Publications by authors named "Wenli Fang"

25 Publications

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Study protocol for the Sino-Canadian Healthy Life Trajectories Initiative (SCHeLTI): a multicentre, cluster-randomised, parallel-group, superiority trial of a multifaceted community-family-mother-child intervention to prevent childhood overweight and obesity.

BMJ Open 2021 04 1;11(4):e045192. Epub 2021 Apr 1.

Centre de recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada.

Introduction: Childhood overweight and obesity (OWO) is a primary global health challenge. Childhood OWO prevention is now a public health priority in China. The Sino-Canadian Healthy Life Trajectories Initiative (SCHeLTI), one of four trials being undertaken by the international HeLTI consortium, aims to evaluate the effectiveness of a multifaceted, community-family-mother-child intervention on childhood OWO and non-communicable diseases risk.

Methods And Analysis: This is a multicentre, cluster-randomised, controlled trial conducted in Shanghai, China. The unit of randomisation is the service area of Maternal Child Health Units (N=36). We will recruit 4500 women/partners/families in maternity and district level hospitals. Participants in the intervention group will receive a multifaceted, integrated package of health promotion interventions beginning in preconception or in the first trimester of pregnancy, continuing into infancy and early childhood. The intervention, which is centred on a modified motivational interviewing approach, will target early-life maternal and child risk factors for adiposity. Through the development of a biological specimen bank, we will study potential mechanisms underlying the effects of the intervention. The primary outcome for the trial is childhood OWO (body mass index for age ≥85th percentile) at 5 years of age, based on WHO sex-specific standards. The study has a power of 0.8 (α=0.05) to detect a 30% risk reduction in the proportion of children with OWO at 5 years of age, from 24.4% in the control group to 17% in the intervention group. Recruitment was launched on 30 August 2018 for the pilot study and 10 January 2019 for the formal study.

Ethics And Dissemination: The study has been approved by the Medical Research Ethics Committee of the International Peace Maternity and Child Health Hospital in Shanghai, China, and the Research Ethics Board of the Centre Intégré Universitaire de Santé et Services Sociaux de l'Estrie-CHUS in Sherbrooke, Canada. Data sharing policies are consistent with the governance policy of the HeLTI consortium and government legislation.

Trial Registration Number: ChiCTR1800017773.

Protocol Version: November 11, 2020 (Version #5).
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http://dx.doi.org/10.1136/bmjopen-2020-045192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021741PMC
April 2021

[Progranulin (PGRN) promotes invasion and migration of mouse breast cancer 4T1 cells by promoting epithelial-mesenchymal transition of cancer cells and activating ERK1/2 pathway].

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2021 Feb;37(2):125-131

Ministry-of-Education Key Laboratory of Laboratory Medical Diagnostics, Chongqing Medical University, Chongqing 400016, China. *Corresponding author, E-mail:

Objective To investigate the effect of progranulin (PGRN) on the invasion and migration of mouse breast cancer 4T1 cells and its mechanism. Methods After treated with PGRN (1 μg/mL) for 24 hours, the invasion ability of breast cancer 4T1 cells was detected by Transwell invasion assay, the migration ability was detected by scratch test, and the epithelial cadherin (E-cadherin), vimentin mRNA expression was detected by real-time fluorescent quantitative PCR. Western blot assay was used to detect the expression of E-cadherin, vimentin, extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphorylated ERK1/2 (p-ERK1/2). After treated with 1 μg/mL PGRN and ERK1/2 signaling pathway inhibitor U0126 (10 μmol/L) simultaneously, the migration and invasion ability of 4T1 cells and the changes in the expression of E-cadherin, vimentin and p-ERK proteins were detected again. Results After treated with PGRN, the migration and invasion capabilities of breast cancer 4T1 cells were significantly enhanced; E-cadherin expression decreased; vimentin and p-ERK1/2 expression increased. After treated with ERK1/2 signaling pathway inhibitor, the ability of PGRN to promote breast cancer 4T1 cell migration, invasion and epithelial-mesenchymal transition (EMT) was significantly inhibited. Conclusion PGRN can promote the migration and invasion of breast cancer 4T1 cells by promoting EMT and activating the ERK1/2 pathway.
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February 2021

AD Resemblance Atrophy Index as a Diagnostic Biomarker for Alzheimer's Disease: A Retrospective Clinical and Biological Validation.

J Alzheimers Dis 2021 ;79(3):1023-1032

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

Background: Magnetic resonance imaging (MRI) provides objective information about brain structural atrophy in patients with Alzheimer's disease (AD). This multi-structural atrophic information, when integrated as a single differential index, has the potential to further elevate the accuracy of AD identification from normal control (NC) compared to the conventional structure volumetric index.

Objective: We herein investigated the performance of such an MRI-derived AD index, AD-Resemblance Atrophy Index (AD-RAI), as a neuroimaging biomarker in clinical scenario.

Method: Fifty AD patients (19 with the Amyloid, Tau, Neurodegeneration (ATN) results assessed in cerebrospinal fluid) and 50 age- and gender-matched NC (19 with ATN results assessed using positron emission tomography) were recruited in this study. MRI-based imaging biomarkers, i.e., AD-RAI, were quantified using AccuBrain®. The accuracy, sensitivity, specificity, and area under the ROC curve (AUC) of these MRI-based imaging biomarkers were evaluated with the diagnosis result according to clinical criteria for all subjects and ATN biological markers for the subgroup.

