Epigenetic transcripts of LINC01311 and hsa-miR-146a-5p regulate neural development in a cellular model of Alzheimer's disease.

Emerging evidence has shown that Long noncoding RNAs (LncRNAs) are aberrantly expressed and functionally involved in the development of neurodegenerative disorders. In this work, we investigated the regulatory effects of lncRNA of LINC01311 and its competing endogenous RNA target of hsa-miR-146a-5p in a cellular model of Alzheimer's disease (AD). SH-SY5Y cells were treated with synthetic Βeta-Amyloid Peptide (1-42) (AB1-42) in vitro to induce AD-like neural injuries. Expressions of LINC01311 and hsa-miR-146a-5p were monitored by qRT-PCR. LINC01311 was upregulated and hsa-miR-146a-5p downregulated to examine their functional regulations on AB1-42-induced apoptosis, proliferation slowdown, autophagy, and amyloid precursor protein (APP) accumulations. Hsa-miR-146a-5p was also overexpressed in LINC01311-upregulated SH-SY5Y cells to examine their correlated regulations on AB1-42-induced neural injuries. LINC01311 was downregulated whereas hsa-miR-146a-5p upregulated in AB1-42 treated SH-SY5Y cells. LINC01311 upregulation and hsa-miR-146a-5p downregulation protected AB1-42-induced apoptosis, proliferation slowdown, autophagy, and APP accumulations in SH-SY5Y cells. Hsa-miR-146a-5p overexpression reversed the protection of LINC01311 on AB1-42-induced neural injuries. Our work demonstrated that the epigenetic axis of LINC01311/hsa-miR-146a-5p was involved in the functional regulation of human-lineage neurons in a cellular model of AD, thus suggesting a clinical potential of exploring epigenetic network for treating AD patients.

GAA compound heterozygous mutations associated with autophagic impairment cause cerebral infarction in Pompe disease.

Clinical manifestations of the late-onset adult Pompe disease (glycogen storage disease type II) are heterogeneous. To identify genetic defects of a special patient population with cerebrovascular involvement as the main symptom, we performed whole-genome sequencing (WGS) analysis on a consanguineous Chinese family of total eight members including two Pompe siblings both had cerebral infarction. Two novel compound heterozygous variants were found in GAA gene: c.2238G>C in exon 16 and c.1388_1406del19 in exon 9 in the two patients. We verified the function of the two mutations in leading to defects in GAA protein expression and enzyme activity that are associated with autophagic impairment. We further performed a gut microbiome metagenomics analysis, found that the child's gut microbiome metagenome is very similar to his mother. Our finding enriches the gene mutation spectrum of Pompe disease, and identified the association of the two new mutations with autophagy impairment. Our data also indicates that gut microbiome could be shared within Pompe patient and cohabiting family members, and the abnormal microbiome may affect the blood biochemical index. Our study also highlights the importance of deep DNA sequencing in potential clinical applications.

miR­128 is upregulated in epilepsy and promotes apoptosis through the SIRT1 cascade.

The present study aimed to examine the functional and molecular effects of miR­128 in epilepsy, in order to investigate its potential protective mechanisms. Firstly, miR­128 expression in rats with lithium chloride­induced epilepsy was demonstrated to be increased compared with the control rats. Subsequently, results from an in vitro epilepsy model demonstrated that overexpression of miR­128 promoted nerve cell apoptosis, increased the protein expression of tumor protein p53, BCL2 associated X (Bax) and Cytochrome c, and enhanced caspase­3/9 activity, whereas it suppressed the protein expression of sirtuin 1 (SIRT1). In addition, these alterations may be reversed by the downregulation of miR­128. Furthermore, treatment with CAY10602, a SIRT1 agonist, reduced the effects of miR­128 on nerve cells in vitro. Treatment with pifithrin­ß hydrobromide, a p53 inhibitor, was additionally able to mitigate the effects of miR­128 in vitro. In conclusion, the present findings indicated that anti­miR­128 may exert neuroprotective effects in epilepsy, through the SIRT1/p53/Bax/Cytochrome c/caspase signaling pathway.

