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author:("Jia, jianxing")
1.  MicroRNA-181c Exacerbates Brain Injury in Acute Ischemic Stroke 
Aging and Disease  2016;7(6):705-714.
MicroRNA-181 (miR-181) is highly expressed in the brain, and downregulated in miRNA expression profiles of acute ischemic stroke patients. However, the roles of miR-181c in stroke are not known. The clinical relevance of miR-181c in acute stroke patients was evaluated by real-time PCR and correlation analyses. Proliferation and apoptosis of BV2 microglial cells and Neuro-2a cells cultured separately or together under oxidative stress or inflammation were assessed with the Cell Counting Kit-8 and by flow cytometry, respectively. Cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in C57/BL6 mice, and cerebral infarct volume, microglia activation, and expression of pro-apoptotic factors were evaluated by 2,3,5-triphenyl-2H-tetrazolium chloride staining, immunocytochemistry, and western blotting, respectively. Plasma levels of miR-181c were decreased in stroke patients relative to healthy individuals, and were positively correlated with neutrophil number and blood platelet count and negatively correlated with lymphocyte number. Lipopolysaccharide (LPS)/hydrogen peroxide (H2O2) treatment inhibited BV2 microglia proliferation without inducing apoptosis, while miR-181c reduced proliferation but increased the apoptosis of these cells with or without LPS/H2O2 treatment. LPS/H2O2 induced apoptosis in Neuro-2a cells co-cultured with BV2 cells, an effect that was potentiated by miR-181c. In the MCAO model, miR-181c agomir modestly increased infarct volume, markedly decreased microglia activation and B cell lymphoma-2 expression, and increased the levels of pro-apoptotic proteins in the ischemic brain. Our data indicate that miR-181c contributes to brain injury in acute ischemic stroke by promoting apoptosis of microglia and neurons via modulation of pro- and anti-apoptotic proteins.
doi:10.14336/AD.2016.0320
PMCID: PMC5198862  PMID: 28053821
microRNA-181; stroke; microglia; neuron; apoptosis
2.  The efficacy of Cognitive training in patients with VAsCular Cognitive Impairment, No dEmentia (the Cog-VACCINE study): study protocol for a randomized controlled trial 
Trials  2016;17:392.
Background
Vascular cognitive impairment, no dementia (VCIND) refers to cognitive deficits associated with underlying vascular causes that fall short of a dementia diagnosis. There is currently no treatment for VCIND. Computerized cognitive training, which has significantly improved cognitive function in healthy older adults and patients with cognitive impairment has not yet been applied to VCIND.
Methods/Design
The proposed study is a three-center, double-blinded, randomized controlled trial that will include 60 patients with VCIND. The patients will be randomized to either a training or a control group. The intervention is internet-based cognitive training performed for 30 min over 35 sessions. Neuropsychological assessment and functional and structural MRI will be performed before and after 7 weeks training. Primary outcomes are global cognitive function and executive function. Secondary outcome measures are neuroplasticity changes measured by functional and structural MRI.
Discussion
Applying an internet-based, multi-domain, adaptive program, this study aims to assess whether cognitive training improves cognitive abilities and neural plasticity in patients with subcortical VCIND. In addition to the comprehensive assessment of the participants by neuropsychological tests, cerebrovascular risk factors and apolipoprotein E genotyping, neuroplasticity will be used as an evaluation outcome in this study for, to our knowledge, the first time. The combination of functional and structural MRI and neuropsychological tests will have strong sensitivity in evaluating the effects of cognitive training and will also reveal the underlying mechanisms at work.
Trial registration
ClinicalTrials.gov NCT02640716. Retrospectively registered on 21 December 2015.
doi:10.1186/s13063-016-1523-x
PMCID: PMC4974771  PMID: 27496126
Cognitive training; Magnetic resonance imaging; Neuroplasticity; No dementia; Protocol; Randomized controlled clinical trial; Vascular cognitive impairment
3.  Ischemic Conditioning Is Safe and Effective for Octo- and Nonagenarians in Stroke Prevention and Treatment 
Neurotherapeutics  2015;12(3):667-677.
Symptomatic intracranial arterial stenosis (SIAS) is very common in octo- and nonagenarians, especially in the Chinese population, and is likely the most common cause of stroke recurrence worldwide. Clinical trials demonstrate that endovascular treatment, such as stenting, may not be suitable for octogenarians with systemic diseases. Hence, less invasive methods for the octogenarian patients are urgently needed. Our previous study (unique identifier: NCT01321749) showed that repetitive bilateral arm ischemic preconditioning (BAIPC) reduced the incidence of stroke recurrence by improving cerebral perfusion (confirmed by single photon emission computed tomography and transcranial Doppler sonography) in patients younger than 80 years of age; however, the safety and effectiveness of BAIPC on stroke prevention in octo- and nonagenarians with SIAS are still unclear. The objective of this study was to evaluate the safety and effectiveness of BAIPC in reducing stroke recurrence in octo- and nonagenarian patients with SIAS. Fifty-eight patients with SIAS were enrolled in this randomized controlled prospective study for 180 consecutive days. All patients enrolled in the study received standard medical management. Patients in the BAIPC group (n = 30) underwent 5 cycles consisting of bilateral arm ischemia followed by reperfusion for 5 min each twice daily. Those in the control group (n = 28) underwent sham-BAIPC twice daily. Blood pressure, heart rate, local skin status, plasma myoglobin, and plasma levels of thrombotic and inflammatory markers were documented in both groups before beginning the study and for the first 30 days. Finally, the incidences of stroke recurrence and magnetic resonance imaging during the 180 days of treatment were compared. Compared with the control, BAIPC had no adverse effects on blood pressure, heart rate, local skin integrity, or plasma myoglobin, and did not induce cerebral hemorrhage in the studied cohort. BAIPC reduced plasma high sensitive C-reactive protein, interleukin-6, plasminogen activator inhibitor-1, leukocyte count, and platelet aggregation rate and elevated plasma tissue plasminogen activator (all p < 0.01). In 180 days, 2 infarctions and 7 transient ischemic attacks were observed in the BAIPC group compared with 8 infarctions and 11 transient ischemic attacks in the sham BAIPC group (p < 0.05). BAIPC may safely inhibit stroke recurrence, protect against brain ischemia, and ameliorate plasma biomarkers of inflammation and coagulation in octo- and nonagenarians with SIAS. A multicenter trial is ongoing.
