Neuregulin Research Articles

Correlation of rs35753505 polymorphism in Neuregulin 1 gene with psychopathology and intelligence of people with schizophrenia

Background and aimSchizophrenia 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. Materials and methods102 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. ResultsAccording 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. ConclusionIn 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.

Study on inhibitory effect of GC-miR-143 inhibitor nanoparticles on D2 receptor-mediated neurological behavioral damage in lacunar infarction

Blocking the dopamine D2 receptor is a key link in anti-psychiatric disease. Knockdown of miR-143 improved neurological behavioral damage by regulating the D2 receptor signaling pathway. The risk of neurological behavior damage can be increased 20 times by 1–2 lacunar infarction lesions. Based on the fact that miR-143 can target and regulate the D2 receptor signaling pathway, this study focused on analyzing the inhibitory effect of GC-miR-143 inhibitor nanoparticles on neurological behavior damage in lacunar infarction. 60 SD rats were separated into sham operation, model, vehicle, vehicle+inhibitor, inhibitor, or D2 agonist group (n = 10). The vascular dementia (VD) model was made by ligating bilateral common carotid arteries. Morris water maze assessed rats behavioral changes. Quantitative Real-Time Reverse Transcription PCR (QRT-PCR) was applied to detect levels of miRNA-143. Proteins were extracted from the prefrontal cortex, and immunoblotting was performed to measure the downstream of signal proteins of Neuregulin 1 (NRG1) and D2 receptor signaling pathways, p-protein kinase B (AKT) and p-Glycogen Synthase Kinase 3β (GSK3β). On days 1 to 5 of the water maze experiment, the escape latency for the five groups of rats were longer than in sham group; while escape latency for vehicle+inhibitor group and inhibitor group was shorter. Compared to VD model rats, vehicle+inhibitor group and inhibitor group had significantly reduced escape latency. Cross-platform time number for five groups was decreased and it was increased in vehicle+inhibitor group and inhibitor group with decreased number for D2 agonist group w. Compared with D2 agonist group, the vehicle+inhibitor group and inhibitor group showed more cross-platform times. Compared to sham operation group, levels of NRG1, p-AKT/GSK3β in remaining five groups were significantly decreased. Their levels in vector+inhibition group and inhibitor group were dramatically up-regulated, and levels of the above-mentioned proteins in D2 agonist group were significantly decreased. Their levels in vector+inhibitor group and inhibitor group were up-regulated relative to D2 agonist group. The GC-miR-143 inhibitor nanoparticles can up-regulate the expression of NRG1 and antagonize the D2 receptor to weaken the inhibitory effect of D2 receptor-mediated signaling pathways and inhibit neurological behavioral damage in lacunar cerebral infarction.

Dual-targeting therapy against HER3/MET in human colorectal cancers.

Colorectal cancer (CRC) is the most common malignancy in the world, and novel molecular targeted therapies for CRC have been vigorously pursued. We searched for novel combination therapies based on the expression patterns of membrane proteins in CRC cell lines. A positive correlation was observed between the expression of human pidermal growth factor receptor (HER) 3 and mesenchymal-to-epithelial transition factor (MET) on the cell surface of CRC cell lines. The brief stimulation of HER3/MET-high SW1116 CRC cells with both neuregulin-1 (NRG1) and hepatocyte growth factor enhanced ERK phosphorylation and cell proliferation more than each stimulation alone. In addition, a prolonged NRG1 stimulation resulted in the tyrosine phosphorylation of MET. In this context, the Forkhead Box protein M1 (FOXM1)-regulated tyrosine phosphorylation of MET by NRG1 was demonstrated, suggesting the existence of a signaling pathway mediated by FOXM1 upon the NRG1 stimulation. Since the co-expression of HER3 and MET was also demonstrated in in vivo CRC tissues by immunohistochemistry, we investigated whether the co-inhibition of HER3 and MET could be an effective therapy for CRC. We established HER3-and/or MET-KO SW1116 cell lines, and HER3/MET-double KO resulted in the inhibition of in vitro cell proliferation and in vivo tumor growth in nude mice by SW1116 cells. Furthermore, the combination of patritumab, an anti-HER3 fully human mAb, and PHA665752, a MET inhibitor, markedly inhibited in vitro cell proliferation, 3D-colony formation, and in vivo tumor growth in nude mice by SW1116 cells CONCLUSION: The dual targeting of HER3/MET has potential as CRC therapy.

