Neuregulin-4 protects cardiomyocytes against high-glucose-induced ferroptosis via the AMPK/NRF2 signalling pathway.

BACKGROUND: High glucose levels are key factors and key contributors to several cardiovascular diseases associated with cardiomyocyte injury. Ferroptosis, which was identified in recent years, is a mode of cell death caused by the iron-mediated accumulation of lipid peroxides. Neuregulin-4 (Nrg4) is an adipokine that has protective effects against metabolic disorders and insulin resistance. Our previous study revealed that Nrg4 has a protective effect against diabetic myocardial injury, and the aim of this study was to investigate whether Nrg4 could attenuate the occurrence of high glucose-induced ferroptosis in cardiomyocytes. METHODS: We constructed an in vivo diabetic myocardial injury model in which primary cardiomyocytes were cultured in vitro and treated with Nrg4. Changes in ferroptosis-related protein levels and ferroptosis-related indices in cardiomyocytes were observed. In addition, we performed back-validation and explored signalling pathways that regulate ferroptosis in primary cardiomyocytes. RESULTS: Nrg4 attenuated cardiomyocyte ferroptosis both in vivo and in vitro. Additionally, the AMPK/NRF2 signalling pathway was activated during this process, and when the AMPK/NRF2 pathway was inhibited, the beneficial effects of Nrg4 were attenuated. CONCLUSION: Nrg4 antagonizes high glucose-induced ferroptosis in cardiomyocytes via the AMPK/NRF2 signalling pathway.

Disrupted neuregulin 1-ErbB4 signaling: Consequences of prenatal morphine exposure in rat pups and molecular gateway to neurological impairment.

Objective: Morphine exposure during pregnancy has detrimental effects on both the mother and her offspring, both during and after childbirth. This study aimed to investigate the impact of prenatal morphine exposure on rat pups and dams, specifically focusing on changes in Neuregulin-1 (Nrg-1)/ErbB4 gene expression, inflammation, and brain-derived neurotrophic factor (BDNF) levels. Materials and methods: Twenty female rats were randomized into two experimental groups:1-Morphine Group: Dams received morphine throughout pregnancy. 2-Control Group: Dams received no interventions.At the end of gestation, blood samples were collected from the dams. Subsequently, dams and their pups underwent tissue collection from the cortical area of the brain to evaluate the following parameters: Interleukin-6 (IL-6), Interleukin-10 (IL-10), total antioxidant capacity (TAC), Malondialdehyde (MDA), and Brain-derived neurotrophic factor (BDNF).Additionally, RNA was extracted from the pup's cortical brain tissue for the assessment of gene expression levels of Neuregulin-1 (NRG-1) and ErbB-4 using quantitative real-time polymerase chain reaction (qrt-PCR). Results: The molecular investigation revealed a decrease in NRG-1 and ErbB-4 expressions in the brain cortex of offspring exposed to morphine during prenatal development. Additionally, the levels of IL-6 and IL-10 in both the serum and brain of both the mothers and their offspring in the morphine group were significantly higher compared to the control group. The morphine-exposed group also exhibited significantly lower levels of TAC and higher levels of MDA, indicating increased oxidative stress. Furthermore, the levels of BDNF in the morphine group were significantly lower compared to the control group. Conclusion: Prenatal morphine exposure in rats has detrimental effects on both the dams and their offspring. This study demonstrates that prenatal morphine exposure disrupts critical molecular pathways involved in neurodevelopment, inflammation, oxidative stress, and neurotrophic signaling. These findings suggest that prenatal morphine exposure can have long-lasting consequences for the offspring, potentially contributing to neurodevelopmental disorders and other health issues later in life.

Neuregulin 4 Attenuates Podocyte Injury and Proteinuria in Part by Activating AMPK/mTOR-Mediated Autophagy in Mice.