Clinical Trial Registration: www.clinicaltrials.gov, unique identifier: NCT01570231.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-015-0358-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s13311-015-0358-6
PMCID: PMC4489956  PMID: 25956401
Remote ischemic preconditioning; octogenarian; nonagenarians; intracranial arterial stenosis; stroke; recurrence
4.  Reduction of Endogenous Melatonin Accelerates Cognitive Decline in Mice in a Simulated Occupational Formaldehyde Exposure Environment 
Individuals afflicted with occupational formaldehyde (FA) exposure often suffer from abnormal behaviors such as aggression, depression, anxiety, sleep disorders, and in particular, cognitive impairments. Coincidentally, clinical patients with melatonin (MT) deficiency also complain of cognitive problems associated with the above mental disorders. Whether and how FA affects endogenous MT metabolism and induces cognitive decline need to be elucidated. To mimic occupational FA exposure environment, 16 healthy adult male mice were exposed to gaseous FA (3 mg/m3) for 7 consecutive days. Results showed that FA exposure impaired spatial memory associated with hippocampal neuronal death. Biochemical analysis revealed that FA exposure elicited an intensive oxidative stress by reducing systemic glutathione levels, in particular, decreasing brain MT concentrations. Inversely, intraperitoneal injection of MT markedly attenuated FA-induced hippocampal neuronal death, restored brain MT levels, and reversed memory decline. At tissue levels, injection of FA into the hippocampus distinctly reduced brain MT concentrations. Furthermore, at cellular and molecular levels, we found that FA directly inactivated MT in vitro and in vivo. These findings suggest that MT supplementation contributes to the rescue of cognitive decline, and may alleviate mental disorders in the occupational FA-exposed human populations.
doi:10.3390/ijerph13030258
PMCID: PMC4808921  PMID: 26938543
formaldehyde (FA); melatonin (MT); oxidative stress; spatial memory; reactive oxygen species; l-glutathione
5.  Association between Plasma Leptin and Estrogen in Female Patients of Amnestic Mild Cognitive Impairment 
Disease Markers  2015;2015:450237.
Increasing evidences suggested the association between leptin and cognitive functions. Estrogen is an important factor that regulates the production and metabolism of leptin. However, little is known about the relationship between leptin and estrogen in mild cognitive impairment (MCI). Plasma levels of leptin, total estradiol, and β-amyloid protein (Aβ) were measured in a total of 23 female amnestic MCI (aMCI) patients and 19 female cognitively normal controls. This study showed that female aMCI patients had lower plasma levels of leptin and higher levels of estradiol compared to female normal controls. Leptin and estradiol levels were not correlated with cognitive performances or plasma Aβ levels in either aMCI patients or normal controls. There was a significant negative correlation between leptin and estrogen in female aMCI patients (r = −0.633, p = 0.002) but not in female normal controls. The potential mechanisms of this disease-stage-specific association between leptin and estrogen need further investigations.
doi:10.1155/2015/450237
PMCID: PMC4677007  PMID: 26693203
6.  Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer's disease 
Nature Communications  2015;6:8762.
The age-dependent deposition of amyloid-β peptides, derived from amyloid precursor protein (APP), is a neuropathological hallmark of Alzheimer's disease (AD). Despite age being the greatest risk factor for AD, the molecular mechanisms linking ageing to APP processing are unknown. Here we show that asparagine endopeptidase (AEP), a pH-controlled cysteine proteinase, is activated during ageing and mediates APP proteolytic processing. AEP cleaves APP at N373 and N585 residues, selectively influencing the amyloidogenic fragmentation of APP. AEP is activated in normal mice in an age-dependent manner, and is strongly activated in 5XFAD transgenic mouse model and human AD brains. Deletion of AEP from 5XFAD or APP/PS1 mice decreases senile plaque formation, ameliorates synapse loss, elevates long-term potentiation and protects memory. Blockade of APP cleavage by AEP in mice alleviates pathological and behavioural deficits. Thus, AEP acts as a δ-secretase, contributing to the age-dependent pathogenic mechanisms in AD.