ER-PM Junctions on GABAergic Interneurons Are Organized by Neuregulin 2/VAP Interactions and Regulated by NMDA Receptors.

Neuregulins (NRGs) signal via ErbB receptors to regulate neural development, excitability, synaptic and network activity, and behaviors relevant to psychiatric disorders. Bidirectional signaling between NRG2/ErbB4 and NMDA receptors is thought to homeostatically regulate GABAergic interneurons in response to increased excitatory neurotransmission or elevated extracellular glutamate levels. Unprocessed proNRG2 forms discrete clusters on cell bodies and proximal dendrites that colocalize with the potassium channel Kv2.1 at specialized endoplasmic reticulum-plasma membrane (ER-PM) junctions, and NMDA receptor activation triggers rapid dissociation from ER-PM junctions and ectodomain shedding by ADAM10. Here, we elucidate the mechanistic basis of proNRG2 clustering at ER-PM junctions and its regulation by NMDA receptors. Importantly, we demonstrate that proNRG2 promotes the formation of ER-PM junctions by directly binding the ER-resident membrane tether VAP, like Kv2.1. The proNRG2 intracellular domain harbors two non-canonical, low-affinity sites that cooperatively mediate VAP binding. One of these is a cryptic and phosphorylation-dependent VAP binding motif that is dephosphorylated following NMDA receptor activation, thus revealing how excitatory neurotransmission promotes the dissociation of proNRG2 from ER-PM junctions. Therefore, proNRG2 and Kv2.1 can independently function as VAP-dependent organizers of neuronal ER-PM junctions. Based on these and prior studies, we propose that proNRG2 and Kv2.1 serve as co-regulated downstream effectors of NMDA receptors to homeostatically regulate GABAergic interneurons.

Neuregulin-1/PI3K signaling effects on oligodendrocyte proliferation, remyelination and behaviors deficit in a male mouse model of ischemic stroke

In this study, we investigated the effect of neuregulin-1 (NRG1) on demyelination and neurological function in an ischemic stroke model, and further explored its neuroprotective mechanisms. Adult male ICR mice underwent photothrombotic ischemia surgery and were injected with NRG1 beginning 30 min after ischemia. Cylinder and grid walking tests were performed to evaluate the forepaw function. In addition, the effect of NRG1 on neuronal damage/death (Cresyl violet, CV), neuronal nuclei (NeuN), nestin, doublecortin (DCX), myelin basic protein (MBP), non-phosphorylated neurofilaments (SMI-32), adenomatous polyposis coli (APC), erythroblastic leukemia viral oncogene homolog (ErbB) 2, 4 and serine-threonine protein kinase (Akt) in cortex were evaluated using immunohistochemistry, immunofluorescence and western blot. The cylinder and grid walking tests exposed that treatment of NRG1 observably regained the forepaw function. NRG1 treatment reduced cerebral infarction, restored forepaw function, promoted proliferation and differentiation of neuron and increased oligodendrogliogenesis. The neuroprotective effect of NRG1 is involved in its activation of PI3K/Akt signaling pathway via ErbB2, as shown by the suppression of the effect of NRG1 by the PI3K inhibitor LY294002. Our results demonstrate that NRG1 is effective in ameliorating the both acute phase neuroprotection and long-term neurological functions via resumption of neuronal proliferation and differentiation and oligodendrogliogenesis in a male mouse model of ischemic stroke.

Serum-derived exosomal miR-125a-3p predicts the response to anti-programmed cell death-1/programmed cell death-ligand 1 monotherapy in patients with non-small cell lung cancer

BackgroundVersatile 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.

