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Anna-Eliane Hopf, Christian Andresen, Sebastian Kötter, Malgorzata Isic, Kamila Ulrich, Senem Sahin, Sabine Bongardt, Wilhelm Roell, Felicitas Drove, Nina Scheerer, Leni Vandekerckhove, Gilles W De Keulenaer, Nazha Hamdani, Wolfgang A Linke, Martina Krüger
<u>Rationale:</u> Increased titin-dependent cardiomyocyte tension is a hallmark of heart failure with preserved ejection fraction (HFpEF) associated with type-2 diabetes mellitus (T2DM). However, the insulin-related signaling pathways that modify titin-based cardiomyocyte tension, thereby contributing to modulation of diastolic function, are largely unknown. <u>Objective:</u> We aimed to determine how impaired insulin signaling affects titin expression and phosphorylation and thus increases passive cardiomyocyte tension, and whether metformin or neuregulin-1 can correct disturbed titin modifications and increased titin-based stiffness...
May 14, 2018: Circulation Research
David Lloyd, David Talmage, Cynthia Shannon Weickert, Tim Karl
Mice with a mutation in the transmembrane domain of the schizophrenia risk gene, neuregulin 1 (Nrg1 TM HET), are more susceptible to the neuro-behavioural effects of Δ9 -tetrahydrocannabinol (D9 -THC), the principal psychoactive component in cannabis. However, NRG1 is transcriptionally complex with over 30 different isoforms, most of which carry a transmembrane domain, raising the question which NRG1 isoform(s) may contribute to this phenotype. Type III NRG1/Nrg1 is the most brain abundant isoform and brain studies have identified increased levels of type III NRG1 mRNA in humans carrying a NRG1 risk haplotype for schizophrenia...
May 8, 2018: Pharmacology, Biochemistry, and Behavior
Gonzalo Del Monte-Nieto, Mirana Ramialison, Arne A S Adam, Bingruo Wu, Alla Aharonov, Gabriele D'Uva, Lauren M Bourke, Mara E Pitulescu, Hanying Chen, José Luis de la Pompa, Weinian Shou, Ralf H Adams, Sarah K Harten, Eldad Tzahor, Bin Zhou, Richard P Harvey
In vertebrate hearts, the ventricular trabecular myocardium develops as a sponge-like network of cardiomyocytes that is critical for contraction and conduction, ventricular septation, papillary muscle formation and wall thickening through the process of compaction 1 . Defective trabeculation leads to embryonic lethality2-4 or non-compaction cardiomyopathy (NCC) 5 . There are divergent views on when and how trabeculation is initiated in different species. In zebrafish, trabecular cardiomyocytes extrude from compact myocardium 6 , whereas in chicks, chamber wall thickening occurs before overt trabeculation 7 ...
May 9, 2018: Nature
Fei Xie, Fan Zhang, Su Min, Jingyuan Chen, Jun Yang, Xin Wang
BACKGROUND: Peripheral neuromuscular dysfunctions were found in elderly individuals, and spinal microglia/monocyte plays an important role on this process. This study aims to test whether the glial cell line-derived neurotrophic factor (GDNF) could attenuate age-related neuromuscular dysfunction by inhibiting the activation of spinal microglia/monocyte. METHODS: Male Sprague-Dawley rats were divided into an adult group and an aged group. The aged rats were intrathecally injected with normal saline (NS) and GDNF...
May 9, 2018: BMC Geriatrics
Chun Gui, Zhi-Yu Zeng, Qi Chen, Ya-Wei Luo, Lang Li, Lin-Lin Chen
BACKGROUND/AIMS: Microvascular insufficiency takes a critical role in the development of diabetic cardiomyopathy (DCM). So this study was designed to investigate the effects of Neuregulin-1 (NRG-1) treatment on myocardial angiogenesis and the changes of VEGF/Flk1 and Ang-1/Tie-2 signaling in the rat model of DCM. METHODS: Diabetic rats were induced by a single intraperitoneal injection of Streptozotocin. 12 weeks after the diabetes induction, the rats with NRG-1 treatment were treated with tail vein injection of NRG-1 at the dose of 10µg/kg/d for consecutive 10 days...
