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Background: Neuregulin-1(NRG-1) is a protein that belongs to the group of epidermal growth factors. It plays vital roles in anti-fibrotic effects on the myocardium. The current paper explores the role of NRG-1 in type 2 diabetes mellitus (T2DM) and its relation to atherogenic index as a factor for increasing cardiovascular disease(CVD) risk. Material and methods: In this study, 79 diabetes mellitus patients are independent insulin. These patients consisted of 53 females and 26 males their age were ranged 40–67 years. They were divided into two groups depending on the atherogenic index of plasma (AIP). Group I including48 diabetic patient with high risk of CVD and group II including 31 diabetic patients without risk CVD. Forty healthy individuals were included as control. Result: When compared to the control group, the serum levels of NRG-1 were significantly lower (p = 0.01). Additionally, group I had a much lower NRG-1level than group II. The results of multiple stepwise regression showed that the only independent predictor for NRG-1 level prediction was AIP (β = − 0.600, P = 0.040). When comparing the diabetic patients with high risk factors for CVD to the healthy subject group, the AUC was outstanding (AUC = 0.889, P = 0.001) and had a high diagnosis. Conclusions: We proved low NRG-1 levels in diabetic patients and the association of highest NRG-1 amounts to a better AIP. Moreover, the measurement of NRG-1 levels could be beneficial as laboratory markers to monitor for increasing CVD risk in type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma, a notably malignant tumor within the central nervous system, is distinguished by its aggressive behavior. Silvestrol, a robust inhibitor of the RNA helicase eukaryotic initiation factor 4A (eIF4A), has shown significant potential as an anticancer compound. Yet, the impact of silvestrol on glioblastoma, especially its molecular mechanisms, has not been fully elucidated. Methods: This investigation employed a variety of in vitro assays, such as cell counting kit-8 (CCK-8), clonogenic, 5-ethynyl-2′-deoxyuridine (EDU), wound healing, and flow cytometry, to evaluate cell cycle progression, apoptosis, cell viability, and migration. Western blot analysis was also performed to study the apoptosis and extracellular regulated kinase (ERK) pathways. After the ERK pathway was inhibited, differentially expressed genes (DEGs) in U87 cells were identified, followed by an analysis of target genes using the gene expression profiling interactive analysis (GEPIA) database. Results: Silvestrol significantly suppressed the proliferation, migration, and colony formation of glioma cells. It caused cell cycle arrest and enhanced apoptosis in these cells. Additionally, silvestrol stimulated the ERK pathway, with these effects being reversible by an ERK phosphorylation inhibitor. Transcriptome combined with GEPIA, GSCA, UALCAN, TIMER database screened 4 potential drug targets of silvestrol: chromosome 1 open reading frame 226 (C1ORF226), mannosidase beta A (MANBA), IQ motif and Sec7 domain 2 (IQSEC2), neuregulin 1 (NRG-1). Among them, C1ORF226 was lower risk gene while MANBA, IQSEC2, and NRG-1 were high-risk genes. Furthermore, silvestrol notably reduced MANBA mRNA levels, which could be reversed by inhibiting ERK phosphorylation. Furthermore, silvestrol markedly decreased NRG-1 protein levels, with an additional reduction observed when the ERK pathway was blocked. Conclusion: Silvestrol’s anti-glioma effects are primarily due to the suppression of MANBA expression via the ERK pathway and possibly by hindering the translation of NRG-1 protein, thus reducing its expression. The downregulation of MANBA and NRG-1 proteins may be crucial in hindering glioma development and progression. These results highlight the intricate relationship between the ERK pathway and gene expression regulation in silvestrol’s therapeutic effectiveness against glioma. [ABSTRACT FROM AUTHOR]

Objective: To analyze the correlation between serum neuregulin-1 (NRG-1), neuregulin-4 (NRG-4) and chronic low-grade inflammation status and insulin resistance in patients with polycystic ovary syndrome (PCOS), and to explore the influence for pregnancy outcomes. Methods: 161 patients with PCOS (PCOS group) who were admitted to Beijing Boai Hospital of China Rehabilitation Research Center from January 2018 to October 2021 were selected, another 100 healthy women with age as control (control group) who were came to the hospital for physical examination during the same period were selected. The serum NRG-1, NRG-4, white blood cell count (WBC), C-reactive protein (CRP) levels and homeostasis model assessment-insulin resistance index (HOMA-IR) in the subjects were detected, and the correlation between NRG-1, NRG-4, WBC, CRP, and HOMA-IR was analyzed. The pregnancy outcomes in patients with PCOS were tracked, they were divided into poor pregnancy outcomes group and good pregnancy outcomes group. Univariate and multivariate logistic regression were used to analyze the influencing factors of adverse pregnancy outcomes. The predictive value of NRG-1, NRG-4, CRP, and HOMA-IR in adverse pregnancy outcomes used receiver operating characteristic (ROC) curve analysis. Results: Compared with control group, the NRG-1, NRG-4, CRP, WBC and HOMA-IR levels increased in PCOS group (P<0.05). Pearson correlation analysis showed that NRG-1 and NRG-4 were positively correlated with CRP, WBC, and HOMA-IR(P<0.05). The results of single factor analysis showed that the serum NRG-1, NRG-4, CRP, WBC, and HOMA-IR levels in poor pregnancy outcomes group were higher than those in good pregnancy outcomes group (P<0.05). Multivariate logistic regression analysis showed that NRG-1>10.55 pg/mL, NRG-4>27.20 pg/m, CRP>7.51 mg/L and HOMA-IR>3.35 were all risk factors for poor pregnancy outcomes in PCOS patients (P<0.05). The ROC-AUC (0.95CI) of NRG-1, NRG-4, CRP, and HOMA-IR when used alone or in combination were 0.706 (0.429~0.980), 0.709 (0.405~0.988), 0.749 (0.535~0.938), 0.747 (0.496~0.988), and 0.850 (0.739~0.959), respectively, Joint prediction was greater than a single indicator. Conclusions: The serum NRG-1 and NRG-4 levels are high in patients with PCOS, which are positively correlated with chronic low-grade inflammatory status and insulin resistance indicators, and they are risk factors for affects poor pregnancy outcomes. The combination of NRG-1, NRG-4, CRP, and HOMA-IR has a high predictive value for poor pregnancy outcomes in PCOS patients. [ABSTRACT FROM AUTHOR]

