Publications by authors named "Jingliang Zhang"

23 Publications

  • Page 1 of 1

PKA-RIIβ autophosphorylation modulates PKA activity and seizure phenotypes in mice.

Commun Biol 2021 Mar 1;4(1):263. Epub 2021 Mar 1.

State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China.

Temporal lobe epilepsy (TLE) is one of the most common and intractable neurological disorders in adults. Dysfunctional PKA signaling is causally linked to the TLE. However, the mechanism underlying PKA involves in epileptogenesis is still poorly understood. In the present study, we found the autophosphorylation level at serine 114 site (serine 112 site in mice) of PKA-RIIβ subunit was robustly decreased in the epileptic foci obtained from both surgical specimens of TLE patients and seizure model mice. The p-RIIβ level was negatively correlated with the activities of PKA. Notably, by using a P-site mutant that cannot be autophosphorylated and thus results in the released catalytic subunit to exert persistent phosphorylation, an increase in PKA activities through transduction with AAV-RIIβ-S112A in hippocampal DG granule cells decreased mIPSC frequency but not mEPSC, enhanced neuronal intrinsic excitability and seizure susceptibility. In contrast, a reduction of PKA activities by RIIβ knockout led to an increased mIPSC frequency, a reduction in neuronal excitability, and mice less prone to experimental seizure onset. Collectively, our data demonstrated that the autophosphorylation of RIIβ subunit plays a critical role in controlling neuronal and network excitabilities by regulating the activities of PKA, providing a potential therapeutic target for TLE.
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http://dx.doi.org/10.1038/s42003-021-01748-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921646PMC
March 2021

Irreversible Primary Visual Cortex Impairment in a Mouse Model of High-Risk Schizophrenia.

Neuropsychiatr Dis Treat 2021 29;17:277-282. Epub 2021 Jan 29.

Department of Psychiatry, Wenzhou Kangning Hospital, Wenzhou, Zhejiang Province 325007, People's Republic of China.

Purpose: Although visual deficits can be observed at any stage of schizophrenia, few studies have focused on visual cortex alterations in individuals at high risk of schizophrenia. This study aimed to investigate the pathological changes of the primary visual cortex in a prenatal mouse model of MK801-induced high-risk schizophrenia.

Methods: The high-risk schizophrenia model was generated by MK801 injection into pregnant mice. The male offspring without schizophrenia-like behaviors in early adulthood were defined as the high-risk mouse model of schizophrenia (HRMMS) and divided into two groups. One HRMMS group received the antipsychotic agent risperidone beginning at postnatal week 4 and another group did not receive any treatment. After treatment for 4 weeks, in vivo two-photon calcium imaging was performed to characterize the primary visual cortex activity. The novel object recognition test and the prepulse inhibition apparatus test were also implemented to assess the cognitive and behavioral performance, respectively.

Results: Both groups of HRMMS mice, with or without antipsychotic treatment, had decreased neuronal calcium activity, demonstrating primary visual cortex impairment. More notably, antipsychotic treatment did not normalize the impaired neuronal activities in the primary visual cortex. Correspondingly, the treatment did not improve the cognitive or behavioral impairment.

Conclusion: Visual cortex impairment might be a prominent feature of individuals at high risk of schizophrenia that cannot be normalized by early treatment with antipsychotic medication, indicating the presence of independent regulatory pathways for visual perception disturbance in schizophrenia. Thus, visual system impairment in schizophrenic patients must be further studied.
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http://dx.doi.org/10.2147/NDT.S246163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853429PMC
January 2021

Generation and basic characterization of a gene-trap knockout mouse model of Scn2a with a substantial reduction of voltage-gated sodium channel Na 1.2 expression.

Genes Brain Behav 2021 Apr 18;20(4):e12725. Epub 2021 Jan 18.

Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.

Large-scale genetic studies revealed SCN2A as one of the most frequently mutated genes in patients with neurodevelopmental disorders. SCN2A encodes for the voltage-gated sodium channel isoform 1.2 (Na 1.2) expressed in the neurons of the central nervous system. Homozygous knockout (null) of Scn2a in mice is perinatal lethal, whereas heterozygous knockout of Scn2a (Scn2a ) results in mild behavior abnormalities. The Na 1.2 expression level in Scn2a mice is reported to be around 50-60% of the wild-type (WT) level, which indicates that a close to 50% reduction of Na 1.2 expression may not be sufficient to lead to major behavioral phenotypes in mice. To overcome this barrier, we characterized a novel mouse model of severe Scn2a deficiency using a targeted gene-trap knockout (gtKO) strategy. This approach produces viable homozygous mice (Scn2a ) that can survive to adulthood, with about a quarter of Na 1.2 expression compared to WT mice. Innate behaviors like nesting and mating were profoundly disrupted in Scn2a mice. Notably, Scn2a mice have a significantly decreased center duration compared to WT in the open field test, suggesting anxiety-like behaviors in a novel, open space. These mice also have decreased thermal and cold tolerance. Additionally, Scn2a mice have increased fix-pattern exploration in the novel object exploration test and a slight increase in grooming, indicating a detectable level of repetitive behaviors. They bury little to no marbles and have decreased interaction with novel objects. These Scn2a gene-trap knockout mice thus provide a unique model to study pathophysiology associated with severe Scn2a deficiency.
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http://dx.doi.org/10.1111/gbb.12725DOI Listing
April 2021

Deficiency of anti-inflammatory cytokine IL-4 leads to neural hyperexcitability and aggravates cerebral ischemia-reperfusion injury.