Age is the greatest risk factor for Alzheimer's disease, yet how ageing regulates disease pathology is unclear. Here, the authors find that asparagine endopeptidase expression increases with age and cleaves APP, contributing to ß-amyloid production and cognitive defects in a transgenic mouse model.
doi:10.1038/ncomms9762
PMCID: PMC4659940  PMID: 26549211
7.  Cognitive impairments associated with corpus callosum infarction: a ten cases study 
The aim of this study was to determine whether the cognitive impairment is associated with corpus callosum infarctions. Ten corpus callosum infarction patients were enrolled in this study. Their emotions, cognitive and language abilities, memory, comprehensive perception were assessed using the Chinese version of following measures: Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), World Health Organization-University of California-Los Angeles Auditory Verbal Learning Test (WHO-UCLA AVLT), Wechsler Adult Intelligence Scale (WAIS) Digit Span subtest and so on. The same measurements were performed on healthy control participants as contrast for analysis. Infarction most frequently occurred in the body and/or splenium of the corpus callosum. The scores of the most cognitive tests in the corpus callosum infarction patients were significantly worse than those of the control participants (P<0.05). Except for the naming ability, the patients showed significantly poorer performance at the overall level of MMSE than the controls did (P<0.05). Consistently, the results of MoCA suggested a significant reduction in visuospatial abilities of execution, orientation, attention, calculation, delayed memory, language, and repetition capabilities in the patients with respect to the control (P<0.05). In addition, the scores in the case group were significantly worse than those in the control group in the auditory word learning test, digital span and Rey complex figure test (P<0.05). Corpus callosum infarction can cause cognitive dysfunction, which poses obstacles to memory in the acute phase, accompanied by different degrees of decline in visuospatial abilities, attention and calculating abilities.
PMCID: PMC4724017  PMID: 26885171
Corpus callosum; infarction; cognitive impairment; MMSE; MoCA
8.  A Novel Canine Model of Acute Vertebral Artery Occlusion 
PLoS ONE  2015;10(11):e0142251.
Background
The extended time window and theoretic reduction in hemorrhage make mechanical strategies an attractive approach for the treatment of patients with ischemic stroke. However, a limited availability of suitable animal models of cerebrovascular thrombosis has hampered the study of novel endovascular interventions. The aim of the present study was to develop a new technique for site-specific placement of a thrombus in a canine model that would allow for the evaluation of mechanical thrombectomy and clot retrieval methods and the visualization of thrombus dislocation or fragmentation during angiographic manipulation.
Methods
Angiography and embolization with a preformed thrombus were performed in 12 canines. Under fluoroscopic guidance, an embolism protection device (EPD) was anchored to the middle segment of the left vertebral artery (VA) via the left femoral arterial sheath. A preformed radiopaque clot was injected through the guide catheter into the left VA, via the contralateral femoral artery, proximal to the EPD. After 15 min of occlusion, the EPD was removed and persistent occlusion of the VA was documented angiographically.
Results
Angiography performed during the observation period confirmed the persistence of VA occlusion in each case, and displacement of the radiopaque clots did not occur during the 3-hour observation period. The technique allowed selective embolization of targeted vessels without thrombus fragmentation.
Conclusion
This study demonstrates, for the first time, a canine model of post-circulation embolism induced by autologous blood clot placement. This model can be rapidly formed and easily operated, and the site of thrombosis can be readily controlled.
doi:10.1371/journal.pone.0142251
PMCID: PMC4636284  PMID: 26545253
9.  Clinical analysis on anti-N-methyl-D-aspartate receptor encephalitis cases: Chinese experience 
As a kind of autoimmune encephalitis which was just identified, the clinical manifestations of the anti-N methyl-D aspartate (anti-NMDA) receptor encephalitis are complex, diverse and in severe condition. The immunotherapy has shown good effect on the treatment but in generally, the diagnosis and treatment are still in the experience accumulation stage. More clinical research in different population is necessary, for example, in the Chinese population. This study was completed in anti-NMDA receptor encephalitis patients who were diagnosed in Beijing Xuan Wu Hospital (China) during the time from 2011 to 2013. Total 33 patients were involved with the average age of 29.7 years old when the diseases were onset. With diverse clinical manifestations, most patients displayed positively by NMDAR antibody test and 63.6% of them were associated with elevated CSF-lgA. Patients also showed abnormal MRI and EEG. Only three patients had teratomas. With hormone therapy, gamma globulin treatment or plasma exchange, more than three quarters of patients fully recovered and the others had moderate symptoms. Based on our results, we suggest that NMDAR antibody test would be helpful to make a timely diagnosis and to administer immunotherapy.
PMCID: PMC4694417  PMID: 26770517
Anti-NMDAR; Chinese population; clinical manifestations; treatment
10.  Middle Cerebral Artery Atherosclerotic Plaques in Recent Small Subcortical Infarction: A Three-Dimensional High-resolution MR Study 
BioMed Research International  2015;2015:540217.