Aim: Preeclampsia is a multisystemic disease characterized by hypertension, proteinuria, increased vascular damage and permeability, and superficial placental invasion that occurs during pregnancy. Neuregulin-1 (NRG-1) is an important ligand for embryogenesis, angiogenesis, nervous system development, myogenesis, and gonadogenesis. In our study it was aimed to examine the importance of NRG-1 in preeclampsia using light microscopy. Materials and Methods: Study groups: Group 1 (control group) (n=10): healthy normal pregnants, Group 2 (preeclampsia group) (n=10): pregnant women diagnosed with preeclampsia. Hematoxylin Eosin and Periodic Acid-Schiff stainings were done. NRG-1 immunostaining was performed and scored. Results: In the control group, the syncytiotrophoblast layer, villus stroma, fetal vascular structures and intervillous space were histologically normal. It was observed that the lumen of the villi in the placentas of preeclamptic pregnant women was narrowed and the number of villi was less than that of normal pregnant women. A significant increase in the number of nuclear chains was detected around the syncytial node and villi. It was observed that the number of fetal capillaries and fetomaternal barriers decreased. Intervillous and perivillous fibrin deposition was clearly observed. In the preeclampsia group, it was determined that the staining intensity with anti-NRG-1 around the villus was significantly less than the normal pregnant placentas in the control group (p

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Background: Neuregulin (NRG) plays essential roles in the growth and differentiation of epithelial, neuronal and glial cells. Asthma is a chronic respiratory disease characterized by airway constriction and caused by allergens such as Der p 38. Objective: This study is aimed to investigate the relationship between NRG-1 and asthma-like inflammation due to allergens. Results: Following Der p 38 intranasal or intraperitoneal/intranasal (IP/IN) administration in mice, the expression levels of NRG-1 and its receptors increased in response, including ErbB2 and ErbB4. We further examined the roles of NRG-1 in the human BEAS-2B lung epithelial cell line. Der p 38 enhanced NRG-1 expression in the cells and NRG-1 secretion was also upregulated in BEAS-2B cell supernatants treated with Der p 38. NRG-1 alone did not increase the release of interleukin-6 (IL-6), IL-8, or monocyte chemoattractant protein-1 (MCP-1), but it inhibited cytokine secretion increased by Der p 38. Direct treatment with NRG-1 did not affect alteration of neutrophil apoptosis due to Der p 38, but BEAS-2B cell supernatants treated with Der p 38 and NRG-1 blocked the antiapoptotic effects of Der p 38-treated supernatants on neutrophils by activation of caspase 9 and caspase 3. Conclusion: NRG-1 may exhibit anti-inflammatory effects in a Der p 38-induced allergenic environment, particularly neutrophilic inflammation. The present study on NRG may open up approach opportunities for understanding of pathogenesis and treatment of asthma. [ABSTRACT FROM AUTHOR]

Aim. To determine the median levels of neuregulin-1 (NRG-1; endothelium-derived growth factor and the natural agonist of the ERBB3 and ERBB4 receptors) NRG-1 in healthy volunteers and to study the associations of NRG-1 levels with gender and age.Material and Methods. Ninety seven healthy participants were enrolled (median age of 44 [32-54], men 45 men [46.4%]). The following age groups were identified: 20-29 y.о. (n=20, men – 50.0%), 30-39 y.о. (n=21, men – 52.4%), 40-49 y.о. (n=22, men – 45.5%), 50-59 y.о. (n=22, men – 36.4%); 60-69 y.о. (n=12, men – 50.0%). Peripheral blood samples were collected at the time of enrolment, standard laboratory tests were performed, and NRG-1 levels were determined in the plasma samples by ELISA.Results. In the cohort of 97 healthy participants the median value of NRG-1 was 0.3 [0.121-2.24] ng/ml. NRG-1 levels did not differ significantly between men and women (p=0.145), indicating that NRG-1 levels are not influenced by gender. The levels of NRG-1 were similar in the different age groups: age 20-29 years=0.26 [0.17-0.37] ng/ml; age 30-39=0.24 [0.1-0.39] ng/ml; age 40-49=0.31 [0.19-1.15] ng/ml; age 50-59=0.37 [0.19-1.0] ng/ml; age 60-69=0.4 [0.13-0.81] ng/ml. Correlation analysis between NRG-1 levels and route blood measurements (haemoglobin, lipids, glucose, creatinine, and uretic acid) did not show significant associations.Conclusions. In this study, the median value of NRG-1 plasma levels were determined. The results of the study show that age and gender had no influence on NRG-1 values.

