Human microglial cells synthesize albumin in brain

Albumin has been implicated in Alzheimer's disease since it can bind to and transport amyloid beta, the causative agent; albumin is also a potent inhibitor of amyloid beta polymerization. In a pilot phase study of Human Brain Proteome Project, we found evidence that albumin may be synthesized in immortalized human microglial cells, human primary microglial cells, and human fetal and adult brain tissues. We also found the synthesis and secretion is enhanced upon microglial activation by Amyloid [beta]~1-42~, lipopolysaccharide treatment or human Alzheimer's brain

SoEasy: A Software Framework for Easy Hardware Control Programming for Diverse IoT Platforms

Many Internet of Things (IoT) applications are emerging and evolving rapidly thanks to widespread open-source hardware platforms. Most of the high-end open-source IoT platforms include built-in peripherals, such as the universal asynchronous receiver and transmitter (UART), pulse width modulation (PWM), general purpose input output (GPIO) ports and timers, and have enough computation power to run embedded operating systems such as Linux. However, each IoT platform has its own way of configuring peripherals, and it is difficult for programmers or users to configure the same peripheral on a different platform. Although diverse open-source IoT platforms are widespread, the difficulty in programming those platforms hinders the growth of IoT applications. Therefore, we propose an easy and convenient way to program and configure the operation of each peripheral using a user-friendly Web-based software framework. Through the implementation of the software framework and the real mobile robot application development along with it, we show the feasibility of the proposed software framework, named SoEasy

Relationship between time of emergency department admission and adherence to the Surviving Sepsis Campaign bundle in patients with septic shock

Abstract Background Nighttime hospital admission is often associated with increased mortality risk in various diseases. This study investigated compliance rates with the Surviving Sepsis Campaign (SSC) 3-h bundle for daytime and nighttime emergency department (ED) admissions and the clinical impact of compliance on mortality in patients with septic shock. Methods We conducted an observational study using data from a prospective, multicenter registry for septic shock provided by the Korean Shock Society from 11 institutions from November 2015 to December 2017. The outcome was the compliance rate with the SSC 3-h bundle according to the time of arrival in the ED. Results A total of 2049 patients were enrolled. Compared with daytime admission, nighttime admission was associated with higher compliance with the administration of antibiotics within 3 h (adjusted odds ratio (adjOR), 1.326; 95% confidence interval (95% CI), 1.088–1.617, p = 0.005) and with the complete SSC bundle (adjOR, 1.368; 95% CI, 1.115–1.678; p = 0.003), likely to result from the increased volume of all patients and sepsis patients admitted during daytime hours. The hazard ratios of the completion of SSC bundle for 28-day mortality and in-hospital mortality were 0.750 (95% CI 0.590–0.952, p = 0.018) and 0.714 (95% CI 0.564–0.904, p = 0.005), respectively. Conclusion Septic shock patients admitted to the ED during the daytime exhibited lower sepsis bundle compliance than those admitted at night. Both the higher number of admitted patients and the higher patients to medical staff ratio during daytime may be factors that are responsible for lowering the compliance

Natural Products in the Prevention of Metabolic Diseases: Lessons Learned from the 20th KAST Frontier Scientists Workshop

The incidence of metabolic and chronic diseases including cancer, obesity, inflammation-related diseases sharply increased in the 21st century. Major underlying causes for these diseases are inflammation and oxidative stress. Accordingly, natural products and their bioactive components are obvious therapeutic agents for these diseases, given their antioxidant and anti-inflammatory properties. Research in this area has been significantly expanded to include chemical identification of these compounds using advanced analytical techniques, determining their mechanism of action, food fortification and supplement development, and enhancing their bioavailability and bioactivity using nanotechnology. These timely topics were discussed at the 20th Frontier Scientists Workshop sponsored by the Korean Academy of Science and Technology, held at the University of Hawaii at Manoa on 23 November 2019. Scientists from South Korea and the U.S. shared their recent research under the overarching theme of Bioactive Compounds, Nanoparticles, and Disease Prevention. This review summarizes presentations at the workshop to provide current knowledge of the role of natural products in the prevention and treatment of metabolic diseases

Genetic Susceptibility on CagA-Interacting Molecules and Gene-Environment Interaction with Phytoestrogens: A Putative Risk Factor for Gastric Cancer

