Antibody-Free Determinations of Low-Mass, Soluble Oligomers of Aß42 and Aß40 by Planar Bilayer Lipid Membrane-Based Electrochemical Biosensor.

Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly. Abnormal aggregates of both ß-amyloid peptide (Aß) subtypes, Aß42 and Aß40, are the typical neuropathology hallmarks of AD. However, because of the lack of specific recognition elements such as an antibody and aptamer, it is difficult to differentiate and determine the oligomers of Aß42 and Aß40 in clinic. In this paper, we developed a planar bilayer lipid membrane (BLM)-based electrochemical biosensor. According to the dynamic differences on oligomer-induced BLM damage, both low-mass, soluble oligomers of Aß42 and Aß40 (L-Aß42O and L-Aß40O) were measured in turn by electrochemical impedance spectroscopy. The BLM was supported by a porous 11-mercaptoundecanoic acid layer on a gold electrode, which amplified the impedance signal corresponding to the membrane damage and improved the detection sensitivity. The weakly charged surface of the BLM ensured the low non-specific adsorption of coexisting proteins in cerebrospinal fluid (CSF). Using the electrochemical biosensor, L-Aß42O was determined within 20 min, with a linear range from 5 to 500 pM and a detection limit of 3 pM. Meanwhile, L-Aß40O was determined within 60 min, with a linear range from 60 pM to 6.0 nM and a detection limit of 26 pM. The recoveries in oligomer-spiked artificial CSF and human CSF samples confirmed the accuracy and applicability of this proposed method in clinic. This work provides an antibody-free, highly selective, and sensitive method for simultaneous detections of L-Aß42O and L-Aß40O in real CSF samples, which is significant for the early diagnosis and prognosis of AD.

Estradiol exerts a neuroprotective effect on SH-SY5Y cells through the miR-106b-5p/TXNIP axis.

Alzheimer's disease (AD) is a neurodegenerative disease. Thioredoxin and thioredoxin-interacting protein (TXNIP) complexes help sustain cell oxidation/reduction balance. In the present study, we verified the neuroprotective role of estradiol against amyloid-beta 42 in SH-SY5Y cells through inhibiting TXNIP expression, promoting cell viability and DNA synthesis ability, inhibiting cell apoptosis, and affecting caspase and Bax/Bcl-2 apoptotic signaling. miR-106b-5p could bind to TXNIP 3'-untranslated region to inhibit the expression level of TXNIP. Within SH-SY5Y cells, miR-106b-5p inhibition repressed cell viability and DNA synthesis ability and promoted cell apoptosis through caspase and Bax/Bcl-2 apoptotic signaling, while miR-106b-5p overexpression or TXNIP knockdown exerted the opposite effects on SH-SY5Y cells; TXNIP knockdown remarkably attenuated the roles of miR-106b-5p inhibition. In conclusion, estradiol treatment on SH-SY5Y cells downregulates TXNIP expression and upregulates miR-106b-5p expression. miR-106b-5p exerts a neuroprotective effect on SH-SY5Y cells by promoting cell proliferation and inhibiting cell apoptosis through targeting TXNIP.

Melatonin receptor protects cardiomyocyte against oxidative stress-induced apoptosis through the MAPK-ERK signaling pathway.

Context: The role of melatonin receptor in cardiomyocyte oxidative stress has not been investigated.Aim: The aim of our study is to verify the beneficial effects of melatonin receptors on cardiomyocyte viability under oxidative stress.Methods: Cardiomyocytes were treated with hydrogen peroxide. Cell viability was measured via MTT assay and TUNEL staining. Then, anti-oxidative factors measurement and signaling pathway analysis were performed via qPCR and ELISA.Results: Melatonin receptor activation could attenuate hydrogen peroxide-mediated cardiomyocyte death via reducing apoptosis. At the molecular levels, melatonin receptor activation reduced inflammation response and maintained mitochondrial membrane potential. In addition, melatonin receptor activation is associated with decreased oxidative stress and increased anti-oxidative factors. Finally, we found that melatonin receptor activation triggered an elevation in the activity and expression of ERK pathway and blockade of ERK pathway would abolish the beneficial effects exerted by melatonin receptors activation on cardiomyocyte survival under oxidative stress.Conclusions: Our data suggest that melatonin receptor could attenuate oxidative stress injury in cardiomyocyte through regulation of the ERK signaling pathway.

