Publications by authors named "Shenghua Zhu"

26 Publications

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Insufficient Radiofrequency Ablation Promotes Hepatocellular Carcinoma Metastasis through m A mRNA Methylation Dependent Mechanism.

Hepatology 2021 Feb 26. Epub 2021 Feb 26.

Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.

The dynamic N6-methyladenosine (m A) mRNA modification is essential for acute stress response and cancer progression. Sublethal heat stress from insufficient radiofrequency ablation (IRFA) has been confirmed to promote hepatocellular carcinoma (HCC) progression, however, whether m A machinery is involved in IRFA-induced HCC recurrence remains unknown. Using IRFA HCC orthotopic mouse model, we detected higher level of m A reader YTHDF1 in the sublethal-heat-exposed transitional zone close to the ablation center than that in the farther area. In addition, we validated the increased m A modification and elevated YTHDF1 protein level in sublethal-heat-treated HCC cell lines, HCC patient-derived xenograft (PDX) mouse model and patients' HCC tissues. Functionally, gain-/loss-of function assays showed that YTHDF1 promotes HCC cell viability and metastasis. Knockdown of YTHDF1 drastically restrains the tumor metastasis evoked by sublethal heat treatment in tail vein injection lung metastasis and orthotopic HCC mouse models. Mechanistically, we found that sublethal heat treatment increases EGFR m A modification in the vicinity of 5'UTR region and promotes its binding with YTHDF1, which enhances the translation of EGFR mRNA. The sublethal heat induced up-regulation of EGFR level was further confirmed in IRFA HCC PDX mouse model and patients' tissues. Combination of YTHDF1 silencing and EGFR inhibition suppressed the malignancies of HCC cells synergically. CONCLUSION: The m A-YTHDF1-EGFR axis promotes HCC progression after IRFA, supporting the rationale for targeting m A machinery in combined with EGFR inhibitors to suppress HCC metastasis after RFA.
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http://dx.doi.org/10.1002/hep.31766DOI Listing
February 2021

Prognostic factors for pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome: a multicenter study in China.

Ann Transl Med 2021 Jan;9(1):11

Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: In China, one of the major causes of hepatic sinusoidal obstruction syndrome (HSOS) is the intake of herbals containing pyrrolizidine alkaloid (PA). However, prognostic factors for PA-induced HSOS are poorly understood. The aim of this study was to identify the independent prognostic factors for PA-induced HSOS using a multi-center study.

Methods: A total of 117 PA-induced HSOS patients were enrolled for data collection in three university hospitals from November 2003 to September 2018. Univariate and multivariate Cox proportional hazards analysis were used to determine prognostic factors for PA-induced HSOS.

Results: The median age of the PA-induced HSOS patients was 61 years (range, 21-88 years), and 64% of them were male. The survival rates at 1, 3, and 36 months were 89.71%, 72.60%, and 69.19%, respectively. Significant differences in prothrombin time (PT), international normalized ratio, total bilirubin, severity grading [new criteria for severity grading of hematopoietic stem cell transplantation (HSCT)-related HSOS in adults] were found between patients who survived and those who died. Univariate and multivariate survival analysis using Cox's regression model demonstrated low serum albumin (<35 g/L), elevated serum urea (>8.2 mmol/L) and severe or very severe HSOS (European Society for Blood and Marrow Transplantation 2016 criteria) were independent prognostic factors of survival.

Conclusions: Serum albumin, serum urea, and severity grading were independent prognostic factors for patients with PA-induced HSOS, and can contribute to identifying potentially high-risk patients for early effective intervention.

Trial Registration: ChiCTR-DRD-17010709 (www.chictr.org.cn).
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http://dx.doi.org/10.21037/atm-20-731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859749PMC
January 2021

Myofibroblast induces hepatocyte-to-ductal metaplasia via laminin-ɑvβ6 integrin in liver fibrosis.

Cell Death Dis 2020 03 23;11(3):199. Epub 2020 Mar 23.

Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.

Hepatocytes undergo the metaplasia into ductal biliary epithelial cells (BECs) in response to chronic injury, and subsequently contribute to liver regeneration. The mechanism underlying hepatocyte-to-ductal metaplasia has not been explored until now. In mouse models of liver fibrosis, a florid BEC response was observed in fibrotic liver, and the depletion of myofibroblasts attenuated BEC expansion remarkably. Then, in hepatocyte fate-tracing mouse model, we demonstrated the conversion of mature hepatocytes into ductal BECs in fibrotic liver, and the depletion of myofibroblasts diminished the hepatocyte-to-ductal metaplasia. Finally, the mechanism underlying the metaplasia was investigated. Myofibroblasts secreted laminin-rich extracellular matrix, and then laminin induced hepatocyte-to-ductal metaplasia through ɑvβ6 integrin. Therefore, our results demonstrated myofibroblasts induce the conversion of mature hepatocytes into ductal BECs through laminin-ɑvβ6 integrin, which reveals that the strategy improve regeneration in fibrotic liver through the modification of specific microenvironment.
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http://dx.doi.org/10.1038/s41419-020-2372-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090046PMC
March 2020

Ascitic fluid total protein, a useful marker in non-portal hypertensive ascites.