OBJECTIVES: To evaluate whether genes that encode CagA-interacting molecules (SRC, PTPN11, CRK, CRKL, CSK, c-MET and GRB2) are associated with gastric cancer risk and whether an interaction between these genes and phytoestrogens modify gastric cancer risk. METHODS: In the discovery phase, 137 candidate SNPs in seven genes were analyzed in 76 incident gastric cancer cases and 322 matched controls from the Korean Multi-Center Cancer Cohort. Five significant SNPs in three genes (SRC, c-MET and CRK) were re-evaluated in 386 cases and 348 controls in the extension phase. Odds ratios (ORs) for gastric cancer risk were estimated adjusted for age, smoking, H. pylori seropositivity and CagA strain positivity. Summarized ORs in the total study population (462 cases and 670 controls) were presented using pooled- and meta-analysis. Plasma concentrations of phytoestrogens (genistein, daidzein, equol and enterolactone) were measured using the time-resolved fluoroimmunoassay. RESULTS: SRC rs6122566, rs6124914, c-MET rs41739, and CRK rs7208768 showed significant genetic effects for gastric cancer in both the pooled and meta-analysis without heterogeneity (pooled OR = 3.96 [95% CI 2.05-7.65], 1.24 [95% CI = 1.01-1.53], 1.19 [95% CI = 1.01-1.41], and 1.37 [95% CI = 1.15-1.62], respectively; meta OR = 4.59 [95% CI 2.74-7.70], 1.36 [95% CI = 1.09-1.70], 1.20 [95% CI = 1.00-1.44], and 1.32 [95% CI = 1.10-1.57], respectively). Risk allele of CRK rs7208768 had a significantly increased risk for gastric cancer at low phytoestrogen levels (p interaction<0.05). CONCLUSIONS: Our findings suggest that SRC, c-MET and CRK play a key role in gastric carcinogenesis by modulating CagA signal transductions and interaction between CRK gene and phytoestrogens modify gastric cancer risk

Development of cordycepin formulations for preclinical and clinical studies

There is extensive literature on in vivo studies with cordycepin but these studies were generally conducted without validation of the various formulations, especially in terms of the solubility of cordycepin in the dosing vehicles used. Cordycepin is a promising drug candidate in multiple therapeutic areas and there is a growing interest in studies aimed at assessing the pharmacological activity of this compound in relevant animal disease models. It is likely that many reported in vivo studies used formulations in which cordycepin was incompletely soluble. This can potentially confound the interpretation of pharmacokinetics and efficacy results. Furthermore, the presence of particles in intravenously administered suspension can cause adverse effects and should be avoided. Here we present the results from our development of simple and readily applicable formulations of cordycepin based on quantitative solubility assessment. Homogeneous solutions of cordycepin were prepared in phosphate-buffered saline (PBS) at different pH levels, suitable as formulations for both intravenously and oral administration. For the purpose of high-dose oral administration we also developed propylene glycol (PPG)-based vehicles in which cordycepin is completely soluble. The stability of the newly developed formulations was also assessed, as well the feasibility of their sterilisation by filtration. Additionally, an HPLC-UV method for the determination of cordycepin in the formulations, which may also be useful for other purposes, was developed and validated. Our study could provide useful information for improvement of future preclinical and clinical studies involving cordycepin

Toxoplasma gondii Infection in the Brain Inhibits Neuronal Degeneration and Learning and Memory Impairments in a Murine Model of Alzheimer's Disease

Immunosuppression is a characteristic feature of Toxoplasma gondii-infected murine hosts. The present study aimed to determine the effect of the immunosuppression induced by T. gondii infection on the pathogenesis and progression of Alzheimer's disease (AD) in Tg2576 AD mice. Mice were infected with a cyst-forming strain (ME49) of T. gondii, and levels of inflammatory mediators (IFN-γ and nitric oxide), anti-inflammatory cytokines (IL-10 and TGF-β), neuronal damage, and β-amyloid plaque deposition were examined in brain tissues and/or in BV-2 microglial cells. In addition, behavioral tests, including the water maze and Y-maze tests, were performed on T. gondii-infected and uninfected Tg2576 mice. Results revealed that whereas the level of IFN-γ was unchanged, the levels of anti-inflammatory cytokines were significantly higher in T. gondii-infected mice than in uninfected mice, and in BV-2 cells treated with T. gondii lysate antigen. Furthermore, nitrite production from primary cultured brain microglial cells and BV-2 cells was reduced by the addition of T. gondii lysate antigen (TLA), and β-amyloid plaque deposition in the cortex and hippocampus of Tg2576 mouse brains was remarkably lower in T. gondii-infected AD mice than in uninfected controls. In addition, water maze and Y-maze test results revealed retarded cognitive capacities in uninfected mice as compared with infected mice. These findings demonstrate the favorable effects of the immunosuppression induced by T. gondii infection on the pathogenesis and progression of AD in Tg2576 mice