Background: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Introduction: Menopause is a noticeable period in women's life accompanied by some physiological and psychological changes leading to health conditions such as obesity, overweighing, cardiovascular, and other inflammatory diseases. Aim: Due to the importance of health cares in this period and the effectiveness of exercise training to attenuate the symptoms, we aimed to compare the effects of an emerging exercise tool by blood flow restriction in limbs on two public health-related cytokines, IL-6 (Interleukin-6) and NRG-1 (Neuregulin-1) in comparison with traditional training in overweight postmenopausal women. Materials-Methods: 30 overweight post-menopausal women were randomly assigned into BFR (Blood Flow Restriction), HI (High Intensity), LI (Low Intensity) groups (n=10) and performed eight weeks of concurrent training three days a week. Two lower body and two upper body exercises at 20%1RM (20% of one repetition Maximum) load for BFR and LI groups and at 80%1RM (80% of one repetition Maximum) load for HI group in addition to 20 minutes of aerobic training at the end. IL-6 and NRG-1 levels were measured before and after the eight weeks of training sessions. Results: Group differences in IL-6 levels were observed in BFR and HI groups (p=0.001 in both groups) but not in LI group (p=0.29). Differences between groups were significant between BFR and LI (p=0,00) and HI and LI (p=0.007) but not between BFR and HI (p=0.11). For NRG-1 levels, group differences were observed in all three groups (p=0.001), (p=0.003), (p=0.007) and the differences between groups for NRG-1 levels were significant between BFR and LI (p=0.001) and HI and LI (p=0.038) but not between BFR and HI (p=0.065). Conclusion: Low-intensity BFR training and high-intensity traditional resistance training are functioning similarly on the levels of IL-6 and NRG-1 in postmenopausal women and low-intensity training with BFR is more effective than low-intensity traditional training in this proposition. [ABSTRACT FROM AUTHOR]

Olanzapine is an effective antipsychotic medication for treatment-resistant schizophrenia (TRS); however, the therapeutic effectiveness of olanzapine has been found to vary in individual patients. It is imperative to unravel its resistance mechanisms and find reliable targets to develop novel precise therapeutic strategies. Unbiased RNA sequencing analysis was performed using homogeneous populations of neural stem cells derived from induced pluripotent stem cells in 3 olanzapine responder (reduction of Positive and Negative Syndrome Scale score ≥25%) and 4 nonresponder (reduction of Positive and Negative Syndrome Scale score <25%) inpatients with TRS. We also used a genotyping study from patients with TRS to assess the candidate genes associated with the olanzapine response. CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9-mediated genome editing, neurologic behavioral tests, RNA silencing, and microRNA sequencing were used to investigate the phenotypic mechanisms of an olanzapine resistance gene in patients with TRS. Neuregulin-1 (NRG-1) deficiency–induced mitochondrial dysfunction is associated with olanzapine treatment outcomes in TRS. NRG-1 knockout mice showed schizophrenia-relevant behavioral deficits and yielded olanzapine resistance. Notably, miR143-3p is a critical NRG-1 target related to mitochondrial dysfunction, and miR143-3p levels in neural stem cells associate with severity to olanzapine resistance in TRS. Meanwhile, olanzapine resistance in NRG-1 knockout mice could be rescued by treatment with miR143-3p agomir via intracerebral injection. Our findings provide direct evidence of olanzapine resistance resulting from NRG-1 deficiency–induced mitochondrial dysfunction, and they link olanzapine resistance and NRG-1 deficiency–induced mitochondrial dysfunction to an NRG-1/miR143-3p axis, which constitutes a novel biomarker and target for TRS. [ABSTRACT FROM AUTHOR]

Introduction: Several pieces of evidence indicate that maternal exercise during pregnancy can elicit long-lasting and positive effects on brain development and improve the neurobehavioral functions of the offspring. However, the molecular mechanisms involved in such changes are not fully understood. Neuregulin-1 (Nrg-1)/ErbB signaling pathway is critical for neuronal development, migration, myelination, and synaptic formation. This study aimed to assess the effect of maternal exercise during pregnancy on the Nrg-1 and ErbB4 expression in rat pups. Methods: After confirming the pregnancy, the pregnant rats were divided into the control and the exercise groups. The animals of the control group were housed in their cage with any exercise, while the animals of the exercise group were forced to run on a treadmill for 30 min at a mild intensity, from the 10th day of pregnancy until delivery. After parturition, the hippocampus of the 10 days pups was removed to assess the gene expression (RT-PCR) and protein levels (Western blotting) of NRG-1 and ErbB4. Results: This study data have shown the hippocampal gene expression of both NRG-1 (p < 0.01) and ErbB4 (p < 0.01) in exercise group offspring significantly increased compared to the control group. Also, the protein levels of NRG-1 (p < 0.01) and ErbB4 (p < 0.001) in the pups of the exercise group significantly increased compared to the control group. Conclusion: Our findings suggest the potential role of maternal exercises during pregnancy in the offspring's neural development and synaptic plasticity through the improvement of the Nrg-1/ErbB4 signaling pathway. [ABSTRACT FROM AUTHOR]