Results: In the whole groups of AD and NC subjects, the accuracy of AD-RAI was 91%, sensitivity and specificity were 88% and 96%, respectively, and the AUC was 92%. In the subgroup of 19 AD and 19 NC with ATN results, AD-RAI results matched completely with ATN classification. AD-RAI outperforms the volume of any single brain structure measured.

Conclusion: The finding supports the hypothesis that MRI-derived composite AD-RAI is a more accurate imaging biomarker than individual brain structure volumetry in the identification of AD from NC in the clinical scenario.
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http://dx.doi.org/10.3233/JAD-201033DOI Listing
January 2021

An MRI-based strategy for differentiation of frontotemporal dementia and Alzheimer's disease.

Alzheimers Res Ther 2021 01 12;13(1):23. Epub 2021 Jan 12.

Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 Yanjiang West Road, Guangzhou, Guangdong, China.

Background: The differential diagnosis of frontotemporal dementia (FTD) and Alzheimer's disease (AD) is difficult due to the overlaps of clinical symptoms. Structural magnetic resonance imaging (sMRI) presents distinct brain atrophy and potentially helps in their differentiation. In this study, we aim at deriving a novel integrated index by leveraging the volumetric measures in brain regions with significant difference between AD and FTD and developing an MRI-based strategy for the differentiation of FTD and AD.

Methods: In this study, the data were acquired from three different databases, including 47 subjects with FTD, 47 subjects with AD, and 47 normal controls in the NACC database; 50 subjects with AD in the ADNI database; and 50 subjects with FTD in the FTLDNI database. The MR images of all subjects were automatically segmented, and the brain atrophy, including the AD resemblance atrophy index (AD-RAI), was quantified using AccuBrain®. A novel MRI index, named the frontotemporal dementia index (FTDI), was derived as the ratio between the weighted sum of the volumetric indexes in "FTD dominant" structures over that obtained from "AD dominant" structures. The weights and the identification of "FTD/AD dominant" structures were acquired from the statistical analysis of NACC data. The differentiation performance of FTDI was validated using independent data from ADNI and FTLDNI databases.

Results: AD-RAI is a proven imaging biomarker to identify AD and FTD from NC with significantly higher values (p < 0.001 and AUC = 0.88) as we reported before, while no significant difference was found between AD and FTD (p = 0.647). FTDI showed excellent accuracy in identifying FTD from AD (AUC = 0.90; SEN = 89%, SPE = 75% with threshold value = 1.08). The validation using independent data from ADNI and FTLDNI datasets also confirmed the efficacy of FTDI (AUC = 0.93; SEN = 96%, SPE = 70% with threshold value = 1.08).

Conclusions: Brain atrophy in AD, FTD, and normal elderly shows distinct patterns. In addition to AD-RAI that is designed to detect abnormal brain atrophy in dementia, a novel index specific to FTD is proposed and validated. By combining AD-RAI and FTDI, an MRI-based decision strategy was further proposed as a promising solution for the differential diagnosis of AD and FTD in clinical practice.
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http://dx.doi.org/10.1186/s13195-020-00757-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805212PMC
January 2021

Progranulin induces immune escape in breast cancer via up-regulating PD-L1 expression on tumor-associated macrophages (TAMs) and promoting CD8 T cell exclusion.

J Exp Clin Cancer Res 2021 Jan 4;40(1). Epub 2021 Jan 4.

Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, People's Republic of China.

Background: Progranulin (PGRN), as a multifunctional growth factor, is overexpressed in multiple tumors, but the role of PGRN on tumor immunity is still unclear. Here, we studied the effect of PGRN on breast cancer tumor immunity and its possible molecular mechanism.

Methods: The changes of macrophage phenotypes after PGRN treatment were detected by western blot, quantitative polymerase chain reaction (PCR) and flow cytometry. Western blot was used to study the signal molecular mechanism of PGRN regulating this process. The number and localization of immune cells in Wild-type (WT) and PGRN breast cancer tissues were analyzed by immunohistochemical staining and immunofluorescence techniques. The activation and proliferation of CD8 T cells were measured by flow cytometry.

Results: After being treated with PGRN, the expressions of M2 markers and programmed death ligand 1 (PD-L1) on macrophages increased significantly. Signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitor Stattic significantly inhibited the expression of PD-L1 and M2 related markers induced by PGRN. In WT group, CD8 were co-localized with macrophages and PD-L1, but not tumor cells. The number of immune cells in PGRN breast cancer tissue increased, and their infiltration into tumor parenchyma was also enhanced. Moreover, in the co-culture system, WT peritoneal macrophages not only reduced the ratio of activated CD8 T cells but also reduced the proportion of proliferating CD8 T cells. The addition of programmed death receptor 1 (PD-1) and PD-L1 neutralizing antibodies effectively reversed this effect and restored the immune function of CD8 T cells.

Conclusion: These results demonstrate that PGRN promotes M2 polarization and PD-L1 expression by activating the STAT3 signaling pathway. Furthermore, through PD-1/PD-L1 interaction, PGRN can promote the breast tumor immune escape. Our research may provide new ideas and targets for clinical breast cancer immunotherapy.
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http://dx.doi.org/10.1186/s13046-020-01786-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780622PMC
January 2021

PGRN TAMs-derived exosomes inhibit breast cancer cell invasion and migration and its mechanism exploration.

Life Sci 2021 Jan 9;264:118687. Epub 2020 Nov 9.

Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, PR China. Electronic address:

Breast cancer is one of the most malignant diseases world-wide and ranks the first among female cancers. Progranulin (PGRN) plays a carcinogenic role in breast cancer, but its mechanisms are not clear. In addition, there are few reports on the relationship between PGRN and tumor-associated macrophages (TAMs).