Developmental Transcriptomic Features of the Carcinogenic Liver Fluke, Clonorchis sinensis

Clonorchis sinensis is the causative agent of the life-threatening disease endemic to China, Korea, and Vietnam. It is estimated that about 15 million people are infected with this fluke. C. sinensis provokes inflammation, epithelial hyperplasia, and periductal fibrosis in bile ducts, and may cause cholangiocarcinoma in chronically infected individuals. Accumulation of a large amount of biological information about the adult stage of this liver fluke in recent years has advanced our understanding of the pathological interplay between this parasite and its hosts. However, no developmental gene expression profiles of C. sinensis have been published. In this study, we generated gene expression profiles of three developmental stages of C. sinensis by analyzing expressed sequence tags (ESTs). Complementary DNA libraries were constructed from the adult, metacercaria, and egg developmental stages of C. sinensis. A total of 52,745 ESTs were generated and assembled into 12,830 C. sinensis assembled EST sequences, and then these assemblies were further categorized into groups according to biological functions and developmental stages. Most of the genes that were differentially expressed in the different stages were consistent with the biological and physical features of the particular developmental stage; high energy metabolism, motility and reproduction genes were differentially expressed in adults, minimal metabolism and final host adaptation genes were differentially expressed in metacercariae, and embryonic genes were differentially expressed in eggs. The higher expression of glucose transporters, proteases, and antioxidant enzymes in the adults accounts for active uptake of nutrients and defense against host immune attacks. The types of ion channels present in C. sinensis are consistent with its parasitic nature and phylogenetic placement in the tree of life. We anticipate that the transcriptomic information on essential regulators of development, bile chemotaxis, and physico-metabolic pathways in C. sinensis that presented in this study will guide further studies to identify novel drug targets and diagnostic antigens

Lipophilic activated ester prodrug approach for drug delivery to the intestinal lymphatic system

The intestinal lymphatic system plays an important role in the pathophysiology of multiple diseases including lymphomas, cancer metastasis, autoimmune diseases, and human immunodeficiency virus (HIV) infection. It is thus an important compartment for delivery of drugs in order to treat diseases associated with the lymphatic system. Lipophilic prodrug approaches have been used in the past to take advantage of the intestinal lymphatic transport processes to deliver drugs to the intestinal lymphatics. Most of the approaches previously adopted were based on very bulky prodrug moieties such as those mimicking triglycerides (TG). We now report a study in which a lipophilic prodrug approach was used to efficiently deliver bexarotene (BEX) and retinoic acid (RA) to the intestinal lymphatic system using activated ester prodrugs. A range of carboxylic ester prodrugs of BEX were designed and synthesised and all of the esters showed improved association with chylomicrons, which indicated an improved potential for delivery to the intestinal lymphatic system. The conversion rate of the prodrugs to BEX was the main determinant in delivery of BEX to the intestinal lymphatics, and activated ester prodrugs were prepared to enhance the conversion rate. As a result, an 4-(hydroxymethyl)-1,3-dioxol-2-one ester prodrug of BEX was able to increase the exposure of the mesenteric lymph nodes (MLNs) to BEX 17-fold compared to when BEX itself was administered. The activated ester prodrug approach was also applied to another drug, RA, where the exposure of the MLNs was increased 2.4-fold through the application of a similar cyclic activated prodrug. Synergism between BEX and RA was also demonstrated in vitro by cell growth inhibition assays using lymphoma cell lines. In conclusion, the activated ester prodrug approach results in efficient delivery of drugs to the intestinal lymphatic system, which could benefit patients affected by a large number of pathological conditions