Neuregulin 4 (NRG4) is a kind of protein containing epidermal growth factor (EGF)-like domains, mainly expressed and secreted by brown adipocytes. It specifically activates EGF receptor ErbB4 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 4) to stimulate cell proliferation, inhibit apoptosis and improve energy metabolism of cells. Increasing evidence has shown that NRG4 plays an important role in epithelial cell-related diseases, cardiovascular diseases, tumors and glycolipid metabolic diseases, and therefore it could be a potential therapeutic target of some diseases.
Animals ; Apoptosis ; Cardiovascular Diseases ; Cell Proliferation ; Energy Metabolism ; Humans ; Metabolic Diseases ; Neoplasms ; Neuregulins ; physiology ; Receptor, ErbB-4 ; physiology ; Signal Transduction

To explore the effects of recombined Neuregulin on the heart of healthy Macaca mulatta, 10 healthy adult Macaca mulatta were randomly divided into two groups and were injected with the same doses of recombined Neuregulin and normal saline, respectively. At the same time, related indices were detected by 2-dimensional echocardiography and M-mode echocardiography. All indices were compared between the two groups and among different phases. Recombined Neuregulin had effects on LVEDD (left ventricular end-diastolic diameter), LVEDV (left ventricular end-diastolic volume), LVESV (left ventricular end-systolic volume) and SV (Stroke volume), and the effects changed with time. However, no significant changes were seen on EF (Ejection fraction) and FS (Fractional shortening). In conclusion, recombined Neuregulin has effects on the left ventricular volume of healthy Macaca mulatta, but no significant effect on cardiac contractility.
Animals ; Echocardiography ; methods ; Female ; Heart Ventricles ; anatomy & histology ; diagnostic imaging ; drug effects ; Macaca mulatta ; Male ; Myocardial Contraction ; drug effects ; Neuregulins ; biosynthesis ; genetics ; pharmacology ; Random Allocation ; Recombinant Proteins ; biosynthesis ; genetics ; pharmacology ; Stroke Volume ; drug effects

The neuregulins (NRGs) are a family of proteins containing an epidermal growth factor (EGF)-like motif that mediates important functions not only in the nervous system but also in the heart, breast and other organ systems. NRG1 was first found to function in the nervous system in the proliferation of Schwann cells, and in the regulation of nicotinic acetylcholine receptor (AChR) transcription at the neuromuscular junction (NMJ). NRGs have multiple biological functions. In the brain, NRG signaling regulates early fate determination, differentiation, migration, synaptic activity of target cell and the expression of other neurotransmitter receptors and survival of satellite cells, Schwann cells and oligodendrocytes. There is also evidence for involvement of NRGs signaling in the pathogenesis of disease, including breast cancer, multiple sclerosis, traumatic brain injury and Hirschsprung's disease. Especially, both NRG1 and ErbB4 have emerged as susceptibility genes of schizophrenia. In this review, I will summarize the latest findings regarding the spectrum of NRG-ErbB action and signaling pathways in the developing and adult nervous system.
Adult ; Brain ; Brain Injuries ; Breast ; Breast Neoplasms ; Epidermal Growth Factor ; Heart ; Hirschsprung Disease ; Humans ; Multiple Sclerosis ; Nervous System ; Neuregulins ; Neuromuscular Junction ; Oligodendroglia ; Proteins ; Receptors, Neurotransmitter ; Receptors, Nicotinic ; Schizophrenia ; Schwann Cells

Animals ; Antibiotics, Antineoplastic ; administration & dosage ; toxicity ; Apoptosis ; drug effects ; Daunorubicin ; administration & dosage ; toxicity ; Disease Models, Animal ; Female ; In Situ Nick-End Labeling ; Male ; Myocardium ; cytology ; metabolism ; pathology ; ultrastructure ; Neuregulins ; metabolism ; pharmacology ; RNA, Messenger ; metabolism ; Rats ; Rats, Wistar ; Receptor, ErbB-2 ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction

AIMTo characterize the feasibility of the surgical replacement of the penile tunica albuginea (TA) and to evaluate the value of a porcine bladder acellular matrix (BAM) graft.

METHODSAcellular matrices were constructed from pigs' bladders by cell lysis, and then examined by scanning electron microscopy (SEM). Expression levels of the mRNA of the vascular endothelial growth factor (VEGF) receptor, fibroblast growth factor (FGF)-1 receptor, neuregulin, and brain-derived neurotrophic factor (BDNF) in the acellular matrix and submucosa of the pigs'bladders were determined through the reverse transcription-polymerase chain reaction (PCR). A 5 mm X 5 mm square was excised from the penile TA of nine rabbits. The defective TA was then covered in porcine BAM. Equal numbers of animals were sacrificed and histochemically examined at 2, 4 and 6 months after implantation.