Trastuzumab (Trz) is a humanized monoclonal antibody targeting epidermal growth factor receptor 2 (HER2; ErbB2). The combined administration of Trz and doxorubicin (DOX) has shown potent anti-cancer efficacy; however, this regimen may be accompanied by severe cardiac toxicity. Mesenchymal stem cells (MSCs)-derived exosomes are nanosized vesicles that play a crucial role in cell–cell communication and have shown efficacy in the treatment of various diseases. In this study, we aim to investigate the cardioprotective effects of MSCs-derived exosomes in a DOX/Trz- mediated cardiotoxicity model, and the possible mechanisms underlying these effects are elucidated. Forty-nine male rats were randomly assigned into four groups: Group I (control); Group II (Dox/Trz); Group III (protective group); and Group IV (curative group). Cardiac hemodynamic parameters, serum markers of cardiac injury, oxidative stress indices, and cardiac histopathology were investigated. Further, transcript profile of specific cardiac tissue injury markers, apoptotic markers, and fibrotic markers were analyzed using qRT-PCR, while the protein expressions of pAkt/Akt, pERK/ERK, pJNK/JNK, pJNK/JNK, and pSTAT3/STAT3 were evaluated by ELISA. Additionally, cardiac mirR-21 and miR-26a were assessed. A combined administration of DOX/Trz disrupted redox and Ca2+ homeostasis in cardiac tissue induced myocardial fibrosis and myofibril loss and triggered cardiac DNA damage and apoptosis. This cardiotoxicity was accompanied by decreased NRG-1 mRNA expression, HER2 protein expression, and suppressed AKT and ERK phosphorylation, while triggering JNK phosphorylation. Histological and ultra-structural examination of cardiac specimens revealed features typical of cardiac tissue injury. Moreover, a significant decline in cardiac function was observed through biochemical testing of serum cardiac markers and echocardiography. In contrast, the intraperitoneal administration of MSCs-derived exosomes alleviated cardiac injury in both protective and curative protocols; however, superior effects were observed in the protective protocol. The results of the current study indicate the ability of MSCs-derived exosomes to protect from and attenuate DOX/Trz-induced cardiotoxicity. The NRG-1/HER2, MAPK, PI3K/AKT, PJNK/JNK, and PSTAT/STAT signaling pathways play roles in mediating these effects. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are considered a promising treatment for ischemic diseases, but their use is limited due to poor survival after injection. Hypoxia can significantly enhance the survival of MSCs. This study aimed to investigate hypoxia pretreatment of bone marrow mesenchymal stem cells (BM-MSCs) in hindlimb ischemia (HI) and the underlying mechanism. The HI mouse model was established and human BM-MSCs were injected into ischemic skeletal muscles. The blood flow reperfusion and capillary density were measured. In vitro, human BM-MSC cells were treated with hypoxia. The expression of NRG-1 and associated angiogenic factors were measured after knockdown or overexpression of NRG-1. The conditioned medium (CdM) of BM-MSCs was prepared and co-cultured with human umbilical vein endothelial cells (HUVECs), and then, the proliferation, migration, and angiogenesis of HUVECs were detected. After hypoxia pretreatment, NRG-1 expression, clone formation, proliferation, and angiogenic factor secretion from BM-MSCs were increased, while knockdown of NRG-1 reversed these results. In normoxia condition, overexpression of NRG-1 enhanced above factors. Additionally, hypoxia pretreatment of BM-MSCs induced the proliferation and migration of HUVECs and angiogenesis. Moreover, the injection of hypoxia pretreatment of BM-MSCs improved blood reperfusion and capillary density in HI mice, while knockdown of NRG-1 reversed the effect. Furthermore, the PI3K inhibitor and activator reversed the effect of NRG-1 overexpression and knockdown on angiogenesis. We concludes that hypoxia pretreatment of BM-MSCs facilitates angiogenesis and alleviates HI injury via NRG-1/PI3K/AKT pathway. [ABSTRACT FROM AUTHOR]