In this study, we investigate the effect of neuregulin 4 (NRG4) on podocyte damage in a mouse model of diabetic nephropathy (DN) and we elucidate the underlying molecular mechanisms. In vivo experiments were conducted using a C57BL/6 mouse model of DN to determine the effect of NRG4 on proteinuria and podocyte injury, and in vitro experiments were performed with conditionally immortalized mouse podocytes treated with high glucose and NRG4 to assess the protective effects of NRG4 on podocyte injury. Autophagy-related protein levels and related signaling pathways were evaluated both in vivo and in vitro. The involvement of the adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway was detected using chloroquine or AMPK inhibitors. The results showed that the AMPK/mTOR pathway was involved in the protective roles of NRG4 against high glucose-mediated podocyte injury. Also, NRG4 significantly decreased albuminuria in DN mice. PAS staining indicated that NRG4 mitigated glomerular volume and mesangium expansion in DN mice. Consistently, western blot and RT-PCR analyses confirmed that NRG4 decreased the expression of pro-fibrotic molecules in the glomeruli of DN mice. The immunofluorescence results showed that NRG4 retained expression of podocin and nephrin, whereas transmission electron microscopy revealed that NRG4 alleviated podocyte injury. In DN mice, NRG4 decreased podocyte apoptosis and increased expression of nephrin and podocin, while decreasing the expression of desmin and HIF1α. Overall, NRG4 improved albuminuria, glomerulosclerosis, glomerulomegaly, and hypoxia in DN mice. The in vitro experiments showed that NRG4 inhibited HG-induced podocyte injury and apoptosis. Furthermore, autophagy of the glomeruli decreased in DN mice, but reactivated following NRG4 intervention. NRG4 intervention was found to partially activate autophagy via the AMPK/mTOR signaling pathway. Consequently, when the AMPK/mTOR pathway was suppressed or autophagy was inhibited, the beneficial effects of NRG4 intervention on podocyte injury were diminished. These results indicate that NRG4 intervention attenuates podocyte injury and apoptosis by promoting autophagy in the kidneys of DN mice, in part, by activating the AMPK/mTOR signaling pathway.

Low circulating levels of neuregulin 4 as a potential biomarker associated with the severity and prognosis of obesity-related metabolic diseases: a systematic review.

BACKGROUND: Neuregulin 4 (Nrg4) is a brown adipose tissue-derived adipokine that greatly affects systemic metabolism and improves metabolic derangements. Although abnormal circulating levels of Nrg4 are common in obesity, it remains elusive whether low or elevated levels of this batokine are associated with the onset of metabolic diseases. AIM: To assess Nrg4 levels and its role as a feasible biomarker to predict the severity of obesity, gestational diabetes mellitus (GDM), type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases (CVD). METHODS: A search for relevant studies was performed systematically using prominent search engines, including PubMed, Google Scholar, and Embase, by following PRISMA guidelines. RESULTS: Ample clinical evidence reported low serum/plasma levels of Nrg4 in obesity and these were inversely proportional to the indices of metabolic syndrome, including body mass index, waist circumference, triglycerides, fasting plasma glucose, and homoeostatic model assessment for insulin resistance as well as high-sensitivity C-reactive protein. Low circulating Nrg4 levels may aid in the prediction of morbid obesity, and subsequent GDM, T2DM, NAFLD, and CVD. CONCLUSION: Current clinical evidence emphasizes that the circulating levels of Nrg4 are decreased in morbid obesity, and it also highlights that Nrg4 May serve as a potential prognostic biomarker for obesity-related metabolic diseases.

Immobilized NRG1 Accelerates Neural Crest like Cell Differentiation Toward Functional Schwann Cells Through Sustained Erk1/2 Activation and YAP/TAZ Nuclear Translocation.

