MCP-1 levels in astrocyte-derived exosomes are changed in preclinical stage of Alzheimer's disease.

Background: Alzheimer's disease (AD) is the most common form of dementia in older adults. There is accumulating evidence that inflammatory processes play a critical role in AD pathogenesis. In this study, we investigated whether inflammatory factors in plasma and astrocyte-derived exosomes (ADEs) from plasma are differentially expressed in the early stages of AD and their potential role in pathological processes in the AD continuum. Method: We included 39 normal controls (NCs), 43 participants with subjective cognitive decline (SCD), and 43 participants with amnestic mild cognitive impairment (aMCI)/AD. IL-6, IL-8, and MCP-1 in plasma and ADEs from plasma were evaluated using a commercial multiplex Luminex-based kit. Results: Pairwise comparisons between the groups showed no significant differences in plasma levels of IL-6, IL-8, or MCP-1. However, ADEs in the SCD group showed an increase in MCP-1 levels compared to the NC group. To differentiate the preclinical group, discriminant analysis was performed using sex, age, years of education, and genotype. This revealed a difference between the SCD and NC groups (area under the curve: 0.664). A Spearman correlation analysis of MCP-1 in plasma and ADEs showed no or weak correlation in the SCD (R = 0.150, p = 0.350) and aMCI/AD (R = 0.310, p = 0.041) groups, while a positive correlation in the NC group (R = 0.360, p = 0.026). Conclusion: Plasma IL-6, IL-8, and MCP-1 levels were not significantly different. However, the concentration of MCP-1 in ADEs is slightly altered during the preclinical phase of AD, which could be a potential role of the central neuron system (CNS) immune response in the AD continuum. Clinical trial registration: www.ClinicalTrials.gov, identifier: NCT03370744.

Effect of Laser Irradiation and Tensile Stress on Microstructure and Magnetic Properties of Fe-Based Amorphous Alloys.

The effect of laser irradiation and tensile stress on the microstructure and soft magnetic properties of the FeSiBNbCu nanocrystalline alloy prepared using a continuous laser has been investigated. The experimental results indicate that a decreased laser scanning speed provides more thermal energy to induce nanocrystals and encourage grain growth. When the scanning speed is excessively high, the crystallization process will cease due to a lack of energy to drive diffusion phase transitions. Nevertheless, the introduction of tensile stress could significantly promote crystallization in FeSiBNbCu alloy samples irradiated at these high laser scanning speeds. This phenomenon can be attributed to the augmentation of compressive thermal stress at the interface between the laser-treated track and the untreated region. This heightened compressive stress promotes the diffusivity of atoms, and, as a result, the transformation from amorphous to crystalline states can be enhanced. As the applied tensile stress increases, both grain size and crystalline volume fraction exhibit a proportional augmentation. Consequently, these changes manifest in the soft magnetic properties. The crystalline volume fraction can reach 62%, and the coercivity is 2.9 A/m at the optimized scanning speed; these values correspond to 54% and 3.3 A/m under specific tensile stress loading.

Brain microglia activation and peripheral adaptive immunity in Parkinson's disease: a multimodal PET study.

BACKGROUND: Abnormal activation of immune system is an important pathogenesis of Parkinson's disease, but the relationship between peripheral inflammation, central microglia activation and dopaminergic degeneration remains unclear. OBJECTIVES: To evaluate the brain regional microglia activation and its relationship with clinical severity, dopaminergic presynaptic function, and peripheral inflammatory biomarkers related to adaptive immunity. METHODS: In this case-control study, we recruited 23 healthy participants and 24 participants with early-stage Parkinson's disease. 18F-PBR06 PET/MR for microglia activation, 18F-FP-DTBZ for dopaminergic denervation, total account of T cells and subpopulations of T helper (Th1/Th2/Th17) cells, and the levels of serum inflammatory cytokines were assessed. Sanger sequencing was used to exclude the mix-affinity binders of 18F-PBR06-PET. RESULTS: Compared to healthy controls, patients with Parkinson's disease had an increased 18F-PBR06-PET standardized uptake value ratio (SUVR) in the putamen, particularly in the ipsilateral side of the motor onset. 18F-PBR06-PET SUVR was positively associated with 18F-FP-DTBZ-PET SUVR in the brainstem and not associated with disease severity measured by Hoehn and Yahr stage, MDS-UPDRS III scores. Patients with Parkinson's disease had elevated frequencies of Th1 cells and serum levels of IL10 and IL17A as compared to healthy controls. No significant association between peripheral inflammation markers and microglia activation in the brain of PD was observed. CONCLUSION: Parkinson's disease is associated with early putaminal microglial activation and peripheral phenotypic Th1 bias. Peripheral adaptive immunity might be involved in microglia activation in the process of neurodegeneration in PD indirectly, which may be a potential biomarker for the early detection and the target for immunomodulating therapy.