RESULTSSEM of the BAM showed collagen fibers with many pores. VEGF receptor, FGF-1 receptor and neuregulin mRNA were expressed in the porcine BAM; BDNF mRNA was not detected. Two months after implantation, the graft sites exhibited excellent healing without contracture, and the fusion between the graft and the neighboring normal TA appeared to be well established. There were no significant histological differences between the implanted tunica and the normal control tunica at 6 months after implantation.

CONCLUSIONThe porcine BAM graft resulted in a structure which was sufficiently like that of the normal TA. This implantation might be considered applicable to the reconstruction of the TA in conditions such as trauma or Peyronie's disease.

Animals ; Brain-Derived Neurotrophic Factor ; genetics ; Cyclophilins ; genetics ; Disease Models, Animal ; Male ; Microscopy, Electron, Scanning ; Neuregulins ; genetics ; Penis ; surgery ; Polymerase Chain Reaction ; Receptors, Fibroblast Growth Factor ; genetics ; Receptors, Vascular Endothelial Growth Factor ; genetics ; Reconstructive Surgical Procedures ; Surgery, Plastic ; Swine ; Urinary Bladder ; physiology ; surgery ; ultrastructure

OBJECTIVE: To explore the protective effect of neuregulin against cardiac myocyte injury in pacing-induced heart failure in rhesus monkeys and its mechanism. METHODS: Rapid pacing was used to induce heart failure in rhesus monkeys. Aorta intubation was used to perform hemodynamic measurements such as the peak positive rate of of left ventricular pressure (LVdP/dtmax) and left ventricular systolic, end-diastolic blood pressures (LVSP and LVEDP, respectively) 17 days after the pacing. N-terminal pro-brain natriuretic peptide (BNP), as molecular marker of heart failure, was also measured by electrochemical luminescence immunoassay. The apoptosis of cardiac myocyte was observed by Tunel method. Western blot was used to detect the PKB activity and the relative amounts of Bcl-xl protein in the left ventricular free walls. RESULTS: After the daily intravenous injection of 3microg/kg recombinated neuregulin for 10 days, LVdP/dtmax increased significantly while BNP decreased remarkably. The apoptotic index was obviously lower, and Bcl-xl and activity of PKB were higher. CONCLUSION Neuregulin protects against rapid pacing-induced apoptosis in heart failure in rhesus monkeys and the mechanism might be attributed to the increase of the activity of PKB and Bcl-xl protein.
Animals ; Apoptosis ; drug effects ; Blotting, Western ; Cardiac Pacing, Artificial ; adverse effects ; Heart Failure ; etiology ; physiopathology ; In Situ Nick-End Labeling ; Macaca mulatta ; Male ; Myocardial Contraction ; drug effects ; Myocytes, Cardiac ; drug effects ; metabolism ; pathology ; Neuregulins ; pharmacology ; Phosphatidylinositol 3-Kinases ; metabolism ; Proto-Oncogene Proteins c-akt ; metabolism ; Signal Transduction ; drug effects ; bcl-X Protein ; metabolism

In the present study, we investigate the expression profile of the epidermal growth factor receptor family, which comprises EGFR/ErbB1, HER2/ErbB2, HER3/ErbB3 and HER4/ErbB4 in oral leukoplakia (LP). The expression of four epidermal growth factor receptor (EGFR) family genes and their ligands were measured in LP tissues from 14 patients and compared with levels in 10 patients with oral lichen planus (OLP) and normal oral mucosa (NOM) from 14 healthy donors by real-time polymerase chain reaction (PCR) and immunohistochemistry. Synchronous mRNA coexpression of ErbB1, ErbB2, ErbB3 and ErbB4 was detected in LP lesions. Out of the receptors, only ErbB4 mRNA and protein was more highly expressed in LP compared with NOM tissues. These were strongly expressed by epithelial keratinocytes in LP lesions, as shown by immunohistochemistry. Regarding the ligands, the mRNA of Neuregulin2 and 4 were more highly expressed in OLP compared with NOM tissues. Therefore, enhanced ErbB4 on the keratinocytes and synchronous modulation of EGFR family genes may contribute to the pathogenesis and carcinogenesis of LP.
Adult ; Aged ; Amphiregulin ; Betacellulin ; EGF Family of Proteins ; Epidermal Growth Factor ; metabolism ; Epiregulin ; Female ; Gene Expression Profiling ; Glycoproteins ; metabolism ; Heparin ; metabolism ; Heparin-binding EGF-like Growth Factor ; Humans ; Intercellular Signaling Peptides and Proteins ; metabolism ; Keratinocytes ; metabolism ; Leukoplakia, Oral ; metabolism ; Lichen Planus, Oral ; metabolism ; Ligands ; Male ; Middle Aged ; Mouth Mucosa ; metabolism ; Nerve Growth Factors ; Neuregulins ; metabolism ; RNA, Messenger ; metabolism ; Real-Time Polymerase Chain Reaction ; Receptor, Epidermal Growth Factor ; metabolism ; Receptor, ErbB-2 ; metabolism ; Receptor, ErbB-3 ; metabolism ; Receptor, ErbB-4 ; Receptors, Cell Surface ; metabolism ; Transforming Growth Factor alpha ; metabolism ; Up-Regulation ; physiology