Purpose. Conventional two-dimensional vessel wall imaging has been used to depict the middle cerebral artery (MCA) wall in patients with recent small subcortical infarctions (RSSIs). However, its clinical use has been limited by restricted spatial coverage, low signal-to-noise ratio (SNR), and long scan time. We used a novel three-dimensional high-resolution MR imaging (3D HR-MRI) technique to investigate the presence, locations, and contrast-enhanced patterns of MCA plaques and their relationship with RSSI. Methods. Nineteen consecutive patients with RSSI but no luminal stenosis on MR angiography were prospectively enrolled. 3D HR-MRI was performed using a T1w-SPACE sequence at 3.0 T. The presence, locations, and contrast-enhanced patterns of the MCA plaques on the ipsilateral and contralateral sides to the RSSI were analyzed. Results. Eighteen patients successfully completed the study. MCA atherosclerotic plaques occurred more frequently on the ipsilateral than the contralateral side to the RSSI (72.2% versus 33.3%, P = 0.044). The occurrence of superiorly located plaques was significantly higher on the ipsilateral than the contralateral side of the MCA (66.7% versus 27.8%; P = 0.044). Conclusions. Superiorly located plaques are closely associated with RSSI. 3D high-resolution vessel wall imaging may be a potential tool for etiologic assessment of ischemic stroke.
doi:10.1155/2015/540217
PMCID: PMC4619811  PMID: 26539508
11.  Sex Differences in Neuropsychiatric Symptoms of Alzheimer's Disease: The Modifying Effect of Apolipoprotein E ε4 Status 
Behavioural Neurology  2015;2015:275256.
Sex differences in neuropsychiatric symptoms of Alzheimer's disease (AD) have been demonstrated in previous studies, and apolipoprotein E (ApoE) ε4 status influences psychiatric manifestations of AD. However, whether ApoE ε4 status modifies the sex differences in neuropsychiatric symptoms of AD is still unclear. In this study, sex differences in neuropsychiatric abnormalities were stratified and analyzed by ApoE ε4 status in mild AD and moderate to severe AD separately. The Clinical Dementia Rating (CDR) scale and the Neuropsychiatric Inventory (NPI) were used to assess dementia severity and neuropsychiatric symptoms. No sex differences were found in mild AD. In moderate to severe AD, among ε4 positive individuals, disinhibition was significantly more prevalent (8.0% in men versus 43.2% in women, p = 0.003) and severer (p = 0.003) in female patients. The frequency (16.0% in men versus 51.4% in women, p = 0.005) and score (p = 0.004) of irritability were of borderline significance after strict Bonferroni correction. In conclusion, this study supported the modifying effect of ApoE ε4 status on sex differences in neuropsychiatric symptoms of AD, and this modifying effect was pronounced in moderate to severe stage of AD. The interaction between gender and ApoE ε4 status should be considered in studies on neuropsychiatric symptoms of AD.
doi:10.1155/2015/275256
PMCID: PMC4619911  PMID: 26538817
12.  Aging-associated formaldehyde-induced norepinephrine deficiency contributes to age-related memory decline 
Aging Cell  2015;14(4):659-668.
A norepinephrine (NE) deficiency has been observed in aged rats and in patients with Alzheimer’s disease and is thought to cause cognitive disorder. Which endogenous factor induces NE depletion, however, is largely unknown. In this study, we investigated the effects of aging-associated formaldehyde (FA) on the inactivation of NE in vitro and in vivo, and on memory behaviors in rodents. The results showed that age-related DNA demethylation led to hippocampal FA accumulation, and when this occurred, the hippocampal NE content was reduced in healthy male rats of different ages. Furthermore, biochemical analysis revealed that FA rapidly inactivated NE in vitro and that an intrahippocampal injection of FA markedly reduced hippocampal NE levels in healthy adult rats. Unexpectedly, an injection of FA (at a pathological level) or 6-hydroxydopamine (6-OHDA, a NE depletor) can mimic age-related NE deficiency, long-term potentiation (LTP) impairments, and spatial memory deficits in healthy adult rats. Conversely, an injection of NE reversed age-related deficits in both LTP and memory in aged rats. In agreement with the above results, the senescence-accelerated prone 8 (SAMP8) mice also exhibited a severe deficit in LTP and memory associated with a more severe NE deficiency and FA accumulation, when compared with the age-matched, senescence-resistant 1 (SAMR1) mice. Injection of resveratrol (a natural FA scavenger) or NE into SAMP8 mice reversed FA accumulation and NE deficiency and restored the magnitude of LTP and memory. Collectively, these findings suggest that accumulated FA is a critical endogenous factor for aging-associated NE depletion and cognitive decline.
doi:10.1111/acel.12345
PMCID: PMC4531079  PMID: 25866202
formaldehyde; long-term potentiation; norepinephrine; senescence-accelerated prone 8; spatial memory; spontaneous discharge
13.  FOXQ1 is overexpressed in laryngeal carcinoma and affects cell growth, cell cycle progression and cell invasion 
Oncology Letters  2015;10(4):2499-2504.
Forkhead box Q1 (FOXQ1) is a forkhead transcription factor that is involved in numerous biological processes and has been shown to participate in tumorigenesis. However, the clinical significance of the expression of this protein in laryngeal carcinoma, and the mechanisms underlying its regulation in this disease remain unclear. The aim of present study was to measure the expression of FOXQ1 in laryngeal carcinoma, and to examine its effect on tumorigenesis. In the present study, reverse transcription-quantitative polymerase chain reaction and western blotting were employed to measure FOXQ1 expression in laryngeal carcinoma tissue samples, small interfering RNA specific to FOXQ1, was transfected into Hep2 cells and its effect on cell proliferation, cell cycle progression and cell migration was examined, using a CCK-8 assay, flow cytometry and a transwell migration assay, respectively. The results showed overexpression of FOXQ1 mRNA and protein in laryngeal cancer tissue samples. Inhibition of FOXQ1 suppressed cell growth and invasion, and arrested cells in the G0/G1 phase. Overexpression of FOXQ1 is associated with the development of laryngeal carcinoma and may enhance tumorigenesis through its effects on cell proliferation, cell cycle progression and cell migration.
doi:10.3892/ol.2015.3530
PMCID: PMC4579982  PMID: 26622879
laryngeal carcinoma; forkhead box Q1; proliferation; invasion
14.  APOE Effects on Default Mode Network in Chinese Cognitive Normal Elderly: Relationship with Clinical Cognitive Performance 
PLoS ONE  2015;10(7):e0133179.