May 4, 2018: Cellular Physiology and Biochemistry
Dimitrios Kotzadimitriou, Wiebke Nissen, Melinda Paizs, Kathryn Newton, Paul J Harrison, Ole Paulsen, Karri Lamsa
Hypofunction of N -methyl-d-aspartate receptors (NMDARs) in inhibitory GABAergic interneurons is implicated in the pathophysiology of schizophrenia (SZ), a heritable disorder with many susceptibility genes. However, it is still unclear how SZ risk genes interfere with NMDAR-mediated synaptic transmission in diverse inhibitory interneuron populations. One putative risk gene is neuregulin 1 ( NRG1 ), which signals via the receptor tyrosine kinase ErbB4, itself a schizophrenia risk gene. The type I isoform of NRG1 shows increased expression in the brain of SZ patients, and ErbB4 is enriched in GABAergic interneurons expressing parvalbumin (PV) or cholecystokinin (CCK)...
March 2018: ENeuro
Hai-Yang Xu, Pan Wang, Ying-Jian Sun, Ming-Yuan Xu, Li Zhu, Yi-Jun Wu
Organophosphate-induced delayed neuropathy (OPIDN) is characterized by progressive axonal degeneration and demyelination of the spinal cord and sciatic nerves. The neuregulin 1/epidermal growth factor receptor (ErbB) signaling pathway is crucial for axonal myelination. In this study, we investigated whether the neuregulin 1/ErbB signaling pathway mediated the progression of OPIDN. Adult hens were given tri- o -cresyl phosphate (TOCP), a typical neuropathic organophosphorus compound, to induce OPIDN. The ErbB inhibitor lapatinib was administered to hens 4 h prior to and 4 days after TOCP exposure...
2018: Frontiers in Molecular Neuroscience
Stanley Artap, Lauren J Manderfield, Cheryl L Smith, Andrey Poleshko, Haig Aghajanian, Kelvin See, Li Li, Rajan Jain, Jonathan A Epstein
The Hippo signaling pathway has been implicated in control of cell and organ size, proliferation, and endothelial-mesenchymal transformation. This pathway impacts upon two partially redundant transcription cofactors, Yap and Taz, that interact with other factors, including members of the Tead family, to affect expression of downstream genes. Yap and Taz have been shown to regulate, in a cell-autonomous manner, myocardial proliferation, myocardial hypertrophy, regenerative potential, and overall size of the heart...
May 1, 2018: Developmental Biology
Pijun Yan, Yong Xu, Qin Wan, Jian Feng, Hua Li, Jun Yang, Haihua Zhong, Zhihong Zhang
Neuregulin 4 (Nrg4) has been proposed to play a role in the pathogeneses of obesity, insulin resistance, and dyslipidemia. However, information about the link between Nrg4 and metabolic syndrome (MetS) is scarce, especially in patients with newly diagnosed type 2 diabetes mellitus (nT2DM). This study aimed at investigating whether Nrg4 is associated with MetS in nT2DM patients. A total of 311 patients with nT2DM were recruited. Plasma Nrg4 concentration was determined by ELISA. Plasma Nrg4 concentration was lower in nT2DM patients with MetS than in nT2DM patients without MetS ( P = 0...
2018: Disease Markers
Jin Chen, Qun Ren, Yuanming Cai, Tingting Lin, Weimin Zuo, Jin Wang, Rong Lin, Ling Zhu, Ping Wang, Huiyue Dong, Hu Zhao, Lianghu Huang, Yunfeng Fu, Shunliang Yang, Jianming Tan, Xiaopeng Lan, Shuiliang Wang
We had previously demonstrated that increased expression of ErbB3 is required for ErbB2-mediated paclitaxel resistance in breast cancer cells. In the present study, we have explored the possible role of mesenchymal stem cells (MSCs) in regulating the paclitaxel-sensitivity of ErbB2/ErbB3-coexpressing breast cancer cells. We show that human umbilical cord-derived MSCs express significantly higher level of neuregulin-1 as compared with ErbB2/ErbB3-coexpressing breast cancer cells themselves. Coculture or treatment with conditioned medium of MSCs not only decreases the anti-proliferation effect of paclitaxel on ErbB2/ErbB3-coexpressing breast cancer cells, but also significantly inhibits paclitaxel-induced apoptosis...