SPR immunosensor combined with Ti4+@TiP nanoparticles for the evaluation of phosphorylated alpha-synuclein level.

A highly sensitive and specific surface plasmon resonance (SPR) method using one anti-alpha-synuclein antibody (anti-αS) and titanium phosphate nanoparticles (Ti4+@TiP) was developed for quantitative evaluation of phosphorylated αS level which was defined by the ratio of p-αS to total alpha-synuclein (t-αS) (p-αS/t-αS). The close affinities of anti-αS to αS (0.975 pM-1) and p-αS (0.938 pM-1) were obtained. Based on this fact , both αS forms were simultaneously captured and the t-αS was quantified using the anti-αS immobilized Au chip. With the selective recognition of Ti4+@TiP nanoparticles, the p-αS was quantified. The dynamic ranges of our method were 1.0~20.0 pg mL-1 for the detection of t-αS and 0.1~10.0 pg mL-1 for that of p-αS. The analysis of αS- and p-αS-spiked artificial cerebrospinal fluid samples revealed the high accuracy of the method. Furthermore, the concentrations of αS and p-αS in clinical CSF samples collected from three healthy donors were determined and displayed a high correlation with the results from a commercial ELISA kit, confirming the viability and of the proposed method. The method is convenient, economical, and practical for the evaluation of phosphorylated αS level with high sensitivity and selectivity. It is of great significance for the early diagnosis of PD and the evaluation of PD progression.Graphical abstract.

An electrochemical aptasensor for amyloid-ß oligomer based on double-stranded DNA as "conductive spring".

In order to overcome the antibody-based sensor's shortcomings, an electrochemical aptamer (Apt)-based sensor was developed for amyloid-ß40 oligomer (Aß40-O). The aptasensor was constructed by locating Apt and ferrocence (Fc) on streptavidin-modified gold (SA-gold) nanoparticles. The obtained AptFc@SA-gold nanoparticles were linked onto the Au electrode via the connection of double-stranded DNA (dsDNA) as a "conductive spring." The determination of Aß40-O was performed with square-wave voltammetry (SWV). Upon bio-recognition between Apt and Aß40-O, the conformation of Apt changed and the formed Apt/Aß40-O complex separated from the SA-gold surface. As a result, the surface charge of SA-gold positively shifted, weakening the electrostatic attraction between the SA-gold and the positively charged Au electrode surface (at potential range of 0.1~0.5 V, corresponding to the Fc redox transformation), and stretching the dsDNA chain. Based on the exponential decay of dsDNA's electron transfer efficiency on its chain stretching, the oxidation current density from Fc decreased and displayed linear correlation to the concentration of Aß40-O. A wide linear range of 0.100 nM to 1.00 µM with a low detection limit of 93.0 pM was obtained. The aptasensor displayed excellent selectivity toward Aß40-O in contrast to other possible interfering analogs (Aß40 monomer, Aß42 monomer, and oligomer) at × 100 higher concentrations. The recoveries for Aß40-O-spiked artificial cerebrospinal fluid and healthy human serum were 94.0~104% and 92.8~95.4%, respectively. The electrochemical aptasensor meets the demands of clinic determination of Aß40-O, which is significant for the early diagnosis of AD. Graphical abstract Schematic representation of the electrochemical aptasensor for amyloid-ß oligomer based on the surface charge change induced by target binding.

Coimmunocapture and Electrochemical Quantitation of Total and Phosphorylated Amyloid-ß40 Monomers.

