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HER-2 as a Prognostic and Predictive Biomarker in Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Alexandra S. Zimmer, Suparna B. Wedamb, Stanley Lipkowitza
Homozygous deletion of HER-2 in mice results in embryonic lethality due to defective development ofcardiac trabeculae [22]. Also, HER-2 null mice have abnormal development of the nervous system and the neuromuscular junction [22–25]. Homozygous deletion of neuregulin, which binds to HER-3 and HER-4 and stimulates heterodimerization of these receptors with HER-2 and activation of the HER-2 kinase activity, causes similar developmental defects in the heart and nervous system [26]. In the developing heart, HER-2 is expressed in embryonic myocytes while the ligand neuregulin is expressed in the adjacent endocardium, consistent with a paracrine developmental signal (reviewed in [27]). Thus, HER-2 is essential for cardiac and neural development. Also, HER-2 serves important functions in the adult heart. Mice with conditional deletion of HER-2 targeted to cardiomyocytes have normal embryonic heart development but develop dilated cardiomyopathy at 3 months of age [28]. Doxorubicin treatment of mice with a heterozygous deletion of neuregulin-1 results in increased cardiac damage and mortality and induces less phosphorylation of HER-2, HER-4, ERK 1 and 2, AKT, and 70S6K in the heterozygous neuregulin deficient mice compared to wild type mice [29]. Together these data demonstrate a role for HER-2 in normal homeostasis and response to damage in the adult heart. This is likely to explain the cardiac toxicity observed in breast cancer patients treated with the anti-HER-2 antibody trastuzumab (reviewed in [30]).
Etiopathogenesis
Published in Vineet Relhan, Vijay Kumar Garg, Sneha Ghunawat, Khushbu Mahajan, Comprehensive Textbook on Vitiligo, 2020
Dario Didona, Biagio Didona, Giovanni Paolino, Raffaele Dante Caposiena Caro
Both peripheral nerve sheath and melanocytes arise from neural crest cells (NCC). These cells migrate from the neural tube to dorsolateral and ventral directions [38] (Figure 5.5). On the one hand, cells with only a dorsolateral trajectory are committed to melanocytic fate; on the other hand, cells with a ventral trajectory are committed to neuronal, glial/melanocyte, or endoneurial fibroblast fate [38]. It has been shown that SOX10+ NCCs fail to initiate the neuronogenesis, adopting a glial pathway to give rise to Schwann cells and melanocytes, highlighting the link between pigmentary disorders (as vitiligo) and neural cells [38]. Neuregulin 1 is an axon-derived growth factor which, when overexpressed, promotes glial fate and suppresses melanocytic activity [39]. Furthermore, melanocytes with the overexpression of embryo retinal epithelium can dedifferentiate back to their unpigmented glial progenitor [39].
Schizophrenia
Published in Divya Vohora, The Third Histamine Receptor, 2008
Kaitlin E. Browman, Min Zhang, Gerard B. Fox, Lynne E. Rueter
The neurodevelopmental hypothesis states that “schizophrenia is the behavioral outcome of an aberration in neurodevelopmental processes that begins long before the onset of clinical symptoms and is caused by a combination of environmental and genetic factors” [22]. It has been postulated that these aberrations in neurodevelopment result in inappropriate connections between key brain regions such as the striatum, nucleus accumbens, and frontal cortex [23]. Evidence in support of the theory comes from various sources. First, there is a typical progression of the disorder itself from a prodromal phase in childhood and the early teen years to a typical progressive worsening of both symptoms and prognosis across the life of the disorder [12]. Second, there is a significant genetic component to the risk of developing schizophrenia, for example, while there is about 1% prevalence in the general population, the risk increases to 10-15% if a first-order relative is diagnosed with schizophrenia and to 30–65% if an identical twin is diagnosed [2]. Genetic association studies further support this as susceptibility genes such as neuregulin 1 and dysbindin play roles in neural development and neuronal connectivity [19]. Third, various pre- and perinatal risk factors have been identified including prenatal infections, famine during pregnancy, and obstetric complications [2]. Finally, brain morphology is often altered in schizophrenia patients, with increases in the volume of the lateral ventricle being one of the most common changes described [22].
