Jing-Cheng Li

Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory

Non-fibrillar soluble oligomeric forms of amyloid-β peptide (oAβ) and tau proteins are likely to play a major role in Alzheimer’s disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oAβ initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Aβ, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAβ levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAβ to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and Aβ on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with Aβ and tau pathology.

Association between NADPH Oxidase p22phox C242T Polymorphism and Ischemic Cerebrovascular Disease: A Meta-Analysis

Background Epidemiological studies have evaluated the association between nicotinamide adenine dinucleotide phosphate (NADPH) oxidase p22phox C242T polymorphism and risk of ischemic cerebrovascular disease (ICVD), but the results remain inconclusive. This meta-analysis was therefore designed to clarify these controversies. Methodology/Principal Findings Systematic searches of electronic databases Embase, PubMed and Web of Science, as well as hand searching of the references of identified articles and the meeting abstracts were performed. Statistical analyses were performed using software Review Manager (Version 5.1.7) and Stata (Version 11.0). The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were performed. Fixed or random effects model was separately used depending on the heterogeneity between studies. Publication bias was tested by Beggs funnel plot and Eggers regression test. A total of 6 studies including 1,948 cases and 2,357 controls were combined showing no statistical evidence of association between NADPH oxidase p22phox C242T polymorphism and overall ICVD (allelic model: OR = 1.08, 95%CI = 0.93–1.26; additive model: OR = 1.33, 95%CI = 0.81–2.17; dominant model: OR = 1.00, 95%CI = 0.86–1.15; recessive model: OR = 1.06, 95%CI = 0.77–1.45). Significant association was found in large-artery atherosclerotic stroke subgroup (allelic model: OR = 1.12, 95%CI = 0.88–1.41; additive model: OR = 1.36, 95%CI = 0.60–3.09; dominant model: OR = 1.25, 95%CI = 0.74–2.11; recessive model: OR = 2.17, 95%CI = 1.11–4.23). No statistical evidence of significant association was observed for small-vessel occlusive stroke, as well as Asian subgroup and Caucasian subgroup. Statistical powers on the combined sample size (total and subgroup) were all lower than 80%. Conclusions/Significance This meta-analysis indicates that NADPH oxidase p22phox C242T polymorphism is more associated with large-artery atherosclerotic stroke than small-vessel occlusive stroke. However, this conclusion should be interpreted with caution due to the small sample size. Larger sample-size studies with homogeneous ICVD patients and well-matched controls are required.

An overview of potential molecular mechanisms involved in VSMC phenotypic modulation

The fully differentiated medial vascular smooth muscle cells (VSMCs) of mature vessels keep quiescent and contractile. However, VSMC can exhibit the plasticity in phenotype switching from a differentiated and contractile phenotype to a dedifferentiated state in response to alterations in local environmental cues, which is called phenotypic modulation or switching. Distinguishing from its differentiated state expressing more smooth muscle (SM)-specific/selective proteins, the phenotypic modulation in VSMC is characterized by an increased rate of proliferation, migration, synthesis of extracellular matrix proteins and decreased expression of SM contractile proteins. Although it has been well demonstrated that phenotypic modulation of VSMC contributes to the occurrence and progression of many proliferative vascular diseases, little is known about the details of the molecular mechanisms of VSMC phenotypic modulation. Growing evidence suggests that variety of molecules including microRNAs, cytokines and biochemical factors, membrane receptors, ion channels, cytoskeleton and extracellular matrix play important roles in controlling VSMC phenotype. The focus of the present review is to provide an overview of potential molecular mechanisms involved in VSMC phenotypic modulation in recent years. To clarify VSMC differentiation and phenotypic modulation mechanisms will contribute to producing cell-based therapeutic interventions for aberrant VSMC differentiation-related diseases.

Influence of ATP-binding cassette transporter 1 R219K and M883I polymorphisms on development of atherosclerosis: a meta-analysis of 58 studies.

Background Numerous epidemiological studies have evaluated the associations between ATP-binding cassette transporter 1 (ABCA1) R219K (rs2230806) and M883I (rs4149313) polymorphisms and atherosclerosis (AS), but results remain controversial. The purpose of the present study is to investigate whether these two polymorphisms facilitate the susceptibility to AS using a meta-analysis. Methods PubMed, Embase, Web of Science, Medline, Cochrane database, Clinicaltrials.gov, Current Controlled Trials, Chinese Clinical Trial Registry, CBMdisc, CNKI, Google Scholar and Baidu Library were searched to get the genetic association studies. All statistical analyses were done with Stata 11.0. Results Forty-seven articles involving 58 studies were included in the final meta-analysis. For the ABCA1 R219K polymorphism, 42 studies involving 12,551 AS cases and 19,548 controls were combined showing significant association between this variant and AS risk (for K allele vs. R allele: OR = 0.77, 95% CI = 0.71–0.84, P<0.01; for K/K vs. R/R: OR = 0.60, 95% CI = 0.51–0.71, P<0.01; for K/K vs. R/K+R/R: OR = 0.69, 95% CI = 0.60–0.80, P<0.01; for K/K+R/K vs. R/R: OR = 0.74, 95% CI = 0.66–0.83, P<0.01). For the ABCA1 M883I polymorphism, 16 studies involving 4,224 AS cases and 3,462 controls were combined. There was also significant association between the variant and AS risk (for I allele vs. M allele: OR = 0.85, 95% CI = 0.77–0.95, P<0.01). Conclusions The present meta-analysis suggested that the ABCA1 R219K and M883I polymorphisms were associated with the susceptibility to AS. However, due to the high heterogeneity in the meta-analysis, the results should be interpreted with caution.