Neural Crest cells (NC) are a multipotent cell population that give rise to a multitude of cell types including Schwann cells (SC) in the peripheral nervous system (PNS). Immature SC interact with neuronal axons via the neuregulin 1 (NRG1) ligand present on the neuronal surface and ultimately form the myelin sheath. Multiple attempts to derive functional SC from pluripotent stem cells have met challenges with respect to expression of mature markers and axonal sorting. Here, they hypothesized that sustained signaling from immobilized NRG1 (iNRG1) might enhance the differentiation of NC derived from glabrous neonatal epidermis towards a SC phenotype. Using this strategy, NC derived SC expressed mature markers to similar levels as compared to explanted rat sciatic SC. Signaling studies revealed that sustained NRG1 signaling led to yes-associated protein 1 (YAP) activation and nuclear translocation. Furthermore, NC derived SC on iNRG1 exhibited mature SC function as they aligned with rat dorsal root ganglia (DRG) neurons in an in vitro coculture model; and most notably, aligned on neuronal axons upon implantation in a chick embryo model in vivo. Taken together their work demonstrated the importance of signaling dynamics in SC differentiation, aiming towards development of drug testing platforms for de-myelinating disorders.

Study on the relationship between Methylation of Neuregulin (NRG) Gene and Cervical Carcinoma.

Objective: To investigate the relationship between the DNA methylation state of NRG1 promoter and its expression changes, and to analyze the clinical significance of its regulatory mechanism of DNA methylation in cervical carcinoma. Methods: This was a retrospective study. One-hundred and twenty patients from the Department of Gynecology of Cangzhou People's Hospital from September 2017 to September 2019 were selected, including 40 cases of cervical SCC, 40 cases of high grade squamous intraepithelial lesions(HSIL) and 40 cases of control cervical tissues. RT-qPCR, immunohistochemistry and DNA methylation-specific PCR(MSP) were used to detect the mRNA and protein expression of NRG1 and DNA methylation status in different tissue types. Results: Immunohistochemical results showed that the positive protein expression rate of NRG1 gene in the SCC group was lower than that in both HSIL and Control groups. RT-qPCR results showed that the mRNA gene of NRG1 gradually decreased in expression with the increase of cervical tissue lesions, with a statistically significant difference. Similarly, it also found that the mRNA expression level of NRG1 in the SCC group was independent of patients' age (p>0.05), but significantly correlated with tumor pathological staging, surgical pathology staging and lymphatic metastasis (p<0.05). Furthermore, methylation-specific PCR results revealed a significantly higher DNA methylation rate of NRG1 gene in the SCC group than in both HSIL and Control groups, with a statistically significant difference. Moreover, the methylation degree of NRG1 gene in SCC tissues was negatively correlated with its mRNA expression (p<0.05). Conclusions: Abnormal DNA hypermethylation of NRG1 gene inhibits the expression of mRNA and protein in the progression of cervical tissue from normal to cancerous state, which is involved in the occurrence and development of cervical carcinoma.

Analysis on the pathogenesis and treatment progress of NRG1 fusion-positive non-small cell lung cancer.

Lung cancer persistently leads as the primary cause of morbidity and mortality among malignancies. A notable increase in the prevalence of lung adenocarcinoma has become evident in recent years. Although targeted therapies have shown in treating certain subsets of non-small cell lung cancers (NSCLC), a significant proportion of patients still face suboptimal therapeutic outcomes. Neuregulin-1 (NRG1), a critical member of the NRG gene family, initially drew interest due to its distribution within the nascent ventricular endocardium, showcasing an exclusive presence in the endocardium and myocardial microvessels. Recent research has highlighted NRG1's pivotal role in the genesis and progression across a spectrum of tumors, influencing molecular perturbations across various tumor-associated signaling pathways. This review provides a concise overview of NRG1, including its expression patterns, configuration, and fusion partners. Additionally, we explore the unique features and potential therapeutic strategies for NRG1 fusion-positive occurrences within the context of NSCLC.

COMT and Neuregulin 1 Markers for Personalized Treatment of Schizophrenia Spectrum Disorders Treated with Risperidone Monotherapy.