Acta Pharm Sin B 2020 Sep 20;10(9):1634-1645. Epub 2020 May 20.

Department of Molecular and Cellular Pharmacology, State Key Laboratory of Natural and Biomimetic Drugs, Peking University School of Pharmaceutical Sciences, Beijing 100191, China.

Systematic administration of anti-inflammatory cytokine interleukin 4 (IL-4) has been shown to improve recovery after cerebral ischemic stroke. However, whether IL-4 affects neuronal excitability and how IL-4 improves ischemic injury remain largely unknown. Here we report the neuroprotective role of endogenous IL-4 in focal cerebral ischemia-reperfusion (I/R) injury. In multi-electrode array (MEA) recordings, IL-4 reduces spontaneous firings and network activities of mouse primary cortical neurons. IL-4 mRNA and protein expressions are upregulated after I/R injury. Genetic deletion of gene aggravates I/R injury and exacerbates oxygen-glucose deprivation (OGD) injury in cortical neurons. Conversely, supplemental IL-4 protects cortical neurons against OGD injury. Mechanistically, cortical pyramidal and stellate neurons common for ischemic penumbra after I/R injury exhibit intrinsic hyperexcitability and enhanced excitatory synaptic transmissions in mice. Furthermore, upregulation of Nav1.1 channel, and downregulations of KCa3.1 channel and 6 subunit of GABA receptors are detected in the cortical tissues and primary cortical neurons from mice. Taken together, our findings demonstrate that IL-4 deficiency results in neural hyperexcitability and aggravates I/R injury, thus activation of IL-4 signaling may protect the brain against the development of permanent damage and help recover from ischemic injury after stroke.
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http://dx.doi.org/10.1016/j.apsb.2020.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564329PMC
September 2020

Characterization of Low Molecular Weight Sulfate Ulva Polysaccharide and its Protective Effect against IBD in Mice.

Mar Drugs 2020 Sep 29;18(10). Epub 2020 Sep 29.

Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China.

Inflammatory bowel disease (IBD) has been gradually considered a public health challenge worldwide. Sulfated polysaccharides, extracted from seaweed, have been shown to have an anti-inflammatory effect on the disease[...].
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http://dx.doi.org/10.3390/md18100499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601132PMC
September 2020

Comparison of Ga-PSMA-617 PET/CT with mpMRI for the detection of PCa in patients with a PSA level of 4-20 ng/ml before the initial biopsy.

Sci Rep 2020 07 3;10(1):10963. Epub 2020 Jul 3.

Department of Urology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an, 710032, Shaanxi, China.

The study was aimed at assessing the diagnostic performance of Ga-PSMA-617 PET/CT in the detection of prostate cancer (PCa) in patients with a prostate-specific antigen (PSA) level of 4-20 ng/ml and to compare its efficacy with that of multiparametric MRI (mpMRI). We analyzed the data of 67 consecutive patients with PSA levels of 4-20 ng/ml who almost simultaneously underwent Ga-PSMA-617 PET/CT and mpMRI. Ga-PSMA-617 PET/CT and mpMRI diagnostic performances were compared via receiver operating characteristic (ROC) curve analysis. Of the 67 suspected PCa cases, 33 had pathologically confirmed PCa. Ga-PSMA-617 PET/CT showed a patient-based sensitivity, specificity, and positive and negative predictive values (PPVs and NPVs) of 87.88%, 88.24%, 87.88%, and 88.24%, respectively. The corresponding values for mpMRI were 84.85%, 52.94%, 63.64%, and 78.26%. The area under the curve values for Ga-PSMA-617 PET/CT and mpMRI were 0.881 and 0.689, respectively. Ga-PSMA-617 PET/CT showed a better diagnostic performance than mpMRI in the detection of PCa in patients with PSA levels of 4-20 ng/ml.
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http://dx.doi.org/10.1038/s41598-020-67385-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334214PMC
July 2020

Interaction with CD68 and Regulation of GAS6 Expression by Endosialin in Fibroblasts Drives Recruitment and Polarization of Macrophages in Hepatocellular Carcinoma.

Cancer Res 2020 09 26;80(18):3892-3905. Epub 2020 Jun 26.