با توجه به اهمیت تنظیم تعادل گلایسمیک در پیشگیری از عوارض قلبی-عروقی دیابت، کنترل گلوکز خون و مقاومت به انسولین بسیار اهمیت دارد. ازجمله عوامل محافظتی در مقابل آسیب­های ناشی از گلوکز خون بالا، پپتید شبه‌گلوکاگون-یک (GLP-1)، نوروگلین-یک (NRG-1) و اینترلوکین-33 (IL-33) است که تحت‌تأثیر تمرینات ورزشی نیز قرار می­گیرند؛ بنابراین، پژوهش حاضر با هدف بررسی تأثیر هشت هفته تمرین مقاومتی و هوازی تناوبی بر مقادیر عوامل حفاظتی GLP-1، NRG-1 و IL-33 در زنان با دیابت انجام شد. 30 زن با دیابت (09/5 ± 9/51 سال) به‌طور تصادفی در سه گروه (10 نفری)، تمرین مقاومتی، تمرین هوازی تناوبی و کنترل داوطلب انجام پژوهش شدند. تمرین هوازی تناوبی با شدت 75-60 درصد MHR و تمرین مقاومتی با شدت 75-30 درصد 1RM به‌مدت هشت هفته و سه جلسه در هفته اجرا شد. مقادیر GLP-1، NRG-1 و IL-33 با استفاده از روش ELISA اندازه­گیری شد. برای تجزیه‌وتحلیل داده­ها از آزمون­ آماری ANCOVA استفاده شد (0.05 > P). نتایج پژوهش حاضر نشان داد که تمرین مقاومتی نسبت به گروه کنترل (0.007P =) باعث افزایش معنا­داری GLP-1 شد.تمرین هوازی(0.037P =) و مقاومتی (0.001P =) نسبت به گروه کنترل و تمرین مقاومتی نسبت به تمرین هوازی (0.008P =) باعث افزایش معنا­داری IL-33 شد؛ درحالی‌که تغییرات NRG-1 در دو گروه تمرینی معنا­دار نبود. به‌نظر می­رسد تمرین مقاومتی با تنظیم مثبت GLP-1 و IL-33 تأثیر بهتری بر کنترل گلایسمیک، گلوکز خون و درنهایت، بهبود شرایط قلبی-عروقی در زنان با دیابت نوع دو داشته باشد.

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Neuregulin (NRG)-1 plays fundamental roles in several organ systems after binding to its receptors, ErbB2 and ErbB4. This study examines the role of NRG-1 in atopic dermatitis (AD), a chronic skin disease that causes dryness, pruritus, and inflammation. In mice administered Der p 38, the skin presents AD-like symptoms including filaggrin downregulation and infiltration of neutrophils and eosinophils. Noticeably, there is an increased expression of NRG-1, ErbB2, and ErbB4 in the skin. Upregulation of these proteins is significantly correlated to the clinical skin severity score. In human keratinocyte HaCaT cells, exposure to Der p 38 decreased filaggrin expression, and NRG-1 alone had no effect on the expression. However, co-treatment of Der p 38 with NRG-1 enhanced the filaggrin expression decreased by Der p 38. Pre-treatment with AG879 (an ErbB2 inhibitor) or ErbB4 siRNA blocked the recovery of filaggrin expression in the cells after co-treatment with Der p 38 and NRG-1. Der p 38 treatment enhanced the secretion of interleukin-6 (IL-6), IL-8, and monocyte chemoattractant protein-1 (MCP-1). Co-treatment of Der p 38 with NRG-1 lowered the cytokine secretion increased by Der p 38, although NRG-1 alone was not effective on cytokine alteration. Neutrophil apoptosis was not altered by NRG-1 or supernatants of cells treated with NRG-1, but the cell supernatants co-treated with Der p 38 and NRG-1 blocked the anti-apoptotic effects of Der p 38-treated supernatants on neutrophils, which was involved in the activation of caspase 9 and caspase 3. Taken together, we determined that NRG-1 has anti-inflammatory effects in AD triggered by Der p 38. These results will pave the way to understanding the functions of NRG-1 and in the future development of AD treatment. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The aim of this study was to investigate the role of microRNA-233-5p (miR-233-5p) in spinal cord injury (SCI), and to explore the possible underlying mechanism. MATERIALS AND METHODS: Microglia were first isolated from neonate rats and cultured in a suitable environment in vitro. Lipopolysaccharide (LPS) and interleukin-4 (IL-4) were used to activate microglia. The expressions of miR-223-5p, inducible nitric oxide synthase (iNOS) and arginase 1 (Arg-1) were measured by qRT-PCR, respectively. After transfection of miR-233-5p inhibitor, the expression levels of miR-223-5p, iNOS and Arg-1 in cells were detected as well. A moderate SCI model was successfully established in rats (10 g fallen on T10 spinal cord at the height of 5 cm). Subsequently, inflammation indexes at miR-223-5p peak moment were observed. Meanwhile, its neuro-protective effect at 28 days after SCI was estimated. Finally, Basso, Beattie, and Bresnahan (BBB) rating scale was applied to evaluate the hindlimb locomotor function of rats at 1, 3, 7, 14, 21, 28 days after SCI. RESULTS: MiR-223-5p inhibitor significantly promoted M2 microglia expression and degenerated M1 microglia expression in vitro. SCI obviously elevated the level of miR-223-5p in injured spinal cord tissues within one week, which reached a peak at 5 days after injury. Meanwhile, miR-223-5p inhibitor remarkably reduced the expressions of inflammatory factors, including interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) at 3 days after SCI, as well as increased neuregulin1 (NRG-1) expression. However, miR-223-5p inhibitor significantly declined the levels of apoptosis key enzyme-caspase-3 and glia reaction marker-glial fibrillary acidic protein (GFAP) at 7 and 28 days after SCI, respectively. As a result, BBB rating scale demonstrated that hindlimb locomotor function was significantly recovered in miR-223-5p injection group. CONCLUSIONS: MiR-223-5p was up-regulated in M1 microglia, whereas down-regulated in M2 microglia. MiR-223-5p inhibitor could significantly increase M2 microglia expression, while decrease M1 microglia expression in vitro. In vivo, miR-223-5p inhibitor suppressed the inflammatory response and reinforced NRG-1 level to reduce glia reaction and neuron apoptosis. Thereby, its treatment promoted the hindlimb locomotor function of rats. [ABSTRACT FROM AUTHOR]

