars and keloids are forms of abnormal wound healing. Both entities are the result of exuberant fibroblast response in the dermis. Nevertheless, their clinical and histopathological characteristics, as well as their pathogenesis, are differentThe aim of this study was to study the role of neuregulin- 1 in the pathogenesis of hypertrophic scars and keloids and studying the change in tissue expression after intralesional bleomycin injection. This prospective case - control study was carried on20patients who were suffering from keloids or hypertrophic scarsand were treated by intra lesional bleomycin injection, in addition to 20 apparently healthy individuals as a control group. Assement of hypertrophic scars and keloids before and after treatment byVancouver scar scale laboratory investigations including punch biopsies from hypertrophic scars, keloids and normal tissues, qRT-PCRfor gene expression of Neuregulin1 RNA was done. HTS group before treatment showed significantly higher level of neuregulin 1 but significantly lower after treatment and neuregulin 1 sensitivity was 80%, specificity was 100%,and accuracy was 90%.Neuregulin 1 before treatment showed significant positive correlation with Neuregulin 1after treatment.Better response was significantly associated with Lower baseline neuregulin 1.Higher neuregulin 1 was considered as risk predictor of HTS or keloid susceptibility and severity. Bleomycin usage has a better result and minimal complications and less recurrence rate, which shows its usefulness as the first-line treatment modality for management of keloids and hypertrophic scars.

Bisphenol A (BPA ) is a substance commonly used in the production of plastics. Previous studies have described that it shows multidirectional harmful effects on the living organism. It is known that BPA causes liver damage, but knowledge about the roles of intrahepatic nerves in these mechanisms is extremely scanty. On the other hand, the exact roles of some neuronal substances in the nervous structures located in the liver still remain unknown. One of such substance, which is allocated a role in the stimulation of cell survival is neuregulin 1 (NRG-1). The aim of the present study was to investigate the distribution of NRG-1-like immunoreactive (NRG-1-LI) nerves in the liver in physiological conditions and under the influence of various doses of BPA using routine double immunofluorescence staining. The results (for the first time) show the presence of NRG-1 in the intrahepatic nerves, and co-localization of NGR-1 with neuronal isoform of nitric oxide synthase (nNOS) and vasoactive intestinal polypeptide (VIP). Moreover, it has been observed that high doses of BPA increase the density of NRG-1-LI intrahepatic nerves and the degree of co-localization of NRG-1 with VIP. These observations suggest that NRG-1 located in intrahepatic nerves may play functions in processes connected with liver damage and/or regeneration under the impact of BPA.

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 cellsThe experiment was conducted with three groups-control, TAK 165, and HRG-off. In the control group, we used the classical induction method of adding β-ME, RA, FSK, b-FGF, PDGF, and neuregulin (HRG); the cells were collected on the 7Our 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.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 。.

As regards acute myocardial infarction, great success has been achieved in therapies that reduce the effects of myocardial ischemic injury, while few interventions have achieved satisfactory outcomes for myocardial ischemia‑reperfusion (IR) injury. Thus, new research is urgently required to achieve breakthroughs in promising treatments. Neuregulin‑1 (NRG‑1), which is an endothelium‑derived protein and the ligand of ErbB receptors, exerts cardioprotective effects and is rapidly upregulated during IR. NRG‑1/ErbB activates several downstream signaling pathways in response to myocardial IR injury. Previous studies have revealed the protective effects of NRG‑1 during heart failure, and numerous experiments have explored the mechanisms underlying the NRG‑1‑induced cardioprotective effects against myocardial IR injury. In the present review, the progress made in the research of NRG‑1 as a cardioprotective agent during IR and related conditionings is summarized. Furthermore, the potential benefits of NRG‑1 against myocardial IR injury are listed with the prospective use of NRG‑1 in clinical applications.

Amyotrophic lateral sclerosis (ALS) is a devastating motoneuron (Mn) disease without effective cure currently available. Death of MNs in ALS is preceded by failure of neuromuscular junctions and axonal retraction. Neuregulin 1 (NRG1) is a neurotrophic factor highly expressed in MNs and neuromuscular junctions that support axonal and neuromuscular development and maintenance. NRG1 and its ErbB receptors are involved in ALS. Reduced NRG1 expression has been found in ALS patients and in the ALS SOD1(G93A) mouse model; however, the expression of the isoforms of NRG1 and its receptors is still controversial. Due to the reduced levels of NRG1 type III (NRG1-III) in the spinal cord of ALS patients, we used gene therapy based on intrathecal administration of adeno-associated virus to overexpress NRG1-III in SOD1(G93A) mice. The mice were evaluated from 9 to 16 weeks of age by electrophysiology and rotarod tests. At 16 weeks, samples were harvested for histological and molecular analyses. Our results indicate that overexpression of NRG1-III is able to preserve neuromuscular function of the hindlimbs, improve locomotor performance, increase the number of surviving MNs, and reduce glial reactivity in the treated female SOD1(G93A) mice. Furthermore, the NRG1-III/ErbB4 axis appears to regulate MN excitability by modulating the chloride transporter KCC2 and reduces the expression of the MN vulnerability marker MMP-9. However, NRG1-III did not have a significant effect on male mice, indicating relevant sex differences. These findings indicate that increasing NRG1-III at the spinal cord is a promising approach for promoting MN protection and functional improvement in ALS. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-019-00811-7) contains supplementary material, which is available to authorized users.

