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This article reports on novel imidazothiazole derivatives as first-in-class potent and selective ErbB4 (HER4) inhibitors. There are no other reported selective inhibitors of this kinase in the literature, that's why they are considered as first-in-class. In addition, none of the reported non-selective ErbB4 inhibitors possesses imidazothiazole nucleus in its structure. Therefore, there is novelty in this work in both kinase selectivity and chemical structure. Compounds Ik and IIa are the most potent ErbB4 kinase inhibitor (IC50 = 15.24 and 17.70 nM, respectively). Compound Ik showed promising antiproliferative activity. It is selective towards cancer cell lines than normal cells. Its ability to penetrate T-47D cell membrane and inhibit ErbB4 kinase inside the cells has been confirmed. Moreover, both compound Ik and IIa have additional merits such as weak potency against hERG ion channels and against CYP 3A4 and 2D6. Molecular docking and dynamic simulation studies were carried out to explain binding interactions.

Epidermal growth factor receptor (EGFR) plays a pivotal role in collective cell migration by mediating cell-to-cell propagation of extracellular signal-regulated kinase (ERK) activation. Here, we aimed to determine which EGFR ligands mediate the ERK activation waves by gene knockout. Four of the seven known EGFR ligands are expressed in MDCK cells. We found that epidermal growth factor (EGF)-deficient cells exhibited lower basal ERK activity than the cells deficient in heparin-binding EGF (HBEGF), transforming growth factor alpha (TGFα) or epiregulin (EREG), but all cell lines deficient in a single EGFR ligand retained the ERK activation waves. Therefore, we knocked out the EGFR ligand genes in decreasing order of expression. ERK activation waves were markedly suppressed, albeit incompletely, only when all four EGFR ligands were knocked-out. Re-expression of the EGFR ligands revealed that all but HBEGF could restore the ERK activation waves. Aiming at complete elimination of the ERK activation waves, we further attempted to knockout Nrg1, a ligand for ErbB3 and ErbB4, and found that Nrg1 deficiency induced growth arrest in the absence of all four EGFR ligand genes expressed in MDCK cells. Collectively, these results showed that EGFR ligands exhibit remarkable redundancy in the propagation of ERK activation waves during collective cell migration.

This study aimed to investigate the effect of the neuregulin-1/epidermal growth factor 4 (NRG1/ErbB4) signaling pathway on visual cortex synaptic plasticity in adult amblyopic rats with monocular deprivation (MD). Compared with the control group, the P wave latency and amplitude of the MD group were prolonged and low, respectively, with reduced synaptic plasticity-related protein expression, lower number of visual cortex neurons, and increased apoptosis of visual cortex neurons. Recombinant neuregulin-1 (rNRG1) administration activated the NRG1/ErbB4 signaling pathway and improved the visual cortex synaptic plasticity in MD amblyopic rats. However, the effects of rNRG1 were reversed by AG1478 (ErbB4 receptor blockers). The NRG1/ErbB4 signaling pathway in the parvalbumin neurons from MD rats was also inactivated. Amblyopic rats had significantly low cell activity and downregulated expression of synaptic plasticity-related proteins. Thus, exogenous administration of NRG1 can activate ErbB4 signal transduction and improve the damaged synaptic plasticity of the visual cortex among amblyopic rats. Further studies are warranted to explore the potential for clinical management of amblyopia.