The C825T Polymorphism of the G-Protein β3 Subunit Gene and Its Association with Hypertension and Stroke: An Updated Meta-Analysis

Objective Several epidemiological studies have evaluated the association between the GNB3 C825T polymorphism and hypertension or stroke. The results of these studies were inconsistent; therefore, we performed a meta-analysis to clarify these discrepancies. Methods We systematically searched the PubMed, Embase, Web of Science, CNKI, and CBM databases, and manually searched reference lists of relevant papers, meeting abstracts, and relevant journals. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for dominant, recessive, and allelic models. A fixed or random effects model was separately adopted depending on study heterogeneity. Subgroup and sensitivity analyses were performed to detect study heterogeneity and examine result stability, respectively. Publication bias was tested using funnel plots, the Eggers regression test, and Beggs test. Results We screened 66 studies regarding hypertension and eight concerning stroke. A combined analysis showed that only the allelic model found a marginal association with hypertension (OR = 1.07, 95% CI = 1.01–1.13) and female gender (OR = 1.11, 95% CI = 0.99–1.24). However, no comparison models found an association with stroke (allelic model: OR = 1.11, 95% CI = 0.94–1.32; dominant model: OR = 1.16, 95% CI = 0.92–1.48; and recessive model: OR = 1.05, 95% CI = 0.97–1.14). Sensitivity analysis suggested that all models did not yield a relationship to hypertension or stroke among Asians. Besides, there was a lack of statistical association with hypertension in Caucasians, which maybe due to a small sample size. When we restricted the included studies to normal populations according to the Hardy–Weinberg equilibrium, no association was found. Conclusions There was no evidence indicating that the 825T allele or TT genotype was associated with hypertension or stroke in Asians or hypertension in Caucasians. However, further studies regarding Africans and other ethnicities are needed to identify further correlations.

Influence of interleukin-6 gene -174G>C polymorphism on development of atherosclerosis: a meta-analysis of 50 studies involving 33,514 subjects.

Increasing epidemiological studies have focused on the associations between interleukin-6 (IL-6) gene -174G>C polymorphism and atherosclerotic diseases, but the results are still controversial. This meta-analysis was designed to identify whether this association exists. PubMed, Embase, Web of Science, Cochrane database, Clinicaltrials.gov and Current Controlled Trials, Chinese Clinical Trial Registry, CBMdisc, CNKI and Google Scholar were searched to get the genetic association studies. The crude odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were used to estimate the association between the IL-6 gene -174G>C polymorphism and atherosclerosis ( AS ) risk. The subgroup analyses were made on the following: ethnicity, atherosclerotic diseases and source of controls. Finally, 50 studies (15,029 cases and 18,485 controls) were included in this meta-analysis. Overall, no significant association was found between the IL-6 gene -174G>C polymorphism and AS risk (for C allele vs. G allele: OR=1.02, 95% CI=0.94-1.11, p=0.64; for C/C vs. G/G: OR=1.01, 95% CI=0.85-1.21, p=0.88; for C/C vs. C/G+G/G: OR=0.97, 95% CI=0.84-1.12, p=0.68; for C/C+C/G vs. G/G: OR=1.07, 95% CI=0.97-1.17, p=0.18). In the subgroup analyses, significant associations were found between the IL-6 gene -174G>C polymorphism and AS in non-Caucasian group (for CC+CG vs. GG: OR=1.22, 95% CI=1.06-1.41, p=0.005), other atherosclerotic diseases group (for C allele vs. G allele: OR =0.75, 95% CI=0.61-0.93, p=0.008; for C/C vs. G/G: OR=0.56, 95% CI=0.38-0.81, p=0.002; for C/C vs. C/G+G/G: OR=0.60, 95% CI=0.45-0.79, p=0.0004) and population-based group (for C allele vs. G allele: OR=1.09, 95% CI=1.00-1.18, p=0.04; for CC+CG vs. GG: OR=1.15, 95% CI=1.04-1.27, p=0.005). In summary, the present meta-analysis suggests that the IL-6 gene -174G C polymorphism is associated with the susceptibility to AS. However, due to the high heterogeneity in the meta-analysis, the results should be interpreted with caution.