J Gastroenterol Hepatol 2020 Feb 15;35(2):271-277. Epub 2019 Jul 15.

Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background And Aims: Diagnostic performance of ascitic fluid total protein (AFTP) concentration remained unsettled. Our aim was to determine diagnostic value of AFTP in differential diagnosis of causes of ascites.

Methods: Seven hundred four consecutive patients with new-onset ascites were prospectively enrolled in this study.

Results: In the training cohort, diagnostic performance of quantitative AFTP assay was superior to that of Rivalta test in differential diagnosis of ascites. At the predetermined cut-off value of 25 g/L, quantitative AFTP assay was more useful in the differentiation of non-portal hypertensive ascites from portal hypertensive ascites compared with the exudate-transudate classification, area under curve of receiver operating characteristic curve was 0.958. Quantitative AFTP assay was superior to serum-ascites albumin gradient in the detection of non-portal hypertensive ascites, especially malignant ascites and tuberculous peritonitis. In mixed ascites, AFTP was useful in identifying peritoneal lesions.

Conclusions: Ascitic fluid total protein is a useful marker in non-portal hypertensive ascites; thus, it should be determined in diagnostic work-up of the patients with ascites.
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http://dx.doi.org/10.1111/jgh.14768DOI Listing
February 2020

Editorial: ascitic cholesterol - is it superior to serum-ascites albumin gradient? Authors' reply.

Aliment Pharmacol Ther 2019 03;49(6):815-816

Division of Gastroenterology, Union Hospital, Tongji Medical College Huazhong, University of Science and Technology, Wuhan, China.

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http://dx.doi.org/10.1111/apt.15105DOI Listing
March 2019

Ascitic cholesterol is superior to serum-ascites albumin gradient in the detection of non-portal hypertensive ascites and the diagnosis of mixed ascites.

Aliment Pharmacol Ther 2019 01 15;49(1):91-98. Epub 2018 Nov 15.

Division of Gastroenterology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, China.

Background: The diagnostic value of ascitic cholesterol in the differential diagnosis of ascites is controversial.

Aim: To investigate the diagnostic performance of ascitic cholesterol in the differential diagnosis of ascites.

Methods: Consecutive patients with new-onset ascites were enrolled prospectively. The pertinent data were collected from 629 patients with all forms of ascites.

Results: In the training cohort, determination of the ascitic cholesterol level was a highly effective method of distinguishing non-portal hypertension (NPH) from portal hypertension (PH). At the pre-determined cut-off value of 45 mg/dL, the sensitivity of ascitic cholesterol was superior to the serum-ascites albumin gradient (SAAG) in identifying NPH-related ascites; the area under the receiver operating characteristic curve was 0.945. In the patients misdiagnosed based on SAAG classification, the diagnostic accuracy of ascitic cholesterol was 69%. The ascitic cholesterol level showed excellent performance in identifying peritoneal lesions in patients with mixed ascites.

Conclusion: Ascitic cholesterol is an excellent measure for detecting NPH ascites and for identifying peritoneal lesions in mixed ascites. Thus, this simple and cost-effective measure should be determined in patients with new-onset ascites (www.chictr.org.cn; ChiCTR-DCD-15006907).
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http://dx.doi.org/10.1111/apt.15042DOI Listing
January 2019

T, diffusion tensor, and quantitative magnetization transfer imaging of the hippocampus in an Alzheimer's disease mouse model.

Magn Reson Imaging 2018 07 12;50:26-37. Epub 2018 Mar 12.

Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB R3E 0T6, Canada; Radiology, University of Manitoba, Winnipeg, MB R3E 0T6, Canada; Physics, University of Winnipeg, R3B 2N2, Canada.

Alzheimer's disease (AD) pathology causes microstructural changes in the brain. These changes, if quantified with magnetic resonance imaging (MRI), could be studied for use as an early biomarker for AD. The aim of our study was to determine if T relaxation, diffusion tensor imaging (DTI), and quantitative magnetization transfer imaging (qMTI) metrics could reveal changes within the hippocampus and surrounding white matter structures in ex vivo transgenic mouse brains overexpressing human amyloid precursor protein with the Swedish mutation. Delineation of hippocampal cell layers using DTI color maps allows more detailed analysis of T-weighted imaging, DTI, and qMTI metrics, compared with segmentation of gross anatomy based on relaxation images, and with analysis of DTI or qMTI metrics alone. These alterations are observed in the absence of robust intracellular Aβ accumulation or plaque deposition as revealed by histology. This work demonstrates that multiparametric quantitative MRI methods are useful for characterizing changes within the hippocampal substructures and surrounding white matter tracts of mouse models of AD.
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http://dx.doi.org/10.1016/j.mri.2018.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461204PMC
July 2018

The role of neuroinflammation and amyloid in cognitive impairment in an APP/PS1 transgenic mouse model of Alzheimer's disease.

CNS Neurosci Ther 2017 Apr 12;23(4):310-320. Epub 2017 Feb 12.

Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.