Institute of Medical Research, Northwestern Polytechnical University, Xi'an, China.

Fibroblasts and macrophages play key roles in the development of hepatocellular carcinoma (HCC). However, cross-talk between these two kinds of cells has not been well studied. Endosialin (CD248/TEM1) is a transmembrane glycoprotein that is expressed in certain cancer cells, tumor stromal cells, and pericytes. In this study, we found that endosialin is mainly expressed in cancer-associated fibroblasts (CAF) in HCC and its expression inversely correlates with patient prognosis. Endosialin interacted with CD68 to recruit macrophages and regulated expression of GAS6 in CAFs to mediate M2 polarization of macrophages. The fully human antibody IgG78 bound glycosylated endosialin and induced its internalization in CAFs, thus weakening the cross-talk between CAFs and macrophages. In subcutaneous and orthotopic xenograft models of HCC in nude mice, treatment with IgG78 significantly inhibited tumor growth. These results indicate that endosialin-positive CAFs promote HCC progression and highlight IgG78 as a promising therapeutic candidate for HCC treatment. SIGNIFICANCE: These findings highlight CAF-expressed endosialin as a primary regulator of macrophage recruitment and polarization and demonstrate endosialin inhibition as a potential treatment strategy for HCC. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/18/3892/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2691DOI Listing
September 2020

Quicker, deeper and stronger imaging: A review of tumor-targeted, near-infrared fluorescent dyes for fluorescence guided surgery in the preclinical and clinical stages.

Eur J Pharm Biopharm 2020 Jul 8;152:123-143. Epub 2020 May 8.

Department of Urology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an 710032, China. Electronic address:

Cancer is a public health problem and the main cause of human mortality and morbidity worldwide. Complete removal of tumors and metastatic lymph nodes in surgery is significantly beneficial for the prognosis of patients. Tumor-targeted, near-infrared fluorescent (NIRF) imaging is an emerging field of real-time intraoperative cancer imaging based on tumor-targeted NIRF dyes. Targeted NIRF dyes contain NIRF fluorophores and specific binding ligands such as antibodies, peptides and small molecules. The present article reviews recently updated tumor-targeted NIRF dyes for the molecular imaging of malignant tumors in the preclinical stage and clinical trials. The strengths and challenges of NIRF agents with tumor-targeting ability are also summarized. Smaller ligands, near infrared II dyes, dual-modality dyes and activatable dyes may contribute to quicker, deeper, stronger imaging in the nearest future. In this review, we highlighted tumor-targeted NIRF dyes for fluorescence-guided surgery and their potential clinical translation.
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http://dx.doi.org/10.1016/j.ejpb.2020.05.002DOI Listing
July 2020

Evaluation of cadmium hyperaccumulation and tolerance potential of Myriophyllum aquaticum.

Ecotoxicol Environ Saf 2020 Jun 20;195:110502. Epub 2020 Mar 20.

Yellow River Engineering Consulting Co., Ltd., Zhengzhou, 450001, China.

Enrichment of the hyperaccumulator bank is important for phytoremediation, and studying new hyperaccumulators has become a research hotspot. In this study, cadmium (Cd), the main representative factor of heavy-metal-polluted water, was the research object, and the Cd bioenrichment ability and tolerance of Myriophyllum aquaticum were studied for the first time. The experiment was conducted for 28 days by establishing experimental groups with different Cd concentrations (0, 10, 20, 40, 80, and 160 mg/L). The results show that M. aquaticum is a new Cd hyperaccumulator. There was no notable damage in the 40 mg/L Cd treatment group, and the Cd enrichment ability of M. aquaticum reached 17,970 ± 1020.01 mg/kg, while the bioconcentration factor (BCF) reached 449.25. At the same time, the antioxidant system (superoxide dismutase (SOD) and peroxidase (POD)) and proline (Pro) levels of M. aquaticum maintained normal plant physiology, but there were physiological anomalies in M. aquaticum at high concentrations and under long-term treatment. The results show that M. aquaticum has a high Cd bioenrichment ability and tolerance in water and can be used for phytoremediation of river water polluted by Cd.
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http://dx.doi.org/10.1016/j.ecoenv.2020.110502DOI Listing
June 2020

Neutrophil exosomes enhance the skin autoinflammation in generalized pustular psoriasis activating keratinocytes.

FASEB J 2019 06 27;33(6):6813-6828. Epub 2019 Feb 27.

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.