Review of Experimental Models of Schizophrenia

Schizophrenia is a severe psychiatric disease that has a lifetime prevalence of 1% in most of the populations studied. The neuropathology and psychopathology of Schizophrenia are still poorly understood. This is attributed to the paucity of adequate animal models. Schizophrenia is a disorder of the human brain. Consequently, the potency of animal models in Schizophrenia research is limited to certain aspects of the disease. One of the most difficult aspects of modelling Schizophrenia in animals has been the lack of a clear and explicit conceptual framework for this disorder. This review discussed drug-induced animal models of Schizophrenia such as Ketamine (NMDA receptor antagonist), Phencyclidine (NMDA receptor antagonist) etc. It also discussed genetic animal models of Schizophrenia which include but not limited to Schizophrenia susceptibility Genes, Neuregulin-1(NRG1), DAT gene, Zinc finger DHH-type3 containing 8 (ZDHHC8) and Dysbindin. It went further to discuss fetal models Schizophrenia, postweaning social isolation and ended with In-Vitro animal models. The use of animal models to improve understanding of the neurochemical and structural CNS changes that precipitate development of Schizophrenia, rather than a focus on treating the symptoms, is a prerequisite to enable new more effective therapeutic strategies to be developed. Because of the complexity and ambiguity of gene-gene and gene-environment interactions in the aetiology of schizophrenia, the challenge of developing more reliable predictive animal models of this disorder, most likely through multiple early-life interventions, is still ongoing.

Treatment of pancreatic cancer in 2022.

Pancreatic ductal adenocarcinoma (PDAC) is usually diagnosed at an advanced, incurable, stage and has an extremely poor prognosis. Systemic chemotherapy represents the standard treatment either in the pre-operative, adjuvant and palliative setting, which is associated with only modest improvement in survival. More recently, advances in cancer genomic sequencing have unravelled the molecular heterogeneity of PDAC and identified small patient subgroups harbouring unique actionable aberrations in BRCA, NTRK, NRG1 and mismatch repair genes paving the way to a more personalised approach for this tumour. However, the evolution of PDAC treatment towards a successful precision approach presents many challenges. In this review, we discuss the current standard treatments of PDAC, from early stage to advanced disease, and we illustrate the opportunities and challenges of precision medicine for this deadly cancer.

Neuregulin-1 reverses anxiety-like behavior and social behavior deficits induced by unilateral micro-injection of CoCl2 into the ventral hippocampus (vHPC)

Neuregulin-1 (NRG1) is an epidermal growth factor family member with essential roles in the developing and adult nervous systems. In recent years, establishing evidence has collectively suggested that NRG1 is a new modulator of central nervous system (CNS) injury and disease, with multifaceted roles in neuroprotection, remyelination, neuroinflammation, and other repair mechanisms. NRG1 signaling exerts its effects via the tyrosine kinase receptors ErbB2-ErbB4. The NRG1/ErbB network in CNS pathology and repair has evolved, primarily in recent years. In the present study, we demonstrated that a unilateral microinjection of CoCl2 into the ventral hippocampus (vHPC) induced hypoxic insult and led to anxiety-related behaviors and deficit sociability in mice. NRG1 treatment significantly alleviated the CoCl2-induced increase of hypoxic-related molecules and behavioral abnormalities. Furthermore, NRG1 reduced the CoCl2-induced neuroinflammation and neuronal deficits in the vHPC or primary hippocampal neurons in mice. Collectively, these results suggest that NRG1 ameliorates hypoxia by alleviating synaptic deficits and behavioral abnormalities of the CoCl2-induced vHPC hypoxic model.