Purpose Hypoxia-mediated neurotoxicity contributes to various neurodegenerative disorders, including Alzheimer disease. Neuregulin-1 (NRG1) plays an important role in the development and plasticity of the brain. The aim of the present study was to investigate the neuroprotective effect and the regulating hypoxic inducible factor of NRG1 in cobalt chloride (CoCl2) induced hypoxia. Methods Hypoxia was induced in SH-SY5Y cells by CoCl2 treatment. SH-SY5Y cells were pretreated with NRG1 and then treated with CoCl2. Western blotting, immunocytochemistry, and lactate dehydrogenase (LDH) release assays were performed to examine neuroprotective properties of NRG1 in SH-SY5Y cells. Results Our data showed that CoCl2 induced cytotoxicity and changes of hypoxia-inducible factor-1α (HIF-1α) and p53 expression in SH-SY5Y cells. However, pretreatment with NRG1 inhibited CoCl2-induced accumulation of HIF-1α and p53 stability. In addition, NRG1 significantly attenuated cell death of SH-SY5Y induced by CoCl2. Conclusion NRG1 can regulate HIF-1α and p53 to protect neurons against hypoxic damage.

Biomarkers serve as indicators of disease progression or therapeutic response of an medical intervention, and means for enabling a reliable and sensitive biomarker detection are therefore vital in clinical settings. Most biosensor assays require high-affinity interactions in combination with an enzyme or fluorescent tag to enable detection and frequently employ extensive washing procedures prior to signal readout. Attempts to overcome this limitation by using natural biological partners tend to be demanding, because their very low affinity is frequently not compatible with the need of reaching low limits of detection (LODs), especially for circulating biomarkers that possess short half-lives. To address these challenges, we developed a label-free surface plasmon resonance (SPR) platform for the detection of neuregulin 1 (NRG1) using ErbB4-modified liposomes offering both signal amplification and affinity enhancement via functional multivalent interactions. Through the functional avidity interaction between NRG1 and ErbB4, an LOD of 3.5 picomolar was reached, which is about 60-fold higher than traditional SPR and miniaturized immunoassays. The biosensor displays also an 8-fold higher sensitivity when compared with a single-molecule immunoassay employing the natural binding partner rather than a high-affinity antibody as one of the interaction partners. In fact, the liposome-induced avidity between NRG1 and ErbB4 offered an LOD that was comparable to that obtained using a high-affinity antibody and enabled detection of NRG1 in plasma with a LOD of 36 pM. Employing the liposome-enhanced platform in conjunction with a low-affinity biomarker receptor thus enables the assessment of the functional state of the biomarker at competitive LODs and eliminates the need for high-affinity antibodies.

Neuregulin 1 (NRG1) is an epidermal growth factor (EGF)-like ligand that activates receptor tyrosine kinases of the ErbB family of receptors. NRG1 gene fusions, which are rare (1%) but recurrent events in solid tumors, are an emerging oncogenic driver that is potentially actionable using ErbB-targeted tyrosine kinase inhibitors. Largely characterized only in carcinomas, we describe three cases of NRG1-rearranged sarcomas. The patients were all female, aged 32-47 years old. Two cases were deep-seated tumors in the lower extremities (right thigh and calf); one case presented as a uterine mass. The tumors measured 9-11.5 cm in the greatest dimensions. Histologically, all three tumors were high-grade spindle cell sarcomas composed of monomorphic spindle cells arranged in interlacing fascicles. The tumor cells were set in the loose collagenous stroma with branching, curvilinear thin-walled vasculature in the background. Cytologically, the neoplastic cells displayed ovoid to fusiform nuclei with finely stippled chromatin, inconspicuous nucleoli, scant to moderate clear to eosinophilic cytoplasm, occasional cytoplasmic vacuoles, and elongated cytoplasmic processes. Mitotic activity was elevated ( 20/10 high power fields) and tumor necrosis was present. None of the tumors expressed lineage-specific immunophenotypical markers. Targeted RNA-sequencing uncovered gene fusions involving NRG1 and the 5' untranslated regions of PPHLN1, HMBOX1, or MTUS1. In all cases, the C-terminal EGF-like domain of NRG1 was preserved in the predicted chimeric protein product. All three patients developed metastatic disease within 2 years from initial presentation and were alive with disease at last follow-up (mean follow-up period = 19 months). In conclusion, we present the first case series of NRG1-rearranged sarcomas characterized by high-grade fascicular spindle cell morphology, non-specific immunoprofile, and aggressive clinical behavior. Further studies are needed to determine whether this distinct subgroup of spindle cell sarcomas are amenable to targeted therapies.

Extensive evidence suggests a dysfunction of the glutamate NMDA receptor (NMDAR) in schizophrenia, a severe psychiatric disorder with putative early neurodevelopmental origins, but clinical onset mainly during late adolescence. On the other hand, pharmacological models using NMDAR antagonists and the clinical manifestation of anti-NMDAR encephalitis indicate that NMDAR blockade/hypofunction can trigger psychosis also at adult stages, without any early developmental dysfunction. Previous genetic models of NMDAR hypofunction restricted to parvalbumin-positive interneurons indicate the necessity of an early postnatal impairment to trigger schizophrenia-like abnormalities, whereas the cellular substrates of NMDAR-mediated psychosis at adolescent/adult stages are unknown. Neuregulin 1 (NRG1) and its receptor ErbB4 represent schizophrenia-associated susceptibility factors that closely interact with NMDAR. To determine the neuronal populations implicated in “late” NMDAR-driven psychosis, we analyzed the effect of the inducible ablation of NMDARs in ErbB4-expressing cells in mice during late adolescence using a pharmacogenetic approach. Interestingly, the tamoxifen-inducible NMDAR deletion during this late developmental stage did not induce behavioral alterations resembling depression, schizophrenia or anxiety. Our data indicate that post-adolescent NMDAR deletion, even in a wider cell population than parvalbumin-positive interneurons, is also not sufficient to generate behavioral abnormalities resembling psychiatric disorders. Other neuronal substrates that have to be revealed by future studies, may underlie post-adolescent NMDAR-driven psychosis.