Background
Functional connectivity in default mode network (DMN) may be changed in Alzheimer’s disease (AD) patients and related risk populations, such as amnestic mild cognitive impairment (aMCI) patients and APOE ε4 carriers. Exploring DMN changes and related behavioral performance of APOE ε4 population might provide valuable evidence for better understanding the development of AD.
Methods
Subjects were enrolled from a population-based cohort established in a multi-center study in China. Forty-nine cognitive normal individuals were enrolled after standardized cognitive evaluations, MRI examination and APOE genotyping. Regions of interest (ROI)-based functional connectivity analyses were performed, and voxel-based analyses were used to validate these findings. The correlation between DMN functional connectivity and behavioral performance was further evaluated between APOE ε4ε3 and ε3ε3 carriers.
Results
Comparing to ε3ε3 carriers, functional connectivity between left parahippocampal gyrus and right superior frontal cortex (LPHC-R.Sup.F), left parahippocampal gyrus and medial prefrontal cortex (ventral) (LPHC-vMPFC) were significantly increased in ε4ε3 carriers, while connectivity between cerebellar tonsils and retrosplenial was decreased. LPHC-R.Sup.F connectivity was positively correlated with the changes of delay recall from baseline to follow-up (r = 0.768, p = 0.009), while LPHC-vMPFC connectivity had a positive correlation with MMSE at baseline (r = 0.356, p = 0.018), and a negative correlation with long-delayed recognition at follow-up (r = -0.677, p = 0.031). Significantly increased functional connectivity in vMPFC was confirmed in voxel-based analyses by taking LPHC as seed region.
Conclusion
APOE ε4 carriers present both increased and decreased functional connectivity in DMN, which is correlated with clinical cognitive performances. DMN changes might be an early sign for cognitive decline.
doi:10.1371/journal.pone.0133179
PMCID: PMC4503593  PMID: 26177270
15.  A preliminary study of the effect of ECRG4 overexpression on the proliferation and apoptosis of human laryngeal cancer cells and the underlying mechanisms 
Molecular Medicine Reports  2015;12(4):5058-5064.
Human esophageal cancer-related gene 4 (ECRG4) is a potential tumor suppressor gene isolated from human esophageal epithelial cells. Studies have shown that ECRG4 effectively inhibits the proliferation of tumor cells and induces apoptosis. However, the role of ECRG4 in laryngeal cancer has not yet been clearly defined. In this study, a human laryngeal cancer cell line stably overexpressing ECRG4 was established. The effect of ECRG4 on the proliferation and apoptosis of laryngeal cancer cells and the associated mechanisms were investigated. The Hep-2 human laryngeal carcinoma cell line exhibited a low basal level of ECRG4 expression and was selected for the present study. The eukaryotic expression plasmid pcDNA3.1-ECRG4 was constructed and introduced into Hep-2 cells by transfection reagents. Western blot analysis, reverse transcription-quantitative polymerase chain reaction and immunofluorescence staining confirmed high-level expression of ECRG4. The 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and colony formation assay showed that ECRG4 over-expression suppressed the proliferative capacity of laryngeal cancer cells in vitro. Cell cycle analysis showed that ECRG4 induced cell cycle arrest at the G0/G1 phase. Flow cytometric analysis and Hoechst staining demonstrated that overexpres-sion of ECRG4 significantly induced apoptosis. Western blot analysis confirmed that Bcl-2-associated X protein, cleaved-caspase-3 and cleaved-poly (ADP-ribose) polymerase were upregulated in the apoptotic process, whereas B-cell lymphoma 2 was downregulated. In conclusion, overexpression of ECRG4 inhibited laryngeal cancer cell proliferation and induced cancer cell apoptosis. Therefore, ECRG4 exhibits potential as an effective target in gene therapy for laryngeal cancer.
doi:10.3892/mmr.2015.4059
PMCID: PMC4581775  PMID: 26165988
human esophageal cancer-related gene 4; laryngeal cancer; Hep-2 cells; proliferation; apoptosis
16.  The Effects of Acupuncture at Real or Sham Acupoints on the Intrinsic Brain Activity in Mild Cognitive Impairment Patients 
Accumulating neuroimaging studies in humans have shown that acupuncture can modulate a widely distributed brain network in mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients. Acupuncture at different acupoints could exert different modulatory effects on the brain network. However, whether acupuncture at real or sham acupoints can produce different effects on the brain network in MCI or AD patients remains unclear. Using resting-state fMRI, we reported that acupuncture at Taixi (KI3) induced amplitude of low-frequency fluctuation (ALFF) change of different brain regions in MCI patients from those shown in the healthy controls. In MCI patients, acupuncture at KI3 increased or decreased ALFF in the different regions from those activated by acupuncture in the healthy controls. Acupuncture at the sham acupoint in MCI patients activated the different brain regions from those in healthy controls. Therefore, we concluded that acupuncture displays more significant effect on neuronal activities of the above brain regions in MCI patients than that in healthy controls. Acupuncture at KI3 exhibits different effects on the neuronal activities of the brain regions from acupuncture at sham acupoint, although the difference is only shown at several regions due to the close distance between the above points.
