MicroRNA expression profiles of neuron-derived extracellular vesicles in plasma from patients with amyotrophic lateral sclerosis.

Circulating microRNAs (miRNAs) in peripheral blood have been extensively investigated as biomarkers for early diagnosis and monitoring of disease progression. However, their cellular origin as well as their link to the pathophysiology, especially neurodegenerative disease, remains largely unknown. In the present study, we isolated neuron-derived extracellular vesicles (EVs) in plasma by immunoaffinity purification and comprehensively analyzed their miRNA expression profiles using microarray. A total of 30 miRNAs were differentially regulated in amyotrophic lateral sclerosis (ALS) plasma relative to healthy control plasma. Gene ontology analysis revealed that biological processes implicated in both up-regulated and down-regulated miRNAs were involved in synaptic vesicle-related pathways. Especially, 4 miRNAs in plasma neuro-derived EVs seemed to be regulated in the similar manner as those in formalin-fixed paraffin-embedded motor cortex samples from ALS patients. The target genes for the 4 miRNAs partly overlapped in STX1B, RAB3B, and UNC13A genes. UNC13A has been reported to be associated with increased odds of sporadic ALS in multiple genome-wide association studies. Our data suggest that miRNAs extracted from neuron-derived EVs in plasma reflect miRNA alterations in the brain as potential biomarkers of ALS.

Self-expandable Metallic Stents Contribute to Reducing Perioperative Complications in Colorectal Cancer Patients with Acute Obstruction.

BACKGROUND/AIM: The self-expandable metallic stent (SEMS) is an excellent non-invasive tool for emergent bowel obstruction. This study was designed to evaluate the clinical usefulness of the SEMS for avoiding perioperative complications. PATIENTS AND METHODS: We analyzed a total of 47 consecutive patients who had a bowel obstruction due to colorectal cancer at initial diagnosis between 2012 and 2017 from hospital records. RESULTS: Perioperative complications occurred in 30% (14/47) of patients. Univariate and multivariate logistic regression analyses identified an age of more than 75 years [p=0.037, OR=6.84 (95% CI=1.11-41.6)] and the absence of an SEMS treatment [p=0.028, OR=18.5 (95% CI=1.36-250.0)] as independent risk factors for perioperative complications. Pneumonia (12.7% (6/47)) was the most common complication. There were no pneumonia patients (0% (0/15)) who were treated with the SEMS. In contrast to patients with the non-SEMS treatment, 18.7% (6/32) of all patients and 35.7% (5/14) of elderly patients had pneumonia. CONCLUSION: The SEMS is a safe and effective treatment for avoiding perioperative complications, particularly pneumonia, and may be a crucial strategy in elderly patients with acute obstruction due to colorectal cancer.

MKC-231, a choline uptake enhancer: (2) Effect on synthesis and release of acetylcholine in AF64A-treated rats.

The effect of MKC-231 on acetylcholine (ACh) synthesis and release was studied in the hippocampus of normal and AF64A-treated rats. AF64A (3 nmol/brain, i.c.v.) produced significant reduction of high-affinity choline uptake (HACU) and high K+-induced ACh release in hippocampal synaptosomes. Treatments with MKC-231 (10(-8) and 10(-7) M) showed significant reverse of the decrease in both HACU and ACh release. In hippocampal slices superfused with choline-containing artificial cerebro-spinal fluid (ACSF), high K+-induced ACh release was gradually decreased by repeated alteration of resting and high K+ stimulations in AF64A-treated rats. However, addition of MKC-231 (10(-8) to 10(-7) M) in the superfusate reduces this decrease. In vivo microdialysis studies indicate MKC-231 (10 mg/kg, p.o.) significantly reversed reduction of basal ACh concentrations in AF64A-treated rats, measured by radioimmunoassay without a cholinesterase inhibitor in the perfusate. These results indicate MKC-231 improves AF64A-induced cholinergic hypofunction by enhancing HACU, subsequently facilitating ACh synthesis and release in vitro and in vivo.

MKC-231, a choline uptake enhancer: (3) Mode of action of MKC-231 in the enhancement of high-affinity choline uptake.

MKC-231, a putative cholinergic activity, is reported to improve learning and memory impaired in AF64A-treated animals. MKC-231 enhances high-affinity choline uptake (HACU) known as the rate-limiting step of acetylcholine (ACh) synthesis. We investigated the mode of action (MOA) of HACU enhancement by MKC-231. Intracerebroventricular (i.c.v.) injections of AF64A (3 nmol/brain) resulted in significant HACU reduction in hippocampal synaptosomes. Treatment with MKC-231 increased Vmax of HACU and Bmax of [3H]-HC-3 binding 1.6 and 1.7-fold, respectively. In studies of [3H]-MKC-231 binding and Biacore analysis, MKC-231 showed noticeable affinity for cloned high-affinity choline transporters (CHT1). The present study suggests that MKC-231 directly affects trafficking of CHT1 and increases the numbers of transporter, working for HACU, at the synaptic membrane.

MKC-231, a choline-uptake enhancer: (1) long-lasting cognitive improvement after repeated administration in AF64A-treated rats.

MKC-231 is reported to increase high-affinity choline uptake (HACU) in vitro and improve learning impairment on a single oral administration in AF64A-treated rats. In this study, we investigated the effects of repeated administration of MKC-231 (1 and 3 mg/kg, p.o., 8 days) on learning impairment in the water-maze task in AF64A-treated rats 1, 24, 48, and 72 h after the last dose. Significant cognitive improvement was observed for 24 h, however, concentration measurement studies indicated MKC-231 was not detected in the brain by this time. We also studied the effects of 8-days repeated administration of MKC-231 on HACU 1, 24, 48, and 72 h after the last dose and observed an increase of HACU similar in time course with cognitive improvement. From these results, we discussed the possibility that MKC-231 could induce long-lasting procognitive effects by changing the choline transporter regulation system.