DNA Nanostructure-Programmed Like-Charge Attraction at the Cell-Membrane Interface.

Cell entry of anionic nano-objects has been observed in various types of viruses and self-assembled DNA nanostructures. Nevertheless, the physical mechanism underlying the internalization of these anionic particles across the negatively charged cell membrane remains poorly understood. Here, we report the use of virus-mimicking designer DNA nanostructures with near-atomic resolution to program "like-charge attraction" at the interface of cytoplasmic membranes. Single-particle tracking shows that cellular internalization of tetrahedral DNA nanostructures (TDNs) depends primarily on the lipid-raft-mediated pathway, where caveolin plays a key role in providing the short-range attraction at the membrane interface. Both simulation and experimental data establish that TDNs approach the membrane primarily with their corners to minimize electrostatic repulsion, and that they induce uneven charge redistribution in the membrane under the short-distance confinement by caveolin. We expect that the nanoscale like-charge attraction mechanism provides new clues for viral entry and general rules for rational design of anionic carriers for therapeutics.

Risk of post-traumatic epilepsy after severe head injury in patients with at least one seizure.

BACKGROUND: To explore the incidence and risk factors, including type of seizures for post-traumatic epilepsy (PTE) after severe traumatic brain injury (TBI). SUBJECTS AND METHODS: This was a retrospective follow-up study of patients discharged from Liaocheng People's Hospital between March 2011 and June 2015 with a diagnosis of post-traumatic seizures. Risk factors for PTE were evaluated in 68 inpatients by using Kaplan-Meier curves and the Cox model. RESULTS: Complete clinical information was available for 68 patients. A total of 54 cases (79.4%) were diagnosed as presenting with PTE, occurring from 10 days to 179 months after severe TBI. Nineteen out of 54 cases (35.2%) had been defined as PTE within the first 6 months after the trauma, 17 cases (31.5%) within 7-12 months, 8 cases (14.8%) within 13-24 months, 2 cases (3.7%) within 25-36 months, and 8 cases (14.8%) within 37-179 months after the TBI. The Kaplan-Meier curves demonstrated that simple partial seizures, surgical treatment, and onset of seizures occurring within 6 months after injury were associated with PTE. CONCLUSIONS: The Cox model indicated that, for patients aged >34 years at the time of injury, the PTE risk was 2.55 times greater than for those aged ≤34 years. In addition, simple partial seizures, surgical treatment and onset of seizures occurring within 6 months after injury were significant risk factors for the development of PTE.

Prior transient ischemic attacks may have a neuroprotective effect in patients with ischemic stroke.

INTRODUCTION: Although functional recovery and survival after ischemic infarction seem to improve in patients with prior transient ischemic attack (TIA), little is known about the role of characteristics of prior TIA in subsequent cerebral infarction. Thus, the objective of this study was to explore how the characteristics of prior TIA have a neuroprotective effect on patients with ischemic stroke. MATERIAL AND METHODS: A total of 221 patients admitted consecutively to a primary care center for first-ever ischemic stroke were divided into two groups on the basis of the presence or absence of prior TIAs. The initial NIHSS modified Rankin Scale was used to measure the severity and disability after the stroke. Subgroups were based on the TIA duration (< 10 min, 10 to 60 min, and > 60 min), TIA frequency (1 time, 2-3 times, more than 3 times), and the interval of stroke (< 1 week, 1-4 weeks, > 4 weeks). The severity of the neurologic picture on admission and functional disability after stroke were compared between patients with and without TIAs and subgroups as well. RESULTS: A total of 132 (59.73%) of the 221 patients had prior TIAs before stroke. Risk factors and the initial clinical picture did not differ between patients with or without TIAs. Patients with prior TIA had a more favorable outcome than those without TIA (59.09% vs. 43.82%), and a significant difference between the two groups was observed (χ² = 4.976, p = 0.026). Furthermore, neurological outcome in patients with prior TIA lasting for 60 min, less than 3 times and shorter intervals within 4 weeks was significantly different from that in the non-TIA group (p < 0.05). CONCLUSIONS: Prior transient ischemic attacks may have a neuroprotective effect on the subsequent ischemic stroke, and this effect might be affected by the characteristics of TIAs. Patients with TIAs of low frequency, short duration and short interval are considered to have better neurological outcomes.