The adult myocardium, including human, harbours a population of resident multi-potent cardiac stem cells (CSCs), which when stimulated under the right conditions can give rise to new cardiomyocytes and vasculature. Elucidation of the cellular and molecular mechanisms that govern CSC biology and their role in myocardial regeneration will allow the design and development of optimal therapeutic interventions. It is now evident that different growth factors and cytokines govern CSC survival, proliferation, migration and differentiation, as well as playing a role in activating cardiac repair mechanisms such as improving angiogenesis, cardiomyocyte survival and limiting fibrosis. This review article will summarize the evidence for a role of VEGF, NRG-1, IGF-1, HGF, EGF, FGF and TGF-β1 in modulating the repair and regeneration of cardiac tissue. It will also discuss the use of exosomes and exercise training as interventions to stimulate the endogenous repair and regenerative mechanisms in the damaged heart. [ABSTRACT FROM AUTHOR]

The neuroprotective effects of neuregulin-1 (NRG-1) on stroke lesions were assessed longitudinally in rats with middle cerebral artery occlusion (MCAo) using MRI. Sprague–Dawley rats (n = 16, 250 ± 20 g) underwent permanent MCAo surgery with cerebral blood flow (CBF) monitored by laser doppler flowmetry at ipsilateral side of bregma for 20 min post-occlusion. A single 50 μl bolus dose of NRG-1 or vehicle was administered into the left internal carotid artery immediately prior to MCAo. The expansion of the ischemic lesion into the cortex was attenuated by NRG-1 over a 48-hour (h) time span as measured by diffusion weighted imaging (DWI). The final infarct volumes of NRG-1 treated rats were significantly smaller than those of the vehicle treated rats at 48 h (264.8 ± 192.1 vs. 533.4 ± 175.5 mm 3 , p < 0.05). The NRG-1 treated rats were further subdivided into 2 subgroups according to their CBF reduction during stroke surgery: mild ischemia (< 70% CBF reduction) or severe ischemia (> 70% CBF reduction). In particular, ischemic infarction was not usually observed in the cortex of NRG-1 treated rats with mild ischemia at 3 and 48 h post-occlusion. Histological results validated the imaging findings and demonstrated that NRG-1 treated rats had fewer injured neurons in peri-infarct areas 48 h post-ischemia. In summary, the neuroprotective effect of NRG-1 in the pMCAo stroke model was demonstrated by prevention of ischemic lesion expansion, reduced infarct volume and protection of neurons from ischemic damage. [ABSTRACT FROM AUTHOR]

Abstract: Myocardial infarction (MI) is the leading cause of death worldwide, and extensive research has therefore been performed to find a cure. Neuregulin-1 (NRG) is a growth factor involved in cardiac repair after MI. We previously described how biocompatible and biodegradable microparticles, which are able to release NRG in a sustained manner, represent a valuable approach to avoid problems related to the short half-life after systemic administration of proteins. The effectiveness of this strategy could be improved by combining NRG with several cytokines involved in cardiac regeneration. The present study investigates the potential feasibility of using NRG-releasing particle scaffold combined with adipose-derived stem cells (ADSC) as a multiple growth factor delivery-based tissue engineering strategy for implantation in the infarcted myocardium. NRG-releasing particle scaffolds with a suitable size for intramyocardial implantation were prepared by TROMS. Next, ADSC were adhered to particle scaffolds and their potential for heart administration was assessed in a MI rat model. NRG was successfully encapsulated reaching encapsulation efficiencies of 92.58±3.84%. NRG maintained its biological activity after the microencapsulation process. ADSCs adhered efficiently to particle scaffolds within a few hours. The ADSC-cytokine delivery system developed proved to be compatible with intramyocardial administration in terms of injectability through a 23-gauge needle and tissue response. Interestingly, ADSC-scaffolds were present in the peri-infarted tissue 2weeks after implantation. This proof of concept study provides important evidence required for future effectiveness studies and for the translation of this approach. [Copyright &y& Elsevier]