Aims: Both amyloid deposition and neuroinflammation appear in the early course of Alzheimer's disease (AD). However, the progression of neuroinflammation and its relationship with amyloid deposition and behavioral changes have not been fully elucidated. A better understanding the role of neuroinflammation in AD might extend our current knowledge to therapeutic intervention possibilities.

Methods: This study systematically characterized changes in behavioral abnormalities in APP/PS1 transgenic mice. Brain pathology measures were performed in post-mortem brain tissues of mice from 2 to 22 months.

Results: APP/PS1 mice exhibited significant memory deficits from 5 months old, which were aggravated at the later stage of life. However, the degree of memory impairments reached a plateau at 12 months. An early appearance of amyloid plaques was at 3 months with a linear increase throughout the disease course. CD11b-positive microglia and glial fibrillary acidic protein-(GFAP) positive astrocytes were first detected at 3 months with a close association with amyloid plaques. Yet, the rate of changes in glial activation slowed down from 12 months despite the steady increase in Aβ.

Conclusion: These findings provided evidence that neuroinflammation might be involved in the development and progression of cognitive deficits in APP/PS1 mice, suggesting novel intervention and prevention strategies for AD.
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http://dx.doi.org/10.1111/cns.12677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492725PMC
April 2017

Nitrosylation of Vesicular Transporters in Brain of Amyloid Precursor Protein/Presenilin 1 Double Transgenic Mice.

J Alzheimers Dis 2017 ;55(4):1683-1692

Kleysen Institute for Advanced Medicine, Health Sciences Centre, Winnipeg, Canada.

Nitric oxide can attack thiol groups of cysteine residues in proteins and induce protein cysteine S-nitrosylation. Cholinergic and glutamatergic systems are dysregulated in Alzheimer's disease. Vesicular acetylcholine transporter (VAChT) and vesicular glutamate transporter 1 (VGLUT1) are important in packaging acetylcholine and glutamate into vesicles, which is an important step for neurotransmission. Previously we found that VAChT and VGLUT1 can be nitrosylated and that S-nitrosylation of these transporters inhibits vesicular uptake of acetylcholine and glutamate. To understand the role of VAChT and VGLUT1 nitrosylation in the pathophysiological development of Alzheimer's disease, we analyzed nitrosylation of VAChT and VGLUT1 in brain of amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice, an animal model for Alzheimer's disease. Using a Morris water maze test, we found that 9- and 12-month-old APP/PS1 mice showed memory deficit, compared to wild type mice. We further found that total protein nitrosylation was increased in frontal cortex and hippocampus of 9- and 12-month-old APP/PS1 mice. Although nitrosylation of VAChT and VGLUT1 was not changed in hippocampus of 9- and 12-month-old APP/PS1 mice, nitrosylation of VAChT and VGLUT1 was significantly increased in frontal cortex of APP/PS1 mice at these ages. We also found that nitrosylation of VAChT and VGLUT1 was increased in hippocampus (but not frontal cortex) of 3-month-old APP/PS1 mice. These findings suggest that nitrosylation of VAChT and VGLUT1 may be associated with dysfunctional acetylcholinergic and glutamatergic neurotransmission in Alzheimer's disease.
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http://dx.doi.org/10.3233/JAD-160700DOI Listing
February 2018

Regulation of astrocyte pathology by fluoxetine prevents the deterioration of Alzheimer phenotypes in an APP/PS1 mouse model.

Glia 2016 Feb 8;64(2):240-54. Epub 2015 Oct 8.

Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada.

Studies have implicated astrocytic dysfunction in Alzheimer's disease (AD). However, the role of astrocytes in the pathophysiology and treatment of the disease is poorly characterized. Here, we identified astrocytes as independent key factors involved in several Alzheimer-like phenotypes in an APP/PS1 mouse model, including amyloid pathology, altered neuronal and synaptic properties, and impaired cognition. In vitro astrocytes from APP/PS1 mice induced synaptotoxicity as well as reduced dendritic complexity and axonal branching of hippocampal neurons. These astrocytes produced high levels of soluble β-amyloid (Aβ) which could be significantly inhibited by fluoxetine (FLX) via activating serotonin 5-HT2 receptors. FLX could also protect hippocampal neurons against astrocyte-induced neuronal damage in vitro. In the same APP/PS1 mice, FLX inhibited activation of astrocytes, lowered Aβ products, ameliorated neurotoxicity, and improved behavioral performance. These findings may provide a basis for the clinical application of FLX in patients, and may also lay the groundwork for exploration of other novel astrocyte-based therapies of AD.
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http://dx.doi.org/10.1002/glia.22926DOI Listing
February 2016

Quetiapine attenuates glial activation and proinflammatory cytokines in APP/PS1 transgenic mice via inhibition of nuclear factor-κB pathway.

Int J Neuropsychopharmacol 2014 Oct 31;18(3). Epub 2014 Oct 31.

Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Drs Zhu and J-F. Wang); Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (Drs Shi and Kong); Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (Dr Li); Department of Psychiatry, Xijing Hospital, The Fourth Military Medical University, Xi'an, China (Dr Zhang); Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (Drs J. Wang, Tempier, and X-M. Li); First Affiliated Hospital, Henan University, Kaifeng, Henan, China (Dr He).