Background Nicotine dependence (ND) is characterized by regular smoking, anxiety, irritation, difficulty concentrating, impatience, restlessness, tremor, dizziness, hunger, nicotine demand, and the individual's reluctance to quit despite knowing the health risks of smoking. Recently, it has been reported that the Neuregulin 3 (NRG3)/Erb-B2 receptor tyrosine kinase 4 (ERBB4) signaling pathway plays a role in ND. NRG3, which is activated after nicotine intake, binds to ERBB4 and causes GABA release. GABA reduces anxiety and tension, which are one of the nicotine withdrawal symptoms. Therefore we aimed to investigate the relationship between NRG3 and ERBB4 gene polymorphisms and ND. Materials and methods The study population was comprised of patients with ND (n = 200) and healthy non-smoker control subjects (n = 200) who were matched for age, sex, and compared for comorbidity factors such as alcohol, smoking, duration, and education (age range 18-60). Genotypes were detected by Real-Time PCR using TaqMan technology. The Fagerstrom Nicotine Dependence Test (FTND) score was 5 and above for the patient group and 0 for the control group. DNA was obtained from whole peripheral blood and six polymorphisms of Neuregulin 3 (NRG3) (rs1836724, rs7562566, and rs10048757) and Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4) (rs1764072, rs6584400, and rs10883934) genes were analyzed by real-time PCR method. Results Our findings show that the six selected SNPs are not significantly associated with ND in the Turkish population and no correlation with dependence levels (p > 0.05). Conclusion Although our findings do not show a relationship between ND and these polymorphisms, it is the first study to investigate these single nucleotide polymorphisms (SNPs) for the first time in ND and to find some genotypes in the Turkish population when compared to other populations. Also, our findings are important in terms of their contribution to the literature and forensic genetics., Green Crescent and Mersin University Scientific Research Project Unit [BAP-SBE TBB (HG) 2014-4 YL], We would like to thank Green Crescent and Mersin University Scientific Research Project Unit for supporting this study as a project coded BAP-SBE TBB (HG) 2014-4 YL.

Chunxiang Li,1 Hengchang Liu,2 Ran Wei,2 Zheng Liu,2 Haipeng Chen,2 Xu Guan,2 Zhixun Zhao,2 Xishan Wang,2 Zheng Jiang2 1Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Zheng JiangDepartment of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District, Beijing, People’s Republic of ChinaTel +86 10-87787110Email zr7780@163.comBackground/Aims: Long non-coding ribonucleic acids (lncRNAs) are involved in the progression of cancers and affect the response to radiation therapy. This study was to investigate the mechanism of lncRNA EGOT in the radiosensitivity of rectal cancer.Methods: The mRNA expression of EGOT, miR-211-5p and ErbB4 in rectal cancer tissues and cells was detected by qRT-PCR. The protein expression of ErbB4 was detected by Western blot. Dual-luciferase reporter assay and ribonucleic acid immunoprecipitation (RIP) were used to confirm the interaction between EGOT and miR-211-5p or miR-211-5p and ErbB4. Transfection technology was used to down-regulate and up-regulate the expression of EGOT and miR-211-5p in rectal cancer cells, respectively. MTT, colony formation and flow cytometry were used to detect the effect of EGOT and miR-211-5p on proliferation, invasion, migration and apoptosis of rectal cancer cells.Results: The expression of EGOT was up-regulated in rectal cancer tissues and cells, and the expression of EGOT was related to the late stage of pathology. EGOT knockdown inhibited the proliferation and colony formation of rectal cancer cells and induced the apoptosis of rectal cancer cells. Moreover, EGOT knockdown was significantly enhanced the effects of radiotherapy on rectal cancer in vivo and in vitro. Furthermore, EGOT was found to serve as a sponge of miR-211-5p, and ErbB4 was a downstream target of miR-211-5p. EGOT enhanced the expression of ErbB4 by regulating miR-211-5p. MiR-211-5p inhibitor restored the effect of EGOT knockdown on the radiosensitivity of rectal cancer.Conclusion: Down-regulation of EGOT could inhibit the growth of rectal cancer cells by regulating the miR-211-5p/ErbB4 axis and improve the radiosensitivity of rectal cancer cells. EGOT may be a new therapeutic target for rectal cancer.Keywords: EGOT, miR-211-5p, ErbB4, rectal cancer, radiosensitivity