Impaired Center-Surround Suppression in Patients with Alzheimer's Disease.

Alzheimer's disease (AD) is often associated with declined visual processing abilities. Here we tested whether the functions of center-surround suppression- a hallmark property in the visual system- are altered by AD. To this end, we recruited three groups of participants (AD, elderly, and young) in a motion direction discrimination task, in which we measured the temporal duration threshold of a  drifting Gabor with varying stimulus sizes. We first replicated the phenomena of center-surround suppression that the required duration for discriminating a high contrast grating decreases with increasing stimulus size. We then showed that the magnitudes of suppression varied among the three groups. There was progressive reduction of suppression in the elderly and AD groups compared with the young group. Interestingly, we found that the levels of suppression can predict the severity of dementia in the AD group. Our results suggest that AD is associated with impaired center-surround functions in the visual motion processing pathway.

Contribution of Pro-inflammatory Cytokine Signaling within Midbrain Periaqueductal Gray to Pain Sensitivity in Parkinson's Disease via GABAergic Pathway.

BACKGROUND/AIMS: Hypersensitive pain response is often observed in patients with Parkinson's disease (PD); however, the mechanisms responsible for hyperalgesia are not well understood. Chronic neuroinflammation is one of the hallmarks of PD pathophysiology. Since the midbrain periaqueductal gray (PAG) is an important component of the descending inhibitory pathway controlling on central pain transmission, we examined the role for pro-inflammatory cytokines (PICs) system of PAG in regulating exaggerated pain evoked by PD. METHODS: We used a rat model of PD to perform the experimental protocols. PD was induced by microinjection of 6-hydroxydopamine to lesion the left medial forebrain bundle. Pain responses to mechanical and thermal stimulation were first examined in control rats and PD rats. Then, ELISA and Western Blot analysis were used to determine PIC levels and their receptors expression. RESULTS: Protein expression of IL-1ß, IL-6, and TNF-α receptors (namely, IL-1R, IL-6R, and TNFR subtype TNFR1) in the plasma membrane PAG of PD rats was upregulated, whereas the total expression of PIC receptors was not significantly altered. The ratio of membrane protein and total protein (IL-1R, IL-6R, and TNFR1) was 1.48 ± 0.15, 1.59 ± 0.18, and 1.67 ± 0.16 in PAG of PD rats (P < 0.05 vs. their respective controls). This was accompanied with increases of PICs of PAG and decreases of GABA (623 ± 21 ng/mg in control rats and 418 ± 18 ng/mg in PD rats; P < 0.05 vs. control rats) and withdrawal thresholds to mechanical and thermal stimuli. Our data further showed that the concentrations of GABA and withdrawal thresholds were largely restored by blocking those PIC receptors in PAG of PD rats. Stimulation of GABA receptors in PAG of PD rats also blunted a decrease in withdrawal thresholds. CONCLUSION: Our data suggest that upregulation of the membrane PIC receptor in the PAG of PD rats is likely to impair the descending inhibitory pathways in regulating pain transmission and thereby plays a role in the development of hypersensitive pain response in PD.

Studies on the active constituents in radix salviae miltiorrhizae and their protective effects on cerebral ischemia reperfusion injury and its mechanism.