Generalized pustular psoriasis (GPP) is a rare and severe inflammatory skin disease that can be life-threatening. Gene mutations are found in some cases, but its immune pathogenesis is largely unknown. Here, we observed that the neutrophil:lymphocyte ratio in patients with GPP was higher than that in healthy controls and decreased after effective treatment. Neutrophils isolated from patients with GPP induced higher expressions of inflammatory genes including , , , , and C-X-C motif chemokine ligands in keratinocytes than normal neutrophils did. Moreover, neutrophils from patients with GPP secreted more exosomes than controls, which were then rapidly internalized by keratinocytes, increasing the expression of these inflammatory molecules activating NF-κB and MAPK signaling pathways. The proteomic profiles in neutrophil exosomes further characterized functional proteins and identified olfactomedin 4 as the critical differentially expressed protein that mediates the autoimmune inflammatory responses of GPP. These results demonstrate that neutrophil exosomes have an immune-regulatory effect on keratinocytes, which modulates immune cell migration and autoinflammation in GPP.-Shao, S., Fang, H., Zhang, J., Jiang, M., Xue, K., Ma, J., Zhang, J., Lei, J., Zhang, Y., Li, B., Yuan, X., Dang, E., Wang, G. Neutrophil exosomes enhance the skin autoinflammation in generalized pustular psoriasis activating keratinocytes.
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http://dx.doi.org/10.1096/fj.201802090RRDOI Listing
June 2019

Chromodomain Y-like Protein-Mediated Histone Crotonylation Regulates Stress-Induced Depressive Behaviors.

Biol Psychiatry 2019 04 5;85(8):635-649. Epub 2018 Dec 5.

State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Beijing, China; Key Laboratory for Neuroscience, Ministry of Education and National Health Commission, Beijing, China. Electronic address:

Background: Major depressive disorder is a prevalent and life-threatening illness in modern society. The susceptibility to major depressive disorder is profoundly influenced by environmental factors, such as stressful lifestyle or traumatic events, which could impose maladaptive transcriptional program through epigenetic regulation. However, the underlying molecular mechanisms remain elusive. Here, we examined the role of histone crotonylation, a novel type of histone modification, and chromodomain Y-like protein (CDYL), a crotonyl-coenzyme A hydratase and histone methyllysine reader, in this process.

Methods: We used chronic social defeat stress and microdefeat stress to examine the depressive behaviors. In addition, we combined procedures that diagnose behavioral strategy in male mice with histone extraction, viral-mediated CDYL manipulations, RNA sequencing, chromatin immunoprecipitation, Western blot, and messenger RNA quantification.

Results: The results indicate that stress-susceptible rodents exhibit lower levels of histone crotonylation in the medial prefrontal cortex concurrent with selective upregulation of CDYL. Overexpression of CDYL in the prelimbic cortex, a subregion of the medial prefrontal cortex, increases microdefeat-induced social avoidance behaviors and anhedonia in mice. Conversely, knockdown of CDYL in the prelimbic cortex prevents chronic social defeat stress-induced depression-like behaviors. Mechanistically, we show that CDYL inhibits structural synaptic plasticity mainly by transcriptional repression of neuropeptide VGF nerve growth factor inducible, and this activity is dependent on its dual effect on histone crotonylation and H3K27 trimethylation on the VGF promoter.

Conclusions: Our results demonstrate that CDYL-mediated histone crotonylation plays a critical role in regulating stress-induced depression, providing a potential therapeutic target for major depressive disorder.
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http://dx.doi.org/10.1016/j.biopsych.2018.11.025DOI Listing
April 2019

Diagnostic performance of Ga-PSMA PET/CT in the detection of prostate cancer prior to initial biopsy: comparison with cancer-predicting nomograms.

Eur J Nucl Med Mol Imaging 2019 Apr 11;46(4):908-920. Epub 2019 Jan 11.

Department of Nuclear Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.

Purpose: To assess the diagnostic performance of Ga-PSMA PET/CT for detecting suspected prostate cancer (PCa) and to compare it with that of two cancer-predicting nomograms.

Methods: We performed a retrospective analysis of 146 consecutive patients with suspected PCa based on symptoms or elevated total prostate-specific antigen (tPSA) levels who underwent Ga-PSMA PET/CT and histopathologic examinations from April 2017 to April 2018 in a large tertiary care hospital in China. The Ga-PSMA PET/CT results (PCa or benignancy) were evaluated by two experienced nuclear medicine specialists. The risk of positive PCa was evaluated using ERSPC and PCPT nomograms. The diagnostic performances of Ga-PSMA PET/CT and that of the two nomograms were compared via receiver operating characteristic (ROC) curve analysis, decision curve analysis, and logistic regression.

Results: A total of 58 patients with tPSA of 0.4-50 ng/ml were included in the final analysis; PCa diagnosis was confirmed in 37 patients and excluded in 21 patients. ROC analysis showed that the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of Ga-PSMA PET/CT were 91.67, 81.82, 89.19, and 85.71%, respectively, in per-patient analyses. Ga-PSMA PET/CT exhibited a higher AUC (0.867) than those of ERSPC-RC3 (0.855) and PCPT-RC (0.770). The net benefit of Ga-PSMA PET/CT was greatest for patients within threshold probabilities of 15-90%. Among the 58 patients, 11 (19%) biopsies suggested by ERSPC-RC3 were unnecessary and could have been avoided if judged by the Ga-PSMA PET/CT results. Multivariate analysis revealed that the maximum standardised uptake value (SUV) and prostate volume were significant predictive factors for positive PCa results.