Neuregulin-1 (NRG-1) is growth factor that has been investigated for its neuroprotective properties following ischemic stroke. While NRG-1 has shown significant promise in preventing neuronal damage following stroke, the mechanisms behind its neuroprotective effects are unclear. The goal of this research was to investigate the effects of NRG-1 treatment on ischemia-induced gene expression profiles following a permanent middle cerebral artery occlusion (MCAO) in rats. Rats were sacrificed twelve hours following MCAO and either vehicle or NRG-1 treatment. RNA extracted from the peri-infarct cortex of the brain was hybridized to an Affymetrix Rat Genome 2.0st Microarray Gene Chip. Data were analyzed using the Affymetrix Transcriptome Analysis Console (TAC) 4.0 software and the STRING Protein-Protein Interaction Networks database. Our results showed that NRG-1 delivery increased the regulation of pro-survival genes. Most notably, NRG-1 treatment upregulated the CREB1 and FOXO1 transcription factor pathways which are involved in increasing anti-inflammatory and cell proliferation responses and decreasing apoptosis and oxidative stress responses, respectively. Luminex multiplex transcription factor assays demonstrated that the activities of CREB1 and FOXO1 were increased by NRG-1 treatment with MCAO. These findings provide novel insight into the molecular mechanisms involved in NRG-1 mediated neuroprotection.

N-methyl-D-aspartate receptors (NMDAR) are downregulated in schizophrenia possibly through microRNAs (miRNAs) that are differentially expressed in this condition. We screened the miRNAs that are altered in schizophrenia against the targets, Grin2A and Grin2B subunits of NMDAR using bioinformatic tools. Among the predicted miRNAs some interacted with the 3’-UTR sequences of Grin2A (miR-296, miR-148b, miR-129-2, miR-137) and Grin2B (miR-296, miR-148b, miR-129-2, miR-223) in dual luciferase assays. This was supported by downregulation of the GluN2B protein in primary hippocampal neurons upon overexpressing Grin2B targeting miRNAs. In two models of schizophrenia-pharmacological MK-801 model and neurodevelopmental methylazoxymethanol acetate (MAM) model which showed cognitive deficits - protein levels of GluN2A and GluN2B were downregulated but their transcript levels were upregulated. MiR-296-3p, miR-148b-5p and miR-137 levels showed upregulation in both models which could have interacted with Grin2A/Grin2B transcripts resulting in translational arrest. In MAM model, reciprocal changes in the expression of the 3p and 5p forms of miR-148b and miR-137 were observed. Expression of neuregulin 1 (NRG1), BDNF and CaMKIIα, genes implicated in schizophrenia, were also altered in these models. This is the first report of downregulation of GluN2A and GluN2B by miR-296, miR-148b and miR-129-2. Mining miRNAs regulating NMDA receptors might give insights into the pathophysiology of this disorder, providing avenues in therapeutics.

Simple Summary Treatment in oncology has and will keep evolving into an agnostic approach where therapies are guided more towards the identification and targeting of genetic abnormalities and less by organ of origin of the cancer, as has been done for decades. With every genetic abnormality being identified as a target, the pharmaceutical development of medications targeting these genes has grown, leading to better survival rates, quality of life and a bigger interest in finding new targets. Lung cancer is one of the best examples where targetable genetic abnormalities have led to substantial survival differences compared to patients undergoing empirical conventional chemotherapy. Translocations in the neuregulin 1 gene (NRG1) are one of many gene fusions that are becoming clinically significant, and it has the potential to become a targetable gene with ongoing clinical trials already in Europe and the US. This review aims to portray the importance and latest developments regarding this new fusion in lung cancer treatment. Abstract Oncogenic gene fusions are hybrid genes that result from structural DNA rearrangements, leading to unregulated cell proliferation by different mechanisms in a wide variety of cancer. This has led to the development of directed therapies to antagonize a variety of mechanisms that lead to cell growth or proliferation. Multiple oncogene fusions are currently targeted in lung cancer treatment, such as those involving ALK, RET, NTRK and ROS1 among many others. Neuregulin (NRG) gene fusion has been described in the development of normal tissue as well as in a variety of diseases, such as schizophrenia, Hirschsprung’s disease, atrial fibrillation and, most recently, the development of various types of solid tumors, such as renal, gastric, pancreatic, breast, colorectal and, more recently, lung cancer. The mechanism for this is that the NRG1 chimeric ligand leads to aberrant activation of ERBB2 signaling via PI3K-AKT and MAPK cellular cascades, leading to cell division and proliferation. Details regarding the incidence of these gene rearrangements are lacking. Limited case reports and case series have evaluated their clinicopathologic features and prognostic significance in the lung cancer population. Taking this into account, NRG1 could become a targetable alteration in selected patients. This review highlights how the knowledge of new molecular mechanisms of NRG1 fusion may help in gaining new insights into the molecular status of lung cancer patients and unveil a novel targetable molecular marker.

Bisphenol A (BPA) is a substance used in the manufacture of plastics which shows multidirectional adverse effects on living organisms. Since the main path of intoxication with BPA is via the gastrointestinal (GI) tract, the stomach and intestine are especially vulnerable to the impact of this substance. One of the main factors participating in the regulation of intestinal functions is the enteric nervous system (ENS), which is characterized by high neurochemical diversity. Neuregulin 1 (NRG1) is one of the lesser-known active substances in the ENS. During the present study (performed using the double immunofluorescence method), the co-localization of NRG1 with other neuronal substances in the ENS of the caecum and the ascending and descending colon has been investigated under physiological conditions and after the administration of BPA. The obtained results indicate that NRG1-positive neurons also contain substance P, vasoactive intestinal polypeptide, a neuronal isoform of nitric oxide synthase and galanin and the degree of each co-localization depend on the type of enteric plexus and the particular fragment of the intestine. Moreover, it has been shown that BPA generally increases the degree of co-localization of NRG1 with other substances.

