Publications by authors named "Hong Lian"

76 Publications

The Risk Threshold for Hemoglobin A1c Associated With Albuminuria: A Population-Based Study in China.

Front Endocrinol (Lausanne) 2021 31;12:673976. Epub 2021 May 31.

Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.

Background: Diabetic kidney disease (DKD) is a kind of common microvascular complication of diabetes. This study aims to explore the possible links between blood sugar level and albuminuria, providing the exact cut point of the "risk threshold" for blood glucose with DKD.

Methods: The relationship between blood glucose and albuminuria was modeled using linear and logistic regression in the REACTION study cohorts (N= 8932). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression model. Two-slope linear regression was used to simulate associations between blood glucose and ACR.

Results: We found that the increase in ACR was accompanied by increased HbA1c, with a turning point at 5.5%. The positive correlation remained highly significant (P<0.001) when adjusted for age, sex, marital status, education, smoking status, drinking status, BMI, waistline, SBP and DBP. In subgroup analyses including gender, obesity, hypertension, and smoking habits, the relationship was significant and stable.

Conclusions: We determined a risk threshold for HbA1c associated with albuminuria in a Chinese population over the age of 40. HbA1c ≥ 5.5% was positively and independently associated with ACR. These results suggest the necessity of early blood glucose control and renal function screening for DKD in at-risk populations.
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http://dx.doi.org/10.3389/fendo.2021.673976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202121PMC
May 2021

Galectin-3/adiponectin as a new biological indicator for assessing the risk of type 2 diabetes: a cross-sectional study in a community population.

Aging (Albany NY) 2021 06 7;13(11):15433-15443. Epub 2021 Jun 7.

Department of Endocrinology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China.

Objective: This study aimed to explore the association between the risk of newly diagnosed type 2 diabetes and galectin-3 and adiponectin and to investigate whether their joint action shows a favorable diabetes assessment performance.

Methods: We conducted a community-based study in 135 newly diagnosed patients with type 2 diabetes and 270 age- and sex-matched nondiabetic patients. Odds ratios and 95% confidence intervals were determined using logistic regression analysis. Receiver operating characteristic curve, decision curve analysis and calibration plot were used to explore their efficacy and clinical utility for models.

Results: High quartiles of galectin-3/adiponectin (quartile 4 vs 1: OR 2.43 [95% CIs: 1.21-5.00]) showed the strongest correlation with an increased risk of type 2 diabetes in the total population, which was consistent in the older population (age≥50 years old) in adjustment models. The combination + lipids + galectin-3/adiponectin model (AUC = 0.72 [95% CIs: 0.66-0.77]) displayed better diabetes assessment performance than the other two models.

Conclusions: High galectin-3 and low adiponectin levels were associated with the high risk of diabetes, and their joint action was a superior promising factor for evaluating diabetes risk. The diabetes discriminative strength of galectin-3/adiponectin was better in the older population than the younger.
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http://dx.doi.org/10.18632/aging.203101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221326PMC
June 2021

ErbB4 regulate extracellular dopamine through the p38 MAPK signaling pathway.

Neurosci Lett 2021 04 17;751:135830. Epub 2021 Mar 17.

NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Center of Brain Science and Brain-machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310058, China; Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address:

ErbB4 loss-of-function in catecholaminergic neurons induces catecholamine dyshomeostasis. Despite ErbB4's significant role in neuropathology, the signaling pathways that regulate these changes are still widely unknown. In this study, we attempt to identify the downstream pathway of ErbB4 that regulates catecholamine homeostasis. The SH-SY5Y human neuroblastoma cell line was used as the in vitro model for catecholaminergic neurons. Western blotting, enzyme-linked immunosorbent assay, and pharmacological and genetic manipulations by agonist/antagonist or small interference RNA were used to investigate the relationship between ErbB4 and extracellular catecholamines. We confirmed that ErbB4 is abundantly expressed in undifferentiated and retinoic acid-differentiated catecholaminergic cells from the SH-SY5Y cell line. ErbB4 inhibition increase the ratio of phosphorylated p38 to total p38 in SH-SY5Y human neuroblastoma cells. Consistent with previous in vivo observations in mice, ErbB4 deficiency led to increases in extracellular dopamine and norepinephrine levels. However, the resulting increase in extracellular dopamine, but not norepinephrine, could be suppressed by p38 inhibitor SB202190. Our results suggest that both extracellular dopamine and norepinephrine homeostasis could be regulated by ErbB4 in human catecholaminergic cells, and ErbB4 may regulate extracellular dopamine, but not norepinephrine, through the p38 MAPK signaling pathway, thus indicating different regulatory pathways of dopamine and norepinephrine by ErbB4 in catecholaminergic neurons.
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http://dx.doi.org/10.1016/j.neulet.2021.135830DOI Listing
April 2021

Associations of GDF-15 and GDF-15/adiponectin ratio with odds of type 2 diabetes in the Chinese population.

Endocrine 2021 05 12;72(2):423-436. Epub 2021 Mar 12.

Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou, 510120, People's Republic of China.

Purpose: We elucidate the effect of Growth differentiation factor-15(GDF-15)/adiponectin ratio in improving the assessment value for odds of type 2 diabetes.

Methods: Cross-sectional design. A total of 405 participants (135 patients with newly diagnosed type 2 diabetes, 135 age- and sex-matched participants with prediabetes, and 135 healthy controls) were collected from Guangzhou and Dongguan, China. The serum GDF-15 and adiponectin levels were measured by ELISA and latex-enhanced immunoturbidimetry. Logistic regression analysis and restricted cubic splines were used to evaluate the associations between diabetes and the indicators.