Role of 5-HT2A Receptor in Modulating Glutamatergic Activity in the Ventrolateral Orbital Cortex: Implication in Trigeminal Neuralgia.

5-HT2A receptors (5-HT2ARs) are widely expressed in the central nervous system, including in the ventrolateral orbital cortex (VLO). The VLO is an important cortical component for pain processing. Brain 5-HT2ARs are implicated in both pro- and anti- nociceptive functions. However, the roles of 5-HT2ARs in the VLO in trigeminal neuralgia and neuronal synaptic function remain to be understood. We used chronic constriction injury of infraorbital nerve (IoN-CCI) model and shRNA mediated gene knockdown in mice to investigate the role of 5-HT2ARs in the VLO in trigeminal neuralgia. We found that knockdown of 5-HT2ARs in the VLO aggravated spontaneous pain and mechanical allodynia in mice after IoN-CCI. At the synaptic level, decreasing 5-HT2AR expression by shRNA or inhibition of 5-HT2AR activity by its antagonist ketanserin decreased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) of the neurons in the VLO, whereas 5-HT2AR partial agonist 2,5-Dimethoxy-4-iodoamphetamine (DOI) enhanced sEPSCs of the neurons in the VLO. In summary, 5-HT2ARs in the VLO modulate the trigeminal pain by regulating neuronal glutamatergic activity.

ß-Amyloid in blood neuronal-derived extracellular vesicles is elevated in cognitively normal adults at risk of Alzheimer's disease and predicts cerebral amyloidosis.

BACKGROUND: Blood biomarkers that can be used for preclinical Alzheimer's disease (AD) diagnosis would enable trial enrollment at a time when the disease is potentially reversible. Here, we investigated plasma neuronal-derived extracellular vesicle (nEV) cargo in patients along the Alzheimer's continuum, focusing on cognitively normal controls (NCs) with high brain ß-amyloid (Aß) loads (Aß+). METHODS: The study was based on the Sino Longitudinal Study on Cognitive Decline project. We enrolled 246 participants, including 156 NCs, 45 amnestic mild cognitive impairment (aMCI) patients, and 45 AD dementia (ADD) patients. Brain Aß loads were determined using positron emission tomography. NCs were classified into 84 Aß- NCs and 72 Aß+ NCs. Baseline plasma nEVs were isolated by immunoprecipitation with an anti-CD171 antibody. After verification, their cargos, including Aß, tau phosphorylated at threonine 181, and neurofilament light, were quantified using a single-molecule array. Concentrations of these cargos were compared among the groups, and their receiver operating characteristic (ROC) curves were constructed. A subset of participants underwent follow-up cognitive assessment and magnetic resonance imaging. The relationships of nEV cargo levels with amyloid deposition, longitudinal changes in cognition, and brain regional volume were explored using correlation analysis. Additionally, 458 subjects in the project had previously undergone plasma Aß quantification. RESULTS: Only nEV Aß was included in the subsequent analysis. We focused on Aß42 in the current study. After normalization of nEVs, the levels of Aß42 were found to increase gradually across the cognitive continuum, with the lowest in the Aß- NC group, an increase in the Aß+ NC group, a further increase in the aMCI group, and the highest in the ADD group, contributing to their diagnoses (Aß- NCs vs. Aß+ NCs, area under the ROC curve values of 0.663; vs. aMCI, 0.857; vs. ADD, 0.957). Furthermore, nEV Aß42 was significantly correlated with amyloid deposition, as well as longitudinal changes in cognition and entorhinal volume. There were no differences in plasma Aß levels among NCs, aMCI, and ADD individuals. CONCLUSIONS: Our findings suggest the potential use of plasma nEV Aß42 levels in diagnosing AD-induced cognitive impairment and Aß+ NCs. This biomarker reflects cortical amyloid deposition and predicts cognitive decline and entorhinal atrophy.

Association of plasma apolipoproteins and levels of inflammation-related factors with different stages of Alzheimer's disease: a cross-sectional study.