Aims: To investigate the effects of exosomes derived from PGRN TAMs on invasion and migration of breast cancer cells.

Main Methods: Mouse breast cancer xenograft model was constructed to explore the effect of PGRN tumor environment (TME) on breast cancer. Flow cytometry was used to compare TAMs of wild type (WT) and PGRN tumor tissue. Transwell assay, wound healing assay and western blot were used to explore the effect of WT and PGRN TAMs and their exosomes on invasion, migration and epithelial-mesenchymal transition (EMT) of breast cancer cells. MicroRNA (miRNA) assay was used to find out the differentially expressed miRNA of negative control (NC) and siPGRN-TAMs exosomes. Quantitative PCR and luciferase report assay were used to explore the target gene.

Key Findings: The lung metastasis of breast cancer of PGRN mice was inhibited. PGRN TAMs inhibited invasion, migration and EMT of breast cancer cells through their exosomes. MiR-5100 of PGRN TAMs-derived exosomes was up-regulated, which might regulate expression of CXCL12, thereby inhibiting the CXCL12/CXCR4 axis, and ultimately inhibiting the invasion, migration and EMT of breast cancer cells.

Significance: Our study elucidates a new molecular mechanism of lung metastasis of breast cancer, so it may contribute to efficient prevention and therapeutic strategies.
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http://dx.doi.org/10.1016/j.lfs.2020.118687DOI Listing
January 2021

Nucleus-located PDK1 regulates growth, invasion and migration of breast cancer cells.

Life Sci 2020 Jul 26;253:117722. Epub 2020 Apr 26.

Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, PR China. Electronic address:

Aims: It is well known that pyruvate dehydrogenase kinase 1 (PDK1) is highly expressed in breast cancer (BC) tissues and promotes tumor growth, but the underlying mechanisms of this process are unclear. Here, we investigated the effects of nuclear PDK1 on growth, migration and invasion in human BC cells.

Main Methods: The sub-cellular localization of PDK1 in BC cells was performed with subcellular fractionation followed by Western blot and immunofluorescence. The localization of PDK1 in breast normal tissue and breast duct carcinoma was detected by Immunohistochemistry. Then the protein-protein interaction between PDK1 and Importin β was verified by co-immunoprecipitation assay. Finally, the effects of nuclear PDK1 on cell proliferation, apoptosis, migration and invasion of BC cells were assessed.

Key Findings: In addition to its well-known sub-cellular localization, PDK1 was present in the nucleus of BC cells, and EGF treatment increased nucleus distribution of PDK1. Moreover, the level of nuclear PDK1 accumulation facilitated the growth of BC cells. We also found that the entry of PDK1 into nucleus mainly relied on the nuclear localization signal (NLS), and NLS mutation inhibited the entry of PDK1 into nucleus; as a result, the migration and invasion abilities of BC cells were impaired, and the number of apoptotic cells was significantly increased.

Significance: Our findings provided a new supplement to the sub-cellular localization of PDK1 in BC cells and uncovered the function of nuclear PDK1 in facilitating BC cells growth, migration and invasion.
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http://dx.doi.org/10.1016/j.lfs.2020.117722DOI Listing
July 2020

[Molecular mechanism of macrophages derived from PGRN gene knockout mice inhibit invasion and migration of breast cancer cells].

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2019 Sep;35(9):769-775

Ministry-of-Education Key Laboratory of Laboratory Medical Diagnostics, Chongqing Medical University, Chongqing 400016, China. *Corresponding author, E-mail:

Objective To explore the functions and mechanisms of macrophages derived from PGRN gene knockout (PGRN ) C57BL/6 mice in the invasion and migration of breast cancer cells. Methods Breast cancer cells were cultured in conditioned medium of macrophages derived from WT and PGRN mice. Transwell assay and scratch assay were used to detect the invasion and migration ability of cancer cells. Western blot analysis was used to detect the expression of E-cadherin and N-cadherin in cancer cells. Cytokine array, real-time quantitative PCR and ELISA were performed to investigate the differences of cytokines secreted by macrophages derived from WT and PGRN mice. Breast cancer cells were treated by the differentially expressed cytokine interleukin-6 (IL-6), and then the above methods were used to investigate its effect on cancer cells. Western blot analysis was used to verify the roles of NF-κB and JAK/STAT3 signaling pathways. Results The macrophages derived from PGRN mice blocked NF-κB signaling pathway, reduced IL-6 secretion, and inhibited the invasion and migration of breast cancer cells. IL-6 activated JAK/STAT3 signaling pathway to promote the invasion and migration of breast cancer cells. Conclusion The macrophages derived from PGRN mice can block the NF-κB and JAK/STAT3 signaling pathways, down-regulate IL-6 expression, and inhibit the invasion and migration of breast cancer cells.
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September 2019

Neurotropin reduces memory impairment and neuroinflammation via BDNF/NF-κB in a transgenic mouse model of Alzheimer's disease.

Am J Transl Res 2019 15;11(3):1541-1554. Epub 2019 Mar 15.

Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University Guangzhou 510120, Guangdong, China.