Rationale: Cardiac sympathetic nerves are required for endogenous repair of the mammalian neonatal heart in vivo, but the underlying mechanism is unclear. Objective: We tested the hypothesis that a combination of cardiac developmental growth factors Wnt3a, BMP4 and Neuregulin (NRG-1), compensate for denervation and support cardiac regeneration in explanted neonatal mammalian hearts. Methods and Results: Hearts from 2-day old neonatal mice were harvested, lesioned at the apex and grown ex vivo for 21 days under defined conditions. Hearts grown in canonical cardiomyocyte culture media underwent complete coagulative necrosis, a process resembling ischemic cell death, by day 14. However, the addition of Wnt3a, BMP-4 and NRG-1, maintained cellular integrity and restored the endogenous regenerative program. None of these factors alone, or in any paired combination, were sufficient to induce regeneration in culture. rNRG-1 alone significantly reduced the accumulation of double strand DNA damage at Day 3; (–NRG-1: 60±12%; +NRG-1: 8±3%; P

SUMMARY Despite the development of second-generation antiandrogens, acquired resistance to hormone therapy remains a major challenge in treating advanced prostate cancer. We find that cancer-associated fibroblasts (CAFs) can promote antiandrogen resistance in mouse models and in prostate organoid cultures. We identify neuregulin 1 (NRG1) in CAF supernatant, which promotes resistance in tumor cells through activation of HER3. Pharmacological blockade of the NRG1/HER3 axis using clinical-grade blocking antibodies re-sensitizes tumors to hormone deprivation in vitro and in vivo. Furthermore, patients with castration-resistant prostate cancer with increased tumor NRG1 activity have an inferior response to second-generation antiandrogen therapy. This work reveals a paracrine mechanism of antiandrogen resistance in prostate cancer amenable to clinical testing using available targeted therapies., In Brief Zhang et al. find that cancer-associated fibroblasts promote antiandrogen resistance in prostate cancer by secreting NRG1 to activate HER3 signaling in prostate cancer cells. Blockade of the NRG1/HER3 axis can re-sensitize prostate cancer models to antiandrogen therapy., Graphical Abstract

Purpose: Gene fusions involving neuregulin 1 (NRG1) have been noted in multiple cancer types and have potential therapeutic implications. Although varying results have been reported in other cancer types, the efficacy of the HER-family kinase inhibitor afatinib in the treatment of NRG1 fusion–positive pancreatic ductal adenocarcinoma is not fully understood. Experimental Design: Forty-seven patients with pancreatic ductal adenocarcinoma received comprehensive whole-genome and transcriptome sequencing and analysis. Two patients with gene fusions involving NRG1 received afatinib treatment, with response measured by pretreatment and posttreatment PET/CT imaging. Results: Three of 47 (6%) patients with advanced pancreatic ductal adenocarcinoma were identified as KRAS wild type by whole-genome sequencing. All KRAS wild-type tumors were positive for gene fusions involving the ERBB3 ligand NRG1. Two of 3 patients with NRG1 fusion–positive tumors were treated with afatinib and demonstrated a significant and rapid response while on therapy. Conclusions: This work adds to a growing body of evidence that NRG1 gene fusions are recurrent, therapeutically actionable genomic events in pancreatic cancers. Based on the clinical outcomes described here, patients with KRAS wild-type tumors harboring NRG1 gene fusions may benefit from treatment with afatinib. See related commentary by Aguirre, p. 4589

BACKGROUND: Neuregulin (NRG) 1 plays an important role in the development of various organ systems in human. Single nucleotide polymorphisms rs35753505 C/Tof the gene encoding NRG1 evident as allele C and T with genotypes of CT, CC, and TT are believed to have an impact on NRG1 levels.AIM: To determine the impact of the NRGrs35753505 C/T polymorphisms on NRG1 levels in preterm infants.METHODS: A cross-sectional study was conducted from February to December 2018, whereas 48 eligible preterm infants with a gestational age of 32- < 37 weeks were enrolled. An umbilical cord blood specimen was collected for determination of NRG1 levels with enzyme-linked immunosorbent assay (ELISA) and NRG1 polymorphisms with polymerase chain reaction (PCR). Statistical analysis was performed with 95%CI and P value of < 0.05 was considered statistically significant.RESULTS: Median value of NRG1 levels (174.4 pg/ml) served as a cut off value. NRG 1 polymorphisms composed distribution of CC (31%), CT (42%), TT (27%) genotypes and distribution of C and T alleles were 52% and 48%. The median NRG1 levels in CC and CT genotypes were significantly lower compared to TT genotype (151.1 pg/ml vs 407.2 pg/ml, P = 0.005 and 159.1 pg/ml vs 407.2 pg/ml, P = 0.009). Subjects with C allele had significantly lower median NRG1 levels than T allele (151.1 pg/ml vs 407.2 pg/ml, P = 0.002). Subjects with CC and CT genotypes had higher risk to develop lower NRG1 levels compared to TT genotype (OR = 8.25, P = 0.016 and OR = 10.74, P = 0.005, respectively).CONCLUSION: Allele C is associated with lower NRG1 levels. Preterm infants with CC and CT genotypes pose a higher risk to have lower NRG1 levels.