OBJECTIVE: Blood-based biomarkers for the early diagnosis of Alzheimer's disease (AD) are a 'Holy Grail' of AD research. Growing evidence shows that levels of apolipoproteins and various inflammation-related factors are altered in the peripheral blood of patients with AD. The purpose of this study was to clear and definite whether these biomarkers are differentially expressed at the early stages of AD, and could be a biomarker as an early diagnosis of the disease. DESIGN: Observation study. SETTING: This study was a part of the Sino Longitudinal Study on Cognitive Decline, an ongoing prospective cohort study (ClinicalTrials.gov identifier: NCT03370744) that centres on Xuanwu Hospital (Beijing, China) in cooperation with an alliance of 94 hospitals from 50 cities across China. PARTICIPANTS: In the present study, 416 right-handed Chinese Han subjects were recruited through standardised public advertisements from 2014 to 2019. OUTCOME MEASURES: Concentrations of plasma apolipoprotein A1, apolipoprotein CIII (ApoCIII), apolipoprotein E (ApoE), A-2-macroglobulin (A2M), complement C3 (C3) and complement factor H (FH) were determined using a commercial multiplex Luminex-based panel in normal controls (NC), subjective cognitive decline (SCD), mild cognitive impairment and AD groups. RESULTS: For individual analysis, pairwise comparisons showed that: (1) For SCD versus NC, no biomarker showed significant difference; (2) For amnestic mild cognitive impairment (aMCI) versus NC, levels of ApoCIII, ApoE, A2M, C3 and FH increased significantly; and (3) For AD versus NC, amounts of C3 increased. For models differentiating clinical groups, discriminant analysis was performed by including all protein markers, age, sex, genotype and education level in the model. This approach could distinguish between patients with aMCI (area under the curve (AUC): 0.743) and AD (AUC: 0.837) from NC. CONCLUSION: Our results suggest that concentrations of certain apolipoproteins and inflammation-related factors are altered at the early stage of AD, and could be useful biomarkers for early diagnosis. TRIAL REGISTRATION NUMBER: NCT03370744.

Chrysin impairs genomic stability by suppressing DNA double-strand break repair in breast cancer cells.

Chrysin, a natural compound isolated from various plants, such as the blue passion flower (Passiflora caerulea L.), exhibits multiple pharmacological activities, such as antitumor, anti-inflammatory and antioxidant activities. Accumulating evidence shows that chrysin inhibits cancer cell growth by inducing apoptosis and regulating cell cycle arrest. However, whether chrysin is involved in regulating genomic stability and its underlying mechanisms in breast cancer cells have not been determined. Here, we demonstrated that chrysin impairs genomic stability in MCF-7 and BT474 cells, inhibits cell survival and enhances the sensitivity of MCF-7 cells to chemotherapeutic drugs. Further experiments revealed that chrysin impairs DNA double-strand break (DSB) repair, resulting in accumulation of DNA damage. Mechanistic studies showed that chrysin inhibits the recruitment of the key NHEJ factor 53BP1 and delays the recruitment of the HR factor RAD51. Thus, we elucidated novel regulatory mechanisms of chrysin in DSB repair and proposed that a combination of chrysin and chemotherapy has curative potential in breast cancers.

The deacetylase SIRT6 promotes the repair of UV-induced DNA damage by targeting DDB2.

The NAD+-dependent deacetylase and mono-ADP-ribosyl transferase SIRT6 stabilizes the genome by promoting DNA double strand break repair, thereby acting as a tumor suppressor. However, whether SIRT6 regulates nucleotide excision repair (NER) remains unknown. Here, we showed that SIRT6 was recruited to sites of UV-induced DNA damage and stimulated the repair of UV-induced DNA damage. Mechanistic studies further indicated that SIRT6 interacted with DDB2, the major sensor initiating global genome NER (GG-NER), and that the interaction was enhanced upon UV irradiation. SIRT6 deacetylated DDB2 at two lysine residues, K35 and K77, upon UV stress and then promoted DDB2 ubiquitination and segregation from chromatin, thereby facilitating downstream signaling. In addition, we characterized several SIRT6 mutations derived from melanoma patients. These SIRT6 mutants ablated the stimulatory effect of SIRT6 on NER and destabilized the genome due to (i) partial loss of enzymatic activity (P27S or H50Y), (ii) a nonsense mutation (R150*) or (iii) high turnover rates (G134W). Overall, we demonstrate that SIRT6 promotes NER by deacetylating DDB2, thereby preventing the onset of melanomagenesis.

Effects of motivational methods on oral hygiene of orthodontic patients: A systematic review and meta-analysis.

OBJECTIVE: The aim of our study was to qualitatively and quantitatively synthesize the evidence regarding ways to improve motivation of oral hygiene among orthodontic patients with fixed appliances and identify the effects of motivational methods via comparing the oral hygiene condition before and after the motivations. METHODS: An electronic search was conducted in PubMed, Ovid, Embase, and the Crochrane Library for relevant random controlled trials (RCT) and clinical controlled trial (CCT) published before May 1, 2017 with manual search in addition. Search and selection of studies, quality assessment, data extraction and synthesis was completed by 2 reviewers independently. Plaque index (PI) and gingival index (GI) at 1, 3, 6-month were pooled with Review Manager 5.3. Bias of included studies was evaluated. RESULTS: In total, 12 studies fulfilled the inclusion criteria of this systematic review, of which, 5 were included in the meta-analysis. Motivational methods had statistically significant advantage regarding PI in the experimental group over control group at 1, 3, 6-month, while GI was significantly better controlled in the study group at 3, 6-month. The quality of included studies was moderate. CONCLUSION: It is worthy for orthodontists to put in additional efforts to motivate patients to maintain good oral hygiene throughout the entire treatment process.