Phosphorylated proteins play important roles in the pathogenesis of Alzheimer's disease (AD). The most abundant constituent in AD's brain deposit is the amyloid-ß40 peptide (Aß40). Based on it, the degree of phosphorylated Aß40 in body fluids (e.g., cerebrospinal fluid, CSF), which is defined by the ratio of phosphorylated Aß40 to total Aß40 (pAß40/tAß40), is anticipated to be an index for early diagnosis of AD. The major challenge in pAß40/tAß40 detection is the large concentration difference between two Aß40 forms in the real samples, which usually requires multichannel equipment and complicated detection process. In this paper, we revealed the unexpected close affinities of the anti-Aß40 antibody to Aß40 (40.2 nM-1) and to pAß40 (42.3 nM-1). Based on it, a convenient coimmunocapture and electrochemical quantitation of tAß40 and pAß40 was achieved on an anti-Aß40 antibody immobilized Au electrode (anti-Aß40/Au). Once Aß40 and pAß40 were synchronously captured on the anti-Aß40/Au electrode, the tAß40 levels in CSF samples were quantified with electrochemical impedance spectroscopy. With the signal amplification from Cd2+/Ti4+-functionalized titanium phosphate nanospheres (Cd2+/Ti4+@TiP) which was selective conjugated to pAß40, concentrations of low abundant pAß40 as low as 1 fM were readily measured by square wave voltammetry. Our results reveal that despite the concentrations of tAß40 and pAß40 fluctuate in each individual case, the concentration ratios of pAß40/tAß40 in CSF samples from AD patients are significant larger than those from healthy donors. It demonstrates that the degree of phosphorylated Aß40 is hopeful to be an effective index for evaluating the AD progress and improving the accuracy of clinic AD diagnosis.

[Role of TXNIP-mediated oxidative stress in delaying Alzheimer's disease by estrogen].

OBJECTIVE: To study the functional mechanism of thioredoxin-interacting protein (TXNIP) in delaying Alzheimer's disease (AD) by estrogen.
 Methods: After estradiol (E2) treatment in Aß-induced AD cell model, reactive oxygen species (ROS), TXNIP, and apoptosis levels were detected. After lentiviral infection with TXNIP overexpression, the effect of E2 on ROS and apoptosis were observed. In the AD rat model, the learning and memory ability and the expression of TXNIP in the hippocampus were observed in the presence of E2. After overexpressing TXNIP, the effect of E2 on the learning and memory ability of AD rat model was observed.
 Results: ROS, TXNIP and apoptosis levels were enhanced in AD cell model, while E2 treatment reduced ROS, TXNIP and apoptosis levels in AD cell model. After enhancing TXNIP, E2 treatment reduced ROS and apoptosis levels in AD cell model. Similar to the cell experiment, E2 enhanced the learning and memory ability in the AD rat model and inhibited the expression of TXNIP in brain, while TXNIP overexpression attenuated the effect of E2 on learning and memory ability in the AD rats.
 Conclusion: Estrogen can inhibit the expression of TXNIP in nerve tissue, reduce nerve damage, and delay the development of AD.

Light-Up Nonthiolated Aptasensor for Low-Mass, Soluble Amyloid-ß40 Oligomers at High Salt Concentrations.

Herein, a light-up nonthiolated aptasensor was developed for low-mass, soluble amyloid-ß40 oligomers (LS-Aß40-O). Au nanoparticles (AuNP) were employed as colorimetric probes, and the nonthiolated aptamers (Apt) were adsorbed on AuNP surfaces, acting as binding elements for LS-Aß40-O. The aggregation of AuNPs was induced when Apt-modified AuNPs (Apt@AuNPs) were under high-salt conditions. However, upon the addition of LS-Aß40-O into the Apt@AuNP solution, the salt tolerance of the AuNPs was greatly enhanced. Further studies confirmed that the formed LS-Aß40-O-Apt complex attached onto the AuNP surfaces via interactions between LS-Aß40-O and Au, which led to electrostatic and steric stabilization of the AuNPs under high-salt conditions. On the basis of this outcome, a sensitive light-up nonthiolated aptasensor for LS-Aß40-O was achieved with a detection limit of 10.0 nM and a linear range from 35.0 to 700 nM in a 175 mM NaCl solution. Cerebrospinal-fluid (CSF) samples from healthy persons and Alzheimer's disease (AD) patients were successfully distinguished by using this proposed method. The concentrations of LS-Aß40-O in the CSF of AD patients were of nanomolar grade, but there was no detectable LS-Aß40-O in those of the healthy persons. This work provides a new insight into the interaction between Apt@AuNPs and Aß40-O and also develops a simple, rapid, highly selective and sensitive, and applicable method for LS-Aß40-O detection in real CSF samples, which is significant for the diagnosis of AD.

Epigenetic modulation of Cdk5 contributes to memory deficiency induced by amyloid fibrils.