BACKGROUND: To extract, purify and identify the active constituents in ethanol extract of Radix Salviae Miltiorrhizae, and to analyze the protective effects of tanshinone IIA on cerebral ischemia-reperfusion injury in rats. MATERIALS AND METHODS: Radix Salviae Miltiorrhizae was extracted by ultrasonic extraction, effective parts were extracted by extraction method, compounds were isolated by preparative TLC and preparative HPLC, and structures of compounds were identified by (1)H NMR and (13)C NMR; the effects of tanshinone IIA on cerebral ischemia-reperfusion injury in rats were determined by establishing rat model of middle cerebral artery occlusion (MCAO). RESULTS: The experimental data show four compounds were isolated, namely tanshinone IIB, hydroxymethylene tanshinone, salvianolic acid B and 9"'-methyl lithospermate B. Tanshinone IIA could alleviate the symptoms of neurological deficit in rats, the neurological deficit alleviating effect became more obvious with the increase of dose; tanshinone IIA experimental groups could reduce the cerebral infarction size and brain water content in rats, different concentrations of tanshinone IIA could decrease the SOD content and increase the MDA content in the frontal and parietal cortices of ischemic hemisphere in the ischemia reperfusion group, the differences were statistically significant compared with the ischemia reperfusion group. CONCLUSION: Radix Salviae Miltiorrhizae has the protective effects on cerebral ischemia reperfusion injury in rats.

[Correlation between diffusion tensor imaging and cognitive dysfunction in patients with delayed encephalopathy after acute carbon monoxide poisoning].

OBJECTIVE: To explore the diagnostic value of magnetic resonance (MR) diffusion tensor imaging (DTI) in detecting brain white matter (WM) damage of patients with delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) and evaluating their cognitive dysfunction. METHODS: Thirteen patients with DEACMP and thirteen age- and sex-matched volunteers underwent DTI using 1.5T MR scanner. FA and ADC values of 16 WM regions of interests (ROIs) were measured on DTI by two experienced radiologists independently with double blind methods, cognitive functions were evaluated by another experienced neurologist blinded to patient's medical history using the Montreal cognitive assessment (MoCA). ADC and FA values in DEACMP patients, and their correlations with cognitive dysfunction were analyzed. RESULTS: ADC values of DEACMP patients increased significantly in all ROIs (P < 0.05) in comparison with the corresponding ROIs of healthy controls, whereas FA values were significantly decreased in all ROIs (P < 0.05) in comparison with that in controls except the bilateral optic radiations, anterior and posterior internal capsules. MoCA scores were positively correlated with FA values of bilateral lower frontal (r(L) = 0.736, P = 0.011; r(R) = 0.762, P = 0.003) lobe, temporal lobe (r(L) = 0.605, P = 0.016; r(R) = 0.559, P = 0.021) and total average WM (r(A) = 0.688, P = 0.001), however it inversely correlated with ADC values of bilateral lower frontal WM (r(L) = -0.674, P = 0.007; r(R) = -0.681, P = 0.019). CONCLUSION: DTI can quantitatively reveal WM microstructure damage of DEACMP patients, indicate the severity of cognitive dysfunctions, and provide important information for pathogenesis and pathological study for DEACMP.

Massage therapy for fibromyalgia: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Although some studies evaluated the effectiveness of massage therapy for fibromyalgia (FM), the role of massage therapy in the management of FM remained controversial. OBJECTIVE: The purpose of this systematic review is to evaluate the evidence of massage therapy for patients with FM. METHODS: Electronic databases (up to June 2013) were searched to identify relevant studies. The main outcome measures were pain, anxiety, depression, and sleep disturbance. Two reviewers independently abstracted data and appraised risk of bias. The risk of bias of eligible studies was assessed based on Cochrane tools. Standardised mean difference (SMD) and 95% confidence intervals (CI) were calculated by more conservative random-effects model. And heterogeneity was assessed based on the I(2) statistic. RESULTS: Nine randomized controlled trials involving 404 patients met the inclusion criteria. The meta-analyses showed that massage therapy with duration ≥ 5 weeks significantly improved pain (SMD, 0.62; 95% CI 0.05 to 1.20; p = 0.03), anxiety (SMD, 0.44; 95% CI 0.09 to 0.78; p = 0.01), and depression (SMD, 0.49; 95% CI 0.15 to 0.84; p = 0.005) in patients with FM, but not on sleep disturbance (SMD, 0.19; 95% CI -0.38 to 0.75; p = 0.52). CONCLUSION: Massage therapy with duration ≥ 5 weeks had beneficial immediate effects on improving pain, anxiety, and depression in patients with FM. Massage therapy should be one of the viable complementary and alternative treatments for FM. However, given fewer eligible studies in subgroup meta-analyses and no evidence on follow-up effects, large-scale randomized controlled trials with long follow-up are warrant to confirm the current findings.

