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Krakowiak Agnieszka, Piotrzkowska Danuta, Kocoń-Rębowska Beata, Kaczmarek Renata, Maciaszek Anna
Phosphorothioate oligonucleotides (PS-oligos) containing sulfur atom attached in a nonbridging position to the phosphorus atom at one or more internucleotide bond(s) are often used in medicinal applications. Their hydrolysis in cellular media proceeds mainly from the 3'-end, resulting in the appearance of nucleoside 5'-O-phosphorothioates ((d)NMPS), whose further metabolism is poorly understood. We hypothesize that the enzyme responsible for (d)NMPS catabolism could be Hint1, an enzyme that belongs to the histidine triad (HIT) superfamily and is present in all organisms...
February 14, 2019: Biochemical Pharmacology
Giorgia Simonetti, Antonella Padella, Italo Farìa do Valle, Maria Chiara Fontana, Eugenio Fonzi, Samantha Bruno, Carmen Baldazzi, Viviana Guadagnuolo, Marco Manfrini, Anna Ferrari, Stefania Paolini, Cristina Papayannidis, Giovanni Marconi, Eugenia Franchini, Elisa Zuffa, Maria Antonella Laginestra, Federica Zanotti, Annalisa Astolfi, Ilaria Iacobucci, Simona Bernardi, Marco Sazzini, Elisa Ficarra, Jesus Maria Hernandez, Peter Vandenberghe, Jan Cools, Lars Bullinger, Emanuela Ottaviani, Nicoletta Testoni, Michele Cavo, Torsten Haferlach, Gastone Castellani, Daniel Remondini, Giovanni Martinelli
BACKGROUND: Aneuploidy occurs in more than 20% of acute myeloid leukemia (AML) cases and correlates with an adverse prognosis. METHODS: To understand the molecular bases of aneuploid acute myeloid leukemia (A-AML), this study examined the genomic profile in 42 A-AML cases and 35 euploid acute myeloid leukemia (E-AML) cases. RESULTS: A-AML was characterized by increased genomic complexity based on exonic variants (an average of 26 somatic mutations per sample vs 15 for E-AML)...
November 27, 2018: Cancer
Xiaowei Wei, Jin Zhou, Lingzhi Hong, Zhi Xu, Huanyu Zhao, Xiaomin Wu, Jinfei Chen
Gastric cancer is a prevalent, malignant tumor that frequently escapes treatment. Histidine triad nucleotide-binding protein 1 (Hint1) is a haploinsufficient tumor suppressor gene which contributes to intercellular communication, helps to regulate cell proliferation and survival, and is frequently underexpressed in gastric cancer. To examine the involvement of Hint1 in gastric cancer, small interfering RNA was used to knock down Hint1 expression in the human gastric cancer cell line SGC-7901. The data revealed that Hint1 inhibited cell proliferation, reduced radiation-induced DNA damage repair and caused G1 phase arrest, which increased the radiosensitivity of gastric cancer cells...
August 2018: Oncology Letters
Zhangyang Wang, Jie Lin, Kai Qiao, Shuang Cai, Victor W Zhang, Chongbo Zhao, Jiahong Lu
Autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM) is a rare form of hereditary neuropathy. Mutations in HINT1 gene have been identified to be the cause of this disorder. We report two unrelated patients who presented gait impairment, progressive distal muscle weakness and atrophy, neuromyotonia and foot deformities. Electrophysiological studies showed axonal motor neuropathy and neuromyotonic discharges. Using Next-generation sequencing, we identified two homozygous mutations, NM_005340.6: c...
July 11, 2018: European Journal of Medical Genetics
Lingchao Meng, Jun Fu, He Lv, Wei Zhang, Zhaoxia Wang, Yun Yuan
Autosomal recessive axonal neuropathy with neuromyotonia (ARANNM) is a rare disease caused by mutations of histidine triad nucleotide binding protein 1 (HINT1) gene. ARANNM has been reported mainly in European countries but little reported so far in China. We describe novel mutations of HINT1 in three Chinese patients with ARANNM from unrelated families. Patient 1 was a 14-year-old girl who presented with progressive distal weakness of upper limbs at two years of age. After that, she reported weakness of both feet, and difficulty in muscle relaxation after making a fist...