Alzheimer's disease (AD) is a frequent neurodegenerative disorder with progressive neuroinflammation, loss of synaptic plasticity in central neurons and memory deficiency. Numerous studies demonstrated the epigenetic modification of the expression of specific genes involved in the pathogenesis of amyloid-associated memory deficiency. It was also reported that dysregulation of cyclin-dependent kinase 5 (Cdk5) activity critically contributed to the synaptic dysfunction and memory deficiency in the rodent model of AD. The present study aims to study the epigenetic mechanism underlying the altered Cdk5 activity and its functional significance in the rats with hippocampal infusion of amyloid fibrils. Significantly increased mRNA and expression of Cdk5 were observed in the hippocampal CA1 in the rats injected with amyloid fibrils. Increased acetylation of histone H3 was detected in the Cdk5 promoter region in hippocampal CA1 in these rats. Further chromatin immunoprecipitation and bisulfite sequencing studies illustrated the decreased cytosine methylation in the Cdk5 promoter region in hippocampal CA1 in the modeled rats. Administration with Cdk5 inhibitor roscovitine significantly attenuated the phosphorylation of tau, recovered the synaptic dysfunction of hippocampal CA1 neurons, and improved the behavioral performance in the Morris water maze test and novel object recognition test in the rats injected with amyloid fibrils. These results elucidate the potential epigenetic mechanism underlying the upregulated expression of Cdk5 induced by amyloid fibrils and provided novel insights into the pathogenic mechanism of Alzheimer's disease.

[Effects of sleep deprivation on the intelligence structure of school-age children in Changsha, China].

OBJECTIVE: To investigate the effects of sleep deprivation on intelligence development in primary school students. METHODS: Between June 2009 and April 2010, 316 grade 5 students aged 10-11 years were selected from four primary schools in four administrative districts of Changsha, China by stratified random sampling. The intelligence characteristics of children with varying degrees of sleep deprivation were investigated using the Chinese Wechsler Intelligence Scale for Children. RESULTS: A total of 286 valid questionnaires were received, with a response rate of 90.5%. The survey was comprised of a sleep deprivation group (sleep time <8 hours per night; n=180) and a control group (sleep time ≥8 hours per night; n=106). The sleep deprivation group had significantly lower subtest scores, verbal intelligence quotient (IQ) (VIQ), performance IQ (PIQ) and full scale IQ (P<0.05) and significantly lower verbal comprehension factor score and memory/attention factor score compared with the control group (P<0.05). Compared with the control group, the moderate sleep deprivation subgroup had significantly decreased VIQ and full scale IQ as well as verbal comprehension factor score and memory/attention factor score (P<0.05), and the severe sleep deprivation subgroup showed decreases in all scores (P<0.05). The sleep deprivation group and moderate and severe sleep deprivation subgroups had significantly higher proportions of children with VIQ-PIQ imbalance than the control group. CONCLUSIONS: Sleep deprivation adversely affects intelligence development, especially VIQ, in primary school students, and the adverse effects of sleep deprivation are mainly seen in students with moderate and severe sleep deprivation.

Effects of Peroxisome Proliferator-Activated Receptor-Gamma Agonists on Cognitive Function: A Systematic Review and Meta-Analysis.

Diabetes mellitus (DM) is known to be a risk factor for dementia, especially in the elderly population, and close associations between diabetes and Alzheimer disease (AD) have been determined. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists are insulin-sensitising drugs. In addition to their anti-diabetic properties, their effectiveness in preventing and decreasing cognitive impairment are the most recent characteristics that have been studied. For this study, we conducted a systematic review and meta-analysis to critically analyse and evaluate the existing data on the effects of PPAR-γ agonist therapy on the cognitive status of patients. For this purpose, we first analysed both early intervention and later treatment with PPAR-γ agonists, according to the disease status. The involved studies indicated that early PPAR-γ agonist intervention is beneficial for patients and that high-dose PPAR-γ therapy may have a better clinical effect, especially in reversing the effects of cognitive impairment. Furthermore, the efficacy of pioglitazone (PIO) seems to be promising, particularly for patients with comorbid diabetes. PIO presented a better clinical curative effect and safety, compared with rosiglitazone (RSG). Thus, PPAR-γ agonists play an important role in the inflammatory response of AD or DM patients, and clinical therapeutics should focus more on relevant metabolic indices.

