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Chetan P Shah, Prashant S Kharkar
Human inosine 5'-monophosphate dehydrogenase 2 (hIMPDH2), being an age-old target, has attracted attention recently for anticancer drug development. Mycophenolic acid (MPA), a well-known immunosuppressant drug, was used a lead structure to design and develop modestly potent and selective analogues. The steep structure-activity relationship (SAR) requirements of the lead molecule left little scope to synthesise newer analogues. Here, newer MPA amides were designed, synthesised and evaluated for hIMPDH2 inhibition and cellular efficacy in breast, prostate and glioblastoma cell lines...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Truong-Giang Huynh, Ann-Chang Cheng, Chia-Chun Chi, Kuo-Hsun Chiu, Chun-Hung Liu
In this study, we examined the synergistic effects of a diet-administered synbiotic comprising galactooligosaccharide (GOS) and the probiotic Lactobacillus plantarum 7-40 on immune responses, immune-related gene expressions, and disease resistance to Vibrio alginolyticus in white shrimp Litopenaeus vannamei. To unravel the regulatory role of the synbiotic in activating the immune system of shrimp, 1 H nuclear magnetic resonance (NMR)-based metabolomic analyses were used to investigate hepatopancreas metabolites, then significantly altered metabolites were confirmed in both the hepatopancreas and plasma by reverse-phase high-performance liquid chromatography (RP-HPLC) and spectrophotometric analyses...
May 17, 2018: Fish & Shellfish Immunology
Galina Shevchenko, Kevin V Morris
Adenosine to inosine (A-to-I) editing is the most abundant form of RNA modification in mammalian cells, which is catalyzed by adenosine deaminase acting on the double-stranded RNA (ADAR) protein family. A-to-I editing is currently known to be involved in the regulation of the immune system, RNA splicing, protein recoding, microRNA biogenesis, and formation of heterochromatin. Editing occurs within regions of double-stranded RNA, particularly within inverted Alu repeats, and is associated with many diseases including cancer, neurological disorders, and metabolic syndromes...
May 16, 2018: FEBS Letters
Yanhan Liu, Yiyu Li, Xiancheng Feng, Zhong Wang, Zhaofei Xia
The aim of this study was to investigate the effects of Clostridium butyricum (C. butyricum) on the performance, serum lipid metabolism, muscle morphology, meat quality, and fatty acid profiles of Peking ducks. A total of 1,500 Peking ducks were randomly divided into five groups with five replicates and were fed a non-antibiotic basal diet (Control) or a basal diet supplemented with either 200, 400, or 600 mg/kg of C. butyricum (2.0 × 109 CFU/g) or 150 mg of aureomycin/kg for 42 d. Compared with the control group, supplementation with C...
May 14, 2018: Poultry Science
Xiaoshi Wei, Qingyan Yin, Huihui Zhao, Yangchun Cao, Chuanjiang Cai, Junhu Yao
The objective of this study was to evaluate alterations in serum metabolites of transition dairy cows affected by biotin (BIO) and nicotinamide (NAM) supplementation. Forty multiparous Holsteins were paired and assigned randomly within block to 1 of the following 4 treatments: control (T0), 30 mg/d BIO (TB), 45 g/d NAM (TN), and 30 mg/d BIO + 45 g/d NAM (TB+N). Supplemental BIO and NAM were drenched to cows from 14 days before the expected calving date. GC-TOF/MS was used to analyze serum samples collected from 8 cows in every groups at 14 days after calving...
May 14, 2018: Journal of Agricultural and Food Chemistry
Meng-Dan Lan, Jun Xiong, Xue-Jiao You, Xiao-Cheng Weng, Xiang Zhou, Bi-Feng Yuan, Yu-Qi Feng
RNA contains diverse modifications that exert important influences in a variety of cellular processes. So far more than 150 modifications have been identified in various RNA species, mainly in ribosomal RNA (rRNA), transfer RNA (tRNA), and messenger RNA (mRNA). In contrast to rRNA, tRNA and mRNA, the known modifications in small RNAs have been primarily limited to 2'-O-ribose methylations in plants and inosine in mammals. Methylation of small RNAs in mammals is still unclear. Current methods widely used in the characterization of small RNAs are mainly based on the strategy of nucleic acid hybridization and sequencing, which cannot characterize modifications in small RNAs...