August 2018: Neuromuscular Disorders: NMD
Yuan Zhou, Hao-Kang Zhang, Fei Liu, Gang Lei, Peng Liu, Tong Jiao, Yong-Hui Dang
In recent years, the environmental impact of artificial light at night has been a rapidly growing global problem, affecting 99% of the population in the US and Europe, and 62% of the world population. The present study utilized a mouse model exposed to long-term artificial light and light deprivation to explore the impact of these conditions on emotion and cognition. Based on the potential links between histidine triad nucleotide binding protein 1 (HINT1) and mood disorders, we also examined the expression of HINT1 and related apoptosis factors in the suprachiasmatic nucleus (SCN), prefrontal cortex (PFC), nucleus accumbens (NAc) and hippocampus (Hip)...
2018: Frontiers in Behavioral Neuroscience
Pilar Sánchez-Blázquez, Elsa Cortés-Montero, María Rodríguez-Muñoz, Javier Garzón
Background: Several currently available animal models reproduce select behavioral facets of human mania as well as the abnormal glutamatergic neurotransmission and dysregulation of glycogen synthase kinase 3β that accompanies this disease. Methods: In this study, we addressed the therapeutic potential of ligands of sigma receptor type 1 (σ1R) in 2 putative models of mania: the "manic" Black Swiss outbred mice from Taconic farms (BStac) and mice with the 129 genetic background and histidine triad nucleotide-binding protein 1 (HINT1) deletion (HINT1-/- mice) that exhibit bipolar-like behaviors...
October 1, 2018: International Journal of Neuropsychopharmacology
Tianhao Bao, Yang Ke, Yifan Wang, Weiwei Wang, Yuehua Li, Yan Wang, Xiang Kui, Qixin Zhou, Han Zhou, Cheng Zhang, Dongming Zhou, Lin Wang, Chunjie Xiao
Taraxasterol has potent anti-inflammatory and anti-tumor activity. However, the effect and potential mechanisms of Taraxasterol on the growth of human liver cancer have not been clarified. Histidine triad nucleotide-binding protein 1 (Hint1) is a tumor suppressor and its downregulated expression is associated with the development of cancer. Here, we report that Taraxasterol treatment significantly suppressed cell proliferation and induced cell cycle arrest at G0/G1 phase and apoptosis in liver cancer cells, but not in non-tumor hepatocytes...
July 2018: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Rachit M Shah, Kimberly M Maize, Harrison T West, Alexander M Strom, Barry C Finzel, Carston R Wagner
Inherited peripheral neuropathies are a group of neurodegenerative disorders that clinically affect 1 in 2500 individuals. Recently, genetic mutations in human histidine nucleotide-binding protein 1 (hHint1) have been strongly and most frequently associated with patients suffering from axonal neuropathy with neuromyotonia. However, the correlation between the impact of these mutations on the hHint1 structure, enzymatic activity and in vivo function has remained ambiguous. Here, we provide detailed biochemical characterization of a set of these hHint1 mutations...
August 17, 2018: Journal of Molecular Biology
Harrison T West, Clifford M Csizmar, Carston R Wagner
Enzymes possess unique qualities that make them ideal regulators of supramolecular assembly. They are uniquely sensitive to biomolecules and biological compartments, catalytic in effecting chemical reactions, and present a biocompatible and degradable platform for assembly regulation. We demonstrate the novel utility of Histidine Triad Nucleotide Binding Protein 1 (HINT1) in regulating supramolecular hydrogel formation. We synthesized nucleoside-phosphoramidate-functionalized self-assembling peptides that we observed to form nanofibers...