Results: The low level of adiponectin and high GDF-15/adiponectin ratio were significantly associated with increased odds of type 2 diabetes, but not for GDF-15. Three clusters were identified based on the K-means clustering analysis. Compared to the lowest quartiles of adiponectin, the OR and 95% CI of the highest adiponectin with type 2 diabetes was 0.24 (0.07-0.74, p trend = 0.004) after adjusting for sex, age, BMI, and DBP only in cluster 1. After adjusting for confounding factors, subjects with the highest GDF-15/adiponectin ratio quartiles had 3.9 times (OR = 3.85, 95% CI = 0.76-24.25) and 3.8 times (OR = 3.80, 95% CI = 1.02-14.68) higher odds of type 2 diabetes in cluster 2 and cluster 3, respectively. The association between the GDF-15/adiponectin ratio and type 2 diabetes was attenuated, but still remarkable (OR = 3.18, 95% CI = 1.11-10.18), in cluster 1.

Conclusions: Higher GDF-15/adiponectin ratio is independently associated with increased odds of type 2 diabetes for all study populations, suggesting that the GDF-15/adiponectin ratio may be a better indicator of type 2 diabetes.
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http://dx.doi.org/10.1007/s12020-021-02632-1DOI Listing
May 2021

Quantitative Assessment of the Physical Virus Titer and Purity by Ultrasensitive Flow Virometry.

Angew Chem Int Ed Engl 2021 04 17;60(17):9351-9356. Epub 2021 Mar 17.

Department of Chemical Biology, MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, P. R. China.

Rapid quantification of viruses is vital for basic research on viral diseases as well as biomedical application of virus-based products. Here, we report the development of a high-throughput single-particle method to enumerate intact viral particles by ultrasensitive flow virometry, which detects single viruses as small as 27 nm in diameter. The nucleic acid dye SYTO 82 was used to stain the viral (or vector) genome, and a laboratory-built nano-flow cytometer (nFCM) was employed to simultaneously detect the side-scatter and fluorescence signals of individual viral particles. Using the bacteriophage T7 as a model system, intact virions were completely discriminated from empty capsids and naked viral genomes. Successful measurement of the physical virus titer and purity was demonstrated for recombinant adenoviruses, which could be used for gene delivery, therapeutic products derived from phage cocktails, and infected cell supernatants for veterinary vaccine production.
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http://dx.doi.org/10.1002/anie.202100872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014667PMC
April 2021

Morphology of Melt-Quenched Lead Telluride Single Crystals.

ACS Appl Mater Interfaces 2021 Feb 29;13(5):6241-6248. Epub 2021 Jan 29.

Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands.

Metastable single crystals of nonstoichiometric PbTe are obtained by rapid cooling from the melt. The composition and crystallographic morphology are studied using X-ray diffraction, scanning electron microscopy, energy-dispersive X-ray spectroscopy, and electron backscatter diffraction. Most single crystals have cubic, pyramidal, or hemispherical shapes with sizes ranging from 50 to 400 μm. All crystals adopt the same face-centered cubic rock salt structure, and the crystal growth direction is ⟨100⟩. The bulk part of the rapidly cooled material solidifies in the form of a Te-rich polycrystalline material in which grains are separated by the PbTe-Te eutectic phase. The stabilization of nonstoichiometric PbTe provides further scope for the optimization of lead telluride-based thermoelectric materials.
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http://dx.doi.org/10.1021/acsami.0c20016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883344PMC
February 2021

Optimized Langendorff perfusion system for cardiomyocyte isolation in adult mouse heart.

J Cell Mol Med 2020 12 4;24(24):14619-14625. Epub 2020 Nov 4.

State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Fuwai Hospital, Beijing, China.

With the rapid development of single-cell sequencing technology, the Langendorff perfusion system has emerged as a common approach to decompose cardiac tissue and obtain living cardiomyocytes to study cardiovascular disease with the mechanism of cardiomyocyte biology. However, the traditional Langendorff perfusion system is difficult to master, and further, the viability and purity of cardiomyocytes are frequently unable to meet sequencing requirements due to complicated devices and manipulate processes. Here, we provide an optimized Langendorff perfusion system with a simplified and standardized operating protocol which utilizes gravity as the perfusion pressure, includes a novel method for bubbles removing and standardizes the criteria for termination of digestion. We obtained stable cardiomyocyte with high viability and purity after multiple natural gravity sedimentation. The combination of the optimized Langendorff perfusion system and the multiple natural gravity sedimentation provides a stable system for isolating adult mouse heart, which will provide higher-quality cardiomyocytes for further experiments.
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http://dx.doi.org/10.1111/jcmm.15773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754046PMC
December 2020

Mydgf promotes Cardiomyocyte proliferation and Neonatal Heart regeneration.

Theranostics 2020 11;10(20):9100-9112. Epub 2020 Jul 11.

State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.