May 14, 2018: Chemistry: a European Journal
Hiroshi Shimura, Takahiko Mitsui, Satoru Kira, Tatsuya Ihara, Norifumi Sawada, Hiroshi Nakagomi, Tatsuya Miyamoto, Sachiko Tsuchiya, Mie Kanda, Masayuki Takeda
OBJECTIVES: To identify metabolites that are associated with an overactive bladder (OAB) using metabolomics. PATIENTS AND METHODS: A total of 58 males without apparent neurological disease completed 24-hr bladder diaries of their micturition behavior and International Prostate Symptom Score (IPSS) for the assessment of micturition behavior and lower urinary tract symptoms. Urgency was defined as an IPSS urgency score of ≥2 (OAB group), and patients with IPSS urgency scores of ≤1 belonged to the control group...
May 9, 2018: Urology
F Takayanagi, T Fukuuchi, N Yamaoka, K Kaneko
In this study, we investigated the alterations in the purine composition of swordfish prepared using a traditional Japanese processing method of soaking in sake lees. These alterations are the byproducts of the yeast fermentation of rice-koji and are renowned for enhancing the umami nature of food. Using a conventional assay method for hydrolyzing all of the purines into four bases and our developed method for simultaneously analyzing purines, we observed the alterations in four purine bases in the soaked sake lees and swordfish...
May 11, 2018: Nucleosides, Nucleotides & Nucleic Acids
Shibin Chacko, Helena I M Boshoff, Vinayak Singh, Davide M Ferraris, Deviprasad R Gollapalli, Minjia Zhang, Ann P Lawson, Michael J Pepi, Andrzej Joachimiak, Menico Rizzi, Valerie Mizrahi, Gregory D Cuny, Lizbeth Hedstrom
New drugs and molecular targets are urgently needed to address the emergence and spread of drug-resistant tuberculosis. Mycobacterium tuberculosis (Mtb) inosine 5'-monophosphate dehydrogenase 2 (MtbIMPDH2) is a promising yet controversial potential target. Inhibition of MtbIMPDH2 blocks the biosynthesis of guanine nucleotides, but high concentrations of guanine can potentially rescue the bacteria. Herein we describe an expansion of the structure-activity relationship (SAR) for the benzoxazole series of MtbIMPDH2 inhibitors and demonstrate that minimum inhibitory concentrations (MIC) of ≤ 1 μM can be achieved...
May 10, 2018: Journal of Medicinal Chemistry
Bin Lian, Jinjun Xia, Xun Yang, Chanjuan Zhou, Xue Gong, Siwen Gui, Qiang Mao, Ling Wang, Pengfei Li, Cheng Huang, Xunzhong Qi, Peng Xie
In the present study, we used a gas chromatography-mass spectrometry-based metabolomics method to evaluate the effects of ketamine on mice hippocampi. Multivariate statistical analysis and ingenuity pathway analysis were then used to identify and explore the potential mechanisms and biofunction of ketamine. Compared with the control (CON) group, 14 differential metabolites that involved amino acid metabolism, energy metabolism, and oxidative stress metabolism were identified. After combination with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX) administration, six of the 14 metabolites remained significantly differentially expressed between the ketamine (KET) and KET+NBQX groups, including glycine, alanine, glutamine, aspartic acid, myoinositol, and ascorbate, whereas no difference was found in the levels of the other eight metabolites between the KET and KET+NBQX groups, including phosphate, 4-aminobutyric acid, urea, creatine, L-malic acid, galactinol, inosine, and aminomalonic...