Alzheimer's disease (AD) is a devastating neurodegenerative disease with limited treatments and no cure. Neurotropin (NTP) is an analgesic drug widely prescribed for neuropathic pain. Increasing evidence suggests that NTP may also protect against neurodegeneration, but NTP's treatment potential against memory impairments of AD remains to be explored. APP/PS1 mice, which model AD, were given NTP for three months then cognitively tested with the Morris water maze. Their Aβ burden, microglial and astrocytic activation, and BDNF levels were compared to untreated controls using immunofluorescent staining. Expression of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and NF-κB pathway related proteins (p65 and IκB-α) were examined by ELISA or Western blots and in the microglia cell line. Lastly, BV-2 cells were pre-treated with the selective BDNF inhibitor ANA-12 and with NTP to examine mechanistic pathways. Taken together, NTP treatment reduced cognitive impairment, Aβ deposits, and glial activation in cortex and hippocampus APP/PS1 mice. IL-1β, IL-6 and TNF-α also decreased after NTP treatment and , and BDNF levels rose. Also, NTP reduced p65 and IκB-α activation and the effect of NTP on pro-inflammatory cytokines and NF-κB pathway related proteins was abolished by BDNF inhibitor. Our results indicate that NTP reduces neuroinflammation and improves the cognitive deficits in APP/PS1 mice possibly via BDNF/NF-κB pathway. NTP may be a new promising drug candidate for patients with AD.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456545PMC
March 2019

Carotid stenosis prevalence after radiotherapy in nasopharyngeal carcinoma: A meta-analysis.

Radiother Oncol 2019 04 4;133:167-175. Epub 2019 Feb 4.

Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Laboratory of RNA and Major Diseases of Brain and Heart, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, China. Electronic address:

Purpose: Radiotherapy (RT) is the most effective treatment for nasopharyngeal carcinoma (NPC) but may cause stenosis of the carotid arteries. This meta-analysis evaluates the prevalence of carotid stenosis after radiation therapy.

Materials And Methods: Online search for studies reporting carotid stenosis in patients with NPC who received radiation therapy (RT) compared to NPC patients who did not receive RT and compared to healthy controls.

Results: Twelve studies were included for a total analysis of 1928 patients (837 received RT and 1091 were controls). RT patients showed a statistically significant higher incidence of overall stenosis (pooled risk ratio = 4.17 [2.44, 7.10], p < 0.00001) and an even greater incidence of significant stenosis (50% or more) (pooled risk ratio = 8.72 [3.53, 21.55], p < 0.00001). Analyzing by individual blood vessels showed that the RT patients had significantly higher incidence of stenosis in common carotid artery (CCA), external carotid artery (ECA), carotid bulb, CCA and internal carotid artery (ICA), and CCA/ICA/carotid bulb.

Conclusions: NPC patients who receive RT have increased risk of developing carotid stenosis, and should be screened after treatment.
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http://dx.doi.org/10.1016/j.radonc.2018.11.013DOI Listing
April 2019

Evolution of the Material Microstructures and Mechanical Properties of AA1100 Aluminum Alloy within a Complex Porthole Die during Extrusion.

Materials (Basel) 2018 Dec 20;12(1). Epub 2018 Dec 20.

Department of Mechanical Engineering, McMaster University, Hamilton, ON, L4S 4L7, Canada.

Microchannel tube (MCT) is widely employed in industry due to its excellent efficiency in heat transfer. An MCT is commonly produced through extrusion within a porthole die, where severe plastic deformation is inevitably involved. Moreover, the plastic deformation, which dramatically affects the final property of the MCT, varies significantly from location to location. In order to understand the development of the microstructure and its effect on the final property of the MCT, the viscoplastic self-consistent (VPSC) model, together with the finite element analysis and the flow line model, is employed in the current study. The flow line model is used to reproduce the local velocity gradient within the complex porthole die, while VPSC model is employed to predict the evolution of the microstructure accordingly. In addition, electron backscatter diffraction (EBSD) measurement and mechanical tests are used to characterize the evolution of the microstructure and the property of the MCT. The simulation results agree well with the corresponding experimental ones. The influence of the material's flow line on the evolution of the orientation and morphology of the grains, and the property of the produced MCT are discussed in detail.
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http://dx.doi.org/10.3390/ma12010016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337609PMC
December 2018

Dual Specificity Phosphatase 6 Protects Neural Stem Cells from β-Amyloid-Induced Cytotoxicity through ERK1/2 Inactivation.

Biomolecules 2018 12 19;8(4). Epub 2018 Dec 19.

Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510120, China.

Alzheimer's disease (AD) is a devastating neurodegenerative disease with limited treatment options and no cure. Beta-amyloid (Aβ) is a hallmark of AD that has potent neurotoxicity in neural stem cells (NSCs). Dual specificity phosphatase 6 (DUSP6) is a member of the mitogen-activated protein kinases (MAPKs), which is involved in regulating various physiological and pathological processes. Whether DUSP6 has a protective effect on Aβ-induced NSC injury remains to be explored. C17.2 neural stem cells were transfected with DUSP6-overexpressed plasmid. NSCs with or without DUSP6 overexpression were administrated with Aβ25⁻35 at various concentrations (i.e., 0, 2.5, 5 μM). DUSP6 expression after Aβ treatment was detected by Real-Time Polymerase Chain Reaction (RT-PCR) and Western blot and cell vitality was examined by the CCK8 assay. The oxidative stress (intracellular reactive oxygen species (ROS) and malondialdehyde (MDA)), endoplasmic reticulum stress (ER calcium level) and mitochondrial dysfunction (cytochrome c homeostasis) were tested. The expression of -ERK1/2 and ERK1/2 were assayed by Western blot. Our results showed that Aβ decreased the expression of DUSP6 in a dose-dependent manner. The overexpression of DUSP6 increased the cell vitality of NSCs after Aβ treatment. Oxidative stress, ER stress, and mitochondrial dysfunction induced by Aβ could be restored by DUSP6 overexpression. Additionally, the Aβ-induced ERK1/2 activation was reversed. In summary, DUSP6 might have a neuroprotective effect on Aβ-induced cytotoxicity, probably via ERK1/2 activation.
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http://dx.doi.org/10.3390/biom8040181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315916PMC
December 2018

Curcumin-loaded PLGA-PEG nanoparticles conjugated with B6 peptide for potential use in Alzheimer's disease.