Pharmacogenetic markers are current targets for the personalized treatment of psychosis. Limited data exist on COMT and NRG1 polymorphisms in relation to risperidone treatment. This study focuses on the impact of COMT rs4680 and NRG1 (rs35753505, rs3924999) polymorphisms on risperidone treatment in schizophrenia spectrum disorders (SSDs). This study included 103 subjects with SSD treated with risperidone monotherapy. COMT rs4680, NRG1 rs35753505, and rs3924999 were analyzed by RT-PCR. Participants were evaluated via the Positive and Negative Syndrome Scale (PANSS) after six weeks. Socio-demographic and clinical characteristics were collected. COMT rs4680 genotypes significantly differed in PANSS N scores at admission: AG>AA genotypes (p = 0.03). After six weeks of risperidone, PANSS G improvement was AA>GG (p = 0.05). The PANSS total score was as follows: AA>AG (p = 0.04), AA>GG (p = 0.02). NRG1 rs35753504 genotypes significantly differed across educational levels, with CC>CT (p = 0.02), and regarding the number of episodes, TT>CC, CT>CC (p = 0.01). The PANSS total score after six weeks of treatment showed a better improvement for TT

Adipokine modulation in obesity: Evaluating the integrative impact of chlorella vulgaris supplementation and interval resistance training in obese males.

Aims: To evaluate the effects of 12-week chlorella vulgaris (CV) combined with interval resistance training (IRT) on plasma levels of leptin, adiponectin and neuregulin-4 (Nrg-4) in obese men. Methods: Obese men (n = 44, BMI of 32.1 ± 1.5 kg/m2) were randomly allocated to the following groups of 11 participants per group: Control Placebo group (CP), CV supplement group (CV), Interval Resistance Training group plus Placebo (IRT + P), and Interval Resistance Training plus CV supplement group (IRT + CV). IRT was performed three times a week for 12 weeks using three sets of 10 repetitions at 60 % 1RM, and integrating an active rest interval with 15 repetitions at 20 % 1RM. Participants consumed either CV (1800 mg daily) or a placebo. Pre- and post-intervention blood samples were obtained to assess adipokines which were measured by ELISA. Results: While CV or IRT separately did not alter plasma levels of leptin (p > 0.05), their combination reduced leptin levels (p = 0.007). IRT and IRT plus CV increased the plasma levels of adiponectin and Nrg-4 (p < 0.01). An intergroup comparison indicated significant elevations of adiponectin and Nrg-4 in the CV compared to the CP group (p < 0.05). Conclusion: The combination of IRT and CV modulates plasma levels of leptin, adiponectin and NRG4 more effectively than either IRT or CV separately in obese men.

The browning and mobilization of subcutaneous white adipose tissue supports efficient skin repair.

Adipocytes in dermis are considered to be important participants in skin repair and regeneration, but the role of subcutaneous white adipose tissue (sWAT) in skin repair is poorly understood. Here, we revealed the dynamic changes of sWAT during wound healing process. Lineage-tracing mouse studies revealed that sWAT would enter into the large wound bed and participate in the formation of granulation tissue. Moreover, sWAT undergoes beiging after skin injury. Inhibition of sWAT beiging by genetically silencing PRDM16, a key regulator to beiging, hindered wound healing process. The transcriptomics results suggested that beige adipocytes in sWAT abundantly express neuregulin 4 (NRG4), which regulated macrophage polarization and the function of myofibroblasts. In diabetic wounds, the beiging of sWAT was significantly suppressed. Thus, adipocytes from sWAT regulate multiple aspects of repair and may be therapeutic for inflammatory diseases and defective wound healing associated with aging and diabetes.

M2 Macrophages Guide Periosteal Stromal Cell Recruitment and Initiate Bone Injury Regeneration.