PPARγ Inhibits VSMC Proliferation and Migration via Attenuating Oxidative Stress through Upregulating UCP2

Increasing evidence showed that abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are common event in the pathophysiology of many vascular diseases, including atherosclerosis and restenosis after angioplasty. Among the underlying mechanisms, oxidative stress is one of the principal contributors to the proliferation and migration of VSMCs. Oxidative stress occurs as a result of persistent production of reactive oxygen species (ROS). Recently, the protective effects of peroxisome proliferator-activated receptor γ (PPARγ) against oxidative stress/ROS in other cell types provide new insights to inhibit the suggests that PPARγ may regulate VSMCs function. However, it remains unclear whether activation of PPARγ can attenuate oxidative stress and further inhibit VSMC proliferation and migration. In this study, we therefore investigated the effect of PPARγ on inhibiting VSMC oxidative stress and the capability of proliferation and migration, and the potential role of mitochondrial uncoupling protein 2 (UCP2) in oxidative stress. It was found that platelet derived growth factor-BB (PDGF-BB) induced VSMC proliferation and migration as well as ROS production; PPARγ inhibited PDGF-BB-induced VSMC proliferation, migration and oxidative stress; PPARγ activation upregulated UCP2 expression in VSMCs; PPARγ inhibited PDGF-BB-induced ROS in VSMCs by upregulating UCP2 expression; PPARγ ameliorated injury-induced oxidative stress and intimal hyperplasia (IH) in UCP2-dependent manner. In conclusion, our study provides evidence that activation of PPARγ can attenuate ROS and VSMC proliferation and migration by upregulating UCP2 expression, and thus inhibit IH following carotid injury. These findings suggest PPARγ may represent a prospective target for the prevention and treatment of IH-associated vascular diseases.

Changes of dendritic spine density and morphology in the superficial layers of the medial entorhinal cortex induced by extremely low-frequency magnetic field exposure.

In the present study, we investigated the effects of chronic exposure (14 and 28 days) to a 0.5 mT 50 Hz extremely low-frequency magnetic field (ELM) on the dendritic spine density and shape in the superficial layers of the medial entorhinal cortex (MEC). We performed Golgi staining to reveal the dendritic spines of the principal neurons in rats. The results showed that ELM exposure induced a decrease in the spine density in the dendrites of stellate neurons and the basal dendrites of pyramidal neurons at both 14 days and 28 days, which was largely due to the loss of the thin and branched spines. The alteration in the density of mushroom and stubby spines post ELM exposure was cell-type specific. For the stellate neurons, ELM exposure slightly increased the density of stubby spines at 28 days, while it did not affect the density of mushroom spines at the same time. In the basal dendrites of pyramidal neurons, we observed a significant decrease in the mushroom spine density only at the later time point post ELM exposure, while the stubby spine density was reduced at 14 days and partially restored at 28 days post ELM exposure. ELM exposure-induced reduction in the spine density in the apical dendrites of pyramidal neurons was only observed at 28 days, reflecting the distinct vulnerability of spines in the apical and basal dendrites. Considering the changes in spine number and shape are involved in synaptic plasticity and the MEC is a part of neural network that is closely related to learning and memory, these findings may be helpful for explaining the ELM exposure-induced impairment in cognitive functions.

The association between leukoaraiosis and carotid atherosclerosis: a systematic review and meta-analysis

The association between large-artery atherosclerosis and leukoaraiosis (LA) has been increasingly reported with inconsistent conclusion. This systematic review examines the relationship between LA and carotid atherosclerosis, manifested as atherosclerotic stenosis, plaques and increased intima-media thickness (IMT). PubMed, Embase, and Web of Science were searched for articles published up to February 2014. Thirty-two studies that examined the relationship between LA and carotid atherosclerosis were included. All statistical analysis was conducted with Review Manager 5.2.4. Finally, 32 studies including 17,721 patients were identified. There were 7 (30%) out of 23 studies reporting significant association between LA and carotid stenosis; 11 (79%) out of 14 studies reporting significant association between LA and carotid plaque; all 9 studies reporting significant association between LA and carotid IMT; one study showing an association between LA and CAWT (similar to the role of the IMT). The quantitative meta-analysis of 10 studies showed that carotid atherosclerosis was not associated with LA (OR: 1.10; 95% CI: 0.61–1.98). A significant association was found between LA and carotid plaque (OR = 3.53; 95% CI = 1.83–6.79), and the result of IMT group showed that IMT increased risk of LA (MD = 0.11; 95% CI = 0.01–0.22). This systematic review suggested that LA has a tendency of association with carotid plaques but no association with simple carotid stenosis.

The role of TRPV1 in improving VSMC function and attenuating hypertension

The transient receptor potential vanilloid type 1 (TRPV1) channel, a ligand-gated cation channel of the TRP subfamily, can be activated by multiple stimuli, including capsaicin. Currently, cumulative studies have demonstrated an interesting link between TRPV1 and cardiovascular diseases, including hypertension. Additionally, the protective effect of TRPV1 against hypertension and its related disorders has been proved to be partly involved with the improved action of vascular smooth muscle cells (VSMCs). This review focuses on the current knowledge of TRPV1 in improving VSMC function and attenuating hypertension.