C-type synaptic boutons (C-boutons) provide cholinergic afferent input to spinal cord motor neurons (MNs), which display an endoplasmic reticulum (ER)–related subsurface cistern (SSC) adjacent to their postsynaptic membrane. A constellation of postsynaptic proteins is clustered at C-boutons, including M2 muscarinic receptors, potassium channels, and s-1 receptors. In addition, we previously found that neuregulin (NRG)1 is associated with C-boutons at postsynaptic SSCs, whereas its ErbB receptors are located in the presynaptic compartment. Cbouton–mediated regulation of MN excitability has been implicated in MN disease, but NRG1-mediated functions and the impact of various pathologic conditions on C-bouton integrity have not been studied in detail. Here, we investigated changes inC-boutons after electrical stimulation,pharmacological treatment, and peripheral nerve axotomy. SSC-linked NRG1 clusters were severely disrupted in acutely stressedMNs and after tunicamycin-induced ER stress. In axotomized MNs, C-bouton loss occurred in concomitance with microglial recruitment and was prevented by the ER stress inhibitor salubrinal.Activatedmicroglia displayed apositive chemotaxis to C-boutons.Analysis of transgenicmice overexpressing NRG1 type I and type III isoforms in MNs indicated that NRG1 type III acts as an organizer of SSC-like structures, whereas NRG1 type I promotes synaptogenesis of presynaptic cholinergic terminals.Moreover,MN-derived NRG1 signals may regulate the activity of perineuronal microglial cells. Together, these data provide new insights into the molecular and cellular pathology of C-boutons in MN injury and suggest that distinct NRG1 isoform–mediated signaling functions regulate the complex matching between pre- and postsynaptic C-bouton elements. The authors thank Klaus A. Nave (Max-Planck-Institute of Experimental Medicine, Göttingen, Germany) for advice and for supplying neuregulin-1–mutant mice; Jesús María López (Universidad Complutense de Madrid, Madrid, Spain), Ester Desfilis, and José Antonio Moreno for providing spinal cord samples from nonrodent animals; Anaïs Panosa and Xavier Calomarde (all from Universitat de Lleida−Institut de Recerca Biomèdica de Lleida) for technical support with confocal and electron microscopy; and the Serveis Científico-Tècnics Anima Facility of the University of Lleida for mouse care and housing. This work was supported by grants to J.E.E. and J.C. from the Spanish Ministerio de Economía y Competitividad cofinanced by the Fondo Europeo de Desarrollo Regional (FEDER; SAF2015-70801-R). S.S. holds a grant from Spanish Ministerio de Educación, Cultura, y Deporte (FPU). M.H.S. holds a Heisenberg Fellowship from the Deutsche Forschungsgemeinschaft (DFG) and acknowledges funding by a DFG research grant (SCHW741/4-1). The authors declare no conflicts of interest.

The aim of this study was to investigate the protective effects of neuregulin-1β (NRG-1β) on sepsis-induced diaphragm atrophy and the possible underlying mechanisms. Sprague-Dawley rats were randomly divided into sham, sepsis and NRG groups. Sepsis was induced by cecal ligation and puncture (CLP). In the NRG group, rats received tail vein injections of NRG-1β (10 μg/kg) every 12 h for 72 h after CLP. At 3 days after surgery, diaphragm contractile forces were measured by determining the force-frequency curve and muscle fiber areas by hematoxylin-eosin staining. Moreover, the NRG-1 expression level in the diaphragm was detected by Western blotting. Furthermore, the proteins in the PI3K/Akt signaling pathway and its downstream Akt-mTOR and Akt-FOXO axes were detected by Western blotting analysis. In L6 myotubes treated with lipopolysaccharide (LPS) and NRG-1β, PI3K/Akt signaling pathway-related protein expression was further determined using the PI3K inhibitor LY294002. Exogenous NRG-1β could compensate for sepsis-induced diminished NRG-1 in the diaphragm and attenuate the reduction in diaphragm contractile forces and muscle fiber areas during sepsis. Moreover, NRG-1β treatment could activate the PI3K/Akt signaling pathway in the diaphragm during sepsis. The inhibition of p70S6K and 4E-BP1 on the Akt-mTOR axis and the increased expression of Murf1 on the Akt-FOXO axis were reversed after NRG-1 treatment. In addition, NRG-1β could activate the PI3K/Akt signaling pathway in L6 myotubes treated with LPS, while the PI3K inhibitor LY294002 blocked the effects of NRG-1β. NRG-1 expression in the diaphragm was reduced during sepsis, and exogenously administered recombinant human NRG-1β could attenuate sepsis-induced diaphragm atrophy by activating the PI3K/Akt signaling pathway.

Charcot-Marie-Tooth (CMT) neuropathies are a group of genetic disorders that affect the peripheral nervous system with heterogeneous pathogenesis and no available treatment. Axonal neuregulin 1 type III (Nrg1TIII) drives peripheral nerve myelination by activating downstream signaling pathways such as PI3K/Akt and MAPK/Erk that converge on master transcriptional regulators of myelin genes, such as Krox20. We reasoned that modulating Nrg1TIII activity may constitute a general therapeutic strategy to treat CMTs that are characterized by reduced levels of myelination. Here we show that genetic overexpression of Nrg1TIII ameliorates neurophysiological and morphological parameters in a mouse model of demyelinating CMT1B, without exacerbating the toxic gain-of-function that underlies the neuropathy. Intriguingly, the mechanism appears not to be related to Krox20 or myelin gene upregulation, but rather to a beneficial rebalancing in the stoichiometry of myelin lipids and proteins. Finally, we provide proof of principle that stimulating Nrg1TIII signaling, by pharmacological suppression of the Nrg1TIII inhibitor tumor necrosis factor-alpha-converting enzyme (TACE/ADAM17), also ameliorates the neuropathy. Thus, modulation of Nrg1TIII by TACE/ADAM17 inhibition may represent a general treatment for hypomyelinating neuropathies.