Myeloid-derived growth factor (Mydgf), a paracrine protein secreted by bone marrow-derived monocytes and macrophages, was found to protect against cardiac injury following myocardial infarction (MI) in adult mice. We speculated that Mydgf might improve heart function myocardial regeneration, which is essential for discovering the target to reverse heart failure. Two genetic mouse lines were used: global Mydgf knockout () and mice. Two models of cardiac injury, apical resection was performed in neonatal and MI was performed in adult mice. Quantitative reverse transcription-polymerase chain reaction, western blot and flow cytometry were performed to study the protein expression. Immunofluorescence was performed to detect the proliferation of cardiomyocytes. Heart regeneration and cardiac function were evaluated by Masson's staining and echocardiography, respectively. RNA sequencing was employed to identify the key involved in Mydgf-induced cardiomyocyte proliferation. Mydgf recombinant protein injection was performed as a therapy for cardiac repair post MI in adult mice. Mydgf expression could be significantly induced in neonatal mouse hearts after cardiac injury. Unexpectedly, we found that Mydgf was predominantly expressed by endothelial cells rather than macrophages in injured neonatal hearts. Mydgf deficiency impeded neonatal heart regeneration and injury-induced cardiomyocyte proliferation. Mydgf recombinant protein promoted primary mouse cardiomyocyte proliferation. Employing RNA sequencing and functional verification, we demonstrated that c-Myc/FoxM1 pathway mediated Mydgf-induced cardiomyocyte expansion. Mydgf recombinant protein improved cardiac function in adult mice after MI injury with inducing cardiomyocyte proliferation. Mydgf promotes cardiomyocyte proliferation by activating c-Myc/FoxM1 pathway and improves heart regeneration both in neonatal and adult mice after cardiac injury, providing a potential target to reverse cardiac remodeling and heart failure.
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http://dx.doi.org/10.7150/thno.44281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415811PMC
June 2021

gp130 Controls Cardiomyocyte Proliferation and Heart Regeneration.

Circulation 2020 Sep 30;142(10):967-982. Epub 2020 Jun 30.

State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (Yandong Li, J.F., S.S., H. Li, H. Lian, L.L., S.H., Y.N.).

Background: A key cause of the high mortality of cardiovascular diseases is the cardiomyocyte inability to renew after cardiac injury. As a promising strategy to supplement functional myocytes for cardiac repair, there is a pressing need to understand the cellular and molecular mechanisms of heart regeneration.

Methods: Seven genetic mouse lines were used: global OSM (oncostatin M) knockout, monocyte-/macrophage-specific OSM deletion, cardiomyocyte-specific lines, including OSM receptor deletion, gp130 (glycoprotein 130) deletion, gp130 activation, and Yap (yes-associated protein) ablation with gp130 activation mice. A series of molecular signaling experiments, including RNA sequencing, immunostaining, coimmunoprecipitation, and imaging flow cytometry, were conducted. Two models of cardiac injury, apical resection and myocardial infarction operation, were performed in neonatal, juvenile, and adult mice. Heart regeneration and cardiac function were evaluated by Masson staining and echocardiography, respectively. Gene recombinant adenovirus-associated virus was constructed and infected myocardial-infarcted mice as a gene therapy.

Results: OSM was identified by RNA sequencing as a key upstream regulator of cardiomyocyte proliferation during neonatal heart regeneration in mice. Cardiomyocyte proliferation and heart regeneration were suspended in neonatal mice after cardiac injury when OSM was conditionally knockout in macrophages. The cardiomyocyte-specific deficiency of the OSM receptor heterodimers, OSM receptor and gp130, individually in cardiomyocytes reduced myocyte proliferation and neonatal heart regeneration. Conditional activation of gp130 in cardiomyocytes promoted cardiomyocyte proliferation and heart regeneration in juvenile and adult mice. Using RNA sequencing and functional screening, we found that Src mediated gp130-triggered cardiomyocyte proliferation by activating Yap (yes-associated protein) with Y357 phosphorylation independently of the Hippo pathway. Cardiomyocyte-specific deletion of Yap in mice blocked the effect of gp130 activation-induced heart regeneration in juvenile mice. Gene therapy with adenovirus-associated virus encoding constitutively activated gp130 promoted cardiomyocyte proliferation and heart regeneration in adult mice after myocardial infarction.

Conclusions: Macrophage recruitment is essential for heart regeneration through the secretion of OSM, which promotes cardiomyocyte proliferation. As the coreceptor of OSM, gp130 activation is sufficient to promote cardiomyocyte proliferation by activating Yap through Src during heart regeneration. gp130 is a potential therapeutic target to improve heart regeneration after cardiac injury.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044484DOI Listing
September 2020

Incerta-thalamic Circuit Controls Nocifensive Behavior via Cannabinoid Type 1 Receptors.

Neuron 2020 08 4;107(3):538-551.e7. Epub 2020 Jun 4.

Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, Joint Institute for Genetics and Genome Medicine between Zhejiang University and University of Toronto, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address:

Pain is a source of substantial discomfort. Abnormal activity in both the zona incerta (ZI) and posterior complex of the thalamus (Po) are implicated in neuropathic pain, but their exact roles remain unclear. In particular, the precise cell types and molecular mechanisms of the ZI-Po circuit that regulate nociception are largely uncharacterized. Here, we found that parvalbumin (PV)-positive neuronal projections from the ventral ZI (ZIv) to the Po (ZIv-Po) are critical for promoting nocifensive behaviors, whereas selectively inhibiting ZIv-Po activity reduces nocifensive withdrawal responses. Furthermore, cannabinoid type 1 receptors (CBRs) are expressed specifically at ZIv-Po axon terminals in this circuit, and cannabinoids attenuate nocifensive responses through presynaptic inhibition. Selective inhibition of the ZIv-Po circuit or administration of cannabinoids into the Po are sufficient to ameliorate pathological pain. These findings identify the critical role of the ZIv-Po circuit and its modulation by endocannabinoids in controlling nocifensive behaviors.
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http://dx.doi.org/10.1016/j.neuron.2020.04.027DOI Listing
August 2020

Hybrid nanostructured plasmonic electrodes for flexible organic light-emitting diodes.

