Dibenzazepine-containing polymers were prepared by various polymerization methods and the effects of adding the obtained polymers to plastics were investigated. Dibenzazepine homopolymers were ...prepared by the oxidative polymerization of commercially available dibenzazepine derivatives and by the dehalogenative polymerization of corresponding dibromodibenzazepines. Dibenzazepine copolymers were prepared from dibromodibenzazepines. The addition of polymers to plastics afforded fluorescent function to them. The fluorescent behavior of a blend composite depended not only on the chemical structure of the polymers, but also on the plastic used as the matrix. The effects of adding dibenzazepine-containing polymer in plastic blends were investigated. When the compatibility of the plastic blend was higher, the fluorescence λmax of the blend became shorter. This suggested that the method using a dibenzazepine-containing polymer is adaptive for estimating of the compatibility of the blend composite by the simple method.
Lipoproteins in the central nervous system (CNS) are not incorporated from the blood but are formed mainly by glial cells within the CNS. In addition, cholesterol in the CNS is synthesized ...endogenously because the blood–brain barrier segregates the CNS from the peripheral circulation. Apolipoprotein (apo) E is a major apo in the CNS. In normal condition, apo E is secreted from glia, mainly from astrocytes, and forms cholesterol-rich lipoproteins by ATP-binding cassette transporters. Subsequently, apo E-containing glial lipoproteins supply cholesterol and other components to neurons via a receptor-mediated process. Recent findings demonstrated that receptors of the low density lipoprotein (LDL) receptor family not only internalize lipoproteins into the cells but also, like signaling receptors, transduce signals upon binding the ligands. In this review, the regulation of lipid homeostasis will be discussed as well as roles of lipoproteins and functions of receptors of LDL receptor family in the CNS. Furthermore, the relation between lipid metabolism and Alzheimer's disease (AD) is discussed.
Neuronal cell death after cerebral ischemia consists various steps including glutamate excitotoxity. Excessive Ca2+ influx through the N-methyl-D-aspartate (NMDA) receptor, which is one of the ...ionotropic glutamate receptors, plays a central role in neuronal cell death after cerebral ischemia. We previously reported that DNA methylation is transiently increased in neurons during ischemic injury and that this aberrant DNA methylation is accompanied by neuronal cell death. Therefore, we performed the present experiments on glutamate excitotoxicity to gain further insight into DNA methylation involvement in the neuronal cell death. We demonstrated that knockdown of DNA methyltransferase (DNMT)1, DNMT3a, or DNMT3b gene in Neuro2a cells was performed to examine which DNMTs were more important for neuronal cell death after glutamate excitotoxicity. Although we confirmed a decrease in the levels of the target DNMT protein after small interfering RNA (siRNA) transfection, the Neuro2a cells were not protected from injury by transfection with siRNA for each DNMT. We next revealed that the pharmacological inhibitor of DNMTs protected against glutamate excitotoxicity in Neuro2a cells and also in primary cultured cortical neurons. This protective effect was associated with a decrease in the number of 5-methylcytosine (5 mC)-positive cells under glutamate excitotoxicity. In addition, the increased level of cleaved caspase-3 was also reduced by a DNMT inhibitor. Our results suggest the possibility that at least 2 or all DNMTs functionally would cooperate to activate DNA methylation after glutamate excitotoxicity and that inhibition of DNA methylation in neurons after cerebral ischemia might become a strategy to reduce the neuronal injury.
Gene editing using CRISPR/Cas9 is a promising method to cure many human genetic diseases. We have developed an efficient system to deliver Cas9 into the adeno-associated virus integration site 1 ...(AAVS1) locus, known as a safe harbor, using lentivirus and AAV viral vectors, as a step toward future in vivo transduction. First, we introduced Cas9v1 (derived from Streptococcus pyogenes) at random into the genome using a lentiviral vector. Cas9v1 activity was used when the N-terminal 1.9 kb, and C-terminal 2.3 kb fragments of another Cas9v2 (human codon-optimized) were employed sequentially with specific single-guide RNAs (sgRNAs) and homology donors carried by AAV vectors into the AAVS1 locus. Then, Cas9v1 was removed from the genome by another AAV vector containing sgRNA targeting the long terminal repeat of the lentivirus vector. The reconstituted Cas9v2 in the AAVS1 locus was functional and gene editing was efficient.
Aging promotes inflammation, a process contributing to fibrosis and decline in organ function. The release of neutrophil extracellular traps (NETs NETosis), orchestrated by peptidylarginine deiminase ...4 (PAD4), damages organs in acute inflammatory models. We determined that NETosis is more prevalent in aged mice and investigated the role of PAD4/NETs in age-related organ fibrosis. Reduction in fibrosis was seen in the hearts and lungs of aged PAD4
mice compared with wild-type (WT) mice. An increase in left ventricular interstitial collagen deposition and a decline in systolic and diastolic function were present only in WT mice, and not in PAD4
mice. In an experimental model of cardiac fibrosis, cardiac pressure overload induced NETosis and significant platelet recruitment in WT but not PAD4
myocardium. DNase 1 was given to assess the effects of extracellular chromatin. PAD4 deficiency or DNase 1 similarly protected hearts from fibrosis. We propose a role for NETs in cardiac fibrosis and conclude that PAD4 regulates age-related organ fibrosis and dysfunction.