Cerebral ischemic stroke is associated with a high rate of incidence, prevalence and mortality globally. Carotid artery stenosis, which is mainly caused by atherosclerosis plaque, results in chronic cerebral hypoperfusion and predominantly increases the risk of ischemic stroke. In the present study, we used bilateral common carotid artery stenosis (BCAS) model by placing microcoils of 0.18 mm diameter encompassing both common carotid arteries respectively, to mimic the pathogenesis of carotid artery atherosclerosis and intensively explore the pathology. We found that BCAS injury for 1 month impaired spatial cognitive functions significantly, and inhibited synaptic plasticity, including hippocampal long-term potentiation (LTP) inhibition, dendritic spine density reduction and synaptic associative proteins disorder. BCAS-induced cerebral hypoperfused mice treated with 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU), a potent soluble epoxide hydrolase (sEH) inhibitor, exhibited amelioration of cognitive dysfunction and improved synaptic plasticity. The neural protective effects of TPPU on BCAS-induced cerebral hypoperfusion might due to activation of neuregulin-1 (NRG1)/ErbB4 signaling, and triggered PI3K-Akt pathways subsequently. Our results suggested that sEH inhibition could exert multi-target protective effects and alleviate spatial cognitive dysfunctions after chronic cerebral hypoperfusion in mice.

Anxiety disorders, especially posttraumatic stress disorder, are marked by an impaired ability to understand that a conditioned stimulus previously paired with a noxious stimulus is no longer noxious. Although previous studies suggest that fear extinction depends on the function of the amygdala, the underlying mechanisms are unclear. We found that NRG1 receptors (ErbB4) were abundantly expressed in the intercalated amygdala (ITC). The NRG1-ErbB4 pathway in the ITC promotes fear extinction. The NRG1-ErbB4 pathway in the ITC did not affect excitatory input to ITC neurons from BLA neurons but increased feed-forward inhibition of CeM neurons through increased GABAergic neurotransmission of ITC neurons. We also found that the NRG1-ErbB4 signaling pathway in ITC might regulate fear extinction through P/Q-type voltage-activated Ca2+ channels (VACCs) but not through L- or N-type VACCs. Overall, our results suggest that the NRG1-ErbB4 signaling pathway in the ITC might represent a potential target for the treatment of anxiety disorders.

Accumulation of amyloid β (Aβ) in the brain is a hallmark of Alzheimer's disease (AD). We previously showed that ErbB4 in parvalbumin-positive (PV) interneurons was associated with Aβ-induced cognitive deficits; however, the underlying mechanism remains undetermined. Here we found that specific deletion of ErbB4 in PV neurons significantly attenuated oligomeric Aβ-induced neuronal toxicity and inhibited Aβ-induced decreases of PSD95 and synaptophysin. Moreover, specific ablation of ErbB4 in PV neurons altered activity-related protein c-Fos and decreased hippocampal PV neurons, especially in the dentate gyrus (DG) of hAPP-J20 mice. Furthermore, c-Jun N-terminal kinase (JNK), a protein downstream of ErbB4, was activated by Aβ but not ErbB4's ligand neuregulin 1 (NRG1) β1, suggesting different downstream pathways for Aβ and NRG1β1. JNK phosphorylation was inhibited by the ErbB4 inhibitor AG1478 and by pretreatment with NRG1β1. More importantly, siRNA knockdown of ErbB4 decreased JNK phosphorylation and expression, tau phosphorylation at Ser396 and Thr 205, and Bax expression. Therefore, ErbB4 might mediate Aβ-induced neuropathology through the JNK/tau pathway and represent a potential therapeutic target in patients with AD. This article is protected by copyright. All rights reserved.

Epidermal Growth Factor (EGF) has long been known for its role in promoting proliferation of intestinal epithelial cells. EGF is produced by epithelial niche cells at the base of crypts in vivo and is routinely added to the culture medium to support the growth of intestinal organoids ex vivo. The recent identification of diverse stromal cell populations that reside underneath intestinal crypts has enabled the characterization of key growth factor cues supplied by these cells. The nature of these signals and how they are delivered to drive intestinal epithelial development, daily homeostasis and tissue regeneration following injury are being investigated. It is clear that aside from EGF, other ligands of the family, including Neuregulin 1 (NRG1), have distinct roles in supporting the function of intestinal stem cells through the ErbB pathway.

Disruptive or excessive repetitive motor patterns (stereotypies) are cardinal symptoms in numerous neuropsychiatric disorders. Stereotypies are also evoked by psychomotor stimulants such as amphetamine. The acquisition of motor sequences is paralleled by changes in activity patterns in the striatum, and stereotypies have been linked to abnormal plasticity in these reinforcement-related circuits. Here, we designed experiments in mice to identify transcriptomic changes that underlie striatal plasticity occurring alongside the development of drug-induced stereotypic behavior. We identified three schedules of amphetamine treatment inducing different degrees of stereotypy and used bulk RNAseq to compare striatal gene expression changes among groups of mice treated with the different drug-dose schedules and vehicle-treated, cage-mate controls. Mice were identified as naive, sensitized, or tolerant to drug-induced stereotypy. All drug-treated groups exhibited expression changes in genes that encode members of the extracellular signal-regulated kinase (ERK) cascades known to regulate psychomotor stimulant responses. In the sensitized group with the most prolonged stereotypy, we found dysregulation of 20 genes that were not changed in other groups. Gene set enrichment analysis indicated highly significant overlap with genes regulated by neuregulin 1 (Nrg1). Nrg1 is known to be a schizophrenia and autism susceptibility gene that encodes a ligand for Erb-B receptors, which are involved in neuronal migration, myelination, and cell survival, including that of dopamine-containing neurons. Stimulant abuse is a risk factor for schizophrenia onset, and these two disorders share behavioral stereotypy phenotypes. Our results raise the possibility that drug-induced sensitization of the Nrg1 signaling pathway might underlie these links.