Drug Deliv 2018 Nov;25(1):1091-1102

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

Alzheimer's disease is a neurodegenerative disorder mainly characterized by β-amyloid deposit and tau hyperphosphorylation with no curative treatments. Curcumin (Cur) has been proved to have potential use in Alzheimer's disease with its anti-amyloid, anti-inflammatory, and anti-oxidant properties, etc. However, its hydrophobicity and low bioavailability hinder its application. In this paper, we designed a novel brain-target nanoparticle, poly(lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-PEG) conjugated with B6 peptide and was loaded with Cur (PLGA-PEG-B6/Cur) and administered it into HT22 cells and APP/PS1 Al transgenic mice. The in vitro assays including dynamic light scattering (DLS), flow cytometry (FCM), red blood cell (RBC) lysis, and thromboelastography (TEG) analysis indicated that this nanoparticle could narrow the diameter of Cur, increase its cellular uptake and possess good blood compatibility. The results from Morris water maze proved that PLGA-PEG-B6/Cur could tremendously improve the spatial learning and memory capability of APP/PS1 mice, compared with native Cur. The ex vivo assays including Bielschowsky silver staining, immunostaining, and western blotting demonstrated that PLGA-PEG-B6/Cur could reduce hippocampal β-amyloid formation and deposit and tau hyperphosphorylation. Thus, we suggested that PLGA-PEG-B6/Cur nanoparticles would be of potential and promising use for the treatment of Alzheimer's disease.
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http://dx.doi.org/10.1080/10717544.2018.1461955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116673PMC
November 2018

Neurotropin inhibits neuroinflammation via suppressing NF-κB and MAPKs signaling pathways in lipopolysaccharide-stimulated BV2 cells.

J Pharmacol Sci 2018 Apr 27;136(4):242-248. Epub 2018 Feb 27.

Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou, China; Laboratory of RNA and Major Diseases of Brain and Heart, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China. Electronic address:

Neurotropin (NTP) is a widely used drug in China and Japan mainly for the treatment of chronic pain and peripheral inflammation. Nevertheless, the effects of NTP on neuroinflammation have not been explored. In this study, we investigated the anti-inflammatory effects of NTP in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and its underlying mechanisms. BV-2 cells were pretreated with NTP for 12 h before exposure to LPS. The expression of pro-inflammatory cytokines (TNF-α and IL-6) were detected by RT-PCR and EILSA at mRNA and protein levels, respectively. Western blotting was conducted to measure the protein levels of major genes in MAPKs and NF-κB signaling pathways. Results demonstrated that NTP could attenuate the production of pro-inflammatory cytokines. Furthermore, NTP inhibited the activation of NF-κB signaling by decreasing the translocation of NF-κB p65 to the nucleus and suppressed the MAPKs signaling pathway via inhibition of the phosphorylation of p38, ERK and JNK. Taken together, these findings suggest that neurotropin exerts anti-inflammatory effects by suppressing the production of pro-inflammatory mediators via inhibition of NF-κB and MAPKs signaling pathways in LPS-stimulated BV-2 cells.
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http://dx.doi.org/10.1016/j.jphs.2018.02.004DOI Listing
April 2018

Bilateral ptosis as first presentation of cytophagic histiocytic panniculitis: a case report.

BMC Ophthalmol 2017 Jul 1;17(1):112. Epub 2017 Jul 1.

Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China.

Background: Cytophagic histiocytic panniculitis (CHP) is a rare form of nodular panniculitis that may progress to panniculitis-like T-cell lymphoma. We report a case of CHP that first manifested as bilateral ptosis, which is the first reported case of this presentation.

Case Presentation: A 25-year-old woman without medical history was referred to the neurology department of our hospital for evaluation of bilateral ptosis. Three months previously, she suddenly complained of bilateral ptosis without apparent cause. Simultaneously, non-painful tender subcutaneous nodules and eschar-like skin lesions were observed on her extremities and trunk. A diagnosis of CHP was made based on skin biopsy from the left thigh showing lobular panniculitis, vasculitis, and adiponecrosis, with infiltration of inflammatory cells, including lymphocytes, histiocytes, and phagocytic histiocytes. Her condition continued to worsen with corticosteroid and immunosuppressive agent (thalidomide) treatment. Significant improvement was noticed after three cycles of chemotherapy of THP-COP (pirarubicin, cyclophosphamide, vincristine, and prednisolone).

Conclusions: CHP is a rare condition whose clinical presentation may include bilateral ptosis and biopsy is required for diagnosis of CHP.
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http://dx.doi.org/10.1186/s12886-017-0511-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493882PMC
July 2017

Late-onset cystic brain necrosis after radiotherapy for nasopharyngeal carcinoma.

Jpn J Clin Oncol 2017 Jun;47(6):499-504

Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong.

Background: Cystic brain radionecrosis (CBRN) is a late-onset devastating complication after radiotherapy for head and neck neoplasms, especially for nasopharyngeal carcinoma (NPC). To our knowledge, it has scarcely been reported.

Methods: We retrospectively reviewed all available medical records of NPC patients with CBRN who were treated with surgical intervention.