Background: In Alzheimer's disease, growing evidence has shown that uncontrolled glial activation and neuroinflammation may contribute independently to neurodegeneration. Antiinflammatory strategies might provide benefits for this devastating disease. The aims of the present study are to address the issue of whether glial activation and proinflammatory cytokine increases could be modulated by quetiapine in vivo and in vitro and to explore the underlying mechanism.

Methods: Four-month-old amyloid precursor protein (APP) and presenilin 1 (PS1) transgenic and nontransgenic mice were treated with quetiapine (5mg/kg/d) in drinking water for 8 months. Animal behaviors, total Aβ levels, and glial activation were evaluated by behavioral tests, enzyme-linked immunosorbent assay, immunohistochemistry, and Western blot accordingly. Inflammatory cytokines and the nuclear factor kappa B pathway were analyzed in vivo and in vitro.

Results: Quetiapine improves behavioral performance, marginally affects total Aβ40 and Aβ42 levels, attenuates glial activation, and reduces proinflammatory cytokines in APP/PS1 mice. Quetiapine suppresses Aβ1-42-induced activation of primary microglia by decresing proinflammatory cytokines. Quetiapine inhibits the activation of nuclear factor kappa B p65 pathway in both transgenic mice and primary microglia stimulated by Aβ1-42.

Conclusions: The antiinflammatory effects of quetiapine in Alzheimer's disease may be involved in the nuclear factor kappa B pathway. Quetiapine may be an efficacious and promising treatment for Alzheimer's disease targeting on neuroinflammation.
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http://dx.doi.org/10.1093/ijnp/pyu022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360237PMC
October 2014

Chronic phencyclidine induces inflammatory responses and activates GSK3β in mice.

Neurochem Res 2014 Dec 1;39(12):2385-93. Epub 2014 Oct 1.

Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, MB, R3E 0T6, Canada.

Use of phencyclidine (PCP) in rodents can mimic some aspects of schizophrenia. However, the underlying mechanism is still unclear. Growing evidence indicates that neuroinflammation plays a significant role in the pathophysiology of schizophrenia. In this study, we focused on inflammatory responses as target of PCP for inducing schizophrenia-like symptoms. 3-month-old C57BL/6J mice received daily injections of PCP (20 mg/kg, i.p.) or saline for one week. PCP-injected mice produced schizophrenia-like behaviours including impaired spatial short-term memory assessed by the Y-maze task and sensorimotor gating deficits in a prepulse inhibition task. Simultaneously, chronic PCP administration induced astrocyte and microglial activation in both the cortex and hippocampus. Additionally, the proinflammatory cytokine interleukin-1β was significantly up-regulated in PCP administrated mice. Furthermore, PCP treatment decreased ratio of the phospho-Ser9 epitope of glycogen synthase kinase-3β (GSK3β) over total GSK3β, which is indicative of increased GSK3β activity. These data demonstrate that chronic PCP in mouse produces inflammatory responses and GSK3β activation.
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http://dx.doi.org/10.1007/s11064-014-1441-9DOI Listing
December 2014

Fluoxetine improves behavioral performance by suppressing the production of soluble β-amyloid in APP/PS1 mice.

Curr Alzheimer Res 2014 ;11(7):672-80

Mental Health Center Shantou University, North Taishan Road, Shantou, Guangdong 515063, China.

Alzheimer's disease (AD) is the most common neurodegenerative disorder of the central nervous system. Current approaches for AD treatment only ameliorate symptoms. Therapeutic strategies that target the pathological processes of the disease remain elusive. Fluoxetine (FLX) is one of the most widely used antidepressants for the treatment of depression and anxiety associated with AD, however, it is unknown if the drug affects the pathogenesis of the disease. We showed that FLX improved spatial memory, learning and emotional behaviors of APP/PS1 mice, a well characterized model of AD. In the same mice, FLX effectively prevented the protein loss of synaptophysin (SYP) and microtubuleassociated protein 2 (MAP2). FLX was unable to prevent plaque formation, but significantly lowered high levels of soluble β-amyloid (Aβ) in brain tissue, cerebrospinal fluid (CSF) and blood sera. FLX also effectively inhibited the phosphorylation of amyloid precursor protein (APP) at T668, which may be a possible mechanism of the reduced Aβ production in APP/PS1 mouse after treatment.
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http://dx.doi.org/10.2174/1567205011666140812114715DOI Listing
May 2015

Unpredictable chronic mild stress not chronic restraint stress induces depressive behaviours in mice.

Neuroreport 2014 Oct;25(14):1151-5

Departments of aPharmacology and Therapeutics bHuman Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba cDepartment of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada dMental Health Center, Shantou University, Shantou, Guangdong, China.

