Correlation between neuregulin receptor degradation protein-1 and Crohn's disease.

Neuregulin receptor degradation protein-1 (Nrdp1) is a newly discovered E3 ligase that plays a role in the apoptosis process of multiple diseases. Previous studies has shown that Nrdp1 exerted a proapoptotic effect in cardiac diseases. The purpose of this study is to investigate the potential involvement of Nrdp1 in the pathological processes of inflammatory bowel disease (IBD). To create a mouse model of experimental colitis, trinitrobenzenesulfonic acid (TNBS) was administered and the severity of colitis was assessed based on changes in weight and histological scores. Using Western blot and immunohistochemistry, significant increase in Nrdp1 expression was observed in intestinal epithelial cells (IECs). This was accompanied with the up-regulation of cleaved PARP and active caspase-3 in IECs, indicating a potential function in IECs. To study this further, we built an in vitro model of tumor necrosis factor-alpha (TNF-α)-induced apoptosis using human IEC line HT-29 cells. When Nrdp1 was knocked down, a decrease in apoptosis was observed, suggesting that Nrdp1 may play a proapoptotic role in IEC apoptosis. The mechanism behind this phenomenon is associated with the suppression of downstream targets of Nrdp1, such as protein kinase B (AKT). Furthermore, immunohistochemistry analysis in patients with Crohn's disease (CD) and normal controls supported the same results as observed in experimental colitis. We conclude that Nrdp1 may be a promising new therapeutic target for ameliorating IBD in humans.

Effects of oleoylethanolamide supplementation on the expression of lipid metabolism-related genes and serum NRG4 levels in patients with non-alcoholic fatty liver disease: A randomized controlled trial.

BACKGROUND: This study investigated the effects of oleoylethanolamide (OEA) supplementation on the expression levels of SIRT1, AMPK, PGC-1α, PPAR-γ, CEBP-α and CEBP-ß genes and serum neuregulin 4 (NRG4) levels in patients with non-alcoholic fatty liver diseases (NAFLD). METHODS: Sixty obese patients with NAFLD were equally allocated into either OEA or placebo group for 12 weeks. The mRNA expression levels of genes were determined using the reverse transcription polymerase chain reaction (RT-PCR) technique. Serum NRG4 level was also assessed using an enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: At the endpoint, mRNA expression levels of SIRT1(p = 0.001), PGC-1α (p = 0.011) and AMPK (p = 0.019) were significantly higher in the OEA group compared to placebo group. However, no significant differences were observed in the expression levels of PPAR-γ, CEBP-α and CEBP-ß between the two groups. Serum NRG4 levels significantly increased in the OEA group compared with the placebo group after controlling for confounders (p = 0.027). In the OEA group, significant relationships were found between percent of changes in the expression levels of the SIRT1, AMPK and PGC-1α as well as serum NRG4 level with percent of changes in some anthropometric measures. Moreover, in the intervention group, percent of changes in high-density lipoprotein cholesterol was positively correlated with percent of changes in the expression levels of the SIRT1 and AMPK. While, percent of changes in triglyceride was inversely correlated with percent of changes in the expression levels of SIRT1. CONCLUSION: OEA could beneficially affect expression levels of some lipid metabolism-related genes and serum NRG4 level. "REGISTERED UNDER IRANIAN REGISTRY OF CLINICAL TRIALS IDENTIFIER NO: IRCT20090609002017N32".

Neuregulin 4 suppresses NASH-HCC development by restraining tumor-prone liver microenvironment.

The mammalian liver comprises heterogeneous cell types within its tissue microenvironment that undergo pathophysiological reprogramming in disease states, such as non-alcoholic steatohepatitis (NASH). Patients with NASH are at an increased risk for the development of hepatocellular carcinoma (HCC). However, the molecular and cellular nature of liver microenvironment remodeling that links NASH to liver carcinogenesis remains obscure. Here, we show that diet-induced NASH is characterized by the induction of tumor-associated macrophage (TAM)-like macrophages and exhaustion of cytotoxic CD8+ T cells in the liver. The adipocyte-derived endocrine factor Neuregulin 4 (NRG4) serves as a hormonal checkpoint that restrains this pathological reprogramming during NASH. NRG4 deficiency exacerbated the induction of tumor-prone liver immune microenvironment and NASH-related HCC, whereas transgenic NRG4 overexpression elicited protective effects in mice. In a therapeutic setting, recombinant NRG4-Fc fusion protein exhibited remarkable potency in suppressing HCC and prolonged survival in the treated mice. These findings pave the way for therapeutic intervention of liver cancer by targeting the NRG4 hormonal checkpoint.