July 9, 2018: Biomacromolecules
Deniz Sahin, Sabriye Karadenizli, Murat Kasap, Berrin Oztas, Hale Maral Kir, Gurler Akpinar, Nurbay Ates
BACKGROUND: The role of intracellular proteins in the pathogenesis of absence epilepsy were mentioned. These proteins are thought to be related to energy generation, signal transduction, inflammation processes and membrane conductance. OBJECTIVES: The investigation of protein profile of the genetically epileptic rat brains was the main subject of this study. METHODS: For this, a 2D-gel electrophoresis based comparative proteome analysis was performed using thalamus tissue of genetic absence epileptic WAG/Rij and age matched Wistar rats...
2018: Protein and Peptide Letters
María Rodríguez-Muñoz, Pilar Sánchez-Blázquez, Luis F Callado, J Javier Meana, Javier Garzón-Niño
The activity of certain G protein-coupled receptors (GPCRs) and of glutamate N-Methyl-D-aspartate receptors (NMDARs) is altered in both schizophrenia and depression. Using postmortem prefrontal cortex samples from subjects with schizophrenia or depression, we observed a series of opposite changes in the expression of signaling proteins that have been implicated in the cross-talk between GPCRs and NMDARs. Thus, the levels of HINT1 proteins and NMDAR NR1 subunits carrying the C1 cytosolic segment were increased in depressives and decreased in schizophrenics, respect to matched controls...
December 18, 2017: Translational Psychiatry
Peng Liu, Zhongwei Liu, Jiabei Wang, Xiancang Ma, Yonghui Dang
Although many studies have investigated the functions of histidine triad nucleotide-binding protein 1 (HINT1), its roles in neurobiological processes remain to be fully elucidated. As a member of the histidine triad (HIT) enzyme superfamily, HINT1 is distributed in almost every organ and has both enzymatic and nonenzymatic activity. Accumulating clinical and preclinical evidence suggests that HINT1 may play an important role as a neuroplastic mediator in neuropsychiatric diseases, such as schizophrenia, inherited peripheral neuropathies, mood disorders, and drug addiction...
2017: Neural Plasticity
Rachit Shah, Andrew Zhou, Carston R Wagner
Histidine Triad Nucleotide Binding Protein 1 (Hint1) has emerged to be an important post-synaptic protein associated with a variety of central nervous system disorders such as pain, addiction, and schizophrenia. Recently, inhibition of histidine nucleotide binding protein 1 (Hint1) with a small nucleoside inhibitor has shown promise as a new therapeutic strategy for the treatment of neuropathic pain. Herein, we describe the first rationally designed small molecule switch-on probes with dual fluorescence and FRET properties to study Hint1...
December 13, 2017: Organic & Biomolecular Chemistry
Yong-Hui Dang, Zhong-Wei Liu, Peng Liu, Jia-Bei Wang
The histidine triad nucleotide binding protein1(HINT1),which belongs to the histidine triad(HIT) enzyme superfamily,exerts its enzymic activities as hydrolase or transferase. Its physiological functions are still unclear. HINT1 protein is expressed in various tissues and plays an important role in transcription and signal transduction. Earlier studies have identified HINT1 as a haplo-insufficient tumor suppressor. Other evidences indicate that HINT1 is involved in a wide variety of physiological processes,some of which are irrelevant with its basic enzymic activities...
October 30, 2017: Zhongguo Yi Xue Ke Xue Yuan Xue Bao. Acta Academiae Medicinae Sinicae
Liankang Sun, Peng Liu, Fei Liu, Yuan Zhou, Zheng Chu, Yuqi Li, Guang Chu, Ying Zhang, Jiabei Wang, Yong-Hui Dang
BACKGROUND: Histidine triad nucleotide-binding protein 1 (HINT1) is regarded as a haplo-insufficient tumor suppressor and is closely associated with diverse neuropsychiatric diseases. Moreover, HINT1 is related to gender-specific acute behavior changes in schizophrenia and in response to nicotine. Stress has a range of molecular effects in emotional disorders, which can cause a reduction in brain-derived neurotrophic factor (BDNF) expression in the hippocampus, resulting in hippocampal atrophy and neuronal cell loss...