The periosteum plays a critical role in bone repair and is significantly influenced by the surrounding immune microenvironment. In this study, we employed 10× single-cell RNA sequencing to create a detailed cellular atlas of the swine cranial periosteum, highlighting the cellular dynamics and interactions essential for cranial bone injury repair. We noted that such injuries lead to an increase in M2 macrophages, which are key in modulating the periosteum's immune response and driving the bone regeneration process. These macrophages actively recruit periosteal stromal cells (PSCs) by secreting Neuregulin 1 (NRG1), a crucial factor in initiating bone regeneration. This recruitment process emphasizes the critical role of PSCs in effective bone repair, positioning them as primary targets for therapeutic interventions. Our results indicate that enhancing the interaction between M2 macrophages and PSCs could significantly improve the outcomes of treatments aimed at cranial bone repair and regeneration.

Neuregulin-1, a member of the epidermal growth factor family, mitigates STING-mediated pyroptosis and necroptosis in ischaemic flaps.

Background: Ensuring the survival of the distal end of a random flap during hypoperfusion (ischaemia) is difficult in clinical practice. Effective prevention of programmed cell death is a potential strategy for inhibiting ischaemic flap necrosis. The activation of stimulator of interferon genes (STING) pathway promotes inflammation and leads to cell death. The epidermal growth factor family member neuregulin-1 (NRG1) reduces cell death by activating the protein kinase B (AKT) signalling pathway. Moreover, AKT signalling negatively regulates STING activity. We aimed to verify the efficacy of NRG1 injection in protecting against flap necrosis. Additionally, we investigated whether NRG1 effectively enhances ischemic flap survival by inhibiting pyroptosis and necroptosis through STING suppression. Methods: A random-pattern skin flap model was generated on the backs of C57BL/6 mice. The skin flap survival area was determined. The blood supply and vascular network of the flap was assessed by laser Doppler blood flow analysis. Cluster of differentiation 34 immunohistochemistry (IHC) and haematoxylin and eosin (H&E) staining of the flap sections revealed microvessels. Transcriptome sequencing analysis revealed the mechanism by which NRG1 promotes the survival of ischaemic flaps. The levels of angiogenesis, oxidative stress, necroptosis, pyroptosis and indicators associated with signalling pathways in flaps were examined by IHC, immunofluorescence and Western blotting. Packaging adeno-associated virus (AAV) was used to activate STING in flaps. Results: NRG1 promoted the survival of ischaemic flaps. An increased subcutaneous vascular network and neovascularization were found in ischaemic flaps after the application of NRG1. Transcriptomic gene ontology enrichment analysis and protein level detection indicated that necroptosis, pyroptosis and STING activity were reduced in the NRG1 group. The phosphorylation of AKT and forkhead box O3a (FOXO3a) were increased after NRG1 treatment. The increased expression of STING in flaps induced by AAV reversed the therapeutic effect of NRG1. The ability of NRG1 to phosphorylate AKT-FOXO3a, inhibit STING and promote flap survival was abolished after the application of the AKT inhibitor MK2206. Conclusions: NRG1 inhibits pyroptosis and necroptosis by activating the AKT-FOXO3a signalling pathway to suppress STING activation and promote ischaemic flap survival.

Decreased serum VEGF and NRG1ß1 levels in male patients with chronic schizophrenia: VEGF correlation with clinical symptoms and cognitive deficits.