EGFR-targeting antitumor therapy: Neuregulins or antibodies?

Malignancies such as lung, breast and pancreatic carcinomas are associated with increased expression of the epidermal growth factor receptor, EGFR, and its role in the pathogenesis and progression of tumors has made this receptor a prime target in the development of antitumor therapies. In therapies targeting EGFR, the development of resistance owing to mutations and single nucleotide polymorphisms, and the expression of the receptor ligands themselves are very serious issues. In this work, both the ligand neuregulin and a bispecific antibody fragment to EGFR are conjugated separately or together to the same drug-delivery system to find the most promising candidate. Camptothecin is used as a model chemotherapeutic drug and superparamagnetic iron oxide nanoparticles as a delivery system. Results show that the lowest LD50 is achieved by formulations conjugated to both the antibody and the ligand, demonstrating a synergy. Additionally, the ligand location in the nucleus favors the antitumor activity of Camptothecin. The high loading capacity and efficiency convert these systems into a good alternative for administering Camptothecin, a drug whose use is otherwise severely limited by its chemical instability and poor solubility. Our choice of targeting agents allows treating tumors that express ErbB2 (Her2+ tumors) as well as Her2- tumors expressing EGFR.

The Role of Neuregulin and Stem Cells as Therapy Post-Myocardial Infarction.

Coronary artery disease, including myocardial infarction (MI), is a leading cause of morbidity and mortality in the United States. Due to the limited self-renewal capacity of cardiac tissue, MIs can lead to progressive heart disease with a lasting impact on health and quality of life. The recent discovery of cardiac stem cells has incited research into their potential therapeutic applications for patients suffering from cardiovascular disease. Studies have demonstrated the ability of stem cells to both generate cardiac tissues in vitro and aid in the recovery of cardiovascular function in vivo in animal models. However, the long-term efficacy of stem cells as regenerative therapy is still unknown. Exploration of alternative therapies is underway, including the use of cardiac growth factor neuregulin-1 (NRG-1). Research has demonstrated that NRG-1 not only has direct effects on cardiomyocytes (CM) but also acts within the tissues supporting the CM. Transplantation of NRG-1 into ischemic cardiac tissue mitigates the progression of heart failure and can reverse cardiac remodeling. Recent publications have sought to study the combined use of these agents, and while the results are promising, they do warrant further research. This review aims to consider these therapies separately as well as in combination.

Transplantation of adipose-derived stem cells combined with neuregulin-microparticles promotes efficient cardiac repair in a rat myocardial infarction model.

Tissue engineering is a promising strategy to promote heart regeneration after a myocardial infarction (MI). In this study, we investigated the reparative potential of a system that combines adipose-derived stem cells (ADSCs) with microparticles (MPs) loaded with neuregulin (NRG), named ADSC-NRG-MPs, on a rat MI model. First, cells were attached to the surface of MPs encapsulating NRG and coated with a 1:1 mixture of collagen and poly-d-lysine. One week after in vivo administration, the system favored the shift of macrophage expression from a pro-inflammatory to a regenerative phenotype. At long-term, the adhesion of ADSCs to MPs resulted in an increased cell engraftment, with cells being detectable in the tissue up to three months. In consonance, better tissue repair was observed in the animals treated with cells attached to MPs, which presented thicker left ventricles than the animals treated with ADSCs alone. Moreover, the presence of NRG in the system promoted a more complete regeneration, reducing the infarct size and stimulating cardiomyocyte proliferation. Regarding vasculogenesis, the presence of ADSCs and NRG-MPs alone stimulated vessel formation when compared to the control group, but the combination of both induced the largest vasculogenic effect, promoting the formation of both arterioles and capillaries. Importantly, only when ADSCs were administered adhered to MPs, they were incorporated into newly formed vessels. Collectively, these findings demonstrate that the combination of ADSCs, MPs and NRG favored a synergy for inducing a greater and more complete improvement in heart regeneration and provided strong evidence to move forward with preclinical studies with this strategy.