The strongest known genetic risk factor for the development of late-onset Alzheimer disease is inheritance of the apolipoprotein (apo) E4 (ε4 allele) although the mechanisms underlying this ...connection are still not entirely clear. In this review, we shall discuss the role of apo E in the brain, particularly in relation to Alzheimer disease. Cholesterol transport and homeostasis in the central nervous system (CNS) are separated from that in the peripheral circulation by the blood–brain barrier. However, the brain operates its own lipoprotein transport system that is mediated by high density lipoprotein-sized, apo E-containing lipoproteins that are synthesized and secreted by glial cells (primarily astrocytes). Several ATP-binding cassette (ABC) transporters are expressed in the brain, including ABCA1 and ABCG1 which play important roles in the transfer of phospholipids and cholesterol to apo E. The astrocyte-derived apo E-containing lipoproteins can bind to, and be internalized by, receptors of the low density lipoprotein receptor superfamily that are located on the surface of neurons. In addition to these receptors serving as endocytosis receptors for lipoproteins, several of these receptors also act as signaling receptors in neurons and activate pathways involved in axonal growth, as well as neuronal survival. These beneficial pathways appear to be enhanced to a greater extent by apo E3 than by apo E4. Apo E has also been implicated in the deposition of amyloid plaques since apo E3, more readily than apo E4, forms a complex with Aß peptides, and mediates the degradation of amyloid deposits.
There are no detailed reports of clinical outcomes in Asian patients with nonalcoholic fatty liver disease (NAFLD) who undergo liver biopsy. We aimed to investigate the clinical outcomes of a large ...cohort of Asian patients with biopsy-proven NAFLD and evaluate the specific effects of nonalcoholic steatohepatitis and fibrosis stage.
This multicenter registry-based retrospective cohort study, called the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) in Asia, included 1398 patients.
The median follow-up period was 4.6 years (range, 0.3-21.6 years), representing a total of 8874 person-years of follow-up. During that time, 47 patients died, and 1 patient underwent orthotopic liver transplantation. The leading cause of death was nonhepatic cancer (n = 10). The leading causes of liver-related death were liver failure (n = 9), hepatocellular carcinoma (HCC) (n = 8), and cholangiocellular carcinoma (n = 4). During follow-up, 37 patients developed HCC, 31 developed cardiovascular disease, and 68 developed nonhepatic cancer (mainly breast, stomach, and colon/rectum). Among our cohort of patients with NAFLD, liver-specific mortality was 2.34/1000 person-years (95% confidence interval CI, 1.52-3.58), overall mortality was 5.34/1000 person-years (95% CI, 4.02-7.08), and HCC incidence was 4.17/1000 person-years (95% CI, 3.02-5.75). Liver fibrosis was independently associated with liver-related events but not overall mortality.
Liver-related mortality was the leading cause of mortality in Asian patients with biopsy-confirmed NAFLD. Although fibrosis stage was independently associated with liver-related events, it was not associated with overall mortality after adjusting for confounders, such as histologic features of steatohepatitis.
Polycondensation via direct C–H arylation of thiophene derivatives gave thiophene- and bithiophene-based alternating copolymers in good yields. The optimization of the reaction conditions was ...investigated in terms of a catalytic system and reaction time. Under optimized conditions, the polycondensation reaction of 3,3′,4,4′-tetramethylbithiophene with 2,7-dibromo-9,9-dioctylfluorene gave poly2,7-(9,9-dioctylfluorene)-alt-5,5′-(3,3′,4,4′-tetramethyl-2,2′-bithiophene) with a molecular weight of 31 800 in 91% yield. The polycondensation reaction proceeded with 2 mol % of Pd(OAc)2 without the addition of a phosphine ligand in a short reaction time (3 h). Six kinds of π-conjugated polymers were synthesized by the polycondensation reaction without the use of bifunctional organometallic reagents as monomers.
Complicated gastric lymphatic drainage potentially undermines the utility of sentinel node (SN) biopsy in patients with gastric cancer. Encouraged by several favorable single-institution reports, we ...conducted a multicenter, single-arm, phase II study of SN mapping that used a standardized dual tracer endoscopic injection technique.
Patients with previously untreated cT1 or cT2 gastric adenocarcinomas < 4 cm in gross diameter were eligible for inclusion in this study. SN mapping was performed by using a standardized dual tracer endoscopic injection technique. Following biopsy of the identified SNs, mandatory comprehensive D2 or modified D2 gastrectomy was performed according to current Japanese Gastric Cancer Association guidelines.
Among 433 patients who gave preoperative consent, 397 were deemed eligible on the basis of surgical findings. SN biopsy was performed in all patients, and the SN detection rate was 97.5% (387 of 397). Of 57 patients with lymph node metastasis by conventional hematoxylin and eosin staining, 93% (53 of 57) had positive SNs, and the accuracy of nodal evaluation for metastasis was 99% (383 of 387). Only four false-negative SN biopsies were observed, and pathologic analysis revealed that three of those biopsies were pT2 or tumors > 4 cm. We observed no serious adverse effects related to endoscopic tracer injection or the SN mapping procedure.
The endoscopic dual tracer method for SN biopsy was confirmed as safe and effective when applied to the superficial, relatively small gastric adenocarcinomas included in this study.
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