MOTS-c and aerobic exercise induce cardiac physiological adaptation via NRG1/ErbB4/CEBPβ modification in rats

AimsTo determine the effects of the mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-c) and aerobic exercise on cardiac structure and function and explore the role of neuregulin-1 (NRG1)- ErbB2 receptor tyrosine kinase 4(ErbB4)- CCAAT-enhancer binding protein β (C/EBPβ) in cardiac physiological adaptation induced by MOTS-c and aerobic training. Main methodsWe used Hematoxylin-Eosin staining(HE)and Transmission Electron Microscope (TEM) to observe the cardiac myocardial structure, carotid artery catheterization to test cardiac function, and real-time quantitative polymerase chain reaction (qRT-PCR) and Western blotting to describe the changes of NRG1, ErbB4, C/EBPβ, and Gata in cardiac physiological adaptation. Key findingsMOTS-c and aerobic training significantly increased heart weight and heart weight index (HWI) (all p < 0.05). Aerobic exercise and MOTS-c treatment thickened myocardial fibers, with a tendency of hypertrophy. Heart rate (HR) (p < 0.001, p = 0.010, p = 0.011), the isovolumic diastolic time constant (Tau) (p < 0.001, p < 0.001, p < 0.001) in exercised (E), MOST-c treated (M) and their combination (ME) decreased significantly, while the dP/dtmax (p < 0.001, p < 0.001, p = 0.039) and dP/dtmin (p < 0.001, p < 0.001, p = 0.001) in groups E, M and ME were significantly higher than those in group C, but EDP (p = 0.903, p = 0.708, p = 0.744) remained unchanged. Moreover, C/EBPβ gene levels were significantly decreased in the differential gene expression between groups C and M transcriptomics sequencing. The levels of ErbB4 mRNA (p < 0.001, p < 0.001, p < 0.001) and Gata4 mRNA (p < 0.001, p < 0.001, p = 0.001) in groups E, M and ME increased significantly, while C/EBPβ mRNA expression decreased significantly (p < 0.001, p = 0.002, p = 0.001), which was consistent with the results of transcriptome sequencing. NRG1 mRNA in group E was significantly higher than that in group C (p = 0.003), but there was no significant difference between groups M and ME (p = 0.804, p = 0.320). The protein expression of NRG1 (p = 0.026, p < 0.001, p < 0.001), ErbB4 (p < 0.001, p < 0.001, p < 0.001) and Gata4 (p = 0.014, p < 0.001, p = 0.006) in groups E, M and ME increased significantly, while C/EBPβ decreased significantly (p < 0.001, p = 0.001, p = 0.002). SignificanceOur findings suggest that MOTS-c and aerobic exercise had similar effects, improving myocardial morphology and structure and enhancing cardiac function through activation of the NRG1-ErbB4-C/EBPβ pathway.

Neuregulin modulates hormone receptor levels in breast cancer through concerted action on multiple signaling pathways.

The Neuregulins (NRGs) are growth factors that bind and activate ErbB/HER receptor tyrosine kinases. Some reports have described an interplay between this ligand-receptor system and hormonal receptors in breast cancer. However, the mechanisms by which NRGs regulate hormonal receptor signaling have not been sufficiently described. Here, we show that in breast cancer cells the activation of NRG receptors down-regulated ERα through a double mechanism that included post-transcriptional and transcriptional effects. This regulation required the concerted participation of three signaling routes: the PI3K/AKT/mTOR, ERK1/2, and ERK5 pathways. Moreover, these three routes were also involved in the phosphorylation of ERα at serines 118 and 167, two residues implicated in resistance to endocrine therapies. On the other hand, NRGs conferred resistance to fulvestrant in breast cancer cells and this resistance could be reversed when the three pathways activated by NRGs were simultaneously inhibited. Our results indicate that estrogen receptor-positive (ER+) breast tumors that can have access to NRGs may be resistant to fulvestrant. This resistance could be overcome if strategies to target the three main pathways involved in the interplay between NRG receptors and ERα could be developed.

Alterations in prefrontal cortical neuregulin-1 levels in post-pubertal rats with neonatal ventral hippocampal lesions.