May 8, 2018: Neuroreport
Mattias Carlsson, Guo-Zhen Hu, Hans Ronne
Purine and pyrimidine analogues have important uses in chemotherapies against cancer, and a better understanding of the mechanisms that cause resistance to these drugs is therefore of importance in cancer treatment. In the yeast Saccharomyces cerevisiae, overexpression of the HAM1 gene encoding inosine triphosphate pyrophosphatase confers resistance to both the purine analogue 6-N-hydroxylaminopurine (HAP) and the pyrimidine analogue 5-fluorouracil (5-FU) (Carlsson et al., 2013, PLoS One 8, e52094). To find out more about the mechanisms of resistance to nucleotide analogues, and possible interdependencies between purine and pyrimidine analogue resistance mechanisms, we screened a plasmid library in yeast for genes that confer HAP resistance when overexpressed...
2018: PloS One
Hua Huang, Katannya Kapeli, Wenhao Jin, Yuk Peng Wong, Thiruma Valavan Arumugam, Joanne Huifen Koh, Sumitra Srimasorn, Karthik Mallilankaraman, John Jia En Chua, Gene W Yeo, Tuck Wah Soong
Adenosine DeAminases acting on RNA (ADAR) catalyzes adenosine-to-inosine (A-to-I) conversion within RNA duplex structures. While A-to-I editing is often dynamically regulated in a spatial-temporal manner, the mechanisms underlying its tissue-selective restriction remain elusive. We have previously reported that transcripts of voltage-gated calcium channel CaV1.3 are subject to brain-selective A-to-I RNA editing by ADAR2. Here, we show that editing of CaV1.3 mRNA is dependent on a 40 bp RNA duplex formed between exon 41 and an evolutionarily conserved editing site complementary sequence (ECS) located within the preceding intron...
May 4, 2018: Nucleic Acids Research
Daewoo Pak, Yunsoo Kim, Zachary F Burton
The genetic code sectored via tRNA charging errors, and the code progressed toward closure and universality because of evolution of aminoacyl-tRNA synthetase (aaRS) and ribosome fidelity mechanisms. Class I and class II aaRS folds are identified as homologs. Five mechanisms toward code closure are highlighted: 1) aaRS proofreading to remove mischarged amino acids from tRNA; 2) accurate aaRS active site specification of amino acid substrates; 3) aaRS-tRNA anticodon recognition; 4) EF-TU and GTP hydrolysis proofreading of the tRNA-mRNA interaction; and 5) modification of tRNA wobble adenine to inosine...
May 4, 2018: Transcription
Yun-Hua Esther Hsiao, Jae Hoon Bahn, Yun Yang, Xianzhi Lin, Stephen Tran, Ei-Wen Yang, Giovanni Quinones-Valdez, Xinshu Xiao
In eukaryotes, nascent RNA transcripts undergo an intricate series of RNA processing steps to achieve mRNA maturation. RNA editing and alternative splicing are two major RNA processing steps that can introduce significant modifications to the final gene products. By tackling these processes in isolation, recent studies have enabled substantial progress in understanding their global RNA targets and regulatory pathways. However, the interplay between individual steps of RNA processing, an essential aspect of gene regulation, remains poorly understood...
May 3, 2018: Genome Research
Meng Wu, Liang Guo, Ke-Cheng Zhu, Hua-Yang Guo, Bo Liu, Shi-Gui Jiang, Dian-Chang Zhang
Toll-like receptors (TLRs) play an essential role in the immune response. Here two Toll-like receptors from golden pompano (Trachinotus ovatus), ToTLR1 and ToTLR2, were characterized, the full-length cDNAs were 3126 bp and 7430 bp, and the deduced proteins consisted of 801 and 825 amino acids, respectively. ToTLR1 and ToTLR2 both contained the typical TLR domain architecture including signal peptide, leucine rich repeat (LRR), C-terminal LRR domain at the extracellular region and Toll/interleukin (IL)-1 receptor (TIR) domain in the cytoplasmic region...
April 30, 2018: Developmental and Comparative Immunology
N Yamada, C Saito, Y Murayama-Chiba, H Kano, Y Asami, H Itoh
Excessive intake of purine-rich foods elevates serum uric acid levels, making it a risk factor for hyperuricemia. We hypothesized that lactic acid bacteria ingested with food might utilize purines and contribute to their decreased absorption in the intestines, thereby preventing hyperuricemia. We previously reported that Lactobacillus gasseri PA-3 (PA-3) incorporates adenosine/inosine and related purines and that oral ingestion of PA-3 reduced the absorption of these purines in rats. However, it is unclear whether PA-3 also decreases the absorption of other purines, such as guanosine 5'-monophosphate (GMP) and guanosine...