Shared peripheral blood biomarkers for Alzheimer's disease, major depressive disorder, and type 2 diabetes and cognitive risk factor analysis.

Background: Alzheimer's disease (AD), type 2 diabetes mellitus (T2DM), and Major Depressive Disorder (MDD) have a higher incidence rate in modern society. Although increasing evidence supports close associations between the three, the mechanisms underlying their interrelationships remain elucidated. Objective: The primary purpose is to explore the shared pathogenesis and the potential peripheral blood biomarkers for AD, MDD, and T2DM. Methods: We downloaded the microarray data of AD, MDD, and T2DM from the Gene Expression Omnibus database and constructed co-expression networks by Weighted Gene Co-Expression Network Analysis to identify differentially expressed genes. We took the intersection of differentially expressed genes to obtain co-DEGs. Then, we performed GO and KEGG enrichment analysis on the common genes in the AD, MDD, and T2DM-related modules. Next, we utilized the STRING database to find the hub genes in the protein-protein interaction network. ROC curves were constructed for co-DEGs to obtain the most diagnostic valuable genes and to make drug predictions against the target genes. Finally, we conducted a present condition survey to verify the correlation between T2DM, MDD and AD. Results: Our findings indicated 127 diff co-DEGs, 19 upregulated co-DEGs, and 25 down-regulated co-DEGs. Functional enrichment analysis showed co-DEGs were mainly enriched in signaling pathways such as metabolic diseases and some neurodegeneration. Protein-protein interaction network construction identified hub genes in AD, MDD and T2DM shared genes. We identified seven hub genes of co-DEGs, namely, SMC4, CDC27, HNF1A, RHOD, CUX1, PDLIM5, and TTR. The current survey results suggest a correlation between T2DM, MDD and dementia. Moreover, logistic regression analysis showed that T2DM and depression increased the risk of dementia. Conclusion: Our work identified common pathogenesis of AD, T2DM, and MDD. These shared pathways might provide novel ideas for further mechanistic studies and hub genes that may serve as novel therapeutic targets for diagnosing and treating.

Exploration and Clinical Verification of the Blood Co-Expression Genes of Type 2 Diabetes Mellitus and Mild Cognitive Dysfunction in the Elderly.

With the development of society, the incidence of dementia and type 2 diabetes (T2DM) in the elderly has been increasing. Although the correlation between T2DM and mild cognitive impairment (MCI) has been confirmed in the previous literature, the interaction mechanism remains to be clarified. To explore the co-pathogenic genes in the blood of MCI and T2DM patients, clarify the correlation between T2DM and MCI, achieve the purpose of early disease prediction, and provide new ideas for the prevention and treatment of dementia. We downloaded T2DM and MCI microarray data from GEO databases and identified the differentially expressed genes associated with MCI and T2DM. We obtained co-expressed genes by intersecting differentially expressed genes. Then, we performed GO and KEGG enrichment analysis of co-DEGs. Next, we constructed the PPI network and found the hub genes in the network. By constructing the ROC curve of hub genes, the most valuable genes for diagnosis were obtained. Finally, the correlation between MCI and T2DM was clinically verified by means of a current situation investigation, and the hub gene was verified by qRT-PCR. A total of 214 co-DEGs were selected, 28 co-DEGs were up-regulated, and 90 co-DEGs were down-regulated. Functional enrichment analysis showed that co-DEGs were mainly enriched in metabolic diseases and some signaling pathways. The construction of the PPI network identified the hub genes in MCI and T2DM co-expression genes. We identified nine hub genes of co-DEGs, namely LNX2, BIRC6, ANKRD46, IRS1, TGFB1, APOA1, PSEN1, NPY, and ALDH2. Logistic regression analysis and person correlation analysis showed that T2DM was correlated with MCI, and T2DM increased the risk of cognitive impairment. The qRT-PCR results showed that the expressions of LNX2, BIRC6, ANKRD46, TGFB1, PSEN1, and ALDH2 were consistent with the results of bioinformatic analysis. This study screened the co-expressed genes of MCI and T2DM, which may provide new therapeutic targets for the diagnosis and treatment of diseases.

Geriatric Nutritional Risk Index assessment in elderly patients during the COVID-19 outbreak.