October 2017: Brain and Behavior
Aniekan Okon, Marcos Romário Matos de Souza, Rachit Shah, Raquel Amorim, Luciana Jesus da Costa, Carston R Wagner
This work describes the synthesis and biological evaluation of an anchimerically activated proTide of 2'- C -β-methylguanosine as an inhibitor of dengue virus 2 (DENV-2). The proTide incorporates a chemically cleavable 2-(methylthio)ethyl moiety and a HINT1 hydrolyzable tryptamine phosphoramidate. Inhibition of DENV-2 replication by proTide 6 was 5-fold greater than the parent nucleoside while displaying no apparent cytotoxicity. Furthermore, we demonstrate with a HINT1 inhibitor that the anti DENV-2 activity of the proTide correlates with the activity of HINT1...
September 14, 2017: ACS Medicinal Chemistry Letters
Maike F Dohrn, Nicola Glöckle, Lejla Mulahasanovic, Corina Heller, Julia Mohr, Christine Bauer, Erik Riesch, Andrea Becker, Florian Battke, Konstanze Hörtnagel, Thorsten Hornemann, Saranya Suriyanarayanan, Markus Blankenburg, Jörg B Schulz, Kristl G Claeys, Burkhard Gess, Istvan Katona, Andreas Ferbert, Debora Vittore, Alexander Grimm, Stefan Wolking, Ludger Schöls, Holger Lerche, G Christoph Korenke, Dirk Fischer, Bertold Schrank, Urania Kotzaeridou, Gerhard Kurlemann, Bianca Dräger, Anja Schirmacher, Peter Young, Beate Schlotter-Weigel, Saskia Biskup
Hereditary neuropathies comprise a wide variety of chronic diseases associated to more than 80 genes identified to date. We herein examined 612 index patients with either a Charcot-Marie-Tooth phenotype, hereditary sensory neuropathy, familial amyloid neuropathy, or small fiber neuropathy using a customized multigene panel based on the next generation sequencing technique. In 121 cases (19.8%), we identified at least one putative pathogenic mutation. Of these, 54.4% showed an autosomal dominant, 33.9% an autosomal recessive, and 11...
December 2017: Journal of Neurochemistry
Ju-Ping Li, Peng Liu, Gang Lei, Zheng Chu, Fei Liu, Chao-Feng Shi, Yong-Hui Dang, Teng Chen
Drug addiction is a chronically relapsing disorder in humans; yet, the underlying mechanism remained unclear. Recent studies suggested that the histidine triad nucleotide binding protein 1 (HINT1) may play significant roles in diverse neuropsychiatric diseases including drug addiction. In our present study, we used different batches of mice to establish the different stages of methamphetamine (METH)-induced conditioned place preference (CPP) to explore the dynamic changes throughout the process of addiction in different brain regions, including prefrontal cortex (PFC), nucleus accumbens (NAc), corpus striatum (CPu), and hippocampus (Hip)...
February 2018: Neurotoxicity Research
Rachit Shah, Tsui-Fen Chou, Kimberly M Maize, Alexander Strom, Barry C Finzel, Carston R Wagner
Human histidine triad nucleotide binding protein 1 (hHint1) is a purine nucleoside phosphoramidase and adenylate hydrolase that has emerged as a potential therapeutic target for the management of pain. However, the molecular mechanism of Hint1 in the signaling pathway has remained less clear. The role of metal ions in regulating postsynaptic transmission is well known, and the active site of hHint1 contains multiple histidines. Here we have investigated the effect of divalent metal ions (Cd2+ , Cu2+ , Mg2+ , Mn2+ , Ni2+ , and Zn2+ ) on the structural integrity and catalytic activity of hHint1...
September 23, 2017: Biochemical and Biophysical Research Communications
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