Results: Sixteen patients were identified in this study and the mean latency of CBRN was 9.2 ± 0.9 years. The total irradiation dose of the nasopharynx ranged from 60 to 78 Gy. Cyst-like lesions were observed and there were slightly enhancements on the cyst wall in five patients on patients' brain MRI. All the included patients underwent surgical resection of the cystic necrotic lesion thought temporal approach. Specimens from surgery revealed reactive gliosis and immunopositive cytokines including TNF-α, IL-6 and HIF-2α. Only one patient experienced recurrence and received reoperation after surgery. All the other patients made a good recovery and no operation-related mortality was observed.

Conclusions: CBRN is a delayed but irreversible neurological sequel in irradiated NPC patients. Post-radiotherapy follow-up is quite necessary for those with high risk of CBRN. Proper treatment is needed for early CBRN patients to suppress inflammation in the brain. Timely neurosurgery may benefit patients with late-stage CBRN by alleviating increased intracranial pressure and inflammatory responses.
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http://dx.doi.org/10.1093/jjco/hyx028DOI Listing
June 2017

Magnesium Elevation Promotes Neuronal Differentiation While Suppressing Glial Differentiation of Primary Cultured Adult Mouse Neural Progenitor Cells through ERK/CREB Activation.

Front Neurosci 2017 23;11:87. Epub 2017 Feb 23.

Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen UniversityGuangzhou, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen UniversityGuangzhou, China; Laboratory of RNA and Major Diseases of Brain and Heart, Sun Yat-sen Memorial Hospital, Sun Yat-sen UniversityGuangzhou, China.

This study aimed to explore the influence of magnesium elevation on fate determination of adult neural progenitor cells (aNPCs) and the underlying mechanism . Adult neurogenesis, which is the generation of functional neurons from neural precursors, occurs throughout life in restricted anatomical regions in mammals. Magnesium is the fourth most abundant ion in mammals, and its elevation in the brain has been shown to enhance memory and synaptic plasticity . However, the effects of magnesium on fate determination of aNPCs, which are vital processes in neurogenesis, remain unknown. NPCs isolated from the dentate gyrus of adult C57/BL6 mice were induced to differentiate in a medium with varying magnesium concentrations (0.6, 0.8, and 1.0 mM) and extracellular signal-regulated kinase (ERK) inhibitor PD0325901. The proportion of cells that differentiated into neurons and glial cells was evaluated using immunofluorescence. Quantitative real-time polymerase chain reaction and Western blot methods were used to determine the expression of β-III tubulin (Tuj1) and glial fibrillary acidic protein (GFAP). The activation of ERK and cAMP response element-binding protein (CREB) was examined by Western blot to reveal the underlying mechanism. Magnesium elevation increased the proportion of Tju1-positive cells and decreased the proportion of GFAP-positive cells. Also, the expression of Tuj1 was upregulated, whereas the expression of GFAP was downregulated. Moreover, magnesium elevation enhanced the activation of both ERK and CREB. Treatment with PD0325901 reversed these effects in a dose-dependent manner. Magnesium elevation promoted neural differentiation while suppressing glial cell differentiation, possibly via ERK-induced CREB activation.
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http://dx.doi.org/10.3389/fnins.2017.00087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322230PMC
February 2017

Hearing impairment and risk of Alzheimer's disease: a meta-analysis of prospective cohort studies.

Neurol Sci 2017 Feb 28;38(2):233-239. Epub 2016 Nov 28.

Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou, China.

Observational studies suggested an association between hearing impairment and cognitive disorders. However, whether hearing impairment is an independent risk factor or a harbinger of Alzheimer's disease remains controversial. Our goal was to assess the association between hearing impairment (HI) and the risk of Alzheimer's disease (AD) by conducting a meta-analysis of prospective cohort studies. We comprehensively searched the PubMed, Embase, Web of Science and Cochrane Library databases on January 19, 2016 to incorporate all the prospective cohort studies meeting the inclusion criteria to perform a systematic review and meta-analysis. Four prospective cohort studies with comparison between hearing impairment and normal hearing were incorporated, with 7461 participants. The outcomes of three studies were the incidence of Alzheimer's disease and the outcome of the fourth study was the incidence of mild cognitive impairment. The overall combined relative risk of people with hearing impairment to develop Alzheimer's disease was 4.87 (95% CI 0.90-26.35; p = 0.066), compared with the control group. Since both Alzheimer's disease and mild cognitive impairment are cognitive disorders, we incorporated all the four studies and the overall combined relative risk was 2.82 (95% CI 1.47-5.42; p = 0.002), indicating that the difference was significant. This meta-analysis suggests that hearing impairment significantly increases the risk of cognitive disorders and future well-designed prospective cohort studies are awaited to confirm the association between hearing impairment and risk of Alzheimer's disease.
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http://dx.doi.org/10.1007/s10072-016-2779-3DOI Listing
February 2017

Graphene quantum dots conjugated neuroprotective peptide improve learning and memory capability.

Biomaterials 2016 11 17;106:98-110. Epub 2016 Aug 17.

Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou, 510120, China; Laboratory of RNA and Major Diseases of Brain and Heart, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China. Electronic address:

Alzheimer disease (AD) is a neurodegenerative disorder and the most common form of dementia. Histopathologically is characterized by the presence extracellular neuritic plaques and with a large number of neurons lost. In this paper, we design a new nanomaterial, graphene quantum dots (GQDs) conjugated neuroprotective peptide glycine-proline-glutamate (GQDG) and administer it to APP/PS1 transgenic mice. The in vitro assays including ThT and CD proved that GQDs and GQDG could inhibit the aggregation of Aβ1-42 fibrils. Morris water maze was performed to exanimate learning and memory capacity of APP/PS1 transgenic mice. The surface area of Aβ plaque deposits reduced in the GQDG group compared to the Tg Ctrl groups. Furthermore, newly generated neuronal precursor cell and neuron were test by immunohistochemical. Besides, neurons were impregnated by DiI using gene gun to show dendritic spine. Results indicated enhancement of learning and memory capacity and increased amounts of dendritic spine were observed. Inflammation factors and amyloid-β (Aβ) were tested with suspension array and ELISA, respectively. Several pro-inflammatory cytokines (IL-1α, IL-1β, IL-6, IL-33, IL-17α, MIP-1β and TNF-α) had decreased in GQDG group compared with Control group. Reversely, anti-inflammatory cytokines (IL-4, IL-10) had increased in GQDG group compared with Control group. Thus, we demonstrate that the GQDG is a promising drug in treatment of neurodegenerative diseases such as AD.
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http://dx.doi.org/10.1016/j.biomaterials.2016.08.021DOI Listing
November 2016

Curcumin ameliorates hippocampal neuron damage induced by human immunodeficiency virus-1.

Neural Regen Res 2013 May;8(15):1368-75

Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine, Medical College of Jinan University, Guangzhou 510632, Guangdong Province, China ; Institute of Brain Research, Medical College of Jinan University, Guangzhou 510632, Guangdong Province, China ; Joint Laboratory for Brain Function and Health of Jinan University and the University of Hong Kong, Guangzhou 510632, Guangdong Province, China.

Our previous studies have shown that infection with the gp120 V3 loop can cause human immunodeficiency virus-1 associated neurocognitive disorders. Curcumin has been shown to improve these effects to some degree, but the precise mechanisms remain unknown. The present study analyzed the neuroprotective effect and mechanism of curcumin in relation to hippocampal neurons. Results showed that 1 nmol/L gp120 V3 loop suppressed the growth of synapses. After administration of 1 μmol/L curcumin, synaptic growth improved. Curcumin is neuroprotective against gp120 V3 loop-induced neuronal damage by inhibiting the activation of L-type calcium currents, relieving intracellular Ca(2+) overload, promoting Bcl-2 expression, and inhibiting Bax activation. The effect of curcumin was identical to nimodipine, suggesting that curcumin has the same neuroprotective effects against gp120 V3 loop-induced neuronal damage.
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http://dx.doi.org/10.3969/j.issn.1673-5374.2013.15.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107768PMC
May 2013

Prevalence and severity of behavioral and psychological symptoms of dementia (BPSD) in community dwelling Chinese: findings from the Shanghai three districts study.

Aging Ment Health 2013 3;17(6):748-52. Epub 2013 Apr 3.

Department of Disease Control for Mental health, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, China.

Objectives: Studies of the prevalence and risk factors for behavioral and psychological symptoms of dementia (BPSD) have primarily been conducted in nursing home and clinic populations. Few population-based studies have been conducted in community-living persons with dementia.

Methods: In this cross-sectional study, persons aged 65 and above who were living in the community were screened for dementia with the Chinese version of Mini-Mental State Examination (CMMSE) and Ability of Daily Living (ADL-14) scale. Participants with a diagnosis of dementia according to DSM-IV criteria made by trained neuropsychiatrists s were with the Neuropsychiatric Inventory assessed for BPSD by informant interview.

Results: Among 1271 persons with dementia, 50.1% had at least one BPSD. Sleep disturbance was the most common symptom (21.9%), followed by irritability (19.6%), and apathy (15.7%). About 40% (N = 501) of these problems were clinically significant (NPI score > 4). The NPI score was significantly associated with the CMMSE score, ADL score and education.

Conclusion: BPSD are common among community living Chinese people with dementia, but the relatively lower prevalence rate and different pattern of symptoms from those reported in the USA, UK and Japan suggest the possible influence of cultural background and psychosocial environment.
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http://dx.doi.org/10.1080/13607863.2013.781116DOI Listing
March 2014

Effectiveness of a rehabilitative program that integrates hospital and community services for patients with schizophrenia in one community in Shanghai.

Shanghai Arch Psychiatry 2012 Jun;24(3):140-8

Changning District Hospital, Shanghai, China.

Background: One possible reason for the less than satisfactory long-term outcomes for schizophrenia is the lack of coordination between inpatient and community-based services.

Aim: Assess the effectiveness of a rehabilitation model for schizophrenia that integrates hospital and community services.

Methods: Ninety patients with schizophrenia participating in an integrated rehabilitation program at 10 community centers in Changning, Shanghai (intervention group) and 52 community-based patients with schizophrenia randomly selected from all patients in Changning participating in routine outpatient care (control group) were assessed at enrollment using the Positive and Negative Syndrome Scale (PANSS) and the Morningside Rehabilitation Status Scale (MRSS) and then re-assessed 1 year later by clinicians who were blind to the group assignment of the patients. The patients' registered guardians (the vast majority were co-resident family members) were assessed at the same times using the Family Burden Scale (FBS), the Self-rating Depression Scale (SDS), the Self-rating Anxiety Scale (SAS) and the Social Support Rating Scale (SSRS).