Conclusion: In suspected PCa patients with tPSA of 0.4-50 ng/ml, Ga-PSMA PET/CT outperformed the nomograms in predicting cancer and reducing unnecessary biopsies. In addition, the risk of PCa was positively correlated with a higher SUV and lower prostate volume, which could help clinicians in making preliminary estimates of individual cancer risk, monitoring Ga-PSMA PET/CT false-positive results and making biopsy decisions in daily medical practice.
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http://dx.doi.org/10.1007/s00259-018-4255-1DOI Listing
April 2019

Targeting JNK pathway promotes human hematopoietic stem cell expansion.

Cell Discov 2019 8;5. Epub 2019 Jan 8.

1State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology & Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, 518055 China.

The limited number of human hematopoietic stem cells (HSCs) has restrained their widespread clinical application. Despite great efforts in recent years, the in vitro expansion of HSCs remains a challenge due to incomplete understanding of the signaling networks underlying HSC self-renewal. Here, we show that culturing human cord blood (CB) CD34 cells with JNK-IN-8, an inhibitor of the JNK signaling pathway, can enhance the self-renewal of HSCs with a 3.88-fold increase in cell number. These cultured CD34 cells repopulated recipient mice for 21 weeks and can form secondary engraftment that lasted for more than 21 weeks. Knockdown of , a major downstream target in the JNK pathway, promoted the expansion of hematopoietic stem and progenitor cells (HSPCs). Our findings demonstrate a critical role of the JNK pathway in regulating HSC expansion, provide new insights into HSC self-renewal mechanism, and may lead to improved clinical application of HSCs.
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http://dx.doi.org/10.1038/s41421-018-0072-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323118PMC
January 2019

ERG3 potassium channel-mediated suppression of neuronal intrinsic excitability and prevention of seizure generation in mice.

J Physiol 2018 10 7;596(19):4729-4752. Epub 2018 Sep 7.

State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China.

Key Points: ERG3 channels have a high expression level in the central nervous system. Knockdown of ERG3 channels enhances neuronal intrinsic excitability (caused by decreased fast afterhyperpolarization, shortened delay time to the generation of an action potential and enhanced summation of somatic excitatory postsynaptic potentials) in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. The expression of ERG3 protein is reduced in human and mouse hippocampal epileptogenic foci. Knockdown of ERG3 channels in hippocampus enhanced seizure susceptibility, while mice treated with the ERG channel activator NS-1643 were less prone to epileptogenesis. The results provide strong evidence that ERG3 channels have a crucial role in the regulation of neuronal intrinsic excitability in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells and are critically involved in the onset and development of epilepsy.

Abstract: The input-output relationship of neuronal networks depends heavily on the intrinsic properties of their neuronal elements. Profound changes in intrinsic properties have been observed in various physiological and pathological processes, such as learning, memory and epilepsy. However, the cellular and molecular mechanisms underlying acquired changes in intrinsic excitability are still not fully understood. Here, we demonstrate that ERG3 channels are critically involved in the regulation of intrinsic excitability in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. Knock-down of ERG3 channels significantly increases neuronal intrinsic excitability, which is mainly caused by decreased fast afterhyperpolarization, shortened delay time to the generation of an action potential and enhanced summation of somatic excitatory postsynaptic potentials. Interestingly, the expression level of ERG3 protein is significantly reduced in human and mouse brain tissues with temporal lobe epilepsy. Moreover, ERG3 channel knockdown in hippocampus significantly enhanced seizure susceptibility, while mice treated with the ERG channel activator NS-1643 were less prone to epileptogenesis. Taken together, our results suggest ERG3 channels play an important role in determining the excitability of hippocampal neurons and dysregulation of these channels may be involved in the generation of epilepsy. ERG3 channels may thus be a novel therapeutic target for the prevention of epilepsy.
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http://dx.doi.org/10.1113/JP275970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166062PMC
October 2018

Anticonvulsant effect of dipropofol by enhancing native GABA currents in cortical neurons in mice.

J Neurophysiol 2018 09 20;120(3):1404-1414. Epub 2018 Jun 20.

State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center , Beijing , China.