doi:10.1155/2015/529675
PMCID: PMC4433670  PMID: 26064166
17.  Factors Related to Long-Term Post-Stroke Cognitive Impairment in Young Adult Ischemic Stroke 
Background
Post-stroke cognitive impairment is common and a decisive prognostic factor. However, few studies have reported on post-stroke cognition in young adults, especially long-term cognition. This study was designed to investigate the influence of baseline factors, treatments, and functional outcome on the long-term cognitive outcome in young adults with ischemic stroke.
Material/Methods
Consecutive patients aged 18–45 years between January 1, 2006 and December 31, 2010, with a first-ever ischemic stroke, were recruited for cognitive assessment by telephone from December 10 to December 31, 2013 using modified versions of “Telephone Instrument for Cognitive Status” (TICS-m) scale. The relationship of cognitive impairment with baseline factors, treatments, and functional outcome were evaluated.
Results
A total of 350 patients with an average age of 41.0±6.8 years (69.7% males and 30.3% females) were reviewed. The average follow-up period was 5.8±3.2 years, and cognitive impairment existed in 39.4% of patients at follow-up. Stroke severity on admission, functional outcome (modified Rankin Scale, mRS >2) at discharge, left anterior circulation syndrome, and stroke recurrence were markedly associated with post-stroke cognitive impairment (all P<0.01). Post-stroke cognition was also significantly related to mRS at follow-up (r=−0.563, P<0.001).
Conclusions
Post-stroke cognition was related to functional outcome: hence, treatment directed toward reducing functional disability might also reduce cognitive impairment.
doi:10.12659/MSM.892554
PMCID: PMC4354446  PMID: 25729006
Adult; Hypoxia-Ischemia, Brain; Mild Cognitive Impairment
18.  A Randomized Trial of Chinese Diaoshi Jifa on Treatment of Dizziness in Meniere's Disease 
Background. Meniere's disease is characterized by refractory dizziness and hearing disturbance. We aimed to investigate the efficacy and tolerance of Diaoshi Jifa, a Chinese hand skill for treating dizziness in Meniere's disease. Methods. An open-labeled, randomized, controlled intervention trial was conducted. Twenty-seven patients diagnosed with Meniere's disease were randomly allocated to control group or experimental group. Both groups were assessed by DHI (dizziness handicap inventory (DHI)) questionnaire score before and within 24 hours of receiving treatment, respectively. Results. Twenty-six participants completed the study, and no adverse event was reported due to Diaoshi Jifa treatment. The difference in the DHI scores between baseline and posttreatment reached significant difference in both groups (63.88 ± 19.94 versus 10.25 ± 9.77 and 54.36 ± 17.97 versus 49.6 ± 20.50). Significant difference in DHI scores was observed between the two groups after treatment (10.25 ± 9.77 versus 49.6 ± 20.50). Further investigation of DHI subscales in the experimental group revealed significant improvement posttreatment in the physical domain, functional domain, and emotional domain. Although higher rate of improvement in the emotional domain compared to physical or functional domains was found, the difference was not statistically significant. Conclusions. Diaoshi Jifa might be a fast, effective, and well-tolerated method for alleviating dizziness in Meniere's disease.
doi:10.1155/2014/521475
PMCID: PMC4052476  PMID: 24955104
19.  Selective Changes of Resting-State Brain Oscillations in aMCI: An fMRI Study Using ALFF 
BioMed Research International  2014;2014:920902.
Mild cognitive impairment (MCI) refers to a transitional state between normal aging and dementia and is a syndrome with cognitive decline greater than expected for an individual's age and educational level. As a subtype of MCI, amnestic mild cognitive impairment (aMCI) most often leads to Alzheimer's disease. This study aims to elucidate the altered brain activation in patients with aMCI using resting-state functional magnetic resonance. We observed Frequency-dependent changes in the amplitude of low-frequency fluctuations in aMCI patients (n = 20), and normal subjects (n = 18). At the same time, we took gray matter volume as a covariate. We found that aMCI patients had decreased amplitude of low-frequency fluctuation signal in left superior temporal gyrus, right middle temporal gyrus, right inferior parietal lobe, and right postcentral gyrus compared to the control group. Specially, aMCI patients showed increased signal in left superior and middle frontal gyrus. Our results suggested that increased activation in frontal lobe of aMCI patients may indicate effective recruitment of compensatory brain resources. This finding and interpretation may lead to the better understanding of cognitive changes of aMCI.
doi:10.1155/2014/920902
PMCID: PMC4005061  PMID: 24822220
20.  Peroxiredoxin 2 battles PARP1- and p53-dependent pro-death pathways following ischemic injury 
Background and Purpose
Ischemic/reperfusion neuronal injury is characterized by accumulation of reactive oxygen species (ROS) and oxidative DNA damage, which can trigger cell death by various signaling pathways. Two of these modes of death include poly(ADP-ribose) polymerase 1 (PARP1)-mediated death or p53- and Bax-mediated apoptosis. The present study tested the hypothesis that peroxiredoxin2 (PRX2) attenuates DNA damage-mediated pro-death signaling using in vitro and in vivo models of ischemic injury. The impact of this peroxide scavenger on p53- and PARP1-mediated ischemic death is unknown.