Nanotechnology 2020 Sep 20;31(37):375203. Epub 2020 May 20.

School of Mechatronic Engineering and Automation, Key Laboratory of Advanced Display and System Applications, Ministry of Education, Shanghai University, 200072, Shanghai, People's Republic of China.

Improved performance in flexible organic light-emitting diodes (OLEDs) is demonstrated by using a hybrid nanostructured plasmonic electrode consisting of silver nanowires (AgNWs) decorated with silver nanoparticles (AgNPs) and covered by exfoliated graphene sheets. Such all-solution processed electrodes show high optical transparency and electrical conductivity. When integrated in an OLED with super yellow polyphenylene vinylene as the emissive layer, the plasmon coupling of the NW-NP hybrid plasmonic system is found to significantly enhance the fluorescence, demonstrated by both simulations and photoluminescence measurements, leading to a current efficiency of 11.61 cd A and a maximum luminance of 20 008 cd m in OLEDs. Stress studies reveal a superior mechanical flexibility to the commercial indium-tin-oxide (ITO) counterparts, due to the incorporation of exfoliated graphene sheets. Our results show that these hybrid nanostructured plasmonic electrodes can be applied as an effective alternative to ITO for use in high-performance flexible OLEDs.
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http://dx.doi.org/10.1088/1361-6528/ab94dfDOI Listing
September 2020

The protective role of Neuregulin1-ErbB4 signaling in a chronic social defeat stress model.

Neuroreport 2020 06;31(9):678-685

Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Major depressive disorder (MDD) is a highly prevalent debilitating psychiatric disease and a serious public health problem worldwide. Brain structural MRI and postmortem studies on patients with depression have revealed changes in the anatomy and functionality in various brain regions, including the amygdala, thalamus, hippocampus, and prefrontal cortex (PFC). The alterations in these brain regions could be a result, in part, of the dysregulation of the neurotrophic factors. Neuregulin1 (NRG1) is one of the neurotrophic factors, and our previous study showed that the NRG1-ErbB4 signaling pathway plays a critical role in epilepsy. In this study, we established a chronic social defeat stress (CSDS) model to investigate the role of the NRG1-ErbB4 signaling pathway in depression-like behaviors. In CSDS mice, we found that the NRG1 protein expression levels were significantly decreased both in the medial prefrontal cortex (mPFC) and hippocampus, while phosphorylated ErbB4 only decreased in the mPFC. In addition, lateral ventricle NRG1 administration significantly rescued depression-like behaviors in the susceptible group. The current study suggests that the NRG1-ErbB4 signaling pathway may exert a protective role in MDD.
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http://dx.doi.org/10.1097/WNR.0000000000001464DOI Listing
June 2020

CACCT: An Automated Tool of Detecting Complicated Cardiac Malformations in Mouse Models.

Adv Sci (Weinh) 2020 Apr 20;7(8):1903592. Epub 2020 Feb 20.

State Key Laboratory of Cardiovascular Disease Fuwai Hospital National Center for Cardiovascular Disease Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100037 China.

Congenital heart disease (CHD) is the major cause of morbidity/mortality in infancy and childhood. Using a mouse model to uncover the mechanism of CHD is essential to understand its pathogenesis. However, conventional 2D phenotyping methods cannot comprehensively exhibit and accurately distinguish various 3D cardiac malformations for the complicated structure of heart cavity. Here, a new automated tool based on microcomputed tomography (micro-CT) image data sets known as computer-assisted cardiac cavity tracking (CACCT) is presented, which can detect the connections between cardiac cavities and identify complicated cardiac malformations in mouse hearts automatically. With CACCT, researchers, even those without expert training or diagnostic experience of CHD, can identify complicated cardiac malformations in mice conveniently and precisely, including transposition of the great arteries, double-outlet right ventricle and atypical ventricular septal defect, whose accuracy is equivalent to senior fetal cardiologists. CACCT provides an effective approach to accurately identify heterogeneous cardiac malformations, which will facilitate the mechanistic studies into CHD and heart development.
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http://dx.doi.org/10.1002/advs.201903592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175298PMC
April 2020

[Intestinal absorption of phenolic acids in Rhus chinensis extracts by in situ single-pass perfusion model in rats].

Zhongguo Zhong Yao Za Zhi 2019 Jun;44(11):2373-2378

College of Integrative Medicine, Fujian University of Traditional Chinese Medicine Fuzhou 350122, China.

The intestinal absorption properties of four main effective components(gallic acid, ocinolglucoside, ethyl gallate and penta-O-galloyl-β-D-glucose) in Rhus chinensis extracts were investigated by in situ single-pass intestinal perfusion model in rats. The liquid accumulation of perfusion was corrected by gravimetry. The HPLC method was established to determine the concentration of the four effective components in the intestinal perfusion. It showed significant differences(P<0.05) in absorption rate constant(K_a) and effective permeability(P_(eff)) among the three concentrations of components, and the absorption of the four effective components in different intestinal segments was saturated at high concentrations. At the same concentration, there were significant differences in K_a and P_(eff) of the four components in each intestinal segment(P<0.05). The order of K_a and P_(eff) of the four components in the intestine was penta-O-galloyl-β-D-glucose>ethyl gallate>gallic acid>ocinolglucoside, with significant differences between them(P<0.05). In conclusion, gallic acid, orpheolglucoside, ethyl gallate and pentacyl-glucose could be absorbed in the whole intestine. Their absorption rate and permeation ability were related to the intestinal section and the perfusate concentration. These results indicated potential active transport or facilitated diffusion in the intestinal transport process of the four effective components.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20190318.502DOI Listing
June 2019

PDGFR-β Signaling Regulates Cardiomyocyte Proliferation and Myocardial Regeneration.