Background and Aims: Globally, coronavirus disease-2019 (COVID-19) is persistent in many countries and presents a major threat to public health. Critically, elderly individuals, especially those with underlying disease, poor nutritional and immune functions, are highly susceptible. Therefore, we analyzed the epidemiological features in elderly COVID-19 patients. Methods: In total, 126 patients were recruited in the Fifth Affiliated Hospital of Sun Yat-sen University, China from January 2020 to March 2020 (including 103 confirmed COVID-19 patients and 23 elderly suspected cases). Epidemiological, demographic, clinical, laboratory, radiological, and treatment data were collected and analyzed. We assessed nutritional risks in elderly patients by calculating the Geriatric Nutritional Risk Index (GNRI). Results: When compared with young patients, elderly patients were more likely to have underlying comorbidities and received nutritional support and intensive care unit treatment. Elderly patients had significantly lower levels of the following: lymphocyte percentages, red blood cell counts, hemoglobin levels, and serum albumin values. When compared with suspected COVID-19 elderly cases, elderly patients had significantly lower red blood cell counts and hemoglobin levels. The average GNRI of suspected cases and confirmed patients indicated no nutritional risk. There were no marked differences in GNRI values between groups. Conclusion: Nutritional risk assessments may provide valuable information for predicting a COVID-19 prognosis, especially in elderly patients. Anemia prevention and management should be actively and timely provided. GNRI is a potentially prognostic factor for hospitalized elderly patients. Moreover, it is also important to follow up discharged patients for continuous nutritional observations.

Elevated serum uric acid is associated with cognitive improvement in older American adults: A large, population-based-analysis of the NHANES database.

Background: The many studies revealing a connection between serum uric acid (SUA) and dementia have reported conflicting results. This study sought to investigate the relations between SUA and cognitive function in older adults. Materials and methods: The sample was 2,767 American adults aged ≥60 years from the National Health and Nutrition Examination Survey 2011-2014. Cognitive performance was evaluated by the Consortium to Establish a Registry for Alzheimer's Disease test, animal fluency test, digit symbol substitution test, and composite z-score. Multivariate linear regression analyses were conducted to estimate the association between SUA and cognitive function. Results: SUA level and cognitive function were significantly, positively correlated. Age significantly correlated with the association between SUA and cognitive function. Conclusion: These findings support a connection between SUA and cognition, showing a positive link between SUA and cognitive scores among older American adults. We contend that a slight rise in uric acid within the normal range is advantageous for enhanced cognition. To confirm the precise dose-time-response relation, more tests will be needed.

Gut microbial involvement in Alzheimer's disease pathogenesis.

Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disease characterized by memory loss, inability to carry out everyday daily life, and noticeable behavioral changes. The essential neuropathologic criteria for an AD diagnosis are extracellular ß-amyloid deposition and intracellular accumulation of hyperphosphorylated tau. However, the exact pathogenic mechanisms underlying AD remain elusive, and current treatment options show only limited success. New research indicates that the gut microbiota contributes to AD development and progression by accelerating neuroinflammation, promoting senile plaque formation, and modifying neurotransmitter production. This review highlights laboratory and clinical evidence for the pathogenic role of gut dysbiosis on AD and provides potential cues for improved AD diagnostic criteria and therapeutic interventions based on the gut microbiota.

Melatonin Attenuates ox-LDL-Induced Endothelial Dysfunction by Reducing ER Stress and Inhibiting JNK/Mff Signaling.

Endothelial dysfunction, which is characterized by damage to the endoplasmic reticulum (ER) and mitochondria, is involved in a variety of cardiovascular disorders. Here, we explored whether mitochondrial damage and ER stress are associated with endothelial dysfunction. We also examined whether and how melatonin protects against oxidized low-density lipoprotein- (ox-LDL-) induced damage in endothelial cells. We found that CHOP, GRP78, and PERK expressions, which are indicative of ER stress, increased significantly in response to ox-LDL treatment. ox-LDL also induced mitochondrial dysfunction as evidenced by decreased mitochondrial membrane potential, increased mitochondrial ROS levels, and downregulation of mitochondrial protective factors. In addition, ox-LDL inhibited antioxidative processes, as evidenced by decreased antioxidative enzyme activity and reduced Nrf2/HO-1 expression. Melatonin clearly reduced ER stress and promoted mitochondrial function and antioxidative processes in the presence of ox-LDL. Molecular investigation revealed that ox-LDL activated the JNK/Mff signaling pathway, and melatonin blocked this effect. These results demonstrate that ox-LDL induces ER stress and mitochondrial dysfunction and activates the JNK/Mff signaling pathway, thereby contributing to endothelial dysfunction. Moreover, melatonin inhibited JNK/Mff signaling and sustained ER homeostasis and mitochondrial function, thereby protecting endothelial cells against ox-LDL-induced damage.