Genetic studies in humans have implicated the gene encoding neuregulin-1 (NRG-1) as a candidate susceptibility gene for schizophrenia. Furthermore, it has been suggested that NRG-1 is involved in regulating the expression and function of the N-methyl-D-aspartate receptor and the GABAA receptor in several brain areas, including the prefrontal cortex (PFC), the hippocampus, and the cerebellum. Neonatal ventral hippocampal lesioned (NVHL) rats have been considered as a putative model for schizophrenia with characteristic post-pubertal alteration in response to stress and neuroleptics. In this study, we examined NRG-1, erb-b2 receptor tyrosine kinase 4 (erbB4), and phospho-erbB4 (p-erbB4) levels in the PFC and the distribution of NRG-1 in the NVHL rats by using immunoblotting and immunohistochemical analyses. Neonatal lesions were induced by bilateral injection of ibotenic acid in the ventral hippocampus of postnatal day 7 Sprague-Dawley (SD)-rats. NVHL rats showed significantly decreased levels of NRG-1 and p-erbB4 in the PFC compared to sham controls at post-pubertal period, while the level of erbB4 did not differ between sham and NVHL rats. Moreover, microinjection of NRG-1 into the mPFC improved NVHL-induced prepulse inhibition deficits. Our study suggests PFC NRG-1 alteration as a potential mechanism in schizophrenia-like behaviors in the NVHL model.

Astragaloside VI Ameliorates Post-Stroke Depression via Upregulating the NRG-1-Mediated MEK/ERK Pathway.

Post-stroke depression (PSD) has been identified as one of the most commonly occurring complications attributed to stroke. Astragaloside VI (AsVI), which is an active Radix Astragali (AR)-derived compound, has been reported to be a potential drug for post-stroke therapy, but its effects on PSD and the underlying mechanisms remain uncovered. In this study, healthy male SD rats underwent a middle cerebral artery occlusion (MCAO) stroke model. To create a PSD model, these rats were then kept in isolated houses and subjected to chronic unpredictable mild stress. The rats were examined every five days for a series of behavioral tests of depression. The antidepressant properties of AsVI were also investigated in vitro in a corticosterone (CORT)-induced major depression model using a CCK-8 assay. The release of neurotransmitters dopamine (DA)/5-hydroxytryptamine (5-HT) was measured using HPLC. The expression of the neurotrophic factor Neuregulin 1 (NRG-1) in rat brain tissues was detected by immunostaining. The protein expression of NRG-1, p-MEK1, and p-ERK1/2 was analyzed utilizing western blotting. AsVI treatment significantly reduced depression-like behaviors in PSD rats and attenuated the CORT-induced apoptotic cell death in neuronal PC-12 cells. Besides, AsVI treatment remarkably prevented the decrease of the levels of DA and 5-HT in the PSD rat brains and in CORT-induced PC-12 cells. Furthermore, AsVI treatment upregulated the NRG-1-mediated MEK/ERK pathway, which is associated with the improvement of PSD. These findings suggest that AsVI could improve PSD at least partially by upregulating NRG-1-mediated MEK/ERK pathway. AsVI could be a novel therapeutic option for treating PSD.

Cyclosporin A Promotes Invasion and Migration of Extravillous Trophoblast Cells Derived from Human-Induced Pluripotent Stem Cells and Human Embryonic Stem Cells.

Extravillous trophoblast (EVT) cells play an essential role in the maternal-fetal interaction. Although abnormal development and function of EVT cells, including impaired migration and invasion capability, are believed to be etiologically linked to severe pregnancy disorders including pre-eclampsia, the associated molecular mechanisms are not clear due to the lack of an appropriate cell model in vitro. Cyclosporin A (CsA) is a macrolide immunosuppressant and also used in clinic to improve pregnancy outcomes. However, whether CsA has any effects on the function of EVT cells has not been well investigated. In this study, we induced differentiation of human-induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) into EVT cells (hiPSC-EVT and hESC-EVT cells, respectively) by Y27632, neuregulin-1 (NRG1), A83-01, and matrigel, and collected these derived EVT cells by flow cytometry for sorting cells positive for double human leukocyte antigen-G (HLA-G) and Cytokeratin7 (KRT7), both of which are EVT markers. We then investigated the effects of CsA on the invasion and migration of these derived EVT cells. We found that the hiPSC-EVT and hESC-EVT cells expressed high levels of the EVT markers such as KRT7, integrin alpha 5 (ITGA5), and HLA-G but low levels of OCT4, a stem cell marker, and that CsA significantly promoted the invasion and migration of hiPSC-EVT and hESC-EVT cells compared with HTR-8/SVneo cells. These results represent a possible cell model for studying the function of EVT cells and mechanism of pregnancy-related disorders associated with EVT. In addition, CsA may be used to treat pregnancy complications in clinic associated with deficient EVT function.