Pancreatic cancer (PC) remains an incurable disease with few treatment options Recently, promising targets have been identified and novel therapeutic drugs are currently under development in KRAS wild-type PC. It has been reported that KRAS wild-type PC has the genomic alterations such as oncogenic derivers and kinase fusions. NRG1 fusion, which encodes the neuregulin 1 and is the main ligands for ERRB3, has been identified in approximately half of younger patients with PC with KRAS wild-type tumors by RNA sequencing. There are several promising targeted therapies for NRG1 fusion-positive tumors, such as EGFR-tyrosine kinase inhibitor, HER3, HER2 antibodies. BRAF, NTRK, and ALK fusion are also potentially actionable alterations in KRAS wild-type PC and novel therapies targeting certain aberrations have shown activity in clinical trials.

Multiple sclerosis is characterized by immune mediated neurodegeneration that results in progressive, life-long neurological and cognitive impairments. Yet, the endogenous mechanisms underlying multiple sclerosis pathophysiology are not fully understood. Here, we provide compelling evidence that associates dysregulation of neuregulin-1 beta 1 (Nrg-1β1) with multiple sclerosis pathogenesis and progression. In the experimental autoimmune encephalomyelitis model of multiple sclerosis, we demonstrate that Nrg-1β1 levels are abated within spinal cord lesions and peripherally in the plasma and spleen during presymptomatic, onset and progressive course of the disease. We demonstrate that plasma levels of Nrg-1β1 are also significantly reduced in individuals with early multiple sclerosis and is positively associated with progression to relapsing-remitting multiple sclerosis. The functional impact of Nrg-1β1 downregulation preceded disease onset and progression, and its systemic restoration was sufficient to delay experimental autoimmune encephalomyelitis symptoms and alleviate disease burden. Intriguingly, Nrg-1β1 therapy exhibited a desirable and extended therapeutic time window of efficacy when administered prophylactically, symptomatically, acutely or chronically. Using in vivo and in vitro assessments, we identified that Nrg-1β1 treatment mediates its beneficial effects in EAE by providing a more balanced immune response. Mechanistically, Nrg-1β1 moderated monocyte infiltration at the blood-CNS interface by attenuating chondroitin sulphate proteoglycans and MMP9. Moreover, Nrg-1β1 fostered a regulatory and reparative phenotype in macrophages, T helper type 1 (Th1) cells and microglia in the spinal cord lesions of EAE mice. Taken together, our new findings in multiple sclerosis and experimental autoimmune encephalomyelitis have uncovered a novel regulatory role for Nrg-1β1 early in the disease course and suggest its potential as a specific therapeutic target to ameliorate disease progression and severity.

Spinal cord injury (SCI) causes sensorimotor and autonomic impairment that partly reflects extensive, permanent loss of neurons at the epicenter and penumbra of the injury. Strategies aimed at enhancing neuronal protection are critical to attenuate neurodegeneration and improve neurological recovery after SCI. In rat SCI, we previously uncovered that the tissue levels of neuregulin-1beta 1 (Nrg-1β1) are acutely and persistently downregulated in the injured spinal cord. Nrg-1β1 is well-known for its critical roles in the development, maintenance and physiology of neurons and glia in the developing and adult spinal cord. However, despite this pivotal role, Nrg-1β1 specific effects and mechanisms of action on neuronal injury remain largely unknown in SCI. In the present study, using a clinically-relevant model of compressive/contusive SCI in rats and an in vitro model of glutamate toxicity in primary neurons, we demonstrate Nrg-1β1 provides early neuroprotection through attenuation of reactive oxygen species, lipid peroxidation, necrosis and apoptosis in acute and subacute stages of SCI. Mechanistically, availability of Nrg-1β1 following glutamate challenge protects neurons from caspase-dependent and independent cell death that is mediated by modulation of mitochondria associated apoptotic cascades and MAP kinase and AKT signaling pathways. Altogether, our work provides novel insights into the role and mechanisms of Nrg-1β1 in neuronal injury after SCI and introduces its potential as a new neuroprotective target for this debilitating neurological condition.

Neuregulin‐1 (NRG‐1) is reported to be cardioprotective through the extracellular‐regulated protein kinase (ERK) 1/2 pathway in myocardial ischaemia‐reperfusion injury (MIRI). NOX4‐induced ROS activated NLRP3 inflammasome and exacerbates MIRI. This study aims to investigate whether NRG‐1 can suppress NOX4 by ERK1/2 and consequently inhibit the NLRP3/caspase‐1 signal in MIRI. The myocardial infarct size (IS) was measured by TTC‐Evans blue staining. Immunohistochemical staining, real‐time quantitative PCR (RT‐qPCR) and Western blotting were used for detection of the factors, such as NOX4, ERK1/2, NLRP3, caspase‐1 and IL‐1β .The IS in the NRG‐1 (3 μg/kg, intravenous) group was lower than that in the IR group. Immunohistochemical analysis revealed NRG‐1 decreased 4HNE and NOX4. The RT‐qPCR and Western blot analyses revealed that NRG‐1 mitigated the IR‐induced up‐regulation of NOX4 and ROS production. Compared with the IR group, the NRG‐1 group exhibited a higher level of P‐ERK1/2 and a lower level of NLRP3. In the Langendorff model, PD98059 inhibited ERK1/2 and up‐regulated the expression of NOX4, NLRP3, caspase‐1 and IL‐1β, which exacerbated oxidative stress and inflammation. In conclusion, NRG‐1 can reduce ROS production by inhibiting NOX4 through ERK1/2 and inhibit the NLRP3/caspase‐1 pathway to attenuate myocardial oxidative damage and inflammation in MIRI.