The role of neuregulin/ErbB2/ErbB4 signaling in the heart with special focus on effects on cardiomyocyte proliferation.

The signaling complex consisting of the growth factor neuregulin-1 (NRG1) and its tyrosine kinase receptors ErbB2 and ErbB4 has a critical role in cardiac development and homeostasis of the structure and function of the adult heart. Recent research results suggest that targeting this signaling complex may provide a viable strategy for treating heart failure. Clinical trials are currently evaluating the effectiveness and safety of intravenous administration of recombinant NRG1 formulations in heart failure patients. Endogenous as well as administered NRG1 has multiple possible activities in the adult heart, but how these are related is unknown. It has recently been demonstrated that NRG1 administration can stimulate proliferation of cardiomyocytes, which may contribute to repair failing hearts. This review summarizes the current knowledge of how NRG1 and its receptors control cardiac physiology and biology, with special emphasis on its role in cardiomyocyte proliferation during myocardial growth and regeneration.

[Interfering effect of neuregulin upon cerebral ischemic reperfusion injury in rhesus monkeys].

OBJECTIVE: To study the interfering effect of neuregulin-1beta (NRG-1beta) on the cerebral ischemic reperfusion injury in monkeys. METHODS: The models with middle cerebral artery occlusion reperfusion (MCAO/R) were established by inserting a micro-balloon catheter intra-arterially into MCA from femoral artery in 12 adult healthy monkeys. The NRG-1beta was injected into MCA from micro-balloon catheter in the animals of treatment group at 2 h post-ischemia while the normal saline was simultaneously injected in the animals of control group. Then the micro-balloon catheter was withdrawn from the MCA to perfuse for 22 h. The nervous behavioral function was evaluated by task-oriented score and the infarct volume measured by TTC and MRI. RESULTS: The animals of control group had an onset of nervous functional disorders at 2 h post-ischemia and had no significant difference at reperfusion 22 h (59.8 +/- 15.7); the nervous function of monkeys had no improvement after NFG-1beta treatment (61.3 +/- 16.2) (P > 0.05). The diffuse weight imaging (DWI) showed a high signal area but T(1) and T(2) imaging had no significant changes at 2 h post-ischemia in control group animals; while the T(1) and T(2) imaging showed a typical high signal areas, DWI high signal area expanded and TTC staining ischemic area appeared at reperfusion 22 h. The T(1), T(2) and DWI abnormal signal areas and TTC cerebral infarct volume did not shrink significantly in NFG-1beta treatment group (P > 0.05). CONCLUSION: The neuroprotective effects of NRG-1beta upon cerebral ischemic reperfusion injury needs to be further studied.

[Effects of neregulin on rhesus monkey heart failure induced by rapid pacing].

OBJECTIVE: To investigate the effects of Recombined Human Neuregulin (NRG) on the expression of Glucose transporter (Glut1) in myocardium tissue of Rhesus Monkeys with Pacing-induced Heart Failure and the heart function. METHODS: Twenty four rhesus monkeys were randomly divided into three groups (shame operated group, heart failure group and NRG treated group), each with 8 monkeys. Heart failures were induced by rapid pacing (240 heart beats/min). Daily intravenous injection of recombined human NRG [3 microg/(kg x d)] and normal saline were given to the monkeys for 10 days for the NRG treated group and heart failure group respectively. Hemodynamic measurements including +dp/dt(max) and left ventricular systolic, end-diastolic blood pressures (LVSP and LVEDP) were conducted. The RT-PCR was applied to detect the expression level of PKB, Glut1 mRNA in the left ventricular cardiac muscle. RESULTS: The monkeys in the heart failure group had lower levels of + dp/dt(max) and LVSP and higher levels of LVEDP than those in the shame operated group (P < 0.05). The monkeys in the NRG treated group had higher levels of +dp/dt(max) than those in the heart failure group (P < 0.05). Lower expression of PKB, Glut1 mRNA in the heart failure group was observed compared with the shame operated group (P < 0.05) while the NRG treated group had a higher expression level of PKB,Glut1 mRNA by compared with the heart failure group (P < 0.05). CONCLUSION: Recombined human NRG can relieve heart failure syndroms through up-regulating the expression of PKB, Glut1 mRNA and improving energy supply of the ischemic cardiac muscle.