Diabetes mellitus is a major debilitating disease whose global incidence is progressively increasing with currently over 463 million adult sufferers and this figure will likely reach over 700 million by the year 2045. It is the complications of diabetes such as cardiovascular, renal, neuronal and ocular dysfunction that lead to increased patient morbidity and mortality. Of these, cardiovascular complications that can result in stroke and cardiomyopathies are 2- to 5-fold more likely in diabetes but the underlying mechanisms involved in their development are not fully understood. Emerging research suggests that members of the Epidermal Growth Factor Receptor (EGFR/ErbB/HER) family of tyrosine kinases can have a dual role in that they are beneficially required for normal development and physiological functioning of the cardiovascular system (CVS) as well as in salvage pathways following acute cardiac ischemia/reperfusion injury but their chronic dysregulation may also be intricately involved in mediating diabetes-induced cardiovascular pathologies. Here we review the evidence for EGFR/ErbB/HER receptors in mediating these dual roles in the CVS and also discuss their potential interplay with the Renin-Angiotensin-Aldosterone System heptapeptide, Angiotensin-(1-7), as well the arachidonic acid metabolite, 20-HETE (20-hydroxy-5, 8, 11, 14-eicosatetraenoic acid). A greater understanding of the multi-faceted roles of EGFR/ErbB/HER family of tyrosine kinases and their interplay with other key modulators of cardiovascular function could facilitate the development of novel therapeutic strategies for treating diabetes-induced cardiovascular complications.

Anxiety disorders, especially posttraumatic stress disorder, are marked by an impaired ability to understand that a conditioned stimulus previously paired with a noxious stimulus is no longer noxious. Although previous studies suggest that fear extinction depends on the function of the amygdala, the underlying mechanisms are unclear. We found that NRG1 receptors (ErbB4) were abundantly expressed in the intercalated amygdala (ITC). The NRG1-ErbB4 pathway in the ITC promotes fear extinction. The NRG1-ErbB4 pathway in the ITC did not affect excitatory input to ITC neurons from BLA neurons but increased feed-forward inhibition of CeM neurons through increased GABAergic neurotransmission of ITC neurons. We also found that the NRG1-ErbB4 signaling pathway in ITC might regulate fear extinction through P/Q-type voltage-activated Ca2+ channels (VACCs) but not through L- or N-type VACCs. Overall, our results suggest that the NRG1-ErbB4 signaling pathway in the ITC might represent a potential target for the treatment of anxiety disorders.

The genes encoding for neuregulin1 (NRG1), a growth factor, and its receptor ErbB4 are both risk factors of major depression disorder and schizophrenia (SZ). They have been implicated in neural development and synaptic plasticity. However, exactly how NRG1 variations lead to SZ remains unclear. Indeed, NRG1 levels are increased in postmortem brain tissues of patients with brain disorders. Here, we studied the effects of high-level NRG1 on dendritic spine development and function. We showed that spine density in the prefrontal cortex and hippocampus was reduced in mice (ctoNrg1) that overexpressed NRG1 in neurons. The frequency of miniature excitatory postsynaptic currents (mEPSCs) was reduced in both brain regions of ctoNrg1 mice. High expression of NRG1 activated LIMK1 and increased cofilin phosphorylation in postsynaptic densities. Spine reduction was attenuated by inhibiting LIMK1 or blocking the NRG1–LIMK1 interaction, or by restoring NRG1 protein level. These results indicate that a normal NRG1 protein level is necessary for spine homeostasis and suggest a pathophysiological mechanism of abnormal spines in relevant brain disorders.

Accumulation of amyloid β (Aβ) in the brain is a hallmark of Alzheimer's disease (AD). We previously showed that ErbB4 in parvalbumin-positive (PV) interneurons was associated with Aβ-induced cognitive deficits; however, the underlying mechanism remains undetermined. Here we found that specific deletion of ErbB4 in PV neurons significantly attenuated oligomeric Aβ-induced neuronal toxicity and inhibited Aβ-induced decreases of PSD95 and synaptophysin. Moreover, specific ablation of ErbB4 in PV neurons altered activity-related protein c-Fos and decreased hippocampal PV neurons, especially in the dentate gyrus (DG) of hAPP-J20 mice. Furthermore, c-Jun N-terminal kinase (JNK), a protein downstream of ErbB4, was activated by Aβ but not ErbB4's ligand neuregulin 1 (NRG1) β1, suggesting different downstream pathways for Aβ and NRG1β1. JNK phosphorylation was inhibited by the ErbB4 inhibitor AG1478 and by pretreatment with NRG1β1. More importantly, siRNA knockdown of ErbB4 decreased JNK phosphorylation and expression, tau phosphorylation at Ser396 and Thr 205, and Bax expression. Therefore, ErbB4 might mediate Aβ-induced neuropathology through the JNK/tau pathway and represent a potential therapeutic target in patients with AD. This article is protected by copyright. All rights reserved.