The chronic stress model was developed on the basis of the stress-diathesis hypothesis of depression. However, these behavioural responses associated with different stress paradigms are quite complex. This study examined the effects of two chronic stress regimens on anxiety-like and depressive behaviours. C57BL/6 mice were subjected to unpredictable chronic mild stress or to chronic restraint stress for 4 weeks. Subsequently, both anxiety-like behaviours (open field, elevated plus maze and novelty suppressed feeding) and depression-like behaviours (tail suspension, forced swim and sucrose preference) were evaluated. Both chronic stress models generated anxiety-like behaviours, whereas only unpredictable chronic mild stress could induce depressive behaviours such as increased immobility and decreased sucrose consumption. These results of the present study provide additional evidence on how chronic stress affects behavioural responses and point to the importance of the validity of animal models of chronic stress in studying depression.
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http://dx.doi.org/10.1097/WNR.0000000000000243DOI Listing
October 2014

Unpredictable chronic mild stress induces anxiety and depression-like behaviors and inactivates AMP-activated protein kinase in mice.

Brain Res 2014 Aug 24;1576:81-90. Epub 2014 Jun 24.

Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

The unpredictable chronic mild stress (UCMS) model was developed based upon the stress-diathesis hypothesis of depression. Most effects of UCMS can be reversed by antidepressants, demonstrating a strong predictive validity of this model for depression. However, the mechanisms underlying the effects induced by UCMS remain incompletely understood. Increasing evidence has shown that AMP-activated protein kinase (AMPK) regulates intracellular energy metabolism and is especially important for neurons because neurons are known to have small energy reserves. Abnormalities in the AMPK pathway disturb normal brain functions and synaptic integrity. In the present study, we first investigated the effects of UCMS on a battery of different tests measuring anxiety and depression-like behaviors in female C57BL/6N mice after 4 weeks of UCMS exposure. Stressed mice showed suppressed body weight gain, heightened anxiety, and increased immobility in the forced swim and tail suspension tests. These results are representative of some of the core symptoms of depression. Simultaneously, we observed decrease of synaptic proteins in the cortex of mice subjected to UCMS, which is associated with decreased levels of phosphorylated AMP-activated protein kinase α (AMPKα) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase). Our findings suggest that AMPKα inactivation might be a mechanism by which UCMS causes anxiety/depression-like behaviors in mice.
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http://dx.doi.org/10.1016/j.brainres.2014.06.002DOI Listing
August 2014

Desvenlafaxine prevents white matter injury and improves the decreased phosphorylation of the rate-limiting enzyme of cholesterol synthesis in a chronic mouse model of depression.

J Neurochem 2014 Oct 8;131(2):229-38. Epub 2014 Jul 8.

Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.

Serotonin/norepinephrine reuptake inhibitors antidepressants exert their effects by increasing serotonin and norepinephrine in the synaptic cleft. Studies show it takes 2-3 weeks for the mood-enhancing effects, which indicate other mechanisms may underlie their treatment effects. Here, we investigated the role of white matter in treatment and pathogenesis of depression using an unpredictable chronic mild stress (UCMS) mouse model. Desvenlafaxine (DVS) was orally administrated to UCMS mice at the dose of 10 mg/kg/day 1 week before they went through a 7-week stress procedure and lasted for over 8 weeks before the mice were killed. No significant changes were found for protein markers of neurons and astrocytes in UCMS mice. However, myelin and oligodendrocyte-related proteins were significantly reduced in UCMS mice. DVS prevented the stress-induced injury to white matter and the decrease of phosphorylated 5'-AMP-activated protein kinase and 3-hydroxy-3-methyl-glutaryl-CoA reductase protein expression. DVS increased open arm entries in an elevated plus-maze test, sucrose consumption in the sucrose preference test and decreased immobility in tail suspension and forced swimming tests. These findings suggest that stress induces depression-like behaviors and white matter deficits in UCMS mice. DVS may ameliorate the oligodendrocyte dysfunction by affecting cholesterol synthesis, alleviating the depression-like phenotypes in these mice. We examined the possible role of oligodendrocyte and myelin in the pathological changes of depression with an unpredictable chronic mild stress (UCMS) mouse model. Oligodendrocyte-related proteins in the mouse brain were specifically changed during the stress period. The depressive-like behaviors and oligodendrocyte deficits could be prevented by the administration of desvenlafaxine. Oligodendrocyte and myelin may be an essential target of desvenlafaxine for the treatment of depression.
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http://dx.doi.org/10.1111/jnc.12792DOI Listing
October 2014

Astrocyte-dependent protective effect of quetiapine on GABAergic neuron is associated with the prevention of anxiety-like behaviors in aging mice after long-term treatment.

J Neurochem 2014 Sep 18;130(6):780-9. Epub 2014 Jun 18.

Mental Health Center, Shantou University, Shantou, Guangdong, China; Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.