Temporal lobe epilepsy (TLE), the most common pharmacoresistant focal epilepsy disorder, remains a major unmet medical need. Propofol is used as a short-acting medication for general anesthesia and refractory status epilepticus with issues of decreased consciousness and memory loss. Dipropofol, a derivative of propofol, has been reported to exert antioxidative and antibacterial activities. Here we report that dipropofol exerted anticonvulsant activity in a mouse model of kainic acid-induced seizures. Whole cell patch-clamp recordings of brain slices from the medial entorhinal cortex (mEC) revealed that dipropofol hyperpolarized the resting membrane potential and reduced the number of action potential firings, resulting in suppression of cortical neuronal excitability. Furthermore, dipropofol activated native tonic GABA currents of mEC layer II stellate neurons in a dose-dependent manner with an EC value of 9.3 ± 1.6 μM (mean ± SE). Taken together, our findings show that dipropofol activated GABA currents and exerted anticonvulsant activities in mice, thus possessing developmental potential for new anticonvulsant therapy. NEW & NOTEWORTHY The anticonvulsant effect of dipropofol was shown in a mouse model of kainic acid-induced seizures. Whole cell patch-clamp recordings of brain slices showed suppression of cortical neuronal excitability by dipropofol. Dipropofol activated the native tonic GABA currents in a dose-dependent manner.
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http://dx.doi.org/10.1152/jn.00241.2018DOI Listing
September 2018

High mobility group box 1 promotes the epithelial-to-mesenchymal transition in prostate cancer PC3 cells via the RAGE/NF-κB signaling pathway.

Int J Oncol 2018 Aug 23;53(2):659-671. Epub 2018 May 23.

Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.

High mobility group box 1 (HMGB1), a critical damage-associated molecular pattern molecule, has been implicated in several inflammatory diseases and cancer types. The overexpression of HMGB1 protein occurs in prostate cancer, and is closely associated with the proliferation and aggressiveness of tumor cells. However, the underlying mechanisms of HMGB1-induced tumor metastasis in prostate cancer remain unclear. In the present study, it was demonstrated that the expression of HMGB1 was high in prostate cancer samples, particularly in the metastatic tissues. Furthermore, recombinant HMGB1 (rHMGB1) enhanced the invasive and metastatic capabilities of the prostate cancer cells. Molecular phenotype alterations of epithelial-to-mesenchymal transition (EMT) and elevated expression levels of matrix metalloproteinase (MMP)-1, -3 and -10 were observed. In addition, advanced glycosylation end-product specific receptor (RAGE) and its downstream molecule nuclear factor (NF)-κB pathway were activated during rHMGB1-induced metastasis. Silencing RAGE or NF-κB reversed the upregulation of MMP and EMT marker expression levels, thus reducing the migration and invasiveness of tumor cells. Taken together, these results suggest that highly expressed HMGB1 drives EMT and the overexpression of MMP-1, -3, -10 via the RAGE/NF-κB signaling pathways, which facilitates the metastasis of prostate cancer and may be a potential therapeutic target for metastatic prostate cancer.
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http://dx.doi.org/10.3892/ijo.2018.4420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017266PMC
August 2018

Association between MDR/CYP3A4/OPRM gene polymorphisms and the post-caesarean fentanyl analgesic effect on Chinese women.

Gene 2018 Jun 27;661:78-84. Epub 2018 Mar 27.

Department of Anesthesiology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China. Electronic address:

Objective: Our study aimed to evaluate the association between the multidrug resistance 1 (MDR)/cytochrome P450 3A4 (CYP3A4)/μ-opioid receptor (OPRM) gene polymorphisms and the post-caesarean analgesic effect of fentanyl on Chinese women.

Methods: We recruited 240 patients who received lower segment caesarean section surgeries. Sanger sequencing was used to analyze the MDR1236C > T/CYP3A4*1G/OPRMA118G polymorphisms. We evaluated post-operative fentanyl consumption and the effect of intravenous analgesia in patients with different genotypes.

Results: 1. Subjects with the TT genotype at the 1236C > T polymorphism in the MDR gene consumed significantly more fentanyl than that consumed by subjects with the CC and CT genotypes in the first post-operative 24 h and 48 h (P < 0.05), and the MAP/HR/Cor/Ang-1 levels gradually increased immediately after surgery and in the first post-operative 24 h. 2. Subjects with the CYP3A4*1G/*1G genotype needed less fentanyl to achieve pain control than that needed by subjects carrying the CYP3A4*1/*1 and CYP3A4*1/*1G genotypes in the first post-operative 24 h and 48 h (P < 0.05), and the MAP/HR/Cor/Ang-1 levels gradually decreased immediately after surgery and in the first post-operative 24 h. 3. Subjects with the GG genotype at the A118G polymorphism in the OPRM gene consumed significantly more fentanyl than that consumed by subjects with the AA and AG genotypes in the first post-operative 24 h and 48 h (P < 0.05), and the MAP/HR/Cor/Ang-1 levels gradually increased immediately after surgery and in the first post-operative 24 h. 4. There were no significant differences in the adverse reactions to fentanyl in patients with different genotypes (P > 0.05).