Cell Rep 2019 07;28(4):966-978.e4

State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. Electronic address:

Platelet-derived growth factor receptor (PDGFR) signaling is involved in proliferation and survival in a wide array of cell types. The role of PDGFR signaling in heart regeneration is still unknown. We find that PDGFR-β signaling decreases in myocardium with age and that conditional activation PDGFR-β in cardiomyocytes promotes heart regeneration. Employing RNA sequencing, we show that the enhancer of zeste homolog 2 (Ezh2) can be upregulated by PDGFR-β signaling in primary cardiomyocytes. Conditional knockout of Ezh2 blocks cardiomyocyte proliferation and H3K27me3 modification during neonatal heart regeneration with Ink4a/Arf upregulation, even in mice with myocyte-specific conditional activation of PDGFR-β. We also show that PDGFR-β controls EZH2 expression via the phosphatidylinositol 3-kinase (PI3K)/p-Akt pathway in cardiomyocytes. Gene therapy with adeno-associated virus serotype 9 (AAV9) encoding activated PDGFR-β enhances adult heart regeneration and systolic function. Our data demonstrate that the PDGFR-β/EZH2 pathway is critical for promoting cardiomyocyte proliferation and heart regeneration, providing a potential target for cardiac repair.
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http://dx.doi.org/10.1016/j.celrep.2019.06.065DOI Listing
July 2019

A novel cortico-intrathalamic circuit for flight behavior.

Nat Neurosci 2019 06 29;22(6):941-949. Epub 2019 Apr 29.

Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Flight, an active fear response to imminent threat, is dependent on the rapid risk assessment of sensory information processed by the cortex. The thalamic reticular nucleus (TRN) filters information between the cortex and the thalamus, but whether it participates in the regulation of flight behavior remains largely unknown. Here, we report that activation of parvalbumin-expressing neurons in the limbic TRN, but not those in the sensory TRN, mediates flight. Glutamatergic inputs from the cingulate cortex (Cg) selectively activate the limbic TRN, which in turn inhibits the intermediodorsal thalamic nucleus (IMD). Activation of this Cg→limbic TRN→IMD circuit results in inhibition of the IMD and produces flight behavior. Conversely, removal of inhibition onto the IMD results in more freezing and less flight, suggesting that the IMD may function as a pro-freeze center. Overall, these findings reveal a novel corticothalamic circuit through the TRN that controls the flight response.
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http://dx.doi.org/10.1038/s41593-019-0391-6DOI Listing
June 2019

Flow Cytometric Analysis of Nanoscale Biological Particles and Organelles.

Annu Rev Anal Chem (Palo Alto Calif) 2019 06 12;12(1):389-409. Epub 2019 Apr 12.

MOE Key Laboratory of Spectrochemical Analysis and Instrumentation; Key Laboratory for Chemical Biology of Fujian Province; Collaborative Innovation Center of Chemistry for Energy Material; and Department of Chemical Biology, College of Chemistry and Engineering, Xiamen University, Xiamen, Fujian 361005, China; email:

Analysis of nanoscale biological particles and organelles (BPOs) at the single-particle level is fundamental to the in-depth study of biosciences. Flow cytometry is a versatile technique that has been well-established for the analysis of eukaryotic cells, yet conventional flow cytometry can hardly meet the sensitivity requirement for nanoscale BPOs. Recent advances in high-sensitivity flow cytometry have made it possible to conduct precise, sensitive, and specific analyses of nanoscale BPOs, with exceptional benefits for bacteria, mitochondria, viruses, and extracellular vesicles (EVs). In this article, we discuss the significance, challenges, and efforts toward sensitivity enhancement, followed by the introduction of flow cytometric analysis of nanoscale BPOs. With the development of the nano-flow cytometer that can detect single viruses and EVs as small as 27 nm and 40 nm, respectively, more exciting applications in nanoscale BPO analysis can be envisioned.
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http://dx.doi.org/10.1146/annurev-anchem-061318-115042DOI Listing
June 2019

Inhibitory effect of polysaccharide of Sargassum weizhouense on PCV2 induced inflammation in mice by suppressing histone acetylation.

Biomed Pharmacother 2019 Apr 2;112:108741. Epub 2019 Mar 2.

College of Animal Science and Technology, Guangxi University, Nanning, Guangxi 530005, China. Electronic address:

Seaweeds are excellent source of bioactive compounds and seaweed-derived polysaccharides have demonstrated an array of biological effects. Here, we investigated the effect of polysaccharide of Sargassum weizhouense (PSW) on the inflammatory response in porcine circovirus type 2 (PCV2) infected mice and the underlying mechanism was studied according to the histone acetylation. After PCV2 infection, the levels of TNF-α, IL-1β, IL-6, IL-8, IL-10, MCP-1, COX-1, COX-2 and HAT in both serum and spleen were significantly increased (P <0.05). The mRNA expression of TNF-α, IL-6, IL-10 and NF-κB p65 were elevated in PCV2 infected mice (P <0.05). The HDAC content in both serum and spleen as well the mRNA expression of HDAC1 were greatly decreased (P <0.05). PSW treatment dramatically inhibited the secretions of inflammatory cytokines and HATs, reduced mRNA expression of TNF-α, IL-6, IL-10 and NF-κB p65, but promoted HDAC secretion and mRNA expression of HDAC1 in PCV2-infected mice. The acetylation of both H3 and H4 was significantly up-regulated in PCV2-infected mice, and strongly inhibited by PSW treatment (P <0.01). These results suggested that PCV2 mediate the equilibrium between HATs and HDACs, alternate the histone acetylation and thus DNA packaging, and then activate the transcription of inflammatory cytokines. PSW could inhibit the histone acetylation and the production of inflammatory cytokines, showing excellent potentials in improving the resistance of host against PCV2 infection.
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http://dx.doi.org/10.1016/j.biopha.2019.108741DOI Listing
April 2019

Recent Advances in the Optimization of Organic Light-Emitting Diodes with Metal-Containing Nanomaterials.