Proinflammatory macrophages are essential drivers of colitis and express the growth factor receptor ErbB4. This study tested the role of ErbB4 and its specific ligand, NRG4, in regulating macrophage function. We show that endogenous NRG4-ErbB4 signaling limits macrophage production of proinflammatory cytokines in vitro and limits colitis severity in vivo and thus is a potential target for therapeutic intervention.

Epidermal growth factor receptor 2 (HER2/ErbB2/neu), a member of ErbB receptor tyrosine kinase family, forms homo- or heterodimers with ErbB1 (HER1/EGFR), ErbB3 (HER3), or ErbB4 (HER4), to activate signal transduction pathways and promote proliferation, differentiation and tumorigenesis. Preliminary clinical trials of monoclonal antibodies, antibody conjugates and small-molecule tyrosine kinase inhibitors targeting HER2 have indicated that HER2 is a potential therapeutic target in non-small cell lung cancer (NSCLC). HER2 aberrations in NSCLC patients mainly include mutation, amplification, and overexpression. While there are significant differences in the outcome of NSCLC with these HER2 changes, no consensus has been reached for the incidence, detection method and targeted treatments for the three types of HER2 aberration. HER2 mutation is generally considered to have more clinical relevance and response to HER2-targeted therapies. In this review, we discuss HER2 alterations in NSCLC, including diagnostic challenges and treatment strategies particular to the HER2 mutation.

Background: EGFR, ERBB2, ERBB3, and ERBB4 are growth receptors of the ERBB family implicated in the development of epithelial cancers. Studies have suggested a role for EGFR and ERBB3 in the development of prostate cancer (PC), while the involvement of ERBB2 and ERBB4 remains unclear. In this study, we evaluated the expression of all members of the ERBB family in PC tissue from a large cohort and determined their contribution, alone or in combination, as prognostic markers. Methods: Using immunofluorescence coupled with digital image analyses, we quantified the expression of EGFR, ERBB2, ERBB3, and ERBB4 on radical prostatectomy specimens (n = 285) arrayed on six tissue microarrays. By combining EGFR, ERBB2, and ERBB3 protein expression in a decision tree model, we identified an association with biochemical recurrence (log rank = 25.295, p &lt, 0.001), development of bone metastases (log rank = 23.228, p &lt, 0.001), and cancer-specific mortality (log rank = 24.586, p &lt, 0.001). Conclusions: Our study revealed that specific protein expression patterns of ERBB family members are associated with an increased risk of PC progression and mortality.

Mutation of the DNAJC12 gene is typically associated with non-progressive Parkinsonism, but is also detectable in breast carcinoma where its contribution and mechanisms are unexplored. In breast carcinoma, ESR1 was positively correlated with DNAJC12 and ERBB4, and DNAJC12 was positively correlated with ERBB4. We used the GEO2R tool to compare differential gene expression of MCF-7 cells, following ESR1 knockdown (GEO database, E-GEOD-27473 array), and found decreased expression of DNAJC12 and ERBB4 in ESR1-silenced MCF-7 cells. The number of identical genes having correlativity with ESR1, DNAJC12, or ERBB4 was 12,165 (66.41%). These results suggest that ESR1 can promote the expression of DNAJC12 and ERBB4, and DNAJC12 can enhance the expression of ERBB4 in MCF-7 cells, implying that there may be a regulatory network among these three genes.