May 3, 2018: Nucleosides, Nucleotides & Nucleic Acids
Dessislava Mladenova, Guy Barry, Lyndsey M Konen, Sandy S Pineda, Boris Guennewig, Lotta Avesson, Raphael Zinn, Nicole Schonrock, Maina Bitar, Nicky Jonkhout, Lauren Crumlish, Dominik C Kaczorowski, Andrew Gong, Mark Pinese, Gloria R Franco, Carl R Walkley, Bryce Vissel, John S Mattick
The amount of regulatory RNA encoded in the genome and the extent of RNA editing by the post-transcriptional deamination of adenosine to inosine (A-I) have increased with developmental complexity and may be an important factor in the cognitive evolution of animals. The newest member of the A-I editing family of ADAR proteins, the vertebrate-specific ADAR3, is highly expressed in the brain, but its functional significance is unknown. In vitro studies have suggested that ADAR3 acts as a negative regulator of A-I RNA editing but the scope and underlying mechanisms are also unknown...
2018: Frontiers in Neuroscience
Jingjie Li, Lihuan Guan, Huizhen Zhang, Yue Gao, Jiahong Sun, Xiao Gong, Dongshun Li, Pan Chen, Xiaoyan Liang, Min Huang, Huichang Bi
BACKGROUND: The sensitivity and specificity of non-invasive diagnostic methods for endometriosis, especially at early stages, are not optimal. The clinical diagnostic indicator cancer antigen 125 (CA125) performs poorly in the diagnosis of minimal endometriosis, with a sensitivity of 24%. Therefore, it is urgent to explore novel diagnostic biomarkers. We evaluated the metabolomic profile variation of the eutopic endometrium between minimal-mild endometriosis patients and healthy women by ultra-high-performance liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry (UHPLC-ESI-HRMS)...
April 30, 2018: Reproductive Biology and Endocrinology: RB&E
Marion Rother, Erik Gonzalez, Ana Rita Teixeira da Costa, Lea Wask, Isabella Gravenstein, Matteo Pardo, Matthias Pietzke, Rajendra Kumar Gurumurthy, Jörg Angermann, Robert Laudeley, Silke Glage, Michael Meyer, Cindrilla Chumduri, Stefan Kempa, Klaus Dinkel, Anke Unger, Bert Klebl, Andreas Klos, Thomas F Meyer
Chlamydia trachomatis (Ctr) accounts for >130 million human infections annually. Since chronic Ctr infections are extremely difficult to treat, there is an urgent need for more effective therapeutics. As an obligate intracellular bacterium, Ctr strictly depends on the functional contribution of the host cell. Here, we combined a human genome-wide RNA interference screen with metabolic profiling to obtain detailed understanding of changes in the infected cell and identify druggable pathways essential for Ctr growth...
May 9, 2018: Cell Host & Microbe
Xinxin Peng, Xiaoyan Xu, Yumeng Wang, David H Hawke, Shuangxing Yu, Leng Han, Zhicheng Zhou, Kamalika Mojumdar, Kang Jin Jeong, Marilyne Labrie, Yiu Huen Tsang, Minying Zhang, Yiling Lu, Patrick Hwu, Kenneth L Scott, Han Liang, Gordon B Mills
Adenosine (A) to inosine (I) RNA editing introduces many nucleotide changes in cancer transcriptomes. However, due to the complexity of post-transcriptional regulation, the contribution of RNA editing to proteomic diversity in human cancers remains unclear. Here, we performed an integrated analysis of TCGA genomic data and CPTAC proteomic data. Despite limited site diversity, we demonstrate that A-to-I RNA editing contributes to proteomic diversity in breast cancer through changes in amino acid sequences. We validate the presence of editing events at both RNA and protein levels...
April 23, 2018: Cancer Cell
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