54 research outputs found
Sex-inducing effects toward planarians widely present among parasitic flatworms
Summary
Various parasitic flatworms infect vertebrates for sexual reproduction, often causing devastating diseases in their hosts. Consequently, flatworms are of great socioeconomic and biomedical importance. Although the cessation of parasitic flatworm sexual reproduction is a major target of anti-parasitic drug design, little is known regarding bioactive compounds controlling flatworm sexual maturation. Using the planarian Dugesia ryukyuensis, we observed that sex-inducing substances found in planarians are also widespread in parasitic flatworms, such as monogeneans and flukes (but not in tapeworms). Reverse-phase HPLC analysis revealed the sex-inducing substance(s) eluting around the tryptophan retention time in the fluke Calicophoron calicophorum, consistent with previous studies on the planarian Bipalium nobile, suggesting that the substance(s) is likely conserved among flatworms. Moreover, six of the 18 ovary-inducing substances identified via transcriptome and metabolome analyses are involved in purine metabolism. Our findings provide a basis for understanding and modifying the life cycles of various parasitic flatworms.journal articl
Effects of K-877, a novel selective PPARĪ± modulator, on small intestine contribute to the amelioration of hyperlipidemia in low-density lipoprotein receptor knockout mice
Peroxisome proliferator-activated receptor Ī± (PPARĪ±) is a well-known therapeutic target for treating hyperlipidemia. K-877 is a novel selective PPARĪ± modulator (SPPARMĪ±) that enhances PPARĪ± transcriptional activity with high selectivity and potency, resulting in reduced plasma lipid levels. This study aimed to evaluate the effects of K-877 on hyperlipidemia in low-density lipoprotein receptor knockout (Ldlrā/ā) mice, a mouse model of atherosclerosis. We revealed that K-877 administration significantly decreased plasma triglyceride (TG) and total cholesterol (TC) levels and increased plasma high-density lipoprotein cholesterol (HDL-C) levels in Ldlrā/ā mice. K-877 administration to Ldlrā/ā mice efficiently increased the gene expression of PPARĪ± and its target genes related to fatty acid oxidation in the liver and small intestine. The same treatment significantly increased ATP-binding cassette a1 gene expression in the liver and small intestine and reduced Niemann Pick C1-like 1 gene expression in the small intestine, suggesting that K-877 administration induced HDL-C production in the liver and small intestine and reduced cholesterol absorption in the small intestine. In conclusion, K-877 administration had pronounced effects on the liver and small intestine in Ldlrā/ā mice. K-877 is an attractive PPARĪ±-modulating drug for treating hyperlipidemia that works equally well in both the liver and small intestine
Dendritic glycopolymers based on dendritic polyamine scaffolds: view on their synthetic approaches, characteristics and potential for biomedical applications
In this review we highlight the potential for biomedical applications of dendritic glycopolymers based on polyamine scaffolds. The complex interplay of the molecular characteristics of the dendritic architectures and their specific interactions with various (bio)molecules are elucidated with various examples. A special role of the individual sugar units attached to the dendritic scaffolds and their density is identified, which govern ionic and H-bond interactions, and biological targeting, but to a large extent are also responsible for the significantly reduced toxicity of the dendritic glycopolymers compared to their polyamine scaffolds. Thus, the application of dendritic glycopolymers in drug delivery systems for gene transfection but also as therapeutics in neurodegenerative diseases has great promisePublikacja w ramach programu Royal Society of Chemistry "Gold for Gold" 2014 finansowanego przez Uniwersytet ÅĆ³dzk
Selective peroxisome proliferator-activated receptor-Ī± modulator K-877 efficiently activates the peroxisome proliferator-activated receptor-Ī± pathway and improves lipid metabolism in mice