Background Patients with minimal hepatic encephalopathy (MHE) show mild cognitive impairments. Thrombopoietin (TPO) has been shown to be neuroprotective. This study aimed to explore the therapeutic effect of Thrombopoietin receptor agonist eltrombopag (ELT) on MHE and the involvement of NRG1 signaling using primary rat neurons and a MHE rat model. Methods We explored the effects of ELT stimulation on NRG1/ErbB4 signaling and synapse formation in the primary rat neurons. Furthermore, we explored the cerebral TPO expression level and the effect of TPO replacement therapy in an MHE rat model. Results The results showed that ELT stimulation activated NRG1/ErbB4 signaling and enhanced synaptic protein expression in the primary rat neurons via sirtuin 1. An anti-NRG1 antibody, ErbB4 inhibitor, or knockdown of NRG1 or ErbB4 could significantly abolish ELT-induced upregulation of synaptic protein expression in the primary rat neurons. MHE rats had significantly decreased cerebral ELT expression compared with normal rats. ELT activated NRG1/ErbB4 signaling in MHE rat brains. Administration or overexpression of ELT or TPO promoted synapse formation and alleviated cognitive impairments in MHE rats. Conclusions These data suggest that ELT promotes synapse formation in vitro and in vivo via activating NRG1/ErbB4 signaling, serving as a promising therapeutic agent for MHE treatment.

ERBB4 encodes the tyrosine kinase receptor HER4, a critical regulator of normal cell function and neurodevelopmental processes in the brain. One of the key ligands of HER4 is neureglin-1 (NRG1), and the HER4-NRG1 signalling pathway is essential in neural crest cell migration, and neuronal differentiation. Pharmacological inactivation of HER4 has been shown to hasten the progression of epileptogenesis in rodent models, and heterozygous ERBB4 null mice are shown to have cognitive deficits and delayed motor development. Thus far there is only a single case report in the literature of a heterozygous ERBB4 deletion in a patient with intellectual disability (ID). We identified nine subjects from five unrelated families with chromosome 2q34 deletions, resulting in heterozygous intragenic loss of multiple exons of ERBB4, associated with either non-syndromic ID or generalised epilepsy. In one family, the deletion segregated with ID in five affected relatives. Overall, this case series further supports that haploinsufficiency of ERBB4 leads to non-syndromic intellectual disability or epilepsy.

The regulation of neuronal soma size is essential for appropriate brain circuit function and its dysregulation is associated with several neurodevelopmental disorders. A defect in the dendritic growth and elaboration of motor neocortical pyramidal neurons in neonates lacking neuregulin-4 (NRG4) has previously been reported. In this study, we investigated whether the loss of NRG4 causes further morphologic defects that are specific to these neurons. We analyzed the soma size of pyramidal neurons of layer (L)2/3 and L5 of the motor cortex and a subpopulation of multipolar interneurons in this neocortical region in Nrg4+/+ and Nrg4−/− mice. There were significant decreases in pyramidal neuron soma size in Nrg4−/− mice compared with Nrg4+/+ littermates at all stages studied [postnatal day (P)10, P30, and P60]. The reduction was especially marked at P10 and in L5 pyramidal neurons. Soma size was not significantly different for multipolar interneurons at any age. This in vivo phenotype was replicated in pyramidal neurons cultured from Nrg4−/− mice and was rescued by NRG treatment. Analysis of a public single-cell RNA sequencing repository revealed discrete Nrg4 and Erbb4 expression in subpopulations of L5 pyramidal neurons, suggesting that the observed defects were due in part to loss of autocrine Nrg4/ErbB4 signaling. The pyramidal phenotype in the motor cortex of Nrg4−/− mice was associated with a lack of Rotarod test improvement in P60 mice, suggesting that absence of NRG4 causes alterations in motor performance.