BACKGROUND: Vascular endothelial growth factor (VEGF) and neuregulin1 (NRG1) are multifunctional trophic factors reported to be dysregulated in schizophrenia. However, the relationships between serum concentrations and schizophrenia symptoms have differed markedly across studies, possibly because schizophrenia is a highly heterogenous disorder. The aim of this study was to investigate the associations of serum VEGF and NRG1 with clinical symptoms and cognitive deficits specifically in male patients with chronic schizophrenia. METHODS: The study included 79 male patients with chronic schizophrenia and 79 matched healthy individuals. Serum VEGF, NRG1ß1, S100B, S100A8, and neuropilin1 were measured using the Luminex liquid suspension chip detection method, psychopathological symptom severity using the Positive and Negative Symptom Scale (PANSS), and cognitive dysfunction using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). RESULTS: Serum VEGF and NRG1ß1 concentrations were significantly lower in male chronic schizophrenic patients than healthy controls (P < 0.05), while serum S100B, S100A8, and neuropilin1 concentrations did not differ between groups (P > 0.05). Serum VEGF concentration was negatively correlated with PANSS negative subscore (beta = -0.220, t = -2.07, P = 0.042), general psychopathology subscore (beta = -0.269, t = -2.55, P = 0.013), and total score (beta = -0.234, t = -2.12, P = 0.038), and positively correlated with RBANS language score (beta = 0.218, t = 2.03, P = 0.045). Alternatively, serum NRG1ß1 concentration was not correlated with clinical symptoms or cognitive deficits (all P > 0.05). CONCLUSION: Dysregulation of VEGF and NRG1ß1 signaling may contribute to the pathogenesis of chronic schizophrenia in males. Moreover, abnormal VEGF signaling may contribute directly or through intermediary processes to neuropsychiatric and cognitive symptom expression.

Neuregulin 2 Is a Candidate Gene for Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with heterogeneous and complex genetic underpinnings. Our previous microarray gene expression profiling identified significantly different neuregulin-2 gene (NRG2) expression between ASD patients and controls. Thus, we aimed to clarify whether NRG2 is a candidate gene associated with ASD. The study consisted of two stages. First, we used real-time quantitative PCR in 20 ASDs and 20 controls to confirm the microarray gene expression profiling results. The average NRG2 gene expression level in patients with ASD (3.23 ± 2.80) was significantly lower than that in the controls (9.27 ± 4.78, p < 0.001). Next, we conducted resequencing of all the exons of NRG2 in a sample of 349 individuals with ASD, aiming to identify variants of the NRG2 associated with ASD. We identified three variants, including two single nucleotide variants (SNVs), IVS3 + 13A > G (rs889022) and IVS10 + 32T > A (rs182642591), and one small deletion at exon 11 of NRG2 (delGCCCGG, rs933769137). Using data from the Taiwan Biobank as the controls, we found no significant differences in allele frequencies of rs889022 and rs182642591 between two groups. However, there is a significant difference in the genotype and allele frequency distribution of rs933769137 between ASDs and controls (p < 0.0001). The small deletion is located in the EGF-like domain at the C-terminal of the NRG2 precursor protein. Our findings suggest that NRG2 might be a susceptibility gene for ASD.

Lipid metabolic reprogramming mediated by circulating Nrg4 alleviates metabolic dysfunction-associated steatotic liver disease during the early recovery phase after sleeve gastrectomy.

BACKGROUND: The metabolic benefits of bariatric surgery that contribute to the alleviation of metabolic dysfunction-associated steatotic liver disease (MASLD) have been reported. However, the processes and mechanisms underlying the contribution of lipid metabolic reprogramming after bariatric surgery to attenuating MASLD remain elusive. METHODS: A case-control study was designed to evaluate the impact of three of the most common adipokines (Nrg4, leptin, and adiponectin) on hepatic steatosis in the early recovery phase following sleeve gastrectomy (SG). A series of rodent and cell line experiments were subsequently used to determine the role and mechanism of secreted adipokines following SG in the alleviation of MASLD. RESULTS: In morbidly obese patients, an increase in circulating Nrg4 levels is associated with the alleviation of hepatic steatosis in the early recovery phase following SG before remarkable weight loss. The temporal parameters of the mice confirmed that an increase in circulating Nrg4 levels was initially stimulated by SG and contributed to the beneficial effect of SG on hepatic lipid deposition. Moreover, this occurred early following bariatric surgery. Mechanistically, gain- and loss-of-function studies in mice or cell lines revealed that circulating Nrg4 activates ErbB4, which could positively regulate fatty acid oxidation in hepatocytes to reduce intracellular lipid deposition. CONCLUSIONS: This study demonstrated that the rapid effect of SG on hepatic lipid metabolic reprogramming mediated by circulating Nrg4 alleviates MASLD.