PURPOSE: Heregulin is a natural ligand for erbB3 and erbB4. However, very little is known about their roles in the gastric cancer. This retrospective study was performed to evaluate the frequencies of heregulin and erbB family protein expression and to compare their expressions with clinicopathologic parameters. MATERIALS AND METHODS: Immunohistochemical expressions of heregulin and erbB family proteins were examined with tissue micro-array slides. A total of 251 gastric adenocarcinomas were classified as early cancers and advanced cancers and as having and not having lymph node metastases. RESULTS: The positive rates of the heregulin, erbB1, erbB2, erbB3, and erbB4 protein stainings were 64%, 68%, 6%, 88%, and 76%, respectively. Intestinal type gastric adenocarcinomas showed higher expression of heregulin, erbB2, erbB3, and erbB4 proteins. Heregulin and erbB4 proteins showed lower expressions in advanced gastric carcinomas. However, erbB2 protein showed higher expression in advanced gastric carcinomas. The protein expressions of heregulin and erbB family proteins showed no relationship with survival rate. Co-expression groups of heregulin and erbB3 proteins or heregulin and erbB4 proteins showed higher expressions in intestinal type adenocarcinomas and early gastric carcinomas. CONCLUSION: Heregulin, erbB3, and erbB4 proteins may play a role in the early stage of adenocarcinomas.
Adenocarcinoma* ; Humans ; Immunohistochemistry ; Lymph Nodes ; Neoplasm Metastasis ; Neuregulin-1* ; Retrospective Studies ; Stomach Neoplasms ; Survival Rate

Neuregulin-1 (NRG1) signaling participates in the synaptic plasticity, maintenance or regulation of adult brain. Although ErbB4, a key NRG1 receptor, is expressed in multiple regions in the adult animal brain, little is known about its localization in Alzheimer's disease (AD) brains. We previously reported that ErbB4 immunoreactivity showed regional difference in the hippocampus of age-matched control. In the present paper, immunohistochemical characterization of the distribution of ErbB4 receptor in the hippocampus relative to pathology staging were performed in age-matched control (Braak stage 0, n=6) and AD (Braak stage I/V, n=10). Here, we found that ErbB4 immunoreactivity was significantly increased in apoptotic hippocampal pyramidal neurons in the brains of AD patients, compared to those of age-matched control subjects. In AD brains, ErbB4 immunoreactivity was demonstrated to colocalize with the apoptotic signal Bax in apoptotic hippocampal pyramidal neurons. These results suggest that up-regulation of ErbB4 immunoreactivity in apoptotic neuron may involve in the progression of pathology of AD.
Adult ; Alzheimer Disease ; Animals ; Apoptosis ; Brain ; Hippocampus ; Humans ; Neuregulin-1 ; Neurons ; Plastics ; Up-Regulation

Neuregulin-1 (NRG1) has been shown to be able to protect against focal cerebral ischemia. The aim of the present study was to investigate the neuroprotective effect of NRG1 in primary hippocampal neurons and its underlying mechanism. Our data showed oxygen-glucose deprivation (OGD)-induced cytotoxicity and overexpression of ErbB4 in primary hippocampal neurons. Moreover, pretreatment with NRG1 could inhibit OGD-induced overexpression of ErbB4. In addition, NRG1 significantly attenuated neuronal death induced by OGD. The neuroprotective effect of NRG1 was blocked in ischemic neurons after pretreatment with AG1478, an inhibitor of ErbB4, but not after pretreatment with AG879, an inhibitor of ErbB2. These results indicate an important role of ErbB4 in NRG1-mediated neuroprotection, suggesting that endogenous ErbB4 might serve as a valuable therapeutic target for treating global cerebral ischemia.]]>
Anoxia ; Brain ; Brain Ischemia ; Cell Death ; Cognition ; Hippocampus ; Ischemia ; Neuregulin-1 ; Neurons ; Neuroprotection ; Neuroprotective Agents