Objective This study aimed to review the available evidence-based literature on novel psychoactive substances and to inform health care professionals. Methods Internet searches were carried out using Google and Yahoo by using specific key words. For each set of key words, the first 100 websites identified by Google and Yahoo were fully assessed, together with a further 5% of random samples selected by research randomizer of the remaining websites. Thus, a list of unique web forums was identified, and qualitative information was extracted. Available evidence-based literature were reviewed along with a user's experimentation with mephedrone, NRG-1, NRG-2 and Benzofury. Results It showed that when a substance (mephedrone) became controlled, the vendors aggressively promote the sale of other new compounds (NRG-1, NRG-2, Benzofury) to attract vulnerable adults. The characteristics, toxicity and suggested management of these new compounds (NRG-1, NRG-2, Benzofury) are discussed. Conclusions The arrival of hundreds of novel psychoactive substances for sale online has raised a number of public health and legal issues. Although evidence-based literature remains limited, few studies identified that most products do not contain the ingredients as advertised. Better levels of international cooperation and rapid share of available information may be needed to tackle this emerging problem. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Neuregulin-1 (NRG-1), a ligand of receptor tyrosine kinases of the ErbB family, plays a critical role in cardiovascular development and maintenance of adult heart function. Results from cellular, animal, and clinical experiments have shown NRG-1 to be a promising drug candidate for restoring cardiac function after cardiac injury. Various mechanisms have been suggested to be involved in this process, such as improving sarcomeric structure or cell–cell adhesion, promoting proliferation and survival of cardiac myocytes, balancing Ca2+ homeostasis, modulating inotropic effects, promoting angiogenesis, and preventing atherosclerosis. However, the contribution of these effects to the restoration of cardiac function remains to be estimated, and it may depend on the specific events that led to heart failure. Meanwhile, distinct and crossed signaling pathways downstream of NRG-1 may play a role in these underlying mechanisms, resulting in a complicated network of signaling mediating the function of NRG-1. [ABSTRACT FROM AUTHOR]

Abstract: Growing genetic evidence has implicated a role for neuregulin-1 (NRG-1) in schizophrenia pathogenesis as well as alterations in SNAP receptor (SNARE) proteins at both gene and protein levels in post-mortem investigations. In relation to a potential therapeutic mechanism for atypical antipsychotic medications, clozapine has been shown to increase both NRG-1 levels and synaptic markers in rodents. As evidence continues to mount for a potential restoration in connectivity by antipsychotic medications being a mode of efficacy we chose to examine the effects of the atypical antipsychotic clozapine and the typical antipsychotic haloperidol on NRG-1 and SNARE protein transcripts in human brain aggregates exposed to plasma levels chronically for a period of three weeks. At the end of this exposure period we performed quantitative real-time PCR to investigate the mRNA levels of NRG-1, VAMP-1 and SNAP-25. Overall we found that clozapine had the ability to upregulate NRG-1 (+3.58 fold change) and VAMP-1 (+1.92) while SNAP-25 remained unchanged. Changes for haloperidol exposed aggregates were below our cut-off of +1.5. Overall the results of our investigation lend further support to atypical antipsychotic medications having the potential to increase levels of neurotrophic and synaptic markers such as NRG-1 and VAMP-1, the former being a strong candidate susceptibility gene for schizophrenia. In the absence of frank neuronal loss in schizophrenia, restoration of neuronal and synaptic functions by atypical antipsychotics in the brains of schizophrenics maybe a key mechanism of therapeutic efficacy by re-establishing normal connectivity and functioning. [Copyright &y& Elsevier]

Abstract: Neuregulin (NRG)/ErbB receptor signaling pathways have recently been implicated in the reversal of long-term potentiation at hippocampal glutamatergic synapses. Moreover, polymorphisms in NRG-1 and ErbB-4 genes have been linked to an increased risk for developing schizophrenia. ErbB-4 is highly expressed at glutamatergic synapses where it binds to PSD-95 via its carboxyl terminal T–V–V sequence. Here we investigated the expression, localization and trafficking of ErbB-4 in cultured hippocampal neurons by immunocytochemistry, surface protein biotinylation, and live labeling of native receptors. We show that neuronal ErbB-4 is detected at its highest levels in GABAergic interneurons, as observed in vivo. ErbB-4 immunoreactivity precedes PSD-95 expression, with ErbB-4 cluster initially forming in the absence of, but later associating with, PSD-95-positive puncta. By surface protein biotinylation, the fraction of ErbB-4 receptors on the plasma membrane increases from 30% to 65% between 6 and 16 days in vitro (DIV). Interestingly, 30min of NRG stimulation triggers measurable ErbB-4 receptor internalization at DIV 16, despite increased colocalization with PSD-95. We also investigated the role of TNFα-converting enzyme (TACE)-mediated receptor processing in regulating ErbB-4 surface expression. We found that the cleavage-resistant JM-b isoform accounts for 80% of all ErbB-4 transcripts in cultured hippocampal neurons. Receptor stimulation or treatment with phorbol esters does not induce detectable ErbB-4 processing, indicating that neurons mostly rely on endocytosis of the intact receptor to regulate ErbB-4 surface expression. These results enhance our understanding of the regulation of ErbB-4—mediated signaling at glutamatergic synapses. [Copyright &y& Elsevier]