Results: At enrollment the clinical status of patients in the two groups (assessed with PANSS) was similar but the social functioning measures assessed by MRSS were significantly worse in the intervention group than in the control group. After one year the improvement of both clinical symptoms and social functioning measures were significantly greater in the intervention group than in the control group. In the year of follow-up, 3 individuals (3.3%) in the intervention group and 6 individuals (11.5%) in the control group were re-hospitalized (Fisher Exact Test, p=0.074). The feelings of burden, depression, anxiety and reported social support among guardians of patients in the intervention group were not significantly different from those for guardians of patients in the control group either at the time of enrollment or after the 1-year intervention. However, guardians in the intervention group showed a significant decrease in depressive and anxiety symptoms over the one-year follow-up.

Conclusions: Rehabilitative approaches that integrate hospital and community services can improve clinical and social outcomes for patients with schizophrenia. Further development of these programs is needed to increase the proportion of patients who achieve regular employment (i.e., 'community re-integration') and to provide family members with better psychosocial support.
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http://dx.doi.org/10.3969/j.issn.1002-0829.2012.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4198845PMC
June 2012

Survey in Shanghai communities: the public awareness of and attitude towards dementia.

Psychogeriatrics 2011 Jun;11(2):83-9

Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine Shanghai Changning Mental Health Center, Shanghai, China.

Objective: To assess the knowledge of and attitudes towards dementia among Shanghai residents.

Methods: A 10-item optional questionnaire relating to dementia was developed for the project. Questionnaires were randomly distributed to 1806 families, each family had one respondent.

Results: A total of 1531 questionnaires were available. Among them, 45% considered 'dementia is a normal part of ageing' and 29-41% correctly identified the symptoms of mild dementia. Of the respondents, 43% indicated that they would not be ashamed of having a demented relative, and 45% did not think that medical care benefited those with dementia. Subgroups analyses showed there was a wider agreement on the concept 'dementia is a normal part of ageing' in the elderly or the females with primary school education background than the counterpart. According to the educational level, the sequence (from the highest to the lowest) of the proportion of respondents who considered a demented relative to be shameful was as follows: middle school group (60.5%) > primary school group (41.3%) > university group (25.2%); according to age group: adult group (59.8%) > elderly group (37.3%) > youth group (30.2%). There was a higher identification rate of the symptoms of mild dementia in women than in men (P < 0.01). According to the educational level, the sequence (from the highest to the lowest) of identification rate was: university group > primary school group > middle school group; according to age group: elderly group > youth group > adult group. There was a significant difference among groups (P < 0.01). Multivariate regression results suggested that the sex, educational level and age had an influence on the concept of 'dementia is part of normal ageing'; the feeling of shame of having demented relatives was influenced by the educational level and age.

Conclusion: Lack of correct knowledge about dementia and discrimination of dementia are highly prevalent among urban residents in Shanghai.
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http://dx.doi.org/10.1111/j.1479-8301.2010.00349.xDOI Listing
June 2011

Noncanonical and canonical splice sites: a novel mutation at the rare noncanonical splice-donor cut site (IVS4+1A>G) of SEDL causes variable splicing isoforms in X-linked spondyloepiphyseal dysplasia tarda.

Eur J Hum Genet 2009 Apr 12;17(4):510-6. Epub 2008 Nov 12.

Children's Hospital of Chongqing Medical University, Central District, Chongqing, PR China.

X-linked spondyloepiphyseal dysplasia tarda can be caused by mutations in the SEDL gene. This study describes an interesting novel mutation (IVS4+1A>G) located exactly at the rare noncanonical AT-AC consensus splicing donor point of SEDL, which regained the canonical GT-AG consensus splicing junction in addition to several other rarer noncanonical splice patterns. The mutation activated several cryptic splice sites and generated the production of seven erroneous splicing isoforms, which we confirmed by sequencing of RT-PCR products and resequencing of cDNA clones. All the practical splice donors/acceptors were further assessed using FSPLICE 1.0 and SPL(M) Platforms to predict potential splice sites in genomic DNA. Subsequently, the expression levels of SEDL among the affected patients, carriers and controls were estimated using real-time quantitative PCR. Expression analyses showed that the expression levels of SEDL in both patients and carriers were decreased. Taken together, these results illustrated how disruption of the AT donor site in a rare AT-AC intron, leading to a canonical GT donor site, resulted in a multitude of aberrant transcripts, thus impairing exon definition. The unexpected splicing patterns resulting from the special mutation provide additional challenges and opportunities for understanding splicing mechanisms and specificity.
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http://dx.doi.org/10.1038/ejhg.2008.219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2986207PMC
April 2009

The Ser9Gly polymorphism of the dopamine D3 receptor gene and risk of schizophrenia: an association study and a large meta-analysis.

Schizophr Res 2008 Apr 4;101(1-3):26-35. Epub 2008 Mar 4.

Bio-X Center, Shanghai Jiao Tong University, Shanghai 200030, China.

Dopamine D3 receptor (DRD3) binds antipsychotic drugs and is abundant in the limbic system of the brain. It has been shown to play important roles in schizophrenia. A number of studies investigated the Ser9Gly polymorphism of the DRD3 gene to test its possible association with schizophrenia; however, the results were inconsistent. Our study aims to further evaluate the possible association between the Ser9Gly polymorphism and schizophrenia using a case-control association study within the Han Chinese population as well as a meta-analysis covering all previous studies. Our study, based on 329 schizophrenic patients and 288 controls, found no significant difference in the genotype or allele distributions of Ser9Gly polymorphism, the meta-analysis showed that the Ser9Gly polymorphism was not associated with Schizophrenia. Our study does not support the contention that the Ser9Gly polymorphism of the DRD3 gene plays a major role in schizophrenia in the Chinese population.
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http://dx.doi.org/10.1016/j.schres.2007.11.041DOI Listing
April 2008
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