Background: Peripartum cardiomyopathy (PPCM) is a life-threatening disease in women without previously known cardiovascular disease. It is characterized by a sudden onset of heart failure before or after delivery. Previous studies revealed that the generation of a 16-kDa PRL (prolactin) metabolite, the subsequent upregulation of miR-146a, and the downregulation of the target gene Erbb4 is a common driving factor of PPCM. Methods: miRNA profiling was performed in plasma of PPCM patients (n=33) and postpartum-matched healthy CTRLs (controls; n=36). Elevated miRNAs in PPCM plasma, potentially targeting ERBB4 (erythroblastic leukemia viral oncogene homolog 4), were overexpressed in cardiomyocytes using lentiviral vectors. Next, cardiac function, cardiac morphology, and PPCM phenotype were investigated after recurrent pregnancies of HZ (heterozygous) cardiomyocyte-specific Erbb4 mice ( Erbb4 F/+ αMHC-Cre + , n=9) with their age-matched nonpregnant CTRLs (n=9–10). Results: Here, we identify 9 additional highly conserved miRNAs (miR-199a-5p and miR-199a-3p, miR-145a-5p, miR-130a-3p, miR-135a-5p, miR-221-3p, miR-222-3p, miR-23a-3p, and miR19b-3p) that target tyrosine kinase receptor ERBB4 and are over 4-fold upregulated in plasma of PPCM patients at the time of diagnosis. We confirmed that miR-146a, miR-199a-5p, miR-221-3p, miR-222-3p, miR-23a-3p, miR-130a-5p, and miR-135-3p overexpression decreases ERBB4 expression in cardiomyocytes (−29% to −50%; P Erbb4 during pregnancy suffices to induce a variant of PPCM in mice, characterized by left ventricular dilatation (postpartum second delivery: left ventricular internal diameter in diastole, +19±7% versus HZ-CTRL; P P P =0.07; −27±20%, P P Conclusions: ERBB4 is essential to protect the maternal heart from peripartum stress. Downregulation of ERBB4 in cardiomyocytes induced by multiple miRNAs in the peripartum period may be crucial in PPCM pathophysiology. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00998556.

The biological modulatory roles of many circular RNAs (circRNAs) have been validated in glioma. The current study was designed to research the functional mechanism of circ_0001162 in glioma progression. The quantitative real-time polymerase chain reaction (qRT-PCR) was used for assaying the levels of circ_0001162 and microRNA-936 (miR-936). Cell proliferation and colony formation abilities were evaluated via 3-(4, 5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT) and colony formation assay, respectively. Transwell assay was applied to assess cell migration and invasion. The impact of circ_0001162 on glioma growth in vivo was performed using xenograft tumor assay. The target binding was affirmed via the dual-luciferase reporter and RNA pull-down assays. All protein expression levels were examined via Western blot. Circ_0001162 was an overexpressed circRNA in glioma. Circ_0001162 promoted glioma cell proliferation, colony formation, migration and invasion in vitro. Tumorigenesis of glioma in vivo was also enhanced by circ_0001162. Circ_0001162 could directly target miR-936 and the biological function of circ_0001162 in glioma was related to the inhibition of miR-936. ErbB2 receptor tyrosine kinase 4 (ERBB4) was a direct target of miR-936. Additionally, miR-936 inhibited the glioma development via targeting ERBB4. The miR-936/ERBB4 axis was responsible for the oncogenic role of circ_0001162 in glioma. The effects of circ_0001162 on glioma cells were also associated with the positive regulation of ERBB4. These results indicated that circ_0001162 contributed to the glioma progression via regulating the miR-936/ERBB4 axis, which laid a foundation for the pathomechanism and molecular treatment of glioma., Graphical abstract

Background Hsa-miR-548ba expressed in ovarian granulosa cells targets PTEN and LIFR, which are essential for ovarian follicle activation and growth. The expression pattern of hsa-miR-548ba correlates with its host gene follicle-stimulating hormone receptor (FSHR), and FSH has a positive influence on hsa-miR-548ba expression. However, hsa-miR-548ba is a member of a large hsa-mir-548 family with potentially overlapping targets. The current study aims to investigate the co-expression of hsa-mir-548 family members in FSHR-positive reproductive tissues and to explore the potential co-regulation of pathways. Results For the above-described analysis, small RNA sequencing data from public data repositories were used. Sequencing results revealed that hsa-miR-548ba was expressed at the highest level in the ovarian granulosa cells and uterine myometrial samples together with another twelve and one hsa-miR-548 family members, respectively. Pathway enrichment analysis of microRNA targets in the ovarian samples revealed the hsa-miR-548ba and hsa-miR-548b-5p co-regulation of RAB geranylgeranylation in mural granulosa cells. Moreover, other hsa-mir-548 family members co-regulate pathways essential for ovarian functions (PIP3 activates AKT signalling and signalling by ERBB4). In addition to hsa-miR-548ba, hsa-miR-548o-3p is expressed in the myometrium, which separately targets the peroxisome proliferator-activated receptor alpha (PPARA) pathway. Conclusion This study reveals that hsa-mir-548 family members are expressed in variable combinations in the reproductive tract, where they potentially fulfil different regulatory roles. The results provide a reference for further studies of the hsa-mir-548 family role in the reproductive tract.

