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Biochemistry, molecular biology, biophysics, Biochimie, biologie moléculaire, biophysique, Pharmacology drugs, Pharmacologie, galénique, Sciences biologiques et medicales, Biological and medical sciences, Sciences medicales, Medical sciences, Pharmacologie. Traitements medicamenteux, Pharmacology. Drug treatments, Pharmacologie générale, General pharmacology, Pharmacognosie. Homéopathie. Aliment santé, Pharmacognosy. Homeopathy. Health food, Enzyme, Enzima, Inhibiteur histone deacetylase, Histone deacetylase inhibitor, Inhibidor histone deacetylase, Invertebrata, Activité biologique, Biological activity, Actividad biológica, Anticancéreux, Antineoplastic agent, Anticanceroso, Cytotoxicité, Cytotoxicity, Citotoxicidad, Depsipeptide, Depsipéptido, Hydrolases, Inhibiteur enzyme, Enzyme inhibitor, Inhibidor enzima, Milieu marin, Marine environment, Medio marino, Mollusca, Origine animale, Animal origin, Origen animal, Peptide cyclique, Cyclic peptides, Péptido cíclico, Relation structure activité, Structure activity relation, Relación estructura actividad, Cyclodepsipeptide, Histone deacetylase, Cytotoxic activity, Kulokekahilide-2, and Structure-activity relationship

Kulokekahilide-2, a 26-membered cyclodepsipeptide, was isolated from Hawaiian marine mollusk and possessed potent cytotoxicity in mammalian tumor cells. In the present study, we synthesized kulokekahilide-2 and its derivatives and examined the structure-activity relationships of these peptides in human cancer cells (A549, K562, and MCF7 cells). This study demonstrated that the cyclization of depsipeptide and the chirality of the 21 position in Ala in kulokekahilide-2 were important for its cytotoxic property and that addition of halogen at the para position of phenyl group in the 24-D-MePhe in kulokekahilide-2 as well as some derivatives remarkably increased their cytotoxicity in human cancer cells. These results suggest that the modifications of 24-D-MePhe in kulokekahilide-2, preserving its cyclization and the chirality at the 21-position, are promising strategy for exploring new derivative of kulokekahilide-2 as anti-tumor drug.

Neurology, Neurologie, Sciences biologiques et medicales, Biological and medical sciences, Sciences medicales, Medical sciences, Neurologie, Neurology, Maladies dégénératives et hérédodégénératives du système nerveux. Leucodystrophies. Maladies à prions, Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases, Encéphale, Encephalon, Encéfalo, Mammalia, Névroglie, Neuroglia, Rodentia, Système nerveux central, Central nervous system, Sistema nervioso central, Vertebrata, Animal, Astrocyte, Astrocito, Biosynthèse, Biosynthesis, Biosíntesis, Cervelet, Cerebellum, Cerebelo, Facteur croissance fibroblaste basique, Basic fibroblast growth factor, Factor crecimiento fibroblasto básico, Libération, Release, Liberación, Neuropeptide Y, Neuropéptido Y, Pathologie du système nerveux, Nervous system diseases, Sistema nervioso patología, Peptide, Peptides, Péptido, Rat, Rata, Stress oxydatif, Oxidative stress, Estrés oxidativo, Adrenomedullin, Diphenylarsinic acid, FGF-2, and MCP-1

An incident of poisoning occurred in Japan in 2003 when high-level contamination with arsenic, mainly diphenylarsinic acid (DPAA), was found in well water. People using this water particularly experienced cerebellar symptoms. In the present study, we investigated the adverse effects of DPAA on the cerebellum in vitro and in vivo to understand the biological mechanisms that cause cerebellar symptoms. Comprehensive gene expression analyses in primary cultured rat cerebellar cells exposed to 10 μM DPAA for 24 hours indicated significant alterations in the mRNA expression of genes encoding antioxidative stress proteins (heme oxigenase 1 and heat shock protein 72) and neuroactive and vasoactive peptides (neuropeptide Y, adrenomedullin, monocyte chemoattractant protein 1, and fibroblast growth factor 2). Further analyses of proteins revealed that cultured cerebellar astrocytes expressed these antioxidative stress proteins and peptides in response to exposure to DPAA. In addition, these adverse effects were also observed in the cerebellum exposed in vivo to DPAA (100 mg/L) for 21 days. These results suggested that cerebellar astrocytes irregularly secrete neuroactive and vasoactive peptides against DPAA-induced oxidative stress, which leads to abnormal neural functions and disrupted cerebellar autoregulation dynamics and results in the onset of cerebellar symptoms.