Chem Rec 2019 Aug 4;19(8):1753-1767. Epub 2019 Apr 4.

Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China.

Metal-containing nanomaterials have attracted widespread attention in recent years due to their physicochemical, light-scattering and plasmonic properties. By introducing different kinds and different structures of metal-containing nanomaterials into organic light-emitting diodes (OLEDs), the optical properties of the devices can be tailored, which can effectively improve the luminous efficiency of OLEDs. In this review, the fundamental knowledge of OLEDs and metallic nanomaterials were firstly introduced. Then we overviewed the recent development of the optimization of OLEDs through introducing different kinds of metal-containing nanomaterials.
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http://dx.doi.org/10.1002/tcr.201800204DOI Listing
August 2019

Single-particle characterization of theranostic liposomes with stimulus sensing and controlled drug release properties.

Biosens Bioelectron 2019 Apr 19;131:185-192. Epub 2019 Feb 19.

MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, Key Laboratory for Chemical Biology of Fujian Province, Collaborative Innovation Center of Chemistry for Energy Materials, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, People's Republic of China. Electronic address:

Stimuli-responsive nanotheranostic systems, integrated with diagnosis and treatment features, have recently emerged and attracted much interest. However, most of the research mainly focuses on the novelty of nanomaterials, and undervalues the significance of single-particle characterization which can provide detailed physical and biochemical information for performance evaluation and heterogeneity assessment. Due to the small particle size and low content of functional modules, high throughput and multiparameter analysis of individual stimuli-responsive nanoparticles still remains challenging. Here, fabricating a reactive oxygen species (ROS)-responsive liposome ([email protected]) and taking it as an example, we report the development of a strategy for theranostic nanoparticle characterization by a laboratory-built nano-flow cytometer (nFCM). Coincident detection of light scatter and fluorescence intensity provided a measure for liposome quality assessment. Theranostic performance referred to stimuli-responsive capability and drug release behavior upon ROS treatment were obtained in minutes. Besides, the dissociation of functional modules from liposomes and the formation of aggregates under high modification degree were revealed, which was otherwise masked by ensemble-averaged methods. At last, consistent results were also observed in intracellular studies. This nFCM-based method provides a comprehensive approach for the proof-of-principle study, heterogeneity assessment and quality control of biochemical nanosensors and theranostic nanomaterials.
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http://dx.doi.org/10.1016/j.bios.2019.02.016DOI Listing
April 2019

Rolling circle amplification integrated with suspension bead array for ultrasensitive multiplex immunodetection of tumor markers.

Anal Chim Acta 2019 Feb 4;1048:75-84. Epub 2018 Oct 4.

MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, Key Laboratory for Chemical Biology of Fujian Province, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian, 361005, People's Republic of China. Electronic address:

Multiplex detection of ultra-low abundant tumor markers is extremely important for early diagnosis and therapy evaluation. Herein, an ultrasensitive multiplex immunoassay was developed by combination of rolling circle amplification (RCA) and suspension bead array (SBA) technology. Based on a conventional sandwich-type immunoreaction on beads, the detection antibodies were conjugated with DNA primers, so RCA could be implemented to generate long-stranded DNA with abundant repeated sequences allowing for hybridization with fluorochrome-labeled oligonucleotide probes. Thus the fluorescence signal of immunocomplexes on the encoded beads can be greatly enhanced. Using the as-developed immuno-RCA suspension bead array (iRCA-SBA), simultaneous analysis of multiple tumor markers was achieved with the limits of detection of 3.1 pg/mL (∼0.1 pM) for prostate specific antigen (PSA), 9.1 pg/mL (∼50 fM) for carcinoembryonic antigen (CEA), and 0.66 pg/mL (∼9 fM) for α-fetoprotein (AFP), which are two to three orders of magnitude lower than those obtained by the conventional SBA method. The dynamic range were 4.5, 4.7, and 5.5 orders of magnitude for PSA, CEA, and AFP, respectively. Tests on clinical serum samples demonstrate that the tumor marker concentrations measured by the newly developed iRCA-SBA assay agreed well with those obtained by the conventional SBA method. These results indicate that the iRCA-SBA assay significantly increased the detection sensitivity and dynamic range without sacrificing the reliability and accuracy of conventional SBA. Upon the integration with iRCA, SBA could find more applications in the detection of low abundance protein biomarkers for early diagnosis of cancer and other diseases.
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http://dx.doi.org/10.1016/j.aca.2018.10.001DOI Listing
February 2019

Long-term treatment with ivabradine in transgenic atrial fibrillation mice counteracts hyperpolarization-activated cyclic nucleotide gated channel overexpression.

J Cardiovasc Electrophysiol 2019 02 5;30(2):242-252. Epub 2018 Nov 5.

Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Introduction: Recent studies have demonstrated that ivabradine (IVA), is a selective inhibitor of funny current (If) and exerts antiarrhythmic effects in the settings of various diseases such as heart failure and myocardial ischemia. However, little is known regarding the effects of long-term IVA treatment on I current and hyperpolarization-activated cyclic nucleotide gated (HCN) channel overexpression.

Methods And Results: We investigated both the I current and HCN channel expression in wild-type (WT) mice and transgenic (TG) atrial fibrillation (AF) mice (heart-specific overexpressing of (pro) renin receptor TG mice) and examined the effects of IVA on the I current and HCN channel expression, and whether those effects were sufficient to prevent an AF episode. Compared with WT mice, the I current density (at -170 mV: TG, -39.6 ± 4.6 pA/pF; WT, -26.9 ± 3.0 pA/pF; P < 0.001) and activation kinetics (V : TG, -109.45 ± 1.35 mV; WT, -128.20 ± 1.65 mV), as well as HCN2 and HCN4 messenger RNA expression and HCN4 protein expression were significantly increased in the atrial myocytes of TG mice. After 4 months of IVA treatment (7 mg/kg per day orally) the effects of IVA on TG AF mice were accompanied by the inhibition of upregulation of HCN2 and HCN4 protein expression in atrial tissue, and then resulted in a uniform I loss of function. Furthermore, we observed that ivabradine significantly decreased the incidence of AF in the TG mice (41.2% in TG mice, 16.7% in TG + IVA mice; P < 0.01).

Conclusion: IVA reduced the incidence of AF in mice, and the antiarrhythmic effects of IVA are not limited to heart rate reduction, as they partially counteract HCN overexpression and reverse electrophysiological cardiac remodeling by attenuating I gain-of-function.
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http://dx.doi.org/10.1111/jce.13772DOI Listing
February 2019

Histopathologic features of alcoholic cardiomyopathy compared with idiopathic dilated cardiomyopathy.

Medicine (Baltimore) 2018 Sep;97(39):e12259

State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: The histologic difference between alcoholic cardiomyopathy (ACM) and idiopathic dilated cardiomyopathy (IDCM) is unclear. The present study aimed to identify the quantitative pathologic features of ACM compared with IDCM.

Methods: Specimens from 6 regions (anterior left ventricle [LV], lateral LV, inferior LV, interventricular septum [IVS], anterior right ventricle [RV], and inferior RV) were sampled from each explanted heart. Specimens from 4 healthy donor hearts were obtained as normal control. Tissues were sectioned and Masson trichrome stained. Histomorphometry was performed to evaluate the amount of myocyte, fibrosis, fatty tissue, and interstitium by Image-Pro Plus 6.0 (Media Cybernetics).

Results: A total of 408 specimens were obtained from 34 ACMs and 34 IDCMs; 8 specimens were obtained from 4 healthy donor hearts. Compared to healthy donor hearts, we observed an increase in fibrosis which replaces myocytes in myocardium of end-stage cardiomyopathy. The overall myocyte ratio in myocardium was 69.5 ± 8.7% in ACM vs 71.9 ± 7.4% in IDCM (P < .05). The percentage of interstitium was 10.8 ± 4.8% in ACM vs 9.2 ± 6.2% in IDCM (P < .05). A significant difference of fibrosis, fatty tissue was not discovered. Moreover, the myocyte area was 65.37 ± 11.8% in ACM LV vs 70.03 ± 9.0% in IDCM LV (P < .001).

Conclusion: We described histologic characteristics in ACM and IDCM. There might be a quantitative difference of myocyte, interstitium in myocardium between ACM and IDCM, especially in LV. No difference was found in the percentage of fibrosis between the 2 groups.
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http://dx.doi.org/10.1097/MD.0000000000012259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181549PMC
September 2018

ErbB4 deletion in noradrenergic neurons in the locus coeruleus induces mania-like behavior via elevated catecholamines.

Elife 2018 09 4;7. Epub 2018 Sep 4.

Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Dysfunction of the noradrenergic (NE) neurons is implicated in the pathogenesis of bipolar disorder (BPD). ErbB4 is highly expressed in NE neurons, and its genetic variation has been linked to BPD; however, how ErbB4 regulates NE neuronal function and contributes to BPD pathogenesis is unclear. Here we find that conditional deletion of ErbB4 in locus coeruleus (LC) NE neurons increases neuronal spontaneous firing through NMDA receptor hyperfunction, and elevates catecholamines in the cerebrospinal fluid (CSF). Furthermore, -deficient mice present mania-like behaviors, including hyperactivity, reduced anxiety and depression, and increased sucrose preference. These behaviors are completely rescued by the anti-manic drug lithium or antagonists of catecholaminergic receptors. Our study demonstrates the critical role of ErbB4 signaling in regulating LC-NE neuronal function, reinforcing the view that dysfunction of the NE system may contribute to the pathogenesis of mania-associated disorder.
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http://dx.doi.org/10.7554/eLife.39907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6185106PMC
September 2018

Unilateral whisker pad injection of botulinum toxin type a enhances spatial learning in mice.

Neuroreport 2018 08;29(12):987-992

Department of Neurology, Sir Run Run Shaw Hospital.