Elderly Patients with Mild Cognitive Impairment Exhibit Altered Gut Microbiota Profiles.

BACKGROUND: As a transitional state between normal aging and Alzheimer's disease (AD), mild cognitive impairment (MCI) is characterized by a worse cognitive decline than that of natural aging. The association between AD and gut microbiota has been reported in a number of studies; however, microbial research regarding MCI remains limited. METHODS: This study examined 48 participants, of whom 22 were MCI cases and 26 were normal control cases. Fecal samples were collected for 16S ribosomal RNA (rRNA) quantitative arrays and bioinformatics analysis. RESULTS: A principal coordinates analysis (PCoA) and nonmetric multidimensional scaling (NMDS) both demonstrated that the microbial composition of participants with MCI deviated from that of healthy control participants. Multiple bacterial species were significantly increased (e.g., Staphylococcus intermedius) or decreased (e.g., Bacteroides salyersiae) in samples from the MCI group. CONCLUSION: The composition of gut microbiota differed between normal control and MCI cases. This is the first study to identify a signature series of species in the gut microbiota of individuals with MCI. The results provide a new direction for the future development of an early diagnosis and probiotic regimen.

Estrogen protects neuroblastoma cell from amyloid-ß 42 (Aß42)-induced apoptosis via TXNIP/TRX axis and AMPK signaling.

Alzheimer's disease (AD), a massive challenge to global health, is featured with the extracellular plaques made up of amyloid-ß 42 (Aß42) and the intracellular neurofibrillary pathology composed of the microtubule-associated protein tau. Women seem to have a higher vulnerability to AD. In the present study, we identified Thioredoxin-interacting protein (TXNIP) as a specifically highly-expressed gene in the hippocampus in female AD patients by bioinformatics analysis. Consistently, in the hippocampus in female AD mice, apoptosis and TXNIP expression were enhanced while TRX expression was suppressed. In Aß42-stimulated SH-SY5Y cells, the administration of estradiol significantly rescued Aß42-suppressed cell viability and protein level of TRX while inhibited Aß42-induced increases in ROS production, cell apoptosis, ΔΨm, and the protein levels of PERK, IREα, and TXNIP, further confirming the potential role of estrogen in AD progression and the involvement of TXNIP/TRX axis. Furthermore, the protective effects of estradiol against Aß42-induced in vitro neurotoxicity on SH-SY5Y cells could be significantly reversed by AMPK inhibitor, Compound C, indicating that estradiol could improve Aß42-induced AD via TXNIP/TRX and AMPK signaling. In summary, we demonstrated the cellular function of estradiol on Aß42-induced in vitro neurotoxicity on SH-SY5Y cells and a novel mechanism of TXNIP/TRX axis involved in estradiol function via AMPK signaling.

MicroRNA­125b regulates Alzheimer's disease through SphK1 regulation.

The present study aimed to investigate the expression of microRNA (miR)­125b in patients with Alzheimer's disease (AD) and to determine its potential role in AD. Mouse neuroblastoma Neuro2a APPSwe/Δ9 cells were used to generate an in vitro AD model. The results demonstrated that the expression levels of miR­125b were markedly increased in patients with AD compared with in the normal group. In addition, overexpression of miR­125b significantly inhibited cell proliferation, induced apoptosis, and enhanced inflammation and oxidative stress in an in vitro model of AD model. Furthermore, overexpression of miR­125b significantly promoted amyloid precursor protein and ß­secretase 1 expression and ß­amyloid peptide production, and suppressed sphingosine kinase 1 (SphK1) protein expression in vitro. These findings suggested that miR­125b may regulate AD, and neuronal cell growth and apoptosis, via the regulation of inflammatory factors and oxidative stress by SphK1; therefore, miR­125b may be involved in the development of AD.