Methods
Neuronal PRX2 overexpression in primary cortical cultures and transgenic mice was combined with the PARP1 inhibitor AG14361. AG14361 was also applied to p53 and Bax knockout cultures and mice and combined with the JNK inhibitor SP600125. DCF fluorescence, AP sites, single-strand breaks, Comet tail-length, NAD+ depletion, and viability were assessed in response to oxygen-glucose deprivation in cultures or transient focal cerebral ischemia in mice.
Results
PRX2 attenuated ROS, DNA damage, NAD+ depletion, and cell death. PRX2 knockdown exacerbated neuronal death following OGD. PRX2 ameliorated PARP1, p53, Bax, and caspase activation following ischemia. AG14361 reduced ischemic cell death in wild-type and p53 or Bax knockout cultures and animals but had no additional effect in PRX2-overexpressing mice. AG14361 and p53 knockout elicited additive effects with SP600125 on viability in vitro. Our findings support the existence of multiple parallel pro-death pathways with some crosstalk.
Conclusions
The promising therapeutic candidate PRX2 can clamp upstream DNA damage and efficiently inhibit multiple pro-death cascades operating in both parallel and interactive fashions.
doi:10.1161/STROKEAHA.111.680157
PMCID: PMC3891055  PMID: 23429506
PRX2; stroke; apoptosis; necrosis; p53; PARP1; Bax
21.  A Lifespan Observation of a Novel Mouse Model: In Vivo Evidence Supports Aβ Oligomer Hypothesis 
PLoS ONE  2014;9(1):e85885.
Transgenic mouse models are powerful tools in exploring the mechanisms of AD. Most current transgenic models of AD mimic the memory impairment and the main pathologic features, among which the formation of beta-amyloid (Aβ) plaques is considered a dominant pathologic event. Recently, Aβ oligomers have been identified as more neurotoxic than Aβ plaques. However, no ideal transgenic mouse model directly support Aβ oligomers as a neurotoxic species due to the puzzling effects of amyloid plaques in the more widely-used models. Here, we constructed a single-mutant transgenic (Tg) model harboring the PS1V97L mutation and used Non-Tg littermates as a control group. Employing the Morris water maze, electrophysiology, immunohistochemistry, biochemistry, and electron microscopy, we investigated behavioral changes and pathology progression in our single-mutant transgenic model. We discovered the pathological alteration of intraneuronal accumulation of Aβ oligomers without Aβ plaques in the PS1V97L-Tg mouse model, which might be the result of PS1 gene mutation. Following Aβ oligomers, we detected synaptic alteration, tau hyperphosphorylation and glial activation. This model supports an initial role for Aβ oligomers in the onset of AD and suggests that Aβ plaques may not be the only prerequisite. This model provides a useful tool for studying the role of Aβ oligomers in AD pathogenesis.
doi:10.1371/journal.pone.0085885
PMCID: PMC3897547  PMID: 24465766
22.  White Matter Changes in Patients with Amnestic Mild Cognitive Impairment Detected by Diffusion Tensor Imaging 
PLoS ONE  2013;8(3):e59440.
Compared to normal aging adults, individuals with amnestic mild cognitive impairment (aMCI) have significantly increased risk for progressing into Alzheimer’s disease (AD). Autopsy studies found that most of the brains of aMCI cases showed anatomical features associated with AD pathology. The recent development of non-invasive neuroimaging technique, such as diffusion tensor imaging (DTI), makes it possible to investigate the microstructures of the cerebral white matter in vivo. We hypothesized that disrupted white matter (WM) integrity existed in aMCI. So we used DTI technique, by measuring fractional anisotropy (FA) and mean diffusivity (MD), to test the brain structures involved in patients with aMCI. DTI scans were collected from 40 patients with aMCI, and 28 normal controls (NC). Tract-based spatial statistics (TBSS) analyses of whole-brain FA and MD images in each individual and group comparisons were carried out. Compared to NC, aMCI patients showed significant FA reduction bilaterally, in the association and projection fibers of frontal, parietal, and temporal lobes, corpus callosum, bilateral corona radiation, right posterior thalamic radiation and right sagittal stratum. aMCI patients also showed significantly increased MD widespreadly in the association and projection fibers of frontal, parietal and temporal lobes, and corpus callosum. Assessment of the WM integrity of the frontal, parietal, temporal lobes, and corpus callosum by using DTI measures may aid early diagnosis of aMCI.
doi:10.1371/journal.pone.0059440
PMCID: PMC3605411  PMID: 23555673
23.  Genetic association of urokinase-type plasminogen activator gene rs2227564 site polymorphism with sporadic Alzheimer's disease in the Han Chinese population☆ 
Neural Regeneration Research  2012;7(30):2377-2383.