Abstract: Neuregulin (NRG) signaling proteins interact with ErbB receptors leading to the proliferation, differentiation and migration of neurons and glia in the developing brain. NRG-1/ErbB4 are susceptibility genes for schizophrenia, yet little is known about the neuroanatomical expression of ErbB receptors specifically in primates. We find widespread expression of ErbB2, ErbB3 and ErbB4 receptor mRNAs throughout the telencephalon of juvenile and adult monkeys with in situ hybridization, with ErbB2 and ErbB4 mRNA more abundant than ErbB3 mRNA. ErbB2 and ErbB4 mRNA are expressed at higher levels in grey matter compared to white matter, whereas ErbB3 mRNA is expressed at low levels in both grey and white matter. We also characterized ErbB protein expression with immunoblotting and immunohistochemistry. In frontal cortex, ErbB2, ErbB3 and ErbB4 antibodies immunostained neuronal soma and nuclei. The ErbB2 antibody also immunostained glia at the pial surface. Within white matter, ErbB3 and ErbB4 proteins were localized to putative interstitial white matter neurons while ErbB2 protein was found in glia. Western blotting revealed immunopositive bands at ∼180–200 kDa for each ErbB, which is consistent with the size of full-length ErbBs. Smaller immunopositive bands were also identified for each ErbB receptor in whole brain homogenates and separate cytoplasmic and nuclear extracts suggesting nuclear ErbB-back-signaling capacity in the brain. The ubiquitous expression of ErbB receptors indicates that many cell populations throughout the brain of juvenile and adult primates have the potential to respond to NRG-1 in a variety of ways. [Copyright &y& Elsevier]

Abstract: Neuregulin-1 is widely investigated due to its hypothesised association with schizophrenia. Single-nucleotide polymorphisms rs764059, rs2954041 and rs3924999 were investigated (417 patients with schizophrenia and 429 controls). We failed to demonstrate a significant association between rs2954041 and rs3924999 with schizophrenia in the three ethnic groups studied (Malay, Chinese, and Indian), while rs764059 was found to be monomorphic. [Copyright &y& Elsevier]

Here we report that the lncRNA LINC00052 expression correlates positively with HER3/ErbB3 levels in breast cancer cells. Gene silencing of LINC00052 diminished both LINC00052 and HER3 expression and reduced cancer cell growth in vitro and in vivo. LINC00052 overexpression promoted cancer cell growth in vitro and in vivo and increased HER3-mediated downstream signaling. Importantly, neutralization of HER3 signaling with HER3 targeting monoclonal antibodies blocked LINC00052 mediated cancer cell proliferation in vitro and tumor growth in vivo, suggesting LINC00052 promoting cancer growth through HER3 signaling. Taken together, our results indicate that high LINC00052 levels predict activation of HER3-mediated signaling, and LINC00052 expression level may serve as a potential biomarker for HER3 targeted antibody cancer therapies.

Schizophrenia is a serious mental illness with chronic symptoms and significant impairment in psychosocial functioning. Although novel antipsychotics have been developed, the negative and cognitive symptoms of schizophrenia are still unresponsive to pharmacotherapy. The high level of social impairment and a chronic deteriorating course suggest that schizophrenia likely has neurodegenerative characteristics. Inflammatory markers such as pro-inflammatory cytokines are well-known etiological factors for psychiatric disorders, including schizophrenia. Inflammation in the central nervous system is closely related to neurodegeneration. In addition to pro-inflammatory cytokines, microglia also play an important role in the inflammatory process in the CNS. Uncontrolled activity of pro-inflammatory cytokines and microglia can induce schizophrenia in tandem with genetic vulnerability and glutamatergic neurotransmitters. Several studies have investigated the possible effects of antipsychotics on inflammation and neurogenesis. Additionally, anti-inflammatory adjuvant therapy has been under investigation as a treatment option for schizophrenia. Further studies should consider the confounding effects of systemic factors such as metabolic syndrome and smoking. In addition, the unique mechanisms by which pro-inflammatory cytokines are involved in the etiopathology of schizophrenia should be investigated. In this article, we aimed to review (1) major findings regarding neuroinflammation and pro-inflammatory cytokine alterations in schizophrenia, (2) interactions between neuroinflammation and neurogenesis as possible neural substrates for schizophrenia, and (3) novel pharmacological approaches., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Chronic restraint stress leads to increases in brain derived neurotrophic factor (BDNF) mRNA and protein in some regions of the brain, e.g. the basal lateral amygdala (BLA) but decreases in other regions such as the CA3 region of the hippocampus and dendritic spine density increases or decreases in line with these changes in BDNF. Given the powerful influence that BDNF has on dendritic spine growth, these observations suggest that the fundamental reason for the direction and extent of changes in dendritic spine density in a particular region of the brain under stress is due to the changes in BDNF there. The most likely cause of these changes is provided by the stress initiated release of steroids, which readily enter neurons and alter gene expression, for example that of BDNF. Of particular interest is how glucocorticoids and mineralocorticoids tend to have opposite effects on BDNF gene expression offering the possibility that differences in the distribution of their receptors and of their downstream effects might provide a basis for the differential transcription of the BDNF genes. Alternatively, differences in the extent of methylation and acetylation in the epigenetic control of BDNF transcription are possible in different parts of the brain following stress. Although present evidence points to changes in BDNF transcription being the major causal agent for the changes in spine density in different parts of the brain following stress, steroids have significant effects on downstream pathways from the TrkB receptor once it is acted upon by BDNF, including those that modulate the density of dendritic spines. Finally, although glucocorticoids play a canonical role in determining BDNF modulation of dendritic spines, recent studies have shown a role for corticotrophin releasing factor (CRF) in this regard. There is considerable improvement in the extent of changes in spine size and density in rodents with forebrain specific knockout of CRF receptor 1 (CRFR1) even when the glucocorticoid pathways are left intact. It seems then that CRF does have a role to play in determining BDNF control of dendritic spines., (Copyright © 2013 Elsevier Ltd. All rights reserved.)