Toxicology, Toxicologie, Sciences biologiques et medicales, Biological and medical sciences, Sciences medicales, Medical sciences, Toxicologie, Toxicology, Aminoacide excitateur, Excitatory aminoacid, Aminoácido excitador, Mammalia, Neurotransmetteur, Neurotransmitter, Neurotransmisor, Rodentia, Système nerveux central, Central nervous system, Sistema nervioso central, Vertebrata, Animal, Développement, Development, Desarrollo, Encéphale, Encephalon, Encéfalo, Exocytose, Exocytosis, Exocitosis, Exposition, Exposure, Exposición, Expression génique, Gene expression, Expresión genética, Glutamate, Glutamato, Hormone thyroïdienne, Thyroid hormone, Hormona tiroidea, Polychlorobiphényles, Polychlorobiphenyls, Polichlorobifenilos, Prénatal, Prenatal, Rat, Rata, Récepteur glutamate, Glutamate receptor, Receptor glutámato, Toxicité, Toxicity, Toxicidad, Profil d'expression génique, Gene expression profile, Perfil de expresión genética, Brain development, Gene expression profiling, Hydroxylated-polychlorinated biphenyl, and Prenatal exposure

Polychlorinated biphenyls (PCBs), major environmental hormonally active agents, are metabolized into hydroxylated PCBs in the liver to facilitate excretion. Some of hydroxylated PCBs also have potencies disturbing endogenous hormonal activities at least in vitro. Hormonal activities of hydroxylated PCBs raise a possibility of their interfering with normal brain development which is strictly regulated by endogenous hormones. We investigated whether and how prenatal exposure to a congener of hydroxylated PCBs (4-OH-2',3,3',4',5'-penta CB; 4-OH-PCB106) having activities to disrupt thyroid hormone-dependent signals in vitro could perturb normal gene expression in the developing brain in vivo. Pregnant rats were exposed to 4-OH-PCB106 subcutaneously at the dose of 1.0 mg/(kgday) from day 7 of gestation to postnatal day 1. Then three brain regions (cerebral cortex, hippocampus and striatum) were obtained from offspring on postnatal day 1 and subjected to further gene expression analyses. Comprehensive analyses of mRNA expression by oligo DNA microarrays and subsequent validations by quantitative RT-PCR revealed that prenatal exposure to 4-OH-PCB106 affected mRNA expression of glutamate receptors as well as that of thyroid hormone-responsive genes in region-specific manners. Concomitantly 4-OH-PCB106 exposure increased mRNA expression of genes related to exocytosis in the three brain regions. These results raise the possibility that prenatal exposure to some hydroxylated PCBs with thyroid hormone-disrupting potencies leads to abnormal brain development via perturbations on the expression of genes involved in glutamatergic neurotransmission.

Cell biology, histology, Biologie cellulaire, histologie, Neurology, Neurologie, Physiology, morphology, Physiologie, morphologie, Sciences biologiques et medicales, Biological and medical sciences, Sciences biologiques fondamentales et appliquees. Psychologie, Fundamental and applied biological sciences. Psychology, Biologie moleculaire et cellulaire, Molecular and cellular biology, Génétique moléculaire, Molecular genetics, Transcription. Facteurs de transcription. Epissage. Maturation des rna, Transcription. Transcription factor. Splicing. Rna processing, Sciences medicales, Medical sciences, Endocrinopathies, Thyroïde. Axe thyroïdien (pathologie), Thyroid. Thyroid axis (diseases), Pathologie non tumorale. Résistance tissu cible. Tumeurs bénignes, Non tumoral diseases. Target tissue resistance. Benign neoplasms, Endocrinopathie, Endocrinopathy, Endocrinopatía, Mammalia, Pathologie de la thyroïde, Thyroid diseases, Tiroides patología, Rodentia, Système nerveux central, Central nervous system, Sistema nervioso central, Vertebrata, Altération, Alteration, Alteración, Animal, Cervelet, Cerebellum, Cerebelo, Développement, Development, Desarrollo, Encéphale, Encephalon, Encéfalo, Expression génique, Gene expression, Expresión genética, Gène, Gene, Gen, Hormone thyroïdienne, Thyroid hormone, Hormona tiroidea, Hypothyroïdie, Hypothyroidism, Hipotiroidismo, Multiplication cellulaire, Cell proliferation, Multiplicación celular, Mécanisme action, Mechanism of action, Mecanismo acción, Postnatal, Souris, Mouse, Ratón, Thyroxine, Tiroxina, DNA microarray, apoptosis, cell proliferation, cerebellum, development, and thyroid hormone