Conclusion: These results indicated that the MDR/CYP3A4/OPRM gene polymorphisms influenced the fentanyl consumption and the physiological effects of intravenous analgesia in the Chinese women who received lower segment caesarean section surgeries. Moreover, the present study provides an important foundation and theoretical evidence for the gene-directed rationalization and individualization of medication before caesarean section surgeries.
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http://dx.doi.org/10.1016/j.gene.2018.03.081DOI Listing
June 2018

[Establishment of kinetics digital model for hyaluronate lyase production based on fermentation optimization of Arthrobacter globiformis A152].

Sheng Wu Gong Cheng Xue Bao 2017 Nov;33(11):1883-1888

College of Food Science and Engineering, Ocean University of China, Qingdao 266003, Shandong, China.

In order to produce hyaluronate lyase of high yield, we optimized the fermentation Arthrobacter globiformis A152 in quadruple fermentation of 5 L, and studied the kinetics of fermentation. Both the highest biomass and enzyme activity could be achieved when the rotation speed was 400 r/min and the ventilation volume was 3.5 L/min. In addition, digital models of cell growth, product synthesis and substrate consumption were built by equation of logistic, luedeking-piret, product synthesis and substrate consumption. Nonlinear fitting and estimation of optimal parameters were obtained by MATLAB. The model correlated well between prediction and experimental data, and reflected the change rules of cell growth, hyaluronidase synthesis and substrate consumption during the process of producing hyaluronate lyase. The establishment of fermentation kinetics digital models could provide basis for controlling and prediction of the production process.
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http://dx.doi.org/10.13345/j.cjb.160478DOI Listing
November 2017

Bupivacaine effectively relieves inflammation-induced pain by suppressing activation of the NF-κB signalling pathway and inhibiting the activation of spinal microglia and astrocytes.

Exp Ther Med 2017 Mar 18;13(3):1074-1080. Epub 2017 Jan 18.

Department of Pain, Yidu Central Hospital of Weifang Affiliated to Weifang Medical College, Weifang, Shandong 262500, P.R. China.

The pain induced by local acute inflammation results in mild to severe discomfort, in addition to the possibility of physiological dysfunction and psychiatric disorders, such as sleep disorders and depression. However, the pathogenesis of pain is yet to be fully elucidated. In the present study, the effects of bupivacaine were explored in rat models inflammatory pain in order to investigate the anti-pain mechanism of bupivacaine. Complete Freund's adjuvant (CFA) was injected into the right rear foot of the rats to establish a model of transient inflammation-induced pain. Rats were randomly divided into four groups (n=8): CFA, CFA plus bupivacaine, CFA plus saline and untreated. The mechanical withdrawal threshold (MWT) of the rats was detected prior to and following CFA injection, and the results demonstrated that the MWT in the right rear foot significantly decreased from the 1st day of CFA injection (P<0.01; n=8), as compared with the untreated controls. Bupivacaine treatment was demonstrated to significantly increase the MWT of rats treated with CFA stimulation, as compared with the CFA group (P<0.01). Rotarod testing was performed to assess the motor activity of the rats, and the results demonstrated no significant differences among the four groups (P>0.05). Furthermore, the respective body weights of the rats were determined every two days before and after CFA injection, and no significant differences were detected among the four groups (P>0.05). Western blot analysis was performed to analyze expression levels of IκB and nuclear factor (NF)-κB, and the results demonstrated that bupivacaine increased the expression of IκB and decreased the expression levels of NF-κB, as compared with the rats with CFA-induced inflammatory responses, suggesting that bupivacaine inhibited NF-κB activation in the dorsal horn of the lumbar spinal cord of the model rats. Furthermore, reverse transcription-quantitative polymerase chain reaction analysis was performed to analyze the expression levels of inflammatory cytokines, which demonstrated that bupivacaine significantly inhibited the expression of TNF-α, IL-1β and IL-6, as compared with the untreated group (P<0.01). Moreover, bupivacaine treatment significantly decreased the expression of spinal microglial marker OX42 and astrocyte marker-glial fibrillary acidic protein, as compared with the rats in the CFA group (P<0.01). The present findings demonstrated that treatment with bupivacaine significantly decreased the activation of microglia and astrocytes in rat models of inflammatory pain. Therefore, the present results may provide clarification of the pathogenesis and mechanism of inflammation-induced pain and may provide novel therapeutic strategies for the clinical treatment of pain.
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http://dx.doi.org/10.3892/etm.2017.4058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403393PMC
March 2017

Purification and Characterization of Hyaluronate Lyase from Arthrobacter globiformis A152.

Appl Biochem Biotechnol 2017 May 22;182(1):216-228. Epub 2016 Nov 22.

College of Food Science and Engineering, Ocean University of China, 5 Yushan Road, Qingdao, 266003, People's Republic of China.