Biological markers of adipose tissue: Adipokines.

We currently have a large sum of clinical and experimental data documenting the involvement of numerous adipokines in the maintenance of energy homeostasis in healthy individuals and their dysregulation in diseases such as obesity, metabolic syndrome or type 2 diabetes. Despite the impressive discoveries made in this field over many years, much remains to be done before understanding all the physiological and pathological implications, and hoping for the development of other effective and safe therapeutic strategies. Two original adipokines will be taken as examples to illustrate these remarks, chemerin and neuregulin 4.

Effects of Anti-Seizure Medication on Neuregulin-1 Gene and Protein in Patients with First-Episode Focal Epilepsy.

Introduction: Neuregulin-1 (NRG-1) appears to play a role in the pathogenesis of several neuropsychiatric disorders, including epilepsy. We conducted a study to investigate the effect of anti-seizure medication on NRG-1 mRNA and NRG-1 protein levels in patients with first-episode focal epilepsy. Methods: The levels of NRG-1 mRNA isoforms (type I, II, III, and IV) in peripheral blood mononuclear cells (PBMCs) of 39 healthy controls, 39 first-episode focal epilepsy patients before anti-seizure medication (ASM) therapy and four weeks after administration of ASM were measured by RT-qPCR, and the levels of NRG-1 protein in the serum of samples of each group were determined using ELISA. In addition the relationship between efficacy, NRG-1 mRNA expression, and NRG-1 protein expression was analyzed. Results: The levels of NRG-1 mRNA progressively increased in patients with first-episode focal epilepsy treated with ASM and were distinctly different from those before medication, but remained lower than in healthy controls (all P < 0.001). Before and after drug administration, NRG-1 protein levels were substantially higher in epileptic patients than in healthy controls, and no significant changes were detected with prolonged follow-up (P < 0.001). Patients with epilepsy who utilized ASM were able to control seizures with an overall efficacy of 97.4%. There was a negative correlation between NRG-1 mRNA levels and efficacy: as NRG-1 mRNA levels increased, seizures reduced (all P < 0.05). Conclusion: Our research indicated that NRG-1 may play a role in the pathophysiology of epilepsy. NRG-1 mRNA may provide ideas for the discovery of novel epilepsy therapeutic markers and therapeutic targets for novel ASM.

The case for neuregulin-1 as a clinical treatment for stroke.

Ischemic stroke is the leading cause of serious long-term disability and the 5th leading cause of death in the United States. Revascularization of the occluded cerebral artery, either by thrombolysis or endovascular thrombectomy, is the only effective, clinically-approved stroke therapy. Several potentially neuroprotective agents, including glutamate antagonists, anti-inflammatory compounds and free radical scavenging agents were shown to be effective neuroprotectants in preclinical animal models of brain ischemia. However, these compounds did not demonstrate efficacy in clinical trials with human patients following stroke. Proposed reasons for the translational failure include an insufficient understanding on the cellular and molecular pathophysiology of ischemic stroke, lack of alignment between preclinical and clinical studies and inappropriate design of clinical trials based on the preclinical findings. Therefore, novel neuroprotective treatments must be developed based on a clearer understanding of the complex spatiotemporal mechanisms of ischemic stroke and with proper clinical trial design based on the preclinical findings from specific animal models of stroke. We and others have demonstrated the clinical potential for neuregulin-1 (NRG-1) in preclinical stroke studies. NRG-1 significantly reduced ischemia-induced neuronal death, neuroinflammation and oxidative stress in rodent stroke models with a therapeutic window of >13 h. Clinically, NRG-1 was shown to be safe in human patients and improved cardiac function in multisite phase II studies for heart failure. This review summarizes previous stroke clinical candidates and provides evidence that NRG-1 represents a novel, safe, neuroprotective strategy that has potential therapeutic value in treating individuals after acute ischemic stroke.