Despite the indispensable role thyroid hormone (TH) plays in brain development, only a small number of genes have been identified to be directly regulated by TH and its precise mechanism of action remains largely unknown, partly because most of the previous studies have been carried out at postnatal day 15 or later. In the present study, we screened for TH-responsive genes in the developing mouse cerebellum at postnatal day 4 when morphological alterations because of TH status are not apparent. Among the new candidate genes selected by comparing gene expression profiles of experimentally hypothyroid, hypothyroid with postnatal thyroxine replacement, and control animals using oligoDNA micro-arrays, six genes were confirmed by real-time PCR to be positively (orc1l, galr3, sort1, nlgn3, cdk5r2, and zfp367) regulated by TH. Among these, sort1, cdk5r2, and zfp367 were up-regulated already at 1 h after a single injection of thyroxine to the hypothyroid or control animal, suggesting them to be possible primary targets of the hormone. Cell proliferation and apoptosis examined by BrdU incorporation and terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay revealed that hypothyroidism by itself did not enhance apoptosis at this stage, but rather increased cell survival, possibly through regulation of these newly identified genes.

Cell biology, histology, Biologie cellulaire, histologie, Neurology, Neurologie, Physiology, morphology, Physiologie, morphologie, Sciences biologiques et medicales, Biological and medical sciences, Sciences biologiques fondamentales et appliquees. Psychologie, Fundamental and applied biological sciences. Psychology, Vertebres: systeme nerveux et organes des sens, Vertebrates: nervous system and sense organs, Développement. Sénescence. Régénération. Transplantation, Development. Senescence. Regeneration. Transplantation, Mammalia, Rodentia, Système nerveux périphérique, Peripheral nervous system, Sistema nervioso periférico, Vertebrata, Age, Edad, Axone, Axon, Axón, Dégénérescence, Degeneration, Degeneración, Expression génique, Gene expression, Expresión genética, Nerf sciatique, Sciatic nerve, Nervio ciático, Neurofilament, Neurofilamento, Rat, Rata, Sénescence, Senescence, Senescencia, Transport axoplasmique, Axoplasmic transport, Transporte axoplásmico, NF-M, aging, axonal transport, neurofilament, and sciatic nerve

We have made a detailed comparison of neurofilaments (NFs) in the axons of the sciatic nerves between young and aged rats. In young rats, NF density was similar between proximal and distal sciatic nerve, but it became higher in the proximal region of sciatic nerve of aged rats. In accordance with this morphological change, NF protein content decreased dramatically in the middle region of the sciatic nerves of aged rats. The ratio of NF-M to NF-H in aged rats was lower than that in young rats at the proximal region of sciatic nerves and further decreased in the distal region of sciatic nerve. We analyzed transcription and axonal transport of NF proteins in motor neurons in spinal cord which are the major constituents of sciatic nerve axons. Of the transcripts of the NF subunits, NF-M mRNA was particularly reduced in aged rats. Examination of slow axonal transport revealed that the transport rate for NF-M was slightly faster than that for NF-H in young rats, but slightly slower in aged rats. A decrease in both the synthesis and transport rate of NF-M with aging may contribute to the relative reduction in NF-M in the aged rat sciatic nerve. Although the relationship between NF packing and reduced NF-M is not clear at present, these changes in NFs may be associated with age-dependent axonal degeneration diseases.