April 28, 2018: Biochemical and Biophysical Research Communications
Jeroen Claus, Gargi Patel, Flavia Autore, Audrey Colomba, Gregory Weitsman, Tanya N Soliman, Selene Roberts, Laura C Zanetti-Domingues, Michael Hirsch, Francesca Collu, Roger George, Elena Ortiz-Zapater, Paul R Barber, Boris Vojnovic, Yosef Yarden, Marisa L Martin-Fernandez, Angus Cameron, Franca Fraternali, Tony Ng, Peter J Parker
While targeted therapy against HER2 is an effective first-line treatment in HER2+ breast cancer, acquired resistance remains a clinical challenge. The pseudokinase HER3, heterodimerisation partner of HER2, is widely implicated in the resistance to HER2-mediated therapy. Here, we show that lapatinib, an ATP-competitive inhibitor of HER2, is able to induce proliferation cooperatively with the HER3 ligand neuregulin. This counterintuitive synergy between inhibitor and growth factor depends on their ability to promote atypical HER2-HER3 heterodimerisation...
May 1, 2018: ELife
Ariana Centa, Ruth Rodríguez-Barrueco, Juan Carlos Montero, Atanasio Pandiella
The Neuregulins (NRGs) represent a large family of membrane-anchored growth factors, whose deregulation may contribute to the pathogenesis of several tumours. In fact, targeting of NRG-activated pathways has demonstrated clinical benefit. To improve the efficacy of anti-NRG therapies, it is essential to gain insights into the regions of NRGs that favour their pro-oncogenic properties. Here we have addressed the protumorigenic impact of different NRG domains. To do this, deletion mutants affecting different NRG domains were expressed in 293 and MCF7 cells...
April 23, 2018: Molecular Oncology
Alireza Mohammadi, Ehsan Rashidi, Vahid Ghasem Amooeian
Over the last decade, finding a reliable biomarker for the early detection of schizophrenia (Scz) has been a topic of interest. The main goal of the current review is to provide a comprehensive view of the brain, blood, cerebrospinal fluid (CSF), and serum biomarkers of Scz disease. Imaging studies have demonstrated that the volumes of the corpus callosum, thalamus, hippocampal formation, subiculum, parahippocampal gyrus, superior temporal gyrus, prefrontal and orbitofrontal cortices, and amygdala-hippocampal complex were reduced in patients diagnosed with Scz...
April 13, 2018: Psychiatry Research
Carlos Manuel Zapata-Martín Del Campo, Martín Martínez-Rosas, Verónica Guarner-Lans
Corticotrophin releasing factor, vasopressin, oxytocin, natriuretic hormones, angiotensin, neuregulins, some purinergic substances, and some cytokines contribute to the long-term modulation and restructuring of cardiovascular regulation networks and, at the same time, have relevance in situations of comorbid abnormal stress responses. The synthesis, release, and receptor expression of these mediators seem to be under epigenetic control since early stages of life, possibly underlying the comorbidity to coronary artery disease (CAD) and stress-related disorders (SRD)...
April 18, 2018: International Journal of Molecular Sciences
Zhibing Tan, Heath L Robinson, Dong-Min Yin, Yu Liu, Fang Liu, Hongsheng Wang, Thiri W Lin, Guanglin Xing, Lin Gan, Wen-Cheng Xiong, Lin Mei
Top-down attention is crucial for meaningful behaviors and impaired in various mental disorders. However, its underpinning regulatory mechanisms are poorly understood. We demonstrate that the hippocampal-prefrontal synchrony associates with levels of top-down attention. Both attention and synchrony are reduced in mutant mice of ErbB4, a receptor of neuregulin-1. We used chemical genetic and optogenetic approaches to inactivate ErbB4 kinase and ErbB4+ interneurons, respectively, both of which reduce gamma-aminobutyric acid (GABA) activity...