A missense C/T polymorphism in exon 6 (the NCBI rsID is rs2227564) of the urokinase-type plasminogen activator gene has been identified as a possible hot spot for Alzheimer's disease risk. The present study analyzed urokinase-type plasminogen gene polymorphisms of rs2227564 with sporadic Alzheimer's disease by PCR-restriction fragment length polymorphism. Results showed that CC, CT and TT genotype distribution frequencies had significant differences between sporadic Alzheimer's disease patients and healthy controls. In-depth analysis of the association between urokinase-type plasminogen gene rs2227564 polymorphisms and sporadic Alzheimer's disease indicated that people with the C-positive genotype CC + CT were at a higher risk for developing sporadic Alzheimer's disease. These results support the contribution of the polymorphisms of rs2227564 in the urokinase-type plasminogen gene to the pathogenesis of sporadic Alzheimer's disease in the Han Chinese population.
doi:10.3969/j.issn.1673-5374.2012.30.008
PMCID: PMC4268744  PMID: 25538763
Alzheimer's disease; urokinase plasminogen activator; polymorphism; genetic testing; Han Chinese population; neural regeneration
24.  Dissociation between Brain Amyloid Deposition and Metabolism in Early Mild Cognitive Impairment 
PLoS ONE  2012;7(10):e47905.
Background
The hypothetical model of dynamic biomarkers for Alzheimer’s disease (AD) describes high amyloid deposition and hypometabolism at the mild cognitive impairment (MCI) stage. However, it remains unknown whether brain amyloidosis and hypometabolism follow the same trajectories in MCI individuals. We used the concept of early MCI (EMCI) and late MCI (LMCI) as defined by the Alzheimer’s disease Neuroimaging Initiative (ADNI)-Go in order to compare the biomarker profile between EMCI and LMCI.
Objectives
To examine the global and voxel-based neocortical amyloid burden and metabolism among individuals who are cognitively normal (CN), as well as those with EMCI, LMCI and mild AD.
Methods
In the present study, 354 participants, including CN (n = 109), EMCI (n = 157), LMCI (n = 39) and AD (n = 49), were enrolled between September 2009 and November 2011 through ADNI-GO and ADNI-2. Brain amyloid load and metabolism were estimated using [18F]AV45 and [18F]fluorodeoxyglucose ([18F]FDG) PET, respectively. Uptake ratio images of [18F]AV45 and [18F]FDG were calculated by dividing the summed PET image by the median counts of the grey matter of the cerebellum and pons, respectively. Group differences of global [18F]AV45 and [18F]FDG were analyzed using ANOVA, while the voxel-based group differences were estimated using statistic parametric mapping (SPM).
Results
EMCI patients showed higher global [18F]AV45 retention compared to CN and lower uptake compared to LMCI. SPM detected higher [18F]AV45 uptake in EMCI compared to CN in the precuneus, posterior cingulate, medial and dorsal lateral prefrontal cortices, bilaterally. EMCI showed lower [18F]AV45 retention than LMCI in the superior temporal, inferior parietal, as well as dorsal lateral prefrontal cortices, bilaterally. Regarding to the global [18F]FDG, EMCI patients showed no significant difference from CN and a higher uptake ratio compared to LMCI. At the voxel level, EMCI showed higher metabolism in precuneus, hippocampus, entorhinal and inferior parietal cortices, as compared to LMCI.
Conclusions
The present results indicate that brain metabolism remains normal despite the presence of significant amyloid accumulation in EMCI. These results suggest a role for anti-amyloid interventions in EMCI aiming to delay or halt the deposition of amyloid and related metabolism impairment.
doi:10.1371/journal.pone.0047905
PMCID: PMC3480449  PMID: 23112868
25.  Structural and Functional Changes in Subcortical Vascular Mild Cognitive Impairment: A Combined Voxel-Based Morphometry and Resting-State fMRI Study 
PLoS ONE  2012;7(9):e44758.
The present study aimed to investigate changes in structural gray matter (GM) volume and functional amplitude of spontaneous low-frequency oscillations (LFO) and functional connectivity density in patients with subcortical vascular mild cognitive impairment (svMCI). Structural MRI and resting-sate functional MRI data were collected from 26 svMCI patients and 28 age- and gender-matched healthy controls. Structurally, widespread GM atrophy was found in the svMCI patients that resided primarily in frontal (e.g., the superior and middle frontal gyri and medial prefrontal cortex) and temporal (the superior and inferior temporal gyri) brain regions as well as several subcortical brain sites (e.g., the thalamus and the caudate). Functionally, svMCI-related changes were predominantly found in the default mode network (DMN). Compared with the healthy controls, the svMCI patients exhibited decreased LFO amplitudes in the anterior part of the DMN (e.g., the medial prefrontal cortex), whereas increased LFO amplitudes in the posterior part of the DMN (e.g., the posterior cingulate/precuneus). As for functional connectivity density, the DMN regions (e.g., the posterior cingulate/precuneus, the medial prefrontal cortex and the middle temporal gyrus) consistently exhibited decreased functional connectivity. Finally, the overall patterns of functional alterations in LFO amplitudes and functional connectivity density remained little changed after controlling for structural GM volume losses, which suggests that functional abnormalities can be only partly explained by morphological GM volume changes. Together, our results indicate that svMCI patients exhibit widespread abnormalities in both structural GM volume and functional intrinsic brain activity, which have important implications in understanding the pathophysiological mechanism of svMCI.
doi:10.1371/journal.pone.0044758
PMCID: PMC3446994  PMID: 23028606

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