Aims The human epidermal growth factor receptor (HER) family gene is involved in a wide range of biological functions in human cancers. Nevertheless, there is little research that comprehensively analysis the correlation between HER family members and prognosis, tumor microenvironment (TME) in different cancers. Materials and methods Based on updated public databases and integrated several bioinformatics analysis methods, we evaluated expression level, prognostic values of HER family gene and explore the association between expression of HER family gene and TME, Stemness score, immune subtype, drug sensitivity in pan-cancer. Key findings EGFR, ERBB2, ERBB3, and ERBB4 were higher expressed in four cancers, five cancers, ten cancers, and two cancers, respectively. HER family gene expression is related to the prognosis in several cancers from TCGA and has a significant correlation with stromal and immune scores in pan-cancer also has a significant correlation with RNA stemness score and DNA stemness score in pan-cancer. Expression level of HER family gene is associated with immune subtype in head and neck squamous cell carcinoma and kidney renal clear cell carcinoma. EGFR expression was negatively associated with drug sensitivity of Pipamperone, Tamoxifen, Bafetinib and positively related to drug sensitivity of Dasatinib and Staurosporine. ERBB2 expression was negatively related to drug sensitivity of Ifosfamide, Imexon, and Oxaliplatin. ERBB4 expression was positively related to drug sensitivity of E−7820. Significance These findings may elucidate the roles played by HER family gene in cancer progression and providing insights for further investigation of the HER family gene as potential targets in pan-cancer.

The assembly of specific neuronal circuits relies on the expression of complementary molecular programs in presynaptic and postsynaptic neurons. In the cerebral cortex, the tyrosine kinase receptor ErbB4 is critical for the wiring of specific populations of GABAergic interneurons, in which it paradoxically regulates both the formation of inhibitory synapses as well as the development of excitatory synapses received by these cells. Here, we found that Nrg1 and Nrg3, two members of the neuregulin family of trophic factors, regulate the inhibitory outputs and excitatory inputs of interneurons in the mouse cerebral cortex, respectively. The differential role of Nrg1 and Nrg3 in this process is not due to their receptor-binding EGF-like domain, but rather to their distinctive subcellular localization within pyramidal cells. Our study reveals a novel strategy for the assembly of cortical circuits that involves the differential subcellular sorting of family-related synaptic proteins.

Recent studies have shown exercise is effective for adult hippocampus neurogenesis and memory. However, the molecular mechanism of exercise is unclear. In this study, AG1478, an ErbB4 inhibitor, was used to explore the involvement of ErbB4 receptors. Four weeks post-running, cognitive impairment was analyzed using T-maze, Morris water maze (MWM) and contextual fear discrimination learning tests, followed by histological assessment of the proliferation and survival of hippocampal neurons using Ki67, NeuN and BrdU immunostaining respectively. Expression of total and phosphate ErbB4 protein level was evaluated by Western blotting. The results showed that AG1478 significantly impaired the performances in T-maze and MWM (spatial learning and memory), contextual fear conditioning and discrimination learning paradigm (non-spatial working and reference memory), enhanced neurogenesis loss, downregulated the expression of p-ErbB4 and total ErbB4 protein, which could be reversed by running. Taken together, our study suggested that running ameliorates cognitive impairment and neurogenesis via ErbB4 signaling.