Myeloid Cell-Derived IL-1 Signaling Damps Neuregulin-1 from Fibroblasts to Suppress Colitis-Induced Early Repair of the Intestinal Epithelium.

Neuregulin-1 (Nrg1, gene symbol: Nrg1), a ligand of the ErbB receptor family, promotes intestinal epithelial cell proliferation and repair. However, the dynamics and accurate derivation of Nrg1 expression during colitis remain unclear. By analyzing the public single-cell RNA-sequencing datasets and employing a dextran sulfate sodium (DSS)-induced colitis model, we investigated the cell source of Nrg1 expression and its potential regulator in the process of epithelial healing. Nrg1 was majorly expressed in stem-like fibroblasts arising early in mouse colon after DSS administration, and Nrg1-Erbb3 signaling was identified as a potential mediator of interaction between stem-like fibroblasts and colonic epithelial cells. During the ongoing colitis phase, a significant infiltration of macrophages and neutrophils secreting IL-1ß emerged, accompanied by the rise in stem-like fibroblasts that co-expressed Nrg1 and IL-1 receptor 1. By stimulating intestinal or lung fibroblasts with IL-1ß in the context of inflammation, we observed a downregulation of Nrg1 expression. Patients with inflammatory bowel disease also exhibited an increase in NRG1+IL1R1+ fibroblasts and an interaction of NRG1-ERBB between IL1R1+ fibroblasts and colonic epithelial cells. This study reveals a novel potential mechanism for mucosal healing after inflammation-induced epithelial injury, in which inflammatory myeloid cell-derived IL-1ß suppresses the early regeneration of intestinal tissue by interfering with the secretion of reparative neuregulin-1 by stem-like fibroblasts.

Overcoming brain-derived therapeutic resistance in HER2+ breast cancer brain metastasis.

Brain metastasis of HER2+ breast cancer occurs in about 50% of all women with metastatic HER2+ breast cancer and confers poor prognosis for patients. Despite effective HER2-targeted treatments of peripheral HER2+ breast cancer with Trastuzumab +/-HER2 inhibitors, limited brain permeability renders these treatments inefficient for HER2+ breast cancer brain metastasis (BCBM). The scarcity of suitable patient-derived in-vivo models for HER2+ BCBM has compromised the study of molecular mechanisms that promote growth and therapeutic resistance in brain metastasis. We have generated and characterized new HER2+ BCBM cells (BCBM94) isolated from a patient HER2+ brain metastasis. Repeated hematogenic xenografting of BCBM94 consistently generated BCBM in mice. The clinically used receptor tyrosine kinase inhibitor (RTKi) Lapatinib blocked phosphorylation of all ErbB1-4 receptors and induced the intrinsic apoptosis pathway in BCBM94. Neuregulin-1 (NRG1), a ligand for ErbB3 and ErbB4 that is abundantly expressed in the brain, was able to rescue Lapatinib-induced apoptosis and clonogenic ability in BCBM94 and in HER2+ BT474. ErbB3 was essential to mediate the NRG1-induced survival pathway that involved PI3K-AKT signalling and the phosphorylation of BAD at serine 136 to prevent apoptosis. High throughput RTKi screening identified the brain penetrable Poziotinib as highly potent compound to reduce cell viability in HER2+ BCBM in the presence of NRG1. Successful in-vivo ablation of BCBM94- and BT474-derived HER2+ brain tumors was achieved upon two weeks of treatment with Poziotinib. MRI revealed BCBM remission upon poziotinib, but not with Lapatinib treatment. In conclusion, we have established a new patient-derived HER2+ BCBM in-vivo model and identified Poziotinib as highly efficacious RTKi with excellent brain penetrability that abrogated HER2+ BCBM brain tumors in our mouse models.