NRG1 knockdown rescues PV interneuron GABAergic maturation deficits and schizophrenia behaviors in fetal growth restriction mice

Schizophrenia is a highly debilitating mental disorder, those who experienced fetal growth restriction (FGR) in the early stage of life have a greater probability of schizophrenia. In this study, FGR mice showed hyperactivity in locomotor activity test, sociability dysfunction in three chamber test and nesting social behavior tests, cognition decline in Morris water maze and impaired sensory motor gating function in prepulse inhibition test. Mechanistic studies indicated that the number of parvalbumin (PV) interneuron was significantly reduced in FGR mouse media prefrontal cortex (mPFC). And the mRNA and protein level of neuregulin 1(NRG1), which is a critical schizophrenia gene, increased significantly in FGR mouse mPFC. Furthermore, NRG1 knockdown in FGR mouse mPFC improved PV interneuron GABAergic maturation and rescued schizophrenia behaviors including hyperactivity, social novelty defects, cognition decline, and sensorimotor gating deficits in FGR mice. This study indicates that mPFC NRG1 upregulation is one of the main causes of FGR-induced schizophrenia, which leads to significant reduction of PV interneuron number in mPFC. NRG1 knockdown in mPFC significantly rescues schizophrenia behaviors in FGR mouse. This study thus provides a potential effective therapy target or strategy for schizophrenia patients induced by FGR.

Low-intensity pulsed ultrasound promotes proliferation and myelinating genes expression of Schwann cells through NRG1/ErbB signaling pathway

Schwann cells (SCs) are the major component of myelin sheath in the peripheral nervous system, which are necessary in the development, function maintenance, and repair of peripheral nerves. This study aimed to investigate the potential mechanism of low-intensity pulsed ultrasound (LIPUS) affecting the proliferation and myelinating activity of SCs. Rat Schwann cell line RSC96 were cultured and exposed to LIPUS of different duty ratios (control, 20 %, 50 %, 80 %). Results demonstrated that LIPUS with a duty ratio of 50 % showing the maximal effect in facilitating proliferation of SCs. The expressions of Krox20 and myelin basic protein (MBP), the key molecules of SC myelination, and the potent inducer of myelination neuregulin 1 (NRG1) and its receptors ErbB2 and ErbB3 increased significantly by LIPUS. The reaction of these factors to LIPUS were both time- and duty ratio-dependent: namely LIPUS with higher duty ratios took effects when applied repeatedly over more consecutive days. These observations indicated that NRG1/ErbB signaling pathway might contribute to the effects of LIPUS on the proliferation and myelinating status of SCs, which could be one of the mechanisms in the protective role of LIPUS in nerve repair and regeneration. Our work provided novel insights for promising strategies of nerve repair therapy.

Neuregulin 1 (NRG1) modulates oocyte nuclear maturation during IVM and improves post-IVF embryo development

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.

Alteration in Neuregulin 1/ERbB4 in Absence Epilepsy: Regulatory Effect on TRPV1 Expression.