Chronic inflammatory pain is a severe clinical symptom that aggravates the life quality of patients and places a huge economic burden on individuals and society. As one complementary and alternative therapy, electroacupuncture (EA) is widely used in clinical practice to treat chronic inflammatory pain based on its safety and efficacy. Previous studies have revealed the potential role of adenosine, neuropeptides, and inflammatory factors in EA analgesia in various pain models, but the identity of some of the signaling pathways involved remain unknown. In the present study, we explored whether neuregulin1 (NRG1)-ErbB4 signaling is involved in EA analgesia in inflammatory pain. Repeated EA treatment at the acupoints Zusanli (ST36) and Sanyinjiao (SP6) for 3 consecutive days remarkably attenuated mechanical allodynia and thermal hyperalgesia in complete Freund’s adjuvant (CFA)-treated mice, with an increased expression of NRG1 in spinal cord (SC). We found that ErbB4 kinase participated in both the EA and NRG1 mediated analgesic effects on inflammatory pain by pharmacological inhibition or genetic ablation ErbB4 in vivo. Intriguingly, the mice with conditional knockout of ErbB4 from PV+ interneurons in SC showed abnormal basal mechanical threshold. Meanwhile, NRG1 treatment could not relieve tactile allodynia in PV-Erbb4–/– mice or AAV-PV-Erbb4–/– mice after CFA injection. These experimental results suggest that regulating NRG1-ErbB4 signaling in SC could reduce pain hypersensitivity and contribute to EA analgesia in inflammatory pain.

International audience; Major depressive disorder (MDD) is a complex and debilitating illness whose etiology remains unclear. Small RNA molecules, such as micro RNAs (miRNAs) have been implicated in MDD, where they display differential expression in the brain and the periphery. In this study, we quantified miRNA expression by small RNA sequencing in the anterior cingulate cortex and habenula of individuals with MDD and psychiatrically-healthy controls. Thirty-two miRNAs showed significantly correlated expression between the two regions (False Discovery Rate

Background Liquidambaris Fructus is the infructescences of Liquidambar formosana Hance and it has been used to treat some breast disease in Traditional Chinese Medicine. In the previous study we found the anti-breast cancer effect of triterpenoid in Liquidambaris Fructus. This study is a further investigation of the triterpenoids in Liquidambaris Fructus and aims to identify their anti-breast cancer targets, meanwhile, to estimate the rationality of the traditional applications of Liquidambaris Fructus. Methods Triterpenoids in Liquidambaris Fructus were isolated and their structures were identified by NMR spectrums. Potential targets of these triterpenoids were predicted using a reverse pharmacophore mapping strategy. Associations between these targets and the therapeutic targets of breast cancer were analyzed by constructing protein-protein interaction network, and targets played important roles in the network were identified using Molecular Complex Detection method. Binding affinity between the targets and triterpenoids was studied using molecular docking method. Gene ontology enrichment analysis was conducted to reveal the biological process and signaling pathways that the identified targets were involved in. Results Thirteen triterpenoids were identified and 6 of them were the first time isolated from Liquidambaris Fructus. Predicted ADME properties revealed a good druggability of these triterpenoids. We identified 18 protein targets which were closely related to breast cancer progression, especially triple-negative, basal-like or advanced stage breast cancers. The triterpenoids could bind with these targets as their inhibitors: hydrophobic skeleton is a favorable factor for them to stabilize at binding site and polar C17- or C3- substituent was necessary for binding. GO enrichment analysis indicated that inhibition of protein tyrosine kinases autophosphorylation might be the primary mechanism for the anti-breast cancer effect of the triterpenoids, and ErbB4 and EGFR were the most relevant targets. Conclusions The study revealed that triterpenoids from Liquidambaris Fructus might exert anti-breast cancer effect by directly inhibit multiple protein targets and signaling pathways, especially ErbB4 and EGFR and related pathways. This study also brings up another hint that the traditional applications of Liquidambaris Fructus on hypogalactia should be reassessed systematically because it might suppress rather than promote lactation by inhibiting the activity of ErbB4.