Aims/IntroductionPeroxisome proliferator-activated receptor-Ī± (PPARĪ±) is a therapeutic target for hyperlipidemia. K-877 is a new selective PPARĪ± modulator (SPPARMĪ±) that activates PPARĪ± transcriptional activity. The aim of the present study was to assess the effects of K-877 on lipid metabolism in vitro and in vivo compared with those of classical PPARĪ± agonists.Materials and MethodsTo compare the effects of K-877 on PPARĪ± transcriptional activity with those of the classical PPARĪ± agonists Wy14643 (Wy) and fenofibrate (Feno), the cell-based PPARĪ± transactivation luciferase assay was carried out. WT and Pparaā/ā mice were fed with a moderate-fat (MF) diet for 6 days, and methionineācholine-deficient (MCD) diet for 4 weeks containing Feno or K-877.ResultsIn luciferase assays, K-877 activated PPARĪ± transcriptional activity more efficiently than the classical PPARĪ± agonists Feno and Wy. After being fed MF diet containing 0.001% K-877 or 0.2% Feno for 6 days, mice in the K-877 group showed significant increases in the expression of Ppara and its target genes, leading to marked reductions in plasma triglyceride levels compared with those observed in Feno-treated animals. These K-877 effects were blunted in Pparaā/ā mice, confirming that K-877 activates PPARĪ±. In further experiments, K-877 (0.00025%) and Feno (0.1%) equally improved the pathology of MCD diet-induced non-alcoholic fatty liver disease, with increased expression of hepatic fatty acid oxidation genes.ConclusionsThe present data show that K-877 is an attractive PPARĪ±-modulating drug and can efficiently reduce plasma triglyceride levels, thereby alleviating the dysregulation of lipid metabolism
Accumulation of Somatic Mutations in TP53 in Gastric Epithelium WithĀ Helicobacter pylori Infection
Morphogenesis of the middle ear ossicles and spatial relationships with the external and inner ears during the embryonic period
We describe the three-dimensional morphogenesis of the middle ear ossicles (MEOs) according to Carnegie stage (CS) in human embryos. Seventeen samples including 33 MEOs from CS18 to 23 were selected from the Kyoto Collection. The primordia of the MEOs and related structures were histologically observed and three-dimensionally reconstructed from digital images. The timing of chondrogenesis was variable among structures. The stapes was recognizable as a vague condensation of the mesenchymal cells in all samples from CS18, whereas the malleus and incus were recognizable at CS19. Chondrogenesis of all MEOs was evident in all samples after CS21. The chondrocranium was recognizable in all samples by CS18, and the perichondrium border of the auricular cartilage and otic capsule was distinct in all samples at CS23. At CS19, the MEOs were positioned in the anterior to posterior direction, following the order malleus, incus, stapes, which adjusted gradually during development. The MEOs connected in all samples after CS22. The stapes was located close to the vestibular part of the inner ear, although the basal part was not differentiated into the āfootplateā form, even at CS23. The handles of the malleus were close to the tubotympanic recess at CS23, but were distant from the external auditory meatus. Determining the timeline of the formation of MEOs and connection of the external and inner ears can be informative for understanding hearing loss caused by failure of this connection. These data may provide a useful standard for morphogenesis, and will contribute to distinguishing between normal and abnormal MEO development
Tumor Accumulation of PIP-Based KRAS Inhibitor KR12 Evaluated by the Use of a Simple, Versatile Chicken Egg Tumor Model
Background: The KRAS inhibitor KR12, based on pyrrole-imidazole polyamide (PIP), has been developed and shown to exhibit efficacy in mouse experiments. Because some PIP species exhibit tumor accumulation capability, we decided to evaluate whether the PIP portion of KR12 exhibits tumor accumulation. We employed the CAM assay that provides a simple method for tumor accumulation evaluation. Methods: KR12 PIP was synthesized and conjugated to TAMRA to produce a fluorescently labeled reagent (KR12-TAMRA). This reagent was injected into a fertilized chicken egg that has been transplanted with human cancer cells. Distribution of the red fluorescence was examined by cutting out tumor as well as various organs from the embryo. Results: The red fluorescence of KR12-TAMRA was found to overlap with the green fluorescence of the tumor formed with GFP-expressing cancer cells. We also observed nuclear localization of KR12-TAMRA. Treatment of KR12 that contained the alkylating agent CBI in the tumor-bearing chicken egg resulted in tumor growth inhibition. Conclusions: KR12 contains a PIP that has two key features: tumor accumulation and nuclear localization. KR12 conjugated with CBI exhibits inhibition of tumor growth in the CAM model
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