April 3, 2018: Neuron
Yan Guo, Zhihui Duan, Yitao Jia, Chaoying Ren, Jian Lv, Peng Guo, Wujie Zhao, Bin Wang, Suqiao Zhang, Yaxing Li, Zhongxin Li
The present study aimed to evaluate the expression of human epidermal growth factor receptor (HER4) isoforms and their ligand neuregulin 1 (NRG1) isoforms in human primary colorectal cancer (CRC). The mRNA expression of HER4 isoforms JM-a, JM-b, CYT1 and CYT2, and their ligand isoforms NRG1 I, II and III in CRC tissues and adjacent normal tissues were quantified by reverse transcription-quantitative polymerase chain reaction analysis. Univariate analysis and logistic regression analysis were performed to analyze the association between HER4 and NRG1 expression and lymph node metastasis in CRC...
May 2018: Oncology Letters
Michela Morano, Giulia Ronchi, Valentina Nicolò, Benedetta Elena Fornasari, Alessandro Crosio, Isabelle Perroteau, Stefano Geuna, Giovanna Gambarotta, Stefania Raimondo
Neuregulin 1 (NRG1) is a growth factor produced by both peripheral nerves and skeletal muscle. In muscle, it regulates neuromuscular junction gene expression, acetylcholine receptor number, muscle homeostasis and satellite cell survival. NRG1 signalling is mediated by the tyrosine kinase receptors ErbB3 and ErbB4 and their co-receptors ErbB1 and ErbB2. The NRG1/ErbB system is well studied in nerve tissue after injury, but little is known about this system in skeletal muscle after denervation/reinnervation processes...
March 22, 2018: Scientific Reports
David J Clarke, Tariq W Chohan, Mustafa S Kassem, Kristie L Smith, Rose Chesworth, Tim Karl, Michael P Kuligowski, Sandra Y Fok, Maxwell R Bennett, Jonathon C Arnold
One neuropathological feature of schizophrenia is a diminished number of dendritic spines in the prefrontal cortex and hippocampus. The neuregulin 1 (Nrg1) system is involved in the plasticity of dendritic spines, and chronic stress decreases dendritic spine densities in the prefrontal cortex and hippocampus. Here, we aimed to assess whether Nrg1 deficiency confers vulnerability to the effects of adolescent stress on dendritic spine plasticity. We also assessed other schizophrenia-relevant neurobiological changes such as microglial cell activation, loss of parvalbumin (PV) interneurons, and induction of complement factor 4 (C4)...
March 16, 2018: Schizophrenia Bulletin
Juan C Olaya, Carrie L Heusner, Mitsuyuki Matsumoto, Cynthia Shannon Weickert, Tim Karl
Elevated levels of the type III (III) isoforms of neuregulin 1 (NRG1) have been observed in the brains of schizophrenia patients that carry NRG1 HapICE risk alleles, which is thought to contribute to the aetiology of the disease. We generated transgenic mice with forebrain driven Nrg1 III overexpression (Nrg1 III tg) and previously found that male heterozygous Nrg1 type III tg mice exhibit several schizophrenia-relevant behaviours including social and cognitive deficits as well as impaired sensorimotor gating...
March 17, 2018: Behavioural Brain Research
Yannick Poitelon, M Laura Feltri
In the peripheral nervous system, axons dictate the differentiation state of Schwann cells. Most of this axonal influence on Schwann cells is due to juxtacrine interactions between axonal transmembrane molecules (e.g., the neuregulin growth factor) and receptors on the Schwann cell (e.g., the ErbB2/ErbB3 receptor). The fleeting nature of this interaction together with the lack of synchronicity in the development of the Schwann cell population limits our capability to study this phenomenon in vivo. Here we present a simple Boyden Chamber-based method to study this important cell-cell interaction event...
2018: Methods in Molecular Biology
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