The footprint of Neuregulin 1 (NRG1) / ERbB4 in the pathophysiology of some neurological disorders and TRPV1 regulation has been indicated. The alterations in NRG1 and ErbB4 as well as the TRPV1 signaling pathway were investigated during the development of absence epilepsy in the genetic animal model of absence epilepsy. Male WAG/Rij and Wistar rats were divided into four experimental groups of two and six months of age. The protein levels of NRG1, ERbB4, and TRPV1 were measured in the somatosensory cortex and hippocampus. The cortical protein levels of NRG1 and ErbB4 in the 6-month-old WAG/Rij rats were lower than in Wistar rats. Protein levels of TRPV1 were lower in two- and six-month-old WAG/Rij rats compared to age-matched Wistar rats.Hippocampal protein levels of NRG1 in 6-month-old WAG/Rij rats were lower than two-month-old WAG/Rij rats. Low levels of ErbB4 protein in two-month-old and high levels in six-month-old WAG/Rij rats were found compared to Wistar rats. Protein levels of TRPV1 were lower in the two-month-old and higher in the six-month-old WAG/Rij rats compared to age-matched Wistar rats.Furthermore, a high correlation between NRG1/ERbB4 and TRPV1 expressions in the cortex and hippocampus was indicated. The expression of NRG1/ERbB4 and TRPV1 followed a similar pattern during the life span of Wistar and WAG/Rij rats. Our findings indicated the potential role of the NRG1/ErbB4 pathway as well as TRPV1 in the pathogenesis of absence epilepsy. The regulatory effect of the ERbB4 receptor on the TRPV1 expression has been suggested following the similar pattern of expression.

Cerebral Expression of the Neuregulin-1 Gene NRG1 during Induced Spatial Memory Impairment and Its Reversal in Aging Mice.

We studied the effects of chronic intranasal administration of amyloidogenic fibrils of the proinflammatory protein S100A9 alone or in combination with glutamate antibodies on the expression of the neuregulin-1 gene (NRG1), a regulator of various physiological processes, in particular, regulation of neurogenesis and apoptosis, in the hippocampus, prefrontal cortex, and cerebellum of aging C57BL/6 mice under conditions of long-term memory disturbances. Under conditions of amnesia induced by S100A9 fibrils, pronounced (>90%) blockade of the expression of the NRG1 gene was found in all cerebral structures. Glutamate antibodies prevented/corrected disturbances in the cerebral expression of the NRG1 gene, thereby maintaining the activity of the NRG1/ErbB molecular signaling system, probably associated with the formation of spatial memory.

NRG1/ErbB2 axis regulated mitochondrial function and antioxidant enzymes of neural stem cells in the cochlear nucleus partially through PGC-1α

Neuregulin-1 (NRG1)/erythroblastic leukaemia viral oncogene homologues 2 (ErbB2) pathway had been implicated in promoting differentiation and suppressing apoptosis of neuronal stem cells (NSCs) isolated from cochlear nucleus. In the current study, we aimed at determining the effects of NRG1/ErbB2 on mitochondrial (mt) function of NSCs. As expected, NRG1 increased the expression of mitofusin (Mfn) 1 and Mfn2 and decreased the expression of mitochondrial fission protein 1 (Fis1) and dynamin-related protein 1 (Drp1). However, after ErbB2 knockout, Mfn1 and Mfn2 expression decreased while Fis1 and Drp1 increased. Moreover, the increased mtDNA copy number and intracellular ATP level, elevated ATPase activities as well as decreased lactate production induced by NRG1 were partially reversed by ErbB2 knockout. Additionally, NRG1 treatment increased the activities of catalase, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and upregulated the protein expression of catalase, manganese superoxide dismutase (MnSOD), peroxisome proliferator-activated receptor-γ coactlvator-1α (PGC-1α), nuclear respiratory factor 1 (NRF1) and transcription factor A, mitochondrial (TFAM), which were also reversed by ErbB2 knockout. Furthermore, PGC-1α overexpression partially reversed the above effects of ErbB2 knockout. In conclusion, these findings suggest that the promotion of mitochondrial function of NRG1/ErbB2 axis is at least in part mediated by PGC-1α in NSCs from cochlear nucleus.