DNA-gold nanoparticle conjugates-based nanoplasmonic probe for specific differentiation of cell types.

The direct analysis of cancerous cells provides a new way for cancer detection that obviates cell lysis and other tedious steps (e.g., enrichment, purification, and amplification steps). However, the analysis of different cell types remains challenging due to the subtle differences in cell surface features. Here, we have demonstrated nanoplasmonic differentiation of cell types by using DNA-gold nanoparticle nanoconjugates (DNA-AuNPs). Our strategy relies on cross reactive receptors (a collection of DNA-AuNPs) that are employed to bind the different cells that produce fingerprint-like patterns for each type of cell. Because of the enhanced nanoplasmonic effect of AuNPs via seeded-growth, we could effectively differentiate various cell lines, e.g., 786-O, L929, Hela, and RAW264.7, with dark-field microscopy or even naked eyes.

Pattern recognition analysis of proteins using DNA-decorated catalytic gold nanoparticles.

A label-free protein analysis strategy is based on patterns of gold nanoparticle (AuNP) growth. AuNPs pretreated with different oligonucleotides are challenged with various proteins. After Au reduction, the colorimetric patterns are processed with linear discriminant analysis. This method discriminates different proteins, or one protein of different concentrations, in mixed samples or even serum and urine.

The biocompatibility of nanodiamonds and their application in drug delivery systems.

Nanodiamonds (NDs), as a new member of the carbon nanoparticles family, have attracted more and more attention in biomedicine recently due to their excellent physical and chemical properties. This paper summarizes the main results from the in vitro and in vivo safety assessments of NDs and reports the application of NDs in the development of drug delivery systems. In view of the NDs' characteristics of easy formation of a porous cluster structure in solution, an adsorption model for a variety of functional molecules on the ND clusters is proposed, which provides new ideas for developing a novel smart drug with various features such as sustained-release, targeting, and fluorescence imaging.

Relationship between serum bilirubin and carotid atherosclerosis in hypertensive patients.

OBJECTIVE: To investigate the relationship between serum bilirubin and carotid atherosclerosis in patients with hypertension. PATIENTS AND METHODS: Carotid artery ultrasonography was performed in 198 patients (104 males, average age of 65.6+/-7.1 years) with hypertension. Serum levels of bilirubin and C-reactive proteins (CRP) were measured at the same time. RESULTS: Carotid atherosclerosis was detected in 133 patients, 87 of them had carotid artery plaque. The prevalence of stroke (20.3%) and myocardial infarction (13.5%) in the atherosclerosis group was higher than in the non-atherosclerosis group (9.2% and 6.2%, respectively, p<0.05). The average total serum bilirubin in the atherosclerosis group was lower than in the non-atherosclerosis group (12.8+/-1.3 vs 16.8+/-1.5 micromol/L, p<0.01), whereas the average serum of CRP was higher (4.1+/-1.1 vs 2.3+/-0.7 mg/L, p<0.01). After adjusting other factors such as age, total cholesterol, diabetes and systolic blood pressure, total serum bilirubin was negatively associated with carotid atherosclerosis in women and men, with odds ratios of 0.49 (95% CI, 0.28 to 0.71; p<0.01) and 0.66 (95% CI, 0.46 to 0.80; p<0.01). Serum CRP was positively correlated to carotid atherosclerosis, with odds ratios of 1.76 (95% CI, 1.36 to 2.04; p<0.01) in women and 1.95 (95% CI, 1.46 to 2.82; p<0.01) in men. CONCLUSION: Carotid atherosclerosis was associated with a high prevalence of stroke or myocardial infarction in hypertensive patients. Serum bilirubin was negatively associated with carotid atherosclerosis.