Previous studies have demonstrated that quetiapine (QTP) may have neuroprotective properties; however, the underlying mechanisms have not been fully elucidated. In this study, we identified a novel mechanism by which QTP increased the synthesis of ATP in astrocytes and protected GABAergic neurons from aging-induced death. In 12-month-old mice, QTP significantly improved cell number of GABAegic neurons in the cortex and ameliorated anxiety-like behaviors compared to control group. Complimentary in vitro studies showed that QTP had no direct effect on the survival of aging GABAergic neurons in culture. Astrocyte-conditioned medium (ACM) pretreated with QTP (ACMQTP) for 24 h effectively protected GABAergic neurons against aging-induced spontaneous cell death. It was also found that QTP boosted the synthesis of ATP from cultured astrocytes after 24 h of treatment, which might be responsible for the protective effects on neurons. Consistent with the above findings, a Rhodamine 123 test showed that ACMQTP, not QTP itself, was able to prevent the decrease in mitochondrial membrane potential in the aging neurons. For the first time, our study has provided evidence that astrocytes may be the conduit through which QTP is able to exert its neuroprotective effects on GABAergic neurons. The neuroprotective properties of quetiapine (QTP) have not been fully understood. Here, we identify a novel mechanism by which QTP increases the synthesis of ATP in astrocytes and protects GABAergic neurons from aging-induced death in a primary cell culture model. In 12-month-old mice, QTP significantly improves cell number of GABAegic neurons and ameliorates anxiety-like behaviors. Our study indicates that astrocytes may be the conduit through which QTP exerts its neuroprotective effects on GABAergic neurons.
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http://dx.doi.org/10.1111/jnc.12771DOI Listing
September 2014

Serum β-amyloid peptide levels spike in the early stage of Alzheimer-like plaque pathology in an APP/PS1 double transgenic mouse model.

Curr Alzheimer Res 2013 Nov;10(9):979-86

First Affiliated Hospital, Henan University, 357 Ximen Street, Kaifeng, Henan 475001, PR China.

Serum levels of β-amyloid (Aβ) peptides may represent an early biomarker in the diagnosis of Alzheimer's disease (AD). In the present study, we investigated the temporal kinetic changes in the levels of serum Aβ 1-42 and 40 in an amyloid precursor protein (APP)/presenilin (PS)1 double transgenic mouse model of AD. Serum Aβ peptide levels in 2-, 3-, 6-, 9- and 18-month old, and liver Aβ 1-40 level in 6-month old mice were measured using enzyme-linked immunosorbent assay (ELISA) kits. Results revealed that serum Aβ levels peaked in 3-month old transgenic mice, and the Aβ level in non-transgenic and transgenic mice is comparable in liver. Compared to the 6-month old transgenic mice, Congo red staining showed that the 3-month old transgenic mice had minimum brain Aβ plaques, corresponding to the early stage of Alzheimer-like plaque pathology, and confocal microscope images showed that the deposition of Aβ in their cerebral vessels was minimal. Furthermore, results of the water maze test, showed that memory was normal for the 3- month old transgenic mice when compared to age-matched non-transgenic mice. These results suggest that serum Aβ peptide levels may be peaked during the early stage of AD. Monitoring serum Aβ peptide levels in the potential AD population may provide an early diagnosis of AD prior to the appearance of clinical symptoms.
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http://dx.doi.org/10.2174/15672050113106660159DOI Listing
November 2013

Quetiapine modulates conditioned anxiety and alternation behavior in Alzheimer's transgenic mice.

Curr Alzheimer Res 2013 Feb;10(2):199-206

Department of Psychiatry, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.

Quetiapine, an atypical antipsychotic drug, is effective in treating the behavioral and psychological symptoms in Alzheimer's disease (AD). However, it is presently unclear whether quetiapine has beneficial effects on memory and whether the effects of quetiapine on psychological symptoms are associated with its effect on memory in AD. The present study was designed to examine the effect of chronic administration of quetiapine on the conditioned (generalized) anxiety that is related to learning experience of open arm exposure in the elevated T-maze (ETM) test in an amyloid precursor protein (APP)/presenilin 1 (PS1) double transgenic mouse model of AD. In a 2nd experiment, the effect of quetiapine on memory per se was investigated in a Y-maze test in AD mice. Non-transgenic and transgenic mice were treated with quetiapine in drinking water from the age of 2 months. After continuous treatment with quetiapine (5 mg/kg/day) for 10 months, mice were tested for conditioned anxiety on the ETM task. After ETM testing, the expression of brain-derived neurotrophic factor (BDNF), a neuroprotective protein, was examined by immunohistochemistry in the basolateral amygdala (BLA) and hippocampus. In the 2nd experiment, the effect of quetiapine (2.5 or 5 mg/kg/day) on the short-term memory in AD mice was tested in a Y-maze test. After 10 months of administration, quetiapine prevented the decrease of conditioned anxiety and cerebral BDNF in AD mice. In addition, quetiapine also prevented memory impairment in the Y-maze test in AD mice. These findings suggest that the therapeutic mechanism of quetiapine on anxiety in AD may be associated with its beneficial effect on memory and its neuroprotective effect on cerebral BDNF expression.
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http://dx.doi.org/10.2174/1567205011310020010DOI Listing
February 2013

Therapeutic effects of quetiapine on memory deficit and brain β-amyloid plaque pathology in a transgenic mouse model of Alzheimer's disease.

Curr Alzheimer Res 2013 Mar;10(3):270-8

Department of Psychiatry, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.