RATIONALEAppropriate fibrotic tissue formation after myocardial infarction (MI) is crucial to maintenance of the heart’s structure. Reparative or M2-like macrophages play a vital role in post-MI fibrosis by activating cardiac fibroblasts. However, the mechanism by which post-MI cardiac fibrosis is regulated is not fully understood.OBJECTIVEWe investigated the cellular and molecular mechanisms of post-MI fibrotic tissue formation, especially those related to regulation of cellular senescence and apoptosis.METHODS AND RESULTSIn vivoandin vitroexperiments were used to investigate the molecular and cellular mechanisms through which post-MI fibrosis occurs, with a focus on the role of M2-like macrophages. Microarray analysis revealed that CD206+F4/80+CD11b+M2-like macrophages collected from mouse hearts on post-MI day 7 showed increased expression of neuregulin 1 (Nrg1). Nrg1 receptor epidermal growth factor receptor ErbB was expressed on cardiac fibroblasts in the infarct area. In cardiac fibroblasts in which hydrogen peroxide-induced senescence, M2-like macrophage-derived Nrg1 suppressed both senescence and apoptosis of the fibroblasts, whereas blockade of ErbB function significantly accelerated. M2-like macrophage-derived Nrg1/ErbB/PI3K/Akt signaling, which was shown to be related to anti-senescence, was activated in damaged cardiac fibroblasts. Interestingly, systemic blockade of ErbB function in MI model mice enhanced senescence and apoptosis of cardiac fibroblasts and exacerbated inflammation. Further, increased accumulation of M2-like macrophages resulted in excessive progression of fibrosis in post-MI murine hearts. The molecular mechanism underlying regulation of fibrotic tissue formation in the infarcted myocardium was shown in part to be attenuation of apoptosis and senescence of cardiac fibroblasts by activation of Nrg1/ErbB/PI3K/Akt signaling.CONCLUSIONSM2-like macrophage-mediated regulation of Nrg1/ErbB signaling, have a substantial effect on fibrotic tissue formation in the infarcted adult mouse heart, is critical for suppressing the progression of senescence and apoptosis of cardiac fibroblasts.

Pancreatic neuroendocrine tumor (PNET), a heterogenous type of neoplasm with limited treatment options, is relatively rare and to date, the genetic background has remained to be fully elucidated. The present study aimed to determine the mutational landscape of PNET with and without liver metastasis, as well as its clinical application value for treatment. Fresh tumor tissues were collected from 14 patients with PNET following surgery, 4 of whom had developed liver metastasis. Subsequently, targeted next-generation sequencing of 612 cancer-associated genes and comprehensive analysis were performed on the tumor tissues. The results identified 63 somatic mutations in 53 genes in the 14 patients with PNET, amongst which menin 1 was identified as the most recurrently mutated gene. The analysis also identified several novel recurrently mutated genes, including adrenoceptor alpha 2B, ARVCF delta catenin family member, carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase and neuregulin 1. Among the 53 mutated genes, 11 were enriched in the PI3K/AKT signaling pathway (adjusted P=7.12x10-5). In addition, 4 patients with PNET with liver metastasis had distinctly different mutational profiles compared with those without liver metastasis; 13 genes were discovered to be exclusively mutated in the liver metastasis group of the patients with PNET, including ATRX chromatin remodeler, thioredoxin reductase 2, anus kinase 3, ARVCF delta catenin family member, integrin subunit alpha V and RAD50 double strand break repair protein. In addition, two potentially actionable alterations in BRCA2 DNA repair-associated (p.Q548Q) and neurofibromin 1 (p.Q1188X) were identified using the OncoKB database. In conclusion, the present study generated a comprehensive mutational profile of 14 patients with PNET and further described the features of patients with liver metastasis, which highlights potential targets for drug development of PNET.

Endothelial cells (ECs) secrete different paracrine signals that modulate the function of adjacent cells; two examples of these paracrine signals are nitric oxide (NO) and neuregulin-1 (NRG1), a cardioprotective growth factor. Currently, it is undetermined whether one paracrine factor can compensate for the loss of another. Herein, we hypothesized that NRG1 can compensate for endothelial NO synthase (eNOS) deficiency. We characterized eNOS null and wild-type (WT) mice by cardiac ultrasound and histology and we determined circulating NRG1 levels. In a separate experiment, eight groups of mice were divided into four groups of eNOS null mice and WT mice; half of the mice received angiotensin II (ANG II) to induce a more severe phenotype. Mice were randomized to daily injections with NRG1 or vehicle for 28 days. eNOS deficiency increased NRG1 plasma levels, indicating that ECs increase their NRG1 expression when NO production is deleted. eNOS deficiency also increased blood pressure, lowered heart rate, induced cardiac fibrosis, and affected diastolic function. In eNOS null mice, ANG II administration not only increased cardiac fibrosis but also induced cardiac hypertrophy and renal fibrosis. NRG1 administration prevented cardiac and renal hypertrophy and fibrosis caused by ANG II infusion and eNOS deficiency. Moreover

Cortical disinhibition is a common feature of several neuropsychiatric diseases such as schizophrenia, autism and intellectual disabilities. However, the underlying mechanisms are not fully understood. To mimic increased expression of Nrg1, a schizophrenia susceptibility gene in GABAergic interneurons from patients with schizophrenia, we generated gtoNrg1 mice with overexpression of Nrg1 in GABAergic interneurons. gtoNrg1 mice showed cortical disinhibition at the cellular, synaptic, neural network and behavioral levels. We revealed that the intracellular domain of NRG1 interacts with the cytoplasmic loop 1 of Nav1.1, a sodium channel critical for the excitability of GABAergic interneurons, and inhibits Nav currents. Intriguingly, activation of GABAergic interneurons or restoring NRG1 expression in adulthood could rescue the hyperactivity and impaired social novelty in gtoNrg1 mice. These results identify mechanisms underlying cortical disinhibition related to schizophrenia and raise the possibility that restoration of NRG1 signaling and GABAergic function is beneficial in certain neuropsychiatric disorders., The molecular and cellular mechanisms of cortical disinhibition as a common feature of many psychiatric diseases are not fully understood. The authors identify an interaction between NRG1 and Nav1.1 sodium channel as a mechanism of how NRG1 modulates the excitability of GABAergic interneurons.