Agrin and neuregulin, expanding roles and implications for therapeutics.

Agrin and neuregulin are broadly expressed molecules that have significant developmental roles. Here we review the diverse temporal and spatial expression patterns and functions of these molecules and the impact that dysregulation may have on a number of disease states. Many know agrin as a modulator of synaptogenesis and the neuregulins for their prominent role in breast cancer; this review elaborates on many of the other proposed functions for these molecules both in the nervous system and elsewhere. In several instances we discuss the possible use of agrin, neuregulin and related molecules as therapeutic agents.

[Effects of recombined human neuregulin on the contractibility of cardiac muscles of rhesus monkeys with pacing-induced heart failure].

OBJECTIVE: To evaluate the effects of recombined human Neuregulin on the contractibility of cardiac muscles of Rhesus Monkeys with pacing-induced heart failure and to reveal the possible mechanisms involved. METHODS: Twenty four rhesus monkeys were randomly divided into three groups (shame operated group, heart failure group and Neuregulin treated group), each with 8 monkeys. Heart failures were induced by rapid pacing (240 heartbeats/min). Daily intravenous injection of recombined human Neuregulin [3 microg/(kg x d)] and medical salt fluid were given to the monkeys for 10 days for the Neuregulin treated group and heart failure group respectively. Hemodynamic measurements such as peak positive rate of change in left ventricular blood pressure (+dP/dtmax) and left ventricular systolic, and end-diastolic blood pressures (LVSP and LVEDP) were compared between groups. The real-time quantitative RT-PCR was undertaken to detect the expression of myosin heavy chain mRNA in the left ventricular cardiac muscle. RESULTS: The monkeys in the heart failure group had lower levels of +dP/dtmax and LVSP and higher levels of LVEDP than those in the shame operated group (P < 0.05). The monkeys in the Neuregulin treated group had higher levels of + dP/dtmax than those in the heart failure group (P < 0.05). Lower expression of alpha-myosin heavy chain mRNA in the heart failure group was found compared with the shame operated group and Neuregulin treated group (P < 0.05). CONCLUSION: Recombined human Neuregulin can enhance the contractibility of cardiac muscles and relieve heart failure syndrome through reversing the falling of alpha-myosin heavy chain induced by rapid ventricular pacing.

Emerging drugs for sarcopenia: age-related muscle wasting.

Sarcopenia is the term widely used to describe the progressive loss of muscle mass with advancing age. Even before significant muscle wasting becomes apparent, ageing is associated with a slowing of movement and a gradual decline in muscle strength, factors that increase the risk of injury from sudden falls and the reliance of the frail elderly on assistance in accomplishing even basic tasks of independent living. Sarcopenia is recognised as one of the major public health problems now facing industrialised nations, and its effects are expected to place increasing demands on public healthcare systems worldwide. Although the effects of ageing on skeletal muscle are unlikely to be halted or reversed, the underlying mechanisms responsible for these deleterious changes present numerous targets for drug discovery with potential opportunities to attenuate muscle wasting, improve muscle function, and preserve functional independence. Very few drugs have been developed with sarcopenia specifically in mind. However, because many of the effects of ageing on skeletal muscle resemble those indicated in many neuromuscular disorders, drugs that target neurodegenerative diseases may also have important relevance for treating age-related muscle wasting and weakness. This review describes a selection of the emerging drugs that have been developed during the period 1997 - 2004, relevant to sarcopenia.