Our previous study has shown the preventive effects of quetiapine, an atypical antipsychotic drug, on memory impairment and brain pathological changes in a mouse model of Alzheimer's disease (AD). The aim of the present study was to evaluate the therapeutic effects of quetiapine on memory deficit and neuropathology in an amyloid precursor protein (APP)/presenilin-1 (PS1) double transgenic mouse model of AD. The APP/PS1 mice started to have detectable brain β-amyloid (Aβ) at 3 months of age. Non-transgenic and transgenic mice were treated with quetiapine (0, 2.5, or 5 mg/(kg day)) in drinking water from the age of 4 months. After 8 months of continuous quetiapine administration, memory deficit was reversed and brain Aβ plaque pathology was attenuated in the AD mice. Quetiapine also decreased the soluble Aβ peptide levels in brain and cerebrospinal fluid (CSF), and attenuated the decreased synaptic protein levels in the AD mice. Furthermore, quetiapine normalized the abnormal activity of glycogen synthase kinase-3β (GSK-3β), an AD-involved kinase, in the AD mice. These results suggest that quetiapine can treat and alleviate the neuropathology in an APP/PS1 transgenic mouse model of AD, and indicate that quetiapine may have therapeutic effects in the treatment of AD.
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http://dx.doi.org/10.2174/1567205011310030006DOI Listing
March 2013

Myelination deficit in a phencyclidine-induced neurodevelopmental model of schizophrenia.

Brain Res 2012 Aug 29;1469:136-43. Epub 2012 Jun 29.

Department of Psychiatry, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, PR China.

Increasing evidence supports an important role of oligodendrocytes and myelination in the pathogenesis of schizophrenia. Oligodendrocytes are the myelin-producing cells in the central nervous system. To test the myelination dysfunction hypothesis of schizophrenia, possible myelination dysfunction was evaluated in a phencyclidine (PCP)-induced neurodevelopmental model of schizophrenia. On postnatal day (PND) 2, rat pups were treated with a total 14 subcutaneous daily injections of PCP (10mg/kg) or saline. PCP-injected rats showed schizophrenia-like behaviors including hyper-locomotor activity on PND 30 and prepulse inhibition deficit on PND 31. Cerebral myelination was measured by the expression of myelin basic protein (MBP), and cerebral mature oligodendrocytes were measured by the expression of glutathione S-transferase (GST)-π in rats. The results indicate that the expressions of MBP on PND 16, 22 and 32 and GST-π on PND 22 decreased in the frontal cortex of PCP-injected rats. Our results suggest that there was myelination impairment in the phencyclidine-induced schizophrenia animal model, and indicate that myelination may play an important role in the pathogenesis of schizophrenia.
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http://dx.doi.org/10.1016/j.brainres.2012.06.003DOI Listing
August 2012

Sensorimotor gating and memory deficits in an APP/PS1 double transgenic mouse model of Alzheimer's disease.

Behav Brain Res 2012 Jul 15;233(1):237-43. Epub 2012 May 15.

Department of Clinical Psychiatry, Beijing Anding Hospital, Capital Medical University, Beijing 100088, PR China.

Alzheimer's disease (AD) is a neurodegenerative disorder associated with cognitive deterioration and neuropsychiatric symptoms. Sensorimotor gating deficit has been identified in neuropsychiatric diseases. The aim of the present study was to evaluate the possible sensorimotor gating deficit and its correlation to memory impairment and cerebral β-amyloid (Aβ) plaque deposits in an amyloid precursor protein (APP)/presenilin-1 (PS1) double transgenic mouse model of AD. The sensorimotor gating in 3-, 7- and-22-month-old non-transgenic and transgenic mice was evaluated in a prepulse inhibition (PPI) task. Results revealed that the PPI was lower in the 7- and 22-month-old transgenic mice compared with the age-matched control, while the response to startle pulse-alone in the transgenic and non-transgenic mice was comparable. Congo red staining showed that Aβ neuropathology of transgenic mice aggravated with age, and the 3-month-old transgenic mice started to have minimum brain Aβ plaques, corresponding to the early stage of AD phenotype. Furthermore, memory impairment in the 7-month-old transgenic mice was detected in a water maze test. These results suggest that the sensorimotor gating is impaired with the progressing of AD phenotype, and its deficit may be correlated to cerebral Aβ neuropathology and memory impairment in the APP/PS1 transgenic mouse model of AD.
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http://dx.doi.org/10.1016/j.bbr.2012.05.007DOI Listing
July 2012

Quetiapine enhances oligodendrocyte regeneration and myelin repair after cuprizone-induced demyelination.

Schizophr Res 2012 Jun 1;138(1):8-17. Epub 2012 May 1.

Department of Psychiatry, University of Saskatchewan, Saskatoon, SK, Canada.