The central cholinergic nervous system plays an important role in cognition, with acetylcholine hypofunction considered to be a major factor of dementia. Botulinum toxin type A (BoNT/A), a potent poison secreted by Clostridium botulinum, is used widely for dystonia treatment and facial cosmesis. BoNT/A injection inhibits acetylcholine release in the neuromuscular junction through cleavage of synaptosomal-associated protein of 25 kDa in cholinergic terminals. Furthermore, beyond the injection site, BoNT/A undergoes retrograde transport and transcytosis to the central nervous system from peripheral cholinergic terminals. However, whether peripheral BoNT/A injection affects the function of the central nervous system and induces learning deficits remains unclear. We injected mice with different doses of BoNT/A (2, 10, and 50 U/kg) or sterile saline (control) into the left whisker pad to test spatial learning performance at different times after injection using the Morris water maze. At 3 days and 4 weeks after injection, the spatial learning ability of the control and BoNT/A-treated mice showed no significant differences. Surprisingly, however, rather than spatial learning impairment at 6 weeks after injection, BoNT/A-treated mice spent less time than control mice in locating the experimental platform, indicating that BoNT/A facial injection might promote spatial learning. Furthermore, our study suggests that facial application of BoNT/A is safe and could play a positive role in ameliorating the spatial learning deficits associated with neurodegenerative diseases.
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http://dx.doi.org/10.1097/WNR.0000000000001035DOI Listing
August 2018

Microglial Phagocytosis Assay.

Bio Protoc 2016 Nov;6(21)

Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, USA.

Phagocytosis is essential for microglial clearance of apoptotic cells, extracellular protein aggregates, and infectious bacteria in the central nervous system (CNS). While the preparation of primary microglial culture has been described elsewhere, this protocol describes the microglial phagocytosis experimental procedure and the subsequent measurement of microglial phagocytic ability using fluorescent latex beads or fluorescent amyloid beta 42 (Aβ42) peptides.
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http://dx.doi.org/10.21769/BioProtoc.1988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669280PMC
November 2016

Protocol for Primary Microglial Culture Preparation.

Bio Protoc 2016 Nov;6(21)

Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, USA.

Primary microglia, in either mono-culture or co-culture with neurons or astrocytes, are a powerful tool for studying mechanisms underlying microglial inflammatory responses and cell type-specific interactions in the central nervous system (CNS). This protocol provides the details of how to prepare high purity primary microglia from newborn mouse pups. The overall steps include brain cell dissociation, mixed glial cell culture, and microglia isolation.
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http://dx.doi.org/10.21769/BioProtoc.1989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669279PMC
November 2016

Deletion from Medium Spiny Neurons of the Nucleus Accumbens Core Induces Schizophrenia-Like Behaviors via Elevated GABA Receptor α1 Subunit Expression.

J Neurosci 2017 08 30;37(31):7450-7464. Epub 2017 Jun 30.

Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health, Joint Institute for Genetics and Genome Medicine between Zhejiang University and University of Toronto, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310058 China

Medium spiny neurons (MSNs), the major GABAergic projection neurons in the striatum, are implicated in many neuropsychiatric diseases such as schizophrenia, but the underlying mechanisms remain unclear. We found that a deficiency in , a schizophrenia risk gene, in MSNs of the nucleus accumbens (NAc) core, but not the dorsomedial striatum, markedly induced schizophrenia-like behaviors such as hyperactivity, abnormal marble-burying behavior, damaged social novelty recognition, and impaired sensorimotor gating function in male mice. Using immunohistochemistry, Western blot, RNA interference, electrophysiology, and behavior test studies, we found that these phenomena were mediated by increased GABA receptor α1 subunit (GABAR α1) expression, which enhanced inhibitory synaptic transmission on MSNs. These results suggest that in MSNs of the NAc core may contribute to the pathogenesis of schizophrenia by regulating GABAergic transmission and raise the possibility that GABAR α1 may therefore serve as a new therapeutic target for schizophrenia. Although ErbB4 is highly expressed in striatal medium spiny neurons (MSNs), its role in this type of neuron has not been reported previously. The present study demonstrates that deletion in nucleus accumbens (NAc) core MSNs can induce schizophrenia-like behaviors via elevated GABA receptor α1 subunit (GABAR α1) expression. To our knowledge, this is the first evidence that ErbB4 signaling in the MSNs is involved in the pathology of schizophrenia. Furthermore, restoration of GABAR α1 in the NAc core, but not the dorsal medium striatum, alleviated the abnormal behaviors. Here, we highlight the role of the NAc core in the pathogenesis of schizophrenia and suggest that GABAR α1 may be a potential pharmacological target for its treatment.
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http://dx.doi.org/10.1523/JNEUROSCI.3948-16.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596705PMC
August 2017

Increased NRG1-ErbB4 signaling in human symptomatic epilepsy.

Sci Rep 2017 03 10;7(1):141. Epub 2017 Mar 10.

Department of Neurosurgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310009, China.

Previous studies have shown that the neuregulin 1 (NRG1)-ErbB4 signaling pathway may regulate the excitability of fast-spiking neurons in the frontal cortex and participate in primary epilepsy pathogenesis. However, the exact roles and mechanism for NRG1/ErbB4 in human symptomatic epilepsy are still unclear. Using fresh human symptomatic epilepsy tissues, we found that the protein levels of NRG1 and ErbB4 were significantly increased in the temporal cortex. In addition, NRG1-ErbB4 signaling suppressed phosphorylation of GluN2B at position 1472 by Src kinase, and decreased levels of phosphorylation level of GluN2B and Src were detected in human symptomatic epilepsy tissues. Our study revealed a critical role of the NRG1-ErbB4 signaling pathway in symptomatic epilepsy, which is different from that in primary epilepsy, and we propose that the NRG1-ErbB4 signaling may act as a homeostasis modulator that protects the brain from aggravation of epileptiform activity.
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http://dx.doi.org/10.1038/s41598-017-00207-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428003PMC
March 2017