A hyaluronate lyase was obtained by cultivating Arthrobacter globiformis strain A152. The enzyme was purified to homogeneity from the supernatant by ammonium sulfate fractionation, Q Sepharose Fast Flow, and Sephadex G-100 chromatography. The purification resulted in a 32.78-fold increase in hyaluronate lyase activity with specific activity of 297.2 U/mg. The molecular weight of the enzyme determined by SDS-PAGE was approximately 73.7 kDa. Using hyaluronic acid (HA) as a substrate, the maximal reaction rate (V) and the Michaelis-Menten constant (K) of hyaluronate lyase were found to be 4.76 μmol/min/ml and 0.11 mg/ml, respectively. The optimum pH and temperature values for hyaluronate lyase activity were pH 6.0 and 42 °C, respectively. This enzyme was stable at pH 4-10, 5-7, and 5-7 at 4, 37, and 42 °C, respectively. Investigation about temperature effects on hyaluronate lyase displayed that it was stable at 30-37 °C and also showed high activity at 37 °C. The enzymatic activity was enhanced by Ca and was strongly inhibited by Cu and SDS. These properties suggested that the hyaluronate lyase in this study could bring promising prospects in medical and industry applications.
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http://dx.doi.org/10.1007/s12010-016-2321-3DOI Listing
May 2017

Structural analysis of macromolecular levan produced by Bacillus megaterium GJT321 based on enzymatic method.

Int J Biol Macromol 2016 Dec 23;93(Pt A):1080-1089. Epub 2016 Sep 23.

College of Food Science and Engineering, Ocean University of China, 5 Yushan Road, Qingdao, 266003, PR China. Electronic address:

Extracellular polysaccharide (EPS) produced by Bacillus megaterium GJT321 was isolated from fermentation broth and further purified by gel filtration chromatography. The molecular weight of EPS was estimated as 1946kDa by gel permeation chromatography (GPC), so this EPS was determined as macromolecular polysaccharide. Fourier transform infrared spectrometry (FT-IR) showed that the kind of heterocyclic compound composing EPS was furanose. The structural characteristics of EPS were investigated by means of enzymatic method, electrospray ionization mass spectrometry (ESI-MS) and NMR spectra analysis. The structure elucidation of the EPS was accomplished, and it was β - (2, 6) -D- fructofuranose, namely levan.
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http://dx.doi.org/10.1016/j.ijbiomac.2016.09.086DOI Listing
December 2016

Purification and characterization of chondroitinase ABC from Acinetobacter sp. C26.

Int J Biol Macromol 2017 Feb 18;95:80-86. Epub 2016 Oct 18.

College of Food Science and Engineering, Ocean University of China, 5 Yushan Road, Qingdao 266003, PR China. Electronic address:

An extracellular chondroitinase ABC (ChSase ABC, EC 4.2.2.4) produced by cultivating Acinetobacter sp. C26, was purified to homogeneity from the supernatant by ammonium sulfate fractionation, Q-Sepharose Fast Flow and Sephadex G-100 chromatography. The 76kDa enzyme was purified 48.09-fold to homogeneity with specific activity of 348.64U/mg, Using the chondroitin sulfate A (CS-A) as substrate, the maximal reaction rate (Vmax) and Michaelis-Menten constant (Km) of ChSase ABC were found to be 10.471μmol/min/ml and 0.105mg/ml, respectively. The enzyme showed the highest activity at the optimal conditions of pH 6.0 and 42 ∘C, respectively. This enzyme was stable at pH 5-10, 5-9 and 5-7 at 4°C, 37°C and 42°C, respectively. Investigation about thermal stability of ChSase ABC displayed that it was stable at 37°C. ChSase ABC activity was increased in presence of Na, K, Mn, 1,10-phenanthrolin and strongly inhibited by Cu, Hg, Aland SDS. These properties suggested that ChSase ABC from Acinetobacter sp. C26 bring promising prospects in medical and industry applications.
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http://dx.doi.org/10.1016/j.ijbiomac.2016.10.044DOI Listing
February 2017

Free second toe one-stage-plasty and transfer for thumb or finger reconstruction.

Microsurgery 2008 ;28(1):25-31

Department of Hand and Microsurgery, He-Ping Hand Hospital, Shun De, Guangdong, PR China.

Free second toe transfer has become a popular method for the management of thumb or finger reconstruction. However, this creates an obvious appearance defect. A new operating procedure has been used since 1999. To enlarge the perimeter of the reconstructed thumb, a composite tissue strip flap from the fibular of great toe pedicled with the fibular proper plantar digital artery, combined or not with the island dorsal index finger flap, was inlaid with the second toe at the same time before the reconstruction. A crescent double-winged dorsal metatarsus flap, connected with second toe, in combination with the partial metatarsal bone, was also used to reconstruct fingers. There were 36 patients in the study group with a follow-up time of 6 months to 3 years. The thumb and finger reconstructed in this way showed better appearance, with normal caliber and length and without obvious adverse affects. This method has ameliorated the embarrassing appearance of the reconstructed thumb with earlier methods and is a relatively ideal method for thumb or finger reconstruction.
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http://dx.doi.org/10.1002/micr.20447DOI Listing
April 2008