Myelin and oligodendrocyte dysfunctions have been consistently found in patients with schizophrenia. The effect of antipsychotics on myelin disturbances is unknown. The present study examined the effects of quetiapine on oligodendrocyte regeneration and myelin repair in a demyelination animal model. C57BL/6 mice were fed with cuprizone (0.2% w/w) for 12 weeks to induce chronic demyelination and oligodendrocyte degeneration, after which cuprizone was withdrawn to allow recovery. Quetiapine (10mg/kg/day) or vehicle (water) was administrated orally to mice for 0, 2, 3, or 4 weeks after cuprizone withdrawal. Locomotor activity and Y-maze tests were used to evaluate behavioral changes in the mice. Immunohistochemical staining was used to detect morphological and biological changes in the brains. Cuprizone administration for 12 weeks resulted in severe demyelination, locomotor hyperactivity, and working memory impairment in mice. Remyelination occurred when cuprizone was withdrawn. Quetiapine treatment during the recovery period significantly improved the spatial working memory and increased myelin restoration. Quetiapine treatment also enhanced the repopulation of mature oligodendrocytes in the demyelinated lesions, which was associated with down-regulation of transcription factor olig2 in the process of cell maturation. The results of this study demonstrated that quetiapine treatment during the recovery period improves spatial working memory and promotes oligodendrocyte development and remyelination. This study supports the role of oligodendrocyte dysfunction in memory deficits in a schizophrenia mouse model and suggests that quetiapine may target oligodendrocytes and improve cognitive function.
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http://dx.doi.org/10.1016/j.schres.2012.04.006DOI Listing
June 2012

Rhynchophylline attenuates LPS-induced pro-inflammatory responses through down-regulation of MAPK/NF-κB signaling pathways in primary microglia.

Phytother Res 2012 Oct 10;26(10):1528-33. Epub 2012 Feb 10.

Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, PR China.

Excessive activation of microglial cells has been implicated in various types of neuroinflammation. Suppression of microglial activation would have therapeutic benefits, leading to the alleviation of the progression of neurodegeneration. In this study, the inhibitory effects of rhynchophylline (RIN), a tetracyclic oxindole alkaloid component isolated from Uncaria rhynchophylla (Miq.) Jacks., on the production of pro-inflammatory mediators were investigated in lipopolysaccharide (LPS)-stimulated microglia. The results showed that RIN markedly reduced the production of nitric oxide (NO), prostaglandins E(2) (PGE(2) ), monocyte chemoattractant protein (MCP-1), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in LPS-activated microglia. The mRNA expression levels of iNOS and COX-2 were also depressed by RIN in a concentration-dependent manner. Further studies revealed that RIN blocked IκBα phosphorylation and degradation, inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs). In summary, these data suggest that RIN suppresses inflammatory responses of microglia and may act as a potential therapeutic agent for various neurodegenerative diseases involving neuroinflammation.
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http://dx.doi.org/10.1002/ptr.4614DOI Listing
October 2012

Increased hippocampal neurogenesis in the progressive stage of Alzheimer's disease phenotype in an APP/PS1 double transgenic mouse model.

Hippocampus 2009 Dec;19(12):1247-53

Department of Neurology, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, People's Republic of China.

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with senile beta-amyloid (Abeta) plaques and cognitive decline. Neurogenesis in the adult hippocampus is implicated in regulating learning and memory, and is increased in human postmortem brain of AD patients. However, little is currently known about the changes of hippocampal neurogenesis in the progression of AD. As brain tissues from patients during the progression of AD are generally not available, an amyloid precursor protein (APP)/presenilin1 (PS1) double transgenic mouse model of AD was studied. Bromodeoxyuridine (BrdU) labeling supported by doublecortin staining was used to detect proliferating hippocampal cells in the mice. Compared with age-matched wild-type controls, 9-month-old transgenic mice with memory impairment and numerous brain Abeta deposits showed increased numbers of proliferating hippocampal cells. However, 3-month-old transgenic mice with normal memory and subtle brain Abeta deposits showed normal hippocampal proliferation. Double immunofluorescent labeling with BrdU and either NeuN or glial fibrillary acidic protein was conducted in mice at 10 months (28 days after the last BrdU injection) to determine the differentiation of proliferating cells. The number of hippocampal BrdU-positive cells and BrdU-positive cells differentiating into neurons (neurogenesis) in 10-month-old mice was greater in transgenic mice compared with age-matched controls, but the ratio of hippocampal BrdU-positive cells differentiating into neurons and astroglia was comparable. These results suggest hippocampal neurogenesis may increase during the progression of AD. Targeting this change in neurogenesis and understanding the underlying mechanism could lead to the development of a new treatment to control the progression of AD.
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http://dx.doi.org/10.1002/hipo.20587DOI Listing
December 2009

[Study on the association among total immunoglobulin E and eosinophil in nasal polyp].

Lin Chuang Er Bi Yan Hou Ke Za Zhi 2005 Jul;19(13):602-4

Department of Otolaryngology, Shaoyang Central Hospital, Shaoyang, 422000, China.

Objective: To explore the expression of total immunoglobulin E(IgE) and eosinophil in nasal polyp and their roles in the pathogenesis of nasal polyp.

Method: Thirty eight patients with nasal polyp and 15 control cases were chosen. All samples were stained with Chromotrope 2R histochemical and SP immunohistochemical method separately to examine eosinophil and total IgE+ cells in nasal polyp.

Result: (1) The level of total IgE and eosinophil in nasal polyp was all significantly higher than that in normal control specimens (P < 0.01). (2) The positive correlation of total IgE and eosinophil was significant (r = 0.843, P < 0.01).

Conclusion: Nasal polyp is a disease characterized by eosinophils infiltration. Type I allergic reaction mediated by IgE assemble and activate eosinophils which may play an important role in the infiltration pathogenesis of nasal polyp.
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July 2005