The significance of the neuregulin-1/ErbB signaling pathway and its effect on Sox10 expression in the development of terminally differentiated Schwann cells in vitro
Published in International Journal of Neuroscience, 2021
Xizhong Yang, Cuijie Ji, Xinyue Liu, Chaoqun Zheng, Yanxin Zhang, Ruowu Shen, Zangong Zhou
Neuregulin-1 (NRG-1) is a member of the family of regulatory proteins that contain the EGF (epidermal growth factor)-like domain. It is a type of transmembrane protein that regulates the growth and development of glial cells and neurons [8]. The functional receptor of NRG is the ErbB receptor, which includes ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4. ErbB is a member of the EGF receptor family of transmembrane tyrosine kinases. Both ErbB2 and ErbB3 receptors are required in the development of SCs, but these two receptors have different effects; ErbB3 can bind with extracellular ligands with high affinity even though it is inactive, while ErbB2 tyrosine kinase activity can activate downstream signaling [9]. Sox10 belongs to the Sox family, members of which contain a DNA binding domain that is similar to the HMG (high mobility group) domain of the SRY transcription factor family [10]. The structure of Sox10 is highly conserved, especially the structure of its functional domains, such as the N-terminal to C-terminal dimerization domain, the HMG domain, and the protein interaction (K2) domain [11]. The Sox gene family is involved in stem cell maintenance, cell differentiation and tissue formation. Sox10 plays an important role in the formation of the neural crest and peripheral nervous system, the maturation and terminal differentiation of SCs, and the differentiation of melanocytes. Sox10 and Oct6 have synergistic effects on the differentiation and development of SCs [12]. In addition, in the central nervous system and the peripheral nervous system, Sox10 is highly expressed in neural crest cells and glial cells.
Bioavailability and Neuroprotectivity of 3-(3, 4-dimethoxy phenyl)-1-4 (methoxy phenyl) prop-2-en-1-one against Schizophrenia: an in silico approach
Published in Journal of Receptors and Signal Transduction, 2019
Venkataramaiah Chintha, Rajendra Wudayagiri
Schizophrenia is a complex psychiatric disorder that is highly heritable with a strong genetic component [1] which include: (1). ‘Potential candidate schizophrenia genes’, which are proposed to be involved in schizophrenia but have not yet been directly investigated for disease involvement; (2). ‘Candidate schizophrenia genes’, which have some direct evidence of disease involvement but for which the evidence is not yet considered to be susceptibility genes; and (3). ‘Schizophrenia susceptibility gene’, for those few genes that have considerable evidence showing contribution to schizophrenia etiology, few schizophrenia susceptibility genes have been identified which include dysbindin (DTNBP1), neuregulin-1 (NRG1), disrupted-in-schizophrenia-1 (DISC1), and Catechol-O-methyl transferase (COMT). Schizophrenia has a high heritability of 80–87% [2], similar to that of bipolar disorder (79–93%) [3], in contrast to other complex diseases such as Alzheimer’s disease (29–79%) [4], asthma (48–79%) [5] and breast cancer (25–50%) [6]. Psychiatric disorders, including schizophrenia, have added complexity in that they rely on non-biological descriptive measures for the purposes of diagnosis, which has shown limited effectiveness for segregating individuals into phenotypically or genotypically homogeneous disease populations [7].
Treating cardiovascular complications of radiotherapy: a role for new pharmacotherapies
Published in Expert Opinion on Pharmacotherapy, 2018
Nathalie Donis, Cécile Oury, Marie Moonen, Patrizio Lancellotti
Neuregulin-1 is a protein that is expressed by myocytes. It has been involved in several processes including myocardial and conduction system development, cardiac cellular contractility, survival and proliferation, and calcium homeostasis [113]. In a rat model, it has been reported that recombinant human neuregulin-1β (rhNRG-1β) prevented mitochondrial dysfunction and intracellular ATP concentration decrease early after cardiac irradiation. At later stage, rhNRG-1β decreased radiation-induced myocardial fibrosis and cardiomyocyte hypertrophy while preserving cardiac function via the ErbB2-ERK-SIRT1 signaling pathway [114]. rhNRG-1β (NeucardinTM, Zensun) has already been used in a double-blind, randomized phase II clinical trial in patients suffering from chronic heart failure (New York Heart Association functional class II or III). In this trial, a daily dose of rhNRG-1β or placebo was administered to the patients for 10 days, patients were then followed-up for 80 days. rhNRG-1β exhibited encouraging results as it improved cardiac function in patients over time compared to the placebo (increased left ventricular ejection fraction, decreased end-diastolic volume, and end-systolic volume) [115]. Thus, studying the effect of rhNRG